AU8142901A - Substituted pyrimidinone and pyridone compounds and methods of use - Google Patents

Description

-1-

AUSTRALIA

PATENTS ACT 1990 COMPLETE SPECIFICATION FOR A STANDARD PATENT

ORIGINAL

Name of Applicant: Actual Inventors: Address for Service: Amgen Inc.

Jeff A. Zablocki and Nathan B. Mantlo and Ulrike D. Spohr and.

Michael J. Malone BALDWIN SHELSTON WATERS 60 MARGARET STREET SYDNEY NSW 2000 CCN: 3710000352 'SUBSTITUTED PYRIMIDINONE AND PYRIDONE COMPOUNDS AND METHODS OF USE' Invention Title: Details of Original Application No. 55254/98 dated 04 Dec 1997 The following statement is a full description of this invention, including the best method of performing it known to me/us:- File: 33560AUP00 la SUBSTITUTED PYRIMIDINONE AND PYRIDONE COMPOUNDS AND METHODS OF USE BACKGROUND OF THE INVENTION This is a divisional application of AU 55254/98 derived from PCT/US97/22949 which claims priority from US provisional application serial No. 60/032,128 filed December 1996, US provisional application serial No. 60/050,950 filed 13 June 1997 and US nonprovisional patent application No. 08/976,053 filed 21 November 1997, each of which are incorporated herein by reference in their entirety. The present invention comprises a new class of compounds useful in treating diseases, such as TNF-a, IL- 10 1, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. This invention also relates to intermediates and processes useful in the preparation of such compounds.

Interleukin-1 (IL-1) and Tumor Necrosis Factor a (TNF-a) are pro-inflammatory cytokines secreted by a variety of cells, including monocytes and macrophages, in response to many inflammatory stimuli lipopolysaccharide LPS) or external cellular stress osmotic shock and peroxide).

Elevated levels of TNF-a and/or IL-1 over basal levels have been implicated in mediating or exacerbating a number of disease states including rheumatoid arthritis; Pagets disease; osteophorosis; multiple myeloma; uveititis; acute and chronic myelogenous leukaemia; 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; 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 S(Feurstein et al., Neurosci. Lett. 164, 125 (1993)).

oo .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 25 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.

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 cell destruction and diabetes. Pancreatic cells produce insulin which helps mediate blood glucose homeostasis. Deterioration of pancreatic I cells often accompanies type I diabetes. Pancreatic i cell functional abnormalities may occur in patients with type II diabetes. Type II diabetes is characterized by a 25 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 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)).

15

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. o.*o 25 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 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 15 neutralizing TNF- using a monoclonal antibody specific to TNF-a, cA2, has demonstrated improvement in swollen joint count in a Phase II human trial of rheumatoid arthritis (Feldmann et al., Immunological Reviews, pp.

195-223 (1995)). These approaches block the effects of TNF-a and IL-1 by either protein sequestration or receptor antagonism.

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.

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-, IL-10, IL-6 and/or IL-8 mediated diseases and other maladies, such as pain and diabetes. In particular, the compounds of the invention are useful for the prophylaxis and treatment of diseases or conditions involving inflammation. Accordingly, the 15 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 intermediates and processes useful for the preparation of the compounds of the invention.

The compounds of the invention are represented by the following general structure:

X

I R12 wherein the dashed lines represent a double bond between C(R) and V or W or and V, W, X, R, R 1 and R" are defined below.

The foregoing merely summarizes certain aspects of the invention and is not intended, nor should it be construed, as limiting the invention in any way. All patents and other publications recited herein are hereby incorporated by reference in their entirety.

DETAILED DESCRIPTION OF THE INVENTION In accordance with the present invention, there is provided compounds of the formula: or a pharmaceutically acceptable salt thereof, wherein X is-O, S or NR,; preferably, X is 0 or S; and most preferably, X is O;

V

i W R

R

3

N

R21 R2

"N'

N

N RI R4

N

N

N

R4 N N

U

N

N

*r or that the combined total number of aryl, cycloalkyl and heterocyclyl radicals in preferably, 0-2, most preferably, 0-1; "21 provided heteroaryl, -VC(R)W- is 0-3, a first preferred subgroup of

V

W R N- R 3

N

is R,

R

2 a second preferred subgroup of N

R

4 V

N

N is ,N R1o a third preferred subgroup

N

N J1 of

C

C*

*5

N

W R

N

N

N

U R21 N

N\

N

R1 or more preferably, N

N

N

N N-R 21

N

NkN

-R

2 1 NN\4 N N N

R

21 most preferably, N \N N R21 or R21 U is NR2 or CHR:,; 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

R

4 are each independently provided that R 4 is other than a substituted-aryl, (substituted-aryl)methyl or (substituted-aryl)ethyl radical, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y is 0-3; preferably, 0-2; more preferably, 0-1; 15 preferably, R 2 is a radical of hydrogen, C 1

-C

4 alkyl, halo, cyano, hydroxy, C 1

-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; more preferably, R 2 is a radical of 2C hydrogen,

C

1

-C

4 alkyl, halo, cyano, hydroxy, Ci-C 4 .lkoxy, trifluoromethoxy or trifluoromethyl; most Spreferably, R2 is a hydrogen radical; preferably, R3 is a hydrogen radical or o 25 C1-C 8 alkyl or C 2

-C

8 alkenyl 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 -C4 alkoxy, C 1

-C

4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamnino, di-(Cl-C 4 alkyl) amino,

C

1

-C

5 alkanoylanino,

(C

1

-C

4 al1koxy) 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, trifluoromethoxy or trifluoromethy. radicals; more -preferably, R3 is a hydrogen radical or Cl-C 8 alkyl radical optionally substituted by 1-2 radicals of amino, Cl-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,

C

1

-C

4 alkylamino, di- (C 1

-C

4 alkyl) amino, C- 4 alkoxy,C- 4 alkylthio, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl 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-C4'alkoxy, Cl-C 4 alkylthio, cyano, halo,

CI-C

4 alkyl, trifluoromethoxy or trifluoromethyl ****radicals; more preferably,

R

3 is a hydrogen radical or Cl-C 8 alkyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alicylamino, di-(Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy or aryl or'heteroaryl optionally substituted by 1-3. radicals of amino,

C

1

-C

4 alkylamino, di-(Cl-C 4 alkyl)amino,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio, halo, Ca.-C4 alkyl, trifluoromethoxy or trifluoromethyl radicals; more preferably, R3 is a radical of hydrogen or C 1

-C

4 alkyl; more preferably,

R

3 is a hydrogen, methyl or ethyl radical; preferably,

R

4 is cl-c 8 alkyl or C 2

-C

8 alkenyl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(Cl-C 4 alkyl)anino,

C

1 -c 5 alkanoylamino,

(C

1

-C

4 al koxy) c arbonyl amino, C 1

-C

4 alkyl sul fonyl amino, hydroxy, C 1

-C

4 alkoxy, C 1

-C

4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylainino, di-(Cl-C 4 alkyl)amino,

C

1

-C

5 alkanoylamino, (Cl-C 4 al1koxy) c arbonyl amino, C 1

-C

4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, CI-C 4 alkylthio, halo, C 1

-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)anino,

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, C 1

-C

4 alkyl, trif luoromethoxy or trif luoromethyl radicals; more preferably, R4 is

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, Cl-C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (C 1

-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 alkylanino, di- (Cl-C 4 alkyl)amino,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; 12 more preferably,

R

4 is a 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 -C4 alkylamino, di-(Ci-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

4 is a Ci-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, 15 dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, aikanoylamino, alkoxycarbonylamino, alkylsulfonylamino, 2b hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radical optionally substituted by 1 -3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl;preferably, each Z is independently a C1-C 8 alkyl, C 2 -Cs alkenyl or C 2

-C

8 alkynyl radical optionally substituted by 1-3 radicals of amino, CI-

C

4 alkylamino, di-(Ci-C 4 alkyl)amino,

CI-C

alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, Ci-C 4 13 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, C 1

-C

4 alkylthio or halo, and 1-2 radicals of heterocyclyl, aryl. or heteroaryl optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(Cl-C 4 alkyl)amino,

C

1

-C

5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylanino, 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, C 1

-C

4 alkylamino, di-(Cl-C 4 alkyl)amino,

C

1

-C

5 alkanoylanino,

(C

1

-C

4 al koxy) c arbonyl1amino, Cl-C 4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, C 1

-C

4 alkylthio,

C

1

-C

4 alkyl or C 1

-C

4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(Cl-C 4 a be. alkyl) amino,

C-

1

-C

5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino,

C

1

-C

4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, C 1

-C

4 alkylthio, cyano, halo, C 1

-C

4 alkyl be9 20 or C-C 4 haloalkyl of 1-3 halo radicals;_ more preferably, each Z is independently a

C

1

-C

8 alkyl, C 2

-C

8 alkenyl or C 2

-C

8 alkynyl radical optionally substituted by 1-3 radicals of amino, C 1

C

4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Ci-C 4 a lkoxy) carbonyl amino, 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, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylIamino, Cl-C 4 alkyl sul fonyl amino, hydroxy, Cl-C 4 alkoxy, C 1

-C

4 alkylthio, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, 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, cl-c 4 alkoxy,

C

1

-C

4 alkyithia,

C

1

-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, Cl-C 4 alkylsulfonylamino, hydroxy, Cj-C 4 alkoxy, Ci-C 4 alkylthio, cyano, halo, C 1

-C

4 alkyl or C:-C 4 haloalkyl of 1-3 halo radicals; more preferably, each Z is independently a C'-Cs alkyl or C 2

-C

8 alkenyl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(Cl-C 4 alkyl)amino,

CI-C

5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy,

CI-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-(Cl-C 4 alkyl) amino, Cj-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, Cl-C 4 alkyl or C 1

-C

2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 S radicals of amino, di-(Cl-C 4 alkyl)amino, (Ci-C 4 al1koxy) 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,

CI-C

5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1

-C

4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; 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- (Cl-C 2 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 alkoxy)carbonylamino, hydroxy,

C

1

-C

2 alkoxy, Cl-C 2 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-(C 1

-C

2 alkyl)amino,

C

1

-C

5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy,

C

1

-C

4 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di- (Cl-C 2 alkyl) amino, (Cl-C 4 00 0alkoxy) carbonylamino, hydroxy, Cl-C 2 alkoxy,

C

1

-C

2 alkylthio or Cl-C 4 alkyl. radicals; or 0000 5(3) aryl. or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino,

CI-C

alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy,

C

1 0 C 2 alkoxy, C 1

-C

2 alkylthio, cyano, halo, Cl-C 4 alkyl. or 0000trifluoromethyl. radicals; 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- (Cl-C: 2 alkyl)amino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 2 600.00alkoxy, Cl-C 2 alkylthio, or halo, and 1-2 radicals of aryl or heteroaryl. optionally substituted by 1-2 radicals of amino, di-(Cl-C 2 alkyl)amino, acetamido, (Cl-c 4 alkoxy)carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; or aryl. or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino, acetamido, (Cl-C 4 alkoxy) carbonyl amino, hydroxy,

CI-C

2 alkoxcy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluorornethyl radicals; more preferably, each Z is independently a Cl-C 4 alkyl radical optionally substituted by 1-2 radicals of amino, di- (C 1

-C

2 alkyl) amino, (Cl-C 4 a lkoxy) c arbonyl amino, hydroxy,

CI-C

2 alkoxy, Cl-C 2 alkyithic, halo or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy,

C

1

-C

2 alkoxy, Cl-C 2 alkylthio, halo, CI-C 4 alkyl or trifluoronethy. radicals; and most preferably, each Z is independently a CI-C 4 alkyl.

radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, hydroxy, methoxy, methylthio or halo radicals; each Y is independently a hydrogen radical; halo or nitro radical; *.20

-C(O)-R

2 0 or -C(NR5)-NR 5

R

2 1 radical;

-OR

2 1 -0-C (0)-R2 1 -0-C (0)-NR 5

R

2 1 or -0-C (0)-NR 2 2

S(O)

2

-R

20 radical;

-SR

2 1

-S(O)-R

2 0

-S(O)

2

-R

2 0 -S(O)2-NR 5

R

2 1, -S(O) 2 NR22-C(O)-R 2 1 -S(O)2-NR 2 2 -C(O)-0R 2 0 or S02N2-() *25

NR

5

R

2 1 radical; or

-NR

5

R

2 1 -NR22-C(0)-R 2 1 -NR22-C(0)-OR 2 0, -NR 2 2

NR

5

R

2 1 -NR22-C(NR5)-NR 5

R

2 1 -NR22-S(0) 2

-R

2 0 or -NR 2 2 S 2-NR 5

R

2 1 radical; 30 preferably, each Y is independently a hydrogen radical; halo radical; -C -R 2 0 or -C (NR5) -NR5R 2 1 radical; -0R2 1 -0-C -R 2 1 or -0-C

-NR

5

R

2 1 radical;

-SR

2 1 -S(0)-R 2 0 -S(0) 2

-R

2 0 or -S(0)2-NR 5

R

2 radical;

-NR

5

R

2 1, -NR22-C(O)-R 2 1 -NR22--C(O)-OR 2 0O -NR2 2

NR

5

R

2 1 -NR22-C(NR5)-NR 5

R

2 1 -NR22-S(O) 2

-R

2 0 or -R2 S(O)2-NR 5

R

2 1 radical; more preferably, each Y is independently a hydrogen radical;

-C(O)-R

2 o radical;

-OR

2 1

-SR

2 1

-S(O)-R

2 0 -S(O)2-R 2 0 or -S(O)2-NR 5

R

2 1 radical; or

-NR

5

R

2 1 -NR22-C(O)-R 2 1 -NR2 2 -C(O)-0R 2 0 -NR2 2

NR

5

R

2 1 -NR22-S(O) 2

-R

2 0 or -NR22-S(O) 2

-NR

5

R

2 1 radical; more preferably, each Y is independently a hydrogen radical;

-C(O)-R

2 0 radical; -OR2 1

-SR

2 1

-S(O)-R

2 0 -S(O)2-R 2 0 or -S(O)2-NR 5

R

2 radical; or

-NR

5

R

2 1 -NR22-C(O)-R 2 1 or -NR2 2

-S(O)

2

-R

2 o- radical; more preferably, each Y is independently a -C (0)-R 2 0 radical;

-OR

2 1

-SR

2 1

-S(O)-R

2 0, -S(O)2--R 2 0 or -S(O)2-NR5R21 radical; or

-NR

5

R

2 1, -NR22-C(O)-R 2 1 or -NR22-S(O) 2

-R

2 0 radical.

most preferably, each Y is independently a -OR 2 1

-SR

2 1 or -NR 5

R

2 1 radical; *wherein each R5 is independently hydrogen radicals; alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, -SO, H or halo; or aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or 18 cycloalkylalkyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkyithia, alkyl or haloalkyl; preferably, each R 5 is independently hydrogen radicals; cl-c 8 alkyl, C2-C 8 alkenyl or C 2

-C

8 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4-alkyl) amino hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio,

-SO

3 H or halo; or aryl, heteroaryl, aryl-Cl-C 4 -alkyl, heteroaryl-CiC 4 alkyl, heterocyclyl, heterocyclY-l-Cc 4 .alkyl,

C

3

-C

8 cycloalkyl or C3C-ylaky-lC-ly radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylainino, di- (Cl-C4-aJlkyl) amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkyl or CI-C 4 haloalky. of 1-3 halo radicals; .more preferably, each R 5 is independently **20 hydrogen radicals; Cl-C 4 alkyl, C2-C 5 alkenyl or C2-Cs alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 .alkylamino, di- (C1-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Ci-C 4 alkylthio, -SO, H or halo; or aryl, heteroaryl, aryl-Cl-C 4 -alkyl, heteroaryl-Ci-C 4 alkyl, heterocyclyl, heterocyclyl-ClCc 4 .alkyl

C

3 -:C8 cycloalkyl or C3-C-cycloalky-Cl-C 4 -alkyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (CI-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, *30 Cl-C 4 alkylthio, Ci-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 5 is independently hydrogen radicals; cl-c 4 alkyl or C 2

-C

5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, so 3 H or halo; or phenyl-Ci-C 2 -alkyl, heteroaryl-Cl-C 2 .alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-C6-cycloalkylClC 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (C1-C4--alkyl) amino, hydroxy, Cl-C 4 alkoxy,

C

1

C

4 alkylthio,

C

1

-C

4 alkyl or CI-C 2 haloalkyl of 1-3 halo radicals; more preferably, each R 5 is indepenfdently hydrogen radical;

C

1

-C

4 alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C2-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-Ci-C 2 alkyl .radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, c- 2 alkoxy, Cj-

C

2 alkylthio, methox-y, methylthio, Cl-Ca alkyl or :trifluoromethyl'radicals; more preferably, each R 5 is independently hydrogen radical; Cl-C 4 alkyl radical optionally substituted byl1-3 halo radicals; or heny-C 1

-C

2 -alkyl or heteroaryl-C

-C

2 -alkyl, radicals optionally substituted by 1-3 radicals of .*30 amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or trifluoromethyl radicals; more preferably, each R5 is independent ly hydrogen or Cl-C 4 alkyl radical; and most preferably, each R5 is a hydrogen radical; wherein each R 20 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, a lkoxyc arbonyl amino,

N-

(alkoxycarbonyl) (alkyl) amino, alinocarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl. radicals optionally substituted by 1- 3 radicals of amino, alkylamino, dialkylanino, alkanoylamino, al koxycarbonyl amino, alkylsulfonylamino, alkanoyl, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl1, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxyc arbonyl.amino, alkylsul fonyl amino, hydroxy, alkoxy, alkylthio, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, *alkanoylamino, al1koxycarbonyl amino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl; preferably, each R 20 is independently cl-c 8 alkyl, C 2

-C

8 alkenyl or C 2

-C

8 alkynyl. radicals optionally substituted by 1-3 radicals of amino,

CI-C

4 alkylamino, di-(C 1

-C

4 alkyl)aiino, C1-C5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, N- ((Cl-C 4 alkoxy)carbonyl) N- (C 1

-C

4 alkyl)amino, aminoc arbonyj amino, Cl-C 4 alkylsulfonylamirio, hydroxy, 01-04 alkoxy, Cl-C 4 alkylthio, 01-04 alkylsulfinyl, 01-04 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-C1-C4-alkylthic, aryl-Cl-C4alkylsulfonyl, 03-C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(Cl-C 4 21 alkyl) amino, Cl-C 5 alkanoylamino, (C 1

-C

4 a lkoxy) carbonyl amino, C 1

-C

4 alkylsulfonylamino, Cl-C alkaraoyl, hydroxy,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio,

C

1

-C

4 alkylsulfinyl,

C

1

-C

4 alkylsulfonyl, halo, C 1

-C

4 alkyl or

C

1

-C

4 haloalkyl of 1-3 halo radicals; heterocycly. -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, hydroxy,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio,

C

1

-C

4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyithio, cyano, halo, azido, Cl-C 4 alkyl or C 1

-C

4 haloalkyl of 1-3 halo radicals; be. 20 more preferably, each R 20 is independently Cl-C 8 alkyl, C 2

-C

5 alkenyl or C 2

-C

5 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 be alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylanino, (Cl-C 4 alkoxy) c arbonyl amino, (Cl-C 4 alkoxy) carbonyl) N-(Cl-C 4 -alkyl)amino, aminocarbonyl1amino, -Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cj-C 4 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-Cl-C4alkylsulfonyl,

C

3

-C

8 cycloalkyl, heterocyclyl, aryl or a be.

heteroaryl radicals optionally substituted by 1-3radicals of amino, Cl-C 4 alkylamino, di- (C 1

-C

4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Cj-C alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 22 alkylsulfinyl, 01-04 alkylsulfonyl, halo, 01-04 alkyl or

CI-C

4 haloalkyl of 1-3 halo radicals; heterocycly. radical optionally substituted by 1-3 radicals of amino, 01-04 alkylanino, di-(Cl-C 4 alkyl)amino, 01-05 alkanoylamino, (01-04 alkoxy) carbonylamino, 01-04 alkyl sul fonyl amino, hydroxy, 01-04 alkoxy, 01-04 alkylthio, 01-04 alkyl or 01-04 haloalkyl of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-05 alkanoylamino, (01-04 alkoxy) carbonylamino, 01-04 alkylsulfonylamino, (01-04 alkoxy)carbonyl, hydroxy, 01-04 alkoxy, 01-04 alkylthio, cyano, halo, azido, 01-04 alkyl or 01-04 haloalkyl of 1- 3 halo radicals; more preferably, each R 2 0 is independently 01-08 alkyl or 02-05 alkenyl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di-(0 1 -0 4 alkyl)amino, 0.1-05 alkanoylamino, (01-04 al1koxy) c arbonyl amino, N- ((01-04 alkoxy) carbonyl) (01-04 alkyl) amino, aminocarbonyl amino, hydroxy, 01-04 alkoxy, CI-04 alkylthio, 01-04 alkylsulfinyl, 01-04 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-C 1

-C

4 alkylthio, aryl-C1-C4-alkylsulfonyl, 03-06 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, 01-04 alkylamino, di- (01-04 alkyl) amino, 01-05 alkanoylamino, .(01-04 alkoxy) carbonylamino, 01-04 alkylsulfonylamino, 01-05 alkanoyl, hydroxy, 01-04 alkoxy, 01-04 alkylthio, halo, 01-04 alkyl or 01-02 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, 01-04 alkylamino, di-(Cl-0 4 alkyl)amino, 0i-C5 alkanoylamino, (01-04 alkoxy) carbonyl amino, 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, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) c arbonyl amino, 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 Cl-C 2 haloalkyl of 1-3 halo radicals; more preferably, each R 2 0 is independently cl-c 8 alkyl or C 2

-C

5 alkenyl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, 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)anino, aminoc arbonyl amino, hydroxy, CI-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Ci-C 4 -alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C4-al kylsulfonyl,

C

3

-C

6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, *di- (Ci1-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, alkanoyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, cl-c 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl) amino, (Cl-C 4 alkoxy) carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl; or **30 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, acetamido, (cl-C 4 alkoxy) carbonyl amino, Cj- 04 alkylsulfonylamino, (01-04 alkoxy)carbonyl, hydroxy, 01-04 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or trifluoromethyl radicals; more preferably, each R 20 is independently Cl-C 8 alkyl 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- ((Ci-C 4 alkoxy) carbonyl) (Cl-C 4 alkyl) amino, amino carbonylamino, hydroxy,

C

1

-C

4 alkoxy,

C

1

-C

4 alkylthio, Cl-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, (Cl-C 4 alkoxy) carbonylamino,

C

1

-C

4 alkylsulfonylamino, hydroxy,

CI-C

4 alkoxy,

C

1

-C

4 alkylthio, halo, Cl-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substitu ted by 1-2 radicals of hydroxy,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio or C 1

C

4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (Cl-C 4 alkoxy) carbonyl, amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy,

CC

4 alkylthio, cyano, halo, azido,

C-

4 aklo -r..!luorornethyl radicals; more preferably, each R 2 0 is independently Cl-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 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 20 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; most preferably, each R 20 is independently C1-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; each R 21 is independently hydrogen radical or R 20 each R 22 is independently hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; provided when Z is a bond and Y is -NR 22

C(O)-NH

2 then R 2 2 is other then an optionally substituted aryl radical; 20 preferably, each R 2 2 is independently hydrogen radical;

C

1

-C

4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, 25 di-(C 1

-C

4 alkyl)amino,

C

1

-C

5 alkanoylamino,

(C

1

-C

4 alkoxy)carbonylamino,

C

1

-C

4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, C 1

-C

4 alkylthio,

CI-C

4 alkylsulfinyl,

C

1

-C

4 alkylsulfonyl, cyano, halo, CI-C 4 alkyl or Ci-C 4 haloalkyl of 1-3 halo radicals; or 30 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, (Ci-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 CI-C 4 haloalkyl of 1-3 halo radicals; provided when Z is a bond and Y is -NR22-C (0)-NH 2 then 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, di-(Cl-C 2 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy)carbonylanino, hydroxy, Cj-

C

4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; more preferably, each R 22 is independently hydrogen or Cl-C 4 alkyl radical; and most preferably, each R 2 2 is independently hydrogen or methyl radical;

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 radicals; -C (0)-R 3 0 -C -R 2 9

-C(O)-NR

3 lR 3 2 or -C(NR 3 1

NR

3 1

R

3 2 radicals;

-OR

2 9 -0-C(0)-R 2 9

-O-C(O)-NR

3 lR 3 2 or -O-C(O)-NR3 3

S(O)

2

-R

30 radicals;

-SR

2 -S (0)-R3 0 -S 2R 3 O, -S 2NR 31

R

3 2 -S (0)2- NR3 3 -C (0)-R 3 0 -S 2-NR3 3 -C (0)-OR 3 0 or -S 2-NR 3 3 NR3 1

R

3 2 radicals; or

'-NR

3 lR 3 2 -NR33-C(O)-R 2 9 -NR3 3 -C(0)-0R 3 0

-NR

3 3

NR

3 1

R

3 2 -NR33-C(NR 3 1)-NR 3 lR 3 2 -NR33-S(O) 2

-R

3 0 or -NR33- S(O)'2-NR 3 lR 3 2 radicals; **provided that

R

1 1 is other than a 4-pyridyl, 4-.

pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 1 2 is 0-1; preferably,

R

1 1 and R 1 2 are each independently an aryl or heteroary. radical optionally substituted by 1-2 radicals of

R

3 0 halo or cyano radicals;

-C(O)-R

3 0 -C(O)-0R 2 9

-C(O)-NR

3 lR 3 2 or -C(NR 3 j 1

J-

NR

3 1 R32 radicals; -OR2 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

30 radicals;

-SR

2 9

-S(O)-R

3 0 -S(O)2-R 3 O, -S(O)2-NR 3 lR 3 2

-S(O)

2 NR33-C(O)

-R

3 0 -S -NR3 3

-OR

3 0 or -S (O)2-NR 3 3

NR

3 1 R32) radicals; or

-NR

3 1

R

3 2 -NR33-C(O)-R 2 9 -NR3 3 -C(O)-0R 3 0

-NR

3 3

NR

3 1

R

3 2 -NR33-C(NR 3 1)-NR 3 lR 3 2 -NR3 3

-S(O)

2

-R

3 0 or -NR 3 3 S(O)2)-NR 31

R

3 2 radicals; provided that R 11 is other than a 4-pyridyl, 4pyrimidinyl, 4-quinolyl or G-isoquinolinyl radical optionally substituted by 1-2 substituents; and the *20 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, R11 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of

R

3 0 halo or cyano radicals;

-C(O)-R

3 0 -C(O)-0R 2 9

-C(O)-NR

3 lR 3 2 or -C (NR 3 1) **30

NR

3 1

R

3 2 radicals; or

-OR

2 9

-SR

2 9

-S(O)-R

3 0 -S(O)2-R 3 0

-S(O)

2 -NR31R32, -NR3 1

R

3 2 -NR33-C(O)-R 2 9 or -NR 3 3 -C(O)-oR 3 0 radicals; more pref erably, R 1 1 is an aryl radical and R 1 2 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1--2 radicals of

R

3 0 halo or cyano radicals;

-C(O)-R

3 0 -C(O)-0R 2 9

-C(O)-NR

3 lR 3 2 or -CCNR 3 1

NR

31

R

32 radicals; 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

-R

2 9 radicals; more preferably,

R

11 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 R3 0 halo or cyano radicals; or

-C(O)-NR

3 lR 3 2

-OR

2 9

-SR

2 9

-S(O)-R

3 0

-S(O)

2

-R

30 S(O)2-NR 3 lR 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 R30; halo or cyano radicals; or -C(O)-NR 3 lR 3 2

-OR

2 9

-SR

2 9

SCO)-R

3 0

-S(O)

2

-R

3 0 -S(O)2-NR 3 lR 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, rnethylsulfonyl, amrinocarbonyl, methyl or trifluoromethyl radicals; more preferably,

R

1 1 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicalsof amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, arinocarbonyl, methyl or trifluoromethyl radicals; and most preferably,

R

1 1 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

12 is a heteroaryl radical optionally substituted by 1-2 radicals of

R

3 0 halo or cyano radicals; or

-C(O)-NR

3 1

R

3 2

-OR

2 9

-SR

2 9 -NR3 1

R

32 or -NR33-C(O)-R 2 9 radicals; more preferably,

R

12 is a heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; more preferably,

R

12 is a 4 -pyridyl, 4quinolinyl, 4-imidazolyl or 4 -pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; and most preferably,

R

12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals; wherein each R 30 is independently alkyl, alkenyl or alkynyl radicals optionally 20 substituted by 1-3 radicals of -NR 31

R

31 -C02R 23 o hydroxy, alkoxy, alkylthio, alkylsulfinyl, o 9alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of o* 25 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, S" hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl qr haloalkyl; preferably, each R3 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 C02R 2 3, hydroxy,

C

1

-C

4 alkoxy, Cl-C 4 alkylthio,

C

1

-C

4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo or aryl- CI-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-Cl-C 4 alkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C4 alkyl)amino, -Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, CI-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl. or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino,

C

1

-C

4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 20 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylanino, hydroxy,

C

1

-C

4 alkoxy, CI-C 4 alkylthio, cyano, Cl-C 4 alkyl or C 1

C

4 haloalkyl of 1-3 halo radicals; or 0 aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(C 1

-C

4 alkyl)a mino, C 1

-C

5 alkanoylamino, (Cl-C 4 alkoxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hiydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or CI-C 4 haloalkyl of 1-3 halo radicals; 430 more preferably, each R 3 0 is independently cl-c 4 alkyl radical optionally substituted by 1-3 radicals of -NR3 1

R

3 1 Cl-C 4 alkoxy-carbonyl or phenoxycarbonyl or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di- (C1-C4-alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl; or hydroxy, Cl-C 4 alkoxy,

CI-C

4 alkylthio, or phenyl-Cl- C4-alkoxy, phenyl-Cl-C 4 -alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, hydroxy, Cj-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1

-C

4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; Cl-C 4 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino,

C

1

-C

5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy,

C

1

-C

4 alkoxy;-

C

1

-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 333393(a) amino, Ci-C 4 alkylamino or di- (C1-C4-alkyl) amino radicals; or hydroxy, Cl-C 4 alkoxy, heterocyclyl, phenyl or S heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (C 1

-C

4 S alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 3 30 alkoxy) carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 '90*0%alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; Cl-C 2 haloalkyl. of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 33 alkyl)amino,

C

1

-C

5 alkanoylamino,

(C

1

-C

4 alkoxy)carbonylamino, hydroxy,

C

1

-C

4 alkoxy, Ci-C 4 alkylthio, cyano, halo, Ci-C 4 alkyl or trifluoromethyl radicals; more preferably, each R 30 is independently Ci-C 4 alkyl radical optionally substituted by a 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, halo, C1-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 20 phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or o 25 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

-C

4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; each R 29 is independently hydrogen radical or R30 and most preferably,

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; each R 3 1 is independently hydrogen radicals; alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or 20 aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, :alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 31 is independently hydrogen radicals; Cl-C 4 alkyl radical optionally substituted by an C 3

C

8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical 30 optionally substituted by 1-3 radicals of amino, Cl-C4 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,

C

1

-C

4 alkyl or C 1

-C

4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C 3

-C

8 cycloalkyl radical optionally substituted by 1-3 radicals of amino,

C

1

-C

4 alkylamino, di-(Ci-C 4 alkyl)amino,

CI-C

alkanoylamino, (Ci-C 4 alkoxy)carbonylamino,

C

1

-C

4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, Ci-C 4 alkylthio, cyano, C 1

-C

4 alkyl or C1-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 31 is independently hydrogen radicals; or Cl-C 4 alkyl radical optionally substituted by an phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(C 1

-C

4 alkyl)amino,

C

1

-C

5 alkanoylamino,

(C

1

-C

4 alkoxy) carbonylamino, hydroxy,

C

1

-C

4 alkoxy, Ci-C 4 alkylthio, cyano, Ci-C 4 alkyl or trifluoromethyl radicals; more preferably, each R 31 is independently hydrogen or

C

1

-C

4 alkyl radicals; and most preferably, each R 31 is independently hydrogen, methyl or ethyl radicals; each R 32 is independently hydrogen radicals; alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical 25 optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or S* aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 32 is independently hydrogen radicals; 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, Cl-C 4 alkylamino, di-(C 1

-C

4 alkyl) amino, Cl-C 5 alkanoylanino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyjlthio, 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 alkylanino, di-(Cl-C 4 alkyl)anino, Cl-C alkanoylamino, (Cl-C 4 alkoxy)carbonylamino,

CI-C

4 alkyl sul fonyl 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; 1s .9:9 *more preferably, each R 3 2 is independently hydrogen radicals; Cl-C 4 alkyl radical optionally substituted by an C 3

C

6 cycloalkyl, aryl, heterocyclyl or heteroaryl radical 20 optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cj-C 5 alkanoylamino,

CI-C

4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, hyciroxy, 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, Cl-C 4 alkylamino, di-(Cl-C 4 .alkyl)amino, Cl-C .9 alkanoylamino,

(C

1

-C

4 alkoxy)carbonylamino, Cl-C 4 *9alkylsulfonylamino, hydroxy,

C-C

4 alkoxy,

C-C

4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; more preferably, each R 32 is independently hydrogen radicals; 37 C1-C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(C 1

-C

4 alkyl)amino,

CI-C

5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, C 1

-C

4 alkoxy, C 1

-C

4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1

-C

4 alkylamino, di-(C 1

-C

4 alkyl)amino,

C

1

-C

5 alkanoylamino, (CI-C4 alkoxy)carbonylamino, hydroxy, C 1

-C

4 alkoxy, C 1

-C

4 alkyl or trifluoromethyl radicals; more preferably, each R3 2 is independently hydrogen radicals;

CI-C

4 alkyl radical or C 1

-C

2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or 20 phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; most preferably,

R

3 2 is independently 25 hydrogen or C 1

-C

4 alkyl radical; or phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; and wherein each R3 3 is independently hydrogen radical; or alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; preferably, each R 3 3 is independently hydrogen radical; or C1-C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C1-C 4 alkylamino, di-(C1-C 4 alkyl)amino,

C

1

-C

5 alkanoylamino,

(C

1

-C

4 alkoxy)carbonylamino,

C

1

-C

4 alkylsulfonylamino, hydroxy,

C

1

-C

4 alkoxy, C 1

-C

4 alkylthio, cyano, C 1

-C

4 alkyl or C 1

C

4 haloalkyl of 1-3 halo radicals; more preferably, each R 33 is independently hydrogen or C1-C4 alkyl radical; and most preferably, each R 33 is independently hydrogen or methyl radical.

*e The compounds of this invention may have in general several asymmetric centers and are typically depicted in 20 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

O

R11 ICH3

N

R

12 N R1 wherein and R' are one of the combinations given in the following table: R" R 12- Phenyl 4 -Pyridyl 1-Piperazinyl 4-fluorophenyl 4-pyridyl 1 -piperazinyl 3-fluorophenyl 4 -pyridyl 1-piperazinyl 2-fluorophenyl 4 -pyridyl l-piperazinyl 4-chlorophenyl 4 -Pyridyl l-piperazin yl 3-chlorophenyl 4 -py idyl 1- iverazinvi c 2 -chloropheiyl 4-tolyl 3 -tolyl 4-oyridyl 4 4-pyridyl 1-piperazinyl 1 -Piperazinyl 1 -piperaz inyl 1 -piperaz.i nyi z- c0±yl 4-.trifluoromethyip~henvl -~J4-pyridyl 4 -pyridyl 3 -trifluorome thyiphenyl 2,6dihorphenyl

I

4 -pyridyl 4 -pyridyl 1 -piperaz inyl 1 -piperazinyl 1 -piperaz inyl 1 -piperaz inyl i-p iperaz inyl i-p iperaz inyl 2, 6 -dime thyl phenyl

I

4 -pyridyl 3,4dichiorophenyl -4

I

4 -pyridyl 3, 4-dimethyl rherivl

I

4 -pyridyl 2,4dichlororphenvi i 4 -pyridyl l-piperazinyl S.

S

*5 .55555

S

2, 4-dimethyl 4-pyridyl i-piperazinyi phenyl_______ Phenyl 2-ainino-4- 1-piperazinyi pyvridyl 4-f luorophenyl 2-ainino-4- l-piperazinyl pyridyl 3-f luorophenyl 2-ainino-4- l-piperazinyl _pyridyl 2- fluorophenyl 2 -amino-4- 1 -piperazinyl pyridyl 4 -chiorophenyl 2-amino-4- 1-piperazinyl idyl 3 -chiorophenyl 2-amino-4- i-piperazinyi pyridyl 2 -chiorophenyl 2-ainino-4- i-piperazinyi pyridyl 4-tolyl 2-amino-4- l-piperazinyl pyridyl .3-tolyl 2-amino-4- l-piperazinyl pyridyl 2-tolyl 2-axnino-4- l-piperazinyl pyridyl 4-trifluoro- 2-axnino-4- l-piperazinyi methyiphenyl pyridyl 3-trifluoro- 2-ainino-4- l-piperazinyl methylphenyl p.,]yridyl 2,6- 2-amino-4- i-piperazinyi dichiorophenyl pyridyl 2, 6-dimethyl 2-ainino-4- l-piperazinyi phenyl _pyridyl 3,4- 2-amino-4- i-piperazinyl dichlorQphenyl _pyridyl 3, 4-dirnethyl 2-axnino-4- 1-piperazinyl phenyl

I

*5

S

dichloropheny1 /--aMlno-4- -pyr idyl 1 -pLperaz inyl 2, 4-dimethyl 2-amino- phenyl pyidyl Phenyl 2 -ace tamido- -pyridyl 4 -fluorophenyl 2-acetainido- -pyridyl 3 -fluoropheny. 2-acetainido- I 4 -pyridyl z luoropneny.

2 -acetamido- 4-pyridy1 4 -chiorophenyl

-I

3 -chiorophenyl 2 acetamido 4 -pyridyl 2 -ace tainido- 4 -pyridyl 2 -chiorophenyl -7 2-acetamido- :1 -piperazinyl 1 -piperazinyl 1 -piperaz inyl 1 -piperaz inyl 1 -piperaz inyl 1 -piperazinyl 1-piperazinyl 1 -piperaz inyl 1 -piperaz inyl 1 -piperaz inyl 1 -piperaz inyl 1 -p2.peraz inyl 1 -piperaz inyl 1 -piperaz inyl 1 -piperaz inyl 4-tolyl 2-acetami-do- -pyridyl 3-tolyl 2-acetamido- 4-pyridyl 2- tolyl 2-acetamido- -pyridyl 4-trifluoro- 2-acetamidomethylphenyl 4-pyridyl 3-trifluoro- 2-acetamidornethylphenyl 4-pyridyl 2,6- 2-acetamidodichlorophenyl -4-pyridyl

I

2, O-dimetny.

ihenv1 2-acetainido- 4 -n7-kri Awl1 3,4- 2-acetamido- l-piperazinyl dichiorophenyl 4-pyridyl 3, 4-dirnethyl 2-acetaynido- l-piperazinyl pheriyl 4-pyvridyl 2,4- 2-acetarnido- l-piperaziiyl dichloropheny. 4-pyridyl c,4-umetny.

p~henvl 2-acetamido- 1 -piperaz inyl Phenyl 2-arnino-4- l-piperazinyl pyrimi.dinyl 4 -fluorophenyl 2-amino-4- l-piperazinyl pyrimidinj.

3 -fluorophenyl 2-axnino-4- l-piperazinyl pyri idinyl 2 -fluorophenyl 2-ainino-4- l-piperazinyl pyrimidinyl 4 -chlorophenyl 2-amino-4- l-piperazinyl pyrimidinyl 3 -chiorophenyl 2-axnino-4- l-piperazinyl pyriniidinyl 2 -chiorophenyl 2-axnino-4- l-piperazinyl pyrimidiriyl 2-amino-4- ]-piperazinyl Ipyrimidcinyl 3-tolyl -I 2-amjno-4- I-p ipera zinyl a.

a nvrimidi nvl 2-tolyl 2-amino-4- 1-piperazinyl _pyrimidinyl 4-trifluoro- 2-amino-4- l-piperazinyl methylphenyl pyrimidinyl 3-trifluoro- 2-ainino-4- l-piperazinyl methylphenyl pyrimidiiyl 2,6- 2-amino-4- l-piperaziny.

dichlorophenyl pyrimidinyl 2,6-dimethyl 2-aznino-4- l-piperazinyl phenyl pyrimidinyl 3,4- 2-amino-4- l-piperazinyl dichiorophenyl p2yrimidinyl 3, 4-dimethyl 2-amino-4- l-piperazinyl phenyl pyrimidinyl 2,4- 2-amino-4- l-piperazinyl dichlorophenyl pyrimidinyl 2, 4-dimethyl 2-amino-4- 1-piperazinyl pyrimidinyl Phenyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 4-f luorophenyl 4-pyridyl 2- (2-chiorophenyl) ethyl amino 3-f luorophenyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 2-f luorophenyl 4-pyridyl 2- (2-chiorophenyl) thylamino 4-chiorophenyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 3-chiorophenyl 4-pyridyl 2- (2-chiorophenyl) ethyl amino 2-chiorophenyl 4-pyridyl 2- (2-chiorophenyl) e thylainino 4-tolyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 3-tolyl 4-pyridyl 2- (2-chiorophenyl) ethylamino 2-tolyl 4-pyridyl 2- (2-chiorophenyl)ethylamino 4-trifluoro- 4-pyridyl 2- (2-chiorophenyl) me thylphenyl _______ethylamino 3-trifluoro- 4-pyridyl 2- (2-chiorophenyl) me thyiphenyl _______ethylamino 2,6- 4-pyridyl 2 -(2-chlorophenyl) dichiorophenyl _______ethylamino 2, 6-dimethyl 4-pyridyl 2- (2-chiorophenyl) phenyl _______ethylamino 3,4- 4-pyridyl 2 -(2-chlorophenyl) dichiorop~henyl _______ethylamino 3, 4-dimethyl 4-pyridyl 2- (2-chiorophenyl) phenyl _______ethylamino 2,4- 4-pyridyl 2 2 -chlorophenyl) -dichlorophenyl _______ethylamino 2, 4-dimethyl phenyl 4- fluorophenyl 4- fluorophenyl -benzyl benzyl 2 -thienyl 4-pyridyl 2 2 -chalorophenyl) ethylarnino 4-pyridiyl 3- 3 -fluorophenyl) pro-pylamino 2-amino-4- 3 3 -fluorophenyf) Pyrimidiny rplmn y ri idlyl 3- hen 1 ro la n n 4 -pyridyl 3 -phenylpropylamino -4-pyridy. 2- 4 -fluorophenyl) 4 -pridy 3 -hnyoylamino 4-pyridy. 2- 4 -fluorophenyl) 4 -pyridy. 3 -phenylpropylamino 4-pyridyl 2- 4 -fluorophenyl) ethylamino 4- 3-phenyipropylamino 2 thi enyl cyc lohexyl cyclohexyl -tert-butyl tert -butyl 4 -fluoropheny.

4 -fluorophenyl pie iaiy a a. a. a a a *aa..a a Wa*a..

*5 a a a 4- fluorophenyl 4-f luorophenyl Phenyl 4- fluorophenyl 3 -fluorophenyl 2 -fluorophenyl 4 -chiorophenyl 3 -chiorophenyl 2 -chiorophenyl 4-tolyl 3 -tolyl 2 -tolyl 4 -trifluoromethylphenyl 3-trifluorome thylphenyl 2,6dichiorophenyl 2, 6-dimethfyl phenyl1 piper idinyl 4 -pyranyl_ 4 -pyrany.

2 -amino-4pyridyl 2-amino-4pyridyl 2-amino-4pyridy1 2 -amino-4pyridyl 2 -amino-4- _pyridyl 2-amino-4pyridyl 2-amino-4py-ridyl 2-amino-4- 2-amino-4pyridyl 2 -anino-4pyridyl 2 -amino-4- _pyridyl 2- -iino-4- _pyridyl 2-ainino-4p2yrid4yl 2 -amino-4- _pyrid~yl 2- 4 -fluorophenyl) ethylainino 3- -henylpropyl amino 2- 4 -fluorophenyl)_ ethylamino 2- (2-chiorophenyl) ethylamino 2- (2-chiorophenyl) ethylamino 2- (2-chiorophenyl) ethylarnino.

2- (2-chioropheny.) ethyl amino 2- 2 -chlorophenyl) ethylamino 2- (2-chiorophenyl) 2- (2-chiorophenyl) ethylamino 2- (2-chiorophenyl) 2- (2-chlorophenyl) ethylamino 2- (2-chiorophenyl) ethyl amino 2- 2 -chorophenyl)e thylarnino 2- V2-chlorophenyl) ethylamino 2- (2-chiorophenyl) 2- 2 -chlorophenyl) e thylamino 3,4- 2 -azninodichlorophenyl _pyridyl 4&-Qllnethyl 2 -amino-4 2,4dichlorophenyl 2, 4-dimethyl ph enyl2 Phenyl 4-f luorophenyl1 pyridyl 2-amino-4p2yridyl 2 -amino-4pyridyl 2 -acetamido- 4 -pyridyl 2 -acetamido- 4 -pyridyl 3 -fluorophienyl 2 -acetamido- 4-pyri4yl 2- (2-chiorophenyl) ethylamino 2- (2-chiorophenyl) ethyl amino 2- (2-chiorophenyl) ethylainino 2- 2 -chlorophenyl) ethylamino 2- (2-chiorophenyl) ethyl amino 2- (2-chiorophenyl) ethylainino 2- (2-chiorophenyl) ethylamino 2- 2 -chlorophenyl) ethyl amino 2- 2 -chl o roph enyl1 eth lamino 2- (2-chiorophenyl) ethylamino 2- 2 -chlorophenyl) ethylamino 2- (2-chlorophenyl) ethylamino 2-(-chlorophenyl) 2 -fluorophenyl 2 -acetamido- 4 -pyridvi 4 -chiorophenyl -7 2 -acetamdo

I

3 -chiorophenyl 2 -acetamido- 2 -chiorophenyl -t 4 -pyridI 2 -acetaiio- 4 -pyridyl I

S

S. S *5 S S S

S

4 -tolyl 3-tolyl 2-acetamido- 4-pyridyl ~1 2 -acetamido 4-nvrir-l V "M 2-toly 2-acetanido- 2- (2-chiorophenyl) 4 -pyridyl ethylamino 4 -trifluoro- 2-acetamido-- 2- (2-chiorophenyl) methyiphenyl 4-pyridyl ethylamino 3 -trifluoro- 2-acetamido- 2- (2-chiorophenyl) methyiphenyl 14-pyvridyl -ethylamino 2,6-2-acetanido- 2- (2-chiorophenyl) dichlorophenyl 4 -pyridy. ethylamino 2, 6-dimethy. 2-acetamido- 2- 2 -chlorophenyl) pheyl4-pyridyl -ethylamino 3,4-2-acetarnido- 2- (2-chiorophenyl) dichiorophenyl 4-pyridyl _ethylamino 3, 4.-dimethyl 2-acetamido- 2- 2 7chlorophenyl) phenyl 4 -pyridyl _ethylamino 2,4-2-acetamido- 2- (2-chiorophenyl) dichioropheny1 4-pyridyl ethylamino 2, 4-dimethyl. 2 -acetamido- 2- (2-chiorophenyl) phenyl_____ 4 -pyridyl ethyl amino Phenyl 2-amino-4- 2- 2 -chlorophenyl) poyrimidinyl ethylamino 4 -fluorophenyl 2-axnino-4- 2- (2-chiorophenyl) pyrimidinyl eth lamino 3 -fluorophenyl 2-amino-4- 2- 2 -chlorophenyl) P2yrimidinyl _ethylainino 2 fluorophenyl 2 -amino-4- 2- 2 -chlorophenyl) Pyrimidinyl ethylamino 4 -choropenyl 2-axnino-4- 2- 2 -chloropheny.) pyrimidinyl ethylainino 55 S S

S.

*55555

S

0..e 0 0* 00000* 0 0 000000 0 00.

0 *00000 00 0 0 00 000000 0 2 -toly.

4 Z-trifluoromethylphenyl 3 -trifluorome thylphenyl 2,6dichlorophenyl 2, 6-dimethyl phenil 3,4- -dichlorophenyl phenv1 4 -florophenyl 3henlrpey 2-fluoro heny1 4 -chiorophenyl 3-chioropheny1 3 -triloro-nv dichlorophenyl 2crphenyl 34-oy d-iioro n 3 4 -dimehyl myphenyl 2,4dichlorophny 2, 4-dimethyl phenyl Phenyl 2-aznino-4- 2 -chlorophenyl) primidini 1 ethylamino 2-amjno-4- 2- 2 -chlorophenyl) yrimidin eth ,lainino 2-a ino-4- 2-( 2 -chlorophenyl) pyrimidinyl eth lamino 2-axnino-4- 2- 2 -chlorophenyl) P2yrimidinyl ethylainino 2-amino-4- 2 2 -chlorophenyl) pyrimidinyl ethylamino 2-axnjno-;4- 2- 2 -chlorophenyl) pyrimidinyl ethylamiino 2-amino-4- 2- 2 -chlorophenyl) primidiny1 ethylainino 2-amino-4- 2- (2-chioroph-enyl) _pyrimidinyl etahylauino 2-amjno-4- 2-( 2 -chlorophenyl) pyrimidinyl ethylauino 2-amino-4- 2- 2 -chlorophenyl) yrimidiny 1 thlainino 2-pyiyl 3-midazolylp-cl ropylamn 4-yridiyl 3 et dzhpoylamino 4pyridiyl 3 et dzhpoylamino 4 -pyidyl 3 2(-imidaoryopyyl) 4pyridiyl 3 et dzypoylamino 4-pyridyl 3 -imidazolylipropylamin 0 -4-pyridyl 3 -i-idazolyipropylamino p y5id y 3 i m i d a o y p o y a m i n 4 -pyridyl 3 -miazolylpropylamino 4 -pyridyl 3 -imidazolylpropylamino 4-pyridyl 3 -imidazolylpropylamino 4-pyridyl 3 -imidazolylpropylamino 4-pyridyl 3 -imidazolylpropylamino 4 pyridyl 3 -imidiazolylpropylamino 4 -pyvridyl -imidazolyipropylamino 4 -pyridyl 3 -imidazolyipropylamino 4 -pyridyrl 3- imidazolylpropylamino 4 -pyridy 3 -imidazolylpropylamino 2-amino-4- .2yridyl 3 -imidazolylpropylamino 4- fluoropheny. 2 -aiino-4 S'pyridyl 3 -fluorophenyl 2-aznino-4- _2yridyl 2 -fluorophenyl- 2-arnino-4pyri dyl 4 -chloropheny. 2 -aznino-4- -pyridyl 3 -chloropheny. 2 -amino-4 p~yridyl 2 -chiorophenyl 2 -axnino-4 pyridyl 4-toll2 -amino-4pyridyl 2-tolyl2-amino-4- 4-trifuoro- 2-amjno-4- 'ethylphenyl yil 3-trifluoro- 2-axnino-4methylphenyl pyridyl 2,6- 2-amjno-4dichioropheny 1 pyridyl 2, 6-dimethyl 2-arnin-o-4phenyl pyridyl 3,4- 2-ainino-4dichlorophenyl pyr iyl 3, 4-dimethyl 2-ainino-4phenyl pr%-idylA,, 2,4- 2-amino-4dichioropheny1 pyridyl 2, 4-dirnethyl 2-amino-4phenvi p2yridyl Pheniyl 2 -acetaxnido- -pyridyl 4- fluorophenyl 2 -acetamido- 4 -pyridyl 3 -fluoropheny. 2 -acetamzido- -mpyridyl 2 -fluoropheny. 2 -acetamido- 4 -pyridyl- 4 -chiorophenyl 2 -acetamido- 4 -1yr idyl 3 -chiorophenyl 2 -acetamrido- 4 -pyridyl 2 -chlorophenyl 2 -acetaxnido- 4 -Pridy1 4-tolyT 2 -acetamidoridi 3-tolyl 2 -acetamxido- 4 -pyridyl 2-tolyl 2 -acetanido- -pyridyl 3- imidazolylpropylamino 3- iidazo 1YlPrOPYI amin 3 iiazolyl-propylaminc 3- inidazolyLpropylamino 3 -imidaz o~lypropyl amin 3- -indazolYlPrO:P:Y::lamin 3 -imidazolYlpropylamino 3 -imidazolyLpropylamino 3-Iiidazolyipropylamino 3 -ii iazolylpropylamino 3 -imidazolyipropylamin-o 3 -imidazolylpropylamino 3 -iridazolylpropylamino 3 -imidazolylpropyamino 3 -imidazolyipropylamino 3 imi dazo0 ylpropy1 aino 3 -imidazolylpropylamino 3 -imidazolyipropylamino 3 -imidazolylpropy1anino 3 -imidazolyipropylamino 3 -imidazolylpropylamino, 3- imidazolylpropylamino 3 -imidazolylpropylarnino 3- imidazolylpropylamino 4-trifluorome thyiphenyl 3 -trifluorome thyiphenyl 2,6-, dichlorop~henyl 2, 6-dimethyl phenyl 3,4dichlorophenyl

C

*9 C *9 C C

C.

9**C

C

C

C

C.

C 9* 3, 4-dimethyl phenyl 2,4dichlorophenyl 2, 4-dimethyl pheny-1 Phenyl 4-ifluoropheny.

3- fluoropheny.

2-f luoroTphenyl.

4- chiorophenyl 3 -chiorophenyl 2 -chiorophenyl 4 -tolyl 3 -toly.

2 -tolyl d-iloro-nj 2, G-diehyl phentylp ev 3,4dichlorophenyl 3, 4 -dimethyl 2,4dichiorolphenyl 2, 4 -dimethyl pheniyl 4 -fluorophenyl 4.6 2 -acetainido- 3 -imidiazolylpropy-lamino 4 -pyridyl 2 -acetainido- 3- imidazolylpropylamino 4 -pyridyl 2 -acetamido- 3 -imidazolylpropylamino 4 -pyridyl 2 -acetamido- imidazolylpropylamino 4-pyridyl 2 -acetaxnido- 3 -imidazolylpropy1amjno _4-pyridyl 2 -acetamido- 3 imidazolylpropylamino 4-pyri-dyl 2 -acetamido- 3 -imidazolylpropylamino 4 -pyridyl 2-acetamido- 3 -imidazolylpropylamino 4 -pyridyl 2 -amino- 4- 3- imidazo lyipropylainino pyrimidinyl 2 -amino-4- 3 -iridazolylpropyamino pyrimidinyl 2 -amino-4 3 -inidazolylpropylamino pyrimidinyl 2-amino-4- 3 -imidazolylpropylamjno pyrimidinyl 2-amino-4- 3 -imidazolyipropylamino pyr imidinyl 2-axnino-4- 3 -irnidazolylpropylamino pyrimidinyl 2 -amino-4- 3 -iridazolylpropylamjno pyr imidinyl 2-amino-4- 3 imidazolylpropylamjnO pyr imidinyl 2-amino-4- 3 -imidazolylpropylamino pyrimidinyl 2-arnino-.4- 3 -imnidazolyipropylamino nyrimidinyl 2-amino-4 3 -imidazolyipropylamino pyrmidilfl 2-amino-4pyrimidinyl 2-amino-4- Pyrimidinyl 2-amnino-4- Pyrimidinyl 2 -amino-4 ipyrimidinyl 2-axnino-4- Pyrirnidinyl 2 -amino-4- Pyr-imidinyl 2 -amnino-4pyrirnidinyl 4 -pyridyl- 3 -imidazolylpropylanino 3 -imidazolyipropylamino 3 -imidazolylpropylamino 3 -imidazolyipropylamino 3-imiaolylpopylamino 3 -idmidazolyipropylamino 3 -imidazolylpropylamino 2- 2 -chlorophenyl-lmethyl) ethl) amino 4-f luorophenyl 4-f luorophenyl 3- fluorophenyl 2 -fluorophenyl 3 -chiorophenyl 2 -chioropheny.

2 -acetarnido- 4-]2yridyl 2 -amino-4pyrimidinyl 4-pyridy 2-amino-4pyridyl 2 -ace tamido- 4 -pyridyl 2 -amino-4pyr imidinyl 4 -pyridyl 2 -amiio-4 yridyl 4-tolyl 3 -tolyl 9* 2 -tolyJ.

4-trifluoromethyiphenyl 3 -trifluoromethy1 heny1 2,6-.

di chi orophenyl 2, 6-dimethSyl phenyl 3,4dichlorophenyl 3, 4-dimethyl 2 -chiorophenyl 4-thoyl eny 3 -tolyl 2-tolyl 4 -trifluorome thylphenyl 3 -trifluoromethylphenyl 2,6dichloropheny.

2, 6-dirnethyl phenyl 3,4di chiorophenyl 2 -acetaiio 4 -pyridyl 2-ainino-4- Pyrimidinyl 4 -pyridyl 2-amino-4pyridyl 2 -acetamido- 4 -pyridlyl 2-amino-4-

I

pyrimidinyl 4 -pyridyl 2-amino-4- _pyridyl 2 -acetaynido- _47-pyridyl 2-axnino-4pyrimidinyl 4 -pyrridyl 2 -axnino-4 ipyridyl 2 -acetamido- 4 -pyridyl 2 -axino-4- Pyrimidiinyl1 4 -pyridyl 2 -axnino-4pyridy1 2 -acetamidoo..

4 pyridy1 2aino-4 Pyrirnidinl1 4 -pyridyl methyl) ethyl) amino 2( 2 -N-isropropyl-lj-> pehnyiproylamino 2 -N-glycylamoino.

h-e 1rolamino -2-N-soyamino-3- ,_henylpropylamino -2-amn-3-clmio3 _2henylpropylamino 3 )-amino-3 phenylpropylanino -2-amino-3-(2 flohenyl)propylamino (5 -amino-3- (2 Inyphenyl )propylamino 3S-amino-3- 2 fluorophenyl )propylamino -S 2-amino-3 methylphenyl )propylamino 2 -amino-3-2-hy3fluphenyylpropylao 3 -amino-3 2-hl3 eyphenylpropylamino (5 2-aminomt-3phenylpropylanino -2-amino-3-(2 -fluoropheny1)propylamino -2-arnino-3- (2rnethvlphenl propylamino 2 -N-isopropylamino-3- Phenylpropylanino 2 -N-glycylarnino-3- 2 -amino-2-methyl-3 phenyipropyl amino -2-arnino-3- 3 -amino-3 phenylpropylamino 3 -amino-3 (2 fluorophenyl) propylamino 3 -amino-3 (2 methyiphenyl propylamino 3 -amino-2-methyl-3phenylpropylamino -tetrahydroisoquinol- 3 -ylmethylenamino 48 34-dimethyl I4-pyridyl 3 -benzypperazinyl phenyl

I

and 0 R1 A N CH 3 wherein R 12 and R' are one of the combinations given in the following table: 1 R LZ Phenyl 4 -pvr J 4- fluoropheny 4 -pyridyl 3-f luorophaenyl] 4 -pyridyl ±U0ronh~nv] 2-fluron'envI Y -pr1 4-chJlorophenyl 4-p2yridyl 3-chiorophenyl 4 -pyridyl -chJlorophenyl 4-pyridyl 4-tolyl 4-pyridyl 4- pyridyl 4 -pyr-idy1 4-pyridyl 4 -pyridyl 4-pyri dyl 4 -pyridy1 4 -pyridyl 4-pyridyl 4 -pyridyl 4 -pyridyl 4 -pyrIdyl S

S.

S

S

S

S*S

S

S

S

S*

S

S.

j~ 2-tolv1 4- trifluoromethylphenyl 3 -trifluoromethylphenyl 2, 6dich lorophenyl 2, 6-dimethyl phenyl 3.4dichlorophenyl 3, 4-dimethyl phenyl 2,4dichlorophenyl 2, 4-dimethyl 1Dhenyl Phenyl 4-f luorophenyl 3 fl1u orTp-h e nyl1 4 -pyridyl 4 -pyridylI 4 -pyridyl 4-pyridyl 14-pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 2 -amino-4pyridyl 2 -alnino-4 pyr idyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 14 4-pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 2 -fluoropheny.

4 -cho-rophenyl- 3 -chlorophenyl pyridyl 2 -amino-4- _pyridyl 27-amino-4pyr idy 2 -amnino-4 pyridyl 4 -pyridyl 4-pyiy 4 -pyridyl 2 -chiorophenyl 4-tolyl 3 -tolyl 2-toJlyl 4-trifluorome thviphenvi 2-amino-4pyridyl 2 -ainino-4pyridyl 2 -amino-4pyridyl 2 -ainino-4pyridyl 2-axnino-4- 4 pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridy.

go 0.

0 so

S

a pvridcyl 3-trifluoro- 2-amino-4- 4-pyridyl methylphenyl pyriy] 2,6- 2-axnino-4- 4-pyridyl dichlorophenyl pyridyl .2,6-dimethyl 2-amino-4- 4 -pyridyl pheniyl pyridyl______ 3,4- 2-aznino-4- 4-pyridyl dichlorophenyl pyridyl 3,4-dimethyl 2-amno-4- 4-pyridyl phenyl pyridyl 2,4- 2-amino-4- 4-pyridyl dichloropheny. _pyridyl 2,4-dimethyl 2-amino-4- .4-pyridyl phenylpyridyl Phenyl2-acetamido- 4-pyridyl -pyridyl 4 -fluorophenyl 2-acetamido- 4-pyridyl -pyridyl 3 -fluorophenyl 2-acetainido- 4-pyridyl 4-pyridyl 2-f luorophenyl 2 -acetaxnido- 4 -pyridyl -pyridyl 4 -chlorophenyl 2-acetarnido- 4-pyridyl 4-pyridyl 3 -chlorophenyl 2-acetainido- 4-pyridyl 4 -pyrid).

2 -chlorophenyl 2-acetamido- 4-pyridyl 4 -pyridyl 4-tolyl 2 -acetajmido- 4-pyridyl 4 -pyridyl 3 -tolyl 2-acetamido- 4-pyridyl 4 -pyridyl 2 -tolyl 2 -acetamido- 4-pyridyl 4 -triflur-4 4-pyridyl 4-trfluro- 2-acetamido- 4-pyridyl methylphenyl 4 -pyridyl 3-trifluoro- 2 -acetamido- 4-pyridyl methylphenyl 4 -pyridyl 2,6- 2 a c et ai io-- 4-pyridyl dichlorophenyl 4 -pyvridyl 2, 6-dimethyl 2 -acetainido- 4-pyridyl _hnl4 -pyridyl 3,- 2 -acetamido- 4-pyrid) dichlorophenyl 4 -pyridyl 3, 4-dimethyl Dhenvl 2 -acetamido- 4 -pyridyl 4-pyridl~7 2- 1 dichiorop~henvl -actamdo 4 -pyridyl 2, 4-dimethyl phenyl 4-pvril Ir 2 -acetamido- 4-pyr idyl Phenyl 4 2-amino-4pyrimpidinyl 4-f luorophenyl 2-amino-4pyrimidinyl 4 -pyridy.

4 -pyridy.

4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 3- fluorophenyl 2-amino-4pyrimidinyi 2- fluorophenyl ~1 ~1 2-amino-4jrimidinyl 4 -chlorophenyl ~1 2-amino-4pyrimidinyl 2 -axino-4pyrimidinj.

3 -chiorophenyl 2 -chlorophenyl 2-amino-4pyrimidinyl 4-tolyl 3 -tolyl 2-amino-4pyrimidinyl 2-amjno-4-1 pyrimidinvi 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 0006 60 0@ 0 @0 0 @6 6 *066 0060

S

000000 0 00 6 0 00 0 660066 6 0006 6

OSS@

6090 0 0600 0 060000 0 S0 S S 00 0 600000

S

2-tolyl 4-trifluor ometyphenyl 1 2-amino-4pyrimidiny1 2-amjno-4pyrimidinyl 4 -pyridyl 3-trifluorome thyiphenvl 4.

2-amino-4pyrimidinv1 2,6dichiorophenyl 2-axino-4pyrimidinyl 2, 6-dimethyl phenyl

I

2 -amino-4 pyrimidinyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 3,14dichlorophenvi 2-amino-4- Iryrimidn l 3,4-dimethyl -mio4 4-pyridyl phenyl pyrimidinyl 2,4- 2-amino-4- 4-pyridyl dichlorophenj. pyrimidinyl 2 ,4-dimethyl 2-amino-4- 4-pyridyl phenyl _pyrimidinyl Phenyl 4-pyridyl 4-methyl sulfihyiphenyl 4 -fluorophenyl 4 pyridyl 4-methyl sulfinyphenyl 3 -fluorophenyl 4 -pyridyl 4-methyl sulfinyphenyl 2 -fluorophenyl 4 -pyridyl- 4-methyl sulfiniphenyl 4 -chlorophenyl 4-p)yridcyl 4-methyl sulfinyphenyl 3 -chlorop~henvl 4-pyridlyl 4-methyl sulfinylphenyl 4 -tolyl 3 -tolyl 2 -tolyl 4-trifluoromethylphenyl 4-pyridy1 14 -pyridy1l 4 -pyridy.

A sulfinylphenyl A~h sulfinylphenyl ~ysulf inylphenyl

A

sulfinylphenyl 4-methyl sulfinyipheny.

3-trifluoromethvltohenvl T 4 -pyridyl 4-methyl sulfinyiphenyl1 2,6- 4-pyridyl 4-methyl sulfinyiphenyl dichlorophenyl______________ 2-,6-dimethyl 4 -pyrid7yl 4-methyl -sulfinyiphenyl _phenyl 3,4- 4-pyridyl 4-methyl1 sulfinyiphenyl dichlorophenyl 3,4-dimethyl 4-pyridyl 4-methyl sulfinylphenyl phenyl_____ 2, 4- 4 -pyridyl 4-methyl sulfinylphenyl di chi orophenyl 2,4 -dimethyl 4-pyridyl 4-methyl sulfinYiphenyl Phenyl 2 -amino-4 4-methyl sulfinyiphenyl p pridyl 4-f luorophenyl 2-arnino-4- 4-methyl sulfinyiphenyl p~yridyl 3-f luorophenyl 2-amino-4- 4-methyl sulfinyiphenyl _pyridyl 2-f luorophenyl 2-amino-4- 4-methyl sul1finyiphenyl Pyridyl 4-chiorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyridyl 3-chiorophenyl 2-amino-4- 4-methyl sulfinyiphenyl pyridyl 2-chlorophenyl 2-amino-4- 4-methyl sulfinyiphenyl 4 -tolyl 2-amino-4- 4-methyl sulfinyiphenyl pyridyl 3-tolyl 2-amino-4- 4-methyl sulfinylphenyl 2 -tolyl 2-amino-4- 4-methyl sulfinyiphenyl _pyridyl 4-trifluoro- 2-amino-4- 4-methyl sulfinylphenyl rethylphenyl pyridyl___ .3-trifluoro- 2-amino-4- 4-methyl sulfinyiphenyl methyiphenyl pyridyl 2-amino-4- 4-methyl sulfinyipheinyl .dichiorophenyl pyridlyl___ 2, 6-dimethyl 2-amino-4- 4-methyl sulfinyiphenyl phnlpyridyl 3,4-2-amino-4- 4-methyl sulfinyiphenyl dichioropheny1 pyridyl 3,4 -dimethyl 2 -amino-4 4-methyl sulfinylphenyl phnlpyridyl 2,4- 2 -amino-4- 4-methyl sulfinyiphenyl dichiorophenyl _pyridyl___ 2, 4-dimethyl 2-aniino-4- 4-methyl sulfinyiphenyl phnlpyrid yl Pheyl2 -acetamido- 4-methyl sulfinyiphenyl -Tyridyl -fluorophenyl 2 -acetamido- 4-methyl sulfinyiphenyl -pyridyl *too 0:0.

3-f luorophenyl

I

2 -acetamido- 4 -methyl sulfinyiphey 2-f luorophenyl 4-chiorophenyl 3 -chlorophenyl 4 -pvridvl

I

2 -acetainido- 4 -pyridyl 2-acetamido- -4-pyridyl 2 -acetamido- 4 -pyridyl 2 -chioropheny.

4-tolyl

L

2 -acetami do- 4-pyridyl 2 -acetamido- 4 -pyridvi 3 -tolylI 2-acetamido- 4 -pyridyl 4 -methyl sulfinyiphenyl 4 -methyl sul finyiphenyl 4 -methyl suit inylphenyl 4-methyl suit inyiphenyl 4-methyl sulin rylphenyl 4-methyl su.f inylphenyl 4-methyl suit inyiphenyl 4-methyl suit inyiphenyl 4-methyl sulfinyiphenyl 4-methyl sulfinyiphenyl 4-methyl suit inyiphenyl 2-tolyl .1 2 -acetamido- 4-trifluorome thylohenvl 2 -acetamido- 3 -trifluorome thylphenvl I1 4 -pyridvi 2 -acetamido- 4 -pyridyl 2, 6dichlorophenvl

IT

2, 6-dimethyl phenyl 2-acetamido- 4 -pyridyl 2 -acetamido- =1

-I

4 -nvri (Ivl 3,4- 2-acetamido- 4-methyl sulfinyiphenyl dichlorophenyl 4-pyridyl 3,4-dirnethyl 2-acetamido- 4-methyl suit inyiphenyl phenyl .4-pyridyl 2,4- 2-acetainido- 4-methyl sultinyiphenyl dichlorophenyl 4-pyridyl 2, 4-dimethyl 2-acetamido- 4-methyl sultinyiphenyl phenyl pyridvl Phenyl 2-amino-4- 4-methyl sultinyiphenyl pyrimidinyl 3- uorophjenyl 2 -fluorophenyl 4- chiorophenyl 3 -chiorophenyl 2 -chiorophenyl 4 -thoyi eny 3 -tolyl 2 -tolyl 4-trifluoro- .Methylphenyl z y 2flY 2ly 2ly 2- -fl 2- 2pyX aminno-'4rimidinyl amino-4rimidiny 4-methyl sultinyiphenyl 4-methyl sulfinylphenyl amino-4- 4-methyl suit inylphenyl rimidinyl amino-4- 4-methyl sulfinyiphenyl rimidinyl amino-4- 4-methyl sulfinyiphenyl -rimi dinyl amino-4- 4-methyl suit inyiphenyl rimi dinyl amino-4- 4-methyl sultinyiphenyl rimidinyl pyr imidny 2 -amino-4pyrimidinyl 2-amino-4- P1yrimidinyl q -metnyl suit inyiphenyl 4-methyl s-utinyiphenyl 4-methyl suit inyiphenyl 3 -trifluorome thvlnhenvl 2 -amino-4 L i 2rl 4 -methyl sulfinyiphenyl1 4-methyl sul finyiphenyl 1 2,6dichlorophenyi

I

2-amino-4pvrimid 1i 2, 6-dimethyl 2-amino-4- 4-methyl sulfinyiphenyl phenyl pyrimidjijyl 3,4- 2-amjno-4- 4-methyl sulfinyiphenyl dichiorophenyl pyrimidinyl 3, 4-dimethyl 2-amino-4- 4-methyl sulfinylphenyl phenyl pyrimidinyl 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, dichlorobenzyl.

4-f luorophenyl 4-pyridyl 2, 6 -dichlorobenzyl 3-f luorophenyl 4-pyridyl_ 2, 6-dichlorobenzyl 2-f luoro henv1 4-pyridyl 2 ,6-dichlorobenzy.

4-chlorophenyl 4-pyridyl 2, 6-dichlorobenzyl 3-chioropheny1 4-pyridyl 2 6 -dichlorobenzyl 2-chiorophenyl 4-pyridyl 2, 6-dichlorobenzjl 4-toly1 4-pyridyl 2 ,6-dichlorobenzyl -3-tolyl- 4-pyridy. 2 ,6-dichlorobenzy1 2-toly1 4-pyridyl 2 ,6-dichlorobenzyl 4-trifluoro- 4-pyridyl 2, 6-dichlorobenzyl -Rethylphenyl 3-trifluoro- 4-pyridyl 2, 6-dichlorobenzyl methvlphenyl 2,6- 4-pyridyl 2 ,6-dichlorobenzyl dichl orop~henyl 2,6dietyl 4-pyridyl 2, 6-dichlorobenzyl dihioohnl -yiy 2v-ihlrbny 3,4 -dety 4-pyridyl 2, 6-dichlorobenzyl dichioro; henv1 2 4-dimethyl 4-pyridyl 2, 6-dichlorobenzyl p heny l Pheny 2-ayidyl-4 2, 6-dichlorobenzyl 2 4 -luoroheyl 2-amio-4 2, 6-dichlorobenzyl Ph-flrpny 2-amino-4-- 2, 6-dichlorobenzyl pyridyl 2-f luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 4 -luorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 2-clorophenyl 2-amino-4- 2, 6-dichlorobenzyl lpyridyl 2-chiorophenyl 2-amino-4- 2, 6-dichlorobenzyl pyridyl 4-toly.

3-toly.

2-amino-4pyridyl 2-amino-4pridyl 2-amino-4- 2-tolyl 4 4-trifluoromethylphenyl 3 -trifluoromethyiohenvl 1.

2 -ainino-4- -Tpyridvi ~1 2-amino-4- 2,6dichlorophenyl -t pyridvi 2-axnjno-4- 2, E-dichlorobenzylI 2, E-dichlorobenzyl 2, -6-dichlorobenzyl 2, 6 -dichlorobenzyl 2, G-dichlorobenzy.

2,-6-dichlorobenzy1 2, E-dichlorobenzyl 2, G-dichlorobenzyl 2, 6-dimethyl phenyl 2 -axnino-4pyridyl 3,4dichl-ohenyl l 2 -axnino-4- 3, 4-dimethyl ~phenyl 2--amino-4poyridyl 2,4dichlorophenyl 2, 4-dimethyl pheny l Phenyl 4-f luorophenyl 3- fluoropheny.

2-amino-4pyridyl 2-amino-4pyridyl 2 -acetami ido-7 4 -pyridyl 2 -acetaynido- 4 -pyridyl 2 acetamido-1

I.-

2, 6-dichlorobenzyl 2, G-dichlorobenzy.

2, 6-dichlorobenzyl 2, G-dichlorobenzyl 0.

6 .0.

0 2-f luorophenyl 4- chlorophenyl 2 -ace tamido- 4-pyridy.

2-acetamido- 4 -pyridyl 2, E-dichlorobenzyl 3 -chlorophenyl 2 -chiorophenyl 4 -tolyl 3 -tolyl 2 -tolyl 4-trifluorome thyliphenyl 3 -trifluorome thylphenyl 2,6- 2 -acetaxnido- _4pyri dyl -t2, 6 -dichlorobenzyl.

2-acetamido- 4 -pyridyl 2 -acetamido- 4 -pyridyl 2-acetamido- 4 -pyridyl 2 -acetamido- 2, G-dichlorobenzyl 2, 6-dichlorobenzyl 2, 6-dichlorobenzy.- 2, 6-dichlorobenzyl Ary-y 2 -acetamido- 4 -pyridy.

2 -acetainido- 4 -pyridyl 2 -acetamido- 2, E-dichlorobenzyl 2, 6-dichlorobenzyl 2, G-dichlorobenzyl 2, 6-dimethyl 2 -acetaxnido- 2, 6 -dichlorobenzy1 phenyl 4 -ipyridyl 3, 4- 2 -acetamido- 2,6 -ichlorobenzyl dichlorophenyl 4 -pyridyl 3, 4-dimethyl 2 -acetamido- 2, G-dichl-orobenzyl phenyl 4 -Pyridyl 2,4dichlororphenvl 2 -acetamido- 4 -pyridyl 2, 4-dimethyl phenJl 2 -acetamido- Phenyl 2-axnino-4pyrimidinvi 4- fluorophenyl 2-axnjno-4pyrimidinyl 3 -fluorophenyl

-T

~1 2-amino-4pyrimidinyl 2 -fluoropheny.

-r 2 -amino-4pyrimidinyl~1 2, G-dichlorobenzyl [2,6-dichlorobenzy1 2, G-dichlorobenzyl 2, 6 -dichlorobenzyl 2, G-dichlorobenzyfl 2, G-dichlorobenzyl 2, 6 -dichlorobenzyl 2, E-dichlorobenzyl 2, 6 -dichlorobenzyl 2, G-dichlorobenzyl 4 -chlorophenyl 2 -amino-4pyrirnidinyl 3 -chiorophenyl 2-amino-4pyrimidinyl-I 2 -chiorophenyl

-I

2 -amino-4r~vrimidinyl 4-toly.

3 -tolyl 2-amino-4pyrimidinyl

-T

2 -amino-4- S. S S

S.

S

m'.rrmid l~ivY 2-tolyl 2-amino-4- 2, E-dichlorobenzy.

pyrimidinyl 4-trifluoro- 2-amino-4- 2, G-dichlorobenzyl methylpheny. pyrimidinyl 3-trifluoro- 2-amino-4- 2, 6-dichlorobenzy.

methylphenyl pyrimidinyl 2,6- 2-a-mino-4- 2 ,6-dichlorobenzyl dichlorophenyl pyrimidinyl 2, 6-dimethyl 2-amino-4- 2, 6 -dichlorobenzyl phenyl pyrimidinyl 3,4- 2-amino-4- 2 ,6-dichlorobenzyl dichioropheny1 pyrimidinyl 3, 4-dimethyl 2-amino-4- 2, 6-dichlorobenzy.

phenyl pyrimidinyl 2,4- 2-amino-4- 2 6 -dichlorobenzyl dichlorophenyl pyrimidinyl 2, 4-dimethy. 2-amjno-4- 2, 6-dichlorobenzy.

phenyl pyrimidinyl Phenyl 4-pyridyl 2 -(4-fluorophenyl) ethylamino 4 -fluorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylainino- 3 -fluorophenyl 4-pyridyl 2- (4-f luorophenyl) ethyl amino 2 -fluorophenyl 4-pyridyl 2- (4 -fluorophenyl) ethylamino 4 -chlorophenyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 3 -chlorophenyl 4-pyridyl 2- (4-f luorophenyl) 7-77-- ethylamino 2 -chlorophenyl 4-pyridyl 2- 4 -fluorophenyl) 56 -4 L-y pyridyl 2- 4 -fluorophenyl) 3-tolyl 4-pyridyl 2- 4 -fluorophenyl) ethylamino 2-tolyl 4 -pyridyl 2- 4 -fluorophenyl) ethylamino 4-trifluoro- 4-pyrid~yl 2- 4 -fluorophenyl) rnethylphenyl _______ethylainino 3-trifluoro- 4-pyridyl 2- 4 -fluorophenyl) methylphenyl 2,6- 4 -pyridly-l 2 4 fluotophenyl) dichlorophenyl ethylamino 2, 6-dimethy. 4-pyridyl 2- 4 -fluorophenyl) _phenylethlamino 3,4-4-pyridyl 2- 4 -fuorophenyl) dichiorophenyl _______eth2ylamino 3, 4-dimethyl 4-pyridyl 2- 4 fluorophenyl) _phenylethyl amino 2,4- 4 -pyrid!yl 4 fluorophenyl) dichiorophen 1 ethylanuino 2, 4-dimethyl 4 -pyridyl 2- 4 -fluorophenyl) phenyl ethylamino Phenyl 2am-ino-4- 2- 4 -fluorophenyl) poyridyl ethylamino 4 -fluorophenyl 2-amino-4- 2- 4 -fluorophenyl) _pyridyl ethylamino 3 -fluoopenyl 2-axnino74-- 2- 4 -fluorophenyl) p~yridyl ethylamino 2 -fluorophenyl 2-amino-4- 2- (4-f luorophenyl) pyridyl ethylainino 4 -chlorophenyl 2-amino-4- 2- 4 -fluorophenyl) yridyl ethylamino 3 -chlorophenyl 2-axnino-4- 2- 4 -fluorophenyl) 2yridyl ethylamino 2 -chlorophenyl 2-amino-4- 2- 4 -fluorophenyl) pyridyl ethylamino 4-tolyl 2-amino-4- 2 -(4-fluorophenyl) -PYridyl ethylamino 3 -tolyl 2-amino-4- 2- (4-fluorophenyl)_ pyriLdyl ethylamino 2 -tolyl 2 -amino-4- 2- 4 -fluor-ophenyl) pyrdyle thylainino 4-tifuoo- 2-amino-4- 2- 4 -fluorophenyl) .methylphenyl yridy1 ethylamino 3 -trifluoro- 2-amino-4- 2 -(4-fluorophenyl) *methylTphenyl- pyridyl ethylamino 2,-2-amino-4- 2- (4-fluorophenyl) dichioropheny 1 pyridyi ethylamino 2, 6-dimethyl 2-amino-4- 2- 4 -fluorophenyl) hey yridl ehyl anino 3,- 2 -amino-4- 2- 4 -fluorophenyl) dichiorophenyl prid 1 ethylamino 3,4-diinethyl 2 -amino-4- 2- C 4 -fluorophenyl) -penl -,A.Id ethylamino 2,4dichloropohenvl 2 -amino-4pyridyl 2- 4 -fluorophenyl) 2, 4-dirnethyl phenyl.

Phenyl 4- fluoropheny.

3- fluorophenyl 2 -fluoropheiyl 2-amino-4- -pyr idyl 2 -acetamido- -4-pyridyl 2 -acetainido- 4 -pyridyl 2 -acetaxnido- 4 -pyridyl 2-acetamido- 4 -chiorophenyl 2 -acetamidoyrid 1 3 -chiorophenyl 2-acetaxnido- -pyridyl ethylamino 2-(floo enl ethylamino 2-( 4 -fluorophenyl) ethylamino 2- 4 -fluorophenyl) ethylainino 2- 4 -fluorophenyl) e thylamino 2 4 -f luorophenyl) ethylamino 2- 4 -fluorophenyl) ethylamino 2- 4 -fluoropheny.) ethylamino 2- (4-f luorophenyl) ethyjlamino- 2- 4 -fluorophenyl) ethylamino 2- 4 -fluorophenyl) ethy+amInIo 2 -chlorophenyl 4-tolyl 3 -tolyl 2 -tolyl 2-cetamido- 4 -pyrv 2 -acetaxnido- 4 -pyridyl

-I

2 -acetainido- -p r idyl 2-acetanido- 4-pvri e-vl 4-trifluoro- 2-acetamido- 2-Z 4 -luorohe.yW inethyl1 heny 1 4-pyridyl ethylainino 3 -trifluoro- 2-acetainido- 2- (4-fluorophenyl) methylphenyl 4-pyridyl ethylainino 2,6-2-acetamido- 2- (4-f luorophenyl) dichlorophenyl 4 -pyridyl ethylamino 2, 6-dimethyl 2--acetamido- 2- (4-f luorophenyl) 4 -pyridyl ethylamino 3,4-2-acetaynido- 2 4 -fluorophenyl) dichioropheny1 4-pyridyl ethylamino 3, 4-dimethyl 2-acetamido- 2- 4 -fluorophenyl) phenyl4-pyridyl- ethylamino 2,4- 2-acetamido- 2 -(4-fluorophenyl) dichlorop~henyl _4-pyridyl ethylamino 2, 4-dimethyl 2-acetamido- 2- 4 -fluorophenyl)phenyl4-pyridyl ethylamino Phenyl2-amino-4- 2- 4 -fluorophenyl) Poyrimidi nyl ethylamino 4 -fluorophenyl 2-ainino-4- 2- (4-f luorophenyl) P2yrimidinyl ethylamino 3-f luorophenyl 2 -axnino-4- 2- (4-f luorophenyl) _2yrimidiny. ethylamino 2 -fluorophenyl 2-amino-4- 2- 4 -f-luorophenyl) Pyrimidinyl ethylanino ox~...JL o.'hen~±yl 3 -chiorophenyl z-ainfo-4- Pyrimidinyl 2-amjno-4pyrlrnidinyl 4-f luorophenyl) e thylamino 2- (4-f luorophenyl) ethylamino 2- (4-f luorophenyl) ethyl amino 2 -chlorophenyl 2-arnino-4pyrimidinyl

I

4-tolyl 3-tolyl 2 -toly.

4-trifluoromethylphenyl 3 -trifluoromethylphenyl 2-amino-4- 2- 4 -fluorophenyl) _2yrimidinyl _ethylamino 2-amino-4- 2- 4 -fluorophenyl) pyrimidinyl ethylazuino 2-amino-4 2- (1-fluorophenyl) Pyrimidiny. eth rlamino 2-amino-4- 2- 4 -fluorophenyl) Pyrimidinyl ethylamino 2-amino-4- 2- 4 -fluorophenyl) pyrimidinyl ethylamino 2-amino-4- 2- 4 -fluorophenyl) pyrimidinyl ethylamino 2-amino-4- 2- 4 -f luorophenyl) pyrimidinyl _eth lamino 2-amino-4- 2 -(4-fluorophenyl) 2,6- 2, 6-dimethyl phenvl 3,4dichioropheny1 3, 4-dimethyl phenyl 2,4dichloropheny-l 2, 4-dimethyl heny1 Pheniyl 4-f luoropheny1 3-f luorophenyl 2-f luoropheny1 4 -chlorophenyl 3 -chlorophenyl 2 -chiorophenyl 4-tolyl 3-tolyl 2-tolyl 4 -trifluoro- 3, 4-dimehyl myphenyl 2,4di chi orophenyl 2,64-dimethyl dcrphenyl Pheny1 4-enlrpey 3 -fluorophenyl pyr iJyLm1 l 2 -amino-4pyrimidinyl 2-amjno-4pyrimidinyl 2 -amino-4pyrimidinyl 4-pyridyl 4-pyridyl 4 -pyridyl 4 -pyridyl 4-pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl 4-pyridyl 4 -pyridyl 4 -pyridyl 4 -pyridyl ethylamino 2- (4-fluorophenyl) e thylamino 2- 4 -fluorophenyl) e thylamino 2- (4-fluorophenyl) e thylamnino 3 -phenyl-propylainino 3 -phenyl-propylamino -3-pheny1 -propyl amino 3 -phenyl -propylamino -3-phenyl -propylamino 3~-phenyl-propylamino 3 -phenyl-propyjlamino 3 -phenyl -propylamino 3-pheny1-propylamino 3 -phenyl -propylamino 3 -phenyl -propylamino 3 -phenlKpopylamino 3 -phenyl-propylamino 4 -pyridyl 4 -pyridyl 4 -pyridy 4 -pyri-dyl 2 -axnino-4pridcyj_ 2 -amino-4- Py~ridyl 2 -alnino-4yridy1 a 3 -phenyl -propylamino 3 -phenyl -propylainino 3 -phenyl -propylamino 3 -phenyl.-propylainino 3 -phenyl -propylamino 3 -phenyl-propylamino

I

3 -phenyl-propylamino 2-f luoropheny.

4 -chiorophenyl 3 -chiorophenyl 2 -chiorophenyl 4-tolyl 2 -amino-4pyridyl 2-amino-4pyridyl 2 -amino-4pyridyl 2-amino-4p2y.i dj 2 -axnino-4- 3 -tolyl 2-tolyl pyr idvi 2-amino-4- .3 -phenyl-propylamino 3 phenyl -propyl amino 3 -phenyl -propylamino 3 -phenyl -propylamino 3 enyl -propyl amino 3 -phenyl.-propyl amino 3 -phenyl -propylamino 3 -pheny.-propylamino 3 -phlenyl -propylamino 3 -phenyl -propylamino 3 -pheriyl -propylamino pyridyl 2-amino-4pyridyl I 2, 6-dimehyl mypheny 3,4dichloropheny.

3, 4-dimethyl phenyl 2,4dichlorophenyl 2, 4-dimethyl _phenyl Phenyl 2-amino-4- 2-amino-4pyridyl -2-amino-4pyridyl 2-amino-4 pyridyl 2-amino-4- _pyridyl 2-amino-4- _pyr idyl 2 -acmio- 4 pyridyl 2 -acmio- 4 pyridyl 3 -phenyl -propylamino 3 -phenyl -propylamino 3 -phenyl -propylamino 3 -phenyl -propylamino 3 -phenyl -propylamino 3 -pheny].-propylamino 4- fluorophenyl -f!luorophenyl 2-ftluorophenyl 4 -chiorophenyl 3 -chiorophenyl 2 -chioropenyl 2 -acetamido- 3 phenyl -propyl amino -4-pyridyl 2 -acetami do- 3 -phenyl -propyl amino 4 -pyr7i dyl 2-acetamido- 3 -phenyl-propylamino 4 4-pyridy. 2-acetamido- 4 -pyridyl 2 -acetamidoi -phenyl-propylamino 3 -phenyl -propylamino 4 -rpvridvl 4 -tolyl j 2 -acetamido- 3 -phenyil-propylamino .4-pyridyl 3- toiyl 2 -acetamido- 3 -phenyl-propylamino 4-pyridyl x 4 -trifl-uorome thlyphenyl 3 -trifluorome thy iphenyl 4 -pyridyl 2 -acetamido- 4 -pyridy.

2 -acetamido- 4 -pyridyl .i-phenyl -propylamino 3 -phenyl -propylamino 3 -phenyl.-propylamino 2, 6dichiorophen 2.

2, 6-dimethy.

phenyl 3,4dichlorophenyl 3, 4-dimethyl pheny1 2,4dichlorophenyl 2, 4-dimethyl phenyl Phenyl.

2 -acetamido- 4 -pyridyl 2 -acetainido- 4 -Pridyl 2 -acetainido- 4 -pyridyl 2 -acetamido- 4-pyridyl 2 -acetamido- 4 -pyridyl 2 -acetamido- 4 -pyridyl 2-amino-4pyrimidinyl 4- fluorophenyl 2-axino-4- 3 -fluorophenyl 2 -amjino-4pyrimidinyl 3 -phenyl-propylamino 3 -phenyl -propylanino 3 -phenyl -propylanino 3 -phenyl-propylanino 3-phenyl. -propyl amino 3 -phenyl-propylamino 3 -phenyl -propylanino 3 -phenyl -propylamino 3 -phenyl -propylanino 3 -phenyl -propyl amino 3 -phenyl-propylamino 3 -phenyl -propylamino 3 -phenyl -propyl amino 3 -phenyl-propylamino 2 -fluorophenyl

A-

2-amino-4- 4 -chiorophenyl ~1 pyrimidinyl 3 -chiorophenyl 2 -amino-4i~vrimidinyl 2 -chiorophey 4 -tolyl

I

2-amino-4jpyrimidinyl 2 -ainino-4 pyrimdin 3- olyl 2 -axnino-4- Iovrimidinvl 2-toly1 2-amino-4pyrimidinyl 4-trifluoromethylphenyl 3 -trifluorome thyiphenvl 2 -amino-4pyrimidinyl 2 -amino-4

I

3 -phenyl-propylamino 2,6dichloropheny.

2, 6-dimethyl phenvl 2-amino-4pyrimidinyl 2 -amino-4- 3 -phenyl -propyl ami-no pvri midinvl 3,-2 -amino-4- 3 -phenyl-propylamino dichlorophenyl pyrimidinyl 3, 4-dimethyl 2 -amino-4- 3 -phenyl-propylamino Phnlpyrimidinyl 2,-2-amjno-4- 3 -phenyl-propylamino dichlorophenyl _pyrimidinyl 2, 4-dimethyl 2 -amino-4 3 -phenyl-propylamino phenyl pyrimidinyl Phenyl 4-pyridyl (1-methyl-3phenyl )propylamino 4 -fluorophenyl 4 -pyridyl (1-methyl-3phenyl) propylamino 3-f luorophenyl 4 -pyridyl (1 -methyl -3phenyl )propylamino 2- fluorophenyl 4 -pyridyl- 4 -chiorophenyl 4 -pyridyl 3 -chiorophenyl 4 -pyridyl 2-chiorophenyl. 4-pyridyl 4-tolyl 4-pyridyl 3-tolyl 4-pyridyl (1-methyl-3- _heny1)propylamino (--methyl-3 phenyl) propylamino (1-methyl-3 phen yl )propylamino (1-methyl-3 phenyl )propYlanino (1-methyl-3 _phenyl) propylamino (1-methyl-3 2-tolyl 4 -pyridyl 4-trifluorome thylphenyl 3 -tri fluoromethylphenyl 14 -pyridyl 1 4 -pyridyl 4. I 2,6dichlorophenvi 4 -pyridy.

G _e eLy Iprop.ylacmino 2, 6-dimethyl 4-pyridyl (1-methyl-3phenyl .phenyl) propylamnino 3,4- 4-pyridyl (1-xnethyl-3dichloropheny. phenyl) propylamino 3, 4-dimethyl 4-pyridyl (1-methyl-3phenyl propylainino 2,-4-pyridyl (1-methyl-3 dichlorophenyl propylamino 2, 4-dimethyl 4-pyridyl (1-methyl-3phenyl phenyl )propylamino- Pheyl2-amino-4- (1-methyl-3pyridyl p~henyl) propylamino 4 -fluorophenyl 2-ainino-4-- (1-methyl-3pyridyl phenyl) propylainino 3 'luorophenyl 2-amino-4- (1-methyl-3pyridyl phenyl) propylamino 2 -fluorophenyl 2-amino-4- (1-methyl-3lpyridyl phenyl) propylainino 4 -chlorophenyl 2-ainino-4- (1-znethyl-3pyridyl p~henyl) propylamino 3 -chlorophenyl 2-amino-4- (1-methyl-3pyridyl phenyl) propylamino 2 -chlorophenyl 2-amino-4- (1-methyl-3pyridyl pohenyl )propylamino.

4-tolyl 2-amino-4- (1-methyl-3pyridyl phenyl.) propylamino 3-tolyl 2-aznino-4- .(1-methyl-3pyriLdy1 phenyl )propylamino 2 -tolyl 2-amino-4- (1-methyl-3pyridy1 phenyl) propylaynino 4-trifluoro- F2-amnino-4- (1-methyl-3methylphenyl pyridyl phenyl) propylainino 3 -trifluoro- 2-amino-4- (1-methyi-3- Fethylphenyl pyridy lphenyl) propylamino 2,6dichiorophenyl 2,6-dimethyl

I

Phenyl 2 -amino-4pyridy1 2 -amino-4jpyridyl 3,4dichlorophenyl 2-amino-4- 3, 4-dimethyl ~pheny1 _yiv 2-amino-4- 2vridyl 2,4- 2-ainino-4dichlorophenyl -pyridyl 2, 4-dimethyl 2-amino-4 phenyl pyvridyl Phenyl. 2 -acetazido- -pyridyl 4- fluorophenyl 2 -acetamido- -pyridyi -methyl-3 _phenyl) propylamino Fl -methyl -3 pheny 1)propylamino (1-methyl-3 phenyl) propylamino (1-methyl-3- _phenyl )propylainino (1-methyl-3 phenyl) propyvlamino (1-methyl-3phenyl) propylaino (1-methyl-3 phenyl )propylamino (1-methyl-3 pheriyl )propylaynino (1-methyl-3 -phenyl )propylamino (1-methyl-3 phenyl )propylainino (1-methyl-3phenyl) propylamino (1-methyl-3- 3- fluoropheny 2- fluorophenyl -chorophenyl 3 -chl-orophenyj 2 -chiorophenyl 4-tolyl 3 -toly.

2-tolyl 4 -trifluoro- 2-acetamido- 4 -pyridy.

2-acetamido- 4-pyridyl 2 -acetamido- 4-pyridyl 2 -acetamido- 4-pyridyl 2-acetamido- (1-methyl-3- Apy~dy 2 -acetainido- 4-pyridyl 2 -acetamido- 4 -pyridyl 2 -acetamido- 4-pyridyl (1-methyl-3 phenyl )propylamino (1-methyl-3 tee.

S C .5 S C. 0

CO

C.

C

S

C.

S

5 **500*

C

(1-methyl-3

T

me thyiphenyl 3 -trifluorome thyliphenyl 2, 6di chi orophenyl 6-dimethyl phenyl 3,4dichlorophenyl 3, 4-dimethyl phenyl 2,4dich lorophenyl 2, 4-dimethyl phenyl Phenyl* 4 -fluorophenyl 2 -acetamido- 4 -pyridyl (1-methyl-3- 2 -ac etainido- 4 -pyridyl 2 -acetamido- 4 -pyridyl 2 -acetamido- (1-methyl-3 (1-rnethyl-3 p~henyl )propylamino (1-methyl-3 ~pyridy1 henyl propylino 2 -acetamido- (1-methyl-3- 4-pyridyl p~henyl)propylamino 2 -acetanido- (1-methyl-3- 4 -pyridyl _phenyl)propylaxnino 2 -acetamido- (1-methyl-3- 4 -pyridvl phenyl)propylamino 2 -acetainido- (1-methyl-3- 4 -pyrid1 _phenyl) propylamino

C.

C

Os

C

P2Yrimidinyl 2-amjno-w pyrimi dinyl 2 -amino-4pyrimidinyl (1-methyl-3- 3 -fluorophenyl (1-methyl-3- phenyl propyl amino (1-methyi-3phenyl) propylainino 2 -chiorophenyl 4 -tolyl 3T -tolyl 2-tolyl 2 -axnino-4pyrimidinyl 2-amino-4pyrimidinyl 2-amino-4p1yriniidinyl 2-axnino-4pyrimidinyl 2 -amino-4pyrimidinyl 2-amino-4pyrimidinyl 2-amino-4pyrimidinyl 2, 6-dimehyl dichiorophenyl 2, 4-dimethyl pheny1 34- urpey 4- loropheny.

34- luoroheyl phenloohn~ 24- urpey 4-florophenyl 24- luorohyj 4-fnlorpey 4- fluorophenyl 4- fluorophenyl.

4- fluorophenyl 4- fluorophenyl 2 -amino-4pyrimidinyl 2-amino-4pyr imi dinyl 2 -amino-4- _pyrimidinyl 2-amino-4pyrimidinyl 2-amino-4pyrimidinyl 2 -amino-4 pyrimidinyl 2-amino-4- .pyr imidinyl 2 -amino-4pyrimidinyl 4-pyridyl 2 -acetamido- 4 -pyridyl 2-amino-4pyrimidinyl 4 -pyridylnyl 2 -acetamido- 4 -pyridyl 2 -amino-4 pyrimidinyl 4 -pyridyl 2 a c-et a mido 4 -pyridyl 2 -amino-4pyrimidinyl1 4 -pyridyl 2-acetamido- 4-pyridyl 2 -amino-4pyrimidinyl (1-methyl-3- -phenlyl) propyl amino (1-methyl-3- -phenyl) lpro-pyl amino (1-methyl-3phe n1) Proy lamino (1-methyl-3 phenyl) propylamino (1-methyl-3 Pheny1)propylamino (1-methyl-3 pheny1) proplamino (1-methyl-3phIIenyl) propylamino (1-methyl-3pheny1)propylamino (1-methyl-3 phenl) ropylamino 41- lurobnzylmi 4-f loroenylamino 4-f loroenylamino 4 -luropheamnlo1 mpeh 1-eth lamino f luorophenyl) -ethyl) amino 1-dimethyl-2- fluorophenyl) -ethyl) amino 2- 4 -fluorophenyl) -2- 4 -fluorophenyl) -2methyl-ethyl) amino 4 -fluorophenyl) -2methyl-ethyl) amino .64 4 -fluorophenyl J 4-pyridyl-- 4-f luoropheny.

4-f luorophenyl 4 -fluorophenyl 4- fluorophenyl 4 -fluoropheiyl 4-f luorophenyl 2 -acetamido- 4 -pyridyl 2 -amino-4poyr imidinyl 4-pyridyl 2 -acetamido- 4- pyridyl 2 -amino-4 pyrixnidinyl 4 -pyridyl 4 -fluorophenyl a -acetaido-

OVO.

00 0.00 .0.

0:0.

0 0 4-f luorophenyl 4 -fluorophenyl 4-f luorophenyl 4-f luorophenyl.

4- fluoropheny.

4- fluorophenyl 4- fluorophenyl 4- fluorophenyl 4- fluorophenyl 4 -fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4- fluoropheny.

4- fluorophenyl 4- fluorophenyl 4- fluorophenyl *4-pyridyl 2 -amino-4 pyrimniiny 4 -pyridy-L 2 -acetainido- 4 -pyridyl 2 -amino-4pyrimidiny1 4 -pyridyl 2 -acetamido- 4 -p2yridyl 2 -axnino-4 pyrimidinyl 4 -pyridyl 2 -acetamido- 4 -pyridyl 2-amino-4pyrirnidinyl 4 -pyridyl 2 -acetamido- 4:-pyridyl_ 2-axnjno-4- P2yrimidinyl 4 -pyridyl 2 -acetamido- 4 -pyridyl 2 -amino-4- _pyrimidinyl 4 -pyridyl 2 -a:etaxidlo- 4 -pyridyl 2 -amino-4- Pyrimidinyl phenylethvl)amino (2methyl-2- _henylethyl)amino (methyl-2henylethyl)axnino 4 -(rfuooety -PhenyL)ethyl) amino 4 -tyl) etamino (J-tfluoroey pehyl)et mino n (4-tfluoroey -hlethyl)amino (4-tfluoroey ,ehyl)etmino in 2- (4-foilorheylamn eth -lyl hylno (3-fluorophenyl) ethyl) amino meh- (-u(2-ey pyriyl)aetyli ain meh- (-u(2-ey eyriyl)aetyli ain l-dlehyl3 phenylpropyl) amino (2-fluorophenyl)propyl.)amino (2-fluorophenyl)prpyl)amino 4 -luorohlnyl) _propyl) amino 4- fluorophenyl 4 -pyridyl- 4 -fluorophenyl 2 -acetamido- 4-p~yridyl 4-f luorophenyl 2-ainino-4pyrimidinyi 4- fluorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluoropheny.

4 -fluorophenyl 4-f luorophenyl 4 -fluorophenyl 4 -fluorophenyl 4-f luo rophenyl 4 -pyridyl 2 -acetamido- 4 -pyridyl 2-ainino-4pyrimidinyl 4 -pyridyl 2 -acetamido- 4-pyridy.

2-amino-4- _pyrimidinyl 4-pyridyl 2 -acetamido- 4 -pyridyl 2 -amino-4- (4-fluorophenyl) -1methyl -propyl) amino 4 -fluorophenyl) -1- Inethyl-propyl) amino 4 -fJluorophenyl) -1pehnl) -ropyl) amino 2 -fluoropheny l -o propyl)ainiopy~mn (3,-d2fluroheny-4-l) -o ro enl)amino~ mio 2-f luorophenyl propyl) aminopy~m (3-methyl-3 -phenyl)propyl) amino (3-methyl -3-phenyl)- _propyl) amino (3 -metyl-3 -phenyl)propyl) amino (2-methyl -3 -phenyl p2ropyl) amino (2-methyl-3 -phenylpropyl) amino (2-methyl -3 -phenyl propyl) amino (33-imthbtl)amino 3-dime thylbu tyl) amino 4 -fluoropheny. 4-pyridy.

4 -fluo;rophenyl 2 -acetamido- 4-pyridyl -fluorophenyl '2-amino-4- 4-fluorohen l pyrimidinvl 4 -fluorophenyl 4- fluorophenyl 4- fluorophenyl 4 -fluoropheny.

4-f luorophenyl 4- fluorophenyl 4-f luorophenylI 4- fluorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4 -fluorophenyl 4- fluorophenyl 4_-pridyl 2 -acetainido- 4-pyridyl 2-amino-4pyrimidinyl 4 -pyridyl 2 -acetamido- 3-dimethylbutyl) amino isoamylamino is oamyl amino is oamyl amino 2 -amino-4pyrimidinyl 4 -pyridyl 2 -acetamido- 4 -pyridyl amylamino, 2-amino-4yrimidinyl 4 -pyridyl 2 -acetamido- 4-pyridyl 2-amino-4- Primidinyl 4 -pyrridyl 2 -acetamnido- 4 -pyridyl amyl amino 5-dime thyl) pentylamino 5-dimethyl) pentylamino 5-dietyl) etlmn piperaz inyl -iLLurpnni 4 -pyridyl 3 -(3upheny--in..

ro lamino 4 -fluorophenyl 4 -yridyld (3 -enluor-amin-) rimiin 1 ro lamino 3- flopny 4 -pyridyl 3 -phenl -2 -amineth .ai* t i e r c L3 h e o R l m 2-tlyl 4 -pyridyl 2-peny-iuorophenyl -terfutoyl 4 -pyridyl 2- -phnluoropmn.

4-f-uryrieyly4 3 -phen- -amo-am di-chiloro~ty he rn 1 ro heyiplamino 2, 6-dimethyl p~henyl 3,4dichlorophenyl 4 -pyridyl 4 -pyridyl 3 ,4-dimethyl phenyl 2,4dichlorophenyl 2, 4-dimethyl -phenyl Phenyl.

I

4 -pyridyl 4 -pyridy.

4 -pyridyl 4 -pyridyl A I 3p ny-2mnopropylamino 3 -phenyl-2 -aminopropylamino 3 -phenyl-2-aminopropylamino 3 -phenyl-2-aminopropylamino 3 -phenyl-2 -aminopropylamino 3 -phenyl-3 -aminopropylamino 3 -phenyl-3 -aminopropylamino 3 -phenyl -3 -aminopropyl amino 3 -phenyl-3-amjnopropylamino 3 -pheny.-3 -aminopropylamino 3 -phenyl -3 -aminopropyl amino 3 -phenyl-3 -amino- -A-tiuoropnenyi 3 -fluorophenyl I 4-pyridyl

I

4 -pyridyl I_ 2- fluorophenyl 4 -pyridy.

4 .1.

4 -chlorophenyl 4-pyridy. I 3 -chiorophenyl 4 -pyridyl 2 -chlorophenyl

I

4 -pyridy.

oe cutLLL±no 4-tolyl 4-pyridyl 3 -phenyl-3-aminopropylamino 3 -tolyl 4-pyridyl 3 -phenyl-3-aminoylamino 2 -tolyl 4-pyridy. 3 -phenyl-3-amjnopropylamino 7-trifluoro- 4-pyridyl 3 -phenyl-3-amjnomethylphenyl 3-trifluoro- 4-pyridy. 3 -phenyl-3-aminome thylphenyl rplmn 2,6- 4-pyridyl 3 -phenyl-3-aminodichioroohenv 1 propylamino 2, 6-dimethyl 4-pyridyl 3 -phenyl-3-aminophenyl _______propylamino 3,4- 4-pyridyl 3 -phenyl-3-aminodichlorophenyl _______prop7VFlamino 3, 4-dimethyl 4-pyridyl 3 -phenyl-3-aminopheny 1 propylamino 2,4- 4-pyridyl 3 -phenyl-3-aminodichiorophenyl _propylamino 2, 4-dimethyl 4-pyridyl 3 -phenyl-3-aminophenyl ________propylamino and 68 0 R, :)ICH 2

CH

3 R12 N2 R, wherein R and R' are one of the combinations given in the following table: 4- fluorophenyl 4 -pyridyl 4- fluoroTphenyl 2 -acetamido- -pyridyl 4 -fluoropheny. 2-ainino-4pyrimidinyl 4-f luorophenyl 4 -pyridyl 4 -fluoropheny. 2 -acetamido- 4-pyridyl 4 -fluorophenyl 2-axnino-4pyrimidinyl 4-f luorophenyl 4 -pyridyl a 4- fluorophenyl 4- fluorophenyl 4- fluoropheny.

4-f luorophenyl 4-f luoropenyl 4 -fluorophenyl 4- fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4 -fluorophenyl 2 -acetamido- 4 -pyridyl 2-amino-4- Pyrimidinyl 4 -pyridyl 2 -acetaxnido- 4. -pyridyl 2 -amino-4pyrimidinyl 4 -pyridyl 2 -acetam ido- 4 -pyridyl 2-axnino-4 pyrimidinyl 4 -pyridyl

-R

4 -fluorophenyl) ethyl) amino (2 4 -f luorophenyl) ethyl) amino 4 -fluorophenyl) ethyl) amino (3 -phenylpropyl) amin-o (3 -phenylpropyl) amino (3 -phenylpropyl) amino -2-amino-3pjhenylpropylamino -2-amino-3phenylpropylamino -2-amino-3phenylp opylamino 3-amino-3 phenyipropylamino 3 -amino-2 -ehy3phenylpropylamino 3 -axnino-2-methyl-3 -tetrahydroisoquinol- 2-acetamido- -pyridyl 4- fluorophenyl 2 -amino-4 pyrimidinyl 4 -fluorophenyl 4 -pyridyl 4 -fluorophenyl* 2 -acetamido- _4 -pyridy 4 -fLuorophenyl 2-alnino-4andPriiiy yvlme thyl enamino

I

-tetrahydroisoquinol- (3 -ehylpe a zin -3 -benzylpiperazinyl 3 -benzylpiperazinyl in which R 2 is H, methyl or benzyl, and

R'

2 and R' are one of the combinations given in the following table: R" 1R1" -Phenyl 4-pyridyl phenyl -4-f luorophenyl 4-pyridyl p henyl Phenyl. 2-acetamido- phenyl pyridyl 4-f luorophenyl 2 -acetamido- phenyl pyridyl Phenyl &4-pyridyl 4-ethylpheny.

4-f luoropheny1 4-pyridyl 4-ethylrheny.

Phenyl. 2-acetamido- 4 -ethylphenyl pyridyl 4-f luorophenyl 2-acetamido- 4-ethyiphenyl pyridyl Phenyl 4-pyridy 1 2, 4-dimethylphenyl 4 -fluorophenyl 4-pyridy. 2, 4-dimethylphenyl Phenyl 2-acetamido- 2, 4 -dimethylpheny.

4-f luorophenyl 2-acetamido- 2, 4 -dimethylphenyl pyridyl Phenyl 4-pyridyl 2, -dichlorobenzyl 4 -fluorophenyl 4-2yridyl 2, 6 -dichlorobenzyl Phenyl 2-acetamido- 2 6 -dichlorobenzy.

pyridyl 4-f luoropheny. 2 -acetamnido- 2, G-dichlorobenzyl pyridyl Phenyl 4-pyridyl 2- (4-f luorophenyl) ethylamino 4 -fluorophenyl 4-pyridyl 2- (4 -fluorophenyl) thylamino Phenyl 2 -acetamido- 2- (4-f luorophenyl) pyridyl ethylamino 4 -fluorophenyl 2-acetainido- 2- 4 -fluorophenyl) pyridyl ethylamino Phenyl 4 -pyridyl 3 -2henylpropylamino 4 -fluoirophenyl 14-pyridyl -3-phenylpropylamino

I

4 -fluorophenyl Phenyl 4-f uorophenyl pyridyl 2 -acetamidopyridyl .j-prienylpropyl amino 3 -phenylpropylamino 1 -piperazinyl 1 -piperazinyl

I

I

4jpyridyl

I

4 -pYridyl Phenyl 4-f luorophenyl benzyl benzyl 2-thienyl 2 -thienyl cyc lohe.?yl cyclohexyl tert-butyl tert -butyl 4- fluorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl Phenyl 4 -fluoropheny.

Phenyl 4- fluorophenyl Phenyl 4- fluorophenyl Phenyl 4 f luorophenyl Pheniyl 2 -ace pyric 2-acE pyric 4-pyl 4 -py2 4 -py~t 4 -pyx 4 -pyr 4 -pyr 4 -pyr 4-py 4piper 4 -pyr 4 -pyr 4 -pyr 2-ace pyrid, 2-ace _pyrid, 4 -pyr.

4 -pyr: 2 -acel _pyrid' 2-acel pvrid 4 -pyr: 4 -pyr: 2-acet pyrid) 2 -acet pyridg 4 -pyri 4 -pyri 2 -acet _pyrid, atamido- l-piperazinyl Btamido- l-piperazinyl :idyl 3-pheny1 ropylarino :idyl 2- 4 -fluorophenyl) :idy 3-hen1 olamino idyl 3 -phenylpropylam~in 0 idyl 2- 4 -fluorophenyl) 'idyl 3-pheny1propylamino idyl 2- 4 -fluorophenyl) e thylainino idyl 3-phenylpropylamino idyl2- (4-f luorophenyl) idiyl.ethylamino any 3 -phenylpropylamino anyl 2- 4 -fluorophenyl) idinyl ethylamino idyl (S -2-anino-3-r ain ehn 1 ro lmn idTyl -2-amino-3phenylpropylamino tido- -2-ainino-3- -phenylpropylamino tamido- -2-aznino-3 1 phenylpropylamino tid 3S-amino-3- 1 phenylpropylamino idyl 3-amino-3- _phenylpropylamino :aid 3-amino-3phenyipropylamino t.amido- 3-amino-3- 1 _phenylpropylamino tLd 3 -amino-2-Iehl3 1_ __phenylpropylamino Ldyl 3 -amino-2-methyl-3phenylpropylamino ido- 3 -amino-2-methyl-3- 11 phenylpropyliano .amido- 3 -amino 2_-methy3- 1 phenylpropylamino Ldyl i-tetrahy2 roisoquino 1 pheylnethylamino .dyl -tetrahydroisoqu~inol- -ylmethylenamino .aido- -tetrahydroisoquino rl 13- liethylenamino 4 -fluorophenyl 2-acetamidopyridyl Phenyl 4-pyridyl (S)-tetrahydroisoquinol- 3-ylmethylenamino S -3 -ben 7yl Ti e~Oraz T i i-l 4-fluorophenyl 4-pyridyl

S)-

3 -benzylpiperazinvl 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

(CI-C

6 yet more preferably 1-4 carbon atoms (C 1

-C

4 still more preferably 1-3 carbon atoms (C 1

-C

3 and most preferably 1-2 carbon atoms (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 Sradical 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.

30 "Alkenyl", alone or in combination, means a straightchain or branched-chain hydrocarbon radical having one

I

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 i radical of the type wherein is 25 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.

30 "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, 35 sec-butylthio, tert-butylthio and the like.

0* 73 riAlkylsulfinyl", alone or in combination, means a radical of the type wherein is an alkyl radical as defined above and i-s a mono-oxygenated sulfur a-tom. Examples of such alkylsulfinyl radicals include methylsulfinyl, ethylsulfinyl, n-propylsulfi-nyl, 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 a di-oxygenated sulfur atom. Examples of such alkylsulfonyl radicals include methylsulfonyl, ethylsulfonyl, n-propylsulfonyl, isopropylsulfony., n-butylsulfonyl, iso-butylsulfonyl, sec-butylsulfonyl, tert-butylsulfonyl and the like.

"Aryll", alone or in combination, means a phenyl or biphenyl radical, which is optionally benzo fused or heterocyclo fused and which is optionally substituted with one or more substituents selected from alkyl, alkoxy, halogen, hydroxy, amino, azido, nitro, cyano, haloalkyl, carboxy, alkoxycarbonyl, cycloalkyl, alkanoylamino, amido, ainidino, alkoxycarbonylamino,

N-

4 **alkylamidino, alkylamino, dialkylamino, aminoalkyl, alkylaminoalkyl, dialkylaxninoalkyl, N-alkylamido,

N,N-

dialkylamido, 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, 2chiorophenyl, 3 -nitrophenyl, 3 -axninophenyl, 3acetamidophenyl, 2-amino-3- (aminomethyl)phenyl, 6methyl-3 -acetamidophenyl, 6-methyl-2 -aminophenyl, 6methyl-2, 3-diaminophenyl, 2 -amino-3-methylphenyl, 4,6dimethyl-2 -aminophenyl, 4 -hydroxyphenyl, 3 -methyl-4 hydroxyphenyl, 4- 2 -methoxyphenyl )phenyl, 2 -amino-i- 9999..naphthyl, 2-naphthyl, 3 -amino- 2-naphthyl, l-methyl-3amino-2-naphthyl, 2, 3 -diamino-l-naphthyl, 4,8-dimethoxy- 2-naphthyl and the like.

"Aralkyl" and "arylalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by an aryl radical as defined above, such as benzyl, 2phenylethyl, dibenzylmethyl, hydroxyphenylmethyl, methylphenylmethyl, diphenylmethyl, dichlorophenylmethyl, 4 -methoxyphenylmethyl and the like.

"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 o* radical of the type wherein is an alkanoyl radical as defined above, wherein the amino radical may optionally be substituted, such as with 9 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.

20 "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.

25 "Cycloalkyl", alone or in combination, means a saturated or partially saturated, preferably one double bond, monocyclic, bicyclic or tricyclic carbocyclic alkyl Sradical, preferably monocyclic, containing preferably 12 carbon atoms (C 5

-C

12 more preferably 5-10 carbon atoms (C5-C 10 even more preferably 5-7 carbon atoms

(C

5

-C

7 which is optionally benzo fused or heterocyclo fused and which is optionally substituted as defined herein with respect to the definition of aryl. Examples of such cycloalkyl radicals include cyclopentyl, cyclohexyl, dihydroxycyclohexyl, ethylenedioxycyclohexyl, cycloheptyl, octahydronaphthyl, tetrahydronaphthyl, octahydroquinolinyl, dimethoxytetrahydronaphthyl, 2,3-dihydro-lH-indenyl, azabicyclo[3.2.1]octyl and the like.

"Heteroatoms" means nitrogen, oxygen and sulfur heteroatoms.

"Heterocyclo fused" forms a ring system in which a heterocyclyl or heteroaryl group of 5-6 ring members and a cycloalkyl or aryl group have two carbons in common, for example indole, isoquinoline, tetrahydroquinoline, methylenedioxybenzene and the like.

"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 20 members in each ring and even more preferably 5-6 ring members in each ring. "Heterocyclyl" is intended to o 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, 30 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 77 members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated orbenzo-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-1-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-1oxo-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 20 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 25 imidazolyl, l-benzyloxycarbonylimidazol-4-yl, pyrrolyl, .pyrazolyl, pyridyl, 3-(2-methyl)pyridyl, 3-(4trifluoromethyl)pyridyl, pyrimidinyl, 5-(4trifluoromethyl)pyrimidinyl, pyrazinyl, triazolyl, furyl, thienyl, oxazolyl, thiazolyl, indolyl, quinolinyl, 5,6,7, 8 -tetrahydroquinolyl, 5,6,7,8-tetrahydroisoquinolinyl, quinoxalinyl, benzothiazolyl, benzofuryl, benzimidazolyl, benzoxazolyl and the like.

"Heteroaralkyl" and "heteroarylalkyl," alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-2, is replaced by a heteroaryl radical as defined above, such as 3-furylpropyl, 2-pyrrolyl propyl, chloroquinolinylmethyl, 2-thienylethyl, pyridylmethyl, 1-imidazolylethyl and the like.

"Halogen" and "halo", alone or in combination, means fluoro, chloro, bromo or iodo radicals.

"Haloalkyl", alone or in combination, means an alkyl radical as defined above in which at least one hydrogen atom, preferably 1-3, is replaced by a halogen radical, more preferably fluoro or chloro radicals. Examples of such haloalkyl radicals include 1,1,1-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 20 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, anmonium, 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) "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-1i, 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.

20 "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, 25 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 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 20 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 30 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.

8.1 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 20 imidazole or DMF. Methods for silylation of amines and removal of silyl protecting groups are well known to :i 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 25 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 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 R y 0 -CRxRY-

R

Rx NI -NRxRY R-N

R

y -NR- N Prodrugs of the compounds of this invention are also contemplated by this invention. A prodrug is an o* active or inactive compound that is modified chemically through in vivo physicological action, such as hydrolysis, metabolism and the like, into a compound of oo 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 20 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 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 having opposite stereochemistry using wellknown methods, for example, by inversion.

i4(3 H-Pyrimidinones: 2 C For the synthesis of 4 3 H)-pyrimidinones II (or its automer, 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.

84 Scheme 1 0 H 2 N R0 I OR NH N R 12 V R N4 2 k X11 OH 0? R N R R- N R For the synthesis of 2 -substituted 5-(4fluorophenyl) 4 -pyridyl) 4 -hydroxy-pyrimijfleg

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 10 dehydrogenating agent for the conversion of XIII to II, sodium nitrite/acetic acid is suitable.

Scheme 2 0 H 0

N

F,

OR

OHN

N leo

H

2 N x~i

HN

F 0 VF0 NNH

N

N N Ri N NR *Acc ordingly, further compounds of formula II may be obtained in which R' is any other heteroaryl ring within the definition of R' by the appropriate choice of starting material. Such starting materials include but are not limited to 2 -methyl'pyridine-4-carboxaldehyde, 2, G-dimethylpyridine-4-carboxaldehyde (Mathes and Sauermilch, Chem. Ber. 88, 1276-1283 (1955)), quinoline- 4 -carboxaldehyde, pyrimidine-4-carboxaldehyde, 6methylpyrimidine-4-.carbox-aldehyde, 2 -methylpyrim-idine- 4-carboxaldehyde, 2, 6-dimethylpyrimidine4carboxaldehyde (Bredereck et al. Chemn. Ber. 97, 3407-3417 (1964)). The use of 2 -nitropyridine-4-carboxaldehyde would lead to- derivative of f rmula IIwihR1 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".

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 N QOEt

N^

F OEt OEt F

N

OEt

N

XIV

H

2

N

H

2

N

XVI

a a a..

a 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 2 can be obtained, for example by alkylation of XV with alkyl halides. Treatment of XV or XVI with Raney nickel and H, provides compounds of structure II wherein R' is H.

Although Scheme 3 illustrates syntheses in which R" is 4-pyridyl, this approach may be equally applied to 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 2 is represented by a 2-amino-4-pyridyl group (Scheme 4).

Scheme 4 F F 0 O O SN

N

N R N R N N N A

N

NO

2

NH

2 I I Furthermore, methyl 2-acetamido isonicotinate 20 (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., .We Acta Chem. Scand. B 42 384-389 (1988)), a tertbutyldimethylsilyl group, a benzyloxymethyl group, a benzyl group or the like Scheme SCO2Me q CO 2 Me CO 2 Me

NH

2 NHAc NAc

PI

P,

88 Removal of the protecting group Pi of the resulting pyrimidine II with a suitable reagent tetrabutylammonium fluoride in the case where P, is tbutyldimethyl-silyloxymethyl) would then lead to a pyrimidinone II with R" 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 R4 I

N

R

2 )N R 1

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., 20 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 25 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 BuSn) by reaction with e.g. tributylstannyl chloride following lithiation with butyllithium and may then be reacted with an aryl halide in the presence of a catalyst.

(Sandosham and Undheim, Acta Chem. Scand. 43, 684-689 (1989). Both approaches would lead to pyrimidines II in which R" is represented by aryl and heteroaryl groups.

As reported in the literature (Kabbe, Lieb. Ann.

Chem. 704, 144 (1967); German Patent 1271116 (1968)) and displayed in Scheme 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 Rll CN R CO 2 Et N

N

I

In Scheme 7, compounds of the present invention of S• formula XXX can be readily prepared by reacting the methylthio intermediate XXXI with the amine NHRR 2 1 for example by heating the mixture preferably at a 20 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 NHR'R for example by heating the mixture preferably at a temperature greater 25 than 40 0 C, more preferably 50-210 0

C.

Scheme 7 O

O

0 0 0 R R"2 2 R 2 11 R N SMe R N N R N SO 2 Me XXXI

XXX

XXXII

Amines of formula

NHRR

21 are commercially available or can be readily prepared by those skilled in the art from commercially available starting materials. For example, an amide, nitro or cyano group can be reduced under reducing conditions, such as in the prescence of a reducing agent like lithium aluminum hydride and the like, to form the corresponding amine. Alkylation and acylation of amino groups are well known in the art.

Chiral and achiral substituted amines-can be prepared from chiral amino acids and amino acid amides (for example, alkyl, aryl, heteroaryl, cycloalkyl, arylalkyl, heteroarylalkyl, cycloalkylalkyl and the like substituted glycine, E-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. 20 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.

Pyridones: .ooo As displayed in Scheme 8, a suitable route to 2 (lH)-pyridones III involves the cyclization reaction between an a,b-unsaturated ketone XXII and a sufficiently reactive, substituted acetamide in the 30 presence of base (El-Rayyes and Al-Hajjar,

J.

Heterocycl. Chem. 21, 1473 (1984)) and subsequent dehydrogenation.

o Scheme 8 0 R H2o >R1 R 0 NH2 XXII u 00 1 NHR 11NH RR1 R Scheme 9 0 0 R 0 N.

N

0* 0

NNH

R 1.

0NN

XIIN

Accordingly (Scheme pyridine-4-carboxaldehyde a.or other heteroaromatic carboxaldehyde-like pyrimidine- 4 -carboxaldehydes or quinoline- 4 -carboxcyaldehydes may be a reacted with acetyl aryl, acetyl heteroaryi or acetyl cycloalky. derivatives in the presence of piperidine! acetic acid at elevated temperature (Bayer and Hartmann, A-rch. Pharm. (Weinheim) 324, 815 (1991)) as well as pinacolone

(CH

3 -CO-C(CH)) in the presence of sodium hydroxide to provide the unsaturated ketone XXII (or the 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(H)-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 K OEt Ri R12 OEt CN 12 O R12 O

R

1 2 CN O- R R Et XII R H C.

*O

11 1. 0 R R s NH Cl XXIV XXIII

S

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 20 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 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 SR Et

XXVI

R 0 RNH2 11 O S NN

NHR

N

112 1K2 1) R N SMe R N H 14 14 R R XXVIII

XXIX

According to this approach (Shaw and Warrener, J.

°oChem. Soc. 153-156 (1958); Hronowski and Szarek, Can. J.

Chem. 63, 2787 (1985); Agathocleous and Shaw, J. Chem.

1 0 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.

S

Fused 4(3H)-Pvrimidinones: As displayed in Schemes 12 and 13, introduction of 20 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' 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 stabase derivative (see:Basha and Debernardis Tetrahedron Lett 5271, 1984) which protects the amine in the subsequent alkylation step (sodium hydride,

DMF).

Scheme 12 R O Br'm N R N N N SMe Na 12N i s R N2 SMe NaHR N SMe m 2-4

XXXIII

XXXIV

TBAF

Q

RllI

R

11 SN m-i Heat RN12 2 H R N SMe XXXVI

XXXV

Scheme 13 O O 0 0 R11 11 R R R Se 2 N "0 I I I 12) N *RN* R N SMe 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 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

O

R NH HO NH2 R

OH

R N N R

H

XXXIII

XXXVII

MeSO 2 C1 Et 3

N

R

11 OMs R N 1R OMs R 2 m- 1

NH

H

R

12 N m-

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 wherein 3 -phenyl-1-propylamine and benzylamine axe reacted with 3-( 3 -trimethylsilyl-2-propynyl)S5( 4 f luorophenyl) -2-methylthio-6- 4 -pyridyl) -4 (3H) pyrimidinone to afford the corresponding 6, 5 fused system.

Scheme NaH "SMe R TM4S 12

N

XXXIII

/R

21

NH

2

CIX

XXXX

Scheme 16 HN R 21

IC*

NH n N

R

21 N R 21 N Compounds of the invention when U is CHR 2 1 can be prepared according to Scheme 2 above wherein Ri' contains an leaving group or a group which can be converted into a leaving group which can be reacted with a 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 O S. OR H2N a R

H

b. R Et

HN

F F I

I

NH

NH

NR

N~

NN

N

15 a. 2 4 -Fluorophenvl) -3-(4-pvridvl)-acrylic acid: A mixture of 4 -fluorophenylacetic acid (9 g, 58.4 mmol), 4 -pyridinecarboxaldehyde (5.6 ml, 58.6 mmol), pyridine (6 ml) and acetic anhydride (6 ml) was heated at 150°C for 1 h followed by evaporation and co-distillation with water. The resulting material crystallized on addition of ethanol. The solids were filtered and washed with ethanol and ethyl acetate to provide the title compound.

MS 244.0

C

14

H

10 FNO requir. 243.2 'H-NMR 98 (DMSO-d): d 8.43, 6.98 (2d, each 2H, Pyrid.), 7.73 (s, 1H, 7.21 4H, PhF).

b. Ethyl 2-( 4 -fluorophenvl) 4 -pyridyl)-acrylate: Cone. sulfuric acid (2.2 ml) was added carefully to a suspension of 2 -(4-fluorophenyl)- 3 -(4-pyridyl)-acrylic acid (6.7 g, 27.5 mmol) in ethanol (120 ml) and the mixture was heated at reflux for 24 h. The solvent was evaporated, the remainder was taken up in dichloromethane and the organic solution was washed with aqueous sodium hydrogencarbonate and water, followed by drying and evaporation. Flash column chromatography on silica gel (hexane-acetone 2:1) provided the pure title compound. MS 271.8

C,,H

4 FNO, requir.

271.3 '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 20 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 25 mmol) at 44 0 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.

99 The following compounds were prepared accordingly using the appropriate amidine hydrochloride: 1-1 5=( 4 -Fluorophen1)l2-methyl-6-(4-pvridvl) 4 3 H) pyrimidinone: MS 282.2

C

1

,H

12 FNOrequir.

281.3 'H-NMR (DMSO-d,): d 8.46 (n 2H, Pyrid.), 7.2-7.03 6H, PhF, Pyrid.) 2.38 3H, CH) R1 CH 1-2 5-( 4 -Fluorohenvl)-2-isor opViH pyrirnidinone: MS 310.0

C

1 H 16 FN'0 reguir.

309.4 'H-NMR (DMSO-d,) 8.45 2H, Pyrid.), 7.21-7.03 6H, PhF, Pyrid.), 2.90 1H, 1.26, 1.24 (2s, each 3H, 2CHO) R1 (CH,).CH- 1-3 2 2 ,6-Dichlorobenzvl)5-(4-fl uoroohenl) 6 4 vridyl-)-4(3H)-pyrimidinone: MS 426.0 2 H,,C1FN, requir. 426.3 'H-NMR (DMSO-d,): d 8.37 2H, Pyrid.), 7.50 2H, PhCl, 7.35 1H, Phl 2 7.18- 7.08 4H, PhF), 6.96 2H, Pyrid.), 4.36 2H,

CH).

C1 1-4 5-( 4 -Fluorolhpenv1i2-phenvl-6-(4- pridvl) 4 3

H)

TpYriiidinone: MS 344.2

C

21 14

FN

3 0 requir.

343.4 'H-NMR (DMSO-d,) d 8.49 2H, Pyrid.) 8,20 (d, 2H, Ph), 7.66-7.50 3H, Pyrid., Ph), 7.32-7.11 (m, 6H, PhF, Ph).

RI

100 Example 2 General procedure for the preparation of 2-N Substituted (4-fluorophenyl) -3-raethyl (4-pyridyl) -4 (3H) pyrimnidin ones Steip A. S-(4-Fluorolohenvl) 3 -methv1-2-methlthio6-( 4 ipyridyl) -4 (3H) -poyrimidinone: F '0 F 0~

OICH

N. ASH N

SCH

3 N

N

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 potassiumn carbonate (923 mg, 6.68 inmol) in N, N- dime thyl formamide (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 Iatrobead SR (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 C1 7

H

4 FN S requir. 327.4.

'H-NM?

(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 .Stelp B. General procedure: F

F

0 0 N CH 3

NCH

N 1 N

NRR

A mixture of 5- 4 -fluoropheny)3.methyl.2methylthio-6-(4-pyridyl).

4 (3H) -pyrimidinone (103 mg, 0.32 inmol) and the amine HNR 5 R 2 1 (1.2-3.2 mmol) was heated at 190-2001C for 2-48 h. The resulting product 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-fluorophenl)-3 thl 6 4 Pyridyl)-4(3H)-P rimidinone: The reaction was done in a sealed tube at 190 0 C for 5 h.

MS 353.0

C

2

,H

2 FN.0 requir. 352.4.

CH,(CH

2

)INH-

2-2 5-( 4 -Fluorophenvl)-3-methl-2-(entvlamino) 6 4 ridl) -4 -1pvrimidinone: The reaction was done in a sealed tube at 190 0 C for 2.5 h. MS 366.8

C

2 j1 23 FN,O requir. 366.4.

R CH 3

(CH,),NH-

2-3 2 3 3 -Dimethvlbutvlamino)-5-(4.fluorophenvl) 3 methvl-6-(4-Dvridvl)-4(3H)-Dyrimidinone: The reaction was done in a sealed tube at 190 0 C for 5 h. MS 381.2

C

22

H

25 FN.Orequir. 380.5.

R (CH) 3

C(CH

2 2NH- 2-4 2 (Benzvlamino)-5-(4-fluorophenl)-3-methl( 4 Pvridl)-4(3H)-pvrimidinone: The reaction was done at 185 0 C for 6h. MS 387.2

C

23

H

9

FN

4 0 requir.

386.4 N-o R 2 4 -Fluorobenzvlamino-5(4-fuoro~hen y)-3- 00 methyl-6- (4-yridyl) -4 (3H) -pyrimidinone: The reaction was done at 190 0 C for 24 h. MS 405.2

C

23

H

18 FNO requir. 404.4.

N

1H R

O

102 2-6 2-(3-Fluorobenzlanino) 4 -fluorophenvl) -3methyl-6- (4-ipvridyl) -4 (3H) -Ipyimidinone: The reaction was done at 195 0 C for 40 h. MS 405.0

C

23

H

1 8

F

2 N 4 0r equir. 404.4.

R 1 F 2-7 5-(4-Fluorophenvl)-3-methvl-( (R-1p~henylethyl) amino) -(4-pyvridyl) -4 (3H) -pyrimidinone: The reaction was done at 1800C for 4 da ys. MS 401.0

C

2 4 H 21

FN

4 Orequir. 400.5

~CH

3 R' F 2-8 2 2 2 -Chlorohenl)-ethylamino)-5-(4.

fluorophenyl) -3-methyl-6- (4-pyvridyl) -4 (3H) -pyrimidinone:- .The reaction was don-e at 190 0 C for 5 h. MS 435.2

C

24 H 20 C1FN 4 0 rqi. 4 34. 9.

C

2-9 5-( 4 -Fluorophenyl)-2-(2-(4-fluorophenvl)ethylamino) -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

2 0 F 2 N 4 Orequir. 418.5

N~

0:000:20 2-10 2 -Fluorohenyl)-2-(2-(3-fluorohenyl)ethylamino) -3-methyl-6- (4-pyridyl) -4 (3H) -Dyrimidinone: The reaction was done at 190 0 C for 24 h. MS 419.2

C

2 4

H

2

F

2 N 4 requir. 418.5 103

H

N,

R=

F

2-11 5-(2-Fuorophen1)--2-(2- 2 -fluorophenyl)ethylamino) -3-methvl-6- (4-pvridvl)-4(3H) -pyrimidinone: The reaction was done at 190 0 C for 12 h. MS 419.0

C

24

H

20

F

2

N

4 Orequir. 418.5

H

1' II I 2-12 2 -Fluorohenl)-2-((2-hydroxy-2-phennv) ethylamino)-3-methl-6- (4-Dridyl) -4(3H) -ovrimidinone: The reaction was done at 190 0 C for 1.5 h. MS 417.0

C

24

H

21

FN

4 0 2 requir. 416.5.

OHH

9 9* 9

S*

9 .9 9 2-13 5-(4-Fluorophenvl)-3-methyl.> (3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -Dyrimidinone: The reaction was done at 190 0 C for 6 h. MS 415.0 15 C 25

H

23

FN

4 Orequir. 414.5. '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 N) 3.28 3H, 2.82 2H, CHPh), 2.12 2H, CHO).

R

H

2-14 S-(4-Fluorohenvl)-3-3ethvl-2-(-nethl-3phenviprolpl) -amino)-6-(4 -pridyl) -4(3H) -pvrimidinone: The reaction was done at 200 0 C for 48h. MS 429.0

C

26

H

25 FNrequir. 428.5.

104

CH

3 N.e R

H

2-15 5-( 4 -Fluorophenvl) 3-methvl-2-( _R1methyl-3- Phenvlrpropyl) -amino) (4-pyridyl) -4 (3H) -pvyriznidinone: The reaction was done at 200 0 C for 48 h. MS (m/lz): 429.0 C 26

H

2 5 FN 0requir. 428.5.

CH

3 R j

H

2-16 2 3-Diphenvlpropy1). -amino) 5- 4 fluorophenvl) 3-methyl-6- (4-pyri dyl) -4 (3H) -ipriimidinone: The reaction was done at 190 0 C for 6 h. MS 490.8 C 31

H

27 FN 0requir. 490.6.

N

2-17 5- (4-Fluorophenyl) -3-methyl-2- Phenylaminoethyl) -amino)-6- (4-rpyridyl) -4 (3H)pvriniidinone: The reaction was done at 190 0 C for 4 h.

MS (mhz) 416.2 C 24

H,

2 FN0 requir. 415.5.

H

R

H

2-18 5- (4-Fluoropohenyl) -2-C (3-imidazollrropj.) -amino) 3-methvl--6- (4-pyvridyrl) -4 (3H) -lpyrim dinone: The reaction was done at 190 0 C for 2 h. MS 405.0

C

2 2

H

2 1 FN 6 requir. 404.5.

1 N- R

H

2-19 -(4-Fluorophenvl) -3-methvl-2- 2 -(piperazin-1-yl) ethylamino) (4-Pyridyl) -4 (3H) -primidinone: The 105 reaction was done at 1900C for 30 min. MS 409.2 C 22 H 2 5 FN0 requir. 408.5.

R HN

N__

2-20 5-( 4 -Fluoropenl)3.meth6( 4 Didl)- 2 3 (ipvrro 1i din 1 -propyl amijno)_ -4 Q H) -ipyrimi dinone: The reaction was done at 1900C for 2 h. MS 408.2 C 23

H

2

FN

5 Orequir. 407.5.

N-

D

H-

2-21 2- 2 -Amino-3-rhenylpropvl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H)-pyrimidinone hydrochloride: The reaction was done at 190 0 C for 2.5 h.

MS 430.1 C25H24FN5o requir. 429.5 (free base).

R =H CS)2 NEthvl-3 -nhenvlpropyl) -amino (4f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -povriniidinone hydrochloride: The reaction was done at 190 0 C for 4 h.

MS 458.3 C27H28FN 5 0 requir. 457.6 (free base).

N

2-23 2 2 -Amino- 2-meth3=phenvlrpropvl) amino)-5-(4fluorolphenyl) -3-methyl-6- (4-Pyvridyl) -4 (3H)-pyrimidinone hydrochloride: The reaction was done at 190 0 C for 4 h.

MS 444.0 C26H26FN50 requir. 443.5 (free base).

224i 2- (Amnehv3 -p enylpropy)amino) 4 f luorophenyl-3-methyl.

6 (4-pridjL)-4 3H) -pyrimidinone 106 hydrochloride: The reaction was done at 190 0 C for 1 h.

MS (rn/z) 444. 0 C2 6Hi26FN40 requir.- 443 .5 (free base).

R NH 2 .2-25 2 3 -Amino-3-phenlpropyl)-amino) 5(4f luorophenyl) -3-methyl-6- (4-ipvridyl) -4 (3H) -primidinone hydrochloride: The reaction was done at 1900C for h. MS 430.0 C25H24FN50 requir. 429.5 (free base).

NH

2

N

R' 2-26 5-( 4 -Fluorophenyl)-3-methyl...>(3-(2 methylphenvl)propyl) -amino) (4-pyridyl) -4(3H) vyrimidinone: The reaction was done at 190 0 C for 4 h.

MS 429.5 C26H25FN 4 0 requir. 428.5.

H

R= CH 3 2-27 5-( 4 -Fluorophenl)3thlme thv1S)2(R)io 3 2 f luorophenyl) Propl-amino) (4--vridyl) -4 (3H) Pyrimidinone-Wydrochoride: The reaction was done at 1901C for 7 h. MS 448

N

H

R' 2-28 2- R) 2 -Amino-3-phenylpropyl) -amino)-5-(4fluorophenyl) 3-methyl-6- (4-pyridvl) -4 (3H) -yrimidinone hydrochloride: The reaction was done at 190 0 C for 2 h.

MS 430.2 C25W24FN50 requir. 429.5 (free base).

107 R

N-

H

2-29 2 -(((S)-2-N-Methvl-3-phenvlpropy)aino)-5(4.

fluorophenyl) -3-methyl-6--(4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: The reaction was done at 1900C for 4 h.

MS 444.0 C26H26FN50 requir. 443.5 (free base).

1 A N

CH

3 2-30 2-C 2 -phenvlthioethyl)-amino)-5-(4-fluorophenvl).3methyl-6- (4-pyridyl) -4 (3H) -lprimidinone: The reaction was done at 1900C for 16 h. MS 433

H

Rt =a 2-31 2 2 -hvdroxvethl)-amino)--(4..fluorophenv1)-3methyl-6- (4-pyridyl) -4 (3H) -iprimidinone: The reaction was done at 1900C for 16 h. MS 341

HO~

0 N

R=

2-32 2 -((2,2-difethl-3-hydroxropyl)aino)-5(4.

fluorophenyl) -3-methyl-6- (4-pyvridyl) -4 (3H) -pyrimidinone: 0: The reaction was done at 190 0 C for 16 h. MS 383 HO N RI

H

2-33 2-C( 2 2 -dime thy 3-pheny thi oproryl) -ino) 5- (4.

fluorophenyl) -3-methyl-6- 4-pyvridyl) -4 (3H) -pyrimidinone: To a solution of triphenyiphosphine (262 mg, 0.29 inmol) in tetrahydofuran (2 mL) at 0 C was added diisopropyl azodicarboxylate (DIAD) (56 ml, 0.29 nimol). After min at 0 C, (2,2-dimethyl-3-hydroxypropy)..mjno) (4-f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) pyrimidinone (50 mg, 0.14 mxnol) and 2,6dichiorothiophenol in tetrahydrofuran (2 niL) was added.

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:CHCl3 1:3 then 1:2 then 1:1 then 2:1 then 3:1) to afford the title compound: MS 544 HO

N

'H R -H 2-34 2-((3-Amino-3-(2-f luorohenvl) roppl) -amino) -5-4fluorophenyl) -3-methyl-6- 4 -Dvridyl) -4(3H)-Dyrimidinone was prepared from 5-( 4 -fluorophenyl) -3-methyl-2methylthio-6- 4 -pyridyl)- 4(3H) -pyrimidinone and 1-(2fluorophenyl)-1,3-propanediamine according to the General Procedure. The reaction was done at 190 0 C for 3 h. MS

C

2

,H

2 ,F,N,Orequir. 447.5 (free base).

F NH 2

R

1

N

H

2-35 2 3 -Amino-3z (2 methylphenyl) propvl) -amino)-5-(4 fluorophenyvl)-3-methyl-6- (4-pvridyl) -4 3H) -Primidinone hydrochloridewas prepared from 5-( 4 -fluorophenyl) -3methyl-2-methylthio-6- 4 -pyridyl)- 4(3H)-pyrimidinone and l-( 2 -methylphenyl)-13-propanediamine according to the General Procedure. The reaction was done at 185 0

C

for 4 h. MS 444.5 C 6 2

,FN

5 0requir. 443.5 (free base).

CH

3 NH2 R

N

N

H

25 2-36 -3 -amino -3 -Denvl1Dorvl -amino)-5- (4 fluorophenyl)- 3-methyl-6- 4-pvridyl) -yrimidinone hydrochloride was prepared from 5 4 -fluorophenyl)-3methyl-2-methylthio-6-(4-pyridyl)-4 (3H)-pyrimidinone and (S)-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 2 FN.Orequir. 429 .5(free base) 109

NH

2 R N N H 2-37 -3-amino-3-henylropyl) -amino.-5- fluorophenyl) -3-methvl-6- (4-1pyridyl) -4 (MH) -pyrimidinone hydrochloride was prepared from 5-(4-fluorophenyl)-3methyl-2-methylthio-6- (4-pyridyl) -4 (3H) -pyrimidinone and (R)-l-phenyl-1,3-propanediamine according to the General Procedure. The reaction was done at 190 0 C for 3.5 h. MS (mz) 430.7 C 2 5 H FN 5 requir. 429.5 (free base).

N H 2-38 2 2

R,

3 R) 3-Amino- 2-methyl 3 -henylpropDyl) amino) -5-(4-fluorophe-nyl) -3-inethvl-6- (4-pyridyl) -4 C3H) Pvrimidinone hydrochloride was prepared from 5-(4fluorophenyl) -3-methyl-2-methylthio-6- (4-pyridyl) 4 (3H) -pyrimidinone and (2R,3R)-2-methyl-3-phenyl-l,3- V 15 propanediamine according to the General Procedure. The reaction was done at 190*C for 3 h. MS 444.5 C 26

H

26 FN 5 requir. 443. (free base).

HHH

*.2-39 2 -C (2 S, 3S) 3-Amino -2 -methyl 3 -henyliproloyl).pvrimidinone hydrochloride was prepared from 5-(4fluorophenyl) -3-methyl-2-methylthio-6- (4-pyridyl) 4C3H)-pyrimidinone and 2 S,3S)-2-methyl-3-phenyl-1,3- 0 0 propanediamine according to the General Procedure. The *25 reaction was done at 190*C for 2 h. MS (mz) :444.4 C 2 6

H

2 6 FNOrequir. 443.5 (free base)

NH

2 R

N

N H 110 Analogously, the isomers 2-CC (2S, 3 R)-3-Amino-2-methvl.>.

Phenylpropyl) -amino) 4 -fluoroPhenyl) -3-methyl-6- (4- Pvridvl)-4(3H)-pvrimidinone and 2- 2.S--mno-2methyl-3-phenvlpropyl) -amino)1 (4-f luoronhenyl) -3methvl-6- (4-pyridyl.)-4 (3H) -pyrimidinone may be prepared from the corresponding diainines.

2-40 5- (4-Fluorophenvl) 3 -hvdroxv-3-phenvlpropvl) amino) -3-methyl-6- (4-Pvridvl)-4 (3H) -pyrimidinone: The reaction was done at 190*C for 3 h. MS (rn/z) 431.2 C25H 2 3

FN

4 0, reguir. 430.5.

HO

N H Excample 3 Procedure for the preparation of N-substituted pyrimjdjnones 0 LI N

CH

3 i NH 1 SN N

N

a N N-' Cl Cl Cl -Cl 6 -Dichlorobenzyl) 4 -f luoroiDhenyl) 3mehl..6(4rwridyl) -4 (3H) -pyrimid Lnone: Methyl iodide (41 ml, 0. o 4 inmol) was added to a stirring mixture of 2- 6dichlorobenzyl) 4 -f luorophenyl) (4-pyridyl) -4 (3H) 0.0. pyrimidinone (280 mg, 0.61. mmol) and potassium carbonate 0:000 (181 mg, 1.30 mmol) in N, N- dime thyl f oramide (2 ml).

Stirring was continued for 2 h, followed by evaporation and f-lash chromatography of the resulting product on a *25 column of silica gel (hexane-acetone 3:1) -to yield the title compound as a white solid. MS 440.2

C

23

H

16 C1FN0 requir. 440.3.

ExamplIe 4 General procedure for the preparation of 2-N and 2'-N substituted 2 -amino- 5 4 -fluor-ophenyl)3methy-6-(4-(2 amino)pyridyl) -4 (3H) -pyrirnidinones

F

N NRR NR 3 1

R

3 2 Step A. 5-(4-Fluorophenvl) 3 -methyl-2-methylthio-6- (4- (2 -ace tamido) pvridyl) -4 3 H) -pyrimidinone: To a solution of 5-(4-fluorophenyl)-6-(4-(2acetaxnido)pyridyl)-2-thiouracil (600 mg, 1.68 mmol) in DMF (35 mL) was added powdered sodium hydride (60% oil dispersion, 221 mg, 5.56 mmol) over 1 minute at 23'C.

After 45 min, iodomethane (210 ml, 3.37 mmol) was added dropwise. After 45 min, the reaction was concentrated in vacuo (rotovap connected to high vac with a bath 15 temperature no greater than 40 0 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.

Sterp B. 5- (4-Fluorophenyl) -3-methyl-2-( (3-phenvlipropvl)amino) -amino) pyridvl))-4 (3H) primidinone:

A

neat mixture of 5- (4-Fluorophenyl) -3-methyl-2methylthio-6- (2-acetamido)pyridyl) -4 (3H) pyrimidinone (50 mg, 0.13 mmol) and 3-phenyl-lpropylamine (88 mg, 0.65 mmol) was warmed to 190'C for 17 h. Aftet cooling to 23 0 C, the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHCl3 then then then then to afford the desired product: MS 430 112 R

H

R

n

H

R" =H The following compounds were prepared using the above procedure outlined above and an appropriate amine: 4-1 5-(4-Fluorophenvl)-3-methvl-2-((3-phenvlpropyl)amino)-6-(4-(2-acetamido)pyridvl))-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 -0.064 mmol) of acetyl chloride at 23 C.

After 2 h, the reaction was quenched with water (5 .l) 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

H

R H

R

3 Ac 4-2 5-(4-Fluorophenvl)-3-methvl-2- (3-phenvlpropvl)- _amino)-6-(4-(2-methoxvacetamido)pvridvl) pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3methyl-2-((3-phenylpropyl)-amino)-6-(4-(2- 25 amino)pyridyl))-4(3H)-pyrimidinone (11 mg, 0.026 mmol) in 600 .1 of pyridine was added (5 0.064 mmol) of methoxyacetyl chloride at 23 C. After 2 h, the reaction o*o: was quenched with water (5 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 502 113

R'N

R

H

R

32

=H

R 31 C(O)CCH 2 OMe 4-3 5-(4-Fluorophenvl)-3-methvl-2-((3-Dhenvlpro;vl)amino)-6-(4-(2-acetoxvacetamido)pvridvl))- 4 3

H)_

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 2 H

H

R' C(O)CH 2 OAc 4-4 4 -Fluorophenl)-3-methll-2-((3- henlprovl) amino) 2 -hdroxvacetamido)pvridl) 4 Q H) pyrimidinone: To a solution of 5-(4-Fluorophenyl)-3methyl-2- ((3-phenylpropyl) -amino)-6-(4-(2acetoxyacetamido)pyridyl)) -4(3H)-pyrimidinone 2 mg, 0.003 mmol) in 900 p.1 methanol: 100 p.1 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 :see* ~with chloroform (20 mL), dried (Na2SO4), and concentrated to afford the title compound: MS 488 R 0 R C(O)CH 2

OH

5-(4-Fluorophenyl)-3-metthyl-2-(3 -henvlprop1) amino) 2 -methvlsulfonamido)ivridvl) -4 (3H)- Pvrimidinone: To a Solution of 5-( 4 -Fluorophenyl)-3methyl-2-((3-phenylpropyl)-amino)-6-(4-(2- 114 amino) pyridyl) 3 H) -pyrimidinone (11 mg, 0.026 mmol) in 600 41l of pyridine was added 'nethanesulfonyl chloride (4 p.1, 0.051 mmol) at 23 C. After 2 h, the reaction was quenched with water (5 j.U) 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 cozpound:_MS 508 I oo N R

H

R 31 s S 2 Me 4-6 5-( 4 -Fluorophenvl) -3-methvl-2- (3-Dhenvlproiovl) amino) 2 -benzlanino)pvridvl) (3H) -PnYrimidinone: To a solution of 5-( 4 -Fluorophenyl)-3-.methyl-2-(( 3 phenylpropyl) -amino) 2 -axnino)pyridyl) -4 (3H) pyrimidinone (11 mg, 0.026 rnmol) in 600 p.1 of 1,2dichioroethane was added benzaldehyde (8.9 mg, 0.084 mnol) and sodium triace-toxyborohydride (14.8 mg, 0.070 rnmol) at 23 C. After 16 h, the reaction was quenched with wat er (15 p.1) and the reaction was concentrated under a stream of nitrogen. The reaction mixture was applied directly to purification via flas h a...,chromatography (step gradient l%MeOH:CHCl3 then then then then to afford the title compound: *MS 458

=N

R 32

H

R CH 2 Ph S_-loohn1~mtv. 3 -thenlPropvl)aminLo) 2 _me thovpmhenvl) me thamino) pvridyl.) 4 3 H)-vrimiinon: The reaction was done in the manner 115 of the above substituting 2 -methoxybenzaldehyde for benzaldehyde to afford the title compound after chromatography: MS 550 (M+H)I.

R

H

R

32

H

R

3 4-8 5-(4-Fluorophenyl)-3-methvl-2-((3-pheniprolpl)amino) (2-ethvlamino)pyridyl)) -4 (3H)-p rimidinone: The reaction was done in the manner of the above substituting acetaldehyde for benzaldehyde to afford the title compound after chromatography: MS 458 1N R *R R 32

=H

15 R Et 4-9 5-(4-Fluorophenyl) -3-methyl-2-( (3-phenvipropyl) amino) (di (3methvlbutv1 )amino) Pvridvl) -4 (3 H)pyrimidinone: The reaction was done in the manner of the above substituting isovaleradehyde for benzaldehyde 20 to afford the title compound after chromatography:

MS

570

=N

R

H

2 CH CHCH(CH) 2 R 31 CH 2

CH

2

CHCH,)

2 4-10 5-(4-Fluorophenl) -3-methvl-2-( (3-phenvpropyl) amino)-6-(4-(2-diethvlamino)pvridvl))-4(3H)_ pyrimidinone: The reaction was done in the manner of the above substituting acetaldehyde for benzaldehyde to 116 afford the title compound after chromatography:

MS

486 (M+H) o N R=

HN

R Et R" Et 4-11 5-(4-Fluorophenyl)-3-methyl-2- 3-phenv1prop amino)-6-(4-( 2 -phenylaminocarbonv1-amino)pvridvl 4 3 H)-pvrimidinone: To a solution of 5-( 4 -Fluorophenyl)- 3-methyl-2-(( 3 -phenylpropyl)-amino)-6-(4-(2amino)pyridyl))-4(3H)-pyrimidinone (11 mg, 0.026 mmol) in 600 1l of dioxane was added phenyl isocyanate (3.3 mg, 0.03 mmol) at 23°C. After 16 h, the reaction was quenched with water (15 il) 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

R

R =N 1

H

R" =H R NH(CO)NHPh 4-12 5-(4-Fluorophenyl) -3-methvl-2- 3 -henylprovl) amino) 2 -methylaminocarbonvl -amino) pyridl) 4 3 H)-pyrimidinone: The reaction was done in the manner 25 of the above substituting methylisocyanate for phenylisocyanate to afford the title compound after chromatography: MS 487 (M+H) R

H

R

32

H

R

31 NH(CO)NHMe 117 4-13 5-( 4 -Fluorophenvl)-3-methyl>2( (3-lphenyipropvl) amino) 6- (2 amino-i* -oxo-ethvlamino)pyridyl)) 4 3 H) -pvrimidinone: General Procedure for mixed anhydride coupling Isobutyl chioroformate (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 mL) After 20 min at -20-30 0 C, 5 4 -fluorophenyl)-3-methyl.2.

3 -phenylpropyl) -amino) -6 (4 (2 -amnino) pyridyl L) -4 (3H) pyrimidinone (11 mg, 0.026 rnmol) and pyridine (0.6 mL) was added in one portion. The reaction was allowed to warm to 23 0 C. 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 (Na2SO4) The reaction mixture was applied to purification via flash chromatography (step gradient 1%MeOH:CHCl3 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 l%MeOH:CHCl3 then then then- then to af ford the title compound:

MS

to* 487 t~R

=H

R32 H R 31 NH(CO)CH 2 NH 2 V 4-14 5- (4-Fluorophenyl) -3-methyl-2- ((3-phenlpropyvl) amino) -6 W'amino-1' oxo -butl amino) pridvl)) **30 4 QH) -primidinone: 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 515 118

N"

R

H

R 32

=H

R

3

NH(CO)CH

2

CH

2

CH

2

NH

2 4-15 5- 4 -Fluorophenyl)-3-methvl2.. (3-phenyipropyl) amino)-6- (4-(2-(3'-amino-1m-oxo-ropylamino) Dvridl) 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-a-t-Boc-glycine which after deprotection as above afforded the title compound: MS 501

RI

2

H

NH(CO)CH

2

CH

2

NH

2 4-16 2 2 -Amino-3 -henylpropyl) -amino) -5 (4 f luorophenyl) -3-methyl- (2 aminopyr idyl) -4 (3H) pyrimidinone hydrochloride: The reaction was done at 190C for 6 h in the above manner with the following substitution of 2 -diamino-3-phenylpropane for 3 -phenyl-l-propylamine: MS 445 R H R2 H R 32

=H

4-17 2 -Dimethvlamino-3 phenyvpropyl)-amino) 4 -fluorophenvl)-3-methyl-6-(4(2-aminopyridyl))-4(3 pyrimidinone hydrochloride: The reaction was done at e:e.e: 190 0 C for 6 h in the above manner with the following substitution of i-amino- 2 (S)-dimethylamino-3phenylpropane for 3 -phenyl-l-propylamine: MS 473 119 N N R= le N H 32 R _-H

R

31 4-18 2 -Dimethvlamino-3-Dhenylpropy) mino) luorolphenyl) -3 -methyl-6- (2-acetamidopyridyl) 4(3H)-p~vrimidinone hydrochloride: The reaction was done in the manner of example XX substituting Dime thylamino 3-phenylpropyl) -amino) 4 -f luorophenyl) 3 -methyl- 6- (4 (2 -aminopyridyl) -4 (3H) -pyrimidinone hydrochloride for 5.-A4-Fluorophenyi) -3-methyl-2- phenyipropyl) -amino) 2 -amino) pyridyl) -4 (3H) pyrimidinone which afforded the title compound: MS 515

NN

R= N H R 32

=H

R

3 Ac 4-19 2 -3-Amino-3-phenyliprolpyl) -amino) f fluorophenyl) -3-methyl-6- (2-amino-pyridyl) -4 (3H)- Pyrimidinone hydrochloride: The reaction was done at **20 190'C for 12 h in the above manner with the following substitution of (3 R,S)-l,3-diamino-3-phenyl.propane for 3 -phenyl-1-propylamine: MS (mlnz) :445 NH2

_N

I H R 32

=H

R

3

H

4-20 5-w (4-Fluorophenyl) -3-methyl-_2- (phenylme thyl amino) 6- (3'1 -Phenyl l'-oxo -propyl amino) Pyridyl) (2amino) Pyridyl) -4 (3H) -pyrimidinone: A neat mixture of (4-f luorophenyl) 3 -methyl-2-methylthio-6- (2acetamido) pyridyl) 4 (3H) -pyrimidinone (2 60 mg, 0. 13 120 mmol) and benzylamine (88 mg, 2.71 n'mol) 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) 2 -amino)pyridyl)) 4 (3H) -pyrimidinone. The 5- 4 -fluorophenyl) -3-methyl-2- (peymtyaio--(-2aioprdl)-4(3H)pyrimidinone was converted in the manner of the above substituting hydrocinnamoy. chloride for acetyl chloride and 5-(4-fluorophenyl) -3-methyl-2- (phenylmethylamino) -6- 4 2 -amino)pyridyl) -pyrimidinone for 5-(4fluorophenyl) -3-rnethyl-2- ((3-phenylpropyl) -amino) (4- 2 -amino) pyridyl) -4 (3H) -pyrimidinone to af ford the title compound after chromatography: MS 534 R NHCH 2 Ph R 3 2

=H

fR 31 (CO)CH 2

CH

2 Ph *Example General procedure for the preparation of (4-fluorophenyl) (4-pyr-idyl) -2-thioalkyl-4 (3H) pyrimi din ones SteiD A. Ethyl 2 (-fuorophenyl)- oo..(4-TDvridvl)- Tprorplonate: 0 F 0 NOEt QEt i~0 N QEtN 0 0 (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 ref lux and 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 1H, 4

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

CH,-K,E).

Step B. 5-( 4 -fluorophenyl)-6-( 4 -vridvl)-2-thiouracil: F 0

H

2 N F 0 OEt H 2 N

NH

0 N

SH

N

S: 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

C

1

,H

1 OFNOS requir. 299.3 1

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 25 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 122 and a dark brown solid was filtered using a Buclhner 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 Fluorohenvl)-2-(2-henlethl)thio-6-( 4 pyrid) -4(3H)-pyrimidinone: MS 404.2

C

23 H,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).

S-1 R 5-2 5-( 4 -Fluorophenyl)- 2 3 -henl propvl) )thio-6-(4- *vridyl)-4(3H)-pvrimidinone: MS 418.0

C

24

H

20 FN OS requir. 417.5. 'H-NMR (DMSO-d,): d 13.10 (bs, 0.7H), 8.47 2H, Pyrid.), 7.29-7.06 11H, Pyrid., Ph, PhF), 3.18 2H, CHS), 2.71 2H, CHPh), 2.03 2H,

CH,

2

R

123 5-3 5- (4-Fluoroiphenyl) 2 2 -lDhenoxvethvl)thio-.6-(4- Pvridvl)-4(3H)-Pvri -idinone: MS 420.0 CM+H)*;

C

23

H

18 FN 3 0 2 Srequir. 419.5. 'H-NMR (DMSO-d,): d 13.20 (bs, 0.7H), 8.46 (in, 2H, Pyrid.), 7.24-7.07 8H, Pyrid., PhF, Ph), 6.95 2H, Ph), 6.92 Ct, overlapped, lH, Ph), 4.30 2H, CH 2 3.58 2H, CH 2

S).

R

-5-4 5-( 4 -Fluorophenv-L)-2-C2-rphenylaminoethvl)thio-6-(4- Tpvr idyl) 4(3H) -pr iidinone: MS 419.0 C 23 H 1 9

FN

4 OS requir. 418.5. 1 H-NI4R (DMSO-d,) d 13.20 (bs, 0. 8H) 8.48, 7.22- (2m, each 2H, Pyrid. 7.16, 7.10 (2mn, each 2H, PhF) 6.89 2H, Ph) 6.54 Cd, 2H, Ph), 6.48 Ct, 1H, Ph), 5.90 Cbs, 0. 6H, NH) 3.43-3.25 (in, 2CH 2

H

Example 6 General procedure for the preparation of 2-N substituted (4-fluorophenyl) (4-pyridyl) -4 (3H) pyrirnidinones: Step A. 5- 4 -Fluorophenv1)-2-methvlthio-6- (4-pvridyl) 4 3 H)i-pyrimidinone: F NF

N

I

I

NH

NH

0N SH N_ SCH 3 Methyl iodide (90 ml, 1.44 inmol) was added dropwise to a stirred mixture of 5-C( 4 -f luorophenyl) (4pyriyl)2-thourcil 430mg,1.44 inmol) andpoasu carbonate (198 mng, 1.

4 3 mmol) in N,N-dimethylformamide C13 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 Chexane-acetone 124 1:1, 1:2) to provide the title compound as a solid. MS :314.2

C

16 H 12 N 3 Srequir. 313.3.

1H-NMR (DMSO-d,): d 13. 10 (bs) 8.47, 7 .22 (2m, each 2H, Pyrid.) 7.16, 7.10 (2m, each 2H, PhF) 2.56 3H,

CHO)

Step B. General -rocedure: F 0F0 1 NH

NH

N N. .O SH3NN N 5 R21 N H I N

R

A mixture of 5- 4 -fluorophenyl.) -2-methylthio-6-(4pyr idyl) -4 (3 H) pyrimidinone (100 mg, 0.32 minol) and an amine HNR'R 2 1 (1 Inmol) 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-methnol-conc.

amnmonium hydroxide) to provide the target compound.

The following compounds were prepared usi ng the general procedure outlined above and an appropriate amine: 06-1 2 2 z(2-Chlorophenvl)ethv>..amino)-S( 4 f luorophenvl)-6- 4 -ipridvl) -4 (3H) -pyvrimidinone:-

MS

2C 421.2 C 23

H

18 CFNOrequjr. 420.9.

'H-NMR

0 (DMSO-d,): d 11. 24 (bs) 8.44, 7.16 (2mn, each 2H, Pyrid. 7.43, *7.38 (2dd, each 1H, Phl) 7.30, 7.26 f2dt, each 1H, Phdl), 7.10-7.00 (in, 2H, PhF), 6.74 (bs, 1 H, NH); 3.60 2H, CH 2 3.03 2H, C 2

H

C

.6-2 -(4-Fluorohenvl)2.( 3 -henlrovl..&in)-.(4iPvridv1)- 4 3 H)-.pvrimidinone: MS 401.2

C

24

H

2

FN

4 Orequir. 400.5. 'H-NMR (DMSO-d,): d 11.16 (bs), 8.44, 7.14 (2mn, each 2H, Pyrid.), 7.32-7.01 (mn, 9H, Ph, 125 PhF), 6.78 Cbs, NH), 3.36 2H, CH 2 2.67 2H, CHPh) 1.89 2H, CH).

N

R'

H

6-3 5-(4-Fluorophenyl) -2-C(l-methyl-3-phenyl1proovl)amino) (4-Tpyridyl) -4 (3H) -pyrimidinone: A reaction time of 15 h at 180 C was required. MS 415.0

C

5 H 2 3 FNOrequir. 414.5. 'H-NMR (CDC1,): d 8.48 2H, Pyrid.), 7.28-7.08 9H, Pyrid., Ph, PhF), 6.94 Cm, 2H, PhF), 5.67 Cbs, I, NH), 4.08 Cm, 1H, CBCH,), 2.61 t, 2H, CH 2 Ph), 1.67 2H, 1.08 (d, 3H,

CH

3

CH

3

N

R H 6-4 5-(4-Fluorohenyl)-2-((3-imidazolylpropyl) -amino) 6-( 4 -pvridyl)-4(3H)-pvrimidinone: MS Cm/z): 391.0 C 19 FN Orequir. 390.4. H-NMR CDMSO-d.): d 11.24 Cbs), 8.42, 7.12 (2m, each 2H, Pyrid.), 7.62, 7.18 (2s, each 1H, Imid.), 7.08-6.99 4H, PhF), 6.88 Cs, 1H, Imid.), 4.02 t, 2H, CHN), 3.28 (overlapped by water signal, CH 2 NH), 2.00 2H, CH).

11'N ~N .R

H

2-((S)-2-Aino-3-henylproiyl)-amino) fluorophenyl)-6- 4-Dvridyl)-4(3H)-pyvrimidinone hydrochloride: The reaction was done at 170C for 7 h.

MS 416.1 CM+H) C26H22FN 5 0 requir. 415.5.

126 Example 7 4 -Fluorophenyl) -2-hydrazino-6- 4 -pyridyl) -4 (3H) pyrii dinone A mixture of 5-( 4 -fluorophenyl)-6-(4-pyridyl)-2 thiouraci (500 mg, 1.66 mmol) and hydrazine hydrate (800 ml, 14 mmol) was heated at 120'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,HaFN 5 O requir.

297.3. 'H-NMR (DMSO-d,): d 8.41, 7.12 (2m, each 2H, Pyrid.), 7.05, 7.00 (2m, each 2H, PhF).

R =NH-NH, Example 8 General procedure for the preparation of 5-aryl-2, 6dipyri dyl (3H) -pyrimidinones 8-1

H

-CN H ;k' 0

N

QEt N

N

2 1 1" 0 8-2 CN 2

NH

-Nt N

N

NNIO

NA

8-3

N''

1

I

i o 0b N H N KK-AOEtN NN

N

8-4 roN:- CN 0 NH N t 0 127 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 mmol), cyanopyridine (6.24 mmol) and sodium methoxide mmol) in n-butanol (1.2 ml) was heated at 110'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-pyridvl) 4 3 H)pvrimidinone:

MS

327.2

C

20 HN 0requir. 326.4. 'H-NMR (DMSOd 8.78, 8.47, 8.13 (3m, each 2H, Pyrid.), 7.40-7.14 7H, Ph, Pyrid.).

8-2 5-( 4 -Fluorophenyl)-2,6-bis-(4-Dvridyl)-4(3H) pyrimidinone: MS 345.2

C

20 HFNO requir.

344.4 'H-NMR (DMSO-d 6 d 8.80, 8.49, 8.13 (3m, each 2H, Pyrid.), 7.40-7.08 6H, PhF, Pyrid.).

8-3 2,5,6-Tris-(4-pyridyl)-4(3H)-pyrimidinone was prepared according to the general procedure by reacting ethyl 4 -pyridylacetate and 4 -cyanopyridine in the presence of sodium methoxide. MS 328.2 CHNO requir. 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 -Fluorophenvl)-2,6-bis-(3-pyridvl)-4(3H) pyrimidinone: MS 345.2

C

20

H

1 3 FN0 requir.

344.4 'H-NMR (DMSO-d,) d 9.34, 8.77, 8.54, 8.48, 7.78, 30 7.60, 7.34 (7m, 3xlH, 2H, 3x1H, Pyrid.), 7.26, 7.15 (2m, each 2H, PhF).

128 Example 9 3- 3 -triethylsiyl -2 -propynyl) 5 4 -fl uorophenyl -2methyltho-6- (4-pyridyl) -4 (3H) -pyrimidinone

F

NX% 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 -Fiuorophenyl) -2-methyl-i- 3 -phenylpropyl)-7pyri din -4 -yl -1H.imi dazo 2 F 0

SNN

N N Ph A neat mixture of 3 3 -trimethylsilyl-2-propynyl) 4 -fluorophenyl) -2-methylthio6. 4 -pyridyl) -4 (3H) *pyrimidinone (50 mg, 0.12 mmol) and 3 -phenyl-ipropylamine (67 mg, 0.47 mmol) was warmed to 190*C for 17 h. After cooling to 23 0 C, the reaction mixture was applied directly to purification via flash chromatography (step gradient 1%MeOH:CHC13 then then woo*.: to afford the desired product: MS 439 129 Example 11 6-(4-Fluorophenyl)- 2 -methyl-1-benzyl-7-pyridin-4-yl-1Himidazo 2

F

N N N Ph The preparation of the title compound was carried out in the same manner as 6-( 4 -Fluorophenyl)-2-methyl-l- (3-phenyl propyl)- 7 -pyridin-4-yl-1H-imidazo(1,2with the following substitution: benzylamine for 3 -phenyl-l-propylamine; MS 411 Example 12 General procedure for the preparation of 6-substituted 3-phenyl-4-(4-pyridyl)-2(1H)-pyridones Step A. General procedure for the preparation of 1arvl-3-(4-Dvridvl)- 2 -propene-l-one H 0 R 0O

A

N R

N

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 20 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 o* evaporation. The crude product was purified by column chromatography on silica gel (hexane-acetone 3:1).

The following compounds were prepared according to Sthis procedure using the apropriate acetophenone derivative: l-Phenyl-3-(4-pyridyl)-2-propene-l-one: MS 210.1 C,,H,,NOrequir. 209.3.

1.30 1- 4 -Methylpheny.) 4 -pyridyl)-2-propene...one:

MS

2 24. 2

C

1 5H 13 NO reguir. 223.3.

1- Ethyiphenyl) (4-pyridyl) 2 -propene--ofl:

MS

2 37. 8 C 1 6 H 15 NOrequir. 237.3.

1- 4 -Isopropylphenyl) 3 4 -pyridyl) 2 -propene-1-one:

MS

(rn/z) 252. 0

C

1

,H

1 NO req-uir. 251.3.

1- 2 -Methylphenyl) 4 -pyridyl) 3 propene-l-one:

MS

(rn/z) 223.8

C

1 ,H UNO requir. 223.37- 1- 4-Dimethyiphenyl) 4 -pyridyl) 2 -propene-1-one:

MS

2 38.-0 C16 HNO reqir. 237.3.

1- (2-Methoxyphenyl) 3 4 -pyridyl)-2propene.i..one:

MS

2 40. 0

CIS

5

UN

2 requir. 239.3 1- (4-Chiorophenyl) 4 -pyridyl)-2-propene...one:

MS

:244.0 C 14

H

1 ClN~requjr. 243.7.

1- 4 -Cyanophenyl) 4 -pyridyl) 2 -propene-l-one:

MS

235.1

C

15 1 NOrequir. 234.3.

1- (a-Naphthyl) 3 14-pyridyl) 2 -propene-1-one: MS (zn/z): 260.0

C

1 U 1 No requir. 259.3.

lt 3 -Bis-(4-pyridyl)..2propenelone MS 211.0

C

13

H

1

N

2 requir. 210.2.

3-4Prdyl -hinli-poeelone MS (m/1z): 216.0

C

12 HNOSrequir. 215.3.

1- (2-Furyl-3- 4 -pyridyl)-2-propene-l-..one: MS 200.0

C

12

H

9

NO

2 requir. 199.2.

l-Cyclohexyl3(4pyridy)2popn-lon was prepared in the same way using acetylcyclohexane: MS 216.2

C

1 4 H,NOrequir. 215.3.

1- tert-Butyl -3 (4 -pyridyl) 2 -propene- 1-one: A mixture of 3 3 -dimethyl-2-.butanone (2.5 ml, 20. 0 rnmol) 4pyridinecarboxaldehyde (2.15 ml, 22.3 nimol), ethanol 6 ml) and. 4. 5% aqueous sodium hydroxide 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 3: 1) provided the title compound. MS 190.4 C 12 15

N

requir.139.3 131 Step B. General procedure for the preparation of 6substituted 3-phenvl-4-(4-pyridvl)-2(1iH)-pridones: 0 t R 1 0 0 N N H

N

0 NH NR N

R

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 15 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 25 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(1H)-pvridone:

MS

325.4 C 22

H

16 20 requir.. 324.4. 'H-NMR (DMSOd 6 d 8.63 2H, Pyrid.), 7.86 2H), 7.58-7.45, 7.29-7.08 (2m).

132 12-2 6-(4-Methyliphenvl) 3 -phenvl-4-(4-pvridv1)-2 (1H)ipvridone: MS 339.2 c 23 H.NOrequir. 338.4.

1 H-NMR (DMSO-d,): d 8.44 (mn, 2H, Pyrid.), 7.7.9 2H), 7.32 2H1), 7.26-7.01 (in, 7H1, Ph, Pyrid.), 6.67 (bs, 1H).

H

3

C

12-3 6-( 4 -Ethv1Dphen1)3T)henv.4-(4- prid 1)-2 (l1H)- Pvridone: MS (iflz): 353.0 C 24 H 2

N

2 Orequir. 352.4.

'H-NMR (DMSO-d,): d 8.42 (mn, 2H, Pyrid.), 7.79 211), 7.33 7.24-7.06 (mn, 7H, Ph, Pyrid.), 6.65 (bs, 1H, 2.66 2H, CH 2 1.21 3H, CHO).

12-4 6- 4 -Isopropy -heny)-3...henv1-4-(4-pyridv1) 2 pyridone: MS 367.0

C,,H

2

N

2 requir. 366.5.

H-NMR (DMSO-d 6 d 8.45 (mn, 2H, Pyrid.), 7.82 2H), 7.39 211), 7.28-7.10 (mn, 7H1, Ph, Pyrid.), 6.67 (bs, 1H, 2.98 (mn, 1H1, CH(C1 3 1.27, 1.25 (2s, each 31H, 2 CHO) R 3C 20

H

3

C

12-5 6-( 2 -Methylphen1)3-phen1..4-(4- yrid )2(lH) ipyridone: MS 339.2 C 3

H,,N

2 requir. 338.4.

1H-NMR (DMSO-d 6 d 8.40 (mn, 2H, Pyrid.), 7.45-7.09 (in, 1111, Ph, Pyrid.), 6.21 (bs, 1H, CH1=), 2.39 311, CHO).

R=O

O CH 3 12-6 6-( 2 ,4-Dimethv1Dhenv1)3-3 phe n 4 4 idl) 2 (lH)-p~vridone: MS 353.0 C 24

H

20

N

2 0 requir.

352.4. 'H-NMR (DMSO-d,): d 8.42 (mn, 2H1, Pyrid.), 7.29 133 1H), 7.23-7.06 9, Ph, Pyrid.), 6.17 (bs, 1H, 2.34, 2.31 (2s, each 3H, 2CH 3

H

3 C

H

12-7 6-( 2 -Methox2henl)-3phenvl-14(4-vridl) -2(1H)pyridone: MS 355.0

C

23 18 N 2 0 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).

OCH

3 12-8 6-( 4 -Chlorohenv) -3-phenyl-4-(4...vridvl) -2(1H)- Pyridone: MS 359.2

C

22 H C1N 2 Orequir.

358.8. 'H-NMR (DMSO-d d 8.42 2H, Pyrid.), 7.93 (bd, 2H), 7.54 2H), 7.26-7.08 7, Ph, Pyrid.), 6.80 (bs, 1H, CH=).

12-9 6 4 -Cvanolhenvl)-3-phenvl-4-(4-pvridvl) 2 (1H)- Pvridone: MS 350.2

C

2

,H

5 NOrequir. 349.4.

'K-NMR (DMSO-d,): d 8.45 2H, Pyrid.), 8.16 (bd, 2H), 7.98 2H), 7.32-7.00 8, Ph, Pyrid., CK=).

12-10 6-(a-Naphthl) -3:henv4(4-vridyl)-2(1H) vvridone: MS 375.0

C

26 1

,N

2 Orequir. 374.5.

'H-NMR (DMSO-d 6 d 8.38 2H, Pyrid.), 8.06-7.98 (m, 3H), 7.67 (dd, 1H), 7.62-7.54 3K), 7.25-7.11 7H, Ph, Pyrid.), 6.38 (bs, 1K, CH=).

RS

12-11 3-Phenvl-4,6-bis-4-pyrid1)-2(1H)pvridone.

MS 326.0

C

21

H

1 N Orequir. 325.4.

'K-NMR

134 (DMSO-d 6 d 8.69, 8.43 (2m, each 2H, Pyrid.), 7.92 (bs, 2H), 7.28-7.05 8H).

12-12 3 -Phenvl- 4 -(4-vridv) (2-thienvl)2(1H) ipyridoe: MS 331.0

C

2 0H 14 NOSrequir. 330.4.

1H-NMR (DMSO-d): d 8.44 2H, Pyrid.), 7.90, 7.70 (2bd, each 1H), 7.28-7.08 9H).

12-13 6 2 -Furvl)-3-phenvl-4-(4-pvridvl)- 2 (lH) Yridone-: MS 315.0

C

20

H

1

,N

2

O

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-Cvclohexvl-3-henl-4-(4-pyridyl)-2 (1H)- :vridone: MS 331.2

C

22

H

22

N

2 Orequir. 330.4.

H-NNR (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 11H, cyclohex.).

12-15 6-tert-Butv-3-henyl-4- (4-pvridyl) 2 (1H)pyridone: MS 305.0

C

20

H

2

ON

2 Orequir. 304.4.

LH-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 3

(CH

3 3

C-

135 Example 13 Procedure for the Preparation of Ben zyl.ethyl endiarnine Q "0"Y H2NH2 S 2 -Benzvlethylendiamine. The diaxnine was prepared according to the literature Brunner, P. HarIkofer,

U.

Holzinger, B. Treittinger and H. Schoenenberger, Eur. J.

Med. Chem. 25, 35-44, (1990)) by reduction of Lphenylalanine amide with lithium aluminium hydride. The (R)-enantiomer was prepared in the same manner from Dphenylalanine amide.

Example 14 Procedure for the preparation of 2 -(((S)-2-Acetamido-3phenyilpropyl) -amino) (4-f luorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrirnidinone N 1N*N

N

H N-h N 4 N- N Nc 2- -2-Acetanido-3-phenyliprolpvl) -amino) (4fluoroiphenyl) -3-nethyl-6- (4-T~vridyl) -4 (3H) -pyrimidinone: A solution of 2 4 -fluorophenyl)-3-methyl6(4-pyridyl)-4(3)pyrimidinone (25 mg, 0.058 inmol) 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 25 methanol/dichloromethane) provided the title compound.

MS 472.3 C27H26FN50 2 requir. 471.5.

S 5955

S

5*

S

*5

S

S

(555...

5

S.

S

S.

136 Example Procedure for the preparation of 5 4 -Fluorophenyl).2- 2 isopropyl amino -3 phenylpropyl) -amino) -3 me thyl 6- (4 -pyri dyl) -4 (3H) -pyrimidinone hydrochloride 1 0 0

NN

Il NN NN

N

H N H (4-Fluorophenyl) 2 -N-isopropylamino-3 phenvipropyl) -amino) -3-nethyl,-6- (4-Pyridyl) -4 (3H) pyrimidinone hydrochloride: Sodium triacetoxyborohydride (23 mg, 0.109 mmcl) was added to a strirring mixture of 2 -(((S)-2-amino-3-phenylpropyl)amino) (4-f luorophenyl) -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 l, 2 -dichloroethane (07.8 ml). After 4h, the reaction was quenched by the addition of sat. aqu.

sodium hydrogencarbonate, followed by extraction with dihoomtae drin f the organic solution and evaporation. Chromatography on a column of silica gel (Mt~ methanol /chloroform) provided the title compound as 2C a free base which was converted into the ronohydrochloride by the addition of 4N hydrochloric acid/dioxane (21 mml, 0. 08 mmcl) to its methanolic souto (1 ml)~ and subsequent evaporation. MS (m/z) 472. 1 C2 8H3 oFNSO requir. 471. 6 (f ree base) 0 137 Example 16 Procedure for the preparation of 5- (4-Fluorophenyl) -2- 2 -N-cycl ohexyvlamino-3 phenylpropyl) -amino) -3 methyl (4 -pyridyl) -4 (3H) -pyrirnidinorie hydrochloride F 0

NN

NN N N N HN- H NHi 5-(4-FluoroiDhenvl)-2- 2 -N-cvclohexlanino3pherivlorooyl) -amino) -3-methyl-6- (4-Dyridyl) -4 (3H)pvrimidinone hydrochloride: Utilizing cyclohexanone, 4 -f luorophenyl) -2 2 -N-cyclohexylamino-3 phenylpropyl) -amino) 3 -methyl-6- (4-pyridyl) -4 (3H) pyrimidinone was prepared in the same manner as 5-(4f luorophenyl) -2 2 -N-isopropylamino-3 phenylpropyl) -amino) 3-methyl-6 (4 -pyridyl) -4 (3H) pyrimidinone: MS :511.6 KM); C31H34FN5O requir.

511.6 (free base).

Example 17 O0 .6.6Procedure for the preparation of -2-N-n- Bu tyl amino -3 phenylpropyl) -amino) (4-fluorophenyl) -3- C9..methyl- 6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride 0 N leN N

NN

N N N N N N N NH

NH

2 N-H jj 2 -N-n-utvamino-3-Tphenlpropvl) -amino) (4fluoroiphenyl) -3-methvl-6- (4-rjiyl -74 3H) -Tyrimidinone hydrochloride: Sodium triacetoxyborohydride (28 mg, 0.13 mmol) was added to a strirring mixture of 2 -amino -3 -phenylpropyl) -amino) (4-f luorophenyl) -3methyl-6- 4 -pyridyl)-4 (3H) pyrimidinone (41 mg, 0. 095 138 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 C29H32FN 5 0 requir. 485.6 (free base) Example 18 Procedure for the preparation of Dime thyl amino -3 -phenylpropylamine 0 0

H

2 N H 2

N

i 2 N

N

-2 N-Dimethylamino-3 -phenylpropylamine: Sodium triacetoxyhydride (13.0 g, 61.3 mmol) was added to a stirring mixture of phenylalanine amide (3.6 g, 21.9 20 mmol) and 37% formaldehyde solution (4.4 ml, 58.7 mmol) in 1, 2 -dichloroethane (77 ml). After stirring for 2 h, the reaction was quenched by the addition of sat. aqu.

sodium hydrogencarbonate. Then potassium hydroxide ::pellets were added followed by extraction with dichloromethane, drying of the organic solution and evaporation. The resulting 2 -N,N-dimethylamino-3phenylpropylamide was reduced with lithium aluminium hydride according to the literature Brunner,

P.

:=00 Hankofer, U. Holzinger, B. Treittinger and H.

30 Schoenenberger, Eur. J. Med. Chem. 25, 35-44, (1990)) to provide the title compound.

139 Example 19 Procedure for the preparation of 2 Dime thyl amino -3 -phenylpropyl) -amino) -5 4 -fl uorophenyl 3-mnethyl-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride F I i9 N

N

N

N

N N4 N N 1 Steip A. S--(4-Fluorophenvl) 3 -methvl-2-methvlsulfonyl-6 44-ioyridvi) -4 (3H) -pyrimidinone: A mixture of 5- (4f luorophenyl) -3-methyl-2-methylthio-6- (4-pyridyl) -4 (3H) pyrimidinone (400 mg, 1.22 mmol) and OxoneR (potassium peroxymonosulfate, 2.3 g, 3.74 rnmol) in methanol (100 0 0. 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.

Sterp B. 2- 2 -NN-Dimethamino-3-.henvlpropvl) aMino) 4 -f luorophenyl-3 -methvl6- (4-pyridyl) -4 (MI) pyrimidinone hydrochloride: A mixture of crude 5-(4 f luorophenyl) 3 -methyl-2-methylsulfonyl-6,. (4-pyridyl) 4 3 H)-pyrimidinone (430 mg g, 1.19 mmol) and diety mn phnlrplaie(0 mml, -3.4 mmol) was stirred at room temperature for 1h and then briefly warmed at 50OC. 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 rnml, 0.64 mmol) to its methanolic solution (4 ml) and 140 subsequent evaporation. MS 458.0 C27H28FN 5 0 requir. 457.5 (free base).

Example 5- 4 -fluorophenyl) 4 2 -acetamido) -pyridyl)-2thioalkyl-4 (3H) -pyrimidinones Step A. Ethyl 2 4 -fluorophenvl)-3-oxo-3-( 4 2 acetamido) -pvridvl) -oropionate: 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 20 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 2- 30 aminoisonicotinate 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 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)pvridvl))- 2-thiouracil: Ethyl 2-(4-fluorophenyl)-3-oxo-3-(4-(2acetamido)pyridyl)-propionate (1.3 g, 3.78 mmol) and 25 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).

30 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.

142 Example 21 Procedure for the preparation of -2 -N-Ethvl amno-3.phenylpropylamine 0

H

2

NH

2 N I 2 N"

K-

2 -N-Ethvlanino-3-YDhenylproTvlamine. Acetic anhydride (1.2 ml, 12.7 minol) was added to a stirring solution of L-phenylalanine amide (1.0 g, 6.10 Inmol) 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-ethylphenylaJlanine amide (6.1 mmol) was reduced with lithium aluminium hydride (570 mg, 15.0 rnmol) in tetrahydrofuran (65 mnin) at 55 0 C for 4 h. The reaction mixture was poured into sat. aqu. sodium hydrogencarbonate followed by extraction with 15 dichioromethane, drying and evaporation. Column .chromatography on silica gel (chloroform :methanol triethylamine 90:7:3) provided the amine as a yellowish oil. MS 179.1 Clj18N2 requir.

178 .3.

Example 22 Procedure for the preparation of 2-Amino-2-methylz-3phenyipropyvlamine

O****NH

2 -Amino- 2--methyl -3 -TDhenyliprowyl amine. A solution of commercially available D,L-a-methyl phenylalanine methyl ester (5.0 g, 25.7 nimol) 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) 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-3phenylpropylamine NH2 2 -Methyl-3-phenvlpropvlamine: 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).

144 Example 24 Procedure for the preparation of 5 4 -Fluorophenyl)-3methyl 2 -methy-3-phenylpropyl) amino) (4-pyridyl) 4 (3H) -pyrimidinone hydr-ochloride N~ 00 N -z N s 0 II N NNZ NN

N

H

2 N

CH

CH

3 Fl1uo-rophenyl)= -methl 2- 2 -me thy- 3 -phenvlpropyl) amino) (4-pyridyl) -4(3H) prinidinone hdrochloride: A mixture of crude 5- 4 -fluorophenyl) -3-methyl-2methylsulfonyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (520 mg g, 1.45 mmol) and 2-ehl3penlrplmn (1.5 g, 10.1 mmol) was heated at 50'C' for 30 min. Column chromatography on silica gel *methanol /dichlorometliane; hexane-acetone= 2 :1) 0*provided the title compound. MS 429.4 (M+H)+1 C26H25FN40 requir. 428.5 (free base).

Example Procedure for the preparation of l-Phenyl-l,3propan edi ainine

N.,~NH

2 1-ph nyl-1 3 -propanediamine: 3 -Phenyl-3-aminopropionic tee..:acid G. Cohen and S. Y. Weinstein, J. Am. Chem. Soc.

86, 725-728, 1964) was converted into 1-phenyl-l,3propanediamine as reported in the literature Kojima and J. Fujita, Bull. Chem. Soc. Jpn. 55, 1454-1459 (1982)).

14 Analogously, 1- (2-f luorophenyl) 3 -ipropanediamine, 1- -(2-methylphenyl) 3 -propanediaiine and 1- (2chlorolphenyl) 3 -propanedianine have -been prepared.

Example 26 Procedure for the preparation of 3-Ethy.Z-5-(4fluorophenyl) -2-xnethylthjo-6- (4-pyridyl) -4 (3H) pyrimi din one NH N N N s!: (4-f luorophenyl) -2-methvlthio-6- (4-pyridyl) 4 -;Drimidinone: Ethyl bromide (600 ml, 8.03 mmol) was added to a stirred mixture of 5-(4-fluorophenyl)-2methylthio-6-(4-pyridy1).4(3H)-pyrimidinone (1.8 g, 5.97 nunol) and sodium hydri de (60% oily suspension, 320 mg, 8 minol) in N, N- dime thyl-f ormami de (60 ml) at room temperature. More ethyl bromide (2x 600 ml, 2x8.03 mmnol) 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 d--chloromethane, the organic solution was washed with 2C* water, dried and evaporated. Flash chromatography on a column of silica gel- (hexane-acetone 3:1, 2:1).

pr7ovided in the secbii'd main fraction the title compound as a solid.

Example 27 Procedure for the preparation of 3-Ethyl-5-(4fluorophenvyl -2-me thylsulfonyl-6-

H

pyrimidinone F

F.-

N

N

N l NS CH3 N -i,.CH 3 146 1 4 -fluorophenw1)-2-methlsulfonl6( 4 P~vridvl)-4(3H)..Pvrimidinone. A mixture of 3-ethyl-5- (4fluorophenyl) -2-methylthio-6- 4 -pyridyl) -4 (3H) pyrimidinone (300 mg, 0.88 mmol) and Oxone R (potassium peroxymonosulfate, 2.54 g, 4.14 nunol) in methanol (71 ml) and water (33 ml) was stirred for 14 h. The solvent was concentrated to about 35 ml, followed by extraction with dichloromethane, drying and evaporation. The resulting white solid was used without purification in the next step.

Example 28 Procedure for the preparation of 2- M(S) -2-Amino-3phenyipropyl) -amino) -3-ethyl-5- 4 -fluorophenyvl) (4pyridyl) -40(H) -pyrirnidinone hyvdrochloride F N N 2 -Anino-3-phenvlpropyl) -amino) -3-ethvl-5- (4fluorophenyl) (4--pvridvyl-4 (3H) -pyrimidinone hydrochloride: A mixture of 3-ethyl-5- 4 -fluorophenyl) 2-methylthio-6. (4-pyridyl) -4 (3H) -pyrimidinone (150 mg, 0.44 nunol) and (S)-l,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).

0 o.

147 Example 29 Procedure for the preparation of 3-Ethyl-5-(4fluorophenyl) 2 -methy-3-phenylpropyl) amino) (4pyridyl) -4 (3H) -pyrimidinone hydrochloride

N

N N N1.-

CH

3 (4-f luorop~henyl) -2-C 2 -methv-3-phenvlpropvl) aminio) (4-oyridyl) -4 (3H) -pyrimidinoie hydrochloride: A mixture of crude 3 -ethyl-5-(4-fluorophenyl)-2 methylsulfonyl-6 (4-pyridyl) -4 (3H) -pyrimidinone (320 mg g, 0.89 mmol) and 2 -methyl-3-phenylpropylamine (600 ml, -4 inmol) 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 )propylamine aCH 3 3 2 ethylrheny)propvlamine. Diethyl cyanomethylphosphonate (5.0 ml, 30.9 mmol) was added to' a stirring suspension of sodium hydride (60% oily suspension, 1.24 g, 31 mnmol) in tetrahydrofuran (50 ml) under argon. After 3o min, 2 -methylbenzaldehyde (3.6 ml, 31.1 rnmol) 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) 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 a NH 2 F NH 2 Step A. Methyl 2-amino-3-( 2 -fluorophenvl)propionate: (27.3 mmol) of 2 -fluoro-phenyl)alanine was 20 suspended in 50 ml methanolic HC1 and stirred at room temperature for 3 days. The reaction mixture was concentrated in vacuo and dried to give a yellow oil.

MS 198

C

0 oH, 1 FNO, requir. 197.2.

Step B. 2-Amino-3-( 2 -fluorophenvl)propionamide: Methyl 25 2 -amino-3-(2-fluorophenyl) propionate was suspended in ml 30% ammonium hydroxide and stirred at room otemperature 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 30 183.1

C,H

11

FN

2 0 requir. 182.2.

Step C. 2-Amino-3-( 2 -fluorophenyl)-propylamine: 2- Amino-3-( 2 -fluorophenyl)propionamide was added carefully to a chilled (50) mixture of LAH (l.0g, 26.3 mmol) and ml THF under argon. The reaction was then heated at reflux for 10 hrs. The reaction was cooled to 50C 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

C,HFN

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

N

N NtN 0) -NH 2 5-(4-Fluorophenvl)-2-(((S)- 2 -N-qlyclamino-3phenvlpropyl)-amino)-3-methyl-6-(4-pyridvl)-4(3H)- 15 pyrimidinone hvdrochloride: Ethyl chloroformate (56.8 pi, 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 l1, 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 S* 25 dichloromethane, washed with aqueous sodium hydrogencarbonate, followed by drying of the organic solution and evaporation. The resulting material was o. 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 150 sodium hydrogencarbonate, drying of the organic solution and evaporation. Column chromatography on silica gel (dichioromethane methanol conc. ammonium hydroxide= 93 :7 provided the title compound as the free base which was converted into the hydrochloride by the addition of 4N hydrogen chloride/dioxane (112 jil, 0.45 mmol) to its methanolic solution (3 ml) followed by evaporation. MS :487.1 C 27

H

27 FN 6 2requir.

486.6 (free base).

Accordingly, 2- CS) 2 -N-arlvcvlamino-3-henylropvl) amino) -3-methyl-5.- -methylphenyl) (4-pyridyl) -4 QH) 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 -hydroxyvacetamido.3.phenyvlpropyl) -amino) 3methyl (4-pyridyl) -4 (3H) -pyriinidinone F V

N

N N ld

N

0 OH 5- (4-Fluorophenyl)-2-C S) 2 7hydroxvacetamido..>.

TPhenvyipro ryl) -amino) -3 -methyl-6- (4-rwridyl) -4 (3H1) iPvrimidinone: Acetoxyacetyl chloride (55 jil, 0. 51 inmol) was added at ice-bath temperature to a stirring solution of 2-(M)--mn--hnlrpl aio 5 4fur phenyl) 3 -methyl-6-(4-pyriayl) -4(3H) -pyrimidinone (200 mg, 0.466 mmol) and triethylamine (130 p.1, 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 mehnlwtr/rehlmn (3 ml) and 151 left overnight. Evaporation and subsequent column chromatography methanol/chioroforme) provided the title compound. MS 488.3 C 2 H 26 FN,0 3 requir.

487.5.

Example 34 Procedure for the preparation of 5-(4-ffluorophenyl)-2- ((3-N-methyl urel do) -3-phenyipropyl) -amino) -3-methyl- 6- (4-pyridyl) -4 (3H) -pyrimidinone N IN 0N N N N i, H NH NHCH 3 (4-Fluorophenvl) (3-N-methylureido) -3- Phenylpropyl) -amino) -3-methvl-6- (4-pyridyl) -4 (3H) Tvrimidinone: Methyl isocyanate (6 gi1, 0. 102 rnmol) was added to a solution of 2 2 -amino-3-phenylpropyl)amino) (4-f luorophenyl) -3 -methyl-6- (4-pyridyl) -4 (3H) 15 pyrimidinone (43.6 mg, 0.102 nimol) 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 4 86. 6 C 7 2 ,H2FN 6 0 2 requir. 486. 6.

Example Procedure for the preparation of 5- (4-fluorophenyl) -3me thyl (4 -pyri dyl -2 2 -pyrrol idinyl 3-phenylpropyl) amino) -4 (3H) -pyrimidinone hydrochloride F 0 04NN N NN ?~AT 152 (4-Fluorophenvl) -3--methyl-6- 4 -pvridyl) -2pvrrol idinvl -3 -phenyipropyl). -amino) -4 (3H) -Pvrimidinone hydrochloride: Sodium hydride (60% oily suspension, 84 mg, 2. 1 inmol) was added to a solution of 2- -2arino-3 -phenylpropyl) -amino) 4 -f luoropheny.) -3mehl6(-yiy)43)prmdnn (300 mg, 0.70 mmol) in N,N-dimethylfomamde (8 ml) at ice-bath temperature. After 30 min, l.

4 -dibromobutane (108 gil, 0.91 mmol) was added. Stirring was coritinued 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 (dichioromethane methanol 93 :7; dichioromethane methanol conc. ammonium hydroxide 93 :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 C2,H,FNO requir. 483.6 (free base).

Example 36 V. Procedure for the preparation of 5 4 -fluorophenyl)-2- -3--ispoy mn 3-hnlrpl -amino) -3methyl (4-pyri dyl (3H) -pyvrimidinone hydrochloride F 0 N 0

~N

*NA

N

5- 4 -Fluoro-6henyl) S) 3 -N-isoiproplamo..3 Phenyl ropyvl) -amino) -3-methyl-6- (4-pyvridvl) -4 ipyrimidinone. 'hirdrochloride: Sodium triacetoxyborohydride (12.9 mg, 0.061 mmol) was added to a strirring mixture f luorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (21.8 mg, 0.051 mmol) and acetone (4.5 41, 0.061 inmol) 153 in 1, 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/chloroform) provided the title compound as a free base which was converted into the monohydrochloride by the -addition of 4N hydrochloric acid/dioxane (12.2 Jil) to its methanolic solution (1 ml) and subsequent evaporation. MS 472.0 C28H30FN 5 0 requir. 471.6 (free base) Example 37 Procedure for the preparation of 5-(4-fluorophenyl)-2- 3 i sopropyl amino -3 -phenylpropyl) -amino) -3methyl (4-pyridyl) -4 (3H) -pyrirnidinone hydrochloride N 0

N

N

Ik NN

I

5- 4luorophenyl) 3 -N-isoproplamino-3 phenylpr opyl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) *0pyrimidinone hydoclride aspreared from 5-(4-io

M

P 0 furoehueyfor- th preparaionrofylamino...>.miophenypropyl) -amino) -5-(-lo-pey)-3-methyl-6- (4-yid)-4(H- 472.1yl (38H)N 5 prqir.41.6 fre 154 F i.'1 0 zt NH N NN

NH

2- -3-Acetamido-3-phenylpropyl) -amino) (4fluorophenyl)- 3 -methvl-6-(4-Pyridyl)-4 (3H)lpyrimidinlone: A solutiont of 2 -(((S)-3-amino-3phenylpropyl) -amino) 5- 4 -f luorophenyl) 3-me thyl- 6 4pyridyl)-4(3H)-pyrimidinone (23.8 mg, 0.055 mmol) and acetic anhydride (2O-gl, 0.21 inmol) in methanol(l ml) was kept for 30 min at room temperature. Evaporation was followed by column chromatography (dichloromethanemethanol ammonium hydroxide 93 :7 0.7) to provide the title compound. MS :472.2 C27H 2 6

FN

5 0 2 requir. 471.5.

Example 39 Procedure for the prepara tion of -1 -Phenl 3 propanediamine .NH-tBOC

NH

2 N' N

NH

2 (S)-l-Phenvl-1,3-proloanediamine. S-3-N-tert. Butoxyc arbonyl amino -3 -phenyipropi oni tr i 1e was prepared according to the literature Wheeler. and D.D.

Q'Bannon, J. Label.Compds. Radiopharm. XXXX 305- 315, 1992) from D-(-)-cc-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 (1 *25 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.

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 dichloromethane. The aqueous solution was made basic by the addition of solid potassium hydroxide followed by repeated dichloromethane extractions. Drying and evaporation of the dichloromethane solution left the crude diamine as an oil. MS (rn/z) :150.8 C 9

H

14

N

2 requir. 150.2.

Enantiomeric -1-phenvl-1, 3 -yr panediamine was prepared analogously from L-(+)-ct-phenylglycinol.

MS

15 C 9

H

14 N 2 requir. 150.2.

Example Procedure for the preparation of (2R,3R)-2-methyl-3phenyl 3 -propanediamine ~Ph

NH

2 0 Ph/ N e NH2

NH

2 Step) A: Methyl 2 S,3RaS)-3-(N-benzvl-N-amethylbenzvlamino) -2-methyl -3 -rhenyipropionate was prepared as reported for the 2R,3S,aXR-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-anino-2-methyl-3p~hen lpropionate: A mixturte of methyl (2S, 3R, (XS)-3 (N-benzyl-N-a-methylbenzylamino) -2-methyl-3phenylpropionate (13.0 g, 33.55 mmol) and 10% palladium- 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

C

1 ,HsNO2 requir. 193.3.

Step C: (2S,3R) -3-Amino-2-methvl-3.-henyiroDionamide 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

10

H,

4

N

2 0 requir. 178.2.

Step D: 2

R.

3 R)-2-methyl-3-phenvl-,3- ronediamine: Lithium aluminium hydride (2.3 g, 60.60 mmol) was added in portions to a stirring solution of 2 S,3R)-3-amino-2- 20 methyl-3-phenylpropionamide (2.6 g, 14.59 mmol) in tetrahydrofuran (54 ml) at ice-bath temperature. After 45 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 25 some methanol until hydrogen evolution ceased. The solids were removed by filtration and washed with Sdichloromethane. The combined filtrates were evaporated to provide the title compound. MS 165.2

C

0 H,Nrequir. 164.3.

30 Accordingly, -the enantiomer 1 2 S 3S)-2-methl-3-phenyl- 1, 3 -propanediamine was prepared from methyl (2R,3S,aR)- 3- (N-benzyl -N-a-methylbenzylamino) -2-methyl-3phenylpropionate. MS 165.3

C

1

H,

1 N, requir.

164.3.

157 Analogously, the enantiomers (2R.,S 2 mtvl3pev.

1, 3 -proranediamine and 2

S,

3 R)-2-methv1-3Pheny1,3propanediamine may be prepared from tert.butyl (2S,3S,aR)- and 2 R,3R,aS-)-3-(N-benzylpN-amethylbenzylamino) 2 -methyl-3-phenylpropionate

(S.

Davies et al., J. Chem. Soc. Chem. Commun. 1153-1155, 1993).

Example 41 Procedure for the preparation of Benzylpiperaziny) 4 -fluoropheiyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone hydrochloride 0 F0 NN

HN

0' 0N L N SStep A: 2 -Benzylpijperazine: At ice-bath temperature, lithium aluminium hydride (1.6 g, 42.16 *15 rnmol) was added in portions to a stirring mixture of 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 dichloromethane. The combined filtrates were evaporated to leave a white solid.MS (mz) 177. 1

C

11

H

1

GN

2 requir. 176.3.

Steip B: 3 -Benzvlpoinerazinv).5(-4.fluorophenvl)-3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride: 158 A mixture of crude 5-( 4 -fluorophenyl).3..methyl.2 methylsulfonyl6.(4-pyridyl) -4 3 H)-pyrimidinone (434 mg, 1.21 n'mol) and 2 -benzylpiperazine (426 mg, 2.42 Inmol) -was heated at 105 0 C for 1 h. The crude reaction product was purified by column chromatography on-silica gel (dichloromethane methane 93 dichloromethane methanol conc. ammnonium hydroxide 93 7: 0.7).

The resulting material was converted into its hydrochloride by the addition of 4N hydrogen chioride/dioxane (75 p.1) to its methanolic solution (3 ml) followed by evaporation. MS 456.5

C

27

H

26 FN.O requir. 4 55*.5(f ree base) Example 42 Procedure for the preparation of 5 4 -fluorophenyl)-3me thyl -2 3 -phenylpropoxy) 6- (4 -pyridyl) 4 (3H) pyrimnidinone

NN-

N 0K -(4-fluorophenyl) 3 -methl-2-(3-phenvlrropox)-6( 4 ipyridvi) -40H) -pyrimidinone: Sodium hydride (60% oily 00** 20 suspension, 111 mg, 2.79 inmol) was added to a stirred solution of 3 -phenylpropanol (387 mg, 2.85 mmol) in tetrahydrofuran (1 ml). After gas evolution ceased, 4 -fluorophenyl) 3 -methyl-2-m'ethylsulfnyl-...(4pyiy)43)prmdnn (100 mg, 0.279 mmol) 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 provided the title compound. MS (mn/z) 416.1 C2_9H 2 2

FN

3 0 2 requir. 415.5.

159 Example 43 Procedure for the preparation of 5 (4-fluorophenjyl)-3methyl-2- (4-phenylbutyl) 4 -pyridyl) -4 (3H) pyrimi din one F0 0 N Step A: 5-( 4 -FluoroThenvl)-2-(4-.henybutyj 6 4 r yridyl) -4 (3H) -pvrimidinione: Ethyl 2- (4-f luorophenyl) 3 -oxo- 3 -(4-pyridyj)-propionate (293 mg, 1.02 nimol), 4phenylbu tanec arboxmi dine (315 mg, 1.79 nimol) and pyridiniun p-toluenesulfonate (10 mg) were suspended in p-xylene (10 With efficient stirring, the mixture was heated to ref lux using a Dean-Stark apparatus with continuous removal of water. After 16 h, the solvent was evaporated and the product purified by column chro matography on silica gel (3% methanol /dichloromethane) followed by recrystallization 000:0 00 0 from acetone. MS 400.3 C25H 2 2

FN

3 0 requir.

0 O 399.5.

0:0 @000 Step B: 5-( 4 -Fluorophen vl)-3-methv-2-(4-Dhenvlbutyl)-6 1 0 0 .Sso20 4 -Dpvridvl)-4(3H)-pvrimidinone: Methyl iodide (22 jil, 0.351 nimol) was added to a stirring mixture of 5-(4fluorophenyl) 2 4 -phenylbutyl)6(4pyridyl).4(3)- S pyrimidinone (140 mg, 0.351 inmol) and potassium carbonate (49 mg, 0.351 inmol) in N,N-dimethylformamide 25 (5 ml) After 75 min, it was evaporated and the resultant product purified on a silica gel column (hexane.- acetone =3 1; 2 1) to provide the title *compound. MS 414.3 C26H 2 4

FN

3 0 requir.

413 160 Example 44 The compounds shown in Table I were prepared using the procedures of Examples 1-43.

TABLE I iv Cl N A,

O

MS 464.0 C2SH23FN 5 0 requir. 463.9

N

N -k NC 1 N MS 498.0 22

FN

5 0 requir. 498.4 F 0

N'

N N IH NH 2 MS 464.1 (M C25H23C1FN 5 0 requir. 463.9 F 0

N'

NI

NK NN

N

N H 1 MS (mhz): 448.3 C25H2 3

F

2

N

5 0 2 requir: 447.5 F N0

N'

N2

F

MS 448.2 C25H2 2

F

2

N

5 0 requir. 447.3

N

NH

NH

2 MS 479.7 C29H2 6

FN

5 0 requir. 479.6 F

IN

1 N Il NI

N

N H R1

HNH

2 MS 416.1 (MsH)+; C24H 2 2

FN

5 0 requir. 415 F 0-

N

N.4 H NH 2 MS 414.0 C21H 2 4

FN

5 0S requir. 413.5

F

N"

N NN 11N N .4 H 2 MS 436.2 C25H 3

OFN

5 0 requir. 435.6

F

N 0

N

N

Nk

N!

N o4 H HN- MS 428.1 C25H22FN 5 0 requir. 427.5 161 MS 486.1 C27H2 4

FN

5 0S requ.ir. 485.4 MS 442. 1 (M+H C26H 2 4

FN

5 0 requir. 413. Example The compounds shown in Table II can be prepared using the procedures of Examples 1-43, wherein

R"

represents 3-methylphenyl, 3-chiorophenyl, 3trifluoromethylphenyl, 4 -fluorophenyl, 4 -methylphenyl, 4-chiorophenyl and 3, 4 -dimethylphenyl.

TABLE II C1 H

H

2 N N H

NH

2 LN 1> N

F

N .1o I Ilk H H YN- 0: 162 0 R N" F R

IN

N

NN

H N 2 F N0,01: H N 2

S

N 0 N H2R N H R 0 110 -i

N

NNNk> N N

-S

NH2 6 _N 2 0 0 N

N

N~ I N N NH i12N,-ZNH N- H H 0 0 W'

N

I N N N N

NNHH

Example 46 Procedure for the preparation of 3 -methyl-2-(2(S) -amino- 3 -phenyvlpropyl amino) 3 -trifluoromethyl phenyvl) (4- .pyridyl) -4 (3H) -pyrirnidinone 0 F3C

NCH

3 *N

N

Ste 6 4 -pyridvl)-2-thiouracil: Ethyl isonicotinoylacetate (5g, 25.89 mmol) and thiourea (5.94 g77.64 mmol) were suspended in anhydrous p-xylene (lO0mi) with vigorous stirring. To the mixture, pyridiniumn p-toluenesulfonate (150mg) was added and ref luxed for 12-16 h using a Dean-Stark apparatus with (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 CHNOS 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( 3

H)-

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

1 ,NOS requir. 233.2; 1H- NMR(CDC1,):d 8.75 2H, pyridyl), 7.8 2H, pyridyl), 6.75 1H), 3.58 3H, 2.72 (s, 3H, S-CH,) 25 Step C. -3-Methvl-5-bromo-6-(4-pyridvl) -2-methylthio- 4(3H)-pyrimidinone: 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 (0.5ml, 1.5g 9.38 mmol) was added. The reaction mixture 30 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,,H,,BrNOS requir. 311 and 313. 1H-NMR(DMSO-d6):d 35 8.75 2H, pyridyl) 8.19 2H, pyridyl), 3.67 (s, 3H, 2.80 3H, S-CH 3 164 Step D. 3-Methvl-5- 3 -trifluoromehlphenyl)6( 4 ipyridyl) -2-thiomethyl-4 (3H) -iprimidinone: brorno-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 (30m1) 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 ref luxed for 8-12h. The formation of the product was monitored by TLC. The mixture was cooled, diluted with toluene(2Qml) and washed with water. The organic layer was dried over sodium sulfate, concentrated and product isolated by silica gel chromatgraphy to give the titled coinpoud. MS(m/z): 378.4

C

18

H

14

F

3

N

3 0S requir.

377.39; lH-NMR(CDC,) :d 8.5 (in, 2H, pyridyl) 7.45 7.17-7.25 (in, 3H, pyridyl and Ph-CF,), 6.95 (d, 18, Ph-CF,), 3.67 2.8 (S-CE 3 Step E. 3-nethyl-2- (2 (S)-amino-3-pohen lp~rop~vlaino) 3 -trifluoroinethvlphenvl) (4-pyridvl) -4(3H)- Pyrimidinone: 3-Methyl-5- 3 -trifluoromethylphenyl) (4pyridyl) -2-thioinethyl-4 3 H)-pyriinidinone (0.7g, 1.85 mxnol) and 2 -amino-3-phenyl-l-.propylamine (0.9 ml, 6.00 minol) were mixed in a round bottom flask and heated at 185 0 C for 3h. The mixture was separated on silica gel (dichloromethane: methanol: ammoniumn hydroxide 92:7: 1) to obtain compound titled compound.. MS 480, C 26

HE

2 4

F

3 N.0 requir 479.51; lH-NMR (CDCl) :d 8.49 (in, 28, pyridyl) 7.51-7.17 (mn, 11H, Ph and pyridyl) 5.81 (bin, 1H, NH) 3.91 (in, 1H, CH) 3.53 3H, N-CHO) 3.35 (mn, 2H, CEO), 2-.94 (dd, 18, CH,) 2.82 (dd, 1H,

CE

2 165 Example 47 Using the corresponding starting materials, the following compounds of Table III were prepared using the procedure for 3-methyl-2- -axnino-3phenylpropylamino) 3 -trifluoromethylphenyl) (4pyridyl) -4 (3H) -pyrimidinone.

TAB3LE III 0 N41N W.NHR1 4-tolyl 4 -trifluoromethyl phenyl 3-is opropylphenyl 3 -chloro-4 -fluoro phenyl 3, 5-bis (trifluoro methyl) phenyl 3, 4-dichloro phenyl 1-naphthyl 3- fluorophenyl 3 -cfllorophenyl 3 -inethylphenyl 4 -chiorophenyl 2-chlorophenyl 2- thienyl 3, 4-dimethyiphenyl 3, 5-dichloro phenyl 30 4-tolyl 3 -trifluoromethyl phenyl 4-me thoxyphenyl 4 -trifluoromethyl phenyl 3 -chlorophenyl 3-me thylphenyl 4 -chlorophenyl 2 -chlorophenyl 40 3-nitrophenyl (S aio3phnlpoy 2 (5)-amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propy.

2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 3 )an--phenyll 3 -phenylpropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenylpropyl 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-propy.

3 -phenyl-propyl 3 -phenyl-propy.

166 3-me thoxyphenyl 2 -fluorophenyl benzothienyl 3 -fluorophenyl S 1-naphthyl 3 -trifluoromethyl phenyl 3-me thyiphenyl 3 -chlorophenyl 3 -nitropheny.

3 -phenyl -pr opyl 3 -phenyl -propyl 3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 2 (5)-dimethylarnino- 3 -phenyipropyl 2 3 -phenyipropyl 2 N-dimethylamino.

3 -phenyipropyl 2 CS) N-dimethylamino- 3 -phenyipropyl 2 CS) N-dimethylamino- 3 :-phenyipropyl 2 CS) -N,N-dimethylamino- 3 -phenyipropyl -tetrahydroisoquinol.>.

ylmethylenamino -tetrahydroisoquinol3 ylme thyl enamino 3 -amino-3 -phenyipropylamine 3 -amino-3 -phenyipropylamine 3 -amino-3 -phenylpropylamine 3 -amino-3 -phenyipropylamine 429 461 492 .1 438 440. 6 3-me thoxyphenyl 2-f luorophenyl 3 -trifluoromethy.

phenyl 3-methyiphenyl 3, 4 -dimethylphenyl 3-me thyipheny].

benz othi enyl benzofuranyl

S

S

S

S

S

*SS*

S

S

S*

S

S

Example 48 3 -Methyl-5- (4-methvlsulfinvlpohenvl) (4-pyridyl) -2thiomethyl-4 OH) -yrimidinone: The title compound was prepared in the manner of example 34-D substituting 4methylsulfinylbenzene boronic acid for 3trifluoromethylbenzene boronic.

Example 49 3-methvl-2- 2,3. 4 -tetrahvdrolsocuinolinvl)methyl amino) (4-methvlthiorphenyl) 4-pyridyl) -4 (3H)= 35 ipyrimidi-none: 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 3methyl-5- 3 -trifluoromethylphenyl) (4-pyridyl) -2- 40 thiomethyl-4(3H)-pyrimidinone and 3 (S)-il,2,3,4terhdosqioiy~ehlmn for -2-amino-3phenyl-1-propylamine: MS z) 470 167 Example 3-methvl--2- (3 2 3 .4-tetrahvdroisocrinolinvl)methyl amino) -5S- (4 -me thvl sul fonylphenyl) 6--L (-pvridvl) 4 Q H) Tpvrimidinone: To a solution of 3-methyl-2-(3 2 3 4 -te trahydro isoquino 1inyl)me thylamino) 5 4 methyithiophenyl) -6-(4-pyridyl) -4 (3H) -pyrimidi~none mg, 0.11 mmol) in methanol:water (15 m.L:10 niL) was added oxone (127 mg, 0.21 mmol) as a solid in one portion at 23 0 C. After 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 502 (M+H)I.

Example 51 2- H 3-Amino 3 -henylpropyl) -amino) -3-methvl-6- (4ipyridyl) 3 -trifluoromethylrphenyl) -4 (3H) -pyrimidinone 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 at 190 0 C for 1 h. MS 480.0

C

26

H

24 F 3

N

5 0 requir.

479.5 (free base).

Example 52 2 3 Aio3phenylpropl )amino)3methyl 6 pridyl) 3 -trif luoromethylphenyl) -4 (MH) -yrimidinone hydrochloride was prepared from 3 -methyl-2-methylthio- 6- (4-pyridyl) 3 -trif luoromethylphenyl) -4 (MH) 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 NO requir. 479.5 (free base).

168 Example 53 Procedure for the preparation of 2 -ch1oro-3-methy1-5-(3.

Inethyiphenyl) (4-Pyridyl1) -4 (3H) -pyrimidinone 0' 1 0' 0 N-

N

N N- NNHK-

N

A: 3 -Methvl-5-(3-methvlpenv)6( 4 pvyridl)- 2 4 (lH, 3 H)-pyrimidindione: _10 N Sodium hydroxide ml) and water (50 ml) was added to a-solution of 3- (3-methyiphenyl) -2-methylthio-6-( 4 -pyridyl) 4 3 H)-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.

Stelp B: 2 -Chloro-3-methvl-5-(3..methlphenl) 6 4 1pyridvl) -4(3H) -pyrimidinone: A mixture of 3 -methylphenyl) (4-pyridyl) -2,4 (lH, 3H) -pyrimidindione (12.5 g, 0.043 mol) and phosphorus oxychloride (65 ml) 20 was ref luxed for 16 h. The excess of phosphorus oxychioride was evaporated followed by co-distillation with toluene. The remainder was carefully partitioned between dichloromethane and aqueous sodium hydrogencarbonate. The organic solution was washed with 25 water, dried and evaporated to leave the title compound.

boos MS (rn/z) 312- C17H1 4 ClN 3 O requir. 311.8.

2 -Chloro-3-methvl-6- (4-prdyl) (3so so:trifluoromethvlphenyl) -4 (3H) -primidinone was prepared according to the same procedure.

169 Example 54 Procedure for the preparation of -2-amino-3phenyipropyl) -amino) -3-methyl-5- (3-rethylphenyl) (4pyridyl) -4 (3H) -pyrirnidinone hydrochloride 1N N E I N N NH 2 -2-Amino-3-phenvlpDropyl) -amino) -3-methvl-5- (3methxylphenyl) (4-pT yridyl) -4 (3H) -PYrimidinone hydrochloride: A solution of 2 -chloro-3-methyl-5-(3methyiphenyl) -6-(4-pyridyl)-4 3 H)-pyrimidjnone (3.34 g, 10.71 mmol) and (S)-l-benzyl-1,2-ethanediamine (2.3 g, 15.31 mmol) in ethanol (50 ml) was stirred at room temiperature for 16 h. The solvent was evaporated and the crude product recrystallized from methanol.

MS

(rn/z) 426 1; 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-methyl-5- (3methy.2phenyl) (4-pyridyl) -4 (3H) -pyrimidinone hydrochloride i 0

NN

N N.

3 -mino- 2 2-dime thl -3 phenvlpropvl)....mino) 3 (3-methvlrphenvl) (4-pyvridvl_) -4 (3H) Pvrimidinone hydrochloride: A so lution of 2-chloro-3- (3-methylphenyl) (4-pyridyl) -4 (3H) pyrimidinone (228 mg, 0.73 mmol) arnd 3-phenyl-2,2dimethyl-1,3-propanediamine (178 mg, 1 mmol) (prepared according to:W. Ten Hoeve and H. Wynberg, Synth. Commuun.

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 C28H 3 1

N

5 0 requir. 453. 6 (free base) Accordingly, 2- ((-3-Amino-2. 2 -di ethyl-3-phenvl1)ropyl) amino) -3-methyl-6- 4 -Pvridvl)-5--(3-trifluoromethvl Phenyl) -4 (3H) -pyrimidinone-hydrochloride was prepared.

MS 5 08

C

2 8

H

2 8

F

3 N 0requir. 507. 6 (free base).

Example 56 Procedure for the preparation of 2 -(((S)-3-amino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridy1) (3trifl1uorom ?Thylpheny1) -4 (3H) -pyrimidirione hydrochloride

CF

3

NH

N

N

N

N H 15 3 -Amino-3-henvlropl)aino)3methl-6( 4 pvridyl) 3 -trifluoromethvlphenyl) -4 (3H) -ivrimidinone 00 hydrochloride: Aqueous sat. sodium carbonate (2 ml) was added to a solution of 2 -chloro-3-methy6(4-pyridyl)- 3 -trifluoromethylphenyl, -4(3H-pyrimidinone 00..20 hydrochloride (730 mg, 2 mmol) and (S)-l-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 25 dried and evaporated followed by column chroatography on *silica gel (dichloromethane methanol :conc. ammonium hydroxide 93 :7 MS 480

C

2 6

H

2 4

FN

5 Orequir. 479.5 (free base).

171 Example 57 Procedure for the preparation of 3 -methyl-2-methylthio- (3-methylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 0 I N N SCH 3 3 -Methv1-2-meththio-5-(3-methlhenvl)-6-(4-yridl)- 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 15 (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

CH,,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(1,2-a)pyrimidin- The required pyrimidinones with the varied R" 172 substituents can be prepared using the general procedures described above.

N

I

3, S-dichlorophenyl 4-me thoxyphenyl 3 -tolyl 3 -chiorophenyl 4 -fl'xorophenyl 2 -naphthyl n-butyl 2- thiophene 3 -thiophene 1S 3 -alninophenyl 2- (5-chlorothiophene) 3- isopropylphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluoropfienyl 3, S-Ditrifluorornethylphenyl 4-f luorophenyl 3, 4 -dichloropaenyl 1 -naphthyl 3 -fluoropheny.

2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -axninopheny.

2- (5-chlorothiophiene) 3, S-dichlorophenyl 4 -tolyl, 3 -trifluoromethylphenyl 35 4 -methoxypheny.

4- trifluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4 -dichlorophenyl amfino-phenl-ryl 2( S) -amino-3-phenyl..propyl 2(S)-anmino-3-phenyl.propyl 2(S) -amiflo-3phenyl..propyl 2(S) -axnino-3-phenyl.propyl 2 (S)-amino-3-pheny-propyl 2 (S)-amino-3-phenyl-propyl 2(S) -amino-3-phenyl.propyl 2 -amino-3 -phenyl..propyl 2(S) -axino-3-phenyl..propyl 2(S) -amino-3-phenyl-propyl 3 -phenylpropyl 3 -phenylpropy.

3 -phenylpropyi 3 -phenylpropyl 3 -phenylpropy.

3 -phenylpropy.

3 -phenyipropyl 3 -phenylpropy.

3 -phenylpropyl 3 -phenylpropyl 3 -phenyipropyl 3 -phenylpropy.

3 -phenyipropyl 3 -phenylpropy.

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 -pheny.-propyl 3 -nethyl-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 173 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3-amrinophenyl 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-Ditrifluoromethyiphenyl 4- fluorophenyl 3, 4-dichiorophenyl 1 -raphthyl 3-f luorophenyl 2 -raphthyl n -buty 1 2- thiophene 3- thiophene 3-aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4-rethoxyphenyl 4- tri fl3uororethylphenyl 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 n-butyl 2-thiophene 3- thiophene 45 3-aininophenyl 2- (5-chlorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 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-propf l 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl -propyl 3 -amino-3 -phenyl--propyl 3 -axnino-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-propy.

3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -axnino-3 -phenyl-propyl 3 -ainino-3 -phenyl-propyl 3 -axnino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -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 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -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 -ainino-3 -phenyl propyl 174 3 -isopropyiphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluoropheiyl 3, 4 -dichlorophenyl 1-naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 9* 2 -methyl-2 -amino-3 -phenyl- Propyl 2 -methyl-2-alino.3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpi-opyl 2 -methyl -2 -amino-3 -phenylpropyl 2 -methyl-2-amfl 0 3 -phenylpropyl 2 -methyl-2 -ainino-3 -phenyl propyl 2 -methyl -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 -amnino-3 -phenylpropyl 2-methyl-2-mino 3 -phenylpropyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -methyl-2-amin-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-dimethylaino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -Propyl 2- N-dimethylamino) -3phenyl -propyl 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethylphenyl 4 -methoxyphenyl 4 -trifluoromethylphenyl 3 -isopropylphenyl 3 -tolyl 3 -chloropheny.

3 -chloro-4-fluorophenyl S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4 -dichlorophenyl l-naphthyl 3- fluorophenyl 45 2 -naphthyl n-butyl 2- thi ophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethylphenyl 175 4-me thoxyphenyl 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 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylaxnino) -3phenyl -propy.

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-dimethylaxnino) -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 -propy.

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 -propy.

2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propy).

2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 45 3 -isopropyiphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4 -fluorophenyl 3, 5-Ditrifluoromethylphenyl 3 ,4-dichlorophenyl 176 4 -fluorophenyl 2-(N-methylamino)-3- -naphthyl phenyl-propyl 1-naphthy 2-(N-methylamino)-3- 3 -fluorophenyl phenyl-propyl 2-(N-methylamino)-3- 2-naphthyl phenyl-propyl 2-(N-methylamino)-3n-butyl phenyl-propyl 2-(N-methylamino)-3- 2-thiophene phenyl-propyl 2-(N-methylamino)-3- 3-thiophene phenyl-propyl 2-(N-methylamino)-3- 3 -aminophenyl phenyl-propyl 2-(N-methylamino)-3phenyl-propyl 2-(-chlorothiophene) 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 substituents can be prepared using the general procedures described above. The fused 6, 5 ring system can be prepared as described above affording R2 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) 177 TABLE V a *aaa..

a a a.

a 3, 5-dichiorophenyl 4 -methoxypheny.

3-tolyl 3 -chioropheny.

4-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4 -dichloropheny.

1 -naphthyl 3-f luorophenyl 2 -naphthyl 25 n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, S-dichlorophenyl 4 -tolyl 3- trifluoromethylphenyl 4-me thoxyphenyl 4- tri fluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, -Ditrifluoromethylphenyl 4 -fluoropheny.

3, 4 -dichlorophenyl 2 -naphthyl n -butyl 2- thiophene 3-thiophene -3-aminophenyl

R

21 2 -amino-3-phenyl..propyl 2(S) -alino-3-phenyl..propyl 2 (5)-amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl..propyl 2(S) -amino-3-phenyl-propyl 2 (S)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 (5)-amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenyipropyl 3 -phenylpropyi 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyi 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropy.

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 -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 178 2- 3, S-dichJlorophenyl 4-tolyl 3- trifluoromethylphenyl 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-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene 3-am'inophenyl 2- (5-chiorothiophene) 3, S-dichlorophenyl 4-tolyl 3- tri fluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 3- isopropylphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 fluorophenyl 3, 4 -dichlorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene 3 -aniinophenyl 2- (5-chiorothiophene) 3, S-dichlorophenyl 4-tolyl 45 3 -trifluoromethylphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3- isopropyipheny.

3 -tolyl 3 -'ethyl-3 -phenyl-propyi 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-propy.

3 -amino-3 -phenyl-propy.

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 -amino-3 -phenyl-propy.

3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 2 -amino-3-pheny1-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-pheny1-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 -alino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -alnino-3-phenyl-propyl 2 -am~ino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -methyl-2 -amino-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 -amino-3 -phenyl propyl 2 -methyl-2 -amino-3 -phenyl propyl 179 3 -chlorophenyl 3 -chloro-4-fluoropheny.

3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2- thiophene a a..

a a.

a 3 th iophenre- 3 -aminophenyl 2- (5-chlo~rothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylpheny.

4-methoxyphenyl 4 -trifluoromethylphenyl 3-i sopropyipheny.

3 -tolyl 3-chic rophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluoropheny.

3 ,4-dichiorophenyl 1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 45 3 -axninopheny.

2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-toly.

3 -tri fluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 2 -methyl-2-amino-3-phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2-me thyl-2 -axnino-3 -phenyl propyl 2 -methyl-2 -arnino-3 -phenylpropyl 2 -methyl-2 -amIino-3 -pheiy]propyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2 -amirio-3 -phenylpropyl 2 -methyl-2 -axnino-3 -phenylpropyl 2 -methyl-2-aznino-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-propy.

2-me thyl-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-propy.

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 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2-me thyl-3 -phenyl-propyl 2m-methyl-3 -phenyl-propyl 2- N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propy.

2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propy.

2- (N,N-dimethylamino) phenyl -propyl 180 3 -isopropyiphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4 -dichlorophenyl 1-naphthyl 3 -fluorophenyl 2 -naphthyl n-buty.

2 -thiophene 3 -thiophene 9* 3 '-aminophenyl 2- (5-chlorothiophene) 2- (N,N-dimethylamino) -3phenyl-propyl 2- N-dimethylamino) -3phenyl.-propyl 2- (N,N-dimethylamino) -3pheny.-propyl 2- (N,N-dimethylamino) -3pheny.-propyl 2- (N 1 N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylaiino) -3phenyl -propyl 2- (NN-dimethylamino) -3phenyl-propyl 2- (NN-dimethylamino) -3phenyl-propyl 2- (NN-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl.-propyl 2- N-dimethylamino) -3phenyl.-propy.

2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N-znethylamino) -3phenyl-propyl 2- (N-Inethylamino) -3phenyl -propyl* 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-rnethylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -pr opyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3pheriyl -propyl 2- CN-rethylamino) -3phenyl -propyl 3, S-dichlorophenyl 4-tolyl 35 3 -trifluoromethylphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl 3 -tolyl 45 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrif luoromethylphenyl 3, 4 -dichloropheny.

4- fluorophenyl 1-naphthyl 181 3- fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene .0 3 -aininophenyl 2- (5-chiorothiophene) 2- (N-methylamino) -3pheriyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl Examnple The compounds in table VI can be prepared using the appropriate starting materials and procedures as described above.

TABLE VI 0O 65O55*

S

R

1 3, 5-dichiorophenyl 4-me thoxyphenyl 3-tolyl- 25 3-chiorophenyl 4 -fluoropheny.

2 -naphthyl n-butyl 2 -thiophene 30 3-thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3 -isopropyiphenyl 3 -tolyl 35 3-chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl R 21 2 -amino- 3-phenyl -propyl 2 CS) -amino- 3-phenyl -propyl 2 -aiino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3 -phenyl-propyl 2 (5)-amino-3-phenyl-propyl 2 -aiino-3-phenyl-propyl 2 -amino- 3-phenyl -propyl 2 -amino- 3-phenyl -propyl 2 -aiino-3-phenyl-propyl 2 amino 3-phenyl -propyl 3-phenyipropyl 3 -phenyipropyl 3-phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropy.

3 -phenyipropyl 3 -phenyipropyl 3-phenylpropyl 182

*.OO

0S 9@

S

0* *5 Sees 0

S.

S

S.

0

S

555

S

5.55..

S

S5 5 S

S.

S

*55000

C

2 -thiophene 3 -thiophene 3 -aminophenyl 2- (S-chlorothiophene) 3, S-dichlorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl 3 -toly.

3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4 -dichlorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (S-chlorothiophene) 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethylphenyl 4-me thoxyphenyl 4- trifluoromethylphenyl 3-i sopropyiphenyl 3 -tolyl 30 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluoropheny.

3, 4 -dichlorophenyl 35 1-naphthyl 3 -fluorophenyl 2 -naphthyl n -butyl 2- thiophene 4G- 3 -thiophene 3 -anhinophenyl 2- (5-chiorothiophene) 3 5-dichlorophenyl 4 -_tolyl 3 -trifluoromethylphenyl 4-me thoxyphenyl 4- tri fluoromethyiphenyl 3 -isopropyiphenyl 3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4 -dichlorophenyl l-naphthyl 3 -fluorophenyl 3 -phenylpropy.

3 -phenylpropy.

3 -phenylpropy.

3 -phenylpropy.

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 -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 -propy.

3-me thyl-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-propy.

3 -aznino-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 -axnino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -alnino-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 -amino-3-phenyl-propyl 2 -amino-3-phenyl..propyl 2 -amino-3-phenyl-propyl 2 -amino-3 -phenyl-propyl 2 -alino-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 pheny propyl 183 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, S-dichlorophenyl 4-tolyl 3 -trifluoromethylphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl 3-tolyl 3 -chloropheiy 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3, 4 -dichlorophenyl 2(R) -axino-3-phenyl-.propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -alino-3-phenyl-propyl 2 -alino-3-pheny-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 2-methyl-2-anino-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 -met-hyl-2-axnino-3 -phenylpropyl 2-methyl-2 -amino-3 -phenylpropyl 2 -me thyl-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 -me thyl-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 -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 -me thyl-3 -phenyl -propyl 2-me thyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2-methyl -3 -phenyl -propyl 1 -naphthyl 3.-f luorophenyl 2-naphthyl n-butyl 2- thiophene 3 -thiophene 3 -alninophenyl -45 2- (S-chlorothiophene) 3, 5-dichiorophenyl 4 -tolyl 3- tri fluoromethylpheny.

4 -methoxyphenyl 4 -trifluoromethylphenyl 3 -isopropylphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 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, S-dichlorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4 -m~thoxyphenyl 4- tri fluoromethyiphenyl 3-is opropyipheny.

3 -tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 30 4-f luorophenyl 3, 4-dichiorophenyl 1-naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2- thiophene 45 3 -thiophene 3 -aininophenyl 2- (5-chiorothiophene) 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethylphenyl

C

C

2-methyl -3 -phenyL-propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl-propy.

2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -pheriyl -propyl 2-methyl -3 -phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (NN-dimethylanino) phenyl -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-dimethylanjno) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (1',N-dimethylainino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3pheanyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl

C

C.

C C

C.

185 4 -methoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl 3-tolyl 3 -chloropheny.

3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylpheny.

3, 4 -dichlorophenyl 4- fluorophenyl 2- (N-methylamino) -3phenyl-propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl-propy.

2- (N-methylamino) -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-methylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2 (N-methylamino) -3 phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2 (N-methylanino) -3 phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-rnethylamino) -3phenyl.-propyl 2- (N-nlethylamino) -3phenyl -propyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2- thiophene 3- thiophene 3 -aminophenyl 2- (5-chiorothiophene) Example 61 The compounds in table VII can be prepared using the appropriate starting materials and procedures as described above.

TABLE VII 3, S-dichlorophenyl 4 -methoxyphenyl 3 -tolyl R 21 2 amino -3 -phenyl -propyl 2 amino -3 -phenyl -propyl 2 amino -3 -phenyl -propyl 186 3 -chiorophenyl 4- fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3- thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3 -isopropylpheny.

3-toly.

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-chlorothiophene) 3, S-dichlorophenyl 4-tolyl 3 -trifuoromethylpheny1 4-me thoxyphenyl 4- tri fluoromethylph-enyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl.

3, S-Ditrifluoromethylphenyl 4 f luorophenyl 3,4 -dichiorophenyl 2naphthyl r.-butyl 2- thiophene 3- thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, 5-didhloropheiy 4 -tolyl 3- tri fluoromethyiphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 3 -isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4 -dichlorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl 2(S) -amino-3-pheny-propyl' 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-phenyl-propyl 2(S) -amino-3-pheny1..propyl 2 -alnino-3-phenyl.propyl 2 -amino-3-phenyl-propyl 2 -axnino-3-pheny...propyl 2(S) -axino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropyj.

3 -phenylpropyj.

3 -phenyipropy].

3 -phenylpropyl 3 -phenyipropyl 3 -phenylpropyl 3 -phenylpropy.

3 -phenylpropyl 3 -phenylpropy.

3 -phenyipropyl 3 -phenylpropy.

3 -phenylpropy.

3 -phenyipropyl 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-propy.

3-me thyl-3 -phenyl-propyl 3-me thyl-3 -phenyl-propyl 3 -methyl-3 -phenyl-propyl 3-me thyl-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-propy.

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 -alino-3-phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -axino-3-phenyl-propyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propyl 187 n-butyl 2- thioph-ene 3- thiophene 3 -aminophenyl 2- (S-chlorothiophene) 4 -tolyl 3- trifluoromethylpheiyl 4 -rethoxyphenyl 4 -trifluoromethylphenyl 3- isopropyiphenyl 3 -tolyl 3- chlorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditr.,fluoromethylphenyl 4- fluorophenyl 3, 4-dichioropheny.

1 -raphthyl 3- fluorophenyl 2-naphthyl n -buty 1 2- thiophene 3- thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4-cri fluoromethyiphenyl 3-i sopropyiphenyl 3 -tolyl 40 3 -chlorophenyl.

3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 3 -amino-3 -phenyl-propyl 3 -amino-3 -phenyl-propy.

3 -axnino-3 -phenyl-propyi 3 -axnino-3 -phenyl-propyl 3 -arnino-3 -phenyl -propyl 2 -amino-3-phenyl-pr-opyl 2 CR) -amino-3-phenyl-propyl 2(R) -amino- 3 -phenyj.-propyl 2(R) -alino- 3 -pheny-propyl 2(R) -amino-3-phenyl..propyl 2(R) -amino-3-phenyl.propyl 2(R) -amino-3-phenyl-propyl 2 -ac-ifo- 3 -phery-propyl 2 -amrino- 3 -phenylpropyl 2(R) -anino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2C(R) amino -3 -phenyl -propyl 2 -alino-3-phenyl-propyl 2(R) -amino-3-phenyl-propyl 2 -alino-3-phenyl-propyl 2 amino 3-phenyl -propyl 2 -amino-3-phenyl-propyl 2 CR) -amino-3-phenyl-propyl 2 -methyl-2 -amino-3 -phenyl propyl 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 -amino-3 -phenyl propyl 2-me thyl-2 -amino-3 -phenyl propyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2 -amino-3 -phenylpropyl 2 -me thyl -2 -amino -3 -phenyl propyl 2 -methyl-2-aiuino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropyl 2 -methyl-2-amjno-3 -phenylpropyl 2 -me thyl -2 amino -3 -phenyl propyl 2 -me thyl -2 amino -3 -phenyl propyl 4- fluorophbnyl 3, 4 -dichlorophenyl 1-naphthyl 3- fluorophenyl 2 -naphthyl 188 n-butyl 2- thiophene 3-thiophene 3 -aininophenyl 2- (5-chlorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3 -isopropyiphenyl- 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluo~rophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4-dichiorophenyl l-naphthyl 3 -fluorophenyl 2-naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3 -trifluoromethylphenyl 4-me thoxyphenyl w 2 -methyl -2 -axino-3 -phenyl propyl 2 -methyl-2 -alnino-3 -phenylpropyl 2 -methyl-2-amino-3 -phenylpropy.

2 -methyl -2 -amino- 3-phenyl propyl 2-me thyl-2 -amino-3 -phenyl propyl 2-methyl -3 -phenyl -propyl 2-methyl -3 -pheriyl -propyl 2-methyl -3 -phenyl -propyl 2 -methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propy.

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 -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 -phe§nyl-propyl 2-methyl-3 -phenyl-propyl 2 -methyl-3 -phenyl-propyl 2- (N,N-dimethylanino) -3phenyl-propyl 2- (N,N-dimethylanino) -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 4- tri fluoromethyiphenyl 3-is opropylphenyl 3 -tolyl 45 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl s0 4-f luorophenyl 3 4 -dichlorophenyl l-naphthyl 189 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5 -chiorothiophene) 3, 5-dichiorophenyl 4 -tolyl 3 -trifluoromethyiphenyl 4-ruethoxyphenyl 4- tri fluoromethyipheny.

3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, 5-Ditrifluoromethylpheny.

3, 4-dichiorophenyl 4- fluorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl 45 n-butyl 2- thiophene_ 3 -thiophene 3 -aminopheny.

2- (5-chlorothiophene) 2- N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl.-propy.

2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylanino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamjno) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -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-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-methylamino) -3phenyl -propyl

C

C. 190 Exaniple 62 Using the corresponding starting materials, the following compounds of Table VIII may be prepared using the procedure for 3 -rnethy1-2-(2(S)-amino-3phenylpropylahino) 3 -trifluoromethylphenyl) (4pyridyl) -4 (3H) -py-rimidinone.

TABLE VIII 0

NCH

3

S

S.

*SS*

S*S

S

S*

S S

S.

S

R

11 3 ,5-dichioropheny.

4-me thoxypheny.

3 -tolyl 3 -chloropheiyl 4-f luorophenyl 2 -xaphth) l n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (S-chlorothiophene) 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 25 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4 -dichlorophenyl 1 -naphthyl 3 -fluoropheny.

2-naphthyl n-butyl 2 -thiophene 3- thiophene 3 -aminopheny.

35 2- (5-chlorothiophene) 3, S-dichloropheny.

4 -tolyl 3- tri fluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3-is opropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl R 21 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 2 -amino-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-pheny1-propyl 2 -axino-3-phenyl-propyl 2 -amino-3-phenyl-propyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropy.

3 -phenyipropyl 3 -phenyipropyl 3 -phenylpropy.

3 -phenyipropyl 3 -phenylpropyl 3 -phenyipropyl 3 -phenyipropyl 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-me thyl-3 -phenyl -propyl 3 -methyl-3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl.

191 a.

a.

*a.a.a a 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4-dichiorophenyl 2 -na phthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichlorophenyl 4 -tolyl 3- trifluoromethyiphenyl 4 -methoxyphenyl 4 -trifluoromethyiphenyl 3 -isopropyiphenyl 3-tolyl 3 -chloropheiyl 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 -aminophenyl 2- (5-chiorothiophene) 3 ,5-dichlorophenyl- 4-tolyl 3- trifluoromethylphenyl 4 -methoxyphenyl 4- tri fluoromethyiphenyl 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 45 n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chiorothiophene) 3, 5-dichiorophenyl 4-tolyl 3- tri fluoromethylphenyl 3-me thyl-3 -phenyl -propyl 3 -methyl-3 -phenyl-propyl 3 -methyl-3 -pheriyl-propyl 3 -methyl-3 -phenyl-propy].

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 -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 -pheny.-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 2 -amino-3-phenyl-propyl 2 -alnino-3-phenyl-propy.

2 -anino-3-phenyl-propyl 2 -alino-3-phenyl-propyl 2 -alnino-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 -axino-3-phenyl-propyl 2 -d.mino-3-pheny1-propyl 2 -amino-3-phenyl-propyj.

2 -ainino-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 -methyl-2-amino-3-phenylpropyl 192 4-me thoxypheny.

4 -trifluoromethyiphenyl 3- isopropylphenyl 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 9 3 -thiophene 2-methyl -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 -phenylpropyl 2-me thyl-2 -axnino-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 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 -phenyl.propy.

2-me thyl-2 -amino-3 -phenyl propyl 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-propy.

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 3 -aminophenyl 2- (5-chlorothiophene) 3, 5-dichlorophenyl 4-tolyl 3 -trifluoromethylphenyl 4 -methoxyphenyl 4- trifluoromethyiphenyl 3 -isopropyiphenyl 3 -tolyl- 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 45 4-f luorophenyl 3, 4-dichiorophenyl 1 -naphthyl 3 -fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- (5-chlorothiophene) 3, S-dichlorophenyl 193 4-tolyl 3- trifluoromethylpheny.

4 -methoxyphenyl 4- trifluoromethylphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluoropheny.

3,S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4-dichiorophenyl 1-naphthyl 3 -fluorophenyl

S

S

S

*SS..S

.5* 2 -naphthyl n-butyl 2 -thiophene 2- N-dimethylamjno) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propy.

2- N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2 N- dime thylamino) -3 phenyl -propyl 2 N- dime thyl amino) -3 phenyl -propyl 2- N-dimethylamino) -3phenyl -propyl 2 N- dime thyl amino) -3 phenyl -propyl 2- (N,N-dimethylamino) -3phenyl -propy].

2 N- dime thyl amino) -3 phenyl-propyl 2- N-dimethylamino) -3phenyl -propyl 2 N-dime thylamino) -3 phenyl -propyl 2 (N-methylamino) -3 phenyJ.-propyl 2 (N-rnethylamino) -3 phenyl -propyl 2 (N-rnethylamino) -3 phenyl -propyl 2 (N-methylamino) -3 phenyl -propyl 2 (N-methylamino) -3 phenyl -propyl 2 (N-me thyl amino) -3 phenyl -propyl 2 (N-methylarnino) -3 phenyl -propyl 2 (N-rnethylamino) -3 phenyl -propyl 2 (N-me thyl amino) -3 phenyl -propyl 3 -thiophene 35 3 -aminophenyl 2- (5-chlorothiophene) 3, S-dichlorophenyl 4 -tolyl 3 -trifluoromethyiphenyl 45 4 -methoxyphenyl 4 -trifluoromethylphenyl S S 9 3 -isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 3, 4-dichloropheny.

4-f luorophenyl 1-naphthyl 3-f luoropheny.

2 -naphthyl n-butyl 2-thiophene 3 -thiophene 194 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl-propy.

2- (N-methylamino) -3phenylpopyl 2- (N-methylanino) -3phenyl-propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propyl 2- (N-methylamino) -3phenyl -propyl 2- (N-methylanino) -3phenyl -propy.

2- (N-rnethylamino) -3phenyl -propyl 2- (N-methylamino) -3pherlyl-propyl 3 -aminophenyl 2- (5-chlorothiophene)

S

S S

S.

.5*

S

Excample 63 Procedure for the preparation of 25 triffluoromethylphenyl)phenyvlmethyvl) amino) -3-me thyZ-5- (4fluorophenyl) (4-pyridyvl) -4 (3H) -pyriznidinone F 0

CF

3 N

NCH

3 SNN

N

Stelp A. 2 -bromoThenvlmethyl) amino)-5-(4f luoroiphenyl) (4-ipyridvl) -3-mrethvl1-4 (3H) -primidinone: The compound, 3-methyl-5- (4-fl]uorophenyl) (4-pyridyl) 2 -thiomethyl-4(3H)-pyrimidinone (470 mg, 1.44 mmol) was dissolved in methanol:water mixture(l.8:l, 40m1 and 22.5m1) Potasssium peroxymonosulfate (OXONE Aldrich Chem Co., 2.5g 4.1 mmrol) 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 dichioromethane and the organic layer was washed with water, dried over Na 2 so 4 and was concentrated. The residue (500mg) and o-

SS

S S

S

195 bromobenzylamine were mixed in 1,4-dioxane (20 ml). The clear solution was heated at 85 0 C 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,

23 HBrFN,O requirs: 465.33 1H-NMR (CDC1 3 8.49 (dd, 2H, pyridyl), 7.67-6.81 12H, Ph and pyridyl), 5.44 (t, 1H, NH), 4.92 (d 2H, CHa-Ph), 3.6 3H, N-CH).

SteD B. 2 3 -trifluoromethvlphenvl)phenvlmethyl) amino)-3-methyl-5-(4-fluorophenyl)-6-( (idyl)-

H)

pyrimidinone: 2 -bromophenylmethyl)amino)-5-(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 20 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 C36H22F4N40 requir. 530.53; 1H-NMR(CDC1):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 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.

196 TABLE IX

R

11 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4-f luorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4 -fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophernyl 20 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 3 -trifluoromethyiphenyl 3- tri fluorome thyiphenyl 25 3 -trifluoromethyiphenyl 3 -trifluoromethylphenyl 3- trifluoromethylpheny.

3 -trifluoromethyiphenyl 3- trifluoromethyiphenyl 30 3 -trifluoromethylphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethylphenyl 3- tri fluoromethyiphenyl 3 -trifluoromethylpheny.

3- trifluoromethyiphenyl 3- trifluorome 'thyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 40 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethylphenyl 3, S-dichlorophenyl 4-tolyl 4-me thoxyphenyl 4- tri fluoromethylpheny.

3 -isopropyiphenyl 3-tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 4- fluorophenyl 3, 4 -dichloropheny.

1 -naphthyl 3-f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- 3, 4-tolyl 3- tri fluoromethyiphenyl 4-me thoxyphenyl 4- tri fluoromethyiphenyl.

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- Example Using the corresponding starting materials, the following compounds of Table X may be prepared using the 197 procedure for 2- (3-trifluoromethylphenyl) phenylmethyl) amino) -3-methyl-5- 4 -f luorophenyl) (4pyridyl) -4 (3H) -pyrimidinone.

TABLE X 0

R

1

NH

NI NN 0 00 0 0 0 *000 0.

R

11 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4-f luorophenyl 4 -fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl- 4 -fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luoropheny.

4-f luorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 4-f luorophenyl 3 -trifluoromethyiphenyl 3- trifluoromethylphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- trifluoromethylphenyl 3 -trifluoromethyiphenyl 3- trifluoromethyiphenyl 3 -trifluoromethylpheny.

3- trifluoromethylpheny.

35 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyilphenyl 3- trifluoromefthyiphenyl 3- trifluoromrethyiphenyl 3 -trifluoromethyiphenyl 3- trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3- trifluoromethyiphenyl 3 -trifluoromethyiphenyl 3 -trifluoromethyiphenyl R 40 3, S-dichlorophenyl 4-tolyl 4-me thoxyphenyl 4- tri fluoromethylpheny.

3-is opropyiphenyl 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 -aminophenyl 2- 3, 4-tolyl 3 -trifluorornethyiphenyl 4-me thoxyphenyl 4- tri fluoromethyiphenyl 3- isopropyiphenyl 3 -tolyl 3 -chiorophenyl 3 -chloro-4 -fluorophenyl 3, S-Ditrifluoromethylphenyl 4-f luorophenyl 3' 4-dichiorophenyl 1 -naphthy.

3- fluorophenyl 2 -naphthyl n-butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- 198 ExaaP1e 66 Using the corresponding starting materials, the following compounds of Table XI may be prepared using the procedure for 2- 3 -trifluoromethylphenyl) phenylmethyl)amino) 3 -methyl-5-(4-fJluorophenyl)6( 4 pyridyl) -4 (3H) -pyrimidinone.

TABLE XI

R

40 if.* if...

if...

if if.

*if.* if~~.if* if if.

Oifif**e if

R

1 1 4 -fluorophenyl 4 -fluorophenyl 4-f luorophenyl 4-f luorophenyl 4- fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4- fluorophenyl 4-f luorophenyl 4-f luorophenyl 20 4 -fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4- fluorophenyl 4- fluorophenyl 4 -fluorophenyl 4- fluorophenyl 4-f luorophenyl 4 -fluorophenyl 3- tri flu-oromethyiphenyl 30 3 -trifluoromethylphenyl 3- tri fluoromethylphenyl 3- trifluoromethylphenyl 3- trifluoromethylphenyl 3- tri fluoromethyiphenyl 35 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3- tri fluoromethylpheny.

3 -trifluoromethyiphenyl 3- tri fluoromethylphenyl 3 -trifluoromethyiphenyl 3- tri fluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3 -trifluoromethylphenyl 3, 4-tolyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3-is opropylphenyl 3-tolyl 3 -chlorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluoromethylphenyl 4 -fluorophenyl 3, 4 -dichlorophenyl l-naphthyl 3 -fluorophenyl 2 -naphthyl n -butyl 2 -thiophene 3 -thiophene 3 -aminophenyl 2- 3, S-dichlorophenyl 4-tolyl 3 -tri fluoromethyiphenyl 4-me thoxyphenyl 4 -trifluoromethylphenyl 3-is opropylphenyl.

3 -tolyl 3 -chiorophenyl 3 -chloro-4-fluorophenyl 3, S-Ditrifluorornethylphenyl 4-f luorophenyl 3, 4 -dichlorophenyl l-naphthyl 3 -f luorophenyl 2 -naphthyl n-butyl 2 -thiophene 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-1-0. The second assay measured the inhibition of TNF-a and/or IL-1-0 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 20 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 Ficolo*elo Paque Plus (Pharmacia). PBMCs were suspended at 2 x 6 /ml in DMEM supplemented to contain 2% FCS, 10 mM, 30 0.3 mg/ml glutamate, 100 U/ml penicillin G and 100 mg/ml *streptomycin sulfate (complete media). Cells were plated into Falcon flat bottom, 96 well culture plates (200 pl/well) and cultured overnight at 37 0 C and 6% CO 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.

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 pM. Stocks were diluted initially to 20 200 pM 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 ip 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 20 Flat bottom, 96 well Corning High Binding

ELISA

plates were coated overnight (4 0 C) with 150 uL/well of 3 g/ml murine anti-human TNF-a MAb (R&D Systems #MAB210).

Wells were then blocked for 1 hr at room temperature with 200 uL/well of CaCl 2 -free ELISA buffer supplemented to contain 20 mg/ml BSA (standard ELISA buffer: 20 mM, 150 mM NaCl, 2 mM CaCl,, 0.15 mM thimerosal, pH 7.4).

Plates were washed and replenished with 100 pl of test supernatants (diluted 1:3) or standards. Standards Sconsisted of eleven 1.5-fold serial dilutions from a stock of 1 ng/ml recombinant human TNF (R&D Systems) *0 Plates were incubated at room temperature for 1 hr on orbital shaker (300 rpm), washed and replenished with 100 pl/well of 0.5 pg/ml goat anti-human TNF-a

(R&D

systems #AB-210-NA) biotinylated at a 4:1 ratio. Plates were incubated for 40 min, washed and replenished with 100 pl/well of alkaline phosphatase-conjugated 201 streptavidin (Jackson ImmunoResearch #016-050-084) at 0.02 pg/ml. Plates were incubated 30 min, washed and replenished with 200 4l/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-10, IL-6 and/or IL-8 o. from monocytes by measuring concentrations of IL-10, IL- 6 and/or IL-8 by methods well known to those skilled in the art. In a similar manner to the above described assay involving the LPS induced release of TNF-a from monocytes, compounds of this invention can also be shown to inhibit LPS induced release of IL-10, IL-6 and/or IL- 8 from monocytes by measuring concentrations of IL-1p, IL-6 and/or IL-8 by methods well known to those skilled S* 25 in the art. Thus, the compounds of the invention may lower elevated levels of TNF-a, IL-1, IL-6, and IL-8 levels. Reducing elevated levels of these inflammatory cytokines to basal levels or below is favorable in controlling, slowing progression, and alleviating many disease states. All of the compounds are useful in the methods of treating disease states in which TNF-a, IL- 1P, IL-6, and IL-8 play a role to the full extent of the definition of TNF-a-mediated diseases described herein.

Inhibition of LPS-Induced TNF-a production in mice 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. Ninetyminutes 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.

0 values of 20 gIm or less: 2-26Dclrbny)5(-furpey)3mty--4 pyridyl) -4 (3H) -pyrimidinone 2- (Butylamino) 4 -fluorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone 2- (Benzylamino) 4 -fluorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone 4 -Fluorophenyl) -3-methyl- (R-l-phenylethyl) amino) pyridyl) -4 (3H) -pyrimidinone 2P 2- (2 (2 -Chlo r ophenyl1) e thyl amino) 5- 4 -fl1uo rophenyl1) -3 methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 4 -Fluorophenyl) -2 2 -hydroxy-2 -phenyl) -ethylamino) 4 -Fluorophenyl) -3-methyl-2- 3 -phenylpropyl) -amino) 6- (4-pyridyl)-4 (3H) -pyrimidinone 4 -F luorophenyl) 3-me thyl -2 (1l-me thyl -3 pherlylpropyl) -amino) (4-pyridyl) -4 (3H) -pyrirnidinone 4 -Fluorophenyl) -3 -methyl-2- (R-l-methyl-3 phenylpropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone 5 4 -Fluorophenyl) 3-methyl -2 2 -phenylaminoethyl) amino) 6- pyridyl) 4(3 H) -pyrimidinone 9. 5- 4 -Fluorophenyl) 3 -imidazolylpropyl) -amino) -3methyl-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 (1H) -pyridone 6 (4 -Methylphenyl) 3-phenyl 4- (4 -pyridyl) 2 (1H) -pyr idone 6- (4-Ethyiphenyl) -3-phenyl-4- (4-pyridyl) -2 (lH) -pyridone 6- 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 203 2- 2 -Amino-3-phenylpropyl) -amino) fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- 2 -Amino-3-phenylpropyl) -amino) (4fluorophenyl) -3-methy.-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 -N-Ethyl-3-phenylpropyl)-amino) fJluorophenyl) -3 -methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- 2 -Amino-2-methy-3-phenylpropyl) amino) fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- 2 -Aminomethy-3-phenylpropyl) -amino) (4fluorophenyl-3-methyl-6-(4-pyridyl) -4 (3H) -pyrimidinone 2- ((3-Aiino-3-phenylpropyl) -amino) luorophenyl) -3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- (2rnethylphenyl)propyl) -amino) (4-pyridyl) -4 (3H) pyrimidinone (4-Fluorophenyl) -3-methyl-2- -2-amino-3- -fluorophenyl) -propyl-amino) (4-pyridyl) -4 (3H) pyrimidinone 2- 2 -Acetamido-3-phenylpropyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 5- (4-Fluorophenyl) 2 -N-isopropylamino-3phenylpropyl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) pyrimidinone 2- 2 -N-n-Butylamino-3-phenylpropyl) -amino) (4- 25 fluorophenyl) -3-methyl-6- (4-pyridyl) -4(3H) -pyrimidinone 2- 2 -NN-Dimethylamino-3-phenylpropyl) -amino) fluorophenyl-3-methyl-6-(4-pyridyl) -4(3H) -pyrimidinone 4 -Fluorophenyl) -3-methyl-2- 2 -methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2 -Amino-3-phenylpropyl)amino)3ethyl5( 4 fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone (4-f luorophenyl) 2 -methy-3-phenylpropyl) ~amino) (4-pyridyl) -4 (3H) -pyrimidinone 2- 3 -trifluoromethylphenyl )phenylmethyl) amino) -3methyl-5-(4-fluorophenyl).6(4-.pyridyl)- 4 3

H)-

pyrimidinone 3-Methyl-2-(2 -amino-3-phenylpropylamino) (4-tolyl) 6- (4-pyridyl)_-4(38) -pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (4trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (3isopropyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -amino-3-phenylpro-pylamino) (3-chioro- 4 -fluorophenyl) 4 -pyridyl) -4(3H) -pyrimidinone 204 3-Methyl-2- -amino-3-phenylpropylamino) bis (trifluoromethyl)phenyl) (4-pyridyl) -4 (3H) pyr imidin one 3-Methyl-2- -amino- 3 -phenylpropylamino) (3,4dichiorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (1naphthyl) (4-pyridyl) -4 3 H)-pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (3fluorophenyl) (4-pyridyl) -4(31) -pyrimidinone 3 -Methyl-2-(2(S)-alino-3-phenylpropylamino)5( 3 trifluoromethyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-methyl-2- (3-phenylpropylaiino) 5-dichiorophenyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (3-phenylpropylamino) (4-tolyl) (4pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (3-phenylpropylamino) (3trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (3-phenylpropylamino) (4-methoxyphenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2-(3-phenylpropylamino)-5-(4.

trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- 2 -methyl-3-phenylpropylamino) (3fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2-zethyl-3-phenylpropylamino) (1- 25 naphthyl)-6-(4-pyridyl)-4(3H)..pyrimidinone 5- (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 5- (4-Fluorophenyl) -2-hydroxyacetamido-3- )phenylprQpyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone (4-Fluorophenyl) -2-pyrrolidinyl-3- *35 phenylpropyl) -amiino) -3-methyl.6- (4-pyridyl) (3H) pyrimidinone 2- ((5)-3-Benzylpiperazinyl) (4-fluorophenyl) -3-methyl- 6- (4-pyridyl) (3H) -pyrimidinone 2 3 -Amino-3-(2-fluorophenyl)propyl)-ino.5(4 fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- ((3-Axnino-3- (2-methylphenyl)propyl) -amino) fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 3 -Amino-3-phenylpropyl)-amino).5(4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- 3 -Amino-3-phenylpropyl) -amino) (4fluorophenyly-3-methyl-6.(4-pyridyl) (3H) -pyrimidinone 205 2- 3 -Amino-3-phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- 3 -trifluoromethylphenyl) (31) -pyrimidinone 2- 3 -Amino--3-phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- 3 -trifluoromethylphenyl) (31) -pyrimidinone 3 -Amino-3-phenylpropyl) -amino) -3-methyl-6-(4pyridyl) 5- 3 -trifluoromethylphenyl) (3H) -pyrimidinone 2- ((3-Aznjno-3- (2-methylphenyl)propyl) -amino) -3-methyl-6- (4-pyridyl) 5- 3 -trifluoromethylphenyl) (3H) pyrimidinone 3 -Amino-3-(2-fluoropheny)propy)amino)3methlG (4-pyridyl) 5- 3 -trifluoromethylphenyl) (3H) pyrimidinone 2- 3 -Amino-3-phenylpropyl) -amino) -3-methyl-5- (3methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 3 -Amino-3-(2-fluoropheny)propy)amino- 3 (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 2- ((3-Amino-3- 2 -chlorophenyl)propyl) -amino) (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 3 -Amino-3-phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- 4-dimethyiphenyl) (3H) -pyrimidinone 2- ((2R,3R) 3 -Amino-2-methyl-3-phenylpropy1)-amino) (4-fluorophenyl) -3-methyl-6- (4-pyridyl) (31)pyrimidinone 2- 3S) 3 -Amino-2-methyl-3-phenylpropyl) -amino) 4 -fluorophenyl)-3-methyl-6-.(4pyridyl)- 4 31 pyrimidinone (4-Fluoropheny)"-2- 3 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyr imi dinone S-(4-Fluorophenyl)-2-( ((R)-3-N-isopropylamino-3 phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) pyr imidinone

S-(

4 -Fluoropheny)-3methy6(4pyridy)- 2 tetrahydroisoqinol..3-ylmethylenamino) (3H) pyrimidinone 3-Methyl-6- (4-pyridyl) -tetrahycfroisoquinol-3ylmethylenamino) 5- 3 -trifluorometiylphenyl) -4-(311)pyrimidinone (3-methyiphenyl) (4-pyridyl) tetrahydroisoquino..3-ylmethyleflamino) (3H) pyrimidinone 4 -methylthiophenyl) (4-pyridyl) tetrahydroisoquino3..ylmethyleflajf 0 (3H) pyrimidinone ((S)-2-Amino-3-phenylpropyl) -amino) -3-methyl-5-(3methyiphenyl) 4 -pyridyl) (3H) -pyrimidinone 206 (4-Fluorophenyl) 3 -hydroxy-3-phenylpropyl) -amino) 3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 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) (31) -pyrimidinone 2- C S) -2-Amino-3- (2-chlorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 -N-Isopropylalnino-3-phenylpropyl) -amino) -3methyl-6- (4-pyridyl) 3 -trifluoromethylphenyl) (3H) pyrimidinone 2-(C 2 -N-Isopropylanino-3-phenylpropyl) -amino) -3methyl-5- (3-methylpheny) (4-pyridy)-4-C 3

H)

pyrimidinone (3-Chlorophenyl-2- C(CS) 2 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 2 -N,N-Dimethylamino-3-phenylpropyl)-amino) -3- (3-methyiphenyl) (4-pyridyl) (3H) pyr imidinone .02- 2 -NN-Dimethylamino-3-phenylpropyl) -amino) -3- (3-chiorophenyl) (4-pyridyl) (3H) pyrimidinone 2- 2 -NN-Dimethylamino-3-phenylpropyl) -amino) -3methyl-6- (4-pyridyl) 3 -trifluorophenyl) (3H) pyrimidinone 4 5- (4-Fluorophenyl) -3-methyl-2- -2-N-methylamino-3- *.0*30 phenyipropyl) -amino) (4-pyridyl) (31) -pyrimidinone.

o The following compounds exhibit activities in the monocyte assay (LPS induced TNF release) with IC.

0 values of 5pgM or less: 2- 6-Dichlorobenzyl) 4 -fluorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone 2- (Benzylamino) 4 -fluorophenyl) -3-methyl-6- (4pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl- (R-1I-phenyl ethyl) amino) (4pyridyl) -4 (3H) -pyrimidinone 2- (2-Chlorophenyl) -ethylamino) (4-f luorophenyl) -3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) (4-f luorophenyl) -ethylamino) -3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 5 (4 -Fluorophenyl) 3 -methyl -2 3 -phenylpropyl) -amino) 6- (4-pyridyl) -4 (3H) -pyrimidinone 207 4 -Fluorophenyl) -3-methyl-2- (-methyl-3phenyipropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-2- ((R-1-methyl-3phenyipropyl) -amino) -6-(4-pyridyl) -4 (3H) -pyrimidinone 5- (4-Fluorophenyl) -3-methyl-2- 2 -phenylaminoethyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone (4-Fluorophenyl) -3-methyl-6- (4-pyridyl) (3- (pyrrolidin-1-yl) -propylamino) -4 (3H) -pyrimidinone 6- (4-Ethyiphenyl) -3-phenyl-4- (4-pyridyl) -2(1H) -pyridone 2 -(((S)-2-Amino-3-phenylpropyl)amino)S5( 4 fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- -2-Amino-3-phenylpropyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2- -2-N-Ethyl-3-phenylpropyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridylY-4 C3H) -pyrimidinone 2- 2 -Amino-2-methy-3-phenylpropyl) amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2-C C 2 -Aminomethy-3-phenylpropyl) -amino) (4fluorophenyl-3-methyl-6-(4-pyridyl) -4 (3H) -pyrimidinone 2-C 3 -Amino-3-phenylpropyl) -amino) 4 -fluorophenyl)-3methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone (4-FJluorophenyl) -3-methyl-2- (2methylphenyl)propyl) -amino) (4-pyridyl) -4 (3H) pyrimidinone

S-(

4 -Fluorophenyl)-3methy1-2-((R,S)-2-amino-3-(2'fluorophenyl) -propyl-amino) (4-pyridyl) -4 (3H) pyrimidinone 2 -Acetamido-3-phenylpropyl) -amino) ±iuorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 3C (14-Fluorophenyl)-2-( 2 -N-isopropylamino-3phenylrrpvir1-amino) -3-methyl-6-(4-pyrdyl) -4 (3H)pyrimidinone 2- 2 -N-n-Butylamino-3-phenylpropyl) -amino) (4fluorophenyl) -3-mnethyl-6- (4-pyridyl) -4 (3H) -pyrimidinone 2 -NN-Dimethylamino..3phenylpropyl)amino)5( 4 fluorophenyl-3-methyl-6-.(4-pyridyl) -4 (3H) -pyrimidinone 4 -Fluorophenyl) -3-methyl-2- 2 -methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2 2-Amino 3-phenylpropyl) amino) 3 -ethyl -5 (4 fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3 -E thyl -5 (4 -f 1luorophenyl) 2- 2 -methy -3 -phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone 2 (2 3 tr if 1uo rome thy lphenyl) phenylme thy 1) amino) -3 (4-f luorophenyl) (4-pyridyl) -4 (3H) pyrimidinone 208 3-Methyl-2- -anino-3-phenylpropylamino) (4-tolyl) 6- (4-pyridyl) -4(3H) -pyrimidinone 3-Methyl-2- -amrino-3-phenylpropylamino) (4trifluoromethylphenyl) 4 -pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2-(2 (5)-amino-3-phenylpropylamino)- 5 isopropyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) (3-chioro- 4-f luorophenyl) (4-pyridyl) -4(3H) -pyrimidinone 3-Methyl-2- -amino-3-phenylpropylamino) bis(trifluoromethyl)phenyl)-6.( 4 -pyridyl)-4(3H)pyrimidinone 3-Methyl-2- -arino-3-phenylpropylamino) (3,4dichiorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -arino-3-phenylpropylamino) (1naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- -alnino-3-phenylpropylamino) (3fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (2 (5)-amino-3-phenylpropylamino) (3trifluoromethylphenyl) 4 -pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- 3 -phenylpropylamino) 5-dichiorophenyl) 6- (4-pyridyl) -4 (3H) -pyrimidinonie 3-Methyl-2- 3 -phenylpropylamino) (4-tolyl) (4pyridyl) -4(38) -pyrimidinone 3 -Methyl-2-(3-phenylpropylamino) (3- 25 trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone 3-Methyl-2- (3-phenylpropylamino) (4-methoxyphenyl) -6- (4-pyridyl) -4(38) -pyrimidinone 3-Methyl-2- (3-phenylpropylamino)-5-(4trifluoromethylphenyl) (4-pyridyl) -4(38) -pyrimidinone 3-Methyl-2- 2 -methyl-3-phenylpropylamino)- 5 3 fluorophenyl) (4-pyridyl) -4(3H) -pyrimidinone 3-Methyl-2- 2 -methyl-3-phenylpropylamino)-5- (1naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone 4 -Fluorophenyl) 2 -N-glycylamino-3- Phenyipropyl) -amino) 3 -methyl-6-(4-pyridyl)4(3).

pyrimidinone 9 2- 2 -N-Glycylamino-.3-phenylpropyl) -amino) -3-methyl- 3 -methylphenyl) (4-pyridyl) (3H) -pyrimidinone 4 -Fluorophenyl) 2 -hydroxyacetamido.3-.

phenyipropyl) -amino) 3 -methyl-6-(4-pyridyl).4. (38)pyrimidinone

S-(

4 -Fluorophenyl)-2-( -2-pyrrolidinyl>..

phenyipropyl) -amino) -3-methy.-6- (4-pyridyl) (38)pyrimidinone (S)-3-Benzylpiperazinyl) -5-(4-fluorophenyl)'-3-methyl- 6- 4 -pyridyl) (3H) -pyrimidinone 209 3 -Amino-3- (2-fluorophenyl)propyl)amino) 4 fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidirione 2- (3-Amino-3- (2-methylphenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2 3-Amino 3-phenylpropyl)-amino).-5 4 fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- -3-Arnino-3-phenylpropyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) OHI) -pyrimidinone 2- 3 -Amino 3-phenylpropyl) -amino) -3-methyl-6- (4pyridyl) 5- (3-trif luoromethylphenyl) (3H) -pyrimidinone 2- R) 3-Amino 3-phenylpropyl) -amino) -3-nethyl6-(4 pyridyl) 5- (3-trif luoromethylphenyl) (3H) -pyrimidinone 2- 3-Amino- 3-phenylpropyl) -amino) -3-methyl-6- (4- -pyridyl) 5- (3-trif luoromethylphenyl) (3H) -pyrimidinone 2- (3-Amino-3- 2 -methylphenyl)propyl) -amino) 3-methy.6- (4-pyridyl) 5- 3 -trif luoromethylphenyl) (3H) pyrimidinone 2-(C(3-Aznino-3- (2-f luorophenyl)propyl) -amino) -3-methyl-6- (4-pyridyl) 5- 3 -trif luoromethylpienyl) (3H) pyrimidinone 2-C( (3 -Amino 3-phenylpropyl) amino) 3-methyl 5- (3 methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 2-C( 3 -Amino- 3 luorophenyl) propyl) aino) (3-methyiphenyl) (4-pyridyl) (3H1) -pyrimidinone 2- 3 -Amino- 3 2 -chlorophenyl)propyl)amino) (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone 2 -3 -Amino 3-phenypropy) amino)3 me thy -6 4 4 -dime thyiphenyl) -4 (3H) -pyrimidinone 2 2-C( (2 R, 3 R) 3-Amino 2-me thyl -3 -phenylpropyl) amino) -5 4 fluorophenyl) 3-me thy 6 -pyr idyl) 3 H) pyr imidinone 27( 2 S, 3 S) 3 -Amino -2 -methyl -3 -phenylpropyl)amino) 4 -fluoropheny1)-3-methyl-6-(4-pyridyl)-4-(3H)pyrimidinone, 5-(4-Fluorophenyl)-2-(

S)-

3 -N-isopropylamino-3phenylpropyl) -amino) 3-me thyl 6- (4 -pyridyl) -4 H) pyrimidinone (4-Fluorophenyl) 3 -N-isopropylamino-3phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone 4 -Fluorophenyl) 3-methyl- 6 pyridyl) -2-C tetrahydroisoquinol -3 ymethyelamino) -4 (3H) pyrimidinone 3-Methyl-6- (4-pyridyl) (CS) -tetrahydroisoquinol-3ylmethylenamino)- 5 (3 -tr if luorome thylphenyl) 4-(3 H) pyrimidinone 210 3 -Methyl-5-(3-methylpheny)-6-(4.pyridyl)- 2 tetrahydroisoquinol-3-ylmethylelajf 0 (3H) pyrimidinone (4-methyithiopheny.) (4-pyridyl) tetrahydroisoquinol13>ymethylelajf 0 (3H) pyrimidinone 2- 2 -Amino-3-phenylpropyl) -amino) -3-methyl-5- (3methyiphenyl) (4-pyridyl) (3H) -pyrimidinone (4-Fluorophenyl) 3 -hydroxy-3-pheny lpropyl) -amino) 3-methyl-6- (4-pyridyl) (3H) -pyrimidinone 2- C C(S) 2 -Amino-3-phenylpropyl) -amino) (4fluorophenyl) (4-pyridyl) C3H) -pyrimidinone 2- -2-Amino-3-

C

2 -fluorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrixnidinone 2 2 -Amino-3-(4-fluorophenyl)propy)amino)5( 4 fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidinone CS) -2-Amino-3-

C

2 -chlorophenyl)propyl) -amino) (4fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) -pyrimidi-none 2-CC CS) 2 -N-Isopropylamino-3-phenylpropyl) -amino) -3methyl-6- (4-pyridyl) 3 -trifluoromethylphenyl) (3H)pyrimidinone 2-C(C(S) -2:N-Isopropylamino-3phenylpropy1) -amino) 3.

~methyl-5- (3-methyiphenyl) (4-pyridyrl) C3H) pyrimidinone S-C3-Chlorophenyl-2-((C(S)-2 -N-isopropylamino-3phenyipropyl) -amino) -3-inethyl-6- (4-pyridyl) C3H) pyrimidinone 2-CCCS) 2 -NN-Dimethylamino-3..phenylpropyl) -amino) -3methyl-5-(3-methylphenyl)6-.(4-pyridyl)-4-(3H)- *30 pyrimidinone 2- 2 -NN-Dimethylamino-3-phenylpropyl) -amino) -3- (3-chiorophenyl) (4-pyridyl) C3H) pyrimidinone 2-C C(S) 2 -NN-Dimethylamino-3-phenylpropyl) -amino) -3rethyl-6-C4-pyridyl) 3 -trifluorophenyl)-4-(3H)- *.pyrimidinone 5- (4-Fluorophenyl) -3-methyl-2-(CC(5) 2 -N-methylaznino-3phenyipropyl) -amino) (4-pyridyl) (3H) -pyrimidinone -Compounds of the invention may be shown to have anti-inflammatory properties in animal models of inflammation, including carageenan paw edema, collagen induced arthritis and adjuvant arthritis, such as the carageenan paw edema model CC. A. Winter et al Proc.

Soc. Exp. Biol. Med. (1962) vol 111, p 544; K. F.

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).

1I-Glucagon Binding Screen with CHO/hGLUR Cells The assay is described in WO 97/16442, which is incorporated herein by reference in its entirety.

Reaaents 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 l 0.1N acetic acid (1 pl yields 1 pM final 20 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 S- 25 990 gl Assay Buffer; '"I-Glucagon (NEN, receptorgrade, 2200 Ci/mmol): dilute to 50,000 cpm/25 pl 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.

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 p1.

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 glucagon binding-in the presence of compounds of Formula I. The reagents are combined as follows: Compound/ 250 AM 125I- CHO/hGLUR Vehicle Glucagon Glucagon Cells Total /5 pl 25 pl 100 Binding 5 p l 25 pl 100 pl Compound Nonspecif /5 p. 1 p. 25 Il 100 p.

"ic Binding The mixture is incubated for 60 min. at 22 0 C on a shaker at 275 rpm. The mixture is filtered over pre-soaked polyethylimine (PEI)) GF/C filtermat using an 20 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 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 370C 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 SHank's Buffered Saline (HBS) at a concentration of 2.5 x 106 cells/mL and plated in 96-well culture plates at a 20 density of 5 x 10' 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 25 enzyme activity determined as described below.

COX-2 Assay For the COX-2 assay, subconfluent HOSC are trypsinized and resuspended at 3 x 10' 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 104 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 18-22 214 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, 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 E 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; 30 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, 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.

20 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 25 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 f 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; 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-10, 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 S. 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 20 arachidonic acid/prostaglandin pathway.

In still another aspect, this invention provides a pharmaceutical composition comprising an effective

TNF-

a, IL-10, 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 a pharmaceutical composition adapted to such a 30 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-10, IL-6, and IL-8 mediated diseases and/or hyperglycemia, the compounds of 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 0: 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 S* invention can be processed in accordance with conventional methods of pharmacy to produce medicinal 25 agents for administration to patients, including humans and other mammals.

oooo• 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 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 20 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 30 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 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 Sencapsulated for conventional administration.

Alternatively, the compounds of this invention may be 20 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 30 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.

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.

S* Compounds of the present invention can possess one or more asymmetric carbon atoms and are thus- capable of 20 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.

SExamples of appropriate acids are tartaric, diacetyltartaric, dibenzoyltartaric, ditoluoyltartaric, and camphorsulfonic acid and then separation of the mixture of diastereoisomers by crystallization followed 30 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 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, 2- :o 20 naphthalenesulfonate, oxalate, palmoate, pectinate, persulfate, 2-phenylpropionate, picrate, pivalate, Spropionate, 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 30 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 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 20 and scope thereof, can make various changes and modifications of the invention to adapt it to various usages and conditions.

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Claims (31)

1. A compound of formula X R 1 R 1 2 W R or a pharmacutically acceptable salt thereof, wherein X is 0, S or NR,; V 0. 1. 0. N -R 3 N R 1 R 2 S/R 4 N NNR 1 N N R4 N R 2 1 N N" U N N N-R 2 1 R21 c L or 21 provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-3; U is NR, 2 or CHR,; and n is an integer of 1-3; R 1 and R 2 are each independently -Y or and R3 and R 4 are each independently provided that R4 is other than a'hydrogen, substituted-aryl, (substituted- aryl)methyl or (substituted-aryl)ethyl radical, and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in each -Y and -Z-Y is 0-3; 224 wherein each Z is independently a alkyl, alkenyl or alkynyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamjno. alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano or halo, and 1-2 radicals of heterocyclyl, aryl or heteroary. optionally substituted by 1-3 radicals of amino, alkylamino, dialkylanino, alkanoylaniino, 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, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroary. radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylaiino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; each Y is independently a hydrogen radical; halo, cyano or nitro 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 (0)-R 2 1 -0-C (0)-NR 5 R 2 1 or -0-C (0)-NR 2 2 S(O) 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 NR22-C(Q)-R 2 1 -S(O)2-NR2 2 -C(o)..oR 2 0 or S02N2-() NR 5 R 21 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR22-C(c,)-0R 2 0 -NR 2 2 NR 5 R 2 1 -NR22-C(NR 5 )-NR 5 R 2 1 -NR22-S(0) 2 -R 2 0 or -R2 S(O)2-NRSR 2 1 radical; 225 wherein each R 5 is independently hydrogen radicals; alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano or halo; or aryl, heteroaryl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, cycloalkyl or cycloalkylalky radicals optionally substituted by 1-3 radicals of amino, alky.amino, dialkylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and wherein each R20 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -C02R 2 3 amino, alkylamino, dialkylamino, alkanoylanino, alkoxycarbonylamino, N-(alkoxycarbonyl)-N-(alkyl)amino, aminocarbonylanino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, cycloalkyl, heterocyclyl, aryl or heteroaryl radicals 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; heterocyclyl radical optionally substituted by'l-3 radicals of amino, alkylanino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substi'tuted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonyamino, alkoxycarbonyl, hydroxy, alkoxy, alkylthio, cyano, halo, azido, alkyl or haloalkyl; 226 each R 21 is independently hydrogen radical or R 2 0 each R 2 2 is independently hydrogen radical; alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylaynino, dialkylanino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydrox-y, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylanino, dialkylanino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and each R 2 3 is independently hydrogen or alkyl, or aryl, heteroaryl, aralkyl or heteroaralkyl optionally substituted by 1-3 radicals of amino, alkylaniino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; and R 1 1 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 radicals of R 3 0 halo or cyano radicals; *.30 -R 3 0 -OR 2 9 -NR 3 lR 32 or -C(NR 3 1 NR 3 1 R 32 radicals; -OR 2 9 -O-C(O)-R 2 9 -O-C(O)-NR 3 lR 3 2 or -O-C(O)-NR33- S(O) 2 -R 3 0 radicals; -SR 2 9 -S(O)-R 3 0 -S(O) 2 -R 3 0 -S(O)2-NR 3 lR 3 2 -S(0)2- NR33-C(O)-R 3 0 -S(O)2-NR 3 3 -C(O)-OR 3 0 or -S(O)2-NR 3 3 NR 3 1 R 3 2 radicals; or 227 -NR 3 1 R 3 2 -NR 3 3 -C(O)-R 2 9 -NR33-C(O)-0R 30 -NR33-C(O)- NR 3 1 R 3 2 -NR33-C(NR 3 1 )-NR 3 lR 3 2 -NR33-S(O) 2 -R 3 0 or -R3 S (0)2-NR 3 1 R 3 2 radicals; provided that R 11 is other than a 4-pyridyl, 4- pyrimidinyl,

4-quinolyl or G-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 1 2 is 0-1; wherein each R 30 is independently alkyl, alkenyl or alkynyl radicals optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 -C0 2 R 2 3 hydroxy, alkoxy, alkylthio, alkylsulfinyl, 1S alkylsulfonyl, cyano, halo or aralkoxy, aralkylthio, aralkylsulfonyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonyl amino, alkylsulfonylamino, hydroxy, 20 alkoxy, alkylthio, alkylsulfinyl, alkylsulfonyl, cyano, halo, alkyl or haloalkyl; heterocyclyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, alkylamino, dialkylanino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylanino, hydroxy, alkoxy, alkylthio, cyano, halo, alkyl or haloalkyl; each R 2 9 is independently hydrogen radical or each R 3 1 and R32 are each independently hydrogen radicals; 228 alkyl radical optionally substituted by an cycloalkyl, aryl, heterocyclyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; or aryl, heteroaryl, heterocyclyl or cycloalkyl radical optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl; and wherein each R 33 is independently hydrogen radical; or alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, alkylamino, dialkylamino, alkanoylamino, alkoxycarbonylamino, alkylsulfonylamino, hydroxy, alkoxy, alkylthio, cyano, alkyl or haloalkyl. 2. The compound of Claim 1 or a pharmaceutically acceptable salt thereof, wherein 4 25 wherein each Z is independently a 1 C 1 -C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radical optionally substituted by 1-3 radicals of amino, C 1 C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, C 1 -C 4 30 alkylsulfonylamino, hydroxy, C 1 -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 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, 229 Cl-C 4 alkoxy, Cj-C 4 alkyithia, 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-(C 1 -C 4 alkyl)amino, Cl-C5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, Cl-C 4 alkyl or Cj- 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, Cj-C5 alkanoylamino, (Cj-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, Cj-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each Y is independently a (1)'hydrogen radical; halo, cyano or nitro 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 -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; -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 NR22-C(O)-R 2 1 -S(O)2-NR 2 2 -C(O)-0R 2 0 or -S(O)2-NR 2 2 NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 l, -NR22-C(O)-0R 2 0 -NR 2 2 NR 5 R 21 -NR22-C(NR 5 )-NR5R 2 l, -R22-S(O) 2 -R 2 0 or -NR22- S(O)2-NR 5 R 2 1 radical; each R 5 is independently hydrogen radicals; Cl-C 8 alkyl, C 2 -C 8 alkenyl. or C 2 -C 8 alkynyl radicals optionally substituted by 1-3 radicals of amino, Cl-C4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, CI-C 4 alkylthio, cyano or halo; or 230 aryl, heteroaryl, aryl-Cl-C4-alkyl, heteroaryl-Cl- C4-alkyl heterocyclyl, heeoyllC-4akl C 3 -C 8 cycloalkyl or C3-C8-cycloalkyl-Cl.C 4 -alkyl radicals optionally substituted byl1-3 radicals of amino, Cl-C 4 alkylamino, di-(C1-C4-alkyl)amino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, Cl-C 4 alkyl or C 1 -C 4 haloalkyl of 1-3 halo radicals; each R 2 0 is independently Cj-C 8 alkyl, C 2 -C 8 alkenyl or C 2 -C 8 alkynyl radicals optionally substituted by 1-3 radicals of -C02R 2 3 amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-c alkanoylamino, (Cl-C 4 alkoxy) carbonylanino, N- ((Cl-C 4 alkoxy)carbonyl) (Ci-C 4 alkyl)amino, axinocarbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo or aryl-cJ1-C4-alkox,c aryl- Cl-C4-alkylthio, aryi-C1-C4-alkylsulfonyl, C 3 -C 8 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, (C-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Ci-C., alkanoyl, (Ci-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, C 1 -C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-3 radicals of amino, Ca.-C4 alkylamino, di- (Cl-C 4 alkyl) aminio, C 1 -C 5 alkanoylainino, (Cl-C 4 930 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, (Ci-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, CI-C 4 alkylthio, cyano, C 1 -C 4 alkyl or CI-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 4 231 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, 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 R22 is independently hydrogen radical;' CI-C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or h~teroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Ci-C4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 a..a:alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; or heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 aklamnCl-C 5 alkanoylamino, (Cl-C4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, Cl-C 4 ailkoxy, Cl-C 4 alkyltnio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 2 3 is independently hydrogen or Cl-C 4 alkyl, or aryl, heteroaryl, -aryl -Cl-C4-alkyl or heteroaryl -Cl-C 4 a alkyl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, C 1 -C 4 alkyl sul fonyl amino, hydroxy, Cl-C 4 -alkoxy, C 1 -C 4 alkylthio, Cl-c 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, cyano, halo, Cl-C4 alkyl or CI-C 4 haloalkyl of 1-3 halo radicals; 232 R 11 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-3 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 2 9 -O-C(O)-R 2 9 -O-C(O)-NR 3 lR 3 2 or 0CONR3 S(O) 2 -R 30 radicals; -SR 29 -S(O)-R 3 0 -S(O)2-R 3 O, -S-(O)2-NR 3 lR 3 2 -S(O) 2 NR3 3 -C (0)-R 3 0 -S (O)2-NR 3 3 -OR 3 0 or -S 2-NR3 3 NR 3 1 R 3 2 radicals; or -NR 3 1 R 3 2 -NR33-C(O)-R 2 9 -NR33-C(O)-0R 3 0 -NR3 3 NR 3 1 R 3 2 -NR33-C(NR 3 1)-NR 3 lR 3 2 -NR33-S(0) 2 -R 3 0 or -NR 3 3 S(0)2-NR 3 lR 3 2 radicals; provided that R 11 is other than a 4-pyridyl, 4- pyrirnidinyl, 4 -quinolyl or G-isoquinolinyl radical :optionally substituted by 1-2 substituents;-and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R 12 is 0-1; 0 each R 30 is independently cl-c 4 alkyl, C 2 -C 4 alkenyl or C 2 -C 4 alkynyl radicals optionally substituted by 1-3 radicals of -NR3 1 R 31 C02R 2 3 hydroxy, C 1 -C 4 alkoxy, Cl-C4-alkylthio, CI-C 4 o: alkylsulfinyl, Cj-C 4 alkylsulfonyl, cyano, halo or aryl- C1-C4-alkoxy, aryl-Cl-C4-alkylthio, aryl-Cl-C 4 o. 0. o alkylsulfony. heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylanino, di-(CI-C 4 alkyl)amino, C 1 -c 5 alkanoylamino, (Cl-C 4 -al1koxy) carbonyl amino, CI-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, 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, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C5 alkanoylamino, (Ct-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, cl-c4 alkoxy, Cl-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, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, Cl-C 4 alkyl sul fonyl.amino, hydroxy, Cl-C 4 alkoxy, Cl-C4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 29 is independently hydrogen radical or R 3 0 each R 31 and R32 are each independently hydrogen radicals; C- 4 alkyl radical optionally substituted by anC- C 8 cycloalkyl, aryl, heterocyclyl or heteroaryl radical *20 optionally substituted by 1-3 radicals of amino, Cl-C 4

9.....alkylamino, di- (Ci-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) c arbonyl.amino, Cl-C 4 alkylsulfonylamino, 9 hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C4 haloalkyl of 1-3 halo radicals; or aryl, heteroaryl, heterocyclyl or C3-C 8 cycloalkyl o: radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, alkanoylamino, (Ct-C 4 alkoxy)carbonylanino, CI-C 4 alkylsulfonylanino, hydroxy, Ci-C4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; and each R 3 3 is independently hydrogen radical; or 234 C1-C 4 alkyl radical optionally substituted by a radical of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Ci-C 4 alkylamino, di-(Ci-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, C 1 -C 4 alkyl or CI- C 4 haloalkyl of 1-3 halo radicals; and wherein heterocyclyl is a radical of a monocyclic or bicyclic saturated heterocyclic ring system having 5-8 ring-members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally partially unsaturated or benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic or bicyclic aromatic heterocyclic ring system having 5-6 ring members per ring, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or 20 saturated C3-C4-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-(C1-C 4 alkyl) amino, C 1 -C 30 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, CI-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or halo and 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, C1-C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, 235 Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or Cl-C 4 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) carbonylamino, C 1 -C 4 alkylsulfonylanino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, C 1 -C 4 alkyl or lC 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, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; each R 5 is independently ()hydrogen radicals; Cl-C 4 alkyl, C 2 -C 5 alkenyl or C 2 -C 5 alkynyl radicals optionally substituted by 1-3 radicals of amino, CI-C 4 alkylamino, di- (Cl-C4-alkyl) amino, hydroxy, Cl-C 4 9. alkoxy, Cl-C 4 alkylthio or halo; or aryl, heteroaryl, ary1-Cl-C 4 -alkyl, heteroaryl-Cl- C4-alkyl, heterocyclyl, heterocyclyl-C 1 C 4 -alkyl, C 3 -C 8 cycloalkyl or C3-C8-cycloalkyl-Cl-C 4 -alkcyl radicals 25 _optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (CI-C4-alkyl) amino, hydroxy, Cl-C 4 alkoxy, Ci-C 4 alkylthio, cyano, Cl-C 4 alkyl or Cl-C 4 9 9 .0 haloalkyl of 1-3 halo radicals; 900909 each R 20 is independently Cj-C 8 alkyl, C 2 -C 5 alkenyl. or C 2 -C 5 alkynyl radicals optionally substituted by 1-3 radicals of -CO 2 R 2 3 amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)anino, Cl-C alkanoylamino, (Cl-C 4 al1koxy) c arbonyl amino, Cc-C 4 alkoxy) carbonyl) (Cl-C 4 alkyl) amino, 236 aminoc arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, Cl-C 4 alkylsulfinyl, CI-C 4 alkylsulfonyj., halo or aryl-Cl-C4-alkoxy, aryl-Cl-C 4 alkylthio, aryl-C1-C4-alkylsulfonyl, C 3 -C 8 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, CI-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfony.amino, Cj-C alkanoyl, (C 1 -C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, cyano, halo, Cl-C 4 alkyl or lC haloalkyl of 1-3 halo radicals; heterocyclyl- radical optionally substituted by 1-3 radicals of amino, C.I-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Ci-C 4 alkoxy) carbonylamino, -C 1 -C 4 alkylsulfonylamino, (Ci-C 4 alkoxy)car!Donyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, :C 1 -C 4 alkyl or C1.-C 4 haloalkyl. of 1-3 halo radicals; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) c arbonyl.amnino, C 1 -C 4 alkylsulfonylamino, (Ci-C 4 alkoxy)carbonyl, hydroxy, Cl-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 CI-C 4 alkyl radical optionally substituted by 1-3 radicals of -NR 3 1 R 3 1 Cl-C 4 alkoxy-carbonyl or phenoxcycarbony. or phenylmethoxycarbonyl optionally substituted by 1-3 radicals of amino, alkylamino, di- (Cl-C4-alkyl) amino, 237 Cl-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, CI-C 4 alkyl or trifluoromethyl; or hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, or phenlyl-Cl- C4-alkoxy, phenyl.-Ci-C 4 -alkylthio, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-.C 4 alkylanino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylanino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or CI-C 4 haloalkyl of 1-3 halo radicals; Cl-C 4 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylanino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 ~.:alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; each R 29 is independently hydrogen radical or R3 0 each R 31 is independently hydrogen radicals; or Cl-C4_ alkyl radical optionally substituted by an phenyl 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 a~aalkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, Cl-C 4 alkyl or trifluoromethyl radicals; and each R 3 2 is independently hydrogen radicals; 238 cl-c 4 alkyl radical optionally substituted by an C 3 C 6 cycloalkyl, aryl, heterocycly. 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-, (C 1 -C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1 -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, Cl-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, Cl-C alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, CI-C 4 alkyl or Cl-C 4 haloalkyl of 1-3 halo radicals; and each R 33 is independently hydrogen or Cl-C 4 alkyl radical. 204 h o p u d o l i r a p a m c u i a l too** .9 ac e t b e sl9t e ef h r i R, 259 accetabl sal tReof wrien htteomie oa radisal 0 n or S;-3 239 Z is a cl-c 8 alkyl or C 2 -C 8 alkenyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkox'y, 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)anino, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1 -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, (Ct-C 4 al koxy) 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)carbonylamino, Cl-C 4 alkylsulfonylamino, hydroxy, C CCl-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; halo radical; -C(O)-R 2 0 -C(O)-0R 2 1 -C(O)-NR 5 R 2 1 or -C(NR 5 )-NR 5 R 2 1 radical; -OR 2 1 -O-C(O)-R 2 1 or -O-C(O)-NR 5 R 2 1 radical; 530 -SR 2 1 -S(O)-R 2 0 -S(O) 2 -R 2 0 or -S(O)2-NR 5 R 2 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR22-C(O)-0R 2 0 -NR 2 2-C(O)- NR 5 R 2 1 -NR22-C(NR 5 )-NR 5 R 2 1, -NR22-S(O) 2 -R 2 0 or -NR22- S 2NR 5 R 2 1 radical; 240 each R 5 is independently (1),hydrogen radicals; cl-c 4 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, or halo; or phenyl-Cl-C 2 -alkyl, heteroaryl-Cl-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3C-ylaky-lC-ly radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C4-alkyl) amino, hydroxy, C 1 -C 4 alkoxy, Cj- C 4 alkylthio, cyano, Ci-C 4 alkyl or Cl-C 2 haloalkyl of 1- 3 halo radicals; each R2 0 is independently Cj-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, Cl-C 5 alkanoylamino, (Cl -C 4 alkoxy) carbonylamino, N- (Cl -C 4 alkoxy) carbonyl) N- (Cl-C 4 alkyl)amino, aininocarbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-CI-C 4 alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3rdcl faio Cl-C 4 alkylamino, 'di- (Cl-C4 1 -alkyl) amino, Cl-c 5 alkanoylanino., (Cl-C 4 alkoxy)carbonylamino, CI-C 4 alkylsulfonylamino, Cl-C alkanoyl, (Cl-C 4 a.lkoxy)carbonyl, hydroxy, C 1 -c 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or Cl-C 2 o 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, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, or Cl-C 4 alkyl; or 241 aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, (Cl-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 R21. is independently hydrogen radical or R 2 0 each R 22 is independently hydrogen radical; or C 1 -c 4 alkyl radical optionally substituted by a radical of phenyl or heteroaryl optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino, Cl-C alkanoylanino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cj- C 4 alkoxy, Cl-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 hydrogen or Cl-C 4 alkyl, or phenyl, heteroaryl, phenyl-Ci-C 2 -alkyl or heteroaryl-Cl- C2-alkyl optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)amino, Cl-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; R 2 is a radical of hydrogen, Cl-C 4 alkyl, halo, cyano, *.*hydroxy, Cl-C 4 alkoxy, Cl-C 2 haloalkoxy of 1-3 halo radicals, Cl-C 4 alkylthio, amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino or Cl-C 2 haloalkyl of 1-3 halo radicals; R 3 is a hydrogen radical or 242 cl-c 8 alkyl or C 2 -C 8 alkenyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, C 1 -C 4 alkyl sul fonyl amino, hydroxy, Cl-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 l.-3 radicals of amino, Cl-C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, C 1 -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 and R 12 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; -C(O)-R 3 0 -C(O)-0R 2 9 -C(O)-NR 3 lR 3 2 or -C(NR 3 1 NR 31 R 3 2 radicals; or -0R 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 -NR33-C(O)-R 2 9 or -NR33-C(O)-0R 3 0 radicals; provided that R 1 1 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinoly. or E-isoquinolinyl radical .optionally substituted by 1-2 substituents; and the total num~ber of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 1 2 is 0-1;- each R 30 is independently Cl-C 4 alkyl radical optionally substituted by 243 amino, Cl-C 4 alkylamino, or di-(C1-C4-alkyl)aino radicals; or hydroxy, C 1 -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, C 1 -C 5 alkanoylanino, (Cl-C 4 alkoxy)carbonylarnino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoronethy. radicals; C 1 -C 2 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amhino, Cl-C 4 alikylainino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, CI-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; each R 2 9 is independently hydrogen radical or R 3 0 each R 31 is independently hydrogen or Cl-C 4 alkyl radicals; and each R3 2 is independently hydrogen radicals; Cl-C 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cj-C 5 alkanoylainino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, CI-C 4 alkoxy, Cl-C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)anino, Cl-c 5 alkanoylainino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyl or trifluoromethyl radicals; and 244 each R 33 is independently hydrogen or methyl radical; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms. which is optionally benzo-fused or saturated C3-C4-carbocyclic-fused. 5. The compound of Claim 4 or a pharmaceutically acceptable salt thereof, wherein Z is a C1-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 25 alkoxy)carbonylamino, hydroxy, C 1 -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, Ci-C 4 alkylamino, di-(C 1 -C 2 alkyl)amino, C 1 -C 5 alkanoylamino, (C1-C 4 alkoxy)carbonylamino, hydroxy, Ci-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C1-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C 1 -C 2 alkyl)amino, (C1-C 4 alkoxy)carbonylamino, hydroxy, Ci-C 2 alkoxy, Ci-C 2 alkylthio or Ci-C 4 alkyl radicals; or 245 aryl or heteroaryl. radical optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl)amino, C 1 -C alkanoylanino, (Ci-C 4 alkoxy)carbonylamino, hydroxy, cj- C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 5 is independently hydrogen radical; cl-c 4 alkyl radical optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio or halo; or phenyl-Cj-C2-alkyl, heteroaryl-Ci-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C 3-C6-cycloalkyl-Cl-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, CI-C 2 alkoxy, Cj- C 2 alkylthio, methoxy, methylthio, cyano, Cl-C 4 al kyl or trifluorornethyl radicals; each R 2 2 is independently hydrogen or Cl-C 4 alkyl radical; each R 2 3 is independently hydrogen or Cl-C 4 alkyl, or phenyl, heteroaryl, phenyl-C1-C2-alkyl or heteroaryl-Cl- C2-alkyl optionally substituted by 1-3 radicals of -amino, di-(Cl-C 2 alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl. *radicals; R 3 is a hydrogen radical or Cj-C 8 alkyl radical optionally substituted by 1-2 radicals of amino, CI-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 4 246 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 4 alkoxy, C 1 -C 4 alkylthio, cyano, 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 substituted by 1-2 radicals of R 3 0 halo or cyano radicals; -C(O)-R 3 0 -C(O)-OR 29 -C -NR 3 1 R 3 2 or -C(NR31 NR 3 1 R 3 2 radicals; or -OR 2 9 -SR 2 9 -S(O)-R 3 0 -S(0)2-R 3 0 -S(0)2-NR31R 3 2 -NR3 1 R 3 2 or -NR 3 3 -C(0)-R 29 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each 20 of R 11 and R 12 is 0-1; each R 30 is independently C1-C 4 alkyl radical optionally substituted by a 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, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted 30 by 1-3 radicals of amino, di-(Ci-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 2 9 is independently hydrogen radical or R 3 0 and each R 32 is independently 247 hydrogen radicals; Ci-C 4 alkyl radical or C 1 -C 2 alkyl radical substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, Ci-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 heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused. 6. The compound of Claim 5 or a pharmaceutically acceptable salt thereof, wherein wherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in RI 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, C1-C 2 alkoxy, C 1 -C 2 alkylthio or halo and 1-2 radicals of aryl or heteroaryl optionally substituted by 1-2 248 radicals of amino, di-(Cl-C 2 alkyl)amjno, acetamido, (Cl-C 4 alkoxy) carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, CI-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-C 4 alkoxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; Y is a hydrogen radical; -C(O)-R 2 0 -C(O)-0R 2 1 or -C(O)-NR 5 R 2 1 radical; -OR 2 1 -SR 21 -S(O)-R 20 -S(O)2-R 2 0 or -S(O)2-NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR22-C(O)-0R 2 0 -NR2 2 -C (0) NR 5 R 2 1 -NR22-S(O) 2 -R 2 o or -NR22-S(O) 2 -NR 5 R 2 1 radical; each R 5 is independently hydrogen radical; Cl-C 4 alkyl radical optionally substituted by 1-3 halo radicals; or phenyl-Cl-C 2 -alkyl or heteroaryl-Cl-C 2 -alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, ethyl or trifluoromethyl radicals; each R 2 0 is independently C 1 -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, Cl-C 5 alkanoylamino, (Cl-C 4 al koxy) carbonyl amino, 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-C4-alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3 -C 6 cycloalkyl, 249 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Ci-C4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, C 1 -C 4 alkylsulfonylamino, C 1 -C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 *alkoxy, Cl-C 4 alkylthio, cyario, halo, Cl-C 4 alkyl or lC haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(C--C 4 alkyl)anino, (Cl-C 4 alkoxy)carbonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, CI-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 alkyl)amino, acetamido, (CI-C 4 a lkoxy) carbonyl amino, C 1 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 trifluoromethyl radicals; each R 2 1 is independently hydrogen radical or each R 2 3 is independently hydrogen or C 1 -C 4 alkyl, or phenyl-Cl-C 2 -alkyl or heteroaryl-Cl-C 2 -alkyl optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl) amino, acetamido, (Cl-C 4 alkoxy) carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1 C 4 alkyl or trifluoromethyl radicals; R2 is a radical of hydrogen, Cl-C 4 alkyl, halo, cyano, a:...:hydroxy, Cl-C 4 alkoxy, trifluoromethoxy or trifluoromethyl; R3 is a hydrogen rad ical or 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, Cl-C 4 alkoxy or aryl or heteroaryl optionally substituted by 1-3 250 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; 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 30 halo or cyano radicals; or -C(O)-NR 3 1 R 32 -OR 2 9 -SR 2 9 -S(0)-R 3 0 -S(0) 2 -R 3 0 S(0)2-NR 31 R 32 -NR 3 1 R 3 2 or -NR33-C(0)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; 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; each R 2 9 is independently hydrogen radical or R 3 0 30 each R 3 1 is independently hydrogen, methyl or ethyl radicals; and each R 3 2 is independently hydrogen radicals; C1-C 4 alkyl radical or C 1 -C 2 alkyl radical substituted by phenyl or heteroaryl radical optionally 251 substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals. 7. The compound of Claim 6 or a pharmaceutically acceptable salt thereof, wherein R3 is a radical of hydrogen or Ci-C 4 alkyl; R 11 is an aryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; or -C(O)-NR 31 R 32 -OR29, -SR 2 9 -S(O)-R 3 0, -S(0)2-R 30 S S(0)2-NR 3 1R 3 2, -NR3 1 R 3 2 or -NR3 3 -C(0)-R 2 9 radicals; and R 1 2 is a heteroaryl radical optionally substituted by 1- 2 radicals of R 3 0 halo or cyano radicals; or -C(0)-NR 31 R 32 -OR 2 9 -SR 2 9 -NR 31 R 32 or -NR3 3 R29 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R12 is 0-1; is independently Ci-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; 252 trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; R 29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and R 32 is independently hydrogen or Ci-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. S" 8. The compound of Claim 7 or a pharmaceutically 20 acceptable salt thereof, wherein Swherein R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl o radicals in R 1 is 0-1; Z is a C 1 -C 4 alkyl radical optionally substituted by 1-2 radicals of amino, di-(Ci-C 2 alkyl)amino, (C1-C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 2 alkoxy, Ci-C 2 alkylthio, halo, or aryl or heteroaryl optionally 30 substituted by 1-2 radicals of hydroxy, CI-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, Ci-C 4 alkyl or trifluoromethyl radicals; each R 5 is independently hydrogen or C 1 -C 4 alkyl radical; 253 each R 2 0 is independently cl-c 8 alkyl radicals optionally substituted by 1-3 radicals of -C02R2 3 amino, Cl-C 4 alkylamino, di- (CI-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (Ci-C 4 al1koxy) c arbonyl amino, N- ((Cl-C 4 alkoxy) carbonyl) (Cl- C 4 alkyl)amino, aminocarbonyl amino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, halo or C 3 -C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 2 radicals of amino, di-(Cl-C 4 alkyl)amino, Cl-C alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, Cl-C 4 alkyl sul fonyl amino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 *:alkoxy, C 1 -C 4 alkylthio or Cl-C 4 alkyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of (Ci-C 4 alkoxy)carbonyl, amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or each R23 is independently hydrogen or Cl-C 4 alkyl, or phenyl-Cl-C 2 -alkyl optionally substituted by 1-2 radicals of hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; R 2 is a hydrogen radical; R3 is a hydrogen, methyl or ethyl radical; 254 R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylanino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, mnethylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, aceta-mido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. 9. The compound of Claim 8 or a pharmaceutically acceptable salt thereof, wherein Z is Cl-C 4 alkyl radical optionally substituted by 1-2 radicals of amino, t-butoxycarbonylamino, dimethylamino, 'eR~e:hydroxy, methoxy, methylthio or halo radicals; Y is a hydrogen radical; e(2) -C (0)-R 2 0 -C -R 2 1 or -C (0)-NR 5 R 2 1 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 -NR22-C(O)-R 2 1 or -NR22-S(O) 2 -R 2 o radical; C R 5 is a hydrogen radical; each R 20 is independently CIC6aly radicals opinal substituted b radicals of -t:02R2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, (t-butoxy)carbonyl)N- (methyl) amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C5-C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 255 1-2 radicals of amino, 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 radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R2.1 is independently hydrogen radical or R 20 each R 22 is independently hydrogen or methyl radical; each R 2 3 is independently hydrogen or C 1 -C 4 alkyl radicals; R 11 is an unsubstituted phenyl or naphthyl radical or a 20 phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R 12 is a 4-pyridyl, 4-quinolinyl, 4-imidazolyl or 4- pyrimidinyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. The compound of Claim 9 or a pharmaceutically acceptable salt thereof, wherein Y is a -C(O)-R 2 0 or -C(0)-NR 5 R 2 1 radical; -OR 2 1 -SR21, -S(0)-R2 0 -S(0) 2 -R 2 0 or -S(0) 2 -NR5R21 radical; or 256 -NR 5 R 2 1 -NR22-C(O)-R 2 1 or -NR2 2 -S(0) 2 -R 2 0 radical; each R 2 0 is independently CI-C 6 alkyl radicals optionally substituted by 1-3 radicals of -CO 2 R 23 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, methylsulfonyl, halo or C 5 -C 6 cycloalkyl, heterocyclyl phenyl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by t- butoxycarbonyl; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; and Seach R 2 1 is independently hydrogen radical or

11. The compound of Claim 10 or a pharmaceutically 25 acceptable salt thereof, wherein Y is a -OR 21 -SR 2 1 or -NR 5 R 2 1 radical; each R 2 0 is independently Cl-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 257 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 11 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; and R 1 2 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. 20 12. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein e.e X is O or S; N /R4 jN V N 41K v N R N is NI W R N RI or R 4 provided that the combined total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in -VC(R)W- is 0-2; wherein R1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-3; Z is a 2.58 cl-c 8 alkyl or C 2 -C 8 alkenyl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di- (Cl-C 4 alkyl)anino, Cl-C 5 alkanoylamino, (Ci.-C 4 al koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, halo, or heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)anino, Cj-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, hydroxy, CI-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, d&i-(Cl-C 4 alkyl~amino, (Cl-C 4 a lkoxy) c arbonyl 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-j radicals of amino, Cl-C 4 alkylainino, di-(Cl-C 4 alkyl)amino, Cl-C 5 -alkanoylanino, (C1--C 4 alkoxy) carbonylainino, Cl-C 4 alkylsulfonylamino, 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; halo radical; -C (0)-R 2 0 -C -R 2 1 -C (0)-NR 5 R 2 1 or -C (NR5) -NR 5 R 2 1 radical; -OR 2 1 -0-C (0)-R 2 1 or -0-C -N 5 R 2 1 radical; -SR 2 1 -S(O)-R 2 0 -S(O) 2 -R 2 0 or -S(O)2-NR 5 R 2 l1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 -NR22-C(O)--R 2 0 -NR 2 2 .0 NR 5 R 2 1 -NR22-C(NR 5 )-NR5R 2 1 -NR22-S(0) 2 -R 2 0 or -NR 2 2 S(O)2-NR 5 R 2 1 radical; each R 5 is independently hydrogen radicals; 259 C 1 -C 4 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)amino, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio or halo; or phenyl-Cl-C 2 -alkyl, heteroaryl-Ci-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-C6-cycloalkyl-Cl-C 2 -alkyl radicals optionally substituted by 1-3 radicals of amino, di- (Ci-C4-alkyl) amino, hydroxy, Cl-C 4 aI-koxy, C 1 C 4 alkylthio, cyano, Cl-C 4 alkyl or C 1 -C 2 haloalkyl of 1- 3 halo radicals; each R 2 0 is independently C 1 -C 8 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals Of -CO 2 R 23 amino, Cl-C 4 alkylamino, di- (Cl-Ca alkyl) amino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, (Cl-C 4 alkoxy) carbonyl) 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 or aryl-Cl-C4-alkoxy, aryl-Cl-C 4 alkylthio, aryl-Cl-C4-aikylsulfonyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, Cl-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, CI-C 4 alkylamino, di-(Cl-C 4 alkyl) amino, Cj-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 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 4 260 alkoxy) carbonylamino, Cl-C 4 alkylsulfonylamino, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or CI.-C 2 haloalkyl of 1- 3 halo radicals; each R 2 1 is independently hydrogen radical or each R 2 2 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, di- (C1-C2 -alkyl) amino, Cl-C alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cj- C 4 alkoxy, Cl-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 hydrogen or Cl-C 4 alkyl, or phenyl, heteroaryl, -phenyl-Cl-C 2 -alkil or heteroaryl-Cl- C2-alkyl optionally substituted by 1-3 radicals of amino, di-(Cl-C 4 alkyl)amn, 1 C alkanoylamino, 1 C 1. akoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or Cl-C 2 haloalkyl of 1-3 halo radicals; R 4 is Cl- 8 aklo 2 C alkenyl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylarnino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Ci-C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or halo, and (b) 1-2 radicals of heterocyclyl, aryl or heteroaryl optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylainino, di-(Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) c arbonyl amino, Cl-C 4 alkylsulfonylamino, 261 hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, halo, C 1 -C 4 alkyl, trifluoromethoxy or trifluoroinethyl radicals; or heteroaryl 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) carbonyl amino, Cl-C 4 alkylsulfonylamino, hydroxy, C 1 -C 4 alkoxy, Cl-c 4 alkylthio, cyano, halo, C 1 -C 4 alkyl, trifluoromethoxy or trifluoromethyl radicals; R 11 and R 1 2 are each independently an aryl or heteroaryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; -C(O)-0R 2 9 -C(O)-NR 3 lR 3 2 or -C(NR 3 1 NR3 1 R 32 radicals; 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 -NR33-C(O)-R 2 9 or -NR33-C(O)-0R 3 0 radicals; provided that R 11 is other than a 4-pyridyl, 4- pyrimidiiyl, 4-quinolyl or G-isoquinolinyl radical optionally substituted by 1-2 substituents; and the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 1 1 and R1 2 is 0-1; each R 30 is independently (1).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- (Ci-C 4 alkyl) amino, Cl-C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trif luoronethyl radicals; 262 C1-C 2 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-(Ci-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 2 9 is independently hydrogen radical or R 30 each R 3 1 is independently hydrogen or C 1 -C 4 alkyl radicals; and each R 3 2 is independently hydrogen radicals; C 1 -C4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C4 alkylamino, di-(C 1 -C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (C 1 -C 4 20 alkoxy)carbonylamino, hydroxy, Ci-C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; and each R 33 is independently hydrogen or methyl radical; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring S* members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and 263 heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or saturated C3-C4-carbocyclic-fused.

13. The compound of Claim 12 or a pharmaceutically acceptable salt thereof, wherein Z is a C1-C 4 alkyl or CZ-C 5 alkenyl radical optionally substituted by 1-3 radicals of amino, di-(C 1 -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, 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, C1-C5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 20 alkylthio, cyano, 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 -C4 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, CI-Cs alkanoylamino, (C1-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 hydrogen radical; C 1 -C 4 alkyl radical optionally substituted by 1-3 radicals of amino, di- (C-C2-alkyl)amino, hydroxy, Ci-C 2 alkoxy, C 1 -C 2 alkylthio or halo; or 264 phenyl-C 1 -C 2 -alkyl, heteroaryl-Ci-C 2 -alkyl, heterocyclyl-Cl-C 2 -alkyl or C3-C6-cycloalky-Cl-C 2 .alkyl radicals optionally substituted by 1-3 radicals of amino, di- (Cl-C2-alkyl) amino, hydroxy, Cl-C 2 alkoxy, C 1 C 2 alkylthio, methoxy, methyithic, cyano, C 1 -C 4 alkyl or trifluoromethyl radicals; each R2 2 is independently hydrogen or Cl-C 4 alkyl radical; each R2 3 is independently hydrogen Or Cl-C 4 alkyl, or phenyl, heteroaryl, phenyl-Ci-C 2 -alkyl or heteroaryl-Cl- C2-alkyl optionally substituted by 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, Cj-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; R 4 is 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, 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 trifluoromethy. radicals; or heteroaryl radical optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di-(Cl-C 4 alkyl)amino, CI-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, cl-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 265 R 30 halo or cyano radicals; -C(O)-R 3 0, -C(O)-OR 2 9 -C(O)-NR 3 1 R 32 or -C(NR 3 1 NR31R 3 2 radicals; or -OR 2 9 -SR 2 9 -S(0)-R 3 0 -S(0)2-R 30 -S(0)2-NR 31 R 32 -NR 3 1 R 3 2 or -NR33-C(O)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R 30 is independently .C-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, CI-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; each R 29 is independently hydrogen radical or R 30 and each R 3 2 is independently hydrogen radicals; C1-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-(C1-C 2 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, C 1 -C4 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, Ci-C 2 alkoxy, C 1 -C 4 alkyl or trifluoromethyl radicals; and 266 wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused.

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 C2-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, C 1 -C 2 alkoxy, Ci-C 2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of amino, di-(C 1 C2 alkyl)amino, acetamido, (Ci-C 4 alkoxy)carbonylamino, hydroxy, Ci-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1 C 4 alkyl or trifluoromethyl radicals; or aryl or heteroaryl radical optionally substituted by 30 1-3 radicals of amino, di-(C 1 -C 2 alkyl)amino, acetamido, (C1-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; Y is a hydrogen radical; 267 -C (0)-R 2 0 -C -R 2 1 or -C (0)-NR 5 R 2 1 radical; -OR21, -SR21, -S(O)-R 2 0 -S(O) 2 -R 2 0 or -S(O)2-NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(OV-R 2 l, -NR2 2 -C(O)-OR 2 0, -NR22-C(O)- NR5R 2 1 -NR2 2 -S(O) 2 -R 2 O or -NR22-S(O) 2 -NR 5 R 2 1 radical; each R 5 is independently hydrogen radical; cl-c 4 alkyl radical optionally substituted by 1-3 halo radicals; or phenyl-Cl-C2-alkyl or heteroaryl-Cl-C 2 -alkyl, radicals optionally substituted by 1-3 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, methyl or &Eifluoromethyl radicals; each R20 is independently Cl-C 8 alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of -CO 2 R 2 3 amino,' C 1 -C 4 alkylamino, di-(Cl-C 4 alkyl)anino, Cj-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonfyl amino, N-((Cl-C 4 alkoxy)carbonyl)- N- (C 1 -C 4 alkyl)amino, aminocarbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, Cl-c 4 alkylsulfinyl, Cl-C 4 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, aryl-Cl-C4- alkylthio, aryl-Cl-C4-alkylsulfonyl, C 3 -C 6 cycloalkyl, 0: 25 heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (C 1 -c 4 alkyl)auino, Cl-C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonyl amino, Cl-C 4 alkylsulfonylamino, C1i-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, di-(Cl-C 4 alkyl) amino, (Cl-C 4 alkoxy) carbonylamino, (Cl-C 4 alkoxy) carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio or Cl-C 4 alkyl; or 268 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, acetamido, (Ci-C 4 alkoxy)carbonylamino, C 1 C 4 alkylsulfonylamino, (C 1 -C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; each R21 is independently hydrogen radical or R 20 each R 23 is independently hydrogen or C 1 -C 4 alkyl, or phenyl-Ci-C2-alkyl or heteroaryl-C1-C2-alkyl optionally substituted by 1-3 radicals of amino, di-(Ci-C2 alkyl)amino, acetamido, (Ci-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 4 is a C 1 -C 8 alkyl radical optionally substituted by 1- 2 radicals of amino, C 1 -C 4 alkylamino, di-(Ci-C 4 alkyl)amino, hydroxy, Ci-C 4 alkoxy or aryl or heteroaryl 20 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, halo, C1-C 4 alkyl, trifluoromethoxy or *o 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 radicals; or -C(O)-NR 31 R 3 2 -OR 2 9 -SR2 9 -S(0)-R 30 -S(0) 2 -R 3 0 S(0)2-NR 31 R 32 -NR 3 1 R 3 2 or -NR33-C(0)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; 269 each R 30 is independently C1-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; each R2 9 is independently hydrogen radical or each R 31 is independently hydrogen, methyl or ethyl radicals; and each R 32 is independently hydrogen radicals; 20 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, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals. 30 15. The compound of Claim 14 or a pharmaceutically acceptable salt thereof, wherein R 4 is a C 1 -C 4 alkyl radical; R11 is an aryl radical optionally substituted by 1-2 radicals of 270 R3 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 1R 32 -NR 3 1 R 3 2 or -NR33-C(O)-R 29 radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of R 3 0 halo or cyano radicals; or -C(O)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -NR 3 1 R 3 2 or -NR33-C(O)- R 29 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; R 3 0- is independently C1-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, 20 hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; trifluoromethyl radical; or oo.o aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; R 2 9 is an aryl or heteroaryl radicals optionally 000* substituted by 1-2 radicals of amino, dimethylamino, 30 acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and C R 32 is independently hydrogen or C 1 -C 4 alkyl radical; or 271 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 R 1 is -Y or provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals in R 1 is 0-1; 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, C 1 -C 2 alkoxy, CI-C 2 alkylthio, halo, or aryl or heteroaryl optionally substituted by 1-2 radicals of hydroxy, C 1 -C 2 alkoxy, C-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 5 is independently hydrogen or C 1 -C 4 alkyl radical; each R 2 0 is independently 25 CI-C 8 alkyl radicals optionally substituted by 1-3 radicals of -C02R 2 3 amino, Ci-C 4 alkylamino, di-(Ci-C 4 alkyl)amino, CI-C 5 alkanoylamino, (Cl-C 4 oo*eo alkoxy) carbonylamino, N-((C 1 -C 4 alkoxy)carbonyl)-N-(C 1 C 4 alkyl)amino, aminocarbonylamino, hydroxy, C 1 -C 4 alkoxy, C1-C 4 alkylthio, Cl-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, halo or C3-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, C1-C 4 alkylsulfonylamino, (C 1 -C 4 alkoxy)carbonyl, hydroxy, Ci- 272 C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; heterocyclyl radical optionally substituted by 1-2 radicals of (C 1 -C 4 alkoxy)-carbonyl, hydroxy, C 1 -C 4 alkoxy, Ci-C 4 alkylthio or CI-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, Ci-C 4 alkoxy, Ci-C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 20 each R 2 3 is independently hydrogen or Ci-C 4 alkyl, or phenyl-C 1 -C 2 -alkyl optionally substituted by 1-2 radicals of hydroxy, Ci-C 2 alkoxy, Ci-C 2 alkylthio, cyano, halo, Ci-C 4 alkyl or trifluoromethyl radicals; R 4 is a methyl or ethyl radical; R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl- 30 radicals.

17. The compound of Claim 16 or a pharmaceutically acceptable salt thereof, wherein 273 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; 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 20 -S(0)2-R 20 or -S(0)2-NR 5 R 2 1 radical; or -NR 5 R 21 -NR22-C(O)-R 2 1 or -NR2 2 -S(0) 2 -R 2 0 radical; is a hydrogen radical; each R 2 0 is independently C1-C 6 alkyl radicals optionally substituted by 1-3 radicals of -C02R 2 3 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, 20 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; 25 heterocyclyl radical optionally substituted by 1-2 radicals of t-butoxycarbonyl, hydroxy, or C 1 -C 4 alkyl; or or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, 30 methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 21 is independently hydrogen radical or R 20 each R 22 is independently hydrogen or methyl radical; 274 each R 2 3 is independently hydrogen or C 1 -C 4 alkyl radicals; 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 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 radicals.

18. The compound of Claim 17 or a pharmaceutically acceptable salt thereof, wherein Y is a 20 -C(O)-R 20 or -C(O)-NR 5 R 2 1 radical; -OR 21 -SR 21 -S(O)-R 20 -S(0) 2 -R 2 0 or -S(0)2-NR 5 R 2 1 radical; or -NR 5 R 2 1 -NR22-C(O)-R 2 1 or -NR22-S(0) 2 -R 2 0 radical; 25 each R 20 is independently C 1 -C 6 alkyl radicals 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, 30 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 275 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; and each R 21 is independently hydrogen radical or R 20

19. The compound of Claim 18 or a pharmaceutically acceptable salt thereof, wherein Y is a.-OR21, -SR 2 1 or -NR 5 R 21 radical; each R 20 is independently Cl-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 20 radicals; heterocyclyl radical; or aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl 25 radicals; each R 21 is independently hydrogen radical or R2o; R 11 -is an unsubstituted phenyl radical or a phenyl 30 radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; and R 12 is a 4-pyridyl radical optionally substituted by a radical of amino, dimethylamino, acetamido, hydroxy, '276 halo, cyano, methoxy, methyl or trifluoromethyl radicals.

20. The compound of Claim 3 or a pharmaceutically acceptable salt thereof, wherein X is 0 or S; N N N'N1Nj N s R21 T-V W, R N R2 N N Nk N R 1N- 2 N R1 or R2 provided that the combined total numiber 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, Ci-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cj-C 5 alkanoylamino, (C1-C 4 alkoxy) carbonylamino, N- ((Cl-C 4 alkoxy) carbonyl) N-(C 1 -C 4 alkyl)anino, aminocarbonylamnino, hydroxy, Ci-C 4 aloy allthio~, C4akysliyl lC alkylsulfonyl, halo or aryl-Cl-C 4 -alkoxy, aryl-Cl-C4- alkylthio, aryl-Cl-C4-alkylsulfonyl, C3-C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C4 alkyl)amino, Cl-C 5 alkanoylanino, (C 1 -C 4 a lkox-y) carbonyl amino, Cl-C 4 alkylsulfonylamino, 277 alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, Cl-C4 alkyithic, cyano, halo, Cl-C 4 alkyl or CI-C 2 haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, Cl-C 4 alkylanino, di- (Cl-C 4 alkyl)amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy) carbonylamino, (Ci-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, CI-C 4 alkylamino, di- (Cl-C 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, Cl-C 4 alkylsuifonylanino, (Cl-C 4 alkoxy)carbonyl,-hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or C 1 -C 2 haloalkyl of 1- 3 halo radicals; each R 23 is independently hydrogen or C 1 -C 4 alkyl, or phenyl, heteroaryl, phenyl-Cl-C2-alkyl or heteroaryl-C- C2-alkyl optionally substituted by 1-3 radicals of amino, di-(Ci-C 4 alkyl) amino, C 1 -C 5 alkanoylamino, (Cl-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or C 1 -C 2 haloalkyl of 1-3 halo radicals; R 11 and R12 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 3 1 R 3 2 radicals; or -OR 2 9 -SR29, -S(O)-R 3 0, -S(O)2-R 3 0 -S(0) 2 -NR 3 lR32, -NR3 1 R3 2 -NR 3 3-C (0)-R29 or -NR33-C (0)-OR 3 0 radicals; provided that R 11 is other than a 4-pyridyl, 4- pyrimidinyl, 4-quinolyl or 6-isoquinolinyl radical optionally substituted by 1-2 substituents; and the 278 total number of aryl, heteroaryl, cycloalkyl and- heterocyclyl radicals substituted on each of RI 1 and R 1 2 is 0-1; each R 3 0 is independently cl-c 4 alkyl radical optionally substituted by amino, Cl-C 4 alkylanino or di- (Cl-C4-alkyl) amino radicals; or hydroxy, Cl-C 4 alkoxy, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylanino, di-(Cl-C 4 alkyl~amino, Cl-C 5 alkanoylamino, WlC-C4 al koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, CI-C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; (2Y C 1 -C 2 haloalkyl of 1-3 halo radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylanino, di-(Cl-C 4 alkyl)amino, CI-C 5 alkanoylamino, (Cl-C 4 a lkoxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or trifluoromethyl radicals; each R 29 is independently hydrogen radical or R3 0 each R 31 is independently hydrogen or C 1 -C 4 alkyl- radicals; and each R 3 2 is independently C30 hydrogen radicals; C 1 -c 4 alkyl radical optionally substituted by phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, Ci-C 4 alkylamino, di- (Cl-c 4 alkyl)amino, Cl-C 5 alkanoylamino, (Cl-C 4 al1koxy) carbonyl amino, hydroxy, Cl-C 4 alkoxy, Cl-C 4 alkyl or trifluoromethyl radicals; or 279 phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, C 1 -C 4 alkylamino, di-(C 1 -C 4 alkyl)amino, Ci-C 5 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, hydroxy, Ci-C 4 alkoxy, Cl-C 4 alkyl or trifluoromethyl radicals; and each R 33 is independently hydrogen or methyl radical; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-3 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused or 20 saturated C3-C4-carbocyclic-fused.

21. The compound of Claim 20 or a pharmaceutically acceptable salt thereof, wherein U is NR,; each R 23 is independently hydrogen or C 1 -C 4 alkyl, or phenyl, heteroaryl, phenyl-Ci-C 2 -alkyl or heteroaryl-C 1 30 C2-alkyl optionally substituted by 1-3 radicals of -amino, di-(C 1 -C 2 alkyl)amino, C 1 -C 5 alkanoylamino, (CI-C 4 alkoxy)carbonylamino, hydroxy, Cl-C 2 alkoxy, Cl-C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; 280 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 30 halo or cyano radicals; -C(O)-R 3 0 -C(0)-OR 2 9 -NR 3 1 R 32 or -C(NR31)- NR 31 R 32 radicals; or -OR 2 9 -SR 2 9, -S(O)-R 3 0 -S(0) 2 -R 3 0 -S(O)2-NR 3 1 R 3 2 -NR31R32 or -NR33-C(O)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R 30 is independently Cl-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 Strifluoromethyl radicals; 20 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, Ci-C 4 alkyl or trifluoromethyl radicals; each R 29 is independently hydrogen radical or R 30 and each R 32 is independently hydrogen radicals; 30 C1-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 alkyl)amino, acetamido, hydroxy, C 1 -C 2 alkoxy, CI-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, 281 acetamido, hydroxy, CI-C 2 alkoxy, Ci-C 4 alkyl or trifluoromethyl radicals; and wherein heterocyclyl is a radical of a monocyclic saturated heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused and optionally substituted by 1-2 oxo or thioxo radicals; aryl is a phenyl or naphthyl radical; and heteroaryl is radical of a monocyclic aromatic heterocyclic ring system having 5-6 ring members, wherein 1-2 ring members are oxygen, sulfur or nitrogen heteroatoms, which is optionally benzo-fused.

22. The compound of Claim 21 or a pharmaceutically acceptable salt thereof, wherein N-R21 *s N NW)K N R21NR N NN R R24 or- R 21 each R 2 1 is independently a hydrogen radical or Cl-C alkyl or C 2 -C 5 alkenyl radicals optionally substituted by 1-3 radicals of -C02R 23 amino, C 1 -C4 alkylamino, di-(C1-C 4 alkyl)amino, C 1 -CS alkanoylamino, (C1-C 4 alkoxy)carbonylamino, N-((C1-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, C 1 -C 4 282 alkylsulfonyl, halo or aryl-Cl-C4-alkoxy, arYl-Cl-C 4 alkylthio, aryl-C1-C4-alkylsulfolyl, C 3 -C 6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, Cl-C 4 alkylamino, di- (Cl-C 4 alkyl) amino, Cl-C 5 alkanoylanino, (C 1 -C 4 a lkoxy) carbonyl amino, C 1 -C 4 alkylsulfonylamino, C 1 -C alkanoyl, (Cl-C 4 alkoxy)carbonyl, hydroxy, Cl-C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, Cl-C 4 alkyl or IC haloalkyl of 1-3 halo radicals; heterocyclyl radical optionally substituted by 1-2 radicals of amino, di-(Cl-C 4 alkyl)amino, (Cl-C 4 a lkoxy) c arbonyl amino, (Cl-C 4 alkoxy) carbonyl, hydroxy, C 1 -C 4 alkoxy, C 1 -C 4 alkylthio or C 1 -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, acetamido, (CI-C 4 alkoxy) carbonyl amino, C 1 C 4 alkyl sul fonyl amino, (Cl-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio, cyano, halo, azido, Cl-C 4 alkyl or trifluoromethyl radicals; 9:99.:each R 2 3 is independently hydrogen or C 1 -C 4 alkyl, or phenyl-Cl-C 2 -alkyl or heteroaryl-Ci-C 2 -alkyl optionally substituted by 1-3 radicals of amino, di-(Cl-C 2 alkyl) amino, acetamido, (Cl-C 4 alkoxy) c arbonyl amino, hydroxy, C 1 -C 2 alkoxy, CI-C 2 alkylthio, cyano, halo, C 1 C 4 alkyl or trifluoromethyl radicals- each R 2 4 is independently a hydrogen or C 1 -C 4 alkyl 999 radical; 9 R 1 1 is an aryl radical and R 1 2 is a heteroaryl radical, wherein the aryl and heteroaryl radicals are optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; or 283 -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 1R 3 2 -NR31R 3 2 or -NR 3 3 -C(0)-R 2 9 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and R 12 is 0-1; each R30 is independently C1-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; each R2 9 is independently hydrogen radical or R 30 each R 31 is independently hydrogen,, methyl or ethyl radicals; and each R 32 is independently 25 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, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl 30 radicals; or phenyl or heteroaryl radical optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, hydroxy, methoxy, methyl or trifluoromethyl radicals.

23. The compound of Claim 22 or a pharmaceutically acceptable salt thereof, wherein 284 R 11 is an aryl radical optionally substituted by 1-2 radicals of R 3 0 halo or cyano radicals; or -C(O)-NR 31 R 32 -OR2 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)-R 2 9 radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of halo or cyano radicals; or -C(O)-NR 3 1 R 3 2 -OR 2 9 -SR 2 9 -NR 3 1 R 3 2 or -NR 3 3 R 29 radicals; provided that the total number of aryl, heteroaryl, cycloalkyl and heterocyclyl radicals substituted on each of R 11 and Ri2 is 0-1; R 3 0 is independently C1-C 4 alkyl radical optionally substituted by a phenyl or heteroaryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; 25 trifluoromethyl radical; or aryl or heteroaryl radicals optionally substituted by 1-3 radicals of amino, dimethylamino, acetamido, I hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; R 29 is an aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, methoxy, methyl or trifluoromethyl radicals; and R 32 is independently 285 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-

24. The compound of Claim 23 or a pharmaceutically acceptable salt thereof, wherein each R2 1 is independently a hydrogen radical or C 1 -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, Ci-C 5 alkanoylamino, (C1-C 4 alkoxy)carbonylamino, N-((C1-C 4 alkoxy)carbonyl)-N-(C 1 C 4 alkyl)amino, aminocarbonylamino, hydroxy, CI-C 4 alkoxy, C 1 -C 4 alkylthio, CI-C 4 alkylsulfinyl, C 1 -C 4 alkylsulfonyl, halo or C3-C6 cycloalkyl, heterocyclyl, aryl or heteroaryl radicals optionally substituted by 1- 2 radicals of amino, di-(C 1 -C 4 alkyl)amino, C 1 -C 20 alkanoylamino, (C 1 -C 4 alkoxy)carbonylamino, C 1 -C 4 alkylsulfonylamino, (CI-C 4 alkoxy)carbonyl, hydroxy, CI- C 4 alkoxy, C 1 -C 4 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; *oo heterocyclyl radical optionally substituted by 1-2 25 radicals of (C1-C 4 alkoxy)carbonyl, hydroxy, C 1 -C 4 alkoxy, Cl-C 4 alkylthio 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 30 alkoxy, C 1 -C 4 alkylthio, cyano, halo, azido, C 1 -C 4 alkyl or trifluoromethyl radicals; each R 23 is independently hydrogen or Ci-C 4 alkyl, or phenyl-C 1 -C 2 -alkyl optionally substituted by 1-2 radicals of hydroxy, Cl-C 2 alkoxy, C 1 -C 2 alkylthio, cyano, halo, C 1 -C 4 alkyl or trifluoromethyl radicals; 286 R 11 is an aryl radical optionally substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and R 12 is a heteroaryl radical optionally substituted by 1- 2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals. The compound of Claim 24 or a pharmaceutically acceptable salt thereof, wherein Y V R 24 is N N W R R 21 or R 2 1 000* S each R 2 1-is independently a hydrogen radical or Cl-C 6 alkyl radicals optionally substituted by 1-3 radicals of -C0 2 R 23 amino, methylamino, dimethylamino, t-butoxycarbonylamino, N-((t-butoxy)carbonyl)-N- (methyl)amino, aminocarbonylamino, hydroxy, butoxy, methoxy, butylthio, methylthio, methylsulfinyl, 25 methylsulfonyl, halo or C5-C 6 cycloalkyl, heterocyclyl, phenyl or heteroaryl radicals optionally substituted by 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 by 1-2 radicals of amino, dimethylamino, hydroxy, 287 methoxy, methylthio, halo, methyl or trifluoromethyl radicals; each R 2 3 is independently hydrogen or C 1 -C 4 alkyl radicals; R11 is an unsubstituted phenyl or naphthyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methylthio, methylsulfinyl, methylsulfonyl, aminocarbonyl, methyl or trifluoromethyl radicals; and 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 radicals. .e

26. The compound of Claim 25 or a pharmaceutically 20 acceptable salt thereof, wherein each R 21 is independently a hydrogen radical or Cl-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 30 aryl or heteroaryl radicals optionally substituted by 1-2 radicals of amino, dimethylamino, hydroxy, methoxy, methylthio, halo, methyl or trifluoromethyl radicals; R 11 is an unsubstituted phenyl radical or a phenyl radical substituted by 1-2 radicals of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, 288 methylthio, methylsulfonyl, methyl or trifluoromethyl radicals; and R 12 is a 4-pyridyl radical optionally substituted by-a radical of amino, dimethylamino, acetamido, hydroxy, halo, cyano, methoxy, methyl or trifluoromethyl radicals.

27. The compound of Claim 1 which is: 2- 6-Dichlorobenzyl) 4 -fluorophenyl) -3-methyl-6- (4- pyridyl) -4 (3H) -pyrimidinone, 2- (Butylamino) (4-f luorophenyl) -3-methyl-6- (4- pyridyl) -4 (3H) -pyrimidinone, 2 -(Benzylamino)-5-(4-fluorophenyl).3...ethyl6( 4 pyridyl) -4 (3H) -pyrimidinone, (4-Fluorophenyl) -3-methyl- ((R-l-phenylethyl)amino) pyridyl) -4 (3H) -pyrimidinone, 2- (2-Chlorophenyl) -ethylamino) luorophenyl) -3- methyl-6- (4-pyridyl) -4 3 H)-pyrimidinone, 5- (4-Fluorophenyl) (4-fluorophenyl) -ethylamino) -3- methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, (4-Fluorophenyl) ((2-hydroxy-2-phenyl) -ethylamino) 3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 25 5- (4-Fluorophenyl) -3-methyl-2-( (3-phenylpropyl) -amino) 6- (4-pyridyl) -4 (3H) -pyrimidirione, (4-Fluiorophenyl) -3-methyl-2- ((l-methyl-3- phenylpropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone, (4-Fluorophenyl) -3-methyl-2- ((R-l-methyl-3- phenyipropyl) -amino) (4-pyridyl) -4 (3H) -pyrimidinone, (4-Fluorophenyl) -3-methyl-2- ((2-phenylaminoethyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone, (4-Fluorophenyl) ((3-imidazolyipropyl).-amino) -3- methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, -4Furpey)3mty6-4prdl2-3 (pyrrolidin-1-yl) -propylamino) -4 (3H) -pyrimidinone, 3, 6-Diphenyl-4- (4-pyridyl) -2 (1H)-pyridone, 6- (4-Methylphenyl) -3-phenyl-4- (4-pyridyl) -2 (lH) pyridone, 6- (4-Ethyiphenyl) -3-phenyl-4- (4-pyridyl) -2 (lH) -pyridone, 6- 4-Dimethylphenyl) -3-phenyl-4- (4-pyridyl) -2(1H) pyridone, 289 3-Phenyl-4- (4-pyridyl) (2-thienyl) -2 (lH)-pyridone, 6- (2-Furyl) -3-phenyl-4- (4-pyridyl) -2(1H) -pyridone, 2- -2-Amino-3-phenylp ropyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2-(((R)-2-Amino-3-phenylpropyl)-amino)5(4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2- -2-N-Ethyl-3-phenylpropyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2- ((2-Axino-2-methy-3-phenylpropyl) amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2- ((2-Arinomethy-3-phenylpropyl) -amino) (4- fluorophenyl-3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2- ((3-Axino-3-phenylpropyl)-amino) -5-(4-fluorophenyl) -3- methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, S.-(4-Fluorophenyl)-3-methyl-2-(3-(2-. methylphenyl)propyl) -amino) -6.-(4-pyridyl) -4 (3H) pyrimidinone, 4 -Fluorophenyl)-3-methyl-2-((R,S)-2-amino-3(2.. fluorophenyl) -propyl-amino) (4-pyridyl) -4 (3H) pyrimidinone, ((5)-2-Acetamido-3-phenylpropyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 1. 5- (4-Fluorophenyl) -2-N-isopropylamino-3- ~phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) -4 (3H) 25 pyrimidinone, -2-N-n-Butylamino-3-phenylpropyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) -4 (3H) -pyrimidinone, 2- -2-N,N-Dimethylamino-3-phenylpropyl) -amino) (4- fluorophenyl-3-methyl-6- (4-pyridyl) -4 (3H-)-pyrimidinone, 30 5- (4-Fluorophenyl) -3-methyl-2- ((2-methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone, 2- ((5)-2-Amino-3-phenylpropyl) -amino) -3-ethyl-5- (4- fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone, (4-f luorophenyl) ((2-methy-3-phenylpropyl) amino) (4-pyridyl) -4 (3H) -pyrimidinone, 002-( ((S)-2-Amino-3-phenylpropyl)-amino.5(4- fluorophenyl) (4-pyridyl) -pyrimidine, 2- (3-trifluoromethyiphenyl) phenylmethyl) amino) -3- (4-fluorophenyl) (4-pyridyl) -4 (3H) pyrimidinone, 3-Methyl-2- -amino-3-phenylpropylamino) (4-tolyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- (2 -amino-3-phenylpropylamino) (4- trifluoromethyiphenyl) (4-pyridyl) -4(3H) -pyrimidinone, 290 3-Methyl-2- (2 -amino-3-phenylpropylamino) isopropyiphenyl) (4-pyridyl) -4 (3H)-pyrimidinone, 3-Methyl-2- (2 (S)-amino-3-phenylpropylamino) -5-(3-chioro- 4-f luorophenyl) (4-pyridyl) -4 (3H)-pyrimidinone, 3-Methyl-2-(2 (S)-amino-3-phenylpropylamino 3 bis (trifluoromethyl)phenyl) 4 -pyridyl) -4 (3H) pyrimidinone,- 3-Methyl-2- -amino-3-phenylpropylamino) (3,4- dichiorophenyl) (4-pyridyl) -4 (3H)-pyrimidinone, 3-Methyl-2-(2 (5)-amino-3-phenylpropylamino)..5.(l- naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- -axnino- 3 -phenylpropylamino) (3- fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- (2 (5)-amino-3-phenylpropylamino) (3- trifluoromethyiphenyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 3 -phenylpropylamino) 5-dichiorophenyl) 6- (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 3 -phenylpropylamino) (4-tolyl) (4- pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 3 -phenylpropylamino) (3- trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 3 -phenylpropylamino) (4-methoxyphenyl) -6- (4-pyridyl) -4 (3H) -pyrimidinone, 25 *~3-Methyl-2- 3 -phenylpropylamino) (4- 2 trifluoromethylphenyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 2 -methyl-3-phenylpropylamino) (3- fluorophenyl) (4-pyridyl) -4 (3H) -pyrimidinone, 3-Methyl-2- 2 -methyl-3-phenylpropylamino) (1- naphthyl) (4-pyridyl) -4 (3H) -pyrimidinone, -(4-Fluorophenyl)-2-(( )2N-lclaio3 phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 2 -N-Glycylamino-3-phenylpropyl) -amino) -3-methyl- (3-methyiphenyl) (4-pyridyl) (3H) -pyrimidinone, 5-(4-Fluorophenyl)-2-( C(S) 2 -hydroxyacetamido-3- phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) *.pyrimidinone, 5-(4-Fluorophenyl)-2-( 2 -pyrrolidinyl-3- phenylpropyl) -amino) -3-methyl-6- (4-pyridyl) pyrimidinone, 2- 3 -Benzylpiperazinyl) (4-f luorophenyl) -3-methyl- 6- (4-pyridyl) (3H) -pyrimidinone, 2- (3-Amino-3- 2 -f luorophenyl)propyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 291 2- ((3-Amino--3- (2-methylphenyl)propyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) (3I) pyrimidinone, 2- -3-Axnino-3-phenylpropyl) -amino) (4- fluorophenyl) 3 -methyl-6-(4-pyridyl)4(3H) pyrimidinone, 2- 3 -Amino-3-phenylpropyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 3 -Amino-3-phenylpropyl)amino).>-methyl6( 4 pyridyl) 5- (3-trifluoromethylphenyl) (3H) -pyrimidinone, 2- -3-Amiflo-3-phenylpropyl) -amino) -3-methyl-6- (4- pyridyl) 5- (3-trifluoromethylphenyl) (3H) -pyrimidinone, 2- ((3-Amino-3-phenylpropyl) -amino) -3-methyl-6- (4- pyridyl) 5- 3 -trifluoromethylphenyl) (3H)'-pyrimidinone, 2- ((3-Amino-3- (2-methylphenyl)propyl) -amino) -3-methyl-6- (4-pyridyl) 5- 3 -trifluoromethylphenyl) (3H) pyrimidinoie-, 2- ((3-Amino-3- (2-f luorophenyl)propyl) -amino) -3-methyl-6- 4 -pyridyl)5-(3-trifluoromethylphenyl)-4(3H)- pyrimidinone, 2- 3 -Amino-3-phenylpropyl) -amino) -3-methyl-5- (3- methyiphenyl) (4-pyridyl) (3H) -pyrimidinone, 3 -Amino- 3 2 25 (3-methyiphenyl) (4-pyridyl) -pyrimidinone, 2- ((3-Amino-3- (2-chl-orophenyl)propyl) -amino) ~(3-methyiphenyl) (4-pyridyl) -pyrimidinone, 3 -Amino- 3 -phenylpropyl)amino)3methy16-(4- pyridyl) 5- 4-dimethyiphenyl) (3H) -pyrimidinone, 2 R, 3 R)- 3 (4-fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 2- (2S,3S) 3 -Amino-2-methyl-3-phenylpropyl) -amino) 4 -fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, (4-Fluorophenyl) 3 -N-isopropylamino-3- phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, (4-Fluorophenyl) 3 -N-isopropylamino-3- phenylpropy1)-amino)-3-methy16-(4pidyl.-4-(3H)- pyrimidinone, 4 -Fluoropheny1)-3-methy-6-(4-pyridy)2.((S. tetrahydroisoquinol-3-ylmethylenamino) (3H) pyrimidinone, 3-Methyl-6- (4-pyridyl) (S)-tetrahydroisoquinol-3- ylmethylenamino)- S-( 3 -trifluoromethylphenyl) pyrimidinone, 292 (3-nmethyiphenyl) (4-pyridyl) tetrahydroisoquinol-3>ylmethylelajfQ) (3H) pyrimidinone, (4-methyithiophenyl) (4-pyridyl) tetrahydroisoquino13ylmethylelajf 0 (3H) pyrimidinone, 2- 2 -Amino-3-phenylpropyl) -amino) -3--methyl- 5- (3- methyiphenyl) (4-pyridyl) (31) -pyrirnidinone, (4-Fluorophenyl) 3 -hydroxy-3-phenylpropyl) -amino) 3 -methyl-6-(4-pyridyl)-4-3H)pyrimidinone, 2- -2-Amiflo-3-phenylpropyl) -amino) (4- fluorophenyl) (4-pyridyl) (3H) -pyrimidinone, 2- -2-Amino-3- 2 -fluorophenyl)propyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 2- -2-Amino-3- 4 -fluorophenyl)propyl) -amino) (4- fluorophenyl) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 2- -2-Amino-3- 2 -chlorophenyl)propyl) -amino) (4- fluorophenyl)-3-methyl..6(4.pyridyl)- 4 3 H)- pyrimidinone, 2- 2 -N-Isopropylamino3.phenylpropyl) -amino) -3- metl-yl-6- (4-pyridyl) 3 -trifluoromethylphenyl) -4-(311)- pyrimidinone, 2 -N-Isopropylamino-3phenylpropyl) -amino) -3- (3-methyiphenyl) (4-pyridyl) (3H) (3-Chloropheny.-2- 2 -N-isopropylamino3- phenyipropyl) -amino) -3-methyl-6- (4-pyridyl) (3H) pyrimidinone, 2- 2 -NN-Dimethylamino-3phenylpropyl) -amino) -3- (3-methyiphenyl) (4-pyridyl) (3H) pyrimidinone, 2- 2 -NN-Dimethylamino-3-phenylpropyl) -amino) -3- 35methyl-5- (3-chloropheny)6(4-pyridyl)- 4 3 H) pyrimidinone, 2- 2 -NN-Dimethylamino.3-phenylpropyl) -amino) -3- methyl-6- (4-pyridyl) 3 -trif luorophenyl) O3H) pyrimidinone or 5- (4-Fluoropheny) 3methyl2. -2-N-methylamino-3- phenylpropyl) -amino) (4-pyridyl) (3H) -pyrimidinone or a pharmaceutically acceptable salt thereof.

28. A pharmaceutical composition comprising a compound of Claims 1 to 27 and a pharmaceutically acceptable carrier. 293

29. A method of prophylaxis or treatment of inflammation comprising administering an effective amount of a compound of Claims 1 to 27. 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, osteophorosis, multiple myeloma, uveititis, acute or 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 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 25 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 Claims 1-27. 30 32. A method of prophylaxis or treatment of rheumatoid arthritis, Pagets disease, osteophorosis, multiple myeloma, uveititis, acute or chronic myelogenous leukemia, pancreatic 6 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 294 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.

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 Claims 1-27.

34. A method of lowering plasma concentrations of either or both TNF-a and IL-1 comprising administering an effective amount of a composition of Claim 28. .2

35. A method of lowering plasma concentrations of either or both IL-6 and IL-8 comprising administering an effective amount of a compound of Claims 1-27. 25 36. A method of lowering plasma concentrations of either or both IL-6 and IL-8 comprising administering an 'effective amount of a composition of Claim 28.

37. A method of prophylaxis or treatment of 30 diabetes disease in a mammal comprising administering an effective amount of a compound according to Claims 1 to 27 to produce a glucagon antagonist effect.

38. A method of prophylaxis or treatment of diabetes disease in a mammal comprising administering an effective amount of a pharmaceutical composition 295 according to Claim 28 to produce a glucagor 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 Claims 1 to 27. 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 administering an effective amount of a compound according to Claims 1 to 27.

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 25 activity in a mammal comprising administering an effective amount of a compound according to Claims 1 to 27.

44. The method of Claim 43 wherein the 30 cyclooxygenase enzyme is COX-2. 9 A method of decreasing cyclooxygenase enzyme activity in a mammal comprising administering an effective amount of a pharmaceutical composition according to Claim 28. 296

46. The method of Claim 45 wherein the cyclooxygenase enzyme is COX-2. DATED this 18th Day of October 2001 AMGEN INC. Attorney: DAVID A. ADAMTH WAITE Fellow Institute of Patent and Trade Mark Attorneys of Australia of BALD WIN SHELSTON WATERS