AU699148B2 - 2,5-substituted aryl pyrroles, compositions containing such compounds and methods of use - Google Patents

Description

i 1 Aryl Pyrroles, Compositions Containing Such Compounds and Methods of Use Background of the Invention The present invention addresses 2,5-substituted aryl pyrroles, as well as compositions containing such compounds and methods of treatment.

Cytokine mediated diseases refers to diseases or conditions in which excessive or unregulated production of one or more cytokines occurs. Interleukin-1 (IL-1) and Tumor Necrosis Factor (TNF) are cytokines produced by a variety of cells, which are involved in immunoregulation and other physiological conditions, such as inflammation.

IL-1 has been demonstrated to mediate a variety of biological activities thought to be important in immunoregulation and other physiological conditions.

[See, Dinarello et al., Rev. Infect. Disease. 6, 51 (1984)]. The myriad of known biological activities of IL- I include the activation of T-helper cells, induction of fever, 15 stimulation of prostaglandin or collagenase production, neutrophil chemotaxis, I induction of acute phase proteins and the suppression of plasma iron levels.

There are many disease states in which IL-1 is implicated. Included among these diseases are rheumatoid arthritis, osteoarthritis, endotoxemia, toxic shock syndrome, other acute or chronic inflammatory diseases, such as the inflammatory reaction induced by endotoxin or inflammatory bowel disease; tuberculosis, c,,c atherosclerosis, muscle degeneration, cachexia, psoriatic arthritis, Reiter's syndrome, rheumatoid arthritis, gout, traumatic arthritis, rubella arthritis; and acute synovitis. Recent evidence also links IL-I activity to diabetes and pancreatic fL cells.

Excessive or unregulated TNF production has been implicated in mediating or exacerbating rheumatoid arthritis, rheumatoid spondylitis,

F

WO 97/05878 PCT/US96/12922 -2osteoarthritis, gouty arthritis, and other arthritic conditions; sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcosis, bone resorption diseases, reperfusion injury, graft vs. host reaction, allograft rejections, fever and myalgias due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexia secondary to acquired immune deficiency syndrome (AIDS), AIDS related complex (ARC), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis and pyresis.

Monokines, such as TNF, have been shown to activate HIV replication in monocytes and/or macrophages [See Poli, et al., Proc. Natl.

Acad. Sci., 87:782-784 (1990)]. Therefore, inhibition of monokine production or activity aids in limiting HIV progression as stated above for T-cells. TNF has also been implicated in various roles with other viral infections, such as the cytomegalovirus (CMV), influenza virus and the herpes virus.

IL-6 is a cytokine effecting the immune system, hematopoiesis and acute phase reactions. It is produced by several mammalian cell types in response to agents such as IL-1 and is correlated with disease states such as angiofollicular lymphoid hyperplasia.

Interleukin-8 (IL-8) is a chemotactic factor first identified and characterized in 1987. Many different names have been applied to IL-8, such as neutrophil attractant/activation protein-1 (NAP-1), monocyte derived neutrophil chemotactic factor (MDNCF), neutrophil activating factor (NAF), and T-cell lymphocyte chemotactic factor. Like IL-1, IL-8 is produced by several cell types, including mononuclear cells, fibroblasts, and endothelial cells. Its production is induced by IL-1, TNF and by lipopolysaccharide (LPS). IL-8 stimulates a number of cellular functions in vitro. It is a chemoattractant for neutrophils, T-lymphocytes and basophils.

It induces histamine release from basophils. It causes lysozomal enzyme release and respiratory burst from neutrophils, and it has been shown to increase the surface expression of Mac-I (CDI lb/CD 18) on neutrophils without de novo protein synthesis. There remains a need for treatment, in this field, for compounds which are cytokine suppressive or antagonistic, .1 iiml ;1 WO 97/05878 PCT/US96/12922 -3compounds which are capable of inhibiting or antagonizing cytokines such as IL-1, IL-6, IL-8 and TNF.

The compounds of formula I are also useful in treating diseases characterized by excessive IL-8 activity. There are many disease states in which excessive or unregulated IL-8 production is implicated in exacerbating and/or causing the disease. These diseases include psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome, thrombosis and glomerulonephritis.

SUMMARY OF THE INVENTION The present invention is directed to a compound represented by formula I: (Ra)o3-- HAr R2

R

1 1 or a pharmaceutically acceptable salt thereof, wherein: and each independently represent a 5-10 membered aryl or heteroaryl group substituted with Ra groups; wherein a and b represents integers, 0, 1, 2 or 3, such that the sum of a plus b is 1, 2, 3 or 4; represents a heteroaryl group containing from 5 to atoms, 1-4 of which are heteroatoms, 0-4 of which heteroatoms are N and 0- 1 of which are O or S, said heteroaryl group being unsubstituted or substituted with 0 -3 R a groups; each R a independently represents a member S r

-JI

WO 97/05878 PCTIUS96/1 2922 -4selected from the group consisting of: halo; CN, NO 2

R

21

OR

23

SR

23

S(O)R

2 1 S02R 21

NR

20

R

23

NR

20 C0R 21

NR

2 0 C02R 2 1

NR

2 0CONR 2

OR

23

NR

20 S0 2

R

2 1

NR

20

C(NR

2 0)NHR 2 0, C0 2

R

23

CONR

2

OR

23 S02NR 20

R

23

SO

2

NR

2 0COR 2 1

SO

2

NR

20

CONR

2

OR

23

SO

2

NR

2

OCO

2 R2l; 0C0NR 2 0

R

23

OCONR

2 0SQ2R 2 0, C(O)OCH2OC(O)R 20

C(NR

2 0)NR 2

OR

23 and C0NR 20 S02R 2 1 RI is selected from the group consisting of: H, aryl, alkyl, C 3 15 alkenyl, C3 15 alkynyl and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, OR 20

SR

20

N(R

20

S(O)R

2 1, S02R 2 1 S02NR 20

R

23

SO

2

NR

2 OCOR2I1, SO2NR 2 0CONR2OR 23

NR

2 0COR2I1, NR 2

OCO

2 R21, NRIOCONR2OR 23

N(R

20

)C(NR

2

())NHR

2 0, CO2R 2 0, CONR2OR 23

CONR

2

OSO

2

R

2 1, NR 20 S02R 2

SO

2

NR

2

OCO

2 R2I, OCONR2OR 2 3 0C0NR 20 S02R 2 1

OCONR

2

O~R

23 and C(O)OCH2OC(O)R 20

R

2 is selected from the group consisting of: H, C I.-i 5 alkyl, C2- 1 5 alkenyl, C 2 -1.

5 alkynyl, halo, N02, heterocyclyl, CN, S (O)R 2 1 S02R 2 1 SO2N(R 20 2 S 02NR 20 C0R 2 1 S O2NR 2 0CON(R 20 2 C0R 20 C0 2

R

2 0, C0NR 20

R

23

CONR

20

SO

2

R

2 and SO2NR 2

OCO

2 R2I1, said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected fromn the group consisting of: halo, heterocyclyl, CN, aryl, heteroaryl, R 20

OR

20

SR

2 0, NR 2 0R 23

S(O)R

21 S02R 2 1 S0 2

)NR

20

R

2 3 SNR CO ISO2)NR 2 0CONR 2

()R

2 3

NR

2 OCOR2I,

NR

2 0CO 2

R

2 1, NR2()CONR2OR 23

NR

20

C(NR

2 0)NHR 2 0, C02R 2 0,

CONR

2

OR

2 3 C0NR 20 S02R 22

NR

2 0SO 2

R

2 S02NR 20 C0 2 R22, 0C0NR 20 S02R 2 1 and 0C0NqR 20

R

2 3;

R

2 0~ represents a member selected from the group consisting of: H, C.I 5 alkyl, 02-15 alkenyl, QC2-1 5 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl; WO 97/05878 PCT/US96/12922

R

2 1 represents a member selected from the group consisting of: alkyl, C2-15 alkenyl, C 2 -1 5 alkynyl, heterocyclyl, aryl and heteroaryl, such alkyl, alkenyl and alkynyl being optionally interrupted with oxo and/or 1-2 heteroatoms selected from O, S, S02 and NR 2 0, said alkyl, alkenyl, alkynyl, aryl and heteroaryl being optionally substituted with from 1-3 of halo, heterocyclyl, aryl, heteroaryl, CN, OR 20 O((CH2)nO)mR 2 0,

NR

2 0((CH2)nO)mR20 wherein n represents an integer of from 2 to 4, and m represents an integer of from 1 to 3; SR 2 0, N(R 2 0) 2 S(0)R 22 S02R 22 SO2N(R 2 0) 2 S02NR 20

COR

22 SO2NR 2 0CON(R20) 2

NR

2 0COR22,

NR

2 0CO 2 R22, NR 2 0CON(R20) 2

NR

2 2

C(NR

22 )NHR22, CO2R20, CON(R20)2, CONR 2 0SO2R 22

NR

2 0SO2R22, S02NR 2 0CO2R22,

OCONR

2 OSO2R22OC(0)R 2 0, C(0)OCH2OC(O)R 2 0 and OCON(R 2 0) 2

R

22 is selected from the group consisting of: CI-15 alkyl, C2- 15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups;

R

2 3 is R 2 1 or H;

R

24 is selected from COR 2 2 C02R 22

CON(R

2 0 S02R 2 2 and R 2 3 and when two R 2 0 groups are present, when R 2 0 and R 2 1 are present, or when R 20 and R 23 are present, said two R 2 0 groups, R 20 and

R

2 1 or said R 20 and R 23 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional 0 or S atom.

Also included in the invention is a pharmaceutical composition which is comprised of a compound of formula I in combination with a pharmaceutically acceptable carrier.

The invention includes a method of treating psoriasis, inflammatory bowel disease, asthma, cardiac and renal reperfusion injury, adult respiratory distress syndrome. thrombosis and glomerulonephritis, in a mammal in need of such treatment which comprises administering to said 1 ;r h'C' r: ;ax aa- iLLI IUCSS~II~ WO 97/05878 PCT/US96/12922 -6mammal a compound of formula I in an amount which is effective for treating said disease or condition.

Also included in the invention is a method of treating a cytokine mediated disease in a mammal, comprising administering to a mammalian patient in need of such treatment an amount of a compound of formula I which is effective to treat said cytokine mediated disease.

DETAILED DESCRIPTION OF THE INVENTION The invention is described herein in detail using the terms defined below unless otherwise specified.

The term "alkyl" refers to a monovalent alkane (hydrocarbon) derived radical containing from 1 to 15 carbon atoms unless otherwise defined. It may be straight, branched or cyclic. Preferred straight or branched alkyl groups include methyl, ethyl, propyl, isopropyl, butyl and tbutyl. Preferred cycloalkyl groups include cyclopentyl and cyclohexyl.

Alkyl also includes a straight or branched alkyl group which contains or is interrupted by a cycloalkylene portion. Examples include the following:

(CH

2 )-ij7

(CH

2 )y and -(CH 2 w

-(CH

2 )z

MI

wherein: x plus y from 0-10 and w plus z from 0-9.

The alkylene and monovalent alkyl portion(s) of the alkyl group can be attached at any available point of attachment to the cycloalkylene portion.

When substituted alkyl is present, this refers to a straight, branched or cyclic alkyl group as defined above, substituted with 1-3 groups as defined with respect to each variable.

The term "alkenyl" refers to a hydrocarbon radical straight, branched or cyclic containing from 2 to 15 carbon atoms and at least one carbon to carbon double bond. Preferably one carbon to carbon double bond is present, and up to four non-aromatic (non-resonating) carboncarbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with 3~ 4 i WO 97/05878 PCTA'S96/12922 -7respect to alkyl, the straight, branched or cyclic portion of the alkenyl group may contain double bonds and may be substituted when a substituted alkenyl group is provided.

The term "alkynyl" refers to a hydrocarbon radical straight, branched or cyclic, containing from 2 to 15 carbon atoms and at least one carbon to carbon triple bond. Up to three carbon-carbon triple bonds may be present. Preferred alkynyl groups include ethynyl, propynyl and butynyl.

As described above with respect to alkyl, the straight, branched or cyclic portion of the alkynyl group may contain triple bonds and may be substituted when a substituted alkynyl group is provided.

Aryl refers to aromatic rings phenyl, substituted phenyl and like groups as well as rings which are fused, naphthyl and the like.

Aryl thus contains at least one ring having at least 6 atoms, with up to two such rings being present, containing up to 10 atoms therein, with alternating (resonating) double bonds between adjacent carbon atoms. The preferred aryl groups are phenyl and naphthyl. Aryl groups may likewise be substituted as defined below. Preferred substituted aryls include phenyl and naphthyl substituted with one or two groups.

The term "heteroaryl" refers to a monocyclic aromatic hydrocarbon group having 5 or 6 ring atoms, or a bicyclic aromatic group having 8 to 10 atoms, containing at least one heteroatom, 0, S or N, in which a carbon or nitrogen atom is the point of attachment, and in which one additional carbon atom is optionally replaced by a heteroatom selected from O or S, and in which from 1 to 3 additional carbon atoms are optionally replaced by nitrogen heteroatoms. The heteroaryl group is optionally substituted with up to three Ra groups.

Heteroaryl thus includes aromatic and partially aromatic groups which contain one or more heteroatoms. Examples of this type are thiophene, purine, imidazopyridine, pyridine, oxazole, thiazole, pyrazole, tetrazole, imidazole, pyrimidine, pyrazine and triazine.

The groups and represent 5-10 membered aryl or heteroaryl, each of which is substituted with 0 3 groups selected from Ra such that a total of 1 to 4 groups is attached to and WO 97/05878 PCT/US96/12922 -8- Preferred are phenyl, naphthyl, pyridyl, pyrimidinyl, thiophenyl, furanyl, imidazolyl, thiazolyl, isothiazolyl, oxazolyl, and isoxazolyl.

HA

r The group represents a heteroaryl group which contains from 5 to 10 atoms. One to four atoms are heteroatoms which are selected from O, S and N. The heteroaryl group may be unsubstituted or substituted with 0 -3 Ra groups.

(HAr) Preferred heteroaryl groups represented by are as follows: pyridyl, quinolyl, purinyl, imidazolyl, imidazopyridine, and pyrimidinyl.

The terms "heterocycloalkyl" and "heterocyclyl" refer to a cycloalkyl group (nonaromatic) in which one of the carbon atoms in the ring is replaced by a heteroatom selected from O, S, SO, SO2 or N, and in which up to three additional carbon atoms may be optionally replaced by heteroatoms.

Heterocyclyl is carbon or nitrogen linked; it carbon linked and contains a nitrogen, then the nitrogen may be substituted by R 2 4 Examples of heterocyclyls are piperidinyl, morpholinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydroimidazo[4,5-c]pyridinyl, imidazolinyl, piperazinyl, pyrolidin-2-onyl, piperidin-2-onyl and the like.

The term "TNF mediated disease or disease state" refers to any and all disease states in which TNF plays a role, either by production of ITNF itself, or by TNF causing another monokine to be released, such as but not limited to IL-I or IL-6. A disease state in which IL-1, for instance, is a major component, and whose production or action, is exacerbated or secreted in response to TNF, would therefore be considered a disease state mediated by TNF.

The term "cytokine" as used herein means any secreted polypeptide that affects the functions of cells and is a molecule which modulates interactions between cells in the immune, inflammatory or I hematopoietic response. A cytokine includes, but is not limited to, jmonokines and lymphokines regardless of which cells produce them.

Examples of cytokines include, but are not limited to, Interleukin-1 (IL-I), WO 97/0}87 PCT/US96112--922 WO 97/05878 PCT/US96/12922 Interleukin-6 Interlukin-8 Tumor Necrosis Factor-alpha (TNF-a) and Tumor Necrosis Factor-beta (TNF-1).

By the term "cytokine interfering or cytokine suppressive amount" is mean an effective amount of a compound of formula I which will, cause a decrease in the in vivo levels of the cytokine or its activity to normal or sub-normal levels, when given to the patient for the prophylaxis or therapeutic treatment of a disease state which is exacerbated by, or caused by, excessive or unregulated cytokine production or activity.

The compounds of the present invention may contain one or more asymmetric carbon atoms and may exist in racemic and optically active forms. All of these compounds are contemplated to be within the scope of the present invention.

Throughout the instant application, the following abbreviations are used with the following meanings: p Bu Bn BOC, Boc calc.

CBZ, Cbz

CDI

FAB-MS

HPLC

KHMDS

LAH

LHMDS

Me MeOH

MPLC

NMR

Ph Pr prep.

Pyr.

TMS

butyl benzyl t-butyloxycarbonyl calculated Benzyloxycarbonyl N,N'-carbonyl diimidazole Fast atom bombardment-mass spectroscopy High pressure liquid chromatography Potassium bis(trimethylsilyl)amide Lithium aluminum hydride Lithium bis(trimethylsilyl)amide methyl methanol Medium pressure liquid chromatography Nuclear Magnetic Resonance phenyl propyl prepared pyridyl Tetramethylsilane i.

I

Mai_ WO 97/05878 PCT/US96/12922 One subset of compounds of the invention includes compounds of formula I wherein Ar and Ar 2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl, and k) napthyl.

Within this subset of compounds, all other variables are as previously defined with respect to formula I.

Another subset of compounds of the invention includes compounds of formula I wherein HAr is selected from: a) pyridyl, b) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridine, and f) pyrimidinyl.

Within this subset of compounds, all other variables are as originally defined with respect to formula I.

Another subset of compounds of formula I includes compounds wherein R1 is hydrogen. Within this subset of compounds, all other variables are as originally defined with respect to formula I.

Another subset of compounds of formula I includes compounds wherein RI represents CI-15 alkyl, unsubstituted or substituted, as originally defined. Within this subset of compounds, all other variables are as originally defined with respect to formula I.

Another subset of compounds of formula I includes compounds wherein R 2 represents a member selected from the group consisting of: i' r i i i r i rr- WO 97/05878 PCTIUS96/1 2922 a) H; b) alkyl; c) halo; d) CN; e) C(O)CI- 6 alkyl; f) C(O)Cj.

6 alkyiphenyl; g) CO2)H; h) C02C 1 -6 alkyl i) C0 2 C 1.-6 alkyiphenyl; j) CONE2; k) CONI-16 alkyl; 1) C(O)N(CI-6 alkyl)2; mn) SO2NH2; n) S02NHC1-6 alkyl and o) SO2N(CI-6 alkyl)2.

Within this subset of compounds, all other variables are as originally defined with respect to formula 1.

Preferred compounds of formula I are realized when: Arl and Ar 2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl and k) napthyl; one, two or three Ra groups are present and attached to Ar 1 and Ar 2 and each Ra is independently selected from the group consisting of: halo, R 2 1, OR 23

NR

2 0

R

23 C02R 2 3

CONR

2

OR

23 S02R 2 1 and

S(O)R

2 1

R

20

R

21 and R 23 are as originally defined; HAr is selected from:

R

2 0 represents a member selected from the group consisting of:- H, C 1 15 alkyl, C2..15 alkenyl, C2- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl. alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl; /3 PCTIUS96/12922 WO 97/05878 12 a) b) c) d) e) f) pyridyl, quinolyl, purinyl, imidazolyl, imidazopyridinyl and pyrimidinyl; RI is: a) H or b) substituted or unsubstiuted alkyl; and

R

2 is selected from the group consisting of: a) H, b) alkyl, c) halo, d) CN, e) C(O)C 1-6 alkyl, f) C(O)CI- 6 alkylphenyl, g) CO2H, h) C0 2 C1 -6 alkyl, i) C0 2 C 1 -6 alkylphenyl, j) CONH12, k) CONHCI-6 alkyl, 1) C(O)N(C 1-6 alkyl)2, M) SO2NH-2, n) SO2)NI-IC 1-6 alkyl and o) SO2N(CI1-6 alkyl)2.

A more preferred subset of compounds of formula I is realized when: (Ra) 1 A-Arl is selected from the group consisting of: a) phenyl, b) 4-fluorophenyl, c) 4-chiorophenyl.

d) 3-fluorophenyl, e) 3-chiorophenyl, f) thiophen-2-yl, g) thiophen-3-yl,

'U

'~1

I

WO 97/05878 PCTIUS96/12922 13 h) i) j) k) 1)

M)

n) 0) p) q)

S)

U)

V)

w)

X)

y)

Z)

aa) bb) cc) dd) ee) ff) gg) 11h) kk) 11) n-m) nn) 00) pp) qq) 4-fluorothiophen-2-yl, 4-fluorothiophen-3 -yl, 5 -fluorothi ophen-2-yl, 5-fluorothiophen-3 -yI, 4-chlorothiophen-2-yI, 4-chlorothiophen-3-yl, 5-chlorothiophen-2-yl, 5-chlorothiophen-3-yl, 3-methyiphenyl, 3 ,4-dichlorophenyl, 3 -hydroxyphenyl, 4-hydroxyphenyl, 3 ,4-dihydroxyphenyl, 3-methyl-2-thiophenyl, 5-methyl-2-thiophenyl, 4-carboxymethyiphenyl, 3-cyanophenyl, 4-cyanophenyl, 2-pyridyl, 2-furoyl, 3-furoyl, 4-methylsulfinyiphenyl, 4-trifluoromethyiphenyl, 3-trifluoromethyiphenyl, 4-methyiphenyl, 4-t-bvtoxypheny1, 3 ,4-dibenzyloxyphenyl, 3-quinolinyl, 3-pyridyl, 4-pyridyl, 2,4-difluorophenyl, 3 ,4-difltiorophenyl, 4-methylsulfinyiphenyl, 4-methylsulfonyiphenyl, 2-methoxyphenyl, 3-methoxyphenyl, WO 97/05878 PTU9/22 PCT/US96/12922 -14- 4-nitrophenyl, 4-aminomethyiphenyl, and 2-chlorophenyl.

(Ra)b-Ar 2 is selected from the group consisting of: a) 4-(methylthio)-phenyl, b) 4-(ethylthio)-phenyl, c) 3-(methylthio)-phenyl, d) 2-(methylthio)-phenyl, e) 3-(ethylthio)-phenyl, f) 4-methylsulfonyiphenyl, g) 4-ethylsulfonyiphenyl, h) 3-methylsulfonyiphenyl, i) 2-methylsulfonyiphenyl, j) 4-methylsulfinyiphenyl, k) 4-ethylsulfonyiphenyl, 1) 3-methylsulfinylphenyl, m) 4-(N -methyl-N-benzyl)aminomethylpheny 1, n) 3-(N-methyl-N-benzyl)aminomethylphenyl, o) 4-methoxyphenyl, p) 4-hy-Ilroxyphenyl, q) 3-methoxyphenyl, r) 2-benzyloxyphenyl, s) 4-methylthiophen-2-yl, t) 4-methylthiophen-3-yl, u) 4-acetylaminophenyl, v) 2-pyrimidinyl, w) phenyl, x) 4-amninomethyiphenyl, y) 4-cyanophenyl, z) 4-fluorophenyl, aa) 4-chlorophenyl, bb) 4-bromophenyl, cc) 4-carboxyethylphenyl, dd) 2-fluorophenyl, ee) 3-nitrophenyl, h it CO WO 97/05878 PCT/US96/12922 15 ff) gg) hh) ii) ii) kk) 11)

MM)

nn) oo) pp) qq) rr) ss) tt) uu) vv) 4-nitrophenyl, 3 -fluorophenyl, 4-carboxyphenyl, 4-.aminopheny 1, 3-aminophenyl, 4-(O(CH2)3NMe2)-phenyl, 4-(O(CH2)2-piperidin- I -yl)-phenyl, 2-niethoxyphenyl, 3 -chl orophenyl, 4-((4-N-COCH3)piperazin- I -yl)-phenyl, 4-trifluoromethyiphenyl, 4-bromothiophen-2-yI, 5 -methylthiophen-2-yl, 2-benzoxazolyl, 2-benzofuranyl, 2,5 -dimethoxyphenyl and 4-morpholinyiphenyl; with the proviso that when (Ra)a-Arl represents aa), bb), Ji) or kk), Ar 2 -(Ra)b does not represent ss) or tt); (Ra)0O3-HAr is selected from the group consisting of: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-arninopyridyl), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, Cg) 9-purinyl, h) 7-(imidazo[4,5-b]pyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridyl, k) 3 ,5-dimethyl-4-pyridyl, 1) 3-quinolinyl, m) 3-pyridazinyl, n) 4-(2-aminobenzyl)pyridyl, and witnout de novo protein synthesis. There remains a need for treatment, in this field, for compounds which are cytokine suppressive or antagonistic, PCTfUS96/12922 WO 97/05878 16 o) 4-(2-amino)pyrimidinyl; R I is: H, and

R

2 is selected from a) b) c) d) e) f) g) h) i) j) k) 1) m) n) o)

P)

the group consisting of:

H,

F,

cl, Br,

CN,

C(O)CI-6 alkyl, C(O)Cj- 6 alkyiphenyl, CO2H, C02C 1-6 alkyl, C02C 1 -6 alkylphenyl, CONH2, CONHCI-6 alkyl, C(O)N(C 1 -6 alkyl)2, SO2NH2,

SO

2 NHC1-6 alkyl and SO2N(CI-6 alkYl)2.

Another more preferred subset of compounds of formula I is realized when: Ra)a-Arl is selected from the group consisting of: a) phenyl, b) 4-fluorophenyl, c) 4-chiorophenyl, d) 3-fluorophenyl, e) 3-chlorophenyl, f) thiophen-2-yl, g) thiophen-3-yl, h) 4-fluorothiopheni-2-yl, i) 4-fluorothiophen-3-yl, j) 5-fluorothiophen-2-yl, k) 5-fluorothiophen-3-yl, 1) 4-chlorothiophen-2-yl, i{

V

WO 97/05878 PCT/US96/12922 17 m) 4-chlorothiophen-3-yl, n) 5-chlorothiophen-2-yl, o) 5 -chlorothiophen-3 -yl, p) 3-methyiphenyl, q) 3,4-dichlorophenyl, r) 3-hydroxyphenyl, s) 4-hydroxyphenyl, t) 3 ,4-dihydroxyphenyl, u) 3-methyl -2-thiophenyl, v) 5-methyl-2-thiophenyl, w) 4-carboxymethyiphenyl, x) 3-cyanophenyl, y) 4-cyanophenyl, z) 2-pyridyl, aa) 2-furoyl, bb) 3-furoyl, cc) 4-methylsulfinyiphenyl, dd) 4-trifluoromethyiphenyl, ee) 3 -trifluoromethyiphenyl, if) 4-methyiphenyl, gg) 4-t-butoxyphenyl, hh) 3 ,4-dibenzyloxyphenyl, ii) 3-quinolinyl, Ji) 3-pyridyl, kk) 4-pyridyl, 11) 2,4-difluorophenyl, mmn) 3 ,4-difluorophenyl, nn) 4-methylsulfinyiphenyl, oo) 4-methylsulfonylphenyl, pp) 2-methoxyphenyl, qq) 3-methoxyphenyl, rr) 4-ni trophenyl, s s) 4-aminoniethyiphenyl, and tt) 2-chiorophenyl.

*1 (Ra)b-Ar 2 is selected from the group consisting of: m~ WO 97/05378 PC /US96/1 2922 i8a) b)

C)

d) e) f) g) h) i) j) k) 1)

M)

n) 0) p) q)

S)

U)

V)

w)

X)

y)

Z)

aa) bb) cc) dd) ee) ff) ggT) hih) 4-(methylthio)-phenyl, 4-(ethylthio)-phenyl, 3 -(methylthio)-phenyl, 2-(methylthio)-phenyl, 3-(ethylthio)-phenyl, 4-methy-,,,ullonylphtjyI, 4-ethylsulfonylphenyl, 3-methylsulf onyiphenyl, 2-methylsulfopyiphenyl, 4-methylsulfinylphenyl, 4-ethylsulfonyiphenyl, 3-methylsulfinyiphenyl, 4-(N-methyl -N-benzyl)aminomethylphenyl, 3 -methyl -N-benzyl )aminomethylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3 -methoxyphenyl, 2-benzyloxyphenyl, 4-methylthiophen-2-yl, 4-methylthiophen-3 -yI, 4-acetylaminophenyl, 2-pyrimidinyl, phenyl, 4-aminomethyiphenyl, 4-c yanophenyl, 4-fluorophenyl, 4-chi orophenyl, 4-bromophenyl, 4-carboxyethylphenyl, 2-fluorophenyl, 3 -nitrophenyl, 4-nitrophenyl, 3-fluorophenyl, 4-carboxyphenyl, 4-aminophenyl, 3-aminophenyl, WO 97/05878 WO 9705878PCTIUS96/1 2922 19kk) 4-(O(CH2)3NMe2)-phenyl, 11) 4-(O(CH2)2-piperidin- 1 -yl)-phenyl, mm) 2-methoxyphenyl, nn) 3-chiorophenyl, oo) 4-((4-N-COCH3)piperazin- 1 -yl)-phenyl, pp) 4-trifluoromethyiphenyl, qq) 4-bromothiophen-2-yl, rr) 5-methylthiophen-2-yl, ss) 2-benzoxazolyl, tt) 2-benzofuranyl, uu) 2,5-dimethoxy-phenyl and vv) 4-morpholinyiphenyl; with-the proviso that when (Ra)a-Arl represents aa), bb), jj) or kk) Ar 2 -(Ra)b does not represent ss) or tt); (Ra)0.3-HAr is selected from the group consisting of: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridy I), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-b~pyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridy,.l, k) 3,5-dimethyl-4-pyridyl, 1) 3-quinolinyl, m) 3-pyridazinyl, n) 4-(2-aminobenzyl)pyridyl, and o) 4-(2-amino)pyrimidinyl; RI is: a) substituted orunsubstituted CI-15~ alkyl; and R2 is selected from the group consisting of:

I

I

bond is present, and up to four non-aromatic (non -resonating) carboncarbon double bonds may be present. Preferred alkenyl groups include ethenyl, propenyl, butenyl and cyclohexenyl. As described above with WO 9705878PCTIUS96/129 2 2 20 a) b)

C)

d) e) f) h) i) k) 1) m) n) o) p)

H,

F,

Cl, Br,

CN;

C(O)CI-6 alkyl; C(O)C 1-6 alkyiphenyl; CO2H; C02CI-6 alkyl C02CI-6 alkyiphenyl; CONH2; CONHC 1-6 alkylI; C(O)NC 1-6 alkyl)2; SO2NH2; S0 2 NHC 1-6 alkyl and

SO

2 N(CI-6 alkyl)2.

A further subset of compounds of the invention includes represented by formnula 1: compounds (Ra), (R%-a (Ra)b wherein:

I.

7 WO 97/05878PCUS6122 PCTIUS96/12922 21 and 9 each independently re-present a 5-10 membered aryl or heteroaryl group; a and b represents integers, 0, 1, 2 or 3, such that the sum of a plus b is 1, 2, 3 or 4; Orepresents a heteroaryl group containing from 5 to atoms, 1-3 of which are Iieteroatoms, 0-3 of which heteroatoms are N and 0- 1 of which are 0 or S, said heteroaryl group being unsubstituted or substituted with 1 -3 Ra groups; each Ra independently represents a member selected from the group consisting of: halo; CN, N02, R 21

OR

23

SR

23

S(O)R

21 S02R 21

NR

2

()R

23

NR

2 0~COR 21

NR

20 C02R 2

NR

2 0CONR 20

R

23

NR

20 S02R 2

NR

2 0C(NR 2 0)NHR 2 C02R 23

CONR

2

O~R

23 S02NR 2

()R

23 S02NR 20 C0R 2 S0 2

NR

20 C0NR 2

()R

23 S02NR 20 C02R 2 1

OCONR

2

()R

23

OCONR

2 OSO2R 20 C(O)OCH2OC(O)R 20 and

C(NR

2 O)NR20R 23

R

1 is selected from the group consisting of: H, aryl, C I 1 alkyl, C2-15 alkenyl, C2..15 alkynyl, and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, OR 20

SR

20

N(R

20

S(O)R

2 1 S02R 2 1 SO2N(R 20 2 S02NR 20 C0R 2 SO2NR 2 0 1

CON(R

20

NR

2 0~COR 21

NR

20 C02R 2

NR

2 0CON(R 20

N(R

2 0)C(NR 2 0)NHR 2 0, C02R 20

CON(R

20 2

CONR

2 O~SO2R 21

NR

20 S02R 2 S02NR 2 ('C02R 2 1

OCON(R

2 0) 2 0C0NR 20 S02R 2 1 and OCONR 2

()R

23

R

2 is selected from the group consisting of: H, C 1 5 alkyl, C2-15 alkenyl, C2-15 alkynyl, halo, N02 and heterocyclyl, said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, heterocyclyl, CN, aryl, heteroaryl, R 2 0

OR

20

SR

2 0, N(R 2

S(O)R

22 S02R 22

A

WO 97/05878 PCT/US96/12922 22 2 N(R 20))2, SO 2

NR

2 0COR 22

SO

2

)NR

2 0CON(R 20 2

N-R

20 C0R 22

NR

20 C0 2

R

2 2 NR20CON(R 2 0)2, NR 22

C(NR

2 2

)NHR

22 C02R 20

CON(R

20 2

CONR

2 S0R 2

NR

20 S0 2

R

22 S02NR 20 C02R 22

OCONR

2

OSO

2

R

22 and OCONR 2

OR

23

R

20 represents a member selected from the group consisting of: H, C Ii1 alkyl, C2l15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl;

R

21 represents a member selected from the group consisting of:

CI-

15 alkyl, C 2 15 alkenyl, C2..

1 5 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl being optionally substituted with from 1-3 of halo, heterocyclyl, aryl, heteroaryl, CN, 0R 20 O((CH2)nO) 1 -nR 20

NR

2 0((CH2)nO)I-nR 20 wherein n represents an integer of from 2 to 4, and m represents an integer of from 1 to 3; heterocyclyl, SR 2 0,

N(R

20 2

S(O)R

22 S02R 22

SO

2

N(R

20 S02NR 20 C0R 22 SO2NR 2 0CON(R 20 2

NR

2 ()C0R 22

NR

20 C0 2

R

22

NR

2 0CON(R 2 2

NR

22

C(NR

22 )NHR2 2 C02R 20

CON(R

2 C0NR 20 S0 2

R

22

NR

20 S0 2

R

22 S0 2

NR

20 C02R 22

OCONR

2

OSO

2

R

2 2 OC(O)R 20 C(O)OCH2OC(O)R 2 0 and OCON(R 20 )2;

R

22 is selected from the group consisting of: CI- 15 alkyl, C2alkenyl, C 2 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups;

R

23 is R 2 1 or H;

R

24 is selected from C0R 2 2 C02R 2 2

CON(R

20 S02R 22 and R 23 and when two R 20 groups are present, when R 20 and R 2 1 are present, or when R 2 0 and R 23 are present, said two R 20 groups, R 20 and R1or said R 20 and R 2 3 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a FL--~s I WO 97/05878 PCT/US96/12922 23 heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional O or S atom.

Another subset of compounds of the invention includes compounds wherein Arl and Ar 2 are independently selected from: a) phenyl, b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, 0) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl and k) napthyl; HAr is selected from the group consisting of:: a) pyridyl, b) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridine. and f) pyrimidinyl; RI is: a) H or b) substituted alkyl; and

SR

2 is selected from the group consisting of:: a) H, or b) alkyl and c) halo.

Still another subset of compounds of the invention includes compounds wherein Arl is selected from the group consisting of: a) phenyl, A b) 4-fluorophenyl,

F:;J

I 7) WO 97/05878 PCTIUS96/1 2922 24 4-chiorophenyl, 3-fluorophenyl, 3-chiorophenyl, thiophen-2-yl, thiophen-3-yl, 4-fluorothiophen-2-yl, 4-fluorothiophen-3 -yl, 5-fluorothiophen-2-yl, 5-fluorothiophen-3 -yl, 4-chlorothiophen-2-yi, 4-chlorothiophen-3-yi, -chiorothi ophen-2-y I, 5-chlorothiophen-3-yl, 3-methyl phenyl, 3,4 dichlorophenyl and 3-hydroxyphenyl; (Ra)b-Ar 2 is selected from the group consisting of:: a) 4-(methylthio)-phenyl, b) 4-(ethylthico)-phenyl, c) 3-(methylthio)-phenyl, d) 2-.(methylthio)-phenyl, e) 3-(ethylthio)-phenyl, f) 4-methylsulfonyiphenyl, g) 4-ethylsulfonyiphenyl, h) 3-methylsulfonyiphenyl, i) 2-methylsulfonyiphenyl, j) 4-m ethyl sulIfinyi phenyl, k) 4-ethylsulfonyiphenyl, 1) 3-methylsulfinylphenyl, m) 4-(N-methyl-N-benzyl)aminomethylphenyl, n) 3-(N-methyl-N-benzyl)aminomethylphenyl, o) 4-methoxyphenyl, p) 4-hydroxyphenyl, q) 3-methoxyphenyl, r) 2-benzyloxyphenyl,

I-

WO 97/05878 PCT/US96/12922 4-methylthiophen-2-yl, 4-methylthiophen-3-yl, 4-acetylaminophenyl and 2-pyrimidinyl; (Ra)0-3-HAr is a) b) c) d) e) f) g) h) i) selected from the group consisting of:: 4-pyridyl, 4-(2-methylpyridyl), 4-(2-aminopyridyl), 4-(2-methoxypyridyl), 4-quinolinyl, 4-pyrimidinyl, 9-purinyl, 7-(imidazo[4,5-b]pyridinyl), and 4-(3-methylpyridyl) RI is: H and

R

2 is selected from the group consisting of:

F,

Cl and Br.

The pharmaceutically acceptable salts of the compounds of formula I include the conventional non-toxic salts or the quartemary ammonium salts of the compounds of formula I formed e.g. from nontoxic inorganic or organic acids. For example, such conventional nontoxic salts include those derived from inorganic acids such as hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric and the like; and the salts prepared from organic acids such as acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, ascorbic, pamoic, sulfanilic, 2-acetoxybenzoic, fumaric, toluenesulfonic, methanesulfonic, ethane disulfonic, oxalic, isethionic and the like.

The pharmaceutically acceptable salts of the present invention can be synthesized from the compounds of formula I which 31'" i" i' i i; j WO 97/05878 PCT/US96/12922 -26contain a basic or acidic moiety by conventional chemical methods.

Generally, the salts are prepared by reacting the free base or acid with stoichiometric amounts or with an excess of the desired salt-forming inorganic or organic acid or base in a suitable solvent or various combinations of solvents.

The compounds of the present invention may have asymmetric centers and occur as racemates, racemic mixtures, and as individual diastereomers, with all possible isomers, including optical isomers, being included in the present invention.

This invention also relates to a method of antagonizing or inhibiting the production or activity of cytokines in a mammal in need thereof which comprises administering to said mammal an effective amount of a compound of formula I to antagonize or inhibit cytokine production or activity such that it is regulated down to normal levels, or in some cases to subnormal levels, so as to ameliorate or prevent the disease state.

The compounds of formula 1 can be used in the manufacture of a medicament for the prophylactic or therapeutic treatment of disease states in mammals, which are exacerbated or caused by excessive or unregulated cytokines production, more specifically IL-1, IL-6, IL-8 or TNF, by such mammal's cells, such as but not limited to monocytes and/or macrophages.

Compounds of formula I inhibit cytokines, such as IL-1, IL-6, IL-8 and TNF and are therefore useful for treating inflammatory diseases, such as rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions.

The compounds of formula I may be used to treat other disease states mediated by excessive or unregulated cytokine production or activity.

Such diseases include, but are not limited to sepsis, gram negative sepsis, septic shock, endotoxic shock, toxic shock syndrome, adult respiratory distress syndrome, cerebral malaria, chronic pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis, bone resorption diseases, such as osteoporosis, reperfusion injury, graft vs. host reaction, allograft rejection, fever and myalgia due to infection, such as influenza, cachexia secondary to infection or malignancy, cachexi, secondary to acquired immune deficiency syndrome (AIDS), AIDS and other viral infections, ARC (AIDs related complex), keloid formation, scar tissue formation, Crohn's disease, ulcerative colitis, pyresis, such as F-t ii ,rt -r

E.

WO 97/05878 PCT/US96/12922 -27cytomegalovirus (CMV), influenza virus and the herpes family of viruses such, as Herpes Zoster or Simplex I and II.

The compounds of formula I may also be used in the treatment of inflammation such as for the treatment of rheumatoid arthritis, rheumatoid spondylitis, osteoarthritis, gouty arthritis and other arthritic conditions; inflamed joints, eczema, psoriasis or other inflammatory skin conditions such as sunburn; inflammatory eye conditions including conjunctivitis; pyresis, pain and other conditions associated with inflammation.

The compounds of formula I are normally formulated as pharmaceutical compositions, which are comprised of a compound of formula I and a pharmaceutically acceptable carrier. The compounds of formula I may also be administered in combination with a second therapeutically active compound. These procedures may involve mixing, granulating and compressing or dissolving the ingredients as appropriate to the desired preparation.

The pharmaceutical carrier employed may be, for example, solid or liquid. Solid carriers include lactose, terra alba, sucrose, talc, gelatin, agar, pectin, acacia, magnesium stearate, stearic acid and the like.

Liquid carriers include syrup, peanut oil, olive oil, water and the like.

Similarly, the carrier may include time delay material, such as glyceryl monostearate or glyceryl distearate, alone or with a wax.

A wide variety of pharmaceutical forms can be employed.

Thus, if a solid dosage form is used, the preparations typically be in the form of a tablet, hard gelatin capsule, a troche or lozenge. The amount of solid will vary widely but preferably will be from about 0.025 mg to about I g. When a liquid dosage form is used, the preparation is typically in the form of a syrup, emulsion, soft gelatin capsule, sterile injectable liquid or nonaqueous liquid suspension.

The compounds of formula I may also be administered topically in the form of a liquid, solid or semi-solid. Liquids include solutions, suspensions and emulsions. Solids include powders, poultices and the like. Semi-solids include creams, ointments, gels and the like.

The amount of a compound of formula I, for the methods of use disclosed herein, vary with the compound chosen, the nature and severity of the condition, and other factors. A representative, topical dose

P

WO 97/05878 PCT/US96/12922 28 of a compound of formula I is from about 0.01 mg to about 1500 mg, administered one to four, preferably one to two times daily.

While it is possible for an active ingredient to be administered alone as the raw chemical, it is preferable to present it as a pharmaceutical formulation. The active ingredient typically comprises about 0.001% to about 90% w/w.

Drops according to the present invention may comprise sterile aqueous or oil solutions or suspensions, and may be prepared by dissolving the active ingredient in a suitable aqueous solution, optionally including a bactericidal and/or fungicidal agent and/or any other suitable preservative, and optionally including a surface active agent. The resulting solution may then be clarified by filtration, transferred to a suitable container which is then sealed and sterilized by autoclaving or maintaining at 98-100°C for half an hour. Alternatively, the solution may be sterilized by filtration and transferred to the container by aseptic technique. Examples of bactericidal and fungicidal agents suitable for inclusion in the drops are phenylmercuric nitrate or acetate benzalkoniumrn chloride and chlorhexidine acetate Suitable solvents for the preparation of an oily solution include glycerol, diluted alcohol and propylene glycol.

Lotions according to the present invention include those suitable for application to the skin or eye. An eye lotion may comprise a sterile aqueous solution optionally containing a bactericide and may be prepared by methods similar to those for the preparation of drops. Lotions or liniments for application to the skin may also include an agent to hasten drying and to cool the skin, such as an alcohol or acetone, and/or a moisturizer such as glycerol or an oil such as castor oil or arachis oil.

Creams, ointments or pastes according to the present invention are semi-solid formulations of the active ingredient for external application.

They may be made by mixing the active ingredient in finely-divided or powdered form, alone or in solution or suspension in an aqueous or nonaqueous liquid, with the aid of suitable machinery, with a greasy or nongreasy base. The base may comprise hydrocarbons such as hard, soft or liquid paraffin, glycerol, beeswax, a metallic soap; a mucilage; an oil of natural origin such as almond, corn, arachis, castor or olive oil; wool fat or its derivatives, or a fatty acid such as steric or oleic acid together with an alcohol such as propylene glycol or macrogels. The formulation may i I i~ jl 1:: i: i i i;

F;

i cf l r WO 97/05878 PCT/US96/12922 -29incorporate any suitable surface active agent such as an anionic, cationic or non-ionic surfactant such as sorbitan esters or polyoxyethylene derivatives thereof. Suspending agents such as natural gums, cellulose derivatives or inorganic materials such as silicas, and other ingredients such as lanolin may also be included.

The methods of the instant invention may also be carried out by delivering the agent parenterally. The term 'parenteral' as used herein includes intravenous, intramuscular, or intradermal and subcutaneous administration. The intravenous and intramuscular forms of administration are preferred. Appropriate dosage forms for such administration may be prepared as described above. The instant invention can also be carried out by delivering the compounds of formula I intranasally, rectally, transdermally or vaginally.

The compounds of formula I may be administered by inhalation. By 'inhalation' is meant intranasal and oral inhalation administration. Appropriate dosage forms for such administration, include an aerosol formulations and metered dose inhalers.

Compounds of formula I are prepared (see Scheme I) by the reaction of compound 1, or a protected version thereof with an acetophenone (commercially available) in the presence of potassium cyanide followed by treatment with an alkyl or aryl amine, ammonia or equivalent thereof (ammonium acetate) at elevated temperature.

jiV PCT/US96/1 2922 SilyI= protecting group such as t-butyl dimethylsilyl or trimethylsilyl <4L (Ra)b Heteroaromatic aldehydes 3 may be converted to their trimethylsilyl cyanohydrins 4. Deprotonation and reaction with an aldehyde WO 97/05878 PCT/US96/12922 -31 will provide trimethyl silyl protected benzoins 1. (See, Hunig, S.et al., Chem. Ber. 112, 2062 (1979)).

SCHEME I (Ra)a-

R'NH

2

CH

3

COOH

900C.

(Ra)a- (Ra)b Condensation of the 1,4-diketone 6 with ammonia or an amine gives rise to pyrroles (Paal Knor Synthesis). Compound 6, a 1,4-diketone, (see Scheme II) is reacted with ammonia, or a compound that gives rise to ammonia such as ammonium acetate or a primary amine, to provide compounds of formula I. This reaction can be conducted in the presence of an acid catalyst, such as acetic acid, or titanium tetrachloride at an elevated temperature. 1,4-diketone 6 is thus regioselectively constructed so that the appropriate groups are present on the pyrrole ring.

WO 97/05878PCIS6122 PCT/US96/12922 32 R 2 Rao- 3 HAr Base, LCHR 2 00Ar 2 (Ra)b Ra 0 3 HArAr DMSO, room temp (Ra) Ar 1 0(R a) Arl~ 0 0 (Ra)b Base= NaH or NaN(TMS) 2 7 L= Leaving group such as 6 Br, 1, OTos, OMs Alkylation of Il-aryl-2-heteroarylethanones 7 with bromoacetophenones or other leaving group substituted acetophenones provides 1,4 diketones 6 (Iyer, R. Gopalachari, R. Ind. J. Chem. HI, 1260, 1973). Bromoacetophenones are readily prepared by bromination of acetophenones (for example by treatment with bromine in acetic acid or benzyltrimethylammoniurn bromide).

LU

Me 1. 1. Lithium diisopropyl amide, 1. H 2 0Hr HAr THF, -780C HAr a a (Ra)a-G Ar 0-3 0-3 0 8 0 N(Me)OMe 9 Ethanone 7 is prepared by the addition of a heteroaryl methyl anion 8 to an activated benzoic acid 9 (for example esters, acid chlorides, At nitriles and N-methoxy-N-methyl amides) (see: Wolfe, J. F. et al J. a, Chem. 39, 2006 1974 and Kaiser, E. M. et al Synthesis 705 1975 and Obsawa A. Chem. Pharmn. Bull. 26, 3633. 1978).

WO 97/05878 PCT/US96/12922 -33- O H

A(R

(Ra)a 1. LDA, THF 2.

TMSCN

Znl2, CH 3

CN

3. H 2 0 L= Br, I, CI, OTos, OMs, O'f (ArR (Ra)a (Ra)o 0 3 HAr

O

7 Compound 7 may also be prepared by alkylation of aryl trimethyl silyl protected cyanohydrins 10. Treatment of 10 with lithium diisopropyl amide in THF and addition of a heteroaryl methyl group finctionalized with a leaving group L (for example: Br, I, Cl tosylate, mesylate) followed by acid catalyzed hydrolysis of the silyl cyanohydrin group provides ethanone 7 (Deuchert, Hertenstein, Hunig, S.; Wehner, G. Chem. Ber. 112, 2045, 1979).

Is;- F' PCTIUS96/12922 WO 97/05878 34 SCHEME IfI Ra0-3- HAr 0 1. 12, Zn 0 T0 4 2. K 2 C0 3 ArCN 12 R ao-3' (R')b The reductive cross coupling of a 1,3 diketone 11 with a nitrite 12 in the presence of zinc and titanium tetrachloride also gives rise to compounds of formula 1, See Scheme III, (Gao, J. Hu, Chen, Yuan, Chen, W. Tet Lett. 34, 1617, 1993). The 1,3 diketone 11 may be prepared by alkylation of 4 with bro moacetophen ones.

I WO 97/05878 PCTIUS96/12922 35 SCHEME IV O H HAr (R a)0 14 Ar 2 (R a)b NaOH 0 catalyst= cyanide, thiazoliumn salt Et 3 N, catalyst (R a)b (Ra)b th lazoli urn salt, Et 3

N

(CH

2 O)n, BU 4

N+OH-,

KOH, THF, H 2 0 The 1,4 diketone 13 can also be prepared as described in Scheme IV. A heteroaryl aldehyde 14 is condensed with a methyl ketone 15 to provide an a43p-unsaturated ketone 16. In the presence of a catalyst such as cyanide or R21 or said R 2 0 and R 2 3 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a V ix.-.

a ~I h ~.II A I: WO 97/05878 PCT/US96/12922 -36a thiazolium salt the aryl aldehyde 17 reacts with 16 to give 13 (Stetter, H.

J. et al Heterocyclic Chem. 14, 573, 1977 and Stetter, H. et. al. Organic Reactions, Vol. 40, 407-496). Condensation of 13 with an amine provides compounds of formula I. Alternatively, variations of Ar 2 may be introduced by addition of Ar 2 aldehydes to alkenes 17b that are readily ,-ailable from the ketones 7 described above.

SCHEME V Br- 0 19 Et0C-j OEt P(OEt) 3 1. LDA 2.21 SOEt 0, Ar (Ra)b 0 1. NaH 2.

-Ra0- 3 14 Et

O

0 (Ra)b 21 Ra 03 HAr 16 Intermediate 16 may be prepared by a Homer-Emmons reaction of the anion of 18 with the heteroaryl aldehyde 14. The reagent 18 may be prepared by reaction of the bromoketone 19 and triethyl phosphite or by reaction of the lithium salt of diethyl methylphosphonate with an ester 21.

r I n-~ i)" k WO 97/05878 PCT/US96/12922 -37- SCHEME VI (Ra) 0 o- HAr.

(R)b HN03,(CH 3

CO)

2 0 Halogenating agent R= ""alo

R

2 =N0 2 (Ra)o.3- (R)a- A nitro group may be introduced into the pyrrole nucleus at the 3 position (generic nomenclature R 2 by electrophilic nitration of a compound such as 22 (or a less advanced intermediate) in the presence of fuming nitric acid and acetic anhydride.

Halogens may be introduced by electrophilic halogation with reagents such as XeF 2

(R

2 N-chlorosuccinimide in DMF (R 2

N-

bromosuccinimide in DMF (R2 3 12 in KI Other reagents are available to carry out this conversion, the choice of reagent being dependent on the presence of functional groups that may be sensitive to the reagent being utilized. See Pyrroles Part 1, R. Alan Jones, ed., Heterocyclic Compounds ,Vol 48 Part 1, John Wiley, New York, 1990. Pages 348-391.

r L .LI*CI1.- !4 i

S

WO 97/0 78 PCT/US96/12922 -38- SCHEME VII acylation L=Leaving group (Ra (Ra) 0 (Ra)a I (Ra)b X=carbon or nitrogen Introduction of alkyl and heterocyclyl alkyl groups at the 3 position is described. Direct introduction is possible as described in the use of 1,4 diketone 6 as a precursor of compounds of formula I. The preparation of the pyrrole 23 containing a hydroxy methyl group at position 3 (R 2 provides an intermediate that is readily elaborated into compounds of formula I.

Acylation of the hydroxyl group with activated acids or isocyanates provides esters and carbamates respectively of formula I.

Conversion of the hydroxy group into a leaving group 24 (for example Br, I, Cl, triflate, etc.) enables the introduction of alkyl, heterocyclyl and amines and thiol groups by displacement with a nucleophile. Suitable nucleophiles include for example, an alkyl or heterocyclyl anion, a primary or secondary amine or a thiol.

!I

i: i i, f o 3r'' ii r-

I

WO 97/05878 PCT/US96/12922 -39- SCHEME VIII

(R

.CI, Br 0

(R

o OEt 27 22 R (R

R

1

NH

2 a)-3 HAr a)a Ar

NH

24 R reducing agent such as LiAIH 4 reducing agent such Sas NaBH 4 -(Rab

I

i 26 Hydroxy methyl substituted pyrroles 23 may be prepared by reduction of esters 25a through the reaction with a reducing agent such as

V

WO 97/05878 PCT/US96/12922 lithium aluminum hydride. The ester 25a may be prepared by treatment of 1,2-disubstituted-2 halo ketones 22 with 3-keto esters 27 and ammonia or an amine, producing ester 25a (Hantzsch. Ber. Dtsch. Chem. Ges. 23, 1474, 1890). Alternatively, a 2-amino ketone 24 reacts with a 3-keto ester 27 to produce A further method of synthesis of 23 is via reduction of the aldehyde 26 with a reducing agent such as sodium borohydride. The aldehyde may be prepared by treatment of the R3 -unsubstituted pyrrole with the Vilismeyer reagent (POC13/DMF).

SCHEME IX Rao3--HAr CI, Br (Ra)a Ar R 2 22

R'NH

2

A

Rao--- HAr (Ra)a Ar N Ra HA Rao- HAr 1. POC1 3

DMF

0 (Ra)a -Ar' N (Ra)a R I (R)b (Ra)b

R

2

COOR

20

CN

-r 2 (Ra)b Oxidation 2. Esterification

H

HArl 26 The ester and nitrile of formula I may be prepared as shown in Scheme IX by treatment of halo ketones 22 with keto esters or keto nitriles 23a witliammonia or an amine producing ester I (Hantzsch. Ber. Dtsch.

Chem. Ges. 23, 17, 1890). Alternatively a 2-amino ketone 24 reacts with a 3-keto ester 23a to produce I. A further method of synthesis of n -l WO 97/05878PC/S/192 PCT/US96/12922 -41 Compounds of formula I is by oxidation and esterification of aldehyde 26.

The aldehyde is prepared by treatment of the pyrrole 25 with the Villsmeyer reagent (POCI 3

IDMF).

SCHIEME X Si iyich oride Et 3 N, 0H 2 C1 2 Ra (Ra)a Ar 1

TMSCI

R 20 S (O)R 20 S(Ra)b R 21

SOCI

P trialkyisilyl pyridine (Ra)a- 1) R 21 COCI pyridine or

RCOCI

AICd 3 2)

TBAF

oxidize 1. TBAF, CH CI 2. oxidize i WO 97/05878 PCT/US96/12922 -42- (Rab ID )erivatize with R 1 (R )a- The pyrrole 22 prepared as described herein may be silylated on the nitrogen atom to give 27 by treatment with a silyl chloride and base in a solvent such as methylene chloride. The pyrrole 27 may then be sulphenylated with a sulphenylchloride under basic conditions to provide 28 Org. Chem. 6317 1990). Oxidation of 28 with a reagent such as mchloroperoxybenzoic acid will give the sulphone 29. Removal of the silyl group and derivatization of the pyrrole will give compounds of Formula I.

Compound 22 may also be converted to the sulphide 30 by reaction of 22 with a symmetrical sulfoxide in the presence of trimethylsilylchloride (TMSCI) to give 30. Oxidation of 30 with a reagent such as mchloroperoxybenzoic acid will give 29. The silyl pyrrole 27 may also be acylated with an acid chloride to give the ketone 31.

H""

I

r C1 i i WO 97/05878 PCT/US96/12922 -43 Removal of the silyl group from 29 and 31 and derivatization of the pyrrole will give compounds of formula I. Pyrroles such as 22 may also be sulfinylated directly without N-protection, by treatment with sulphinyl chloride in a solvent such as dichloromethane at 0°C Org.

Chem. 5336, 1980). Oxidation as described above thus provides pyrroles of formula I where R 3 is S02R 2 1 SCHEME XI (Ra)b- -COX (33) base (Ra), (Ra)b (Ra)-

-KV.

N3 H 32 R' M Me, Et, Bn, t-Bu X= Cl, or other acid activating agent ester dicyclohexylcarbodiimide Ar 2 (Ra)b Ral.s- Ar Note:R 1 may also be a protecting group that may be removed in the final step to give compounds where

R

1 is H.

(R

TBAF tetrabutyl ammonium fluoride 36 3 6 HAr R 2 -CO2 37 R a0-3 'a 1 N Ar (Ra)b R 1

R

2

-CO

2

R

2 2 -CN, -CONR20R 2 3

SO

2

R

2 1

COR

20 The amino acid ester 32 may be acylated with an acid 33 that is suitably activated (acid chloride or other activating group used in amide coupling reactions) to give 34 (Scheme XI). Hydrolysis of the ester protecting group will provide 35. Cyclization by treatment with an acid x i-i WO 97/05878 PCT/US96/12922 -44activating group such as dicyclohexylcarbodiimide (DCC) will give the oxazolium species 36. Addition of an alkyne 37 to 36 may give a pyrrole of Formula I via a 3+2 cycloaddition followed by loss of carbon dioxide.

Various R 3 groups may be incorporated in this manner.

SCHEME XII (Ra)o.3-(HAr R 2 E Ar (RaGa G N\ (Ra) Ar catalyst (Ra)b pyrrole as electrophile (R)o 0 3 HAr R2 )a Ar N (Ra) 0 3 HA R2 /E (Ra)b (Ra)a- r catalyst Ar G N Br, I, OSO 2

CF

3 pyrrole as nucleophile (Ra)b SnMe 3

B(OH)

2 ZnCI, MgBr catalyst=: Pd(PPh 3 4 Pd(PPh 3 2 CI2

P=R

1 or protecting group such as trialkyl silyl, benzyl, substituted benzyl, t-butyloxycarbonyl Aryl and heteroaryl rings may also be appended to the pyrrole ring system by utilization of organometallic coupling technology (Kalinin, V. Synthesis 413 1991). See Scheme XIII. The pyrrole ring may function B as an electrophile or as a nucleophile.

Any of the three appended aromatic or heteroaromatic rings may be attached to the pyrrole ring system (Alvarez, A. J. et al. J. Or.

Chem. 1653, 1992 (use of boronic acid and tributyl stannanes for coupling I to aromatic and heteroaromatic rings)). Attachment of pyrrole pendant groups may be carried out with or without other Ar, HAr, R 2 or R 3 groups attached.

t i, r 1 WO 97/05878 PCT/US96/12922 The synthesis of pyrroles containing nucleophilic groups for coupling reactions depends on the pyrrole substitution pattern. Lithium anions are prepared by metalation of a regioselectively halogenated pyrrole, or the regioselective deprotonation of the pyrrole preferably by the use of a directing functional group. The resulting anion may then be trapped by a trialkyl stannyl halide or a trialkyl borate or transmetalated to magnesium or zinc by treatment with appropriate halide salts. A further method used to incorporate a trialkyl stannyl group is the coupling of a bromo, iodo or triflate substituted pyrrole with hexalkylditin in the presence of a palladium catalyst.

The synthesis of pyrroles incorporating electrophilic groups may be carried out by the regioselective halogenation of a pyrrole (Pyrroles Part 1, R. Alan Jones, ed., Heterocyclic Compounds Vol 48 Part 1, John Wiley, New York, 349-391,1990). The regioselectivity of halogenation will depend on the size, nature and substitution position. on the pyrrole ring as well as the presence or absence of the N-alkyl protecting group. Triflates may be prepared by acylation of hydroxy pyrroles with triflic anhydride.

The reaction conditions used will depend on the nature of the coupling species. In the case of magnesium, zinc and stannyl coupling reactions the solvent employed is toluene, or DMF under anhydrous conditions. In the case of boronic acid couplings, a heterogenous system is used of water, toluene, and dimethoxyethane, or ethanol in the presence of a base such as sodium carbonate, or bicarbonate. In general, the reaction takes place at an elevated temperature (80-100 The catalysts used will most likely depend on the structure of the components to be coupled as well as the functional groups and belong to the group consisting of tetrakistriphenylphosphinepalladium or palladium bis triphenyl phosphine dichloride.

Coupling of alkenes or alkynes with 4-halo pyrroles (Heck reaction, see Kalinin, V. Synthesis 413 1991 for a review) will give rise to

R

2 (generic nomenclature) alkenyl and alkynyl substituted pyrroles that may i be reduced or otherwise modified to provide compounds of formula I.

S: Functional groups such as halogens, sulfides, nitro groups, ethers and other groups stable to the reaction conditions used in the linear synthesis of the pyrroles are incorporated in the initial steps of the reaction sequence. Sulfides may be oxidized to sulfoxides and sulfones with WO 97/05878 PCT/US96/12922 46reagents such as m-chloroperbenzoic acid. Sulfides may also be converted to sulfonyl chlorides by oxidation and chlorination by chlorine in water.

Primary amines are prepared from nitro groups by catalytic (Pd/C, H 2 or Raney Nickel, H 2 or chemical means (CoC1 2 NaBH 4 Alkylation of amines to give secondary and tertiary amines is achieved by reductive alkylation (aldehyde, NaCNBH 4 or alkylation with an alkyl group substituted with a leaving group in the presence of a base such as

K

2 C0 3 Tertiary amines may, alternatively, be carried through the reaction sequence to the pyrroles. Acylation of primary or secondary amines with activated acids, chloroformates, isocyanates and chlorosulfonates will give rise to amides, carbamates, ureas and sulfonamides, respectively.

Other methods of preparing amides and ureas are useful; such as for example, treatment of the amine with phosgene, or an equivalent thereof, followed by acylation of an alcohol or amine with the intermediate activated chloroformamide.

Carboxylic acids are best introduced as esters early in the synthesis. Saponification will provide carboxylic acids. Transesterification or esterification of the acids will give esters. Carboxylic acids may be converted to amides by activation and reaction with amines. Phenols are best introduced in a protected form early in the synthetic sequence to the pyrrole. Removal of the protecting group provides a phenol which may subsequently be alkylated in the presence of an alkylating agent and base to give an ether, or acylated with an isocyanate to give carbamates. Phenols may be converted to aryl ethers by reaction with an aryl bismethane in the presence of copper II acetate.

Aryl and heteroaryl groups may be attached to pyrrole pendant aryl and heteroaryl groups by application of coupling chemistry technology as outlined above.

The sequence and conditions of the reaction steps is dependent on the structure and functional groups present. Protecting groups may be necessary and may be chosen with reference to Greene, et al., Protective Groups in Organic Synthesis, John Wiley Sons, Inc., 1991.

The blocking groups are readily removable, they can be removed, if desired, by procedures which will not cause cleavage or other disruption of the remaining portions of the molecule. Such procedures include chemical and enzymatic hydrolysis, treatment with chemical reducing or oxidizing i WO 97/05878 PCT/US96/12922 -47 agents under mild conditions, treatment with fluoride ion, treatment with a transition metal catalyst and a nucleophile, and catalytic hydrogenation.

Examples of suitable hydroxyl protecting groups are: tbutylmethoxyphenylsilyl, t-butoxydiphenylsilyl, trimethylsilyl, triethylsilyl, o-nitrobenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, benzyloxycarbonyl, tbutyloxycarbonyl, 2,2,2-trichloroethyloxycarbonyl, and allyloxycarbonyl.

Examples of suitable carboxyl protecting groups are benzhydryl, onitrobenzyl, p-nitrobenzyl, 2-naphthylmethyl, allyl, 2-chloroallyl, benzyl, 2,2,2-trichloroethyl, trimethylsilyl, t-butyldimethoylsilyl, tbutldiphenylsilyl, 2-(trimethylsilyl)ethyl, phenacyl, p-methoxybenzyl, acetonyl, p-methoxyphenyl, 4-pyridylmethyl and t-butyl.

The following examples are illustrative and are not limiting of the compounds of this invention.

PREPARATIVE EXAMPLE 1 4-Fluoro-2-(4-pyridyl)acetophenone (1) To a solution of lithium diisopropylamide (Aldrich Chemical Co. 2.0 M in heptane,THF and ethylbenzene) 3.1 mL (6.3 mmol) in 6 mL of anhydrous THF at -780C under nitrogen was added 0.5 g (5.3 mmol) of 4picoline dropwise. The reaction mixture was stirred for 20 minutes and then treated with a solution of 0.9 g (5.3 mmol) of 4-fluoro-(N-methyl-Nmethoxy)-benzamide in THF. The reaction mixture was warmed to 0oC and quenched by addition of 10 mL of brine. The mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic phases were dried over MgSO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give an orange solid (4-Fluoro-2-(4-pyridyl)acetophenone). HI NMR (CDC13 300 MHz): 4.23 s 2H), 7.1-7.18 m 8.02 (dd, 2H), 8.55 (dd, 2H).

PREPARATIVE EXAMPLE 2 4-Fluoro-2-(2-pyridyl)acetophenone (2) To a solution of lithium diisopropylamide (Aldrich Chemical i Co. 2.0M in heptane,THF ethylbenzene) 5.2 mL (10.5 mmol) in 6 mL of anhydrous THF at -78oC under nitrogen was added 0.93 g (10 mmol) of 2picoline dropwise. The reaction mixture was stirred for 20 minutes and then treated with a solution of 1.71 g (5.3 mmol) of 4-fluoro-(N-methyl-N-

V"'

1 WO 97/05878 PCT/US96/12922 48 methoxy)-benzamide in THF. The reaction mixture was warmed to 00C and quenched by addition of 10 mL of brine. The mixture was extracted with ethyl acetate (3 x 10 mL) and the combined organic phases were dried over MgSO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give a solid. Hi NMR (CDC1 3 300 MHz): 4.49 6.0 6.97 7.- 3-7.12 7.62 7.82 8.10 8.28 8.57 The compound exists in a keto/enol equilibrium as determined by HI-NMR.

FAB ms:216 i I

I

WO 97/05878PC/S6122 PCT/US96/12922 49 PREPARATIVE EXAMPLES 3- C" 3 0 H2' r (Ra) 0 3 The following compounds are prepared in the manner described above: TABLE I 0 (Ra )a Ar 1 -I C2"e

R)

Prep Ex (R (Ra) 0 3 3 4-pyridyl 4 phenyl-4-F 4-(3-methyl)-pyridyl phnl4F4-lu inoliny I 6 phenyl-3-Cl 4-pyridyl 7 2henyl-2-CI 4-pyridyl 8 phenyl-4-F 4-pyrimidinyl 9 phenyl-4-F 4-(2-Me)-pyridyI* phenyl-3,4-di-F 4-pyridyl *Purified by chromatography from the side product formed from alkylation of the 2-methyl group of 2,4-d imethylIpyri dine.

I

WO 97/05878 PCT/US96/12922 PREPARATIVE EXAMPLE 11 (Method 1)

F

N

YO,

0 0

F

To a solution of 0.14 g (0.67 mmol) of 4-fluoro-2-(4pyridyl)acetophenone from Preparative Example 1 in 2 mL of anhydrous DMSO under nitrogen at room temperature was added 0.67 mL of a 1.OM solution of sodium hexamethyl disilazide in THF. After 15 minutes a solution of 4-fluoro-bromoacetophenone 0.14 g (0.67 mmol) in DMSO was added dropwise. The reaction mixture was diluted with 5 mL of water after minutes and extracted with ethyl acetate (3x 10 mL). The combined organic extracts were washed with brine and dried over MgSO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give an oil. HI NMR (CDC1 3 300 MHz): 3.26 (dd, 1H); 4.12 (dd, 1H); 5.23 (dd, IH); 7.04-7.13 4H); 7.27 (dd, 2H); 7.95-8.05 4H); 8.51 2H).

PREPARATIVE EXAMPLE 12 (Method 2) 0.2 g (1.02 mM) of the product of Preparative Example 3 in 3 mL of dry DMF under nitrogen was treated with 48.7 mg of 60 sodium hydride dispersion in oil. The reaction mixture was stirred at room temperature for one hour. 298 mg (1.22 mM) of 2-bromo-4'nitroacetophenone dissolved in 1 mL of DMN: was added dropwise. The I,-I

I-

~~-L~~~~L~raR~asu WO 97/05878 PCT/'US96/12922 -51 reaction mixture was stirred at room temperature for 2 hours and was then treated with water and 10% citric acid solution. Ethyl acetate was added and the layers were separated and the aqueous phase was extracted with ethyl acetate, the organic phase was dried over MgS4 filtered and was concentrated in vacuo. The residue was purified by flash chromatography over silica gel eluting with 25-50% EtOAc/Hexanes to give the desired product.

PREPARATIVE EXAMPLES 13-37 0 The compounds of preparative example. 13-37 were prepared using starting materials from the preparative examples above.

0 CH( (Ra-Aa r' CH2"i (Ra)3 0 (Ra) r 2

CH

2 Br WO 97/05878PC/S6122 PCT/US96/12922 52 TABLE 11 Prep. I Example Ra)b ~I~(Ra)o 3 Method 13 Ph-4-F Ph-4-OMe 4-Pyridyl 14 Ph-4-F Ph-2,5-di-OMe 4-Pyridy 1 Ph-4-F Ph-4-Br 4-Pyridyl 16 Ph-4-F Ph-4-Cl 4-Pyridyl 1 17 Ph-4-F Ph-4-SMe 4-Pyridyl 18 Ph-4-F Ph-4-OMe 2-Pyridyl 19 Ph-4-F Ph-4-Br 2-Pyridyl Ph-4-F Ph-4-Cl 2-Pyridyl 1 21 Ph-4-F Ph-2,5-di-OMe 2-Pyridyl1 22 Ph Ph-4-OMe 4-Pyridyl1 23 Ph Ph-4-CI -4-Pyridyl 1 24 Ph Ph-2,5-di-OMe 4-Pyridyl I Ph Ph-4-F 4-Pyridyl1 26 Ph Ph-4-COOEt 4-Pyridyl 2 27 Ph Ph-2-F 4-Pyridyl 2 28 Ph Ph-3-N02 4-Pyridyl 29 Ph-4-F Ph-4-SI e 4-(3-Me)-pyridyl 1 Ph Ph-3-F 4-Pyridyl -2 31 Ph-2-N0 2 4-Pyridy 2 32 Ph-4-F Ph-4-SMe 4 -quinolinyl 33 Ph-2-CL Phenyl 4-Pyridyl:: PCT/US96/12922 WO 97/05878 -53- 34 Ph-3-Cl Ph-4-SMe 4-Pyridyl 1 Ph-4-F Phenyl 4-pyrimidinyl 1 36 Ph-4-F Ph-4-SMe 4-(2-Me)-pyridyl 1 37 Ph-3,4-F Ph-4-SMe I 4-Pyridyl 1 PREPARATIVE EXAMPLE 38

N\

0 To 4.4 mL of dry pyridine under nitrogen was added 2.14 g (0.02 mol) of pyridine-4-carboxaldehyde followed by 2.4 g (0.02 mol) acetophenone and 1.46 g (0.02 mol) diethylamine. The solution was refluxed for 2.5 hours, cooled to room temperature and poured into 100 mL of ice water containing 10 mL of concentrated hydrochloric acid. The resulting solution was adjusted to pH 5.0 by addition of IN NaOH solution while stirring rapidly. The mixture was filtered and the residue was washed with 15 mL of water. The solid was dried in vacuo to give the product.

HI NMR (CDC13 300 MHz): 7.42-7.56 3H); 7.59-7.65 (m, 1H); 7.68 2H); 8.11 (dt, 2H); 8.69 (bd, 2H).

PREPARATIVE EXAMPLE 39 1 -(4-chlorophenvl)-4-phenl-2-(4-pvridyl)-butan- 1,4-dione To 0.019 g (0.039 mMol) of sodium cyanide in 2 ml of dry DMF at 300C was added a solution of 4-chlorobenzaldehyde in 1.5 mL of DMF over 20 minutes. A thick slurry formed. After 30 minutes a solution of the product of preparative example 38 in 1.5 mL of DMF was added WO 97/05878 PCT/US96/12922 54dropwise. The mixture was agitated and stirred for 3 hours. The mixture was diluted with 30 ml of water and extracted with ethyl acetate (2 x mL). The organic phase was washed with brine (1 x 15 mL) and dried over MgSO 4 The mixture was filtered and the filtrate was concentrated in vacuo to give the title compound as an oil.

PREPARATIVE EXAMPLE 4-phenvl-2-(4-pyridyl)- 1 -(4-trifluoromethylphenvl)-butan- 1.4-dione A solution of 0.15 g (0.71 mMol) of 1-phenyl-3-(4-pyridyl)ethene-1-one (Preparative Example 38), 0.14 g (7.8 mMol) of 4trifluoromethylbenzaldehyde, 0.035 g (0.35 mMol) of triethylamine and mg (0.07 mMol) of 3,4-dimethyl-5-(2-hydroxyethyl)-thiazolium iodide in 3 mL on ethanol was heated at 800C for 3 hours. The reaction mixture was cooled to room temperature, diluted with 10 mL of water and was washed with water and brine and dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by MPLC over silica gel eluting with 2.5% MeOH/CH2C12 to give the desired product.

HI NMR (CDCl 3 300 MHz): 7.42-7.56 3H); 7.59-7.65 1H); 7.68 (d, 2H); 8.11 (dt, 2H); 8.69 (bd, 2H).

I, U WO 97/05878PCIS6122 PCT[US96/12922 55 PREPARATIVE EXAMPLES 41-60

CHO

(Ra)a- Following the procedure described above the following compounds are prepared: TABLE III (Ra)a- Prep Ex.# 41 4-methylthio-Ph 42 4-Me-Ph 43 4-t-BuO-Ph 44 3 ,4-dichloro-Ph 3,4-dibenzyloxy-Ph 46 2-thiophenyl 47 3-furoyl 48 3-Cl-Ph 49 2-pyridyl 4-CN-Ph' 51 4-methoxycarbonyi-Ph n III laab2a~B~l(ra~ WO 97/05878 PCT/US96/12922 -56- 52 5-Me-2-thiophenyl 53 3-Me-2-thiophenyl 54 3-quinolinyl 3-Pyridyl 56 4-Pyridyl 57 4-F-Ph 58 2,4-di-F-Ph 59 3-CN-Ph 3,4-di-F-Ph Ph phenyl; Pyr pyridyl; 3,4-di-F 3, 4-difluoro PREPARATIVE EXAMPLE 61 OSi(Me) 2 -t-butyl 0

N

F

To a 2 liter 3 neck flask equipped with a mechanical stirrer under N2 was added 54.6 g (0.59 m) diisopropylethylamine and 150 mL of THF. The solution was cooled to -200C and treated with 268 ml (0.67 m) of 2.5 M butyl lithium over 20 minutes. To the reaction mixture was added 125 g (0.56 mMol) of 4-(t-butyldimethysilyloxymethyl)pyridine in 100 ml of THF over 30 minutes. The reaction mixture was stirred for 1 hour at -150C and then treated with a solution of 108 g (0.59 mMol) of 4-fluoro-(Nmethyl-N-methoxy)-benzamide dissolved in 100 mL of THF dropwise. The reaction was warmed to OOC and stirred for 1 hour and then was warmed to room temperature and was quenched by addition of 1 liter of 20% NH4C1 solution. The aqueous phase was extracted with EtOAc (3 x 500 mL). The combined organic phases were washed with water (1 x 500 mL), 1 x 500 mL brine and were dried over MgSO4. The mixture was filtered and the filtrate was concentrated in vacuo to give a dark oil. The product was purified by flash chromatography over silica gel eluting with 10-20% EtOAc/hexanes.

Ii WO 97/05878 PCT/US96/12922 -57- EXAMPLE 1 2-(4-fluorophenvl)-5-(4-fluorophenvl)-3-(4-pyridyl-pyrrole

H

F

Method 1: To a solution of 0.35 g (0.99 mmol) of the compound of preparative example 11 in 15 mL of glacial acetic acid was added 0.35 g (4.7 mmol) ammonium acetate. The mixture was heated to 110 C over 10 hours at which time a further 1 g of ammonium acetate was added. Heating was continued at 1 10C for 6 hours. The reaction mixture was concentrated to 50% of the original volume, and 25 mL of water was gradually added. A solid formed, which was filtered and dried in vacuo to give the title compound. H 1 NMR (CDC13 300 MHz): 6.61 1H); 6.98- 7.05 4H); 7.20 (dd, 2H); 7.33 (dd, 2H); 7.53 (dd, 2H); 8.29 2H).

FAB ms:333 Method 2: The condensation in method 1 is followed by an alternative work-up procedure. The reaction mixture was diluted with 5 mL of water and extracted with ethyl acetate (3 x 4 mL). The organic extracts are dried over MgS0 4 filtered and the filtrate concentrated in vacuo. The residue was purified by rotary chromatography to give the desired product.

EXAMPLES 2-43 0.15-0.2 g of the 1,4-diketone from Preparative Examples 13- 37 and 39-60 is dissolved in 3 mL of acetic acid to which is added 1.0 g of ammonium acetate. The mixture is heated at 110oC for 1.5-10 hours. The work-up of Method 1 or 2 is then utilized to isolate the compounds (Examples 2-50) listed below in Table IV.

I TABLE IV t WO 97/05878 PTU9/22 PCT[US96/12922 58- Ex FAB ms (Ra )a ArAr (Ra)b (Ra) 0 3 Hr 2 Ph-4-F Ph-4-OMe 4-Pyridyl 345 3 Ph-4-F Ph-2,5-di-OMe 4-Pyridy1 375 4 Ph-4-F Ph-4-Br 4-Pyridyl 393/395 Ph-4-F Ph-4-C1 4-Pyridyl 349 6 h4FPh-4-OMe 2-Pyridyl 345 7 h4FPh-4-Br 2-Pyridyl 393/395 8 h4FPh-4-C1 2-Pyridyl 349 9 Ph-4-F Ph-2,5-di-OMe 2-Pyridyl 375 1PhPh-4-OMe 4-Pyridyl 327 11 Ph Ph-4-Cl 4-Pyridy1 331 12 Ph Ph-2,5-di-OMe 4-Pyridyl 357 13 Ph Ph-4-F 4-Pyridyl 315 14 Ph-4-CI Ph 4-Pyridyl 331 Ph-4-F Ph-4-.SMe 4-Pyridyl 361 16 Ph-4-SMe Ph 4-Py ridyl 325 17 4-CF3-Ph Ph 4-Pyridyl 365 18 4-Me-Ph -Ph 4-Pyridyl 311 19 4-tBuO-Ph Ph 4-Pyridyl 369- 3,4-Cl-Ph Ph 4-Pyridyl 366 21 3,4-di-(OBn)-Ph Ph 4-Pyridyl 509 22 3-Cl-Ph I Ph 4-pyidyl 331 23 4-CN-Ph I Ph 4-Pyridyl 322 r,

A

WO 97/05878 PTU9/22 PCTIUS96/12922 59 24 4-(COOMe)-Ph Ph 4-Pyridyl 355 Ph 4-CO2Et-Ph 4-Pyridyl 369 26 Ph 2-F-Ph 4-Pyridyl 315 27 Ph 3-N02-Ph 4-Pyridyl 342 28 5-Me-thiophen- Ph 4-Pyridyl 317 2-yl__ 29 3-Me-thiophen- Ph 4-Pyridyl 317 2-yl__ 4-F-Ph 4-SMe-Ph 4-(3-Me)-PyridYl 375 31 Ph 2-N02-Ph 4-Pyridyl 342 32 Ph 3-F-Ph 4-Pyridyl 315 33 Ph 4-N02-Ph 4-Pyridyl 342 34 4-F-Ph Ph 4-Pyridyl 315 2,4-F-Ph Ph 4-Pyridyl 333 36 3-CN-Ph Ph 4-Pyridyl 322 37 3,4-F-Ph Ph 4-Pyridyl 333 38 4-F-Ph 4-(SMe)-Ph 4-quinolinyl 411 39 2-Cl-Ph Ph 4-pyridyl 331 3-Cl-Ph 4-(SMe)-Ph 4-pyridyl 377 41 4-F-Ph Ph 4-pyrimidinyl 316 42 4-F-Ph 4-(SMe)-Ph 4-(2-methyl)- 375 _____pyridyl 43 3,4-di-F-Pb 4-(SMe)-Ph 4-pyridyl 379 L)T

A

WO 97/05878 PCT/US96/12922 EXAMPLE 44

N

F

O

H S

CH

3 2-(4-fluorophenvl-5-(4-methylsulfinylphenyl)-3-(4-pyridyl) pyrrole To a solution of Example 15 (55.5 mg (0.15 mmol) in 2 ml of acetic acid and 1.4 ml of water was added potassium persulfate (50.0 mg (0.18 mmol). After stirring for 1.5 hours at room temperature the solution was neutralized by addition of ammonium hydroxide solution. The solid product was recovered by filtration and purified by flash chromatography eluting with 5% MeOH/CH2CI2 to give the product. FAB ms: Calc.: 376 for C22H17N2SOF; Obs.: 377 EXAMPLES 45-49 The following compounds are prepared using the procedures described above. An alternative work up was utilized wherein the reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were dried over MgSO4, filtered and purified by flash chromatography eluting with 5% MeOH/CH2C2 to give the product.

TABLE V Har Aryll N /O H S Example Aryll Har FAB ms 4-F-phenyl 4-(3-Me)-pyridyl 391 46 4-F-phenyl 4-quinolinyl 427 S47 3-Cl-phenyl 4-pyridyl 393 It

I

PCT/US96/12922 WO 97/05878 -61 48 4-F-phenyl 4-(2-Me)-pyridyl 391 49 3,4-F-phenyl 4-pyridyl_ 395 EXAMPLE -S HO 0 2-((4-methvlsulfinvlphenvl)-5-phenvl-3-(4-pyridv) pyrrole The title compound is prepared as in Example 44 using the product of Example 16 as the starting material. FAB ms: Calc.: 366 for C23H17N2SO; Obs.: 367 EXAMPLE 51

NI

H COOH 2-(phenvl)-5-(4-carboxvphenvl)-3-(4-pyridy) pyrrole To a solution of 25 mg (0.068 mmol) 2-phenyl-3-(4-pyridyl)-5- [(4-ethoxycarbonyl)phenyl]-IH-pyrrole (prepared according to Example in 500 RL methanol and 500 gtL THF was added 10 equivalents of a NaOH solution. The reaction mixture was stirred at 60 0 C for 16 hours. After the mixture was cooled to room temperature, volatiles were removed in vacuo. The residue was taken up in methanol and acidified to pH 2 using a 2N HC1 solution. Volatiles were removed in vacuo. The residue was dissolved in a 1:1 mixture of THF/methanol and tritrated. The resulting mixture was centrifuged and filtered to remove sodium chloride. This process was repeated 3 times to ensure total removal of sodium chloride.

Solvents were evaporated in vacuo to afford the desired product as a white

I

ii i, i ii i_il

I~

WO 97/05878 PCT/US96/12922 62 glass, homnogeneous by TLC (10% MCOH/CH2C12). FAB ins: Calc.: 340 for C22H I6N202; Obs.: 341 1).

EXAMPLE 52 24p1henyl)-5-(4-aminophenyl)-3-(4-pvridyl) uvrrole To a suspension of 55 mg 161 mmol) 2-phenyl-3-(4pyridyl)-5- [(4-nitro)phenylj -1H-pyr-role (prepared according to Example 33) in 1.5 ml ethyl acetate and 1.5 ml ethanol was added 10 mg platinum(IV) oxide. The mixture was stirred under H2 for 2 hours. The contents of flask were centrifuged, and the catalyst washed with ethyl acetate three times. The solvents were evaporated in vacuo to afford the desired product as a pale orange solid, homogeneous by TLC MeOH/CH2CI2). FAB ins: Calc.: 312 for C2IH 17 N3; Obs.: 313 EXAMPLE 53 2-(p2henyl)-5-(3-aminop~henvl)-3-(4-pvridvl) pvyrrole The title compound is prepared as desci'ibed above in Example 52 using the product of Example 27 as the staffing material. RAI nl Calc.: 312 for C2lIH 17N3; Obs.: 313 1).

II;_ -si n; *ap l l~ srPr~~ WO 97/05878 PCT/US96/12922 63 EXAMPLE 54

NI

H

N N F H

N

0 2-(4-fluorophenyl)-5-(4-(2-pyridvlmethylaminocarbonvl)-phenyl)-3-(4pyridvl)-pyrrole To a solution of 42 mg (0.124 mmol) 2-phenyl-3-(4-pyridyl)-5- [(4-carboxy)phenyl]-lH-pyrrole (prepared according to Example 51) in 800 uL DMF was added 1.5 equivalents BOP reagent (benzotriazol-1-yloxy-tris- (dimethylamino)phosphonium hexafluorophosphate), 1.2 equivalents 2- (aminomethyl)pyridine, and 2.5 equivalents triethylamine. The mixture was stirred at room temperature for 15 hours. The reaction was quenched by the addition of 5% NaHCO3 solution and ethyl acetate (EtOAc). After separation of phases, the aqueous phase was re-extracted with EtOAc. The combined organic layers were washed with 5% NaHCO3 solution, water, brine, and dried over Na2SO4. After filtration and concentration of the filtrate in vacuo, the crude product was flash chromatographed (gradient elution with MeOH/CH2CI2) to the desired product as a creamcolored solid, homogeneous by TLC. FAB ms: Calc.: 430 for C28H22N40; Obs.: 431 EXAMPLES 55-63 This method is utilized to prepare the compounds listed below by coupling the appropriate amine to the acid derived from Example 51, or coupling an acid to the aniline formed in Example 52 or 53. The compounds are shown below in Table VI.

>7r WO 97/05878 WO 9705878PCTIUS96/1 2922 64 TABLE VI I N Ary1 2

H

f IFAB Example #1Ary1 2 ms 4-(CONHCH2-phenyl)-phenyl 430 4-(NHCO(CH 2 I -piperidinyl))-phenyl 56 0451' H N H KI7~

A

WO 97/05878 PCTIUS96/12922 65 4- (CONHCH2-4-pyr)-phenyl 57 N 431 N NN H 0N! 4-(CON(CH2)2-( -pyridiyl))-phenyl

NN

WO 97/05878 WO 9705878PCT/US96/12922 66 J 4-(CONHCH2-(3-pyridyl))-phenyl

I

N

431 3 -(NHCO(CH9?)3-NMe 2 )-phenyl 62 0 425

N(H)

WO 97/05878 PCT/US96/12922 67 EXAMPLE 63 N

I

IN

HO H 2-(4-hydroxyphenyl)-5-(phenyl)-3-(4-pyridyl) pyrrole 13.2 mg of the product of Example 19 was stirred for 2 hours in a mixture of 50% trifluoroacetic acid in methylene chloride. The reaction mixture was concentrated in vacuo to provide the desired product. FAB ms: Calc.: 312 for C21Hl6N20; Obs.: 313 EXAMPLE 64

NN

HO

H

HO

2-(3,4-dihydroxyphenvl)-5-(phenvl)-3-(4-pyridyl) pyrrole mg of the product of Example 21 was dissolved in 1 mL of acetic acid and was hydrogenated at atmospheric pressure overnight in the presence of a catalytic amount of 10% Pd/C. The reaction mixture was concentrated in vacuo and the residue was purified by rotary chromatography over silica gel eluting with a gradient of 5 to MeOH/CH2CI 2 to provide the desired product. FAB ms: Calc.: 328 for C21H16N202; Obs.: 329 7 WO 97/05878 PCT/US96/12922 68 EXAMPLE

N

o No F H S-Me 2-(4-fluorophenvl)-5-(4-methylsulfonvlphenvl)-3-(4-pvridyl) pyrrole g (1.4 mmol) of the product of Example 44 was dissolved in a mixture of 4 mL of methanol and 16 mL of ethyl acetate. The solution was treated 0.045 g sodium tungstate dihydrate and 0.63 mL (5.6 mmol) of hydrogen peroxide solution while heating at reflux over a period of 4 hours. A further 0.3 mL (2.8 mmol) hydrogen peroxide was added. The mixture was refluxed overnight and then cooled to room temperature. A white solid was recovered by filtration and was washed with water to provide the desired product.

H

1 -NMR (CDCl3): 3.10 3H); 6.92 1H)Hz); 7.09 2H); 7.22 (m, 2H); 7.42 (dd, 2H); 7.72 2H); 7.95 2H); 8.45 2H), 8.95 (bs, IH).

FAB ms:Calc: 392 for C22H17N2S02F; Obs.:393 EXAMPLE 66 2-(3-chlorophenvl)-5-(4-methylsulfonvlphenvl)-3-(4-pyridvl) pyrrole H S -Me

CI

The product of Example 47 was converted to the desired sulfone as described in Example 65. A portion of the product may be isolated by filtration as described in Example 65. The balance of the product was recovered following washing of the reaction mixture with aqueous p WO 97/05878 PTU9/22 PCTIUS96/12922 69 sodium sulfite, water and brine and drying over MgSO4. The crude product was purified by crystalization from CH2CI2/MeOH followed by recrystalizadon from isopropanol.

HI-NMR (CD 3 OD): 3.15 3H); 7.09 IH); 7.39 (in, 4H); 7.50 1H); 7.95 4H); 8.41 2H). FAB ms:Calc: 408 for C 22

H

17

N

2 S0 2 C11I; Obs.:409 EXAMPLES 67-123 0 Using the procedures set forth above, the following compounds can be prepared, as set forth in Table VII.

TABLE VII (Ra) 0 (R a)b (Ra a Ex#t (Ra)a -A 1

A

2 (Ra)b (Ra) 0 3 HRr 67 Ph Ph-4-F 3-quinolinyl H 68 Ph Ph-4-F 4-pyrimidinyl H 69 Ph Ph-4-F 3-pyridazinyl _H Ph Ph-4-F 2-pyrazinyl H 71 Ph Ph-4-CN 4-pyridyl H 72 Ph Ph-2-OMe 4-pyridyl H 73 Ph Ph-3-OMe 4-pyridyl H 74 Ph-3,4-di-P Ph-4-S(O)-Me 4-pyridyl H Ph Ph-4-NMe2 4-pyridyl H 76 Ph 4-(4-(N-COCH3) 4-pyridyl H piperazinyl)-Ph 77 Ph 4-(morpholinyl)- 4-pyridylH I Ph WO 97/05878 PCT/US96/12922 78 Ph Ph-2-C1 4-pyridyl H 79 Ph Ph-3 -Cl 4-pyridyl H Ph Ph-4-CF3 4-pyridyl H 81 Ph Ph-4-S-Me 4-pyridyl H 82 Ph Ph-4-S(O)-Me 4-pyridyl H 83 Ph-4-F (4-methyl)-2- 4-pyridyl H thiophenyl 84 Ph-4-F (4-bromo)-2- 4-pyridyl H thiophenyl Ph-4-F Ph-.4-F-3-CI 4-pyridyl H 86 Ph-4-F 2-benzoxazolyl 4-pyridyl H 87 Ph-4-F 2-benzofuranyl 4-pyridyl H 88 Ph-4-F 4-(O(CH2)3 4-pyridyl H NMe2)-Ph 89 Ph-4-F 4-(O(CH2)2- 4-pyridyl H piperidin-1I -yl)- Ph Ph-4-CI Ph-4-F 4-pyridyl H 91 Ph-3 -Cl Ph-4-F 4-pyridyl H 92 Ph-2-C1 Ph-4-F 4-pyridyl H 93 Ph-3,4-di-CI Ph-4-F 4-pyridyl H 94 Ph-3-CF3 Ph-4-F 4-pyridyl H Ph-4-S -Me Ph-4-F 4-pyridyl H 96 Ph-4-S(O)-Me Ph-4-F 47pyridyl H 97 Ph-2-OBn Ph-4-F 4-pyridyl H 98 Ph-4-Br Ph-4-F 4-pyridyl H 99 Ph-2-OMe Ph-4-F 4-pyridyl -H 100 Ph-3-OMe Ph-4-F 4-pyridyl H 101 Ph-4-OMe Ph-4-F 4-pyridyl H 102 Ph-4-N02 Ph-4-F 4-pyridyl H 103 Ph-4-NMe2 Ph-4-F 4-pyridyl H 104 Ph-4-(4-N- Ph-4- 4-pyridyl H

COCH

3 piperazinyl 105 Ph-4-morpholinyl Ph-4-F 4-pyridyl H 106 2-thiophenyl Ph-4-F 4-pyridyl H 107 3-thiophenyl Ph-4-F 4-pyridyl H 108 2-furoyl Ph-4-F 4-pyridyl_ H 109 3-furoyl Ph-4-F 4-pyridyl H 1 10 I Ph-3-Cl Ph-4-S(O)Me 4-(2-Me)-pyridyl H

I

f

I

1.

PCIVUS96/1 2922 WO 97/05878 -71- 111 Ph-3,4-di-F Ph-4-S(O)Me 4-(2-Me)-pyridyl H 112 Ph-3,4-di-F Ph-4.-S(O)Me 4-pyridyl F 113 Ph-3-CF3 Ph 4-pyridyl H 114 Ph-4-F Ph-4-S(O)Me 4-(2-amnino H benzyl)pyridyl 115 3-guinolinyl Ph 4-pyridyl H 116 Ph-4-F 4-(SMe)-Ph 4-pyridyl Br- 117 Ph-3,4-di-F Ph 4-pyridyl CO2Et 118 Ph-3,4-di-F Ph 4-pyridyl CN 119 3-(CF3)-Ph Ph 4-pyridyl CO2Et 120 3-(CF3)-Ph Ph 4-pyridyl CN 121 Ph Ph-4-F 3-methyl-4- H _____pyridyl 122 Ph-3-C1 Ph-4-S(O)Me 4-(2-amino) H pyrimidinyl 123 Ph Ph-4-F 3,5-dimethyl-4- H I_ I pyri dy] I Bn benzyl, Ph phenyl, Me methyl Et ethyl EXAMP'LE 124 COQEt A mixture of ethyl 2-benzoyl-acetate (0.41 g (2.0 mmnol), 0.5 g (1.44 mmol) of the product of Preparative Example 61 and 0.61 g (8 mmol) of ammonium acetate were heated in acetic acid at reflux until the benzoin was consumed. The reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over MgS 04. The mixture was filtered and the filtrate was concentrated in vacuo and the residue was purified by chromatography over silica gel to give the desired product. H I- NMR (CDCl 3 300 MHz): 0.92 3H); 4.01 2H); 6.94 2H); 7.12 (in, 4H); 7.41 (in, 4H); 7.61 (in, 2H); 8. 10 (in, I 9.20 (bs, I FAB ms:C24H 19N202F=3 86; Observed:387 1).

i- PCT/US96/12922 WO 97/05878 -72- EXAMPLE 125 A mixture of benzyl 2-benzoyl-acetate (2.0 mmol), 0.5 g (1.44 mmol) of the product of Preparative Example 61 and 0.61 g (8 mmol) of ammonium acetate heated in acetic acid at reflux will provide the title compound after purification as recited in Example 124.

EXAMPLE 126

I

p I A mixture of benzyl 2-(4-fluorophenyl)-3-(4-pyridyl)-5phenyl-pyrrole-4-carboxylate from Example 125 (1.0 mmol), 0.01 g of Pd/C in 5 mL of EtOH will yield 2-(4-fluorophenyl)-3-(4-pyridyl)-5phenyl-pyrrole-4-carboxylic acid after treatment with 40 psi H2 followed by filtration.

1

I

WO 97/05878 PCT/US96/12922 -73- EXAMPLE 127 A mixture of 2-(4-fluorophenyl)-3-(4-pyridyl)-5-phenylpyrrole-4-carboxylic acid from Example 126 (1.0 mmol), EDC, Hunig's base and dimethylamine hydrochloride in DMF is stirred at room temperature overnight. The reaction mixture is diluted with water, adjusted to pH 7.0 and extracted with ethyl acetate. The organic extracts are washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by chromatography.

EXAMPLE 128

N-

CN

H 0 A mixture of benzoylacetonitrile 0.5 g (3.4 mmol), 1.17 g (3.4 mmol) of the product of Preparative Example 61 and 1.0 g (13.6 mmol) ammonium acetate are heated in acetic acid at reflux until the benzoin is consumed. The reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over MgS04. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography over silica gel eluting with 5% MeOH/CH2CI2 to give the desired product.

H

1 -NMR (CDC13, 300 MHz): 7.0 2H); 7.24 2H); 7.32-7.48 7.74 (bd, 2H); 8.42 (bs, 1H). FAB ms:C22H14N3F 339; Observed: 340 iti' j

I.

r WO 97/05878 PCT/US96/12922 -74- EXAMPLE 129 S-Pr

CI

The product of Example 5 is dissolved in methylene chloride and treated with 1.05 equivalents of n-propylsulfinyl chloride at OOC under nitrogen. After 30 minutes triethylamine is added to neutralize the reaction W mixture. The reaction mixture is diluted with ethyl acetate and washed with water and brine and dried over MgSO4. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography over silica gel to give the desired product.

EXAMPLE 130 0 S-Pr The product of Example 129 is reacted with 1.05 equivalents of meta-chloroperoxybenzoic acid in CH 2 Cl 2 at 0°C. The reaction mixture is stirred overnight at room temperature. The solution is diluted with EtOAc and washed with saturated sodium bicarbonate solution followed by brine.

The solution is dried over MgSO4, filtered and concentrated in vacuo. The residue is purified by silica gel chromatography to produce the desired product.

EXAMPLE 131 I rp WO 97/05878 PCT/US96/12922

N=

H SMe To 5 ml of DMF at room temperature under nitrogen is added 0.3 g (2 mmol) of POCl3 dropwise. After 15 minutes a solution of 0.37 g (0.86 mmol) of the product of Example 15 is added dropwise. The solution was warmed at 600C until the starting material had been consumed. The reaction mixture was cooled to room temperature and then poured into ice water (20 ml). The mixture was made basic by addition of saturated sodium carbonate solution and then stirred in the presence of 20 ml of chloroform.

The chloroform phase was separated and the aqueous phase was extracted with chloroform (2 x 10 ml). The combined organic phase is washed with water and brine and dried over MgSO4. The mixture is filtered and the filtrate is concentrated in vacuo; the residue is purified by chromatography over silica gel to give the desired product.

,4 V i j WO 97/05878 PCT/US96/12922 -76- EXAMPLE 132

N-

SH

F 1 F !"SMe The product of Example 131 is dissolved in t-butyl alcohol and methyl-2-butene (6:1 ratio). The solution is then treated with 1.5 eq of monobasic sodium phosphate and an aqueous solution of sodium chlorate.

The reaction mixture is stirred at room temperature until the starting material is consumed. The pH is adjusted to 5.5 with dilute HCI. The product is extracted with ethyl acetate and the combined organic phase is washed with water and brine, and dried over MgSO4. The mixture is filtered and the filtrate is concentrated in vacuo to give the desired product.

EXAMPLE 133 F, Br

H

To 5 ml of N,N-dimethylbutyramide at room temperature under nitrogen is added 0.3 g (2 mmol) of POC13 dropwise. After minutes, a solution of 0.37 g (0.86 mmol) of the product of Example 4 is added dropwise. The solution is warmed at 600C until the starting material is consumed. The reaction mixture is cooled to room temperature and then poured into ice water (20 ml). The mixture is made basic by addition of saturated sodium carbonate solution and then stirred in the presence of mL of chloroform. The chloroform phase is separated and the aqueous phase extracted with chloroform (2 x 10 ml). The combined organic phase WO 97/05878 PCT/US96/12922 77 is washed with water and brine and dried over MgSO4. The mixture is filtered and the filtrate is concentrated in vacuo. The residue is purified by chromatography over silica gel to give the desired product.

EXAMPLES 134-203 Using the procedures set forth above, the compounds shown in Table VIII can be prepared.

TABLE VIII I r N Ar 2 (Ra)b

H

Ex. R 134 Ph-4-F Ph-4-OMe 4-pyridyl C(O)Me 135 Ph-4-F Ph-2,5-di-OMe 4-pyridyl C(O)Me 136 Ph-4-F Ph-4-Br 4-pyridyl C(O)Propyl 137 Ph-4-F Ph-4-CI 4-pyridyl C(O)Ethyl 138 Ph-4-F Ph-4-OMe 2-pyridyl C(O)Me 139 Ph-4-F Ph-4-Br 2-pyridyl C(O)NMCe 140 Ph-4-F Ph-2,5-di-OMe 2-pyridyl C(O)Me 141 Ph Ph-4-OMe 4-pyridyl C(O)Me 142 Ph Ph-4-C] -4-pyridyl C(O)Me 143 Ph Ph-2,5-di-OMe 4-pyridyl C(O)Me 144 Ph Ph-4-F 4-pyridyl C(O)Me 145 Ph-4-CI Ph 4-pyridyl C(O)Me 146 Ph-4-F Ph-4-SMe 4-pyridyl C(0)Me 147 Ph-4-SMe Ph 3-rnethyl-4-pyridyl C(Q)Me_

V

2 WO 97/05878 PCT[US96/1 292 -78- 148 Ph-4-F Ph-4-SMe 3.-nethyl-4-pyridyl CN 149 Ph-4-F Ph-4-S(O)Me 3-i-nethyl-4-pyridyl CN 150 Ph-3-CI Ph-4-Cl 4-guinolyl CN 151 Ph-4-F Ph-4-C1 2-meth yl-4-pyrid yl CN 152 Ph Ph-4-F 3,5-diirnethyl-4- CN ______pyridyl 153 Ph Ph-4-F 3-guinolinyl CN 154 Ph Ph-4-F 4-guinolinyl CN 155 Ph Ph-4-F 2-guinolinyl CN 156 Ph Ph-4-F 2-pyrimidinyl CN 157 Ph Ph-4-F 4-pyriinidinyl CN 158 Ph Ph-4-F 3-pyridazinyl CN 159 Ph Ph-4-F 2-pyrazinyl CN 160 Ph Ph-4-F 2-pyriniidinyl CN 161 Ph Ph-4-F 4-pyrimidinyl CN 162 Ph Ph-4-F 2-iinidazo-(4,5-b)- CN pyridin yl 163 Ph Ph-4-F 7-imi dazo-(4,3-b)- CN pyridinyl 164 Ph Ph-4-F 4-pyridyl COMe 165 Ph Ph-4-F 4-pyridyl SO2Me 166 Ph Ph-4-CN 4-p yridyl come 167 Ph Ph-2-OMe 4-pyrid yl COMe 168 Ph Ph-3-OMe 4-pyridyl CN 169 Ph Ph-4-OMe 4-pyridyl CO2Et 170 Ph Ph-4-N02_ 4-pyridyl CN 171 Ph Ph-4-NMe2 4-pyridyl CN 172 Ph4-4(-4prdlC COCH3)- 4prdlC piperazinyl)-Ph 173 Ph 4-(i-noirholinyl)- 4-pyridyl CN 174 Ph Ph-2-CI 4-pyridyl CN WO 97/05878 PTU9/22 PCT/US96/12922 79 175 Ph Ph-3-C1 4-pyrid yl C(O)Me 176 Ph Ph-4-CF3 4-pyridyl SO2Me 177 Ph Ph-4-S-Me 4-pyridyl CN 178 PhPh-4-S(O)-Me 4-pyridyl CN 179 Ph-4-F (4-methyl) 4prdlC thiophen-2 4prylC 180 Ph-4-F (3-methyl) 4prdlCOM thiophen-2y1 -yiylCOM 181 Ph-4-F (4-brorno) -yilS0M thiophen-2yl -yiy OM 182 Ph-4-F (5-methyl) 4-pyridyl CN ~~~thiophen-2yl 183 Ph-4-F Ph-4-F-3-Cl 4-pyridyl CN 184 Ph-4-F 2-benzoxazolyl 4-pyridyl CN 185 Ph-4-F 2-benzofuranyl 4-pyridyl CN 186 4-(O(CH2)3. 4-pyridyl CN Ph-4-F NMe2)-Ph 187 4-(O(CH2)2N- 4prdlC Ph-4-F piperidinyl)-Ph 4prdlC 188 Ph-4-Cl Ph-4-F 4-pyridyl CN 189 Ph-3-CI Ph-4-F 4-pyridyl CN 190 Ph-2-Cl Ph-4-F 4-pyridyl CN 191 Ph-3,4-di-Cl Ph-4-F 4-pyridyl CN 192 Ph-3-CF3 Ph-4-F 4-pyridyl CN 193 Ph-4-S-Me Ph-4-F 4-pyridyl CN 194 Ph-4-S(O)-Me Ph-4-F 4-pyridyl CN 195 Ph-2-OBn Ph-4-F 4-pyridyl CN 196 Ph-4-Br Ph-4-F 4-pyridyl CN 197 Ph-2-QMe Ph-4-F 4-pyridyl CN 198 Ph-3-OMe Ph-4-F 4-pyridyl CN 199 Ph-4-OMe Ph-4-F 4-pyridyl -CN 200 Ph-4NO2 Ph-4-F 4-pyridyl CN 201 Ph-4-NMe2 Ph-4-F 4-pyridyl C1,1 WO 97/05878 PCT/US96/12922 80 202 4(4-(N-COCH3)- Ph-4-F 4-pyridyl CN piperazinyl)-Ph_ 203 4-(morpholinyl)-Ph Ph-4-F 4-pyridyl CN Me methyl, Et ethyl, Ph phenyl, Bn benzyl, BIOLOGICAL ASSAYS.

The ability of compounds of the present invention to inhibit cytokines can be demonstrated by the following in vitro assays.

Lipopolysaccharide mediated production of cytokines Human peripheral blood mononuclear cells (PBMC) are isolated from fresh human blood according to the procedure of Chin and Kostura, J. Immunol. 151, 5574-5585 (1993). Whole blood is collected by sterile venipuncture into 60 mL syringes coated with 1.0 mL of sodiumheparin (Upjohn, 1000 U/mL) and diluted 1:1 in Hanks Balanced Salt Solution (Gibco). The erythrocytes are separated from the PBMC's by centrifugation on a Ficoll-Hypaque lymphocyte separation media. The PBMC's are washed three times in Hanks Balanced Salt Solution and then resuspended to a final concentration of 2 x 106 cell/mL in RPMI (cell culture medium) containing 10% fresh autologous human serum, penicillin streptomycin (10 U/mL) and 0.05% DMSO. Lipopolysaccharide (Salmonella type Re545; Sigma Chemicals) is added to the cells to a final concentration of 100 ng/mL. An aliquot (0.1 mL) of the cells is quickly dispensed into each well of a 96 well plate containing 0.1 mL of the test compound, at the appropriate dilution, and incubated for 24 hours. at 37 0

C

in 5% C02 At the end of the culture period, cell culture supematants are assayed for IL-1 3, TNF-ao, IL-6 and PGE2 production using specific

ELISA.

IL-i mediated cytokine production Human peripheral blood mononuclear cells are isolated from fresh human blood according to the procedure of Chin and Kostura, J.

Immunol. 151, 5574-5585 (1993). Whole blood is collected by sterile venipuncture into 60 mL syringes coated with 1.0 mL of sodium- heparin (Upjohn, 1000 U/mL) and diluted 1:1 in Hanks Balanced Salt Solution (Gibco). The erythrocytes are separated from the PBMC's by i ;rr, 1-- WO 97/05878 PCT/US96/12922 -81 centrifugation on a Ficoll-Hypaque lymphocyte separation media. The PBMC's are washed three times in Hanks Balanced Salt Solution and then resuspended to a final concentration of 2 x 106 cell/mL in RPMI containing fresh autologous human serum, penicillin streptomycin (10 U/mL) and 0.05% DMSO. Endotoxin free recombinant human IL-13p is then added to a final concentration of 50 pMolar. An aliquot (0.1 mL) of the cells is quickly dispensed into each well of a 96 well plate containing 0.1 mL of the compound at the appr'priate dilution. and are incubated for 24 hours at 37 0 C in 5% CO2 At the end of the culture period, cell culture supematants are assayed for TNF-c, IL-6 and PGE2 synthesis using specific ELISA.

Determination of IL-1 f TNF-cx, IL-6 and prostanoid production from LPS or IL- stimulated PBMC's IL-I3 ELISA.

Human IL-1 can be detected in cell-culture supematants or whole blood with the following specific trapping ELISA. Ninety-six well plastic plates (Immulon 4; Dynatech) are coated for 12 hours at 4 0 C with 1 mg/mL protein-A affinity chromatography purified mouse anti-human ILlb monoclonal antibody (purchased as an ascites preparation from LAO Enterprise, Gaithersburg Maryland) diluted in Dulbecco's phosphatebuffered saline (-MgC12, -CaC12). The plates are washed with PBS (phosphate buffered saline)-Tween (Kirkegaard and Perry) then blocked with 1% BSA diluent and blocking solution (Kirkegaard and Perry) for minutes at room temperature followed by washing with PBS Tween.

IL-1 P standards are prepared from purified recombinant IL-I 3 produced from E. coli. The highest concentration begins at 10 ng/mL followed by 11 two-fold serial dilutions. For detection of IL-1 from cell Sculture supematants or blood plasma, 10 25 mL of supematant is added to each test well with 75 90 mL of PBS Tween. Samples are incubated at room temperature for 2 hours then washed 6 times with PBS Tween on an automated plate washer (Dennly). Rabbit anti-human IL-I 3 polyclonal antisera diluted 1:500 in PBS-Tween is added to the plate and incubated for 1 lh ir at room temperature followed by six washes with PBS-Tween.

35 Detection of bound rabbit anti-IL-lp IgG is accomplished with Fab' fragments of Goat anti-rabbit IgG-horseradish peroxidase conjugate 0 I WO 97/05878 PCT/US96/12922 -82 (Accurate Scientific) diluted 1:10,000 in PBS-Tween. Peroxidase activity was determined using TMB peroxidase substrate kit (Kirkegaard and Perry) with quantitation of color intensity on a 96-well plate Molecular Devices spectrophotometer set to determine absortance at 450 nM. Samples are evaluated using a standard curve of absorbance versus concentration. Fourparameter logistics analysis generally is used to fit data and obtain concentrations of unknown compounds.

TNF-a ELISA Immulon 4 (Dynatech) 96-well plastic plates are coated with a mg/mL solution of mouse anti-human TNF-c monoclonal antibody.

The secondary antibody is a 1:2500 dilution of a rabbit anti-human TNF-oa polyclonal serum purchased from Genzyme. All other operations are identical to those described above for IL-lb. The standards are prepared in PBS-Tween 10% FBS (fetal bovine serum) or HS (human serum). Eleven 2 fold dilutions are made beginning at 20 ng/mL TNF-a.

IL-6 ELISA Levels of secreted human IL-6 are also determined by specific trapping ELISA as described previously in Chin and Kostura, J. Immunol.

151, 5574-5585 (1993). (Dynatech) ELISA plates are coated with mouse anti-human IL-6 monoclonal antibody diluted to 0.5 mg/ml in PBS. The secondary antibody, a rabbit anti-human IL-6 polyclonal antiserum, is diluted 1:5000 with PBS-Tween. All other operations are identical to those described above for IL-11 The standards are prepared in PBS-Tween FBS or HS. Eleven 2 fold dilutions are made beginning at 50 ng/mL IL-6.

PGE9 production Prostaglandin E2 is detected in cell culture supematants from LPS or IL-1 stimulated PBMC's using a commercially available enzyme immunoassay The assay purchased from the Cayman Chemical (Catalogue number 514010) and is run exactly according to the manufacturers instructions.

InterleukinS (IL-8) r gEIW p~UC.~'9 WO 97/05878 PCT/US96/12922 -83- The present compounds can also be assayed for IL-8 inhibitory activity as discussed below. Primary human umbilical cord endothelial cells (HUVEC) (Cell Systems, Kirland, Wa.) are maintained in culture medium supplemented with 15% fetal bovine serum (FBS) and 1% CS- HBGF (cell culture additive) consisting of aFGF (acid fibroblast growth factor) and heparin. The cells are then diluted 20-fold before being plated (250 ltl) into gelatin coated 96-well plates. Prior to use, culture medium is replaced with fresh medium (200l). Buffer or test compound (25u1, at appropriate concentrations) is then added to each well in quadruplicate wells and the plates incubated for 6h in a humidified incubator at 37 0 C in an atmosphere of 5% CO2. At the end of the incubation period, supernatant is removed and assayed for IL-8 concentration using an IL-8 ELISA kit obtained from R&D Systems (Minneapolis, MN). All data is presented as mean value (ng/ml) of multiple samples based on the standard curve. values where appropriate are generated by non-linear regression analysis.

The following compounds are found to inhibit cytokines at concentrations of less than 100 pM.

P:-

v n- WO 97/05878 PTU9/22 PCTfUS96/12922 84 TABLE IX (Ra)b I" Arl Ar 2 (Ra)b (Ra) 0 3 HG R 2 H 4-F-Ph 4-F-Ph 4-PyrH H 4-F-Ph 4-OMe-Ph 4-Pyr H H 4-F-Ph 2,5-di-(OMe)-Ph 4-Pyr li- -H 4-F-Ph 4-Br-Ph 4-Pyr H H 4-F-Ph 4-Cl-Ph 4-Pyr H -H Ph 4-OMe-Ph 4-Pyr H H Ph 4-Cl-Ph 4-Pyr H H Ph 2,5-di-(OMe)-Ph 4-Pyr H H Ph 4-F-Ph 4-Pyr H H 4-F-Ph 4-SMe-Ph 4-Pyr H H 4-F-Ph 4-S(O)Me-Ph 4PrH H 4-Cl-Ph Ph 4-Pyr H H 4-SMe-Ph Ph 4-Pyr H H 4-S(O)Me-Ph-4- Ph H Ph Pyr H 4-CF3-Ph Ph 4-Pyr H H 4-Me-Ph Ph 4-Pyr H H 4-OH-Ph Ph 4-Pyr H H 3,4-di-Cl-Ph Ph 4PrH H 3,A-di-OH-Ph Ph 4ElH H 4-F-Ph. Ph 4-y CO2Et WO 97/05878 PTU9/22 PCT[US96/12922 5 H 3-Cl-Ph Ph -4-pyr H H 4-CN-Ph Ph 4-PXE H H Ph 4-CO 2 Et-Ph 4-Pyr H H Ph 2-F-Ph 4-Pyr H H Ph 3-N0 2 -Ph 4-Pyr H H 5-Me-thiophen- Ph 4-Pyr H 2-yl H 3-Me-thiophen- Ph 4-Pyr H 2-yl H 3-quinolinyl Ph 4-Pyr H H 4-F-Ph Ph 4-Pyr CN H 4-F-Ph 4-(SMe)-Ph 4-(3-Me)-Pyr H H 4-F-Ph 4-(SMe)-Ph 4-(3-Me)-Pyr H- H Ph 2-(N0 2 )-Ph 4-Pyr H H Ph 3-F-Ph 4-Pyr H H Ph 4-CO 2 H-Ph 4-Pyr H H Ph 3-NH 2 -Ph 4-Pyr Hq H Ph 4-N0 2 -Ph 4-Pyr H H 4-F-Ph Ph 4-Pyr H- H 2,4-di-F-Ph Ph 4-Pyr H H. 3-CN-Ph Ph 4-Pyr H H 3,4-di-F-Ph Ph 4-Pyr H- H Ph 4-NH 2 -Ph 4-Pyr H H 4-F-Ph 4-S(O)Me-Ph .4-guinolinyl H H 4-F-Ph 4-S Me-Ph 4-pyr Br H 4-F-Ph 4-SMe-Ph 4-guinolinyl H H Ph 4-(CONHCH 2 4-pyr H H Ph 4-(NHCO(CH 2 3 4-pyr H Hl Ph 4-(CONHCH 2 4-pyr H H Ph 4-(CONH(CH 2 2 -yH (I -piperidinyl))-Ph4-yH H Ph 4-(CONH(CH 2 2 -yH methylimidazolyl)-Ph H H Ph 4-(CONHCH 2 4-pyr H pyridyl))-Ph_______ H Ph 4-(CONH(CH 2 4prH (2-pyridyl))-Ph WO 97/05878 PTU9/22 PCT/US96/12922 -86- H h4-(CONHCH 2 4-pyr H H Ph ~(3-pyridyl)-P H h3-(NH-CO(CH 2 4-pyr H H Ph 3NMe 2 )-Ph H Ph 4-(NHCO(CH 2 2 4-pyr H (1-piperidyl))-Ph H 2-Cl-Ph Ph 4pZH H 3-Cl-Ph 4-SMe-Ph 4-pyr H H 4-F-Ph Ph 4-pyrimidinyl F H 4-F-Ph 4-SMe-Ph -4-(2-methyl)-pyr H H 3-Cl-Ph 4-S(O)Me-Ph 4-pyr H H 4-F-Ph 4-S(O)Me-Ph 4-(2-iiethy])-pyr H H 3,4-di-F-Ph 4-SMe-Ph 4-pyr H H 3,4-di-F-Ph 4-S(O)Me-Ph 4-PyrH 11_ 4-F-Ph 4-SO2)Me-Ph 4-pyrH -H 3,4-di-F-Ph Ph 4-pyr CO2Et -H 3,4-di-F-Ph Ph 4-pyr CN H 3-CFI-Ph Ph 4-pyr CO2Et H 3-CF 3 -Ph Ph 4-pyr CN FH 3-Cl-Ph 4-SO 2 )Me-Ph 4-pyr H

Claims (15)

1. A compound of the formula: (Ra) 0 3 HArR2 Ari R 2 Vr and each independently represent a 5-10 membered aryl or heteroaryl group substituted with Ra groups; wherein a and b represents integers, 0, 1, 2 or 3, such that the sumn of a plus b is 1, 2, 3or 4; O represents a heteroaryl group containing from 5 to atoms, 1-4 of which are heteroatorms, 0-4 of which heteroatoms are N and 0- 1 of which are 0 or S, said heteroaryl. group being unsubstituted or substituted with 0 -3 Ra groups; each Ra independently represents a member selected from the group consisting of: halo-, CN, N02, R 2 1 OR 23 SR 23 S(O)R 2 1 S02R 2 1 NR 2 1 R 23 NR 20 C0R 2 1 NR 20 C02R 2 1 NR 2 ()CONR 20 )R 23 NR 2 0S 02R 2 1 NR 20 C(NP. 2 0)NHR 2 C02R 2 3 C0NR 20 )R 2 3 S02NR 20 R 23 S02NR 2 ()C0R 21 S02NR 20 C0NR 20 R 23 SO2NR 2 (lCO2R 21 OCONR 2 ()R 23 0 CONR 2 0~S QR 2 0, C(O)OCH2 OC( 0 R 2 0Q C(NR 20 )NR?- 0 R 23 and CONR 20 S02?R 2 1 R 1 is selected from the gru ossing o:H rl j 1 alkyl, C3- 1 5 alkenyl1, 1 5 alkynyl and heterocyclyl. said alkyl, aryl, alkenyl, alkynyl and heterocyvclyl being optionally substituted with from one WO 97/05878 PCT/US96/12922 to three members selected from the group consisting of: aryl, heteroaryl, heterocyclyl, OR 20 SR 20 N(R 20 S(O)R 2 1 SO2R 2 1 S0 2 )NR2 0 R 23 S02NR 20 C0R 2 1 S2R(CN-)3,N7R 2 COR 2 I, NR20OR1 NR20CONR2OR 23 N(R20)C(NR 2 ())NHR 2 0, C02R 2 0 CONR 2 OR 2 3 C0NR 20 802R 2 1 NR 20 S02R 2 SO2NR 2 ()CO- 2 R 2 I, OCONR?2OR 2 3 1 OCONR 2 0SO 2 R 2 1; 0C0NR 20 )R 23 and C(O)OCH2OC(O)R 20 R 2 is selected from the group consisting of: CI-15 alkyl, C2-15 alkenyl, C2-15 alkynyl, halo, N02, heterocyclyl, CN, S(O)R 2 1 S02R 2 I, SO2N(R 20 SO2NR 20 C0R 2 1 SO2)NR 20 C0N(R20) 2 C0R 2 C02R 20 C0NR 2 ()R 23 CONR 20 SO2R 21 and S02NR 20 C02)R 2 said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, hetrmeyclyl, CN, ai-yl, heteroaryl, R 20 OR 2 0, SR 2 0, NR2()R 2 3 S(O)R 2 S02R 2 1 SO2NR2OR 23 S02NR 2 ()C0R 2 1 SO2NR2 0 C0NR20R 2 3 NR 2t 0COR 2 1 NR 20 C02R 2 J, NR20C0NR20)R2 3 NR 20 C(NR 20 )NJ1R 20 CO2R 2 0 1 CONR 2 0R 23 CONR 20 SO2R 22 NR 2 0SO 2 R) 1, S02NR 20 C02R 22 OCONR 2 0 SO2R 2 1 and OCONR 2 0 R 2 3 R 20 represents a member selected from the group consisting of: H, C 1. 5 alkyl, C2-15 alkenyl, 2- 15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl. alkenyl, alkynyl, heterocyclyl, aryl and heteroaryl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl; f ~R"I represents a member selected from the group consisting of: 'C 1i-15 alkyl, 0-1I5 alkenyl, C2-15 alkynyl. heterocyclyl, aryJl and heteroaryl, such alkyl, alkenyl and alkynyl being optionally interrupted with oxo and/or 1-2 heteroatomns selected from 0, S, S02 and NR 2 0, said alkyl, alkenyl, alkynyl. aryl and heteroaryl being optionally substituted with from 1-3 of halo, heterocyclyL. aryl, heteroaryl, ON, OR 2 O((CH2)nO)mnR 2 0, NR 20 ((CH2)nO)InR 21 wherein n represents an integer of from 2 to 4, and m represents ain integer of from I to 3; SR 2 N(R 20 2 S(O)R22, S02R 2 2, SO,2N(R 2 0>2. SO2NR 2 0COR 22 SO9NR 20 C0N(R20) 2 NR 20 C0R22, 3 5 NR 2t 009,R 22 NR 2 iNR 22 -'C(NR 2 2)NHR22. C02R 20 89 CON(R 2 0 2 CONR 2 0 S0 2 R 2 2 NR 20 S0 2 R 2 2 S0 2 NR 20 C0 2 R 22 OCONR 20 SO 2 R 22 OC(O)R 20 C(0)OCH 2 0C(O)R 20 and OCON(R 20 2 R 22 is selected from the group consisting of: C 1 15 alkyl, C 2 15 alkenyl, C2- 1 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups; R 23 is R 2 1 or H; R 24 is selected from COR 2 2 C0 2 R 22 CON(R 20 2 S0 2 R 22 and R 23 and when two R 20 groups are present, when R 20 and R 2 1 are present, or when R 20 and R 23 are present, said two R 20 groups, R 20 and R 21 or said R 20 and R 23 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional 0 or S atom; wherein each of the terms alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocycloalkyl S 15 and heterocyclyl are as hereinbefore described.

2. A compound in accordance with claim 1 wherein: Arl and Ar 2 are independently and selected from the group consisting of: Si,, a) phenyl, t b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, Sg) thiazolyl, h) isothiazolyl, i) oxazolyl, .1 j) isoxazolyl, and S* napthyl.

3. A compound in accordance with claim 1 wherein HAr is selected from the group of consisting of: i' IN:'L1BC103279:SAK jj.~WO 97/05878 PCTUS96/1 2922 90 pyridyl, quinolyl, purinyl, imidazolyl, imidazopyridyl, pyrimidinyl and pyridazinyl.

4. A compound in accordance with claim 1 wherein RI is hydrogen. A compound in accordance with or unsubstituted C 1- 15 alkyl. claim I wherein RI is substituted represents

6. A compound in accordance with claim I a member selected from the group consisting of: a) H; b) CI16 alkyl; c) halo; d) CN; e) C(O)C 1 6 alkyl; f) C(O)C 1 6 alkyiphenyl; g) CO2H; h) C02C 1-6 alkyl i) C02C 1-6 alkyiphenyl; j) CON}I2; k) CONIC 1 6 alkyl; 1) C(O)N(C 1 6 alkyD)2; m) SO2NH-2; n) S0 2 1NHC 1 6 alkyl and o) SO2N(C] 6 alkyl)?. wherein jZ2

7. A. compound in accordance with. claim I wherein: Anl and Ar 2 are independently selected from: a) phenyl, b) pyridyl, L WO 97/05878 91PCT/US96/12922 c) pyrimidinyl, d) thiophenyl, e) furanyl, f) imidazolyl, g) thiazolyl, h) isothiazolyl, i) oxazolyl, j) isoxazolyl and k) napthyl; one, two or three Ra groups are present and attached to Ar' and Ar 2 and each Ra is independently selected from the group consisting of: halo, R 2 1 OR 2 3 NR 2 0 R 2 3 C02R 2 3 CONR 20 R 2 3 S02R 2 1 and S(O)R 2 1 R 2 0 R 21 and R 2 3 are as originally defined; HAn s selected from: a) pyridyl, Vb) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridyl, f) pyrimidinyl and g) pyridazinyl; R is: a) Hor b) substituted or unsubstiuted alkyl: and 4 R 2 is selected from the group consisting of: a) H, b) alkyl, halo, d) CN, e) C(O)C 1 6 alkyl, f) C(O)C 1 6 alkyiphenyl, g) CO2H, h) C02C 1 alkyl, i) C02C 1-6 alkyiphenyl, 1<' WO 97/05878 PCT/US96/1 2922 92 j) k) I) m) n) 0) CONH2, CON-IC 1-6 alkyl, C(O)N(CI-6 alkyl)2, SO 2 NH2, S0 2 NHC1.-6 alkyl and SO 2 N(C 1 -6 alkyl)2. (Ra)a-/V 1 I S. A compound in accordance with claim I wherein: is selected from the group consisting of: qi) phenyl, b) 4-fluorophenyl, c) 4-chiorophenyl, d) 3-fluorophenyl, e) 3-chiorophenyl, f) thiophen-2-yl, g) thiophen-3-yl, h) 4-fluorothiopheii-2-yl, i) 4-fluorothiophen-3-yi, j) 5-fluorothiophen-2-yl, k) 5-fiuorothiophen-3-yl, 1) 4-chlorothiophen-2-yl, m) 4-chlorothiophen-3-yl, n) 5-chlorothiophen-2-yl, o) 5-chlorothiophen-3-yl, p) 3-methyiphenyl, q) 3,4-dichlorcphenyl, r) 3-hydroxyphenyl, s) 4-hydroxyphenyl, t) 3 ,4-dihydroxyphenyl, u) 3-methyl-2-thiophenyl, v) 5-methyl-2-thiophenyl, w) 4-carboxymethyiphenyl, x) 3-cyanophenyl, y) 4-cyanophenyl, z) 2-pyridyl, aa) 2-furoyl, I J .2.22 WO 97IU05 PCT/US96/12922 93 bb) cc) dd) ee) Mf gg) hh) ii) ii) kk) 11) nun) nin) oo) pp) qq) rr) SO) tt) 3 -furoyl, 4-methylsulfinyiphenyl, 4-trifluoromethyiphenyl, 3 -triflu oromethyiphenyl, 4-methyiphenyl, 4-t-butoxyphenyl, 3 ,4-dibenzyloxyphenyl, 3-quinolinyl, 3-pyridyl, 4-pyridyl, 2,4-difluorophenyl, 3 ,4-difluorophenyl, 4-methylsu ifinyiphenyl, 4-methylsulfonylphenyl, 2-methoxyphenyl, 3-methoxyphenyl, 4-nitrophenyl, 4-aminomethyiphenyl, and 2-chlorophenyl. (Ra)b-Ar 2 is selected from the group consisting of: a) 4-(methylthio)-phenyl, b) 4-(ethylthio)-phenyl, C) 3-(methylthio)-phenyl, d) 2-(methylthio)-phenyl, e) 3-(ethylthio)-phenyl, f) 4-methylsu Ifonyiphenyl, g) 4-ethylsulfonyiphenyl, h) 3-methylsulfonylphenyl, i) 2-methylsulfonyiphenyl, j) 4-methylsulfinyiphenyl, Q) 4-ethylsulfonyiphenyl, 1) 3-methylsulfinyiphenyl, m) 4-(N-methyl-N-benzyl)aminornethylpheny I, n) 3 -(N-methyl-N-benzyiaminomethylphenyl, o) 4-methoxyphenyl, I YT r WO 97/05878 -9-PCT/US96/12922 p) 4-hydroxyphenyl, q) 3-methoxyphenyl, r) 2-benzyloxyphenyl, s) 4-methylthiophen-2-yI, t) 4-methylthiophen-3-yi, u) 4-acetylaminophenyl, v) 2-pyrimidinyl, w) phenyl, x) 4-aminomethyiphenyl, y) 4-cyanophenyl, z) 4-fluorophenyl, aa) 4-chiorophenyl, bb) 4 -bromophenyl, cc) 4-carboxyethylphenyl, dd) 2-fluorophenyl, ee) 3 -nitrophenyl, ff) 4-nitrophenyl, gg) 3-fluorophenyl, hh) 4-carboxyphenyl, ii) 4-aminophenyl, Ji) 3-aminophenyl, kk) 4-(O(CH2)3NMe2)-phenyl, 11) 4-(O(CH2)2-piperidin- I -yi)-phenyl, mm) 2-methoxyphenyl, nn) 3-chiorophenyl, oo) 4-((4-N-COCH3)piperazin- I -yi)-phenyl, pp) 4-trifluoromethyiphenyl, qq) 4-bromothiophen-2-yI, 1~.rr) 5-methylthiophen-2-yI, sq) 2-benzoxazoly], tt) 2-benzofuranyl, uu) 2,5-dimethoxyphenyl and vv) 4-morpholinyiphenyl; 3 with the provis,-,o that when (Ra)a-ArI represents aa), bb), j)or kk) Ar- 2 -(ia)b does not represent ss) or tt); Fir WO 97/05878 PCT[US96/12922 95 (Ra)O-3-HAr is selected from the group consisting of: a) 4 -pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridyl), d) 4-(2-methoxypyridyl), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-blpyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridyl, k) 3,5-dimethyl-4-pyridyl, 1) 3-quinolinyl, m) 3-pyridazinyl, n) 4-(2-arnw 1 enzy)pyridyl, and o) 4-(2-amino)pyrimidinyl; R I is: H; and R 2 is selected from the a) H, b) F, c) Cl, d) Br, e) CN, f) C(C g) C(C h1) GO: i) CO; J) CO: k) COI 1) COI m) C(C n) S02 SO') group consisting of: 1 6 alkyl, ~)CI- 6 alkyiphenyl, )-C16 alkyiphenyl, ',H2, 1 -6 alkyl, ')N(C1-6 alkyl)2, NRH2, .NECI16 al-kyl, L: N.. PCTIUS96/12922 WO 97/05878 96 P) SO 2 N(C 1-6 alkyl)2 qj) CHO and r) 8(0)1-2 C1-6 alkyl. Ra)a-Arl i(s

9. A compound in accordance with claim I wherein: selected from the group consisting of: a) phenyl, b) 4-fluorophenyl, c) 4-chiorophenyl, d) 3-fluorophenyl, e) 3-chiorophenyl, f) thiophen-2-yl, g) thiophen-3-yl, h) 4-fluorothiophen-2-yi, i) 4-fluorothiophen-3 -yl, j) 5-fluorothiophen-2-yI, k) 5-fluorothiophen-3-yl, 1) 4-chlorothiophen-2-yl, m) 4-chlorothiophen-3-yl, n) 5-chlorcthiophen-2-yl, o) 5 -chlorothiophen-3-yl1, p) 3-methyiphenyl, q) 3,4-dichiorophenyl, r) 3-hydroxyphenyl, s) 4-hydroxyphenyl, t) 3,4-dihydroxyphenyl, u) 3-methyl-2-thiophenyl, v) 5-methyl-2-thiophenyl, w) 4-carboxymethyiphenyl, x) 3-cyanophenyl, y) 4-cyanophenyl, z) 2-pyridyl, aa) 2-furoy., bb) 3-furoyl, cc) 4-methylsulfinylphenyl, dd) 4-trifluoromethyiphenyl, WO 97/05878 PCTJUS96/12922 97 ee) 3-trifluoromethyiphenyl, if) 4-methyiphenyl, gg) 4-t-butoxyphenyl, hh) 3 ,4-dibenzyloxyphenyl, ii) 3-quinolinyl, jj) 3-pyridyl, kk) 4-pyridyl, 11) 2,4-difluorophenyl, mam) 3,4-difluorophenyl, nn) 4-methylsulfinyiphenyl, oo) 4-methylsulfonyiphenyl, pp) 2-methoxyphenyl, qq) 3-methoxyphenyl, rr) 4-nitrophenyl, ss) 4-aminomethyiphenyl, tt) 2-chiorophenyl, uu) 4-thiomethyl-phenyl, vv) 2-benzyloxy-phenyl, ww) 4-bromophenyl, xx) 4-methoxyphenyl, yy) 4-dimethylaminophenyl, zz) 4-((4-N-COCH3)-piperazin-4-yl)-phenyl and aaa) 4-(morpholinyl)-phenyl; (Ra)b-Ar 2 is selected from the group consisting of: a) 4-(methylthio)-phenyl, Q~4b) 4-(ethylthio)-phenyl, c) 3 -(methylthio)-phenyl, d) 2-(niethylthio)-phenyl, e) 3-(ethylthio)-phenyl, f) 4-methylsulfonyiphenyl, g) 4-ethylsulfonyiphenyl, h) 3 -methylsulfonylphenyl, i) 2-methylsulfonyiphenyl, j) 4-mnethylsulfinylphenyl, WO 97/05878 PTU9/22 PCT/US96/12922 -98- k) 4-ethyilsulfonyiphenyl, 1) 3-methylsulfirwlphenyl, m) 4-(N-methyl-N-benzy 1)aminomethylphenyl, n) 3 -(N-methyl-N-benzy 1)aminomethylpheny I, o) 4-methoxyphenyl, p) 4-hydroxyphenyl, q) 3-methoxyphenyl, r) 2-benzyloxyphenyl, s) 4-methylthiophen-2-yl, t) 4-methylthiophen-3-yl, u) 4-acetylaminophenyl, v) 2-pyrimidinyl, w) phenyl, x) 4-aminomethyiphenyl, y) 4-cyanophenyl, z) 4-fluorophenyl, aa) 4-chiorophenyl, bb) 4-bromophenyl, cc) 4-carboxyethylphenyl, dd) 2-fluorophenyl, ee) 3-nitrophenyl, if) 4-nitrophenyl, gg) 3-fluorophenyl, hh) 4-carboxyphenyl, ii) 4-aminophenyl, Ji) 3-aminophenyl, kk) 4-(O(CH2)3NMe2)-phenyl, 11) 4-(O(CH2)2-piperidin- I -yI)-phenyl, mm) 2-methoxyphenyl, nn) 3-chiorophenyl, oo) 4-((4-N-COCH3)piperazin- 1 -yl)-phenyl, pp) 4-trifluoromethyiphenyl, qq) 4-bromothiophen-2-yI, rr) 5-methylthiophen-2-yI, ss) 2-benzoxazolyl, tt) 2-benzofuranyl, WO 97/05878 PCT/US96/1 2922 -99- uu) 2,5-dimethoxy-phenyl and vv) 4-morpholinyiphenyl; ww) 2-nitrophenyl, xx) 4-(CONHCH2-2-pyridyl)-phenyl, yy) 4-dimethylaminophenyl, zz) 2-chi orophenyl, aaa) 4-fluoro-3-chloro-phenyl, aab) 4-(CONHCH2-phenyl)-phenyl, aac) 4-(NHCO(CH2)3NMe2)-phenyl, aad) 4-(CONHCH2-4-pyridyl)-phenyl, aae) 4-(CONH(CH2)2-( I -piperidinyl))-phenyl, aaf) 4-(CONH (CH2)2-2-(N -methylimidazolyl)- aa)phenyl, aa)4-(CONH(CH2)2-(2-pyridyl))-pheniyl, aah) 4-(CONHCH2-(3-pyridyl))-pher~yl, aai) 3-(NHCO(CH2)3-NMe2)-phenyl, znd aaj) 4-(NHCO(CH2)2-( I -piperidinyl ))-phenyl, with the proviso that when (Ra)a-Arl represents aa), bb), i)or kk) Ar 2 -(Ra)b does not represent ss) or tt); (Ra)0-3-HAr is selected from the group consisting of: a) 4-pyridyl, b) 4-(2-methylpyridyl), c) 4-(2-aminopyridyl), d) 4-(2-methoxypyridyD), e) 4-quinolinyl, f) 4-pyrimidinyl, g) 9-purinyl, h) 7-(imidazo[4,5-b]pyridinyl), i) 4-(3-methylpyridyl), j) 2-pyridyl, k) 3 ,5-dimnethyl-4-pyridyl, 1) 3-quinolinyl, m) 3-pyridazinyl, n) 4-(2-aminobenzyl)pyridyl, WO 97/05878 PCT/US96/12922 -100- o) 4-(2-amino)pyrimidinyl, p) 2-quinolinyl, r) 2-pyrimidinyl, s) 2-pyrazinyl and t)j 2-(imid&W RI is: substituted or unsubstituted, C I 1 alkyl; and R 2 is selected from the group consisting of: a) H, b) F, c) Cl, d) Br, e) CN; f) C(O)C1 6 alkyl; g) C(O)Cj.. 6 alkyiphenyl; h) CO2H; i) C02C[. 6 alkyl j) C02C 1-6 alkyiphenyl; k) CONH 2 1) CONHCI-6alkyl; m) C(O)N(C 1 -6 alkyl)2; n) SO2NH2; o) SONHC 1 6 alkyl; p) SO2N(C 1-6 alkyl)2; r) CHO and S) S(O)I-2C 1 -C6alkyl.

10. A compound represented by formula L: t WO 97/05878 PCTIUS96/112922 101 (R')b wherein: 9and heteroaryl gr @each independently represent a 5-10 membered aryl or oup; a and b represents integers, 0, 1, 2 or 3, such that the sum of a plus b is 1, 2, 3 or 4; Orepresents a heteroaryl group containing from 5 to atoms, 1-3 of which are heteroatoms, 0-3 of which heteroatoms are N and 0- I of which are 0 or 8, said heteroaryl group being unsubstituted or substituted with 1 -3 Ra groups; each Ra independently represents a member selected from the group consisting of:- halo; CN, N02, R 21 0R 2 3; SR 23 S(O)R 2 1 S02R 2 1 NR 20 R 23 NR 2 0C0R 21 NR 2 0C02)R 21 NR 2 OCONR 2 ()R23; NR 2 OSO 2 R 2 NR 2 0C(NR 2 0)NHR 2 0, C02R 23 CONR 2 OR 2 3; SO2NR 2 OR2 3 SO2NR 2 0COR 2 I1; SO 2 NR 2 ()CONR 2 OR 23 SO2NR 2 (JC0 2 R 2 1; OCONR 2 ()R 2 3; 0C0NR 20 S02R 20 C(O)OCH2OC(O)R 2 0~ and C(NR 2 0)NR 2 0R 2 3; R I is selected from the group consisting of: H, aryl, C I 1 alkyl, C 2 15 alkenyl, C2..15 alkynyl, and heterocyclyl, said alkyl, aryl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: aryl, heteroaryl, WO 97/05878 PCTIUS96/1 2922 -102- heterocyclyl, 0R 20 SR 2 0, N(R 20 S(O)R 21 S0 2 R 2 1 SO 2 N(R 20 )2, S02Nk 2 0C0R 2 1 SO 2 NR 2 OCON(R 20 NR 20 C0R 2 1 NR 20 C02R 2 NR 20 CON(R 20 2 N(R 2 0)C(NR 2 )N-IR 2 C0 2 )R 20 CON(R 20 2 C0NR 20 S0 2 R 21 NR 20 S02R 21 S02NTR 2 ()C0 2 R 2 1 OCON(R 20 )2, OCONR 20 SO2R 2 and 0C0NR 2 0 R 23 R 2 is selected from the group consisting of: H, CI-. 15 alkyl, C 2 15 alkenyl, C 2 15 alkynyl, halo, NO 2 and heterocyclyl, said alkyl, alkenyl, alkynyl and heterocyclyl being optionally substituted with from one to three members selected from the group consisting of: halo, heterocyclyl, CN, aryl, heteroaryl, R 20 0R 2 0, SR 2 0, N(R 2 2 S(O)R 22 S0 2 R 22 SO2N(R 20 2 S0 2 NR 2 ()C0R 2 2 SO2NR 2 0CON (R 20 2 NR 2 0COR 22 NR 2 0C02R 22 NR 2 0CON (R 2 NR 22 C(N1R 22 )NHR 22 C0 2 R 20 CON(R 20 2 C0NR 20 S02R 22 NR 20 S02R 22 S 02NR 20 C02R 22 OCONR 2 (OSO 2 R 22 and OCONR 2 OR 23 R 2 0 1 represents a. member selected from the group consisting of: H, CjI.- 15 alkyl, C2-.l5 alkenyl, C2-15 alkvnyl, heterocyclyl, aryl and v heteroaryl, said alkyl, alkenyl and alkynyl being optionally substituted with 1-3 groups selected from halo, aryl and heteroaryl; R 21 represents a member selected from the group consisting of: C I -1 alkyl, C 2 15 alkenyl, C2l15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, alkenyl, alkynyl, aryl and heteroaryl being optio~nally substituted with from 1-3 of halo, heterocyclyl, aryl, heteroaryl, CN, OR 20 O((CH2)nO)nR 2 NR 2 0 1 ((CH2)nO)nR 2 0 wherein n represewns an integer of from 2 to 4, and m represents an integer of from 1 to 3; IMwterocyclyl, SR 2 0, N (R 20 S (O)R 22, S02)R 22 SO2N(R 2 SO2NR 2 0COR 2 2, SO-NR 2 ()CON (R 20 NR 2 0COR 22 NR 20 C0 2 R 22 NR 2 0CON(R20) 2 NR 22 C(NR2 2 )NHR 22 CO2R 2 CON(R 2 2 CONR 2 OSO 2 R22, NR 2 OSO 2 R2 2 S0 2 NR 20 C0 2 ?R 22 OCONR 2 OSO 2 R22 OC(O)R 2 0, C(O)OCH2?OC(O)R 2 0 and OCON(R 2 2 R 22 is selected from the group consisting of: C I- 15 alkyi. C2- 15 alkenyl, C2-15 alkynyl, heterocyclyl, aryl and heteroaryl, said alkyl, 103 alkenyl, and alkynyl being optionally substituted with 1-3 halo, aryl or heteroaryl groups; R 23 is R 21 or H; R 24 is selected from COR 2 2 C0 2 R 2 2 CON(R 2 0 2 S0 2 R 2 2 and R23; and when two R 20 groups are present, when R 20 and R 2 1 are present, or when R 20 and R 23 are present, said two R 20 groups, R 20 and R 2 1 or said R 20 and R 2 3 may be taken in combination with the atoms to which they are attached and any intervening atoms and represent heterocyclyl containing from 5-10 atoms, at least one atom of which is a heteroatom selected from O, S or N, said hetercyclyl optionally containing 1-3 additional N atoms and 0-1 additional O or S atom; wherein each of the terms alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclnalkyl and heterocyclyl are as hereinbefore described.

11. A compound accordiiig to claim 10 wherein Ar 1 and Ar 2 are independently and optionally selected from: a) phenyl, 15 b) pyridyl, c) pyrimidinyl, d) thiophenyl, e) furanyl, i fI imidazolyl, 20 g) thiazolyl, h) isothiazolyl, i) oxazolyl, f isoxazolyl and k) napthyl; 25 HAr is optionally selected from the group consisting of: a) pyridyl, b) quinolyl, c) purinyl, d) imidazolyl, e) imidazopyridyl and f) pyrimidinyl; I 1 INALBC103279:SAK phenyl, pyridyl, WO 97/05878 PCT/US96/12922 -104- RI is: H or substituted alkyl; and R 2 is selected from the group consisting of:: a) H, b) alkyl and c) halo. 12 selected from the a) b) c) d) e) f) g) h) i) D) k) 1) m) n) o) p) q) 0) A compound according to claim 10 wherein (Ra)a-Arl is group consisting of: phenyl, 4-fluorophenyl, 4-chiorophenyl, 3-fl uorophenyl, 3 -chl orophenyl, thiophen-2-yl, thiophen-3-yl, 4-fluorothiophen-2-yl, 4-fluorothiophen-3 -yl, 5-fluorothiophen-2-yl, 5 -flu orothiophen-3 -yl, 4-chlorothiophen-2-yl, 4-chlorothiophen-3-yl, 5-chlorothiophen-2-yl, 5-chlorothiophen-3 -yl, 3-methyl phenyl, 3,4 dichlorophenyl and 3-hydroxyphenyl; Ar 2 -(Ra)b is selected from the group consisting of-: a) 4-(methylthio)-phenyl, b) 4-(ethylthio)-phenyl, c) 3-(methylthio)-phenyl, d) 2-(methylthio)-phenyl. e) 3'-(ethylthio)-pheny I, Monk PCT/USWE12922 WO 97/05878 105 f) g) h) i) j) k) n) m) n) o) r) Sj) U) t) u) v) a) e) f) g) h) i) 4-methylsulfonyiphenyl, 4-ethylsulfonylphenyl, 3-methylsulfonyiphenyl, 2-methylsulfonyiphenyl, 4-methylsulfinyiphenyl, 4-ethylsulfonyiphenyl, 3 -methylsulfinyiphenyl, 4-(N-methvl-N-benzyl)aminomethylphenyl, 3-(N-methyl-N-benzyl)aminomethylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 3-methoxyphenyl, 2-benzy loxyphenyl, 4-methylthiophen-2-yl, 4-methylthiophen-3-yl, 4-ac.-tylaminophenyl and 2-pyrimidinyl; from the group consisting of:: 4-pyridyl, 4-(2-methylpyridyl), 4-(2-aminopyridyl), 4-(2-methoxypyridyl), 4-.quinolinyl, 4-pyrimidinyl, 9-purinyl, 7-(imidazo[4,5-b]pyridinyl), and 4-(3 I-methylpyridyl) R I is: H and R 2 is selected from the group consisting of: a )H, b) F, c) CI and d) Br. WO 97/05878 PTU9/22 PCT[US96/12922 106

13. A compound in accordance with claim 1 selected from Table IV: TABLE IV (Ra )a- Ex# FAB ms -GAr (Ra)b (Ra) 0 3 Hr 2 Ph-4-F Ph-4-OMe 4-Pyridyl 34 3 Ph-4-F Ph-2,5-di-OMe 4-Pyridyl 375 4 Ph-4-F Ph-4-Br 4-Pyridyl 3931395 Ph-4-F Ph -4-Cl 4-Pyridyl 349 6 Ph-4-F Ph-4-OMe 2-Pyridyl 345 7 Ph-4-F Ph-4-Br 2-Pyridyl 3931395 8 Ph-4-F Ph-4-CI 2-Pyridyl 349 9 Ph-4-F Ph-2,5-di-OMe 2-Pyridyl 375 Ph Ph-4-OMe 4-Pyridyl 327 11I Ph Ph-4-CI 4-Pyridyl 331 12 Ph Ph-2.5-di-OMe 4-Pyridyl 357 13 Ph Ph-4-F 4-Pyridyl 315 14 Ph-4-CI Ph 4-Pyridyl 331 Ph-4-F Ph-4-SMe 4-Pyridyl 361 16 Ph-4-SMe Ph 4-Pyridyl 325 17 4-CF3 -Ph Ph 4-Pyridyl 365 U, 4 WO 97/05878 PCT/US96/12922 107 18 4-Me-Ph Ph 4-Pyridyl 311 19 4-tBuO-Ph Ph 4-Pyridyl 369 3,4-Cl-Ph Ph 4-Pyridyl 366 21 3,4-di-(OBn)-Ph Ph 4-Pyridyl 509 22 3-Cl-Ph Ph 4-pyridyl 331 23 4-CN-Ph Ph 4-Pyridyl 322 24 4-(COOMe)-Ph Ph 4-Pyridyl 355 Ph 4-CO2Et-Ph 4-Pyridyl 369 26 Ph 2-F-Ph 4-Pyridyl 315 27 Ph 3-N02-Ph 4-Pyridyl 342 28 5-Me-2- Ph 4-Pyridyl 317 thiophenyl 29 3-Me-2- Ph 4-Pyridyl 317 thiophenyl 4-F-Ph 4-S Me-Ph 4-(3-Me)-PyridYl 375 31 Ph 2-N02-Ph 4-Pyridyl 342 32 Ph 3-F-Ph 4-Pyridyl 315 33 Ph 4-N02-Ph 4-Pyridyl 342 34 4-F-Ph Ph 4-Pyridyl 315 2,4-F-Ph Ph 4-Pyridyl 333 36 3-CN-Ph Ph 4-Pyridyl 322 37 3,4-F-Ph Ph 4-Pyridyl 333 38 4-F-Ph 4 -(SMe)-Ph 4-quinolinyl 411 39 2-Cl-Ph Ph 4-pyridyl 331 3-Cl-Ph 4-(SMe)-Ph 4-pyridyl 377 41 4-F-Ph Ph 4-pyrimidinyl 316 42 4-F-Ph 4-(SMe)-Ph 4-(2-methyl)- 375 ___pyridyl 43 3,4-di-F-Ph 4-(SMe)-Ph 4-pyridyl 379.

14. A compound in accordance with claim 1 selected from Table V: I ~TABLE VI F PCTIUS96/12922 WO 97/05878 PTU9/22 108 Har AryI 1 N H Example Arl I Har JFAB ms 4 5 4-F-phenyl 4-(3-Me)-pyridyl 391 46 4-F-phenyl 4-guinolinyl 427 47 3-Ci-phenyl 4-pyridyl 393 48 4-F-12henyl 4-(2-Me)-pyridyl 391 49 3,4-F-phenyl 4prdl395. A compound in accordance with claim I selected from Table VI: TABLE VI I N Ary 1 2 H Example 1 Ary1 2 ms 4-(CONHCH2-phenyl)-phenyl 430 H 0 4 PCTIUS96/1 2922 4-(CONH(CH2)2-2-(N-rnethylimidazolyl)I )henyl CH 3 N 447 N. WO 97/05878 PTU9/22 PCT/US96/12922

110- I 4-(CONH(CH2)2-(2-pyridyl))-phenyl I N H 0 445 1 4-(C-ONHCH2-(3-pyridyl))-phenyl 3 -(NH-CO(CH2)3-NMe2)-phenyl 62 0 425 N N(CH 3 2 16. A compound in accordance with claim 1 which is: 2-(4-fluorophenyl)-5 -(4-methylsulfonylphenyl)-3 -(4-pyridyl) pyrrole; 2-(3-chl orophenyl)-5-(4-methylsulfonylphenyl)-3 -(4-pyridyl) pyrrole; -bis-(4-fluorophenyl)-3-(4-pyridyl)-pyrrole; 2-(4-fluorophenyl)-5 -(4-methylsulfinylphenyl)-3 -(4-pyridyl)-pyrrole; 2-(4-methylsulfinyl phenyl)-5-(phenyl)-3 -(4-pyridyl)-pyrrole; 2-(4-phenyl)-5-(4-carboxyphenyl)-3-(4-pyridyl)-pyrrole; 2-(4-phenyl)-5-(4-aminophenyl)-3-(4-pyri dyl)-pyrrole; 2-(4-phenyl)-5-(3-aminophenyl)-3-(4-pyridyl)-pyrrole; F,. F' I4~ t WO 97/05878 PCT[US96II 2922 -1III 2-.(4-phenyl)-5-(4-CONHCH2-2-pyridyl)-phenyl-3 -(4-pyridyl)-pyrrole; 2-(4-hydroxyphenyl)-5 -(phenyl)-3 -(4-pyridyl)-pyrrole or 2-(3 ,4-(OH)2-phenyl)-3 i-(phenyl)-3-(4-pyridyl)-pyrrole. t7. A compound in accordance with claim 1 selected from Table VII: TABLE V11 (Ra)b (R Ex# (Ra) a-A 1 r (Ra)b (Ra) 03 H R2 -67 Ph Ph-47 F -3-quinolinyl H 68 Ph Ph-4-F 4-pyrimidiny I H 69 Ph Ph-4-F 3-pyridazinyl H Ph Ph-4-F 2-pyrazinyI H 71 Ph Ph-4-CN 4-pyridyl H 72 Ph Ph-2-OMe 4-pyridyl H 73 Ph Ph-3-OMe 4-pyridyl H 74 Ph-3,4-di-F Ph-4-S(O)-Me 4-pyrid yl H Ph Ph-4-NMe2 4-pyridyl H 76 Ph 4-(4-(N-COCH3) 4-pyridyl H piperazinyl)-Ph 77 Ph 4-(morpholinyl)- 4-pyridyl H 78 Ph Ph-2-CI 4-pyridyl H 79 Ph Ph-3 -CI 4-pyridyl H Ph Ph-4-CF3 4-pyridyl H 81 Ph Pli-4-S-Me 4-pyridyl H -82 Ph Ph-4-S(O)-Me 4-pyridyl H I" WO 97/05878 PTU9/22 PCT/US96/12922 -112- 83 Ph-4-F (4-methyl)-2- 4-pyridyl H thiophenyl 84 Ph-4-F (4-bromo)-2- 4-pyridyl H thiophenyl Ph-4-F Ph-4-F-3-C] 4-pyridyl H 86 Ph-4-F 2-benzoxazolyl 4-pyridyl H 87 Ph-4-F 2-benzofuranyl 4-pyridyl H 88 Ph-4-F 4-(O(CH2)3 4-pyridyl H NMe2)-Ph 89 Ph-4-F 4-(O(CH2) 2 4-pyridyl H piperidin- I -yl)- Ph-4-Cl Ph-4-F 4-pyridyl H__ 91 Ph-3-CI Ph-4-F 4-pyridyl H 92 Ph-2-CI Ph-4-F 4-pyridyl H 93 Ph-3,4-di-CI Ph-4-F 4-pyridyl H 94 Ph-3-CF3 Ph-4-F 4-pyridyl H Ph-4-S-Me Ph-4-F 4-pyridyl H 96 Ph-4-S(O)-Me Ph-4-F 4-pyridyl H1 97 Ph-2-OBn Ph-4-F 4-pyridyl H 98 Ph-4-Br Ph-4-F 4-pyridyl H 99 Ph-2-OMe Ph-4-F 4-pyridyl H 100 Ph-3-OMe Ph-4-F 4-pyridyl H 101 Ph-4-OMe Ph-4-F 4-pyidyl H 102 Ph-4-N02 Ph-4-F 4-pyridyl H 103 Ph-4-NMe2 Ph-4-F 4-pyridyl H 104 Ph-4-(4-N- Ph-4-F 4-pyridyl H COCH3)- piperazinyl 1 05 Ph-4-morpholinyl Ph-4-F 4-pyridyl H 106 2-thiophenyl Ph-4-F 4-pyfidy! H 107 3-thiophenyl Ph-4-F 4-pyridyl H 108 2-furoyl Ph-4-F -4-pyridyl H 109 3-furoyl Ph-4-F 4-pyridyl H 110 Ph-3-CI Ph-4-S(O)Me 4-(2-Me)-pyridyl H 11I Ph-3,4-di-F Ph-4-S(O)Me 4-(2-Me)-pyridyl H 112 Ph-3,4-di-F Ph-4-S(O)Me 4-pyridyl F 113 Ph-3-CF3 Ph 4-pyridyl H 114 Ph-4-F Ph-4-S(O)Me4 4-(2-amino H _benzyl )2yridyl 115 3-quinolinyl Ph I- 4-pyridyl H I WO 97/05878 PTU9/22 PCT[US96/12922

113- 116 Ph-4-F 4-(SMe)-Ph -4-pyridyl Br 117 Ph-3,4-di-F Ph 4-pyridyl CO2Et 118 Ph-3,4-di-F Ph 4-pyridyl CN 119 Ph 4-pyridyl CO2Et 120 3-(CF3)-Ph Ph 4-pyridyl CN 121 Ph Ph-4-F 3-methyl-4- H ___pyridyl 122 Ph-3-Cl Ph-4-S(O)Me 4-(2-amino) H pyrimidinyl 123 Ph Ph-4-F 3,5-dimethyl-4- H L Bn benzyl, Ph phenyl, Me methyl Et ethyl 1 8. A compound in accordance with claim 1 represented by the structural formula: OH 3 WO 97/05878PCUS6122 PCTIUS96/12922 -114- N-N- HH H HO WO 97/05878 PCTIUS96/12922 -115- C N' N- S-Pr N0*' H cl N- Pr F N H l H ~SM e OH 6 A WO 97/05878 PTU9/22 PCTIUS96/12922

116- 19. A compound in accordance with claim I selected from Table VIII: TABLE VIII r 1 N Ar 2 (R )b H Ex. Ar 1 R) r3R 134 Ph-4-F Ph-4-OMe 4-.pyridyl C(O)Me 135 Ph-4-F Ph-2,5-di-OMe 4-pyridyl C(O)Me 136 Ph-4-F Ph-4-Br 4-pyridyl C(Q)Propyl 137 Ph-4-F Ph-4-CI 4-pyridyl C(O)Ethyl 138 Ph-4-F Ph-4-OMe 2-pyridy1 C(O)Me 139 Ph-4-F P4-r2-pyridyl C(O)Me 140 Ph-4-F Ph-2,5-di-OMe 2-pyridyl C(O)Me 141 Ph Ph-4-OMe 4-pyridyl C(O)Me- 142 Ph Ph-4-C] .4-pyridyl C(O)Me 143 Ph Ph-2,5-di-QMe 4-pyridyl C(O)Me 144 Ph Ph-4-F 4-pyridyl C(Q)Me 145 Ph-4-CI Ph 4-pyridyl C(O)Me 146 Ph-4-F Ph-4-SMe 4- yridy1 C(O)Me 147 Ph-4-SMe Ph 3-irnethyl-4-pyridyl -C(O)Me 148 Ph-4-F Ph-4-SMe 3-methy]-4-pyridyl CN 149 Ph-4-F Ph-4-S(O)Me 3-i-nethyl-4-pyridyl -CN 150 Ph-3-CI Ph-4-CI 4-guinolyl CN 1 Ph-4-F Ph-4-C] 2-methy]-4-pyridyl CN K V I I. w.%usc103279:SAK WO 97/05878 PCTIUS96/12922

117- 152 Ph Ph-4-F 3,5-dimethyl-4- CN ______pyridyl_ 153 Ph Ph-4-F 3-guiriolinyl CN 154 Ph Ph-4-F 4- uinoliny1 CN 155 Ph Ph-4-F 2-guinolinyl CN 156 Ph Ph-4-F 2-pyrimidinyl CN 157 Ph Ph-4.-F 4-pyrir-nidinyI CN 158 Ph Ph-4-F 3-pyridazinyl CN .159 Ph Ph-4-F 2-pyrazinyl C 160 Ph Ph-4-F 2-pyrirnidinyl CN 161 Ph Ph-4-F 4-gyrirnidinyl CN 162 Ph Ph-4-F 2-imidazo-(4,5-b)- CN ____pyridinyl 163 Ph Ph-4-F 7-imiddazo-(4,3-b)- CN 164 Ph Ph-4-F 4-pyridyl come 165 Ph Ph-4-F 4-pyridyl SO2Me 166 Ph Ph-4-CN 4-pyridyl come 167 Ph Ph-2-OMe 4-pyridyl come 168 Ph Ph-3-OMe 4-pyridyl CN 169 Ph Ph-4-OMe 4-pyridyl CO2Et 170 Ph Ph-4-N02 4-pyridyl CN 171 Ph Ph-4-NMe2 4-pyridyl CN 172 Ph4-4N-4prdlC COCH3)- 4prdlC iperazinyl)-Ph 173 Ph 4-(Onorpholinyl)- 4prdlC Ph 4prdlC 174 Ph Ph-2-CI 4-pyridyl CN 175 Ph 1?h-3-CI 4-pyridyl C(O)Me 176 Ph Ph-4-CF3 4-pyridyl SO2Me 177 Ph Ph-4-S-Me 4-pyridyl CN 178 Ph Ph-4-S,(O)-Me 4-pyridyl CN WO 97/05878PCUS6122 PCT/US96/12922 -118- 179 Ph-4-F (4-methyl) 4-pyridyl CN thioph er-2y] 180 Ph-4-F (3-methyl) 4prdlCOM thiophen-2y1 -yiylCOM 181 Ph-4-F (4-bromo) -yilS0M thiophen-2Z14prdy]OM 1.2Ph-4-F (5-1ehl 4-pyridyl CN thiophen-2y1 183 Ph-4-F Ph-4-F-3-Cl 4-pyridyl CN 184 Ph-4-F 2-benzoxazolyl 4-pyridyl CN 185 Ph-4-F 2-benzofuranyl 4-pyridyl CN 186 4-(O(CH2)3.. 4-pyridyl CN Ph-4-F NMe2)-Ph 187 4-(O(CH2)2N- 4prdlC Ph-4-F piperidinyl)-Ph 4prdlC 188 ITh-4-CI Ph-4-F 4-pyridyl CN 189 Ph-3-CI Ph-4-F 4-pyridyl CN 190 Ph-2-CI Ph-4-F 4-pyridyl CN F-191 Ph-3,4-di-CI Ph-4-F 4-pyridyl CN Ph-3-CF3 Ph-4-F 4-pyrid yl CN 93 Ph-4-S-Me Ph-4-F 4-pyridyl CN 194 Ph-4-S(O)-Me Ph-4-F 4-pyridyl CN 195 Ph-2-OBn Ph-4-F 4-pyridyl CN 196 Ph-4-Br Ph-4-F 4-pyridyl CN 197 Ph-2-OMe Ph-4-F 4-pyridyl CN 198 Ph-3-OMe Ph-4-F 4-pyridyl CN 199 Ph-4-OMe Ph-4-F 4pridyI CN 200 -Ph-4NO2 Ph-4-F 4-pyridyl CN 201 Ph-4-NMe2 Ph-4-F 4prdlCN 22 4-(4-(N-COCH3)- Ph4F4yrdlC 22 piperazinyl)-Ph 20 I Xop ol nl)-Ph Ph-4-F 4- yridyl C N Me methyl, Et ethyl. Ph phenyl,_Bn benzyl, WO 97/05878 WO 9705878PCTIUS96/1 2922 -119- A compound in acrordance with cl aim 1 falling within the table IX: TABLE IX ffa)b (Fa) 0 3 H R 2 (R a)a 4-.P L--P H H 4-F-Ph 4-F-P% 4-Pyr H H 4-F-Ph 2,-.*-OMe-Ph 4-Pyr H -H 4-F-Ph 4,-BrO-Ph 4-Pyr H H 4-F-Ph 4-Br-Ph 4-Pyr H -H 4FPh 4-Cl-Ph _4-Py H H Ph 4-C-Ph 4-Pyr H H P h4 C l P h 4 P y r7 -H Ph 2,5-di-(OMe)-Ph 4-Pyr H Hi Ph 4-F-Ph 4-Pyr H H 4-F-Ph 4-SMe-Ph 4-Pyr H H 4-F-Ph 4-S(O)Me-Ph 4-Pyr H H 4-Cl-Ph Ph 4-Pyr H H 4-S Me-Ph Ph 4-Pyr H H 4-S (O)Me-Ph-4- Ph H Ph Pyr__ H 4-CF3-Ph Ph 4-Pyr H H 4-Me-Ph Ph 4-Pyr H H4-OH-Ph Ph 4-Pyr H L H, 3,4-di-Cl-Ph Ph 4-Pyr H Kr I WO 97/05878PCUS6192 PCT[US96/12922 -120- H 3,4-di-OH-Ph Ph 4-P)Z H H 4-F-Ph Ph 4-Pyr CO2Et H 3-Cl-Ph Ph 4-pyr H H 4-CN-Ph Ph 4-Pyr H H Ph 4-CO 2 Et-Ph 4-Pyr H 11 Ph 2-F-Ph 4-Pyr H H Ph 3-N0 2 -Ph 4-Pyr H H 5-Me-thiophen- Ph 4-Pyr H 2-yl H 3-Me-thiophen- Ph 4-Pyr H 2-yl H 3-quinolinXI Ph 4-Pyr H H 4-F-Ph Ph 4-Pyr CN H 4-F-Ph 4-(SMe)-Ph 4-(3-Me)-Pyr H H 4-F-Ph-- 4-(SMe)-Ph 4-(3-Me)-Pyr H H Ph 2-(N0 2 )-Ph 4-Pyr H H Ph 3-F-Ph 4-Pyr Hi H Ph 4-CO 2 H-Ph 4-Pyr H H Ph 3-NI- 2 -Ph 4-Pyr H H Ph 4-N0 2 -Ph 4-Pyr H H 4-F-Ph Ph 4-Pyr H H 2,4-di-F-Ph Ph 4-Pyr H H 3-CN-Ph Ph 4-Pyr H H 3,4-di-F-Ph Ph 4-Pyr H H Ph 4-NH 2 -Ph 4-Pyr H -H 4-F-Ph 4-S (O)Me-Ph 4-guinolinyl H H 4-F-Ph 4-SMe-Ph 4-pyr Br H 4-F-Ph 4-SMe-Ph 4-guinolinyl H H Ph 4-(CONHCH 2 4-pyr H H Ph 4-(NHCO(CH 2 3 4-pyr H NMe2)-Ph____ H Ph 4-(CONHCH 2 4-pyr H H Ph 4-(CONH(CH 2 2 4-pyr H (-2iperidinyl))-Ph H Ph 4-(CONH(CH 2 2 4-pyr H nethyliirnidazolyl)-Ph H Ph4-(CONHCH 2 4-pyr H L~t ar~l~ S S e, 4 S *e S 4SSi a at 4*CUS it I S L 4 '4 4 H Ph 4-(CONH(CH 2 2 -(2-pyridyl))-Ph 4-pyr H H Ph 4-(CONH(CH 2 )-(3-pyridyl))-Ph 4-pyr H H Ph 3-(NHCO(CH 2 )-3NMe 2 )-Ph 4-pyr H H Ph 4-(NHCO(CH 2 2 -(1-piperidyl))-Ph 4-pyr H H 2-CI-Ph Ph 4-pyr H H 3-CI-Ph 4-S-Me-Ph 4-pyr_ H H 4-F-Ph Ph 4-pyrimidyl F H 4-F-Ph 4-SMe-Ph 4-(2-methyl)-pyr H H 3-CI-Ph 4-S(O)Me-Ph 4-pyr H H 4-F-Ph 4-S(O)Me-Ph 4-(2-methyl)-pyr H H 3,4-di-F-Ph 4-S-Me-Ph 4-pyr H H 3,4-di-F-Ph 4-S(O)Me-Ph 4-pyr H H 4-F-Ph 4-SO 2 Me-Ph 4-pyr H H 3,4-di-F-Ph Ph 4-pyr C0 2 Et H 3,4-di-F-Ph Ph 4-pyr CN H 3-CF 3 -Ph Ph 4-pyr C0 2 Et H 3-CF 3 -Ph Ph 4-pyr CN 3-CI-Ph 4-S0 2 Me-Ph 4-pyr H 21. A 2,5-substituted aryl pyrrole derivative, substantially as hereinbefore described with reference to any one of the examples. 22. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 in combination with a pharmaceutically acceptable carrier. 5 23. A pharmaceutical composition made by combining a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable carrier. 24. A method of treating a cytokine mediated disease in a mammal, which method comprises administering to said mammal an effective cytokine interfering amount of a compound according to any one of claims 1 to 21 or of a composition according to claim 10 22 or claim 23. 25. Use of a compound according to any one of claims 1 to 21 in the manufacture of a medicament for treating a cytokine mediated disease in a mammal. 26. A compound according to any one of claims 1 to 21 or a composiiton according to claim 22 or 23 when used for treating a cytokine mediated disease in a mammal. 27. The method according to claim 24, use according to claim 25 or the compound or composition according to claim 26, wherein the cytokine inhibited is IL-I. 28. The method, use, compound or composition according to claim 27, whirein the cytokine inhibited is IL-6. 29. The method, use, compound or composition according to claim 27, wherein the cytokine inhibited is TNF. The method, use, compound or composition according to claim 27, wherein the cytokine inhibited is IL-8. L I" [N:\LIBC103279:SAK 14. 122 31. The method, use, compound or composition according to claim 27, wherein the cytokine mediated disease is septic shock, endotoxic shock, gram negative sepsis or toxic shock syndrome. 32. The method, use, compound or composition according to claim 27, wherein the cytokine mediated disease is bone resorption disease, graft versus host reaction, atherosclerosis, arthritis, osteoarthritis, rheumatoid arthritis, gout, psoriasis or a topical inflammatory disease state. 33. The method, use, compound or composition according to claim 27, wherein the cytokine mediated disease is adult respiratory distress syndrome, asthma or chronic pulmonary inflammatory disease. 34. The method, use, compound or composition according to claim 27, wherein the cytokine mediated disease is cardiac or renal reperfusion injury, thrombosis or glomerulonephritis. The method, use, compound or composition according to claim 27, wherein the cytokine mediated disease is Crohn's disease, ulcerative colitis or inflammatory bowel disease. 36. The method, use, compound or composition according to claim 27, wherein a a. the cytokine mediated disease is cachexia. 37. The method, use, compound or composition according to claim 27, wherein 4, a: 20 the cytokine mediated disease is a viral infection. 38. The method, use, compound or composition according to any one of claims 24, to 37, wherein the mammal is human. 39. A method of treating inflammation mediated by excess production of prostaglandins in a mammal, which method comprises administering to said human an 25 effective cytokine interfering amount of a compound according to any one of-claims 1 to. 21 or of a composition according to claim 22 or claim 23. 40. Use of a compound according to any one of claims 1 to 21 for the manufacture S' of a medicament for treating inflammation mediated by excess production of prostaglandins in a mammal. 41. A compound according to any one of claims 1 to 21 or a composition according to claim 22 or claim 23 when used for treating inflammation mediated by excess production of prostaglandins in a mammal. 42. The method according to claim 29, the use according to claim 40 or the compound or composition according to claim 31, wherein the mammal is human. Dated 13 October, 1998 Merck Co., Inc. O Patent Attorneys for the Applicant/Nominated Person SPRUSON FERGUSON [N:\LIBC103279:SAK INTERNATIONAL SEARCH REPORT Int,..ational application No. PCT/US96/12922 A. CLASSIFICATION OF SUBJECT MATTER IPC(6) :Please See Extra Sheet. US CL :Please See Extra Sheet. According to International Patent Classification (IPC) or to both national classification and IPC B. FIELDS SEARCHED Minimum documentation searched (classification system followed by classification symbols) U.S. Please See Extra Sheet. Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) CAS ONLINE file Registry, CAPlus C. DOCUMENTS CONSIDERED TO BE RELEVANT Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. A SILVESTRI et al. Electrochemical Oxidation of 2,4,5-triaryl- 1-20 substituted pyrroles. II. Oxidation Dimerization of Diphenyl-2-Mesitylypyrrole. J. Het. Chem. March-April 1989, Vol. 26, No. 2, pages 489-492. A SILVESTRI et al. Electrochemical Oxidation of Substituted 1-20 Pyrroles. IV. The Influence of Soluble Bases. J. Het. Chem. December 1992, Vol. 29, No. 7, pages 1847-1850. X KONAKAHARA et al. One-pot'synthesis of pyrroles from N- 1-12 silyl-1-azaallyl anions. Heterocycles. 01 May 1993. Vol. 35, A No. 2, pages 1171-1184, especially page 1175. 13-20 Further documents are listed in the continuation of Box C. See patent family annex. Special categories of cited documents: later document published after the international filing date or priority date and not in conflict with the application but cited to understand the documentdefining the general state of the art which is not considered principle or theory underlying the invention to be of particular relevance S erlierdocument publhed on or after the interonaling document of particular relevance the claimed invention cannot be E earlier docnent published on or after the inaonl filing de considered novel or cannot be considered to involve an inventive step *L document which may throw doubts on priority cloan(s) or which 6 when the documnent is taken alone cited to establish the publication date of another citation or other special reason (as specified) Y" document of particular relevance; the claimed invention cannot be considered to involve an inventive step when the document is document referring to an oral disclosure, use. exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art document published prior to the international filing date but later than document member of the mine patent family the priority date claimed Date of the actual completion of the international search Date of mailing of the international search report 04 NOVEMBER 1996 19 NOV 1996 Name and mailing address of the ISA/US Authorized officer Commissioner of Patents and Trademarks Box PCT RICHARD S. MY s R. Washington, D.C. 20231 Facsimile No. (703) 305-3230 Telephone No. (703) 308-1235 Form PCT/ISA/210 (second sheet)(July 1992)* 1 r INTERNATIONAL SEARCH REPORT In, ational application No. PCT/US96/12922 C (Continuation). DOCUMENTS CONSIDERED TO BE RELEVANT Category* I Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No. PETRUSO et al. Oxidative reactions of polyarylpyrroles. Part 3. Oxidation Trimerization of 2,5-Diphenylpyrrole. J.C.S. Perkins I. October 1981, Vol. 10, pages 2642-2646. 1-20 Form PCTIISAI21O (continuation of seLznd sheet)(July 1992)* INTERNATIONAL SEARCH REPORT In ational application No. PCT/US96/12922 A. CLASSIFICATION OF SUBJECT MATI'ER: IPC A61K 31/44, 31/50, 311445, 31/495, 31/505, 31/535; C07D 211/68, 211/80, 213/02, 239/02, 401/00, 401/04, 471/02, 473/00 A. CLASSIFICATION OF SUBJECT MATITER: US CL: 514/235.5, 252, 253, 256, 303, 274, 275, 314, 318, 341, 343; 544/124, 238, 272.2, 318, 331, 332, 335, 363, 364, 405; 546/119, 167, 194, 208, 256, 275.1, 276.4 B. FIELDS SEARCHED Minimum documentation searched Classirkation System: U.S. 514/235.5, 252, 253, 256, S,03, 274, 275, 314, 318, 341, 343; 544/124, 238, 272.2, 318, 331, 332, 335, 363, 364, 405; 546/119, 167, 194, 208, 256, 275.1, 276.4 I Form PCT/ISA]210 (extra sheeQ)(July 1992)*