Login| Sign Up| Help| Contact|

Patent Searching and Data


Title:
BICYCLIC KINASE INHIBITORS
Document Type and Number:
WIPO Patent Application WO/1999/020624
Kind Code:
A1
Abstract:
The present invention relates to compounds of Formula (I) that are p-38 MAP kinase inhibitors, pharmaceutical compositions containing them, their use, a process for preparing these compounds and intermediates useful in this process.

Inventors:
CHENG SOAN
GOLDSTEIN DAVID MICHAEL
MARTIN TERESA ALEJANDRA TREJO
SJOGREN ERIC BRIAN
Application Number:
PCT/EP1998/006472
Publication Date:
April 29, 1999
Filing Date:
October 13, 1998
Export Citation:
Click for automatic bibliography generation   Help
Assignee:
HOFFMANN LA ROCHE (CH)
International Classes:
A61K31/4355; A61K31/4365; A61K31/437; A61K31/444; A61K31/4545; A61K31/4985; A61K31/5025; A61K31/519; A61K31/5377; A61P1/02; A61P1/04; A61P3/10; A61P9/02; A61P9/10; A61P11/00; A61P19/02; A61P19/10; A61P25/14; A61P25/28; A61P29/00; A61P31/04; A61P31/06; A61P37/06; A61P43/00; C07D213/26; C07D213/70; C07D213/74; C07D213/75; C07D237/20; C07D241/18; C07D471/04; C07D487/04; C07D491/04; C07D491/048; C07D495/04; (IPC1-7): C07D471/04; A61K31/435; A61K31/495; C07D491/048; C07D487/04; C07D495/04; C07D213/74; C07D213/75; C07D213/26; C07D213/70; C07D237/20; C07D241/18
Domestic Patent References:
WO1997005878A11997-02-20
WO1998022457A11998-05-28
Foreign References:
US4767766A1988-08-30
Attorney, Agent or Firm:
Loeschner, Thomas (Grenzacherstrasse 124 Basel, CH)
Download PDF:
Claims:
Claims
1. A compound selected from the group of compound represented by Formula (I): wherein: Rl is heteroaryl; represents a bond between either B and Cru or Q and Cru suc that: (i) when is between Q andCRlthen: B is nitrogen; R2 is aryl; and Q isCRwherein: R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, ORs (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),COOR' (where R7 is hydrogen or alkyl) orCONR'R" (where R'and R"independently represent hydrogen, alkyl or heteroalkyl); and (ii) when is between B andCRlthen: B is carbon; R2 is aryl or heteroaryl; and Q isNR4, O, orSwherein: R4 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,ORs (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), SO2R" (where R"is alkyl, amino, monosubstituted amino or disubstituted amino), CONR'R" (where R'and R"independently represent hydrogen, alkyl or heteroalkyl), (alkylene)Z or (alkylene)CO(alkylene)Zwherein: Z is cyano; COOR'where R'is hydrogen or alkyl; CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or (alkylene)COOR7, or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independentlyC(=NR10)(NR11R12)where represent hydrogen or alkyl, or R10 and Rll together are(CH2) n where n is 2 or 3 and R12 is hydrogen or alkyl; or COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and is a group represented by formula (S), (T), (U), (V) or (W); where: R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, COOR14, R14ishydrogenoralkyl),CONR15R16(alkylene)COOR14(where (where Rls and Rls independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),S (O)nR17 (where n is an integer from 0 to 2 and Rois alkyl, amino, monosubstituted amino or disubstituted amino), OR18 (where Rl8 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),NRC (O) R" (where R is hydrogen, alkyl or hydroxyalkyl and R"is hydrogen, alkyl, cycloalkyl or (alkylene)X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or S (O) nRi (where n is 0 to 2 and R'is alkyl)], NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or (alkylene)X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino orS (O)nR' (where n is 0 to 2 and R'is alkyl)]; and R3 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, OR19 (where Rl9 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), COOR20 (where R 20 is hydrogen or alkyl), CONR2lR22 (where RZ'and R22independently represent hydrogen, alkyl or heteroalkyl, or R21 and R22 together with the nitrogen atone to which they are attache form a heterocycle),S (O) nR23 (where n is an integer from 0 to 2 and R23 is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), (alkylene)CO(alkylene)Z"wherein:(alkylene)Z"or Z"is cyano; COOR24 where R24 is hydrogen or alkyl; CONR25R26 where R25 and R26 independently represent hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; C (=NR2') (NRZ8R29) where R27, R21 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are (CH2) n where n is 2 or 3 and R29 is hydrogen or alkyl; or COR30 where R30 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R3 and Rs are not either amino, monosubstituted amino or disubstituted amino.
2. The compound of claim 1, wherein R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, COOR14, (alkylene) COOR 14 (where R14 is hydrogen or alkyl), CONR15R16 (where R15 and Rls independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle), S (O) aRl' (where n is an integer from 0 to 2 and Rl7 is alkyl, amino, monosubstituted amino or disubstituted amino) orOR 18 (where Rl8 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl).
3. The compound of claim 1 or 2 selected from the group of compound represented by Formula (I): wherein: Q OorSwherein:NR4, R4 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,oR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), (alkylene)Z or (alkylene)CO (alkylene)Z wherein Z is: cyano; COOR'where R'is hydrogen or alkyl; R8andR9independentlyrepresentCONR8R9where hydrogen, alkyl or alkoxy, or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independentlyC(=NR10)(NR11R12)where represent hydrogen or alkyl, or R10 and R11 together are (CH2)n where n is 2 or 3 and R12 is hydrogen or alkyl; or COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; one of A and D is nitrogen and the other is CR6wherein : R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, COOR14, (alkylene)COOR14 (where R14 is hydrogen or alkyl), R15andR16independentlyrepresenthydrogenCONR15R16(where or alkyl or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),S (O)nR17 (where n is an integer from 0 to 2 and Rois alkyl, amino, monosubstituted amino or disubstituted amino) orOR" (where Rl$ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl); Ru vis heteroaryl; R2 is aryl or heteroaryl; and R3 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, OR19 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), COOR20 (where R20 is hydrogen or alkyl), CONR21R22 (where R21 and R22 independently represent hydrogen or alkyl, or R21 and R22 together with the nitrogen atom to which they are attache form a heterocycle),S (O) nR23 (where n is an integer from 0 to 2 and R23 is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino), (alkylene)Z" or Z"is:(alkylene)CO(alkylene)Z"wherein cyano; CoOR24 where R24 is hydrogen or alkyl; R25andR26independentlyrepresentCONR25R26where hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; C (=NR2') (NR2$R29) where R2', R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are (CHZ) a where n is 2 or 3 and R29 is hydrogen or alkyl; or COR3°where R3° is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers.
4. The compound of claim 1 or 2 wherein is between B and CR1, is a group represented by formula (S), (V) or (W), and Q is NR4.
5. The compound of claim 1,2 or 4, wherein Rl is a 4pyridyl or 4 pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or (alkylene)X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole orS (O) nR' (where n is 0 to 2 and R'is alkyl)],NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or (alkylene)X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino orS (O)nR' (where n is 0 to 2 and R'is alkyl) orOR (where R is alkyl or heteroalkyl).
6. The compound of claim 1,2,4 or 5, wherein RZ is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo orOR where R is alkyl.
7. The compound of any one of claims 1,2 and 46, wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and Rl is a 4pyridyl ring optionally substituted at the 2position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonyl amino, 2hydroxyethyl, 2hydroxyethylamino, 3hydroxypropylamino, 2 aminoethylamino, 2aminoethyl, 3aminopropyl, 2dimethylaminoethyl, methoxy, 2hydroxyethoxy or 2dimethylaminoethoxy.
8. The compound of any one of claims 1,2 and 47, wherein R6 is hydrogen; RZ is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and R3 is hydrogen, methyl, chloro, fluoro, 2hydroxyethyl, 2aminoethyl or 2dimethylaminoethyl.
9. The compound of any one of claims 1,2 and 48, wherein R4 is hydrogen, methyl, ethyl, 2hydroxyethyl, 3hydroxypropyl, 2amino ethyl, 3aminopropyl, 2methylaminoethyl, 3methylaminopropyl, 2 dimethylaminoethyl, 3dimethylaminopropyl, 2 (morpholin4yl) ethyl, 3 (morpholin4yl) propyl, 2 (piperidin1yl) ethyl, 3 (piperidin1yl) propyl, 2 (piperazin1yl) ethyl, 3 (piperazin1yl) propyl, hydroxy, methoxy, 2 hydroxyethoxy, 3hydroxypropoxy, 2methylaminoethoxy, 3methyl aminopropoxy, 2dimethylaminoethoxy, 3dimethylaminopropoxy, 2 (morpholin4yl)ethoxy,3(morpholin4yl)propoxy, 2(piperidin1 yl) ethoxy, 3 (piperidin1yl) propoxy, 2 (piperazin1yl) ethoxy or 3 (piperazin1yl) propoxy.
10. Compound of any one of claims 1 and 49 selected from 3 (4 fluorophenyl)2[2(2hydroxyethylamino)pyridin4yl]lHpyrrolo[2(2hydroxyethylamino)pyridin4yl]lHpyrrolo [3,2 b] pyridine and 6[2acetylaminopyridin4yl]7(4fluorophenyl)5H pyrrolo[2,3b]pyrazine.
11. Compound of any one of claims 2 and 49 selected from 3 (4 fluorophenyl)lmethyl2 (pyridin4yl)lHpyrrolo [3, 2b]pyridine and 7(4fluorophenyl)6(pyridin4yl)5Hpyrrolo[2,3b]pyrazine.
12. Compound of any one of claims 39 selected from 3(4fluoro phenyl)2(pyridin4yl)1Hpyrrolo[3,2b]pyridine,3(4fluorophenyl)1 methoxy2(pyridin4yl)1Hpyrrolo[3,2b]pyridine,3(4fluorophenyl)1 [2 (morpholin4yl) ethoxy]2 (pyridyl4yl)lHpyrrolo [3,2b] pyridine, 3 (4fluorophenyl)1hydroxy2(pyridin4yl)lHpyrrolo [3,2b] pyridine, 3 (4fluorophenyl)I (2piperidin1yl) ethoxy]2 (pyridin4yl)lH pyrrolo [3,2b] pyridine, 3(4fluorophenyl)1(2piperidin1yl) ethyl]2 (pyridin4yl)lHpyrrolo [3,2b] pyridine; and 3 (4fluorophenyl)1 [2 (morpholin4yl) ethyl]2 (pyridin4yl)lHpyrrolo [3, 2b]pyridine.
13. Compound as in any one of claims 112 for use as pharmaceuti cally active substances, particularly for the treatment of inflammatory diseases.
14. Compound of the formulas wherein Y and Z are groups convertible to the group and ,BR1,R2, and Q are as in claim 1. 15.
15. Process for the manufacture of compound according to any one of claims 112, which comprises a) cyclizing a compound of the general formula wherein is a group as defined in claim 1 and Y and Z are groups convertible to the group and R1, R2, , B and Q are as in claim 1, or b) introducing a substituent R and/or R4 in a compound of formula wherein R1, R2 and B are as in claim 1, and Q1 isCH orNH, or c) introducing a substituent Ri in a compound of formula wherein and R2 are as in claim 1, or d) converting a compound of formula wherein P° represents a group represented by formula (S°), (T°), (V°) or (W°); wherein R60 is chloro or bromo and R3 is as in claim 1 into a compound of formula I, wherein RÓ is alkoxy, monosubstituted or disubstituted amino, cyano or alkyl, or e) for the manufacture of a pharmaceutically acceptable salt of a compound of formula I carrying an acidic and/or basic substituent, converting such compound of formula I into such salt.
16. A pharmaceutical preparation containing a compound prepared according to any one of claims 1 to 12 and a therapeutically inert carrier, particularly for the treatment and prophylaxis of inflammatory diseases.
17. Compound according to any one of claims 1 to 12, whenever prepared according to the process claimed in claim 15 or by an obvious chemical equivalent thereof.
18. The use of the compound prepared according to any one of claims 1 to 12 in the treatment and prophylaxis of inflammatory diseases or for the manufacture of medicaments for the treatment and prophylaxis of inflammatory diseases.
19. The novel compound, formulations, processes and methods substantially as described herein.
Description:
BICYCLIC KINASE INHIBITORS This invention relates to compound that inhibit p38 MAP kinase, pharmaceutical compositions containing them, their use, a process for preparing these compound and intermediates useful in this process.

TNF and IL-1 have been shown to be central players in the pathological processes underlying many chronic inflammatory and autoimmune diseases. IL-1 is implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((sexe., Arend, W. P. Arthritis & Rheumatism 38 (2): 151-160, (1995)), osteoarthritis, bone resorption, toxic shock syndrome, tuberculosis, atherosclerosis, diabetes, Hodgkin's disease (see., Benharroch, D.; et. al. Euro. Cytokine NetworA 7 (1): 51-57) and Alzheimer's disease. Excessive or unregulated TNF production has been implicated in mediating or exacerbating diseases such as rheumatoid arthritis ((sexe., Maini, R. N.; et. al. APMIS. 105 (4): 257-263, (1997); Feldmann, M., J. of the Royal College of Physicians of London 30 (6): 560-570, (1996); Lorenz, H. M.; et. al. J. of Immunology 156 (4): 1646-1653, (1996)) osteoarthritis, spondylitis, sepsis, septic shock ((sexe., Abraham, E.; et. al. JAMA. 277 (19): 1531-1538, (1997), adult respiratory distress syndrome, asthma ((sexe., Shah, A.; et. al. Clin. & Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. & Exp. Immitnol. 94 (1): 105-110, (1993)), bone resorption diseases, fever ((sexe., Cooper, A. L., et. al. Am. J. of Physiology 267 (6 Pt. 2): 1431-1436)), encephalomyelitis, demyelination ((see., Klindert, W. E.; et al. J. of Neuroimmunol. 72 (2): 163-168, (1997)) and periodontal diseases.

Clinical trials with IL-1 and TNF receptor antagonists have shown that blocking the ability of these cytokines to signal through their receptors leads to significant improvement, in humans, in inflammatory diseases. Therefore, modulation of these inflammatory cytokines is considered one of the most effective strategies to block chronic inflammation and have positive therapeutic outcomes.

It has also been shown that p38 MAP kinase plays an important role in the translational control of TNF and IL-1 and is also involved in the biochemical signaling of these molecules ((sexe., Lee, J. C., et al.

Nature 372 (6508): 739-46, (1994)). Compound that bind to p38 MAP are effective in inhibiting bone resorption, inflammation, and other immune and inflammation-based pathologies. The characterization of the p38 MAP kinase and its central role in the biosynthesis of TNF and IL-1 have made this kinase an attractive target for the treatment of diseases mediated by these cytokines.

It would therefore be desirable to provide p38 MAP kinase inhibitors and thereby provide a means of combating diseases mediated by pro-inflammatory cytokines such as TNF and IL-1. This invention fulfills this and related needs.

In a first aspect, this invention provides compound selected from the group of compound represented by Formula (I): wherein:

Rl is heteroaryl; ------represents a bond between either B and Cru or Q and Cru suc that: (i) when------is between Q and-CRl-then: B is nitrogen; RZ is aryl; and la is-CR-wherein: R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino,- ORs (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),-COOR' (where R7 is hydrogen or alkyl) or-CONR'R" (where R'and R"independently represent hydrogen, alkyl or heteroalkyl); and (ii) when------is between B and-CRl-then: B is carbon; RZ is aryl or heteroaryl; and Q is-NR4-,-O-, or-S-wherein: R4 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,-OR' (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -SO2R" (where R"is alkyl, amino, monosubstituted amino or disubstituted amino),- CONR'R" (where R'and R"independently represent hydrogen, alkyl or heteroalkyl),- (alkylene)-Z or - (alkylene)-CO- (alkylene)-Z wherein:

cyano;Zis -COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or - (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl, or R10 and R11 together are -(CH2)n- where n is 2 or 3 and R12 is hydrogen or alkyl; or (-COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and is a group represented by formula (S), (T), (U), (V) or (W); where: R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, -COOR14, - (alkylene)-COOR14 (where R'4 is hydrogen or alkyl), -CONR15R16 (where Rl5 and R16 independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),-S (O) nRl' (where n is an integer from 0 to 2 and Rois alkyl, amino, monosubstituted amino or disubstituted (whereR18ishydrogen,alkyl,-OR18 heteroalkyl or heterocyclylalkyl),-NRC (O) R" [where R is hydrogen, alkyl or hydroxyalkyl and R"is hydrogen, alkyl, cycloalkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or

-S (O)nR (where n is 0 to 2 and R'is alkyl)], -NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)nR@ (where n is 0 to 2 and R'is alkyl)]; and R3 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, -OR19 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -COOR20 (where R20 is hydrogen or alkyl),- CONRZ1R22 (where R21 and R22 independently represent hydrogen, alkyl or heteroalkyl, or R21 and R22 together with the nitrogen atom to which they are attache form a heterocycle), -S (O) nR23 (where n is an integer from 0 to 2 and R23 is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted or-(alkylene)-CO-(alkylene)-Z"wherein:amino),-(alkylene)-Z" Z"is cyano; -COOR24 where R24 is hydrogen or alkyl; R25andR26independentlyrepresent-CONR25R26where hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NRZ') (NRZ$R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CH2) a where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR3°where R3° is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers, provided that both R3 and R6 are not either amino, monosubstituted amino or disubstituted amino.

In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.

In a third aspect, this invention provides a process for preparing the compound of Formula I and their pharmaceutically acceptable salts as well as intermediates useful in this process.

Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: "Alkyl"means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branche saturated monovalent hydrocarbon radical of three to six carbon atoms, e. g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.

"Cycloalkyl"means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e. g., cyclopropyl, cyclohexyl, and the like.

"Alkylene"means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branche saturated divalent hydrocarbon radical of three to six carbon atoms, e. g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.

"Alkenyl"means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branche monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e. g., ethenyl, propenyl, and the like.

"Alkenylene"means a linear divalent hydrocarbon radical of two to six carbon atoms or a branche divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e. g., ethenylene, propenylene, and the like.

"Alkynyl"means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branche monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e. g., ethynyl, propynyl, and the like.

"Alkoxy"means a radical-OR where R is alkyl as defined above, e. g., methoxy, ethoxy, propoxy, 2-propoxy, the like.

"Acyl"means a radical-C (O) R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, e. g., acetyl, benzol, thenoyl, and the like.

"Acyloxy"means a radical-OC (O) R where R is hydrogen, alkyl, alkenyl, cycloalkyl, haloalkyl, heterocyclyl or-NRR' (where R and R'are independently of each other hydrogen or alkyl), e. g., acetoxy, and the like.

"Acylamino"means a radical-NRC (O) R'where R is hydrogen or alkyl and R'is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, e. g., acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.

"Sulfonylamino"means a radical-NRSO2R'where R is hydrogen or alkyl and R'is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, amino, monosubstituted amino, disubstituted amino, aryl, aralkyl, heteroaryl or heteroaralkyl, e. g., methylsulfonylamino, benzylsulfonylamino, phenylsulfonylamino, and the like.

"Halo"means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro.

"Haloalkyl"means alkyl substituted with one or more same or different halo atoms, e. g., -CH2Cl,-CF3,-CH2CF3,-CH2CCl3, and the like.

"Monosubstituted amino"means a radical-NHR where R is alkyl, alkenyl, heteroalkyl, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl or an amino protecting group, e. g., methylamino, (1-methylethyl) amino, phenylamino, and the like.

"Disubstituted amino"means a radical-NRR'where R and R'are independently alkyl, alkenyl, heteroalkyl, haloalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl.

Representative examples inclue, but are not limited to, dimethylamino, methylethylamino, di (1-methylethyl) amino, methylbenzylamino, and the like.

"Aryl"means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, heterocyclylalkyl, cycloalkyl, cycloalkylalkyl, halo, nitro, cyano, acyloxy, optionally substituted phenyl, heteroaryl, heteroaralkyl,-COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl),-NRR' (where R and R'are, independently of each other, hydrogen, alkyl or heteroalkyl),-OR (where R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl or optionally substituted phenyl),-NRC (O) R' (where R is hydrogen or alkyl and R'is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl),-COOR,- (alkenylene)- COOR,- (alkylene)-COOR (where R is hydrogen or alkyl),-CONR'R"and - (alkylene)-CONR'R" (where R'and R"are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term aryl inclues, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.

"Optionally substituted phenyl"means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano,-OR (where R is hydrogen or alkyl),-NRR' (where R and R'are independently of each other hydrogen or alkyl),-COOR (where R is hydrogen or alkyl) or- CONR'R" (where R'and R"are independently selected from hydrogen or alkyl).

"Heteroaryl"means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C.

The aromatic radical is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, hydroxylamino, heteroalkyl, halo, nitro, cyano, heterocyclylalkyl, optionally substituted phenyl,-COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl),-NRR' (where R and R' are independently of each other hydrogen, alkyl, cycloalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroalkyl, heterocyclylalkyl or optionally substituted phenyl),-OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, heteroalkyl, heterocyclylalkyl or optionally substituted phenyl),-NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl)], _NR aC (o) Rb [where Ra vis hydrogen or alkyl and Rb is hydrogen, alkyl,- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, optionally substituted heteroaryl ring or-S (O) nR' (where n is 0 to 2 and R'is alkyl)],-S (O) nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl or cycloalkylalkyl),-SO2NRR' (where R and R'are independently of each other hydrogen, alkyl cyanoalkyl, carboxyalkyl, alkoxycarbonylalkyl, hydroxyalkyl, aminoalkyl,

alkylaminoalkyl, dialkylaminoalkyl or alkoxyalkyl),-COOR, - (alkenylene)-COOR,- (alkylene)-COOR (where R is hydrogen or alkyl), -CONR'R"and- (alkylene)-CONR'R" (where R'and R"are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term heteroaryl inclues, but is not limited to, pyridyl, pyrimidinyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl, imidazolyl and derivatives thereof.

"Optionally substituted heteroaryl"means a pyridyl, pyrimidinyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl or imidazolyl ring which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano,-OR (where R is hydrogen or alkyl),-NRR' (where R and R'are independently of each other hydrogen or alkyl),-COOR (where R is hydrogen or alkyl) or-CONR'R" (where R'and R"are independently selected from hydrogen or alkyl).

"Heteroalkyl"means an alkyl, alkenyl, alkynyl or cycloalkyl radical as defined above, carrying one or two substituents selected from <BR> <BR> <BR> <BR> -NRaRb,-OR,-S (O) nRd or-S03 X+ wherein n is an integer from 0 to 2, X+ is an alkali metal, Rais hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxy, amino, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, optionally substituted phenyl, optionally substituted heteroaryl, optionally substituted heterocyclylalkyl, optionally substituted heteroaralkyl-SO2R (where R is alkyl),-SO2NRR' (where R and R'are, independently of each other, hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkylaminoalkyl) or- (alkylene)-COOR (where R is hydrogen or alkyl), Rb is hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or optionally substituted heteroaralkyl, Re is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylamino-

alkyl, dialkylaminoalkyl,-COR (where R is alkyl, haloalkyl, cycloalkyl or cycloalkylalkyl) or- (alkylene)-COOR (where R is hydrogen or alkyl) and Rd is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or-NRR' (where R and R'are independently of each other hydrogen, alkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl or dialkyl- aminoalkyl). Representative examples inclue, but are not limited to, 2- methoxyethyl, phenoxymethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2- hydroxyethoxy, 2-dimethylaminoethoxy, and the like.

"Heterocycle"or"Heterocyclyl"means a cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O or S (O) n (where n is an integer from 0 to 2), the remaining ring atoms being C where one or two C atoms may optionally be replace by a carbonyl group. The heterocycle ring may be optionally substituted independently with one or two substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl, alkoxyalkyl, optionally substituted phenyl, optionally substituted phenylalkyl, imidazole, halo, cyano, acyl, acylamino,-OR (where R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, imidazole or optionally substituted phenylalkyl),-NRR' (where R and R'are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), -S (O) nR (where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, alkenyl, cycloalkyl or cycloalkylalkyl),-SO2NRR' (where R and R'are independently hydrogen, alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl), an amino protecting group,-COOR, - (alkylene)-COOR (where R is hydrogen or alkyl),-CONR'R"or- (alkylene)-CONR'R" (where R'and R"are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted

phenyl or optionally substituted phenylalkyl). More specifically the term heterocycle inclues, but is not limited to, tetrahydropyranyl, pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, azepine, and derivatives thereof.

"Optionally substituted heterocyclyl"means a tetrahydropyranyl, pyrrolidino, piperidino, piperazino, homopiperazino or morpholino ring which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano,-OR (where R is hydrogen or alkyl),-NRR' (where R and R'are independently of each other hydrogen or alkyl),-COOR (where R is hydrogen or alkyl) or-CONR'R" (where R'and R"are independently selected from hydrogen or alkyl).

"Hydroxyalkyl"means an alkyl radical as defined above, carrying one or more, preferably one, two or three hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples inclue, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)- 2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1- (hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2- (hydroxymethyl)- 3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1- (hydroxymethyl)-2-hydroxyethyl.

"Aminoalkyl"means an alkyl radical as defined above, carrying one or two amino groups, e, g., 2-aminoethyl, 2-aminopropyl, 3-aminopropyl, 1- (aminomethyl)-2-methylpropyl, and the like.

"Alkylaminoalkyl"means an alkyl radical as defined above, carrying one or two-NHR groups where R is an alkyl group as defined above. Representative examples inclue, but are not limited to,

2-methylaminoethyl, 3-ethylaminopropyl, 1- (methylaminomethyl)-2- methylpropyl, and the like.

"Dialkylaminoalkyl"means an alkyl radical as defined above, carrying one or two-NRR groups where R is an alkyl group as defined above. Representative examples inclue, but are not limited to, 2-dimethylaminoethyl, 2-dimethylaminopropyl, 1- (dimethylamino- methyl)-2-methylpropyl, and the like.

"Alkoxyalkyl"means an alkyl radical as defined above, carrying one or two alkoxy group as defined above, e. g., 2-methoxyethyl, 2-methoxypropyl, and the like.

"Cycloalkylalkyl"means a radical -RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e. g., cyclopropyl- methyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.

"Aralkyl"means a radical-RaRb where Ra is an alkylene group and Rb is an aryl group as defined above e. g., benzyl, phenylethyl, 3- (3- chlorophenyl)-2-methylpentyl, and the like.

"Heteroaralkyl"means a radical-RaRb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e. g., pyridin-3- ylmethyl, 3- (benzofuran-2-yl) propyl, and the like.

"Heterocyclylalkyl"means a radical-RBRb where Ra vis an alkylene group and Rb is a heterocyclyl group as defined above e. g., 2- (morpholin- 4-yl) ethyl, 3- (piperidin-1-yl)-2-methylpropyl, and the like.

"Optional"or"optionally"means that the subsequently described event or circumstance may but need not occur, and that the description inclues instances where the event or circumstance occurs and instances in which it does not. For example,"aryl group optionally mono-or di-substituted with an alkyl group"means that the alkyl may but need not be present, and the description inclues situations where

the aryl group is mono-or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.

"Amino protecting group"refers to those organic groups intended to protect nitrogen atoms against undesirable rections during synthetic procedures e. g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like.

The compound of this invention may possess one or more asymmetric centers; such compound can therefore be produced as individual (R)-or (S)-stereoisomers or as mixtures thereof. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of "Advanced Organic Chemistry", 4th edition J. March, John Wiley and Sons, New York, 1992).

A"pharmaceutically acceptable excipient"means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and inclues an excipient that is acceptable for veterinary use as well as human pharmaceutical use. A"pharmaceutically acceptable excipient" as used in the specification and claims inclues both one and more than one such excipient.

A"pharmaceutically acceptable salt"of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include: (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric

acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3- (4- hydroxybenzoyl) benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzene- sulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo [2.2.2]-oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4'-methylenebis- (3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynaphthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or (2) salts formed when an acidic proton present in the parent compound either is replace by a metal ion, e. g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.

"Pro-drugs"means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compound of Formula (I) wherein a hydroxy, amino, or sulfhydryl group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs inclue, but are not limited to esters (e. g., acetate, formate, and benzoate derivatives), carbamates

(e. g., N, N-dimethylaminocarbonyl) of hydroxy functional groups in compound of Formula (I), and the like.

"Treating"or"treatment"of a disease inclues: (1) preventing the disease, i. e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease, (2) inhibiting the disease, i. e., arresting or reducing the development of the disease or its clinical symptoms, or (3) relieving the disease, i. e., causing regression of the disease or its clinical symptoms.

A"therapeutically effective amount"means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount"will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

The nomenclature used in this application is generally based on the IUPAC recommendations, for example: (i) a compound of Formula (I) where B is carbon, (a is-NR4-,-O- or-S-, and is a group of formula (S) is numbered and named as follows:

where Q is-NH-, Rl is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo [3,2- b]pyridine.

(ii) a compound of Formula (I) where B is carbon, Q is-NR4-, -O- or-S-, and is a group of formula (T) is numbered and named as follows: where la is-NH, Rl is 4-pyridyl, R2 is phenyl and R3 and Rs are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo [3,2- c]pyridine.

(iii) a compound of Formula (I) where B is carbon, Q is -NR4-, -O- or-S-, and is a group of formula (U) is named and numbered as follows: where Q is-NH-, Rl is 4-pyridyl, R2 is phenyl and R3 is hydrogen, is named as 7-phenyl-6- (pyridin-4-yl)-5H-pyrrolo [3,2- c]pyridazine.

(iv) a compound of Formula (I) where B is carbon, Q is -NR4-, -O- or-S-, and is a group of formula (V) is named and numbered as follows:

where Q is-NH-, Rl is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo [3,2- d]pyrimidine.

(v) a compound of Formula (I) where B is carbon, Q is -NR4-, -O- or-S-, and is a group of formula (W) is named and numbered as follows: where Q is-NH-, R1 is 4-pyridyl, R2 is phenyl and R6 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo [2,3- b]pyrazine.

(vi) a compound of Formula (I) where B is nitrogen, Q is-CH-, and is a group of formula (S) is named and numbered as follows: where Rl is 4-pyridyl, RZ is phenyl and R3 and R6 are hydrogen, is named as 1-phenyl-2-(pyridin-4-yl)-1H-pyrrolo [2,3- b]pyridine.

(vi) a compound of Formula (I) where B is nitrogen, Q is-CH-, and is a group of formula (T) is named and numbered as follows:

where Ru vis 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as I-phenyl-2- (pyridin-4-yl)-lH-pyrrolo [2,3- c]pyridine.

(vii) a compound of Formula (I) where B is nitrogen, Q is-CH-, and is a group of formula (U) is named and numbered as follows: where Ru vis 4-pyridyl, R2 is phenyl and R6is hydrogen, is named as 7-phenyl-6- (pyridin-4-yl)-7H-pyrrolo [2, 3-c]pyridazine.

(viii) a compound of Formula (I) where B is nitrogen, Q is-CH-, and is a group of formula (V) is named and numbered as follows: where Q is-NH-, Rl is 4-pyridyl, R2 is phenyl and R3 and Rs are hydrogen, is named as 7-phenyl-6- (pyridin-4-yl)-7H-pyrrolo [2,3- d]pyrimidine.

Representative compound of this invention are as follows: I. Compound of Formula (I) where B is carbon, Q is -NR4-, R3 is hydrogen, is a group of formula (S), and the other groups are as

defined below are: CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 1 4-pyridyl 4-fluoro- hydroxy hydrogen 225-228 phenyl 2 4-pyridyl 4-fluoro- methyoxy hydrogen 168-171.5 phenyl 3 4-pyridyl 4-fluoro- 2-(morpholin-4-yl)ethoxy hydrogen 139-141 phenyl 4 4-pyridyl 4-fluoro- 2-(piperidin-1-yl)ethoxy hydrogen 95.9-98.7 phenyl 5 4-pyridyl 4-fluoro- 2-(pyrrolidin-1-yl)ethoxy hydrogen 123-129 phenyl 6 4-pyridyl 4-fluoro- hydrogen hydrogen > 285 phenyl 7 4-pyridyl 4-fluoro- ethyl hydrogene 204-206 phenyl 8 4-pyridyl 4-fluoro- 2-(morpholin-4-yl)ethyl hydrogen 171.2-153.3 phenyl 9 4-pyridyl 4-fluoro- 2-(piperidin-1-yl)ethyl hydrogen 148.1-153.3 phenyl CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 10 4-pyridyl 4-fluoro- 3-dimethylaminopropyl hydrogen 375 phenyl 11 4-phridyl 4-fluoro- 2-(1-methylpyrrolidin-2- hydrogen 401 phenyl yl)ethyl 12 4-pyridyl 4-fluoro- 3-hydroxypropyl hydrogen 348 phenyl 13 4-pyridyl 4-fluoro- 3-(1-methylpiperazin-4- hydrogen 430 phenyl yl)propyl 14 4-pyridyl 4-fluoro- 3-(trimethylamino)propyl hydrogen 390 phenyl .HCl salt 15 4-pyridyl 4-fluoro- 2-(RS)-(dimethylamino- hydrogen 389 phenyl methyl)propyl 16 4-pyridyl 4-fluoro- 3-cyanopropyl hydrogen 357 phenyl 17 4-pyridyl 4-fluoro- 2-aminocarbonylethyl hydrogen 361 phenyl 18 4-pyridyl 4-fluoro- ethyl. dihydrochloride hydrogen >285 phenyl 19 4-pyridyl 4-fluoro- dimethylaminocarbonylm hydrogen 375 phenyl ethyl.TFA salt. 20 4-pyridyl 4-fluoro- methylmethoxyaminocar hydrogen 391 phenyl bonylmethyl.TFA salt. CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 21 4-pyridyl 4-fluoro- -CH2COCH2CO2CH3.TFA hydrogen 404 phenyl salt. 22 4-pyridyl 4-fluoro- -CH2COCH3.TFA salt. hydrogen 346 phenyl 23 4-pyridyl 4-fluoro- -(CH2)3NH(CH2)2NH2.3 hydrogen 390 phenyl TFA salt. 24 4-pyridyl 4-fluoro- 3-(3-aminocarbonyl- hydrogen 458 phenyl piperidin-1-yl)propyl 25 4-pyridyl 4-fluoro- 3-(piperidin-1-yl)propyl hydrogen 415 phenyl 26 4-pyridyl 4-fluoro- 3-(piperazin-1-yl)propyl hydrogen 416 phenyl .3 TFA salt. 27 4-pyridyl 4-fluoro- 3-(homopiperazin-1- hydrogen 430 phenyl yl)propyl.3 TFA salt. 28 4-pyridyl 4-fluoro- 3-hydroxylaminopropyl.2 hydrogen 363 phenyl TFA salt. 29 4-pyridyl 4-fluoro- 3-(morpholin-4-yl)propyl hydrogen 417 phenyl .2 TFA salt. 30 4-pyridyl 4-fluoro- 3-(4-hydroxypiperidin-1- hydrogen 431 phenyl yl)propyl.2 TFA salt. 31 4-pyridyl 4-fluoro- 3-imidazol-1-ylpropyl.3 hydrogen 398 phenyl TFA salt CPD# R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 32 4-pyridyl 4-fluoro- 3-aminopropyl.2 TFA hydrogen 347 phenyl salt 33 4-pyridyl 4-fluoro- 3-(2-aminocarbonyl- hydrogen phenyl pyrrolidin-1-yl)propyl.2 TFA salt 34 4-pyridyl 4-fluoro- 3-[3-(2-hydroxyethyl)- hydrogen 459 phenyl piperidin-1-yl]-propyl.2 TFA salt 35 4-pyridyl 4-fluoro- 3-[2-(hydroxymethyl)- hydrogen 445 phenyl piperidin-1-yl]-propyl.2 TFA salt 36 4-pyridyl 4-fluoro- 3-(pyrrolidin-1-yl)propyl. hydrogen 401 phenyl 2 TFA salt 37 4-pyridyl 4-fluoro- 3-(3-hydroxypyrrolidin-1- hydrogen 431 phenyl yl)propyl.2 TFA salt 38 4-pyridyl 4-fluoro- 3-{[tris(hydroxymethyl)- hydrogen 451 phenyl methyl]amino}-propyl.2 TFA salt 39 4-pyridyl 4-fluoro- 3-[3-(hydroxymethyl)- hydrogen 445 phenyl piperidin-1-yl)-propyl.2 TFA salt CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 40 4-pyridyl 4-fluoro- 3-[(5-aminocarbonylimi- hydrogen 456 phenyl dazol-4-yl)-amino]propyl. 2 TFA salt 41 4-pyridyl 4-fluoro- 3-[3-hydroxypropyl- hydrogen 405 phenyl amino]propyl. 2 TFA salt 42 4-pyridyl 4-fluoro- 3-[(piperizin-1-ylethyl)- hydrogen 459 phenyl amino]propyl . 2 TFA salt 43 4-pyridyl 4-fluoro- 2-methoxyethyl .2 HCl hydrogen 54-59 phenyl salt 44 4-pyridyl 4-fluoro- methyl . HCl salt hydrogen 219-220 phenyl 45 4-pyridyl 4-fluoro- 3-(3-aminopiperidin-1- hydrogen 430 phenyl yl)propyl . 3 TFA salt 46 4-pyridyl 4-fluoro- 3-(3-hydroxypyrrolidin-1- hydrogen 417 phenyl yl)propyl .2 TFA salt 47 4-pyridyl 4-fluoro- 3-[(tetrahydropyran-2- hydrogen 431 phenyl ylmethyl)amino]propyl .2 TFA salt 48 4-pyridyl 4-fluoro- 3-(2,6-dimethylmor- hydrogen 445 phenyl pholin-4-yl)propyl . 2 TFA salt CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 49 4-pyridyl 4-fluoro- aminocarbonylmethyl . hydrogen 347 phenyl TFA salt 50 4-pyridyl 4-fluoro- -(CH2)2SO3- Na+ salt hydrogen 398 phenyl 51 4-pyridyl 4-fluoro- -(CH2)2CH(SO3-)(CH2)3 hydrogen 534 phenyl SO3-.2 Na+ salt 52 4-pyridyl 4-fluoro- carboxymethyl .TFA salt hydrogen 348 phenyl 53 4-pyridyl 4-fluoro- 4-(morpholin-4-yl)butyl . hydrogen 431 phenyl 2 TFA salt 54 4-pyridyl 4-fluoro- 4-methylaminobutyl . 2 hydrogen phenyl TFA salt 55 4-pyridyl 4-fluoro- 4-(pyrrolidin-1-yl)butyl . hydrogen 415 phenyl 2 TFA salt 56 4-pyridyl 4-fluoro- 4-(piperidin-1-yl)butyl . 2 hydrogen 429 phenyl TFA salt 57 4-pyridyl 4-fluoro- 2-hydroxyethyl . 2 HCl hydrogen 232.8-237.9 phenyl salt 58 4-pyridyl 4-fluoro- -(CH2)3SO3#NA+ salt. TFA hydrogen 412 phenyl salt 59 4-pyridyl 4-fluoro- carboxymethylaminocar- hydrogen 405 phenyl bonylmethyl . HCl CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 60 4-pyridyl 4-fluoro- cyanomethyl hydrogen 233.1-233.7 phenyl 61 4-pyridyl 4-fluoro- 2-(pyrrolidin-1-yl)ethyl hydrogen 148.1-153.3 phenyl 62 4-pyridyl 4-fluoro- 3-[(bis(2-hydroxyethyl)- hydrogen 435 phenyl amino]propyl . 2 TFA salt 63 4-pyridyl 4-fluoro- 3- hydrogen 386 phenyl (cyanomethylamino)prop yl . 2 TFA salt 64 4-pyridyl 4-fluoro- 2-aminoethyl . 2 TFA salt hydrogen 333 phenyl 65 4-pyridyl 4-fluoro- 4-aminobutyl . 2 TFA salt hydrogen 361 phenyl 66 4-phyridyl 4-fluoro- 2-(4-methylpiperazin-1- hydrogen 416 phenyl yl)ethyl . 3 TFA salt 67 4-pyridyl 4-fluoro- 2-imdiazol-1-ylethyl . 2 hydrogen 384 phenyl TFA salt 68 4-pyridyl 4-fluoro- 2-cyanoethyl hydrogen 171.3-172.5 phenyl 69 4-pyridyl 4-fluoro- methylsulfonyl hydrogen 206.6-207.1 phenyl CPD # R1 R2 R4 R6 M.Pt. °C Mass Spec. m/e 70 4-pyridyl 4-fluoro- 1-(hydroxymethyl)propyl hydrogen 176.6-178.2 phenyl 71 4-pyridyl 4-fluoro- 4-cyanobutyl . TFA hydrogen 371 phenyl 72 4-pyridyl 4-fluoro- 3-guanidinopropyl . 2 hydrogen 389 phenyl TFA 73 4-pyridyl 4-fluoro- 2-guanidinoethyl . 2 TFA hydrogen 375 phenyl 74 4-pyridyl 4-fluoro- 3-(4-methylimidazol-1- hydrogen phenyl yl)propyl . 2 TFA 75 4-pyridyl 4-fluoro- 3-(2-nitroimidazol-1- hydrogen phenyl yl)propyl .2 HCl 76 4-pyridyl 4-fluoro- 3-(2-methylimidazol-1- hydrogen phenyl yl)propyl . 2 TFA 77 4-pyridyl 4-fluoro- hydrogen methoxy 244 phenyl 78 4-pyridyl 4-fluoro- 3-[N,N-bis(pyridin-3- hydrogen phenyl ylmethyl)amino]propyl 79 4-pyridyl 4-fluoro- -(CH2)3N[(CH2)3N(CH3)2]2 hydrogen phenyl II. Compound of Formula (I) where B is carbon, Q is-NR4-, is a group of formula (S), and the other groups are as defined below are: CPD R1 R3 R2 R4 R6 M.P # 80 4-pyridyl hydrogen 3-chloro-4-fluoro- hydrogen hydrogen 293.5 phenyl 296.5 81 4-pyridyl hydrogen 3-chlorophenyl hydrogen hydrogen >280 82 4-pyridyl hydrogen 3-trifluoromethyl- hydrogen hydrogen 226.2@ phenyl 226.9 83 4-pyridyl hydrogen 3-methyoxyphenyl hydrogen hydrogen 240.4@ 240.6 84 4-pyridyl hydrogen 2-methylphenyl hydrogen hydrogen > 300 85 4-pyridyl hydrogen 2-methoxyphenyl hydrogen hydrogen > 300 86 4-pyridyl hydrogen 3-trifluoromethyl- methyl hydrogen . 220-25@ phenyl HCl 87 4-pyridyl hydrogen 3-chloro-4-fluoro- methyl hydrogen . 220-23@ phenyl HCl 88 4-pyridyl hydrogen 4-fluorophenyl methyl chloro . HCl 250-25@ 89 4-pyridyl hydrogen 4-fluorophenyl hydrogen ethyl . 2 HCl 195-19@ CPD R1 R3 R2 R4 R6 M.P # 90 4-pyridyl hydrogen 4-fluorophenyl hydrogen methoxy . 2 244 HCl 91 4-pyridyl 6-chloro 4-fluorophenyl hydrogen hydrogen 229.5@ 231.2 92 4-pyridyl 6-trifluoro- 4-fluorophenyl 2-morpholin- hydrogen 126.4@ methyl 4-ylethoxy 128.2 93 2-(2-hydroxyethyl- hydrogen 4-fluorophenyl hydrogen hydrogen . amino)-4-pyridyl HCl 94 2-[HO(CH2)2O hydrogen 4-fluorophenyl hydrogen hydrogen . (CH2)2-NH]-4- HCl pyridyl 95 2-(2-methylamino hydrogen 4-fluorophenyl hydrogen hydrogen . ethylamino)-4- HCl pyridyl 96 2-(3-methoxy- hydrogen 4-fluorophenyl hydrogen hydrogen . propyl-amino)-4- HCl pyridyl 97 2-n-propylamino-4- hydrogen 4-fluorophenyl hydrogen hydrogen . pyridyl HCl CPD R1 R3 R2 R4 R6 M.P # 98 2-(3-hydroxy- hydrogen 4-fluorophenyl hydrogen hydrogen . propyl-amino)-4- HCl pyridyl 99 2-methylamino-4- hydrogen 4-fluorophenyl hydrogen hydrogen . pyridyl HCl 100 2-acetylamino-4- hydrogen 4-fluorophenyl hydrogen . hydrogen pyridyl HCl III. Compound of Formula (I) where B is carbon, Q is -O-, R3 and R6 are hydrogen, is a group of formula (S), and the other groups ai as defined below are:

CPD R1 R2 M. Pt. OC # 101 4-pyridyl 4-fluorophenyl 141-143 102 2-chloropyrimidin-4-yl 4-fluorophenyl 224.8-225.2 103 2-aminopyrimidin-4-yl 4-fluorophenyl 252.9-253.7 104 2-methylthiopyrimidin-4-fluorophenyl 182.5-183.9 4-yl IV. Compound of Formula (I) where B is carbon, Q is-NR4-, R3 and R6 are hydrogen, is a group of formula (T), and the other groups are as defined below is: CPD R1 R2 R4 M. Pt. OC 105 4-pyridyl 4-fluorophenyl hydrogen 256-257 V. Compound of Formula (I) where B is carbon, Q is-NR4-, R6 is hydrogen, is a group of formula (W), and the other groups are as

defined below are: CPD R1 R2 R4 Mass # Spec. m 106 4-pyridyl 4-fluorophenyl hydrogen 107 4-pyridyl 4-fluorophenyl hydrogen . HCl salt 108 4-pyridyl 4-fluorophenyl 3-cyanopropyl 358 109 4-pyridyl 4-fluorophenyl 3-(imidazol-1-yl)propyl 399 110 4-pyridyl 4-fluorophenyl methyl . HCl salt 305 111 4-pyridyl 4-fluorophenyl ethyl . HCl salt 318 112 2-[(2-hydroxyethyl)amino]-4- 4-fluorophenyl hydrogen . HCl salt 350 pyridyl 113 2-[(2-aminoethyl)amino]-4- 4-fluorophenyl hydrogen . HCl sat 349 pyridyl 114 2-[(3-hydroxypropyl)amino]-4- 4-fluorophenyl hydrogen . HCl salt 364 pyridyl 115 2-methylamino-4-pyridyl 4-fluorophenyl hydrogen . HCl salt 320 116 2-bromo-4-pyridyl 4-fluorophenyl hydrogen . HCl salt 369 CPD R1 R2 R4 Mass # Spec. m 117 2-methoxy-4-pyridyl 4-fluorophenyl hydrogen . HCl salt 321 118 2-[(3-aminopropyl)amino]-4- 4-fluorophenyl hydrogen . HCl salt 363 pyridyl 119 2-hydroxylamino-4-pyridyl 4-fluorophenyl hydrogen . HCl salt 322 120 2-carboxymethylamino-4- 4-fluorophenyl hydrogen . HCl salt 364 pyridyl 121 4-pyridyl 4-fluorophenyl 3-(2-nitroimidazol-1-yl)propy . HCl 444 salt 122 4-pyridyl 4-fluorophenyl 3-(4-methylimidazol-1-yl)propyl. HCl 413 salt 123 4-pyridyl 4-fluorophenyl 3-(4-methylpiperazin-1-yl)propyl . 431 HCl salt 124 4-pyridyl 4-fluorophenyl 3-(morpholin-4-yl)propyl . HCl salt 418 125 4-pyridyl 4-fluorophenyl 3-methylaminopropyl . HCl salt 362 126 4-pyridyl 4-fluorophenyl 3-(4-nitroimidazol-1-yl)propyl . HCl 444 salt 127 2-acetylamino-4-pyridyl 4-fluorophenyl hydrogen . HCl 348 VI. Compound of Formula (I) where B is carbon, Q is-NR4-, R6 is hydrogen, is a group of formula (W), and the other groups are as defined below are: CPD R1 R2 R6 R4 Ma # Spec. 128 2-methylamino-4-pyridyl 4-fluorophenyl 6-methylamino hydrogen . 2 HCl 349 129 2-imidazol-1-ylmethyl 4-fluorophenyl hydrogen hydrogen . 2 HCl 414 carbonylamino-4-pyridyl 130 2-dimethylaminomethyl- 4-fluorophenyl hydrogen hydrogen . 2 HCl 391 carbonylamino-4-pyridyl 131 2-methylaminomethyl 4-fluorophenyl hydrogen hydrogen . 2 HCl 377 carbonylamino-4-pyridyl 132 2-piperidin-1-ylmethyl- 4-fluorophenyl hydrogen hydrogen . 2 HCl 431 carbonylamino-4-pyridyl 133 2-(4-methylpiperazin-1- 4-fluorophenyl hydrogen hydrogen . 2 HCl 446 yl-methylcarbonylamino- 4-pyridyl 134 4-pyridyl 4-fluorophenyl 6-dimethylamino hydrogen . 2 HCl 334 135 4-pyridyl 4-fluorophenyl 6-methoxy hydrogen . HCl 321 136 4-pyridyl 4-fluorophenyl 6-methylthio hydrogen . HCl 337 CPD R1 R2 R6 R4 Ma # Spec. 137 2-(2-methylthioethyl- 3-chlorophenyl hydrogen hydrogen . 2 HCl 396 amino)-4-pyridyl 138 4-pyridyl 4-fluorophenyl 6-acetylamino hydrogen. HCl 348 139 2-(2-hydroxyethylamino)- 4-fluorophenyl 6-methylamino hydrogen . 2 HCl 379 4-pyridyl 140 2-acetylamino-4-pyridyl 4-fluorophenyl 6-acetylamino hydrogen . HCl 405 141 2-methoxymethylcar- 4-fluorophenyl hydrogen hydrogen . HCl 378 bonyl-amino-4-pyridyl 142 2-(2-dimethylaminoethyl- 4-fluorophenyl hydrogen hydrogen . 2 HCl 405 carbonylamino)-4-pyridyl 143 2-chloro-4-pyridyl 3-chlorophenyl hydrogen hydrogen . HCl 341 144 2-chloro-4-pyridyl 4-fluorophenyl 6-chloro hydrogen . HCl 359 145 2-(2-hydroxyethylamino)- 4-fluorophenyl 6-(2-hydroxyethyl- hydrogen . 2 HCl 409 4-pyridyl amino) 146 2-(3-hydroxypropyl- 4-fluorophenyl 6-(3-hydroxy- hydrogen . 2 HCl 437 amino)-4-pyridyl propyl-amino) 147 2-(4-hydroxybutylamino)- 4-fluorophenyl 6-(4-hydroxybutyl- hydrogen . 2 HCl 466 4-pyridyl amino) CPD R1 R2 R6 R4 Ma # Spec. 148 2-(2-methoxyethylamino)- 4-fluorophenyl 6-(2-methoxy- hydrogen . 2 HCl 437 4-pyridyl ethyl-amino) 149 2-(3-methoxypropyl- 4-fluorophenyl 6-(3-methoxy- hydrogen . 2 HCl 465 amino)-4-pyridyl propyl-amino) 150 2-(3-aminopropylamino)- 4-fluorophenyl 6-(3-aminopropyl- hydrogen . 4 HCl 435 4-pyridyl amino) VII. Compound of Formula (I) where B is nitrogen, Q is-CH-, R3 and R6 arehydrogen, is a group of formula (S), and the other groups are as defined below is: CPD # R1 R2 M. Pt. OC 151 4-fluorophenyl 4-pyridyl 202.1-206

VIII. Compound of Formula (I) where B is carbon, Q is-NH-, R3 and R6 are hydrogen, is a group of formula (V), and the other groups are as defined below is: CPD # R'R2 Mass Spec. m/e 152 4-pyridyl 4-fluorophenyl 290

While the broadest definition of the compound of this invention is set forth above, certain compound of Formula (I) are preferred. For example,

A preferred group of compound is that wherein------is between B and-CR'-.

Within this group, more preferred groups are as follows: (1) First, a more preferred group of compound is that wherein: Q is-NR4-; and is a group represented by formula (S).

Within these preferred and more preferred groups, an even more preferred group of compound is that wherein: R3 is at the 7-position; and R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.

Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compound is that wherein: Rl is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O) nR' (where n is 0 to 2 and R'is alkyl)],-NRS02R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) aR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl), more preferably Rl is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from

amino, acetylamino, methylamino, dimethylamino, methylsulfonyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy.

RZ is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl; and R3 is hydrogen, alkyl, halo or heteroalkyl, more preferably hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2- dimethylaminoethyl, most preferably hydrogen.

Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compound is that wherein: R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-OR' (where R5 is hydrogen, alkyl, heteroalkyl or or-(alkylene)-CO-(alkylene)-Zwherein:heterocyclylalkyl),-(al kylene)-Z Z is cyano; -COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or - (alkylene)-COOR', or R3 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl, or R10 and R11 together are -(CH2)n- where n is 2 or 3; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2- methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3-

dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3- hydroxypropoxy, 2-methylnminoethoxy, 3-methylaminopropoxy, 2- dimethylaminoethoxy, 3-dimethylamino-propo, 2- (morpholin-4- yl) ethoxy, 3-(morpholin-4-yl) propoxy, 2-(piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1- yl) propoxy, more preferably hydrogen, methyl, hydroxy, methoxy, 2- (morpholin-4-yl)-ethyl, 2- (morpholin-4-yl) ethoxy or 2- (piperidin-1- yl)ethyl.

(2) Another more preferred group of compound is that wherein: Q and-NR4-; is a group represented by formula (W).

Within these preferred and more preferred groups, an even more preferred group of compound is that wherein: R6 is at the 6-position of ring (W) and is selected from hydrogen, alkyl, halo, -NRC (O) R" [where R is hydrogen, alkyl or hydroxyalkyl and R"is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or-S (O)NR' (where n is 0 to 2 and R'is alkyl)] or -NRSO2R" [where R is hydrogen or alkyl and R" is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)NR' (where n is 0 to 2 and R'is alkyl)], preferably hydrogen, methyl, methoxy, fluoro, chloro, amino or acetylamino, most preferably hydrogen.

Within these preferred and more preferred groups, particularly preferred group of compound is that wherein: Rl is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O) nR' (where n is 0 to 2 and R'is alkyl)], -NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl), more preferably Rl is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy.

RZ is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR (where R is alkyl), more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl; and Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compound is that wherein: R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or- (alkylene)-CO- (alkylene)-Z wherein: Z is cyano;

-COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl, R9 is alkoxy or - (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl, or R10 and R11 together are -(CH2)n- where n is 2 or 3; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2- methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3- hydroxypropoxy, 2-3-methylaminopropoxy, dimethylaminoethoxy, 3-dimethylaminopropoxy, 2- (morpholin-4- yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propxy, 2-(piperazin-1-yl) ethoxy or 3- (piperazin-1- yl) propoxy, more preferably hydrogen, hydroxy, methoxy, 2- (morpholin- 4-yl) ethyl, 2-(morpholin-4-yl)ethoxy or 2-(piperidin-1-yl) ethyl.

(3) Another more preferred group of compound is that wherein: Q and-O-; is a group represented by formula (S). Within these preferred and more preferred group of compound, an even more preferred group of compound is that wherein: R3 is at the 7-position;

R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.

Within these preferred and more preferred groups, particularly preferred group of compound is that wherein: R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O) aR' (where n is 0 to 2 and R'is alkyl)],-NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl), more preferably Rl is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-nminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy.

RZ is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl, more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.

Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compound is that wherein:

R3 is hydrogen, alkyl, cycloalkyl, heteroalkyl, halo, heterocyclylalkyl, -OR19 (where Rl9 is hydrogen, alkyl, heteroalkyl or or-(alkylene)-CO-(alkylene)--(alkylene)-Z" Z"wherein: Z"is cyano; -COOR24 where R24 is hydrogen or alkyl; R25andR26independentlyrepresent-CONR25R26where hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NRZ') (NRZ8R29) where R27, R23 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CHz) n where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR3°where R3° is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2- methylaminoethyl, 3-methylaminopropyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, 2-(morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3- hydroxy-propoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2- dimethylaminoethoxy, 3-dimethylamino-propoxy, 2- (morpholin-4- yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1- yl) propoxy, more preferably hydrogen, hydroxy, methoxy, 2- (morpholin- 4-yl)ethyl, 2-(piperidin-1-yl)ethyl.or (4) Another more preferred group of compound is that wherein: Q and-O-; is a group represented by formula (W).

Within these preferred and more preferred groups, an even more preferred group of compound is that wherein: R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen.

Within these preferred and more preferred groups, particularly preferred group of compound is that wherein: Rl is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra vis hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O)"R' (where n is 0 to 2 and R'is alkyl)],-NRS02R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl), more preferably Rl is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy.

R2 is an aryl ring, preferably a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl, more preferably a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy, most preferably 4-fluorophenyl.

Exemplarv particularly preferred compound are: 3- (4-Fluorophenyl)-l-hydroxy-2- (pyridin-4-yl)-lH-pyrrolo [3,2-b]- pyridine.

3-(4-Fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo[3,2 -b]- pyridine.

3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridin e.

3-(4-Fluorophenyl)-2- [2-(2-hydroxyethylamino) pyridin-4-yl]-lH- pyrrolo [3,2-bl pyridine.

3-[4-Fluorophenyl)-1-[2-(piperidin-1-yl)ethoxy]-2-(pyridin-4 -yl)-1H- pyrrolo[3,2-b]-pyridine.

3-(4-Fluorophenyl)-1-[2-(morpholin-4-yl)ethoxy]-2-(pyridin-4 -yl)- 1H-pyrrolo[3,2-b]-pyridine.

3-(4-Fluorophenyl)-1-[2-(morpholin-4-yl)ethyl]-2-(pyridin-4- yl)-1H- pyrrolo[3,2-b]-pyridine.

3-(4-Fluorophenyl)-1-[2-(piperidin-1-yl)ethyl]-2-(pyridin-4- yl)-1H- pyrrolo[3,2-b]pyridine, 7-(4-Fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazin e.

6-(2-Acetylaminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[ 2,3-b]- pyrazine.

A further preferred compound is: 3-(4-Fluorophenyl)-1-methyl-2-(pyridin-4-yl)-1H-pyrrolo[3,2- b]- pyridine.

It is further noted that particularly preferred compound of Formula (I) are those wherein RI is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, -NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl, heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl,

heterocyclyl, optionally substituted phenyl, imidazole or-S (O) nRI (where n is 0 to 2 and R'is alkyl) ],-NRS02R" [where R is hydrogen or alkyl and <BR> <BR> R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino,<BR> <BR> alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl); particularly wherein------is between B and-CR1-, and is a group represented by formula (S), (V) or (W); particularly wherein R2 is an aryl ring; particularly wherein is a group represented by formula (S); R3 is at the 7-position; and R6 is hydrogen, alkyl, alkoxy or halo; particularly wherein Q is <BR> <BR> <BR> <BR> -NR4- ; particularly wherein R3 is hydrogen, alkyl, halo or heteroalkyl; particularly wherein RI is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl, -NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O) nR' (where n is 0 to 2 and R'is alkyl) ],-NRS02R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and R'is alkyl) ) or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is ;alkyl particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or - (alkylene)-CO- (alkylene)-Z wherein: Z is cyano;

-COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl and R9 is alkoxy or - (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl or R10 and R11 together are -(CH2)N- where n is 2 or 3 and R12 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and Ru vis a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and R3 is hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2- dimethylaminoethyl; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2- methylaminoethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2-(piperidin-1-yl)(piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3- hydroxypropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2- dimethylamino-ethoxy, 3-dimethylaminopropoxy, 2-(morpholin-4- yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2-(piperidin-1-yl) ethoxyj 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1- yl) propoxy; particularly wherein Rl is 2- (2-hydroxyethylamino)-4- pyridyl; R2 is 4-fluorophenyl; R3 is hydrogen; and R4 is hydrogen;

namely,3-(4-fluorophenyl)-2-[2-(2-hydroxyethylamino)-pyridin -4-yl]-1H- pyrrolo-[3,2-b]pyridine.

Among those preferred compound of formula I in which------is between B and-CRl-, and is a group represented by formula (S), (V) or (W) also such are preferred wherein Q is-0- ; particularly wherein R3 is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo, -ORl9 (where Rl9 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Z"or-(alkylene)-CO-(alkylene)-Z"wherein(alkylene )-Z"or-(alkylene)-CO-(alkylene)-Z"wherein : Z"is cyano; -COOR24 where R24 is hydrogen or alkyl; R25andR26independentlyrepresent-CONR25R26where hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NRZ') (NRZ8R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are -(CH2)n- where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR30 where R30 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein Ru vis a 4- pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), -NRaC (O) Rb [where Ra vis hydrogen or alkyl and Rb is hydrogen, alkyl or - (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O)nR' (where n is 0 to 2 and R'is alkyl)], -NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl); particularly wherein RZ is a phenyl ring optionally substituted with one

or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and Ru vis a 4-pyridyl ring optionally substituted with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2- aminoethyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2- dimethylaminoethoxy; particularly wherein R6 is hydrogen; and R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R3 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-amino- propyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethylamino- ethyl, 3-dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4- yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin- 1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2- dimethylaminoethoxy, 3-dimethylaminopropoxy, 2- (morpholin-4-yl)- ethoxy, 3- (morpholin-4-yl) propoxy, 2-(piperidin-1-yl) ethoxy, 3-(piperidin- 1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1-yl) propoxy.

Among those preferred compound of formula I in which------is between B and -CR1-, and is a group represented by formula (S), (V) or (W) and R2 is an aryl ring, also such are preferred wherein is a group represented by formula (W); and R6 is hydrogen, alkyl, halo,-NRC (O) R" [where R is hydrogen, alkyl or hydroxyalkyl and R"is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or-S (O)nR' (where n is 0 to 2 and R'is alkyl)] or -NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)nR' (where n is 0 to 2 and R'is alkyl)]; particularly wherein Q is-NR4-; particularly

wherein Ri ils a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb [where Ra is hydrogen or alkyl and Rb is hydrogen, alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or-S (O) nR' (where n is 0 to 2 and R'is alkyl)], -NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)nR' (where n is 0 to 2 and R'is alkyl)] or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-OR' (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Zwherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; -CONR8R9 where r8 is hydrogen or alkyl and R9 is alkoxy or - (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl or Rl° and Rli together are- (CHZ) n where n is 2 or 3 and R12 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is at the 6-position and is selected from hydrogen, methyl, methoxy, fluoro, chloro, amino or acetylamino; and Rl is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonyl-

amino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethyl-aminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; particularly wherein Rs is hydrogen; and R9 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3- methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methylamino- ethoxy, 3-methylaminopropoxy, 2-dimethylamino-ethoxy, 3-dimethyl- aminopropoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl)- ethoxy or 3- (piperazin-1-yl) propoxy; particularly wherein Rl is 2-acetyl- aminopyridyl, R2 is 4-fluorophenyl, and R4 is hydrogen namely 6- [2- acetylaminopyridin-4-yl]-7- (4-fluorophenyl)-5H-pyrrolo [2,3-b] pyrazine.

Among those preferred compound of formula I in which------is between B and-CRl-, R2 is an aryl ring, is a group represented by formula (W); and R6 is hydrogen, alkyl, halo,-NRC (O) R" [where R is hydrogen, alkyl or hydroxyalkyl and R"is hydrogen, alkyl, cycloalkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, heterocyclyl or-S (O). R' (where n is 0 to 2 and R'is alkyl)] or-N-RSO 2R" [where R is hydrogen or alkyl and R"is alkyl or -(alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O)nR' (where n is 0 to 2 and R'is alkyl)], also such are preferred wherein Q is -O-; particularly wherein Ru vis a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are, independently of each other, hydrogen, alkyl, heterocyclylalkyl or heteroalkyl),-NRaC (O) Rb

[where Ra vis hydrogen or alkyl and Rb is hydrogen, alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino, cycloalkyl, heterocyclyl, optionally substituted phenyl, imidazole or -S (O) nR' (where n is 0 to 2 and R'is alkyl)],-NRSO2R" [where R is hydrogen or alkyl and R"is alkyl or- (alkylene)-X where X is hydroxy, alkoxy, amino, alkylamino, dialkylamino or-S (O) nR' (where n is 0 to 2 and Ris alkyl)] or-OR (where R is alkyl or heteroalkyl); particularly wherein RZ is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and Ru vis a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, acetylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethyl- amino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3- aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2- dimethylaminoethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy.

A subgroup of the compound of formula I are those wherein R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, -COOR14, - (alkylene)-COOR14 (where R14 is hydrogen or alkyl),-CONR15Rl6 (where R15 and Riz independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),-S (O) nR17 (where n is an integer from 0 to 2 and R17 is alkyl, amino, monosubstituted amino or disubstituted amino) or-OR18 (where R'8 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl). Among these compound such are preferred wherein------is between B and -CR1-,and is a group represented by formula (S), (V) or (W) ; particularly wherein R2 is an aryl ring; particularly wherein is a group represented by formula (S); R3 is at the 7-position; and R6 is

hydrogen, alkyl, alkoxy or halo; particularly wherein ll is-NR4- ; particularly wherein R3 is hydrogen, alkyl, halo or heteroalkyl; particularly wherein Ru ils a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl), or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or- (alkylene)-CO- (alkylene)-Z wherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl and R9 is alkoxy or- (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NRl°) (NR11R12) where R10, R11 and R12 independently represent hydrogen or alkyl or R10 and R11 together are -(CH2)n- where n is 2 or 3 and R12 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and R'is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxy- ethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethyl-aminoethyl, methoxy, 2-hydroxyethoxy or 2- dimethylamino-ethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and R3 is hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3- methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2-

(morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methyl- aminoethoxy, 3-methylaminopropoxy, 2-dimethylamino-ethoxy, 3- dimethylaminopropoxy, 2- (morpholin-4-yl) ethoxy, 3-(morpholin-4- yl) propoxy, 2-(piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3-(piperazin-1-yl)propoxy ; particularly wherein Rl is 4-pyridyl; R2 is 4-fluorophenyl; R3 is hydrogen; and R4 is methyl; namely, 3-(4-fluorophenyl)-1-methyl-2-(pyridin-4-yl)-1H-pyrrolo- [3,2- b]pyridine.

Among those preferred compound of formula I in which R5 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino,-COOR -(1lkylene)-COOR14 (where R14 is hydrogen or ALKYL), -CONR15R16 (where R15 and R16 independently represent hydrogen or alkyl, or Rls and Rls together with the nitrogen atom to which they are attache form a heterocycle),-S (O) nRl' (where n is an integer from 0 to 2 and Rois alkyl, amino, monosubstituted amino or disubstituted amino) or -OR18 (where Rl$ is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), ------ is between B and-CRl-, R2 is an aryl ring and is a group represented by formula (S); R3 is at the 7-position; and R5 is hydrogen, alkyl, alkoxy or halo also such are preferred wherein Q is -O-; particularly wherein R3 is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo,-OR'9 (where R'9 is hydrogen, alkyl, heteroalkyl or or-(alkylene)-CO-(alkylene)-Z"-(alkylene)-Z" wherein: Z"is cyano; -COOR24 where R24 is hydrogen or alkyl;

-CONR25R26 where R25 and R26 independently represent hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NR2') (NR28R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CH2) n where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR3°where R3° is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R1 is a 4- pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl) or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or -OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and R1 is a 4-pyridyl ring optionally substi- tuted with a substituent selected from amino, methylamino, dimethyl- amino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-aminoethyl, 2-dimethyl- aminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy, particularly wherein R6 is hydrogen; and R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R3 is hydrogen, methyl, ethyl, 2-hydroxy- ethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylamino- ethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylamino- propyl, 2-(piperidin-1-3-(morpholin-4-yl)propyl, yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3-(piperazin-1- yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxy-propoxy, 2- methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3- dimethylaminopropoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4- yl) propoxy, 2-(piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3-(piperazin-1-yl) propoxy.

Among those preferred compound of formula I in which R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino,-COOR14, - (alkylene)-COOR14 (where R14 is hydrogen or alkyl),-CONRI5Rl6 (where R15 and R16 independently represent hydrogen or alkyl, or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),-S (O) nRl7 (where n is an integer from 0 to 2 and R17 is alkyl, amino, monosubstituted amino or disubstituted amino) or-OR18 (where R18 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),------is between B and-CRl-, and is a group represented by formula (S), (V) or (W) and R2 is an aryl ring, also such are preferred wherein is a group represented by formula (W); and R6 is hydrogen, alkyl or halo; particularly wherein Q is-NR4- ; particularly wherein Rl is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl) or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or -OR where R is alkyl; particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-OR' (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or - (alkylene)-CO- (alkylene)-Z wherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; -CONR8R9 where R8 is hydrogen or alkyl and R9 is alkoxy or - (alkylene)-COOR', or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle;

-C (=NRl°) (NR11R12) where Rl°, R"and Rl2 independently represent hydrogen or alkyl or R10 and R11 together are -(CH2)n- where n is 2 or 3 and Ri2 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and RI is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxy- ethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethyl-aminoethyl, methoxy, 2-hydroxyethoxy or 2- dimethylaminoethoxy; particularly wherein R6 is hydrogen; and R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3- aminopropyl, 2-methylaminoethyl, 3-methylamino-propyl, 2-dimethyl- aminoethyl, 3-dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2- hydroxyethoxy, 3-hydroxypropoxy, 2-methylaminoethoxy, 3-methyl- aminopropoxy, 2-dimethylamino-ethoxy, 3-dimethylaminopropoxy, 2- 2-(piperidin-1-(morpholin-4-yl)ethoxy,3-(morpholin-4-yl)prop oxy, yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1-yl) propoxy; particularly wherein R1 is 4-pyridyl; R2 is 4- fluorophenyl; and R4 is hydrogen; namely, 7- (4-fluorophenyl)-6- (pyridin- 4-yl)-5H-pyrrolo[2,3-b]pyrazine.

Among those preferred compound of formula I in which R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino,-COOR14, - (alkylene)-COOR14 (where R14 is hydrogen or alkyl),-CONR15R'6 (where R15 and Riz independently represent hydrogen or alkyl, or R'5 and R16 together with the nitrogen atom to which they are attache

form a heterocycle),-S (O) nRl7 (where n is an integer from 0 to 2 and R17 is alkyl, amino, monosubstituted amino or disubstituted amino) or-OR18 (where R18 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),------is between B and-CR1-, R2 is an aryl ring and is a group represented by formula (W); and R6 is hydrogen, alkyl or halo also such are preferred wherein Q is-0- ; particularly wherein R1 is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl), or-OR (where R is alkyl or hetero- alkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, methoxy, fluoro or chloro; and RI is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2- aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethyl-aminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylnminoethoxy; particularly wherein R6 is hydrogen; and R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy.

Another subgroup of the compound of formula I is the group of compound represented by Formula (ira): wherein: Q is-NR4-,-O-or-S-wherein:

R4 iS hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl,-OR' (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), - (alkylene)-Z or - (alkylene)-CO- (alkylene)-Z wherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; R8andR9independentlyrepresent-CONR8R9where hydrogen, alkyl or alkoxy, or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl, or Rl° and R11 together are -(CH2)n- where n is 2 or 3 and Rl2 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; one of A and B is nitrogen and the other is-CR6-wherein: R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, (whereR14ishydrogenoralkyl),-COOR14,-(alkylene)COOR14 -CONR15R16 (where R15 and Rls independently represent hydrogen or alkyl or R15 and R16 together with the nitrogen atom to which they are attache form a heterocycle),-S (O)nR17 (where n is an integer from 0 to 2 and Rl7 is alkyl, amino, monosubstituted amino or disubstituted amino) or-OR" (where Rl8 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl); Ru vis heteroaryl; RZ is aryl or heteroaryl; and R3 is hydrogen, alkyl, alkenyl, alkynyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, cycloalkylthio, aralkyl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, acylamino,

sulfonylamino, -OR19 (where Rl9 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -COOR20 (where R20 is hydrogen or alkyl), R21andR22independentlyrepresenthydrogen-CONR21R22(where or alkyl, or R21 and R22 together with the nitrogen atom to which they are attache form a heterocycle),-S (O) nR23 (where n is an integer from 0 to 2 and R23 is alkyl, heteroalkyl, amino, monosubstituted amino or disubstituted amino),- (alkylene)-Z" or - (alkylene)-CO- (alkylene)-Z" wherein: Z"is cyano; -COOL24 where R24 is hydrogen or alkyl; R25andR26independentlyrepresent-CONR25R26where hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NRZ') (NR28R29) where R27, R23 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CH2) n where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR3°where R3° is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and their pharmaceutically acceptable salts, prodrugs, individual isomers, and mixtures of isomers. Among the compound such are preferred wherein A is nitrogen; particularly wherein Q is-NR4- ; particularly wherein Q is-NR4-, particularly wherein R2 is an aryl ring; particularly wherein R3 is at the 7-position; and R6 is hydrogen, alkyl or halo; particularly wherein R3 is hydrogen, alkyl, halo or heteroalkyl; particularly wherein Ru ils a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl), or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl,

heterocyclylalkyl,-oR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or- (alkylene)-CO- (alkylene)-Z wherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; R8andR9independentlyrepresent-CONR8R9where hydrogen or alkyl or Rg and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl or Rl° and Rll together are- (CHZ) n where n is 2 or 3 and R12 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is hydrogen, methyl, fluoro or chloro; and Ru ils a 4-pyridyl ring optionally substituted with a substituent selected from amino, methyl- amino, dimethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2- aminoethyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2- dimethylaminoethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and R3 is hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3- hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3- methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methylamino- ethoxy, 3-dimethyl-2-dimethylamino-ethoxy, aminopropoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl)- ethoxy or 3- (piperazin-1-yl) propoxy; particularly wherein R3 and R4 are hydrogen; RI is 4-pyridyl; and R2 is 4-fluorophenyl; namely, 3- (4-

fluorophenyl)-2-(pyridyl-4-yl)-1H-pyrrolo [3,2-b] pyridine; particularly wherein R3 is ;hydrogen R4 is ;methoxy Rl is 4-pyridyl; and R2 is 4- fluorophenyl; namely, 3-(4-fluorophenyl)-1-methoxy-2-(pyridyl-4-yl)-lH- pyrrolo [3,2-b] pyridine; particularly wherein R3 is ;hydrogen R4 is 2- (morpholin-4-yl) ethoxy; Ru ils 4-pyridyl; and R2 is 4-fluorophenyl; <BR> <BR> <BR> <BR> namely, 3-(4-fluorophenyl)-1- [2-(morpholin-4-yl) ethoxy]-2-(pyridyl-4-yl)- lH-pyrrolo [3,2-b] pyridine; particularly wherein R3 is hydrogen, R4 is hydroxy, RI is 4-pyridyl, and R2 is 4-fluorophenyl; namely 3- (4- fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-lH-pyrrolo(pyridin- 4-yl)-lH-pyrrolo [3,2-b] pyridine; <BR> <BR> <BR> <BR> particularly wherein R3 is hydrogen, R4 is 2- (piperichn-1-yl) ethoxy, Ru ils 4-pyridyl, and R3 is 4-fluorophenyl, namely 3- (4-fluorophenyl)-1- (2- piperidin-1-yl) ethoxy]-2-(pyridine-4-yl)-1H-pyrrolo [3,2-b] pyridine; particularly wherein R3 is ;hydrogen R4 is 2- (morpholin-4-yl) ethyl; R1 is 4-pyridyl; and R2 is 4-fluorophenyl; namely, 3-(4-fluorophenyl)-1-[2- (morpholin-4-yl) ethyl]-2- (pyridyl-4-yl)-lH-pyrrolo [3,2-b] pyridine; particularly wherein R3 is hydrogen, R4 is 2- (piperidin-1-yl) ethyl; Rl is 4-pyridyl, and R3 is 4-fluorophenyl, namely 3- (4-fluorophenyl)-1- (2- piperidin-1-yl) ethyl]-2- (pyridin-4-yl)-lH-pyrrolo [3,2-b] pyridine.

Among those preferred compound of formula Ia wherein A is nitrogen also such are preferred wherein Q is-O-or-S-; particularly wherein R2 is an aryl ring, and R3 is at the 7-position; particularly wherein R3 is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo, -OR19 (where Rl9 is hydrogen, alkyl, heteroalkyl or heterocyclyl- or-(alkylene)-CO-(alkylene)-Z"wherein:alkyl),-(alkylene)-Z" Z"is cyano; -COOR24 where R24 is hydrogen or alkyl; -CONR25R26 where R25 and R26 independently represent hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle;

-C (=NRZ') (NRZ8R29) where R27, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CH2) n- where n is 2 or 3 and R 29 is hydrogen or alkyl; or -COR30 where R30 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein ru is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl) or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, fluoro or chloro; and Ru ils a 4-pyridyl ring optionally substituted with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-aminoethyl, 2-dimethylamino- ethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; particularly wherein R6 is hydrogen; and R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R3 is hydrogen, methyl, ethyl, 2-hydroxy- ethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylamino- ethyl, 3-methylamino-propyl, 2-dimethylaminoethyl, 3-dimethylamino- propyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1- yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1- yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxy-propoxy, 2- methylaminoethoxy, 3-methylaminopropoxy, 2-dimethylaminoethoxy, 3- dimethylaminopropoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4- yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1-yl) propoxy.

Among the compound of formula la also such are preferred wherein B is nitrogen; particularly wherein Q is-NR4- ; particularly wherein R2 is an aryl ring; particularly wherein R3 is at the 7-position; and R6 is hydrogen, alkyl or halo; particularly wherein R3 is hydrogen,

alkyl, halo or heteroalkyl; particularly wherein, R1 is a 4-pyridyl or 4- pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl) or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl,-oR5 (where Rs is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z or- (alkylene)-CO- (alkylene)-Z wherein: Z is cyano; -COOR'where R'is hydrogen or alkyl; R8andR9independentlyrepresent-CONR8R9where hydrogen or alkyl, or R8 and R9 together with the nitrogen atom to which they are attache form a heterocycle; R10,R11andR12independently-C(=NR10)(NR11R12)where represent hydrogen or alkyl or Rl° and Rll together are- (CH2) n where n is 2 or 3 and R12 is hydrogen or alkyl; or -COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R6 is hydrogen, methyl, fluoro or chloro; and Ru ils a 4-pyridyl ring optionally substituted with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-aminoethyl, 2- dimethylamino-ethyl, methoxy, 2-hydroxyethoxy or 2-dimethylamino- ethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; and R3 is hydrogen, methyl, chloro, fluoro, 2- hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl; particularly wherein R4 is hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylamino- propyl, 2-dimethylaminoethyl, 3-dimethylaminopropyl, 2- (morpholin-4- yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3-(piperidin-1-

yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3-hydroxypropoxy, 2-methylaminoethoxy, 3- methylaminopropoxy, 2-dimethylamino-ethoxy, 3-dimethylamino- propoxy, 2- (morpholin-4-yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl) ethoxy, 3- (piperidin-1-yl) propoxy, 2-(piperazin-1- yl) ethoxy or 3-(piperazin-1-yl)propoxy.

Among those preferred compound of formula Ia wherein B is nitrogen also such are preferred wherein Q is-0-or-S- ; particularly wherein R2 is an aryl ring, and R3 is at the 7-position; particularly wherein R3 is hydrogen, alkyl, cycloalkyl, heteroalkyl, heterocyclylalkyl, halo,-ORl9 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl),- (alkylene)-Z" or- (alkylene)-CO- (alkylene)-Z" wherein: Z"is cyano; -COOR24 where R24 is hydrogen or alkyl; -CONR25R26 where R25 and R26 independently represent hydrogen or alkyl or R25 and R26 together with the nitrogen atom to which they are attache form a heterocycle; -C (=NR27) (NR28R29) where R21, R28 and R29 independently represent hydrogen or alkyl, or R27 and R28 together are- (CHZ) n where n is 2 or 3 and R29 is hydrogen or alkyl; or -COR30 where R30 is alkyl, heteroalkyl, heterocyclyl- alkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; particularly wherein R is a 4-pyridyl or 4-pyrimidinyl ring optionally substituted with a substituent selected from heteroalkyl,-NRR' (where R and R'are independently of each other hydrogen, alkyl or heteroalkyl), or-OR (where R is alkyl or heteroalkyl); particularly wherein R2 is a phenyl ring optionally substituted with one or two substituents selected from alkyl, halo or-OR where R is alkyl; particularly wherein R6 is hydrogen, methyl, fluoro or chloro; and Rl is a 4-pyridyl ring optionally substituted

with a substituent selected from amino, methylamino, dimethylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 2-aminoethyl, 2-dimethylamino- ethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; particularly wherein R6 is hydrogen; R2 is a phenyl ring substituted with one or two substituents selected from methyl, fluoro, chloro or methoxy; particularly wherein R3 is hydrogen, methyl, ethyl, 2- hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2- methylaminoethyl, 3-methyl-aminopropyl, 2-dimethylaminoethyl, 3- dimethylaminopropyl, 2- (morpholin-4-yl) ethyl, 3- (morpholin-4-yl) propyl, 2- (piperidin-1-yl) ethyl, 3- (piperidin-1-yl) propyl, 2- (piperazin-1-yl) ethyl, 3- (piperazin-1-yl) propyl, hydroxy, methoxy, 2-hydroxyethoxy, 3- hydroxypropoxy, 2-methylaminoethoxy, 3-methylaminopropoxy, 2- 2-(morpholin-4-dimethylamin-ethoxy,3-dimethylaminopropoxy, yl) ethoxy, 3- (morpholin-4-yl) propoxy, 2- (piperidin-1-yl)-ethoxy, 3- (piperidin-1-yl) propoxy, 2- (piperazin-1-yl) ethoxy or 3- (piperazin-1- yl)propoxy.

The compound of the present invention are manufactured by a process which comprises a) cyclizing a compound of the general formula wherein is a group as defined above and Y and Z are groups convertible to the group and R1,R2,-----, B and Q are as above, or b) introducing a substituent R and/or R4 into a compound of formula

wherein Rl, RZ and B are as above, and Ql is- CH or-NH-, or c) introducing a substituent R'in a compound of formula

wherein and R2 are as abpve, or d) converting a compound of formula wherein P° represents a group represented by formula (S°), (T°) (V°) or (yV°);

wherein R60 is chloro or bromo and R3 is as above, into a compound of formula I, wherein R6 is alkoxy, monosubstituted or disubstituted amino, cyano or alkyl, or e) for the manufacture of a pharmaceutically acceptable salt of a compound of formula I carrying an acidic and/or basic substituent, converting such compound of formula I into such salt.

Compound of this invention can be made by the methods depicted in the rection schemes shown below.

The starting materials and r; eagents used in preparing these compound are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wisconsin, USA), Bachem (Torrance, California, USA), Emka-Chemie, or Lancaster (Windham, NH, USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser's Reagents for Organic Synthesis, Volumes 1-17 (John Wiley and Sons, 1991); Rodd's Chemistry of Carbon Compound, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Rections, Volumes 1-40 (John Wiley and Sons, 1991), March's Advanced Organic Chemistry, (John Wiley and Sons, 4th Edition), and Larock's Comprehensive Organic Transformations (VCH Publishers Inc., 1989).

These schemes are merely illustrative of some methods by which the compound of this invention can be synthesized, and various

modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.

The starting materials and the intermediates of the rection may be isolated and purifie if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.

Schemes A-M describe methods to synthesize compound of Formula (I).

Scheme A Compound of Formula (I) where------is between B and-CRl-, Q is-NR4-, is a group of formula (S) or (T) and other groups are as

defined in the Summary of the Invention are prepared as described below. R2CH2CN 2 RIOMe + R1R base 3 CN 1- in c/ NH2 1 2 NH X Rs I 4/ RsN Rs N X 6Z s Rs Nw Rs Nw X R2 3 X 8 R1 _ R6 1 1 R2 R6 N R2 Rs N/ Rs II/ N R1 N R1 H H (z) (y Rs 1 R R R3 n/ R3 Y R R1/R R1 4 4 (I) (I) (R4 not H) (R4 not H)

Rection of an ester of formula 1 with an acetonitrile derivative of formula 2 in the presence of a suitable base such as sodium ethoxide or potassium t-butoxide, each in its respective alcohol as solvent gives a ß- keto-acetonitrile intermediate of formula 3 ((sexe., Ivan Lantos, I. et al. J.

Org. Chem. 53,4223-4227 (1988)). Alternatively, the rection can be carried out in the presence of lithium diisopropylamide or lithium hexamethyldisilazane in tetrahydrofuran.

In general, compound of formula 1 are commercially available or they can be prepared by methods well known in the art. For example, methylisonicotinate is commercially available. Others can be prepared from suitable starting materials such as 2-chloropyridine-4-carboxylic acid, 3-or 4-quinolinecarboxylic acid, 2-pyrazinecarboxylic acid, 4- methyl-5-pyrimidine-carboxylic acid, 4-pyrimidinecarboxylic acid, 2- pyrazinecarboxylic acid under standard esterification rection conditions.

Compound of formula 2 such as 2-phenylacetonitrile, 4- fluorophenylacetonitrile, pyridylacetonitrile, and the like are commercially available.

Hydrolysis and decarboxylation of the cyano group in 3 in a suitable aqueous acid such as hydrobromic acid provides a ketone of formula 4. Alternatively, a compound of formula 4 can be prepared directly, by reacting the sodium salt of an acid of formula R1C00 Na+ with a Grignard reagent of formula R2CH2MgX (where X is halo).

Condensation of 4 with a 3-aminopyridine of formula 5 or a 4- aminopyridine of formula 6 where X is a halo group (e. g., chloro, bromo or iodo) gives an enamine of formula 7 or 8 respectively. The condensation rection is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid in an aromatic hydrocarbon as a solvent e. g., toluene or xylene.

Compound of formula 5 are either commercially available or they can be prepared by methods well known in the art. For example, 3- amino-2-chloropyridine is commercially available. 3-amino-2-chloro-6- bromopyridine and 3-amino-2-bromo-6-methoxypyridine can be prepared by following the procedure described in Proudfoot, J. R., et al., J. Med. Chem., 38 (24), 4830, (1995). 3-amino-2,6-dichloro-4- methylpyridine can be prepared by following the procedure described in

Grozinger, K. G., et al., J. Heterocycl. Chem., 32 (1), 259, (1995). 3- amino-2,5-dichloropyridine can be prepared by first converting 5-chloro- 3-nitro-2-pyridinone to 2,5-dichloro-3-nitropyridine as described in J.

Heterocycl. Chem., 31 (1), 73, (1994)) followed by reduction of the nitro group as described in Berrie et al., J. Chem. Soc., 2042 (1952).

Compound of formula 6 such as 4-amino-3-chloropyridine and 4- amino-3-chloro-6-methylpyridine can be prepared by following the procedures described in Sugasawa, T., et al. J. Am. Chem. Soc., 4842- 4851 (1978) and turne J. A., J. Org. Chem., 48,3401-3408 (1983) respectively. 4-amino-3-fluoro-6-methoxypyridine can be prepared by following the procedure described in Nesnow, H. J. Heterocycl. Chem., 12,941, (1975).

Cyclization of the enamine 7 or 8 provides the 1H-pyrrolo [3,2- b] pyridine or the 1H-pyrrolo [3,2-c) pyridine of Formula (I), respectively.

The cyclization rection is carried out in the presence of a palladium (II) catalyst such as dichlorobis (triphenylphosphine) palladium (II) in the presence of a tertiary amine such as DABCOT"^ and in an inert organic solvent such as dimethylformamide ((sexe., Chen, C. et al. J. Org. Chem., 62,2676-2677 (1997) and Sakamoto, T. et al. Synthesis, 215 (1990)).

A compound of Formula (I) can be converted, if desired, to other compound of Formula (I). For example, (i) A a1H-pyrrolo-[3,2-c]pyridineofor Formula (I), where R4 is hydrogen can be converted to its corresponding compound of Formula (I) where R4 is not hydrogen by reacting it with an alkylating agent R4Y where Y is a leaving group under alkylating conditions (such as halo, mesylate, tosylate and the like) or an acylating R4COL where L is leaving group under acylating rection conditions such as halo (preferably chloro). The rection is carried out in the presence of a strong base such as sodium hydride and in an aprotic

organic solvent such as tetrahydrofuran, dimethylformamide, and the like.

(ii) A 1H-pyrrolo [3,2-b] pyridine or a 1H-pyrrolo- [3, 2-c) pyridine of Formula (I) can be substituted at the 7-position (R3 = 7-position) using an ortho lithiation protocol. Thus, protection of the N1 nitrogen with an ortho directing protecting group such as trimethylsilylethoxymethyl (SEM), tert-butoxycarbonyl or N-tert-butyl carbamoyl, followed by lithiation with a strong base such as lithium diisopropylamide, lithium 2,2,6,6-tetramethylpiperidine, n-butyllithium or tert-butyllithium in tetrahydrofuran or diethylether would lithiate the 7-position of the pyrrolo [3,2-b]pyridine/ pyrrolo-[3,2-c]pyridine ring. Treatment of the 7- lithio species with an electrophile such as alkyl disulfide, iodine, dimethylformamide, carbon diode will give a corresponding pyrrolo [3, 2-b]pyridine/ pyrrolo-[3,2-c]pyridine of Formula (I) substituted at the 7-position with an iodo, formyl or carboxy group respectively ((sexe Gharpure, M.; et al. Synthesis, 12,1079-82 (1991)).

Scheme B Scheme B describes an alternative method to synthesize a compound of Formula (I) where------is between B and-CRl-, Q is -NR4-, is a group of formula (S) or (T) and other groups are as defined in the Summary of the Invention.

Condensation of a compound of formula 9 with a 3-aminopyridine of formula 5 or 4-aminopyridine of formula 6 where X is a halo group (e. g., chloro, bromo or iodo) gives an enamine of formula 10 or 11 which is then cyclized to the 1H-pyrrolo [3, 2-b]pyridine 12 or 1H-pyrrolo [3, 2-c]-

pyridine 13 respectively, by proceeding as described in Scheme A above.

The condensation rection is carried out in the presence of a suitable base such as sodium hydrie and in an aprotic solvent e. g., tetrahydrofuran or dimethylformamide.

Bromination of 12 or 13 with bromine in dimethylformamide gives the corresponding 3-bromo derivative which upon treatment with boronic acid of formula RZB (OH) 2 (where R2 is as defined in the Summary of the Invention) under Suzuki coupling rection conditions ((sexe., Miyaura, N. Chem. Commun., 866, (1979)) gives 1H-pyrrolo- [3, 2-b]pyridine or 1H-pyrrolo [3, 2-c]pyridine of Formula (I) respectively.

A 1H-pyrrolo [3, 2-b]pyridine or 1H-pyrrolo [3,2-c) pyridine of Formula (I) where R3, Rand rare hydrogen can be converted to the corresponding 1H-pyrrolo[3,2-c]pyridineofor Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above.

Scheme C Scheme B describes an alternative method to synthesize a compound of Formula (I) where------is between B and-CRl-, Q is -NR4-, is a group of formula (T) and other groups are as defined in the Summary of the Invention. o NHPG R2ß4L PGHN ° 15 Rs i ZON Nu 14 16 NH 0 14 16 R X R2 18 2-' R N R6 base 19 -19 3 N 3 R2 R2 , R3 N, N Ri N R1 Ra (I) (I) (R4 not H)

Rection of a 4-aminopyridine of formula 14 where PG is an ortho- directing amino protecting group such as tert-butoxyearbonyl, pivaloyl or benzol, preferably pivaloyl, with a compound of formula 15, where L is a leaving group under acylating conditions [e. g., alkoxy (preferably methoxy or ethoxy), dialkylamino, halo (preferably chloro), or preferably N, O-dimethylhydroxylamino] gives a 3-acyl-4-aminopyridine derivative of formula 16. The rection is carried out in the presence of a strong base such as n-butyllithium in an aprotic polar organic solvents such as diethyl ether, tetrahydrofuran, and the like ((sexe., Sugasawa, T. et al. J.

Am. Chem. Soc. 4842-4851 (1978)). 4-Aminopyridine is commercially available.

Deprotection of the amino group, followed by treatment of the resulting 4-aminopyridine 17 with an acyl halide of formula 18 in the presence of a non-nucleophilic base (such as triethylamine, pyridine and the like) gives a 4-amido-3-acylpyridine of formula 19. The deprotection

is carried out under acidic hydrolysis rection conditions. Suitable acids are inorganic acids such as hydrochloric acid.

Compound of formula 18 where X is chloro can be prepared from suitable starting materials such as 2-chloropyridine-4-carboxylic acid, 3- or 4-quinolinecarboxylic acid, 2-pyrazinecarboxylic acid, 4-methyl-5- pyrimidinecarboxylic acid, 4-pyrimidinecarboxylic acid, 2- pyrazinecarboxylic acid by treatment with a chlorinating agent such as thionyl chloride, oxalyl chloride, and the like.

The 4-amido-3-acylpyridine 19 is converted to the 1H-pyrrolo [3,2- c]pyridine of Formula (I) (R4 is hydrogen) by following the procédure described in Furstner, A et al., J. Org. Chem., 59,5215-5229, (1994).

A compound of Formula (I) where R4 is hydrogen can be converted to other compound of Formula (I) where R4 is not hydrogen as described in Scheme A above.

Scheme D Compound of Formula (I) where------is between B and-CRl-, Q is-NORS-, is a group of formula (S) or (T) and other groups are as defined in the Summary of the Invention are prepared as described below.

Rection of a ketone of formula 4 with a 2-chloro-3-nitropyridine 20 or a 3-chloro-4-nitropyridine 21 under nucleophilic substitution rection conditions gives an a- (3-nitro-2-pyridyl) ketone of formula 22 or a- (4- nitro-3-pyridyl) ketone of formula 23 respectively. The rection is carried out in the presence of a strong non-nucleophilic base such as sodium hydride in an aprotic organic solvent such as dimethylformamide, and the like.

Compound of formula 20 and 21 are either commercially available or they can be prepared by methods known in the art. For example, 2-

chloro-3-nitropyridine, 3-chloro-4-nitropyridine, 2-chloro-4-methyl-3- nitropyridine, 2-chloro-6-methoxy-3-nitropyridine are commercially available. Compound such as 2,5-dichloro-3-nitropyridine, 2-chloro- 5,6-dimethyl-3-nitropyridine and 3-fluoro-4-nitro-2,6-dimethylpyridine can be prepared by the procedures described in Berrie et al., J. Chem.

Soc. , 2042, (1952), Wai, J. S., et al., J. Med. Chem., 36 (2), 249, (1993), and Markley, E., J. Med. Chem., 16,297, (1973), respectively Conversion of 22 or 23 to the corresponding triflate derivatives 24 or 25, followed by nitro group reduction and concomitant ring cyclization gives the 1-hydroxy-lH-pyrrolo [3,2-b] pyridine or 1-hydroxy- 1H-pyrrolo [3, 2-c]pyridine (I) (Rs = H), respectively. The triflate rection is carried out by rection 22 or 23 with triflic anhydride in the presence of a non-nucleophilic base such as triethylamine, pyridine, preferably pyridine. Suitable solvents are halogenated hydrocarbons such as dichloromethane, chloroform, and the like. The reductive cyclization rection is carried out using tin (II) chloride dihydrate or titanium (III) chloride in solvents such as ethanol or ethyl acetate or it can be carried out under standard hydrogenolysis rection conditions.

Alternatively, the 1-hydroxy-lH-pyrrolo [3, 2-b]pyridine and 1- hydroxy-lH-pyrrolo [3, 2-c]pyridine (I) can be prepared directly from 22 and 23 respectively, under the same ring cyclization rection conditions without proceeding through the triflate intermediate.

A compound of Formula (I) where R5 is hydrogen can be converted its corresponding compound of Formula (I) where W is other than hydrogen by reacting it with an alkylating agent RY, as described in Scheme A above.

Scheme E Compound of Formula (I) where------is between B and-CRl-, Q is-O-, is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as described below. 0 R6XSN C02Et R C02Et R2M l f3 3 i V _OHOPG 28 R 26 27 29 X R2 BrCH2CO2Et oCRH22CO2Et S CO2H BrCH2C02Et R N Rs R Y C02H OH base pCH2C02Et 30 31 32 6 R2 R2 R2 s LDA 3 SnR3 R'X 3 Ri Cu'i R3SnCl', O, O 33 34 (I) Protection of the hydroxy group in an ethyl 3-hydroxy-2-picolinate of formula 26 with a suitable protecting group (such as tert- butyldimethylsilyl, and the like) followed by treatment with an organometallic reagent such as an organolithium or Grignard reagent of formula 28 under nucleophilic substitution rection conditions gives a 2- ketopyridine of formula 29. The rection with the organometallic reagent is carried out in an inert organic solvent such as diethyl ether or tetrahydrofuran, preferably diethyl ether. Ethyl 3-hydroxy-2- picolinate is prepared from commercially available 3-hydroxypicolinic acid by methods well known in the art.

Removal of the O-protecting group in 29 gives a 2-keto-3- hydroxypyridine of formula 30. The rection conditions used for the deprotection depend on the nature of the protecting group. For example, if tert-butyldimethylsilyl is used then it is removed with

tetrabutylammonium fluoride in an ethereal solvent such as tetrahydrofuran. For other suitable O-protecting groups see T. W.

Greene,"Protective Groups in Organic Synthesis,"Wiley, New York (1991) and J. F. McOmie,"Protective Groups in Organic Chemistry," Plenum Press, London (1973).

Rection of 30 with ethyl bromoacetate in the presence of a non- nucleophilic base such as sodium hydride in a suitable organic solvent such as tetrahydrofuran gives a compound of formula 31. Treatment of 31 with base such as sodium ethoxide in ethanol, followed by thermolysis of the resulting 2-carboxyfuro (3, 2-b) pyridine of formula 32 gives furo [3,2-b] pyridine of formula 33 ((sexe., Shiotani, S., and Moriata, H. J. Heterocyclic Chem., 23,665 (1986)) o-Lithiation of 33 with a base such as lithium diisopropylamide or n-butyllithium, followed by treatment with an organotin reagent such as tributyltin chloride gives 34. Coupling of 34 with an organic halide of formula RX (where X is chloro, bromo or iodo) then provides furo [3,2- b]pyridine of Formula (I). The rection is carried out in the presence of a Pd (II) catalyst such as dichlorobis (triphenylphosphine) palladium (II) in inert organic solvent such as dimethylformamide or xylenes.

Substituting ethyl 3-hydroxy-2-picolinate 26 with ethyl 4- hydroxynicotinate ((see., Bojarska-Dahlig, Nantka-Namirski, Rocz.

Chem., 29, (1955)) and proceeding as described in Scheme E above, gives furo [3, 2-c]pyridine of Formula (I).

Scheme F A compound of Formula (I) where ------ is between B and-CRl-, Q is-S-, is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as described below. 1. BF. Et20 6 R1CH SH R N 2. LEZ R N 2 R 37 F 3. R L F base 35 15 36 R2 R 3"' R base R 3 1 R Rs \R1 SCH2R1 S 38 (I)

Rection of a 3-fluoropyridine of formula 35 with a compound of formula 15 where L is a leaving group under acylating conditions [e. g., alkoxy (preferably methoxy or ethoxy), dialkylamino, halo (preferably chloro), or preferably N, O-dimethylhydroxylamino] gives a 2-acyl-3- fluoropyridine of formula 36. The rection is carried out in the presence of a Lewis acid such as boron trifluoride and a strong base such as lithium diisopropylamide and in an aprotic polar organic solvents such as diethyl ether, tetrahydrofuran, and the like ((sexe., Kessar, S. V. et al.

J. Chem. Soc. Chem. Commun. 570 (1991) and Vedejs, E. and Chen, X.

J. Am. Chem. Soc. 118,1809-1810 (1996)).

Nucleophilic substitution of the fluoro group in 36 by a thiol reagent of formula 37 gives a compound of formula 38. The rection is carried out in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran. A thiol reagent such as (4- pyridyl) methylthiol can be prepared by the procedure described in Barnes, J. H., J. Med. Chem., 23 (3), 211, (1988).

Cyclization of 38 to thieno [3,2-b] pyridine of Formula (I) is achieved upon heating 38 in an alcoholic solvent such as ethanol in the presence of a base such as sodium ethoxide.

Substituting 3-fluoropyridine 35 with 4-fluoropyridine and following the procedure in Marsais, F., et al., J. Heterocycl. Chem.,

25 (1), 81, (1988) gives 3-acyl-4-fluoropyridine which can then be converted to thieno [3, 2-C]pyridine of Formula (I) by proceeding as described in Scheme F above.

Scheme G A compound of Formula (I) where------is between B and-CRl-, Q is-NR4-, is a group of formula (U) and other groups are as defined in the Summary of the Invention can be prepared as described below. R2 +'N\ X acid 1 NH2 Rs i R 4 39 H 40 Condensation of a ketone of formula 4 with a 4-aminopyridazine of formula 39 where X is a halo group (e. g., chloro, bromo or iodo) gives an enamine of formula 40. The condensation rection is carried out in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid or a Lewis acid such as aluminum chloride in an aromatic hydrocarbon as a solvent e. g., toluene or xylene. Compound 40 is then converted to 5H-pyrrolo [3, 2-c]pyridazine of Formula (I) by proceeding as described in Scheme A above.

Compound of formula 39 can be prepared by methods well known in the art. For example, 4-amino-3-chloropyridazine is prepared from commercially available 4,5-dichloropyridaz-3-one by first converting it

to 4-chloro-5-hydrazinopyridaz-3-one by treatment with hydrazine under the rection conditions described in Yakugaku Zasshi, 85,344 (1965). Removal of the hydrazino group with copper sulfate or silver oxide in aqueous medium gives 4-chloropyridaz-3-one which is then converted to 4-amino-3-chloropyridazine by following the procedure described in Linge, D. E., Recueil des travaus chimiques des Pays-Bas, 93 (8), 236-239, (1974).

SchemeH A compound of Formula (I) where------is between B and-CRl-, Q is-NR4-, is a group of formula (V) and other groups are as defined in the Summary of the Invention can be prepared as described below.

(R4 notH) Condensation of a compound of formula 4 with hydrazine gives a hydrazone of formula 41. The rection is carried out in the presence of a

catalytic amount of an acid such as p-toluenesulfonic acid in an alcoholic solvent such as ethanol. Rection of 41 with a pyrimidine of formula 42 provides a compound of formula 43 which is then converted to 5H- pyrrolo [3, 2-d]pyrimidine of Formula (I) by heating 43 in high boiling solvent such as diethylene glycol.

A 5H-pyrrolo-[3,2-d]pyrimidine of Formula (I) where R, W and R 6 are hydrogen can be converted to the corresponding 5H-pyrrolo [3,2- d]pyrimidine of Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above.

Scheme I A compound of Formula (I) where------is between B and-CRl-, Q is-NR4-, is a group of formula (W) and other groups are as

defined in the Summary of the Invention are prepared as described below. H O N NHNH2 acid N : N N Rs R1 tR + R64 R6 4 N R 1 45 46 R2 R2 N 2 diethylene glycol N 4 N R 6 ru heat R w N N Ri N N R1 H R4 (I) (I) A

not H) Condensation of a ketone of formula 4 with a 2-hydrazinopyrazine of formula 45 in the presence of a catalytic amount of an acid such as p- toluenesulfonic acid gives a hydrazone of formula 46 ((sexe, J. C. S. Perkin I, 1361-1363, (1976)). Suitable solvents for the rection are aromatic hydrocarbons such as toluene. Compound of formula 4 are prepared as

described in Scheme A. A compound of formula 45 where R6 is hydrogen is prepared by reacting chloropyrazine with hydrazine under conditions well known in the art ((sexe., Euro. J. Med. Chem., 24 (3), 249-57 (1989) and J. Heterocyclic Chem., 11,697-701, (1974)).

Conversion of 46 to a 5H-pyrrolo [2, 3-b]pyrazine of Formula (I) where R4 is hydrogen is achieved by heating 46 in high boiling solvent such as diethylene glycol. For other suitable cyclization rection conditions see R. J. Sundberg,"Indoles,"Academic Press, San Diego, CA, 1996, p 55.

A compound of Formula (I) where R4 is hydrogen can be converted to other compound of Formula (I) where R4 is not hydrogen as described in Scheme A above.

Scheme J A compound of Formula (I) where------is between B and-CRl-, Q is O or S, is a group of formula (W) and other groups are as defined in the Summary of the Invention are prepared as described below. 0 R2 HOCH2CO2Et6 R2 [E] N \ ase OCH CO E R !''Ri N X R ZnX X N z 2 O s i s 49 I N 1T CI Pd R LNR2) O O R 47 48 RCN2SH R6NR2 6N base SCH R' N 2 N S 50 (I) Rection of a 3-pyrazinecarbonyl chloride of formula 47 (where X is a halo group such as chloro or bromo) with an organozinc reagent of formula R, ZNX under the rection conditions such as those described in Negishi, E. et al., Tet. Lett., 24 (47), 5181, (1983) gives a 2-

ketopyrazine of formula 48.2-chloro-3-pyrazinecarbonyl chlorides can be prepared by following the procedure described in Friary, R. J., Tetrahedron, 49 (33), 7179 (1993).

Nucleophilic substitution of the halo group in 48 by ethyl glycolate or a thiol reagent of formula R1CHZSH gives a compound of formula 49 or 50 respectively. The rection is carried out in the presence of a base such as sodium hydride in a suitable solvent such as tetrahydrofuran. A compound of formula 49 or 50 is then converted to a furo [2, 3-b]pyrazine or a thieno [2, 3-b]pyrazine of Formula (I) respectively, by proceeding as described in Scheme E or F above.

Substituting 2-chloro-3-pyrazinecarbonyl chloride 47 with 5- chloro-4-pyrimidine-carbonyl chloride (see., U. S. Patent 4,110,450) and following the procedures described above gives furo [3,2-dlpyrimidine or a thieno [3, 2-d]pyrimidine of Formula (I), respectively.

Scheme K A compound of Formula (I) where------is between Q and- Cor'-, B is nitrogen, is a group of formula (S) and other groups are as defined in the Summary of the Invention are prepared as describedbelow. s H heat NHNH2 + 1"acid R N heat R 51 52 53 R1

H)(Rnot Condensation of a 2-hydrazinopyridine of formula 51 with a ketone of formula 52 in the presence of a catalytic amount of an acid such as p-toluenesulfonic acid gives a hydrazone of formula 53. Suitable solvents for the rection are aromatic hydrocarbons such as toluene.

Compound of formula 51 are either commercially available or they can be prepared by methods known in the art. For example, 2- hydrazinopyridine is commercially available. 3-chloro-2-hydrazino- pyridine can be prepared by heating 2,3-chloropyridine with hydrazine under conditions well known in the art ((sexe., Euro. J. Med. Chem., 24 (3), 249-57 (1989)). Compound of formula 52 such as 2-, 3-, 4- acetylpyridine, 2-acetylpyrazine are commercially available Conversion of 53 to a 1H-pyrrolo [2,3-b] pyridine of formula 54 is achieved by heating 53 in high boiling solvent such as diethylene glycol.

For other suitable cyclization rection conditions see., R. J. Sundberg, "Indoles,"Academic Press, San Diego, CA, 1996, p 55.

Conversion of 54 to a compound of Formula (I) where R is hydrogen is achieved by reacting 54 with an aryl halide of formula R2X (where RZ is as defined in the Summary of the Invention and X is a halo group) under the rection conditions such as those described in Smith

III, W. J. and Sawyer, J. S., Tet. Lett., Vol. 37 (3), 299-302 (1996) or Zhang, Lin-hua et al., Tet. Lett., Vol. 36 (46), 8387-8390, (1995).

A compound of Formula (I) where R is hydrogen can be converted to the corresponding compound of Formula (I) where R is other than hydrogen by following the procedures described in R. J. Sundberg, "Indoles,"Academic Press, San Diego, CA, 1996, p 105-118.

Substituting 2-hydrazinopyridine 51 with 4-hydrazinopyrimidine, 3-hydrazinopyridazine or 2-hydrazinopyrazine and following the procedure described above gives 7H-pyrrolo [2,3-d) pyrimidine, 7H- pyrrolo [2, 3-c]pyridazine or 5H-pyrrolo [2,3-b] pyrazine respectively.

4-Hydrazinopyrimidine and 3-hydrazinopyridazine can be prepared as described in Barlin, G. B., et al., J. Chem. Soc., Perkin Trans. 1 (1972) and Pinza, M. et al., Farmaco, 49 (11), 683-92 (1994) respectively.

Scheme L An alternative route for preparing a compound of Formula (I) where------is between Q and -CR1-, B is nitrogen, is a group of formula (S) and other groups are as defined in the Summary of the Invention is described below. R 6 N H CI + R2 base R6 N Nv R1- R3i r _NH2-.- R2 _ 56 5 3 55 56 R 57 I-

(R not H) Rection of a 2-chloro-3-iodopyridine of formula 55 with an amine of formula 56 gives a 2-amino-3-iodopyridine of formula 57. The rection is carried out in the presence of a non-nucleophilic base such as pyridine. 2-chloro-3-iodopyridine can be prepared by the procedures described in Guillier, F., et al, Tet. Lett., 35 (35), 6489, (1994) and Rocca, P. et al., Tetrahedron, 49 (1), 49, (1993). Compound of formula 56 such as aniline, 4-fluoroaniline, 4-methylaniline are commercially available.

Coupling of 57 with an alkyne of formula 58 gives 3-alkynyl-2- aminopyridine of formula 59 which is then cyclized to 1H-pyrrolo [2,3-bol- pyridine of formula (I). The alkynyl coupling rection is carried under the rection conditions such as those described in de Souza, P. T., Quim.

Nova, 19 (4), 377 (1996). The cyclization rection is carried out in the presence of a palladium (II) catalyst and in an inert organic solvent such as acetonitrile or tetrahydrofuran ((sexe., Iritani, K. et al. Tet. Lett., 29 (15), 1799 (1988)).

Compound of formula 58 such as 2-ethynylpyridine, 4-ethynyl- pyridine can be prepared by the procedure described in Yashima, E. et al., Japan Chirality, 9 (5/6), 593-600 (1997).

Scheme M Compound of Formula (I) where------is between Q and-CRl-B is nitrogen, is a group of formula (T) and other groups are as

defined in the Summary of the Invention are prepared as described below. Nw Rs Rs NO2 (H3) 2NC (°C2Hs) 2CH3 NX R1COX 3-kan CH3 R3 N (cH3) 2hydrolysis 60 61 2 s s R R H Ri Rs R R reduction N N N N O 3 [ f31 R Rs Rs R 62 63 (I) Rection of a 4-methyl-3-nitropyridine of formula 60 with N, N-dimethylformamide diethyl acetal in N, N-dimethylformamide gives a 4- (2-dimethylaminoethylene)-3-nitropyridine of formula 61.

Treatment of 61 with an acyl halide of formula R'COX (where Rl is as defined in the Summary of the Invention and X is a halo group) gives a ketone of formula 62 which upon reduction either catalytically or with sodium hydrosulfite provides a 2-substituted pyrrolo [2, 3-c]pyridine of formula 63. Conversion of 60 to 63 is carried out under the rection conditions described in Garcia, E. E and Fryer, R. I., J. Heterocyclic Chem., 11,219, (1974).

A compound of formula 63 is then converted to a compound of Formula (I) as described in Scheme K above

Additional Processes Compound of Formula (I) can also be prepared by modification of a group present on a corresponding compound of Formula (I) by known procedures. Some examples of such procedures are described below: (i) A compound of Formula (I) where R6 is alkoxy can be prepared from a corresponding compound of Formula (I) where R6 is chloro or bromo by treating it with an alkoxide under known rection conditions.

De-alkylation of an alkoxy substituent provides a corresponding compound of Formula (I) where R6 is hydroxy which can then be converted to a corresponding compound of Formula (I) where R6 is heteroalkyloxy or heterocyclylalkyloxy by treatment with the appropriate alkylating agent. Alternatively, the heteroalkyloxy can be put on by following literature procedures described in J. Org. Chem., 61, 7240, (1996) and Tetrahedron, 44,91, (1988) respectively.

(ii) Compound of Formula (I) where R6 is monosubstituted amino or disubstituted amino can be prepared by reacting the corresponding compound of Formula (I) where R6 is chloro or bromo with a primary or secondary amine either in the presence or absence of a palladium catalyst as described in Wagaw, S; et al. J. Org. Chem. 61 (21), 7240 (1996) and Wolfe, J. P.; et al. Tet. Lett. 38 (36), 6367 (1997).

(iii) Compound of Formula (I) where R6 is cyano can be prepared by reacting the corresponding compound of Formula (I) where R6is chloro or bromo with copper cyanide in N, N-dimethylformamide or dimethyl sulfoxide as described in Heterocycles, 41 (12), 2799, (1995).

Alternatively, it can be done with potassium cyanide in the presence of nickel or zinc catalyst as described in Bull. Chem. Soc. Jpn., 66 (9), 2776, (1993).

(iv) Compound of Formula (I) where R6 is alkyl can be prepared by reacting the corresponding compound of Formula (I) where R6is chloro

or bromo with alkyllithium or an alkyltin reagent in the presence of a palladium catalyst.

It will be recognized by one skilled in the art that these transformation are not limited to the R6 position but may be carried out at other positions in the compound of Formula (I).

Preparation of 7- (4-fluorophenyl)-6- [2- (3-hydroxypropylamino)- pyridin-4-yl]-5H-pyrrolo [2,3-b] pyrazine from 7- (4-fluorophenyl)-6- [2- describedinExamplebromopyridine-4-yl]-5H-pyrrolo[2,3-b]pyraz ineis 12.

The compound of Formula (I) are p38 MAP kinase and JNK inhibitors and therefore compound of Formula (I) and compositions containing them are useful in the treatment of diseases such as rheumatoid arthritis, osteoarthritis, spondylitis, bone resorption diseases, sepsis, septic shock, toxic shock syndrome, endotoxic shock, tuberculosis, atherosclerosis, diabetes, adult respiratory distress syndrome, chronic pulmonary inflammatory disease, fever, periodontal diseases, ulcerative coatis, pyresis, Alzheimer's and Parkinson's diseases.

The ability of the compound of Formula (I) to inhibit p38 MAP kinase was demonstrated by the in vitro assay described in Example 20.

The ability of the compound of Formula (I) to inhibit the release of TNF-α was demonstrated by the in vitro and the in vivo assays described in detail in Examples 21 and 22, respectively.

In general, the compound of this invention will be administered in a therapeutically effective amount by any of the accepte modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i. e., the active ingredient, will depend upon numerus factors such as the severity of the disease to

be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.

Therapeutically effective amounts of compound of Formula (I) may range from approximately 0.1-50 mg per kilogram body weight of the recipient per day; preferably about 0.5-20 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 35 mg to 1.4 g per day.

In general, compound of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e. g., transdermal, intranasal or by suppository), or parenteral (e. g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tables, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.

The choice of formulation depends on various factors such as the mode of drug administration (e. g., for oral administration, formulations in the form of tables, pills or capsules are preferred) and the bioavailability of the drug substance. Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i. e., decreasing particle size.

For example, U. S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supporte on a crosslinked matrix of macromolecules. U. S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a

surface modifier and then disperse in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.

The compositions are comprise of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art.

Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e. g., peanut oil, soybean oil, mineral oil, sesame oil, etc.

Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.

Compresse gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.

Other suitable pharmaceutical excipients and their formulations are described in Remington's Pharmaceutical Sciences, edited by E. W.

Martin (Mack Publishing Company, 18th ed., 1990).

The amount of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt%) basis, from about 0.01-99.99 wt% of a compound of Formula (I) based on the total

formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt%. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 19.

The following preparations and examples are given to enable those skilled in the art to more clearly understand and to practice the present invention. They should not be considered as limiting the scope of the invention, but merely as being illustrative and representative thereof.

Example 1 Synthesis of 3- (4-Fluorophenyl)-2- (pyridin-4-yl)- 1H-pyrrolo [3,2-bol- pyridine (following Scheme A)

Ste-D1 Sodium metal (5.06 g, 210 mmol) was dissolve in absolut ethanol (150 ml) and then a solution of methyl isonicotinate (20.55 g, 150 mmol) and 4-fluorophenylacetonitrile (20.25 g, 150 mmol) in absolut ethanol (50 ml) was added in one portion. The rection mixture was heated at reflux for 3 h and then cooled to room temperature. The rection mixture was poured into ice water (300 ml) and the pH was adjusted to pH=3 with 10% hydrochloric acid. The yellow precipitate was filtered and dried in vacuo to give 24 g of cyano ketone. This material was suspende in 48% hydrobromic acid (90 ml) and heated at reflux. After 8 h, the rection mixture was cooled to room temperature and carefully poured into ice water (300 ml). The pH was adjusted to pH = 7-8 with

ammonium hydroxide. The product was extracted into ethyl acetate and the combine organic layers were washed with brine, dried over MgSO4 and concentration in vacuo to give 2- (4-fluorophenyl)-1- (pyridin- 4-yl) ethanone (11.8 g) as a tan solid.

Step 2 To a solution of 2- (4-fluorophenyl)-1- (pyridin-4-yl) ethanone (5.20 g, 24 mmol) and 3-amino-2-chloropyridine (4.04 g, 31.4 mmol) in toluene (150 ml) was added p-toluenesulfonic acid monohydrate (457 mg. 2.4 mmol) and the rection mixture was brought to reflux with Dean-Stark removal of the toluene/water azeotrope. After 24 h, toluene was removed in vacuo and the residue was resuspended in ethyl acetate.

The precipitate was collecte by vacuum filtration to give (2- chloropyridine-3-yl)-[2-(4-fluorophenyl)-1-(pyridine-4-yl)-v inyl]amine(5.0 g) as a tan solid. The filtrate was concentrated in vacuo and purifie by flash column chromatography (50%-80% ethyl acetate: hexanes gradient) to give additional 1.50 g of product.

Step 3 To a solution of (2-chloropyridin-3-yl)- [2- (4-fluorophenyl)-1- (pyridine-4-yl)-vinyl]amine (6.0 g, 18.5 mmol) and DABCO# (6.2 g, 55 mmol) in dimethylformamide (75 ml) was added bis (triphenylphos- phine) palladium (II) chloride (650 mg, 0.926 mmol) and the rection mixture was heated at 120°C under an argon atmosphere. After 4 h, <BR> <BR> <BR> <BR> dimethylformamide was removed in vacuo and the residue was heated in ethyl acetate/methanol mixture. The product was filtered off to give a green solid which was redissolved in boiling methanol/chloroform mixture and treated with charcoal. The solution was filtered through a pad of Celite and the filtrate was concentrated to give 3- (4-fluoro- phenyl)-2-(pyridin-4-yl)-lH-pyrrolo(pyridin-4-yl)-lH-pyrrolo [3,2-b] pyridine as a pale yellow solid (5.27 g).

Example 2 Synthesis of l-Ethyl-3- (4-fluorophenyl)-2- (pyridin-4-yl)-lH-pyrrolo- [3,2-b]pyridine (following Scheme A)

To a solution of 3- (4-fluorophenyl)-2- (pyridin-4-yl)-lH-pyrrolo [3,2- blpyridine (100 mg, 0.346 mmol) [prepared as described in Example 1] in dimethylformamide (3 ml) was added sodium hydride (41 mg, 1.025 mmol, 60% in oil). After stirring at room temperature for 10 min., ethyl iodide (31 Fl, 0.385 mmol) was added by syringe. After 2 h, dimethylformamide was removed in vacuo and the residue was redissolved in ethyl acetate (5 ml) and methanol (5 ml). The solution was washed with saturated sodium bicarbonate solution. The organic layer was separated, dried over MgS04 and concentration in vacuo to give a brown oil. Purification by flash column chromatography (50%- 80% ethyl acetate: hexanes gradient) gave a yellow oil (60 mg) which was recrystallized from ethyl acetate: hexanes to give 1-ethyl-3- (4- fluorophenyl)-2- (pyridin-4-yl)-1H-pyrrolo [3, 2-b]pyridine as a white solid.

Example 3 Synthesis of 3- (4-Fluorophenyl)-2-(pyridin-4-yl)-lH-pyrrolo [3, 2-c]- pyridine (following Scheme C)

Step 1 To a solution of 4-pivaloylaminopyridine (7.0 g, 39 mmol) in tetrahydrofuran (100 ml) was added n-butyllithium (39.3 ml, 98 mmol, 2.5 M solution in tetrahydrofuran) at -78 °C under a N2 atmosphere.

The rection mixture was stirred at 0 °C for 5h, re-cooled to-78 °C and quenched with a solution of N-methoxy-N-methyl-4-fluorobenzamide (7.9 g, 43 mmol) in 100 ml tetrahydrofuran. The rection mixture was warmed to room temperature and poured into water. The product was extracted into ethyl acetate. The organic layers were washed with brine, dried over sodium sulfate and evaporated to dryness. The residue was purifie by flash chromatography (10% ethyl acetate/hexanes gradient) to afford N- [3- (4-fluorobenzoyl)-pyridin-4-yll-2,2- dimethylpropanamide (10 g).

Step 2 A solution of N- [3- (4-fluorobenzoyl) pyridin-4-yll-2,2- dimethylpropanamide (2.85 g, 9.5 mmol) in 3 N aqueous HCl (15 ml) was warmed at reflux overnight. After cooling to room temperature, the rection mixture was washed with ether, the aqueous layer was separated and neutralized with potassium carbonate. The product was extracted into ethyl acetate, dried over potassium carbonate/sodium

carbonate and concentrated. The residue was purifie by flash chromatography (5% methanol/methylene chloride gradient) to afford 4- amino-3- (4-fluorobenzoyl) pyridine (1.58 g).

Step 3 4-amino-3- (4-fluorobenzoyl) pyridine (1.5 g, 7.0 mmol) was suspende in methylene chloride (90 ml) and pyridine (2.24,28 mmol).

The rection mixture was cooled to 0 °C and isonicotinoyl chloride (1.4 g, 7.6 mmol) was added. The rection mixture was allowed to warm to room temperature, and stirring was continued for 4 h. Methylene chloride was added and the white precipitate was filtered and dried in vacuo to yield 3- (4-fluorobenzoyl)-4- (isonicotinoylamide) pyridine (1.7 g).

Step 4 A suspension of 3- (4-fluorobenzoyl)-4- (isonicotinoylamide) pyridine (300 mg, 0.75 mmol), titanium trichloride (6.3 ml, 6.3 mmol, 1.0 M solution in dichloromethane/tetrahydrofuran 2: 1), magnesium (309 mg, 12.7 mmol) and pyridine (0.62 ml, 8.0 mmol) in ethylene glycol dimethyl ether (50 ml) was refluxed for lh. The rection mixture was cooled to room temperature, diluted with ethyl acetate and a solution of 5% sodium bicarbonate was added. The rection mixture was vigorously stirred overnight and then filtered through a pad of Celite. The organic layer was separated and concentrated in vacuo. Purification by flash chromatography (5% methanol/methylene gradient) gave 3- (4- fluorophenyl)-2-(pyridin-4-yl)-lH-pyrrolo(pyridin-4-yl)-lH-p yrrolo [3, 2-c]pyridine as a solid (30 mg).

Exemple 4 Synthesis of 3- (4-Fluorophenyl)-1-hydroxy-2- (pyridin-4-yl)- 1H-pyrrolo[3,2-b]pyridine (following Scheme D)

Step 1 To a solution of 2- (4-fluorophenyl)-1- (pyridin-4-yl) ethanone (4.0 g, 18.6 mmol) [prepared as described in Exemple 1 above] and 2-chloro-3- nitropyridine (6.50 g, 41.13 mmol) in dimethylformamide (50 ml) at 0 °C was added sodium hybride (1.65 g, 41 mmol, 60% in oil) under an argon atmosphere. The rection mixture was warmed to room temperature and stirred for an hour. The rection mixture was quenched with water and the product was extracted into ethyl acetate. The combine organic extracts were washed with brine, dried over MgS04 and concentrated in vacuo to give a dark brown oil. Purification by flash column chromatography (10% to 50% ethyl acetate/hexanes gradient) gave 2- (4- fluorophenyl)-2- (3-nitropyridin-2-yl)-l- (pyridin-4-yl) ethanone as a brown oil (4.08 g).

Step 2 A solution of gave 2- (4-fluorophenyl)-2- (3-nitropyridin-2-yl)-l- (pyridin-4-yl)-ethanone (2.0 g, 5.93 mmol) and pyridine (0.52 g, 6.53 mmol) in dichloromethane (30 ml) was added to a cold solution of trifluoromethanesulfonic anhydride (1.1 ml, 6.53 mmol) in dichloromethane (7 ml) at 0 OC. After 1 h, the rection mixture was poured into water (50 ml) and the product was extracted into

dichloromethane. The combine organic extracts were washed with saturated sodium bicarbonate solution and brine and dried over MgSO4.

Concentration in vacuo gave a brown oil which was purifie by flash column chromatography (50%-60% ethyl acetate/hexanes gradient) to give the trifluoromethanesulfonic acid 2- (4-fluorophenyl)-2- (3- nitropyridin-2-yl)-l- (pyridin-4-yl) vinyl ester as a light tan oil (1.56 g).

Step3 To a solution of trifluoromethanesulfonic acid 2- (4-fluorophenyl)-2- (3-nitropyridin-2-yl)-1- (pyridin-4-yl) vinyl ester (1.5 g, 3.20 mmol) in ethyl acetate (50 ml) was added stannous chloride dihydrate (2.89 g, 12.8 mmol) and the rection mixture was warmed to 50 °C. After 1 h, the warm solution was treated with saturated sodium bicarbonate solution (10 ml) and filtered through Celite. The filtrate was washed with brine, dried over anhydrous sodium sulfate and concentrated in vacuo. Purification by flash column chromatography (CHZCl2-95% CHzCl2/MeOH gradient) gave 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4- yl)-lH-pyrrolo [3, 2-b]pyridine as a tan solid (700 mg).

Example 5 Synthesis of 3- (4-Fluorophenyl)-l-methoxy-2- (pyridin-4-yl)-lH- pyrrolo[3,2-b]pyridine (following Scheme D) A solution of 3- (4-fluorophenyl)-l-hydroxy-2- (pyridin-4-yl)-lH- pyrrolo [3, 2-b]pyridine (0.38 g, 1.25 mmol) in chloroform (8 ml) and methanol (2 ml) was added to a solution of diazomethane at 0°C. The

rection was warmed to room temperature and stirred overnight. The solvent was removed in vacuo and the residue was purifie by flash column chromatography (50%-100% ethyl acetate/hexanes gradient) to 3- (4-fluorophenyl)-1-methoxy-2- (pyridin-4-yl)-1H-pyrrolo [3, 2-b]pyridine as an off white solid (210 mg).

Example 6 Synthesis of 3-(4-Fluorophenyl)-1-[2-(morpholin-4-yl)ethoxy]- 2-(pyridin-4-yl)-1H-pyrrolo[3,2-b]pyridine (following Scheme D) To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-lH- pyrrolo [3, 2-b]-pyridine (0.20 g, 0.65 mmol) and 2-chloroethylmorpholine hydrochloride (0.24 g, 6.56 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 60% in oil). The rection mixture was stirred overnight and quenched with 10% HCl (2 ml). The pH was adjusted to pH = 8-9 by the addition of saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The combine extracts were dried over anhydrous MgS04 and concentrated in vacuo to give an oil. Purifie by flash column chromatography (50%- 80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3- (4-fluorophenyl)-1- [2- (morpholin-4- mg)whichyl)ethoxy]-2-(pyridine-4-yl)-1H-pyrrolo[3,2-b]pyridi ne(180 recrystallized from hexanes/ethyl acetate to give a white solid.

Example 7 Synthesis of 3-(4-Fluorophenyl)-1-[2-(piperidin-1-yl)ethoxy]-2-(pyridine- 4- yl)- 1H-pyrrolo[3,2-b]pyridine (following Scheme D)

To a solution of 3- (4-fluorophenyl)-l-hydroxy-2- (pyridin-4-yl)-lH- pyrrolo [3, 2-b]pyridine (0.20 g, 0.65 mmol) and 2-chloroethylpiperidine hydrochloride (0.24 g, 1.31 mmol) in dimethylformamide (5 ml) was added sodium hydride (100 mg, 6.56 mmol, 60% in oil). The rection mixture was stirred overnight and quenched with water (2 ml). The pH was adjusted to pH = 11-12 by the addition of saturated sodium carbonate solution and the product was extracted into ethyl acetate.

The combine extracts were dried over anhydrous MgS04 and concentrated in vacuo to give an oil. Purifie by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3- (4-fluorophenyl)-1- (2- a(piperidin-1-yl)ethoxy]-2-(pyridine-4-yl)-1H-pyrrolo[3,2-b] pyridineas yellow solid (182 mg).

Proceeding as described above but substituting 2-chloroethyl- piperidine hydrochloride with 2-chloroethylpyrrolidine hydrochloride gave 3-(4-fluorophenyl)-2-(pyridine-4-yl)-1-[2-(pyrrolidine-1-yl) ethoxy]-1H- pyrrolo[3,2-b]pyridine.

Example 8 Synthesis of 7- (4-Fluorophenyl)-6- (pyridin-4-yl)-5H-pyrrolo [2,3-bol- pyrazine (following Scheme I)

sep 1 To a solution of chloropyrazine (11.5 g, 0.1 mmol) in absolut ethanol (50 ml) was added anhydrous hydrazine (16 ml, 0.5 mmol) and the rection mixture was refluxed for 3 h. The organics were removed in vacuo and the residue was extracted with benzene to give hydrazinopyrazine (4.2 g).

Step 2 To a suspension of hydrazinopyrazine (2.9 g, 26 mmol) in benzene (120 ml) was added 2- (4-fluorophenyl)-1- (pyridin-4-yl) ethanone (5.6 g, 26 mmol) and p-toluenesulfonic acid (0.30 g). The rection mixture was refluxed with azeotropic removal of water. After 2.5 h, the rection <BR> <BR> <BR> mixture was concentrated in vacuo to give pyrazinylhydrazone (8.8 g) which was used in the next step without further purification.

Step 3 The pyrazinylhydrazone (8.8 g) was suspende in diethylene glycol (75 ml) and the rection mixture was heated at reflux. After 1.5 h, the rection mixture was cooled, and poured in water. The product was extracted into diethyl ether and the ethereal layer was washed with brine and concentrated in vacuo. The crude product was recrystallized

from methanol to give 7- (4-fluorophenyl)-6- (pyridin-4-yl)-5H-pyrrolo [2,3- b]pyrazine as a solid (1.1 g).

Example 9 Synthesis of 1- (3-Chloropropyl)-7- (4-fluorophenyl)-6- (pyridin-4-yl)- 5H-pyrrolo[2,3-b]pyrazine

To a suspension of sodium hydride (1.03 g, 25.8 mmol, 60% in mineral oil) in dry tetrahydrofuran (20 ml) was slowly added 7- (4- fluorophenyl)-6- (pyridin-4-yl)-5H-pyrrolo [2, 3-b]pyrazine (0.75 g, 2.58 mmol) followed by 1-bromo-3-chloropropane (4.05 g, 25.8 mmol). The rection mixture was heated at 65 °C for 72 h. Water was added slowly to quench the excess sodium hydride and the organics were removed in vacuo. Water was added to the residue and the aqueous layer was extracted with ethyl acetate. The organic phase was washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product was purifie by flash chromatography on silica gel, eluting with ethyl acetate, to give 1- (3-chloropropyl)-7- (4-fluorophenyl)- 6- (pyridin-4-yl)-5H-pyrrolo [2,3-blpyrazine as a solid (0.375 g).

Example 10 Synthesis of 7-(4-Fluorophenyl)-1-[3-(4-methyimidazol-1-yl)propyl]- 6-(pyridine-4-yl)-5H-pyrrolo[2,3-b]pyrazine

To a solution of 1- (3-chloropropyl)-3- (4-fluorophenyl)-2- (pyrindin-4- yl)-5H-pyrrolo [2, 3-b]pyrazine (0.050 g, 0.14 mmol) in dimethyl- formamide was added 4-methylimidazole (0.046g, 0.4 mmol) and diisopropylethyl amine (0.12 ml, 0.7 mmol). The solution was heated at 65 °C for 16 h. The compound was purifie by reverse phase chromatography to yield pure 3- (4-fluorophenyl)-1- [3- (4-methyimidazol- 1-yl)propyl]-6-(pyridin-4-yl)-5H-pyrrolo[2,3-b]pyrazine(0.03 9g).

Example 11 Synthesis of 6- (2-Bromopyridin-4-yl)-7- (4-fluorophenyl)- 5H-pyrrolo[2,3-b]pyrazine Step 1 2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspende in methanol (175 ml) and anhydrous hydrogen chloride gas

was slowly bubbled through the rection mixture while cooling in a methanol/water (20/80) dry ice bath. Bubbling was continued for 40 min. during which time the suspension cleared to a partial solution. Ice bath was removed and the rection mixture was heated to reflux under anhydrous conditions for 30 min. to give a clear yellow solution. The solution was cooled in an ice bath and saturated sodium bicarbonate was slowly added with stirring till the pH was neural. The organics were removed in vacuo and the product was extracted into ethyl acetate.

The ethyl acetate layer was dried over sodium sulfate, filtered, and concentrated in vacuo to yield 2-chloropyridine-4-carboxylic acid methyl ester as a brown liquid.

Step 2 4-Fluorophenylacetonitrile (11.13 g, 82 mmol) was dissolve in absolut ethanol (100 ml) and sodium ethoxide (21wt % in EtOH) (46 ml, 123 mmol) was added in one portion. The resulting brown solution was stirred for 10 min. at room temperature. A solution of 2- chloropyridine-4-carboxylic acid methyl ester (14.1 g, 82 mmol) in absolut ethanol (100 ml) was then added to the rection over 3-5 min.

The rection mixture was then refluxed for 2 h during which time the color turned to dark brown. The rection mixture was concentrated in vacuo and water (100 ml) was added to the resulting residue. The pH of the rection mixture was adjusted to 3 using 10% hydrochloric acid.

The product was extracted with ethyl acetate and the combine ethyl acetate extracts were dried over sodium sulfate, filtered and concentrated in vacuo to yield 1- (2-chloropyridin-4-yl)-2-cyano-2- (4- fluorophenyl) ethanone as a dark brown solid which was used without further purification (22.0 g).

Step 3 To 1- (2-chloropyridin-4-yl)-2-cyano-2- (4-fluorophenyl) ethanone (22.0 g, 80 mmol) was added 48% hydrobromic acid (75 ml) and the rection mixture was heated at reflux in an oil bath at 135 °C. After 4 h, the rection mixture was allowed to cool to room temperature and then further cooled in an ice bath. Saturated sodium bicarbonate (100 ml) was carefully added, followed by solid portions of sodium bicarbonate until the pH of the rection mixture was neural. The rection mixture was then extracted with ethyl acetate and the ethyl acetate layer was dried over sodium sulfate, filtered and concentrated to a brown semi-solid (2.8 g). The crude product was purifie by flash chromatography on silica gel, eluting with 1: 1 mixture of ethyl acetate/hexanes to give 1- (2-bromopyridin-4-yl)-2- (4- fluorophenyl) ethanone (1.9 g).

Step 4 Hydrazinopyrazine (0.71 g, 6.4 mmol) and 1- (2-bromopyridin-4-yl)- 2- (4-fluorophenyl) ethanone (1.9 g, 6.4 mmol) were suspende in benzene (30 ml) and p-toluenesulfonic acid monohydrate (0.02 g) was added. The rection mixture was then refluxed with azeotropic removal <BR> <BR> <BR> <BR> of water via Dean Stark trap. The benzene was then removed in vacuo to give the crude N- [I- (3-bromopyridin-4-yl)-2- (4-fluorophenyl)- ethylidene]-N'-pyrazin-2-ylhydrazine as a yellow semi-solid which was used without further purification (2.4 g).

Step 5 N-[1-(3-Bromopyridine-4-yl)-2-(4-fluorophenyl)ethylidene]-N' - pyrazin-2-ylhydrazine (2.4 g, 6.2 mmol) was suspende in di (ethylene glycol) (30 ml) and heated in an oil bath at 250 °C. After 1 h, the rection mixture was allowed to cool and then poured into a separatory funnel containing water (50 ml). The rection mixture was then

extracted with diethyl ether. The ether extracts were combine, dried over sodium sulfate, filtered, and concentrated in vacuo to yield the crude brown solid (2.0 g). The solid was recrystallized from ethyl acetate/methanol 1: 1 (25 ml) mixture to yield the 6-(2-bromopyridin-4- yl)-7-(4-fluorophenyl)-5H-pyrrolo [2,3-b] pyrazine as a tan solid (0.650 g).

Example 12 Synthesis of the 7- (4-Fluorophenyl)-6- [2- (3-hydropropyl- amino) pyridin-4-yll- 5H-pyrrolo [2, 3-b]pyrazine hydrochloride salt Step 1 6-(2-Bromopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3- b]pyrazine (0.05 g, 0.135 mmol) was dissolve in 3-amino-1-propanol (0.5 ml, 6.5 mmol) and the rection mixture was heated in a sealed vial at 110 °C. After 20 h, the rection mixture was purifie by reverse phase chromatography to yield the 7-(4-fluorophenyl)-6-[2-(3- hydroxypropylamino)pyridin-4-yl]-5H-pyrrolo[2,3-b]pyrazine trifluoroacetate salt as a yellow oil (0.018 g).

Step 2 7-(4-Fluorophenyl)-6-[2-(3-hydroxypropylamino)pyridin-4-yl]- 5H- pyrrolo- [2, 3-b]pyrazine trifluoroacetate salt (0.018 g, 0.05 mmol) was treated with HCl/diethyl ether (1.0 ml of a 1.0 M solution) to give a solid. The ethereal layer was decanted off and the resulting solid was

washed twice with ether. Excess ether was carefully blown off with <BR> <BR> nitrogen gas and the resulting yellow solid was dried in vacuo to 7- (4- fluorophenyl)-6- [2- (3-hydroxypropylamino) pyridin-4-yll-5H-pyrrolo [2,3- b]pyrazine hydrochloride salt (0.019 g).

Exemple 13 Synthesis of the 3- (4-Fluorophenyl)-2- (pyridin-4-yl)-furo [3,2-bd pyridine (following Scheme E) sep 1 3-Hydroxypicolinic acid (12.5 g, 900 mmol) was suspende in a mixture of ethanol (300 ml) and benzene (100 ml). Sulfuric acid (5 ml) was added and the rection mixture was heated at reflux with azeotropic removal of water via Dean Stark trap. After the rection was complete, the organics were removed in uacuo. The residue was dissolve in water, basified with sodium carbonate and extracted with ethyl acetate. The ethyl acetate layer was dried over magnesium sulfate, concentrated in vacuo to give ethyl 3-hydroxypicolinate (15 g).

Step 2 A mixture of ethyl 3-hydroxypicolinate (15 g, 900 mmol), tributylsilyl chloride (16.23 g, 110 mmol), imidazole (8.0 g, 120 mmol) in methylene chloride was stirred overnight under a nitrogen atmosphere.

Water was added and the methylene chloride layer was separated and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (1: 4) as the eluant gave ethyl 3- (tributylsilyloxy)- picolinate as a solid (20 g).

Stem 3 A solution of ethyl 3- (tributylsilyloxy) picolinate (19 g, 35 mmol) in tetrahydrofuran (100 ml) was cooled to 0 °C and 4-fluorophenyl- magnesium chloride (52 ml, 1.0 M in tetrahydrofuran) was added dropwise. After 30 min., the rection mixture was quenched with water and the product was extracted with ethyl acetate. The organic layer <BR> <BR> <BR> was dried over sodium sulfate and concentrated in vacuo. Purification on a silica gel column using ethyl acetate-hexane (2: 98) as the eluant gave 2- (4-fluorobenzoyl)-3- (tributylsilyloxy) pyridine (3.75 g).

Step 4 A solution of 2- (4-fluorobenzoyl)-3- (tributylsilyloxy) pyridine (3.75 g, 11.3 mmol) in tetrahydrofuran (17 ml) was cooled to 0 °C and tetrabutylammonium fluoride (17ml, 1.0 M in tetrahydrofuran) was added. After 2 h, the rection mixture was diluted with ethyl acetate.

The organic layer was separated, washed with sodium bicarbonate and brine, and dried over sodium sulfate. The organics were removed in vacuo and the residue was purifie on a silica gel column using ethyl acetate-hexane (2: 8) as the eluant to give 2- (4-fluorobenzoyl)-3- hydroxypyridine (2.2 g).

Step 5 A mixture of give 2- (4-fluorobenzoyl)-3-hydroxypyridine (2.2 g, 11.3 mmol), ethyl bromoacetate (1.6 ml, 14.15 mmol) and potassium carbonate (4.34 g, 31.4 mmol) in acetone (40 ml) was heated at reflux.

After 3 h, the reaction was cooled to room temperature, filtered and concentrated in vacuo to give ethyl 2- [2- (4-fluorobenzoyl) pyridin-3- yloxyl acetate (3.5 g) which was used in the next step without further purification.

Step 6 Sodium ethoxide (1.51 g. 22.6 mmol) was suspende in toluene (25 ml) and ethyl 2- [2- (4-fluorobenzoyl) pyridin-3-yloxyl acetate (3.5 g, 11.5 mmol) was added. The rection was heated at reflux under an argon atmosphere. After 12 h, the rection mixture was cooled to room temperature and the product was extracted into water. The aqueous layer was acidifie with hydrochloric acid to give 2-carboxy-3-(4- fluorophenyl)-furo [3, 2-b]pyridine as a solid (1.8 g).

Step 7 A mixture of 2-carboxy-3- (4-fluorophenyl)-furo (3, 2-b] pyridine (1.8 g, 7 mmol), copper metal (0.56 g, 8.81 mmol) in quinoline (10 ml) was heated at reflux. After 45 min., the rection was cooled to room temperature and the product was extracted into water. The aqueous layer was acidifie with hydrochloric acid and acetic acid. The product was filtered and dissolve in ether. The ether layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography using ethyl acetate-hexanes (1: 9) as the eluant gave 3- (4-fluorophenyl)-furo [3, 2-b]pyridine as a solid (0.85 g).

Step 8 A solution of 3-(4-fluorophenyl)-furo[3,2-b]pyridine (0.40 g, 1.84 mmol) and N, N, N', N'-tetramethylethylenediamine (0.33 g, 7.2 mmol) in tetrahydrofuran (15 ml) was cooled to-78 °C. n-Butyllithium (1.1 ml, 2.5 M in hexanes, 2.7 mmol) was added and the rection mixture was allowed to warm to room temperature. After 1.5 h, the rection mixture was re-cooled to-78 °C and n-tributyltin chloride (0.5 ml, 1.84 mmol) was added. The rection was allowed to warm to room temperature and then quenched with aqueous ammonium chloride. The product was

extracted into ether and the ether layer was dried over sodium sulfate and concentrated in vacuo. Purification by flash chromatography using hexanes, followed by ethyl acetate-hexanes (5: 95) as the eluant gave 3- (4-fluorophenyl)-2-(n-tributyltin)-furo [3,2-b] pyridine (0.72 g).

Step 9 A mixture of 3- (4-fluorophenyl)-2- (n-tributyltin)-furo [3,2-b] pyridine (0.72 g, 1.4 mmol), tetrakis (triphenylphosphine) palladium (II) (0.165 g, 0.14 mmol) and 4-bromopyridine [prepared from 4-bromopyridine hydrochloride (1.4 g, 7.15 mmol)] in xylenes (20 ml) was heated at reflux under an argon atmosphere. After 12 h, the rection mixture was cooled to room temperature and purifie by flash chromatography using hexanes, followed by ethyl acetate-hexanes (5: 95) as the eluant to give Recrystallized3-(4-fluorophenyl)-2-(pyridin-4-yl)-furo-[3,2- b]pyridine. from ethyl acetate-hexanes mixture to give pure product (0.15 g).

Example 14 Synthesis of the 3-(4-Fluorophenyl)-7-methylthio-2-(pyridin-4-yl)- pyrrolo [3,2-bol pyridine stem 1 2,2,6,6-Tetramethylpiperidine (1.76 ml, 10.40 mmol) was dissolve in tetrahydrofuran (39 ml) and placed under an atmosphere of nitrogen.

The solution was cooled to-78 OC and n-butyllithium (3.96 ml, 9.91 mmol, 2.5 M solution of in hexanes) was added at such a rate that the internal temperature did not exceed-70 °C. The rection mixture was

warmed to-10 OC for 30 min., then re-cooled to-78 °C. A solution of 1- tert-butoxycarbonyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-pyrr olo[3,2- 2.47mmol)intetrahydrofuran(32ml)wascooledtob]pyridine(0.965g , -78°C and then added via cannula at such a rate that the internal temperature did not exceed-70 °C. After 1 h, dimethyldisulfide (0.29 ml, 3.22 mmol) was added and the resulting solution was stirred for an additional 1 h at-78 °C. The rection mixture was quenched with saturated ammonium chloride solution and the product was extracted into ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated in vacuo. The crude residue was purifie by flash chromatography using 20% acetone/hexanes as the eluant to give 1-tert-butoxycarbonyl-3-(4- fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b]py ridine.MS: 435 (M).

Step 2 1-Tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyr idin- 4-yl)-pyrrolo [3,2-b] pyridine (29 mg, 0.064 mmol was dissolve in dimethylsulfoxide (1 ml) and the solution was heated to 73 °C. After 20 h, the solution was cooled and partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried <BR> <BR> <BR> <BR> over anhydrous magnesium sulfate, and concentrated in vacuo to give 3- (4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo[3,2-b ]pyridine.

Example 15 Synthesis of the 2- (2-Chloropyrimidin-4-yl)-3- (4-fluorophenyl)- furo[3,2-b]pyridine (following Scheme E)

A mixture of 3-(4-fluorophenyl)-2-(n-tributyltin)-furo[3, 2- b]pyridine (2.38 g, 4.73 mmol), [prepared as described in Example 13 above], bis-dichlorotriphenylphosphine-palladium (0.33 g, 0.47 mmol) and 2,4-dichloropyrimidine (3.52 g, 23.65 mmol)] in dimethylformamide (20 ml) was heated at 100 °C under an argon atmosphere. After 12 h, the rection mixture was cooled to room temperature, quenched with water and the product was extracted into ethyl acetate. The organic layer was dried over sodium sulfate, concentrated in vacuo and the residue was purifie by flash chromatography using 80 % ethyl acetate- hexanes as the eluant to give 2- (2-chloropyrimidin-4-yl)-3- (4- fluorophenyl)-furo[3,2-blpyridine.

Example 16 Synthesis of the 2-(2-Aminopyrimidin-4-yl)-3-(4-fluorophenyl) furo- [3,2-b] pyridine (following Scheme E)

2-(2-Chloropyrimidin-4-yl)-3-(4-fluorophenyl)-furo[3,2-b]pyr idine (0.15 g) was dissolve in ethanol (10 ml) and ammonia was bubbled through the solution until it was saturated. The rection mixture was heated in a sealed tube at 100 °C. After 12 h, the solvent was removed in vacuo and the residue was purifie by flash chromatography using 50 % ethyl acetate-hexanes as the eluant to give 2-(2-aminopyrimidin-4-yl)- 3-(4-fluorophenyl)-furo [3, 2-b]pyridine (0.70 g) as a solid.

Example 17 Synthesis of 1-(4-Fluorophenyl)-4-methyl-2-(pyridin-4-yl)- 1H-pyrrolo[2,3-b]pyridine Stem 1 To a solution of 2-amino-3-bromo-5-methylpyridine (5.48 g, 29 mmol) and 4-acetylpyridine (2.67 ml, 24 mmol) in toluene (200 ml) was added p-toluenesulfonic acid (0.1 g) and the rection mixture was refluxed under argon atmosphere. After 4 days, the rection mixture was cooled to room temperature and the organics were removed in

vacuo. The residue was purifie by flash chromatography using 50 % ethyl acetate-hexanes, followed by ethyl acetate as the eluant to (3- bromo-5-methylpyridin-2-yl)- (l-pyridin-4-ylethylidene) amine (4.29 g) as an oil.

Step 2 To a solution of (3-bromo-5-methylpyridin-2-yl)-(1-pyridin-4- ylethylidene) amine (4.25 g, 14.65 mmol) in dimethylformamide (75 ml) was added DABCO@ (4.93 g, 43.96 mmol) ans 1, bis-dichlorotriphenyl- phosphine palladium (0.52 g, 0.73 mmol). The rection mixture was heated at 120 °C under argon atmosphere. After 1.5 days, the rection mixture was cooled into room temperature and poured into 10 % hydrochloric acid (100 ml). The solution was filtered through Celites and the filtrate was neutralized to pH 7 with 10 % sodium hydroxide and the solid was filtered off to give 4-methyl-2-(pyridin-4-yl)-lH- pyrrolo [2, 3-b]pyridine (1.57 g) as a brown solid.

Step3 To a solution of 4-methyl-2- (pyridin-4-yl)-lH-pyrrolo [2, 3-b]pyridine (0.3 g, 1.43 mmol) in N-methylpyrrolidone (5 ml) was added 4- bromofluorobenzene (0.57 ml, 5.2 mmol), copper bromide (0.205 g, 1.43 mmol) and sodium carbonate (0.15 g, 1.43 mmol) and the rection mixture was heated to 180 °C under argon. After 24 h, the rection mixture was cooled and poured into 10 % hydrochloric acid (50 ml). The solution was filtered through Celites and the filtrate was neutralized to pH 7 with 10 % sodium hydroxide. The solid was filtered off, dissolve in 80 % methanol: methylene chloride and purifie by preparatory thin layer chromatography to give 1- (4-fluorophenyl)-4-methyl-2- (pyridin-4- yl)-lH-pyrrolo [2, 3-b]pyridine (0.03 g) as a tan solid.

Example 18 Synthesis of the 6- [2- (Acetylamino) pyridin-4-yl]-7- (4-fluorophenyl)- salt5H-pyrrolo[2,3-b]pyrazinehydrochloride

Step 1 To a solution of magnesium turnings (7.3 g, 300 mmol) in anhydrous ether (115 ml) was added a few crystals of iodine. A few drops of 4-fluorobenzyl chloride was added dropwise and the solution was heated to initiate the rection. Once the rection had initiated, the rest of 4-fluorobenzyl chloride (43 g, 300 mmol) was added at a rate that maintained a gentle reflux. After the addition was complete, the rection was stirred for 1 h and was used in the next step.

Step 2 Sodium hydride (8.6 g, 220 mmol, 60% dispersion in mineral oil) was washed twice with hexane (50 ml) and suspende in tetrahydrofuran (400 ml). 2-Chloroisonicotinic acid (28 g, 180 mmol) was slowly added and the resulting slurry was heated at reflux. After 2 h, the rection was cooled in an ice-bath and 4-fluorobenzylmagnesium chloride (100 ml, 200 mmol) was added. After stirring overnight, the rection was quenched with 4 M ammonium chloride solution (100 ml).

Water (100 ml) was added and the product was extracted into methylene chloride. The organic layer was washed with sat. sodium bicarbonate solution, dried over magnesium sulfate, filtered and concentrated in vacuo. The crude oil was purifie by flash

chromatography using 25 % ethyl acetate-hexanes as the eluant to 1- (2- chloropyridin-4-yl)-2- (4-fluorophenyl) ethanone (14 g).

Step 3 Hydrazinopyrazine (6.2 g, 57 mmol) and 1- (2-chloropyridin-4-yl)-2- (4-fluoro-phenyl) ethanone (14 g, 57 mmol) were suspende in benzene (250 ml) and p-toluenesulfonic acid monohydrate (0.68 g) was added.

The rection mixture was then refluxed with azeotropic removal of water via Dean Stark trap. After 2 h, the benzene was removed in vacuo and di-ethylene glycol was added. The rection mixture was heated at reflux. After 2 h, the rection mixture was poured into ether with vigorous stirring. Water was added and the product was extracted into ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Methanol was added and the solid was filtered off to give 6- (2-chloropyridin-4-yl)-7- (4-fluorophenyl)- 5H- pyrrolo [2, 3-b]pyrazine (4.9 g) as a solid.

Step 4 6- (2-Chloropyridin-4-yl)-7- (4-fluorophenyl)-5H-pyrrolo [2,3- b]pyrazine (0.5 g, 1.5 mmol) was dissolve in hot dimethylsulfoxide (3 ml) in a glass pressure tube and allowed to cool to room temperature.

Ammonium hydroxide (3 ml) and copper sulfate pentahydrate (0.77 g, 3.0 mmol) were added and the rection vessel was sealed with O-ring screw cap. The rection mixture was heated for 72 h in a sand bath at 150 °C. The rection mixture was poured into ethyl acetate (200 ml) and water (100 ml) and the product was extracted into ethyl acetate.

The organic layer was dried over sodium sulfate, filtered and concentrated in vacuo. The crude product was purifie by reverse phase HPLC to give 6-(2-aminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo [2,3- b]pyrazine trifluoroacetate salt (0.1 g) as a yellow solid.

Step 6 6-(2-Aminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3- b]pyrazine trifluoroacetate salt (0.085 g, 0.28 mmol) was dissolve in tetrahydrofuran and pyridine (0.22 g, 2.8 mmol) was added. Acetyl chloride (0.033 g, 0.42 mmol) in tetrahydrofuran (1 ml) was added and the resulting mixture was stirred at room temperature. After 1 h, the rection mixture was diluted with methanol (2 ml) and the product was isolated by reverse phase HPLC to give 6-(2-acetylaminopyridin-4-yl)-7- (4-fluorophenyl)-5H-pyrrolo [2, 3-b]pyrazine trifluoroacetate salt (0.1 g) as a yellow solid. The product was converted to the hydrochloride salt by suspending the product in ether and adding 1. 0M solution of HCl in ether (2 ml) to give a solid which was filtered off to give 6-(2- <BR> <BR> <BR> <BR> acetylaminopyridin-4-yl)-7- (4-fluorophenyl)-5H-pyrrolo (2, 3-b] pyrazine hydrochloride salt (0.0.44 g) as a yellow solid.

Example 19 The following are representative pharmaceutical formulations containing a compound of Formula (I).

Tablet formulation The following ingredients are mixed intimately and pressed into single scored tables.

Quantity per Ingredient tablet, mg compound of this invention 400 cornstarch 50 croscarmellose sodium 25

lactose 120 magnesium stearate 5 Capsule formulation The following ingredients are mixed intimately and loaded into a hard- shell gelatin capsule.

Quantity per Ingredient capsule, mg compound of this invention 200 lactose, spray-dried 148 magnesium stearate 2 Suspensionformulation The following ingredients are mixed to form a suspension for oral administration.

Ingredient Amount compound of this invention 1.0 g fumaric acid 0.5 g sodium chloride 2.0 g methyl paraben 0.15 g propyl paraben 0.05 g

granulated sugar 25.5 g sorbitol (70% solution) 12.85 g Veegum K (Vanderbilt Co.) 1.0 g flavoring 0.035 ml colorings 0.5 mg distille water q. s. to 100 ml Injectable formulation The following ingredients are mixed to form an injectable formulation.

Ingredient Amount compound of this invention 0.2 g sodium acetate buffer solution, 0.4 M 2.0 ml HCl (1N) or NaOH (1N) q. s. to suitable pH water (distilled, steril q. s. to 20 ml All of the above ingredients, except water, are combine and heated to 60-70°C with stirring. A sufficient quantity of water at 60 °C is then added with vigorous stirring to emulsify the ingredients, and water then added q. s. to 100 g.

Suppositoryformulation A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol0 H-15 (triglycerides of

saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: compound of the invention 500 mg Witepsol0 H-15 balance Example 20 Inhibition Of p-38 (MAP) Kinase... In Vitro Assai The p-38 MAP kinase inhibitory activity of compound of this invention in vitro was determined by measuring the transfer of the y- phosphate form γ-33P-ATP by p-38 kinase to Myelin Basic Protein (MBP), using the a minor modification of the method described in Ahn, N. G.; et al. J. of Biol. Chem. Vol. 266 (7), 4220-4227, (1991) The phosphorylated form of the recombinant p38 MAP kinase was expressed with SEK-1 and MEKK in E. Coli (see, Khokhlatchev, A. et al.

J. of Biol. Chem. Vol. 272 (17), 11057-11062, (1997) and then purifie by affinity chromatography using a Nickel column.

The phosphorylated p38 MAP kinase was diluted in kinase buffer (20 mM 3- (N-morpholino) propanesulfonic acid, pH 7.2,25 mM ß-glycerol phosphate, 5 mM ethylene glycol-bis (beta-aminoethyl ether)-N, N, N', N'- tetraacetic acid, lmM sodium vanadate, lmM dithiothreitol, 40mM magnesium chloride). Test compound dissolve in DMSO or only DMSO (control) was added and the samples were incubated for 10 min. at 30 °C. The kinase rection was initiated by the addition of a substrate cocktail containing MBP and γ-33P-ATP. After incubating for an additional 20 min. at 30 °C, the rection was terminated by adding 0.75% phosphoric acid. The phosphorylated MBP was then separated from the residual y 33P-ATP using a phosphocellulose membrane

(Millipore, Bedfrod, MA) and quantitated using a scintillation counter (Packard, Meriden, CT).

The p-38 inhibitory activities (expressed as IC50, the concentration causing 50% inhibition of the p-38 enzyme being assayed) of some compound of the invention is: CPD IC50,CPD # nM # nM 2 68 106 120 3 221 108 747 5 246 112 34.4 101 85.5

Example 21 Inhibition of LPS-Induced TUF-A Production In THP1 Cells.... In Vitro Assai The ability of the compound of this invention to inhibit the TNF-a release was determined using a minor modification of the methods described in described in Blifeld, C. et al. Transplantation, Vol. 51 (2), 498-503, (1991).

(a) Induction of TNF biossnthesis: THP-1 cells were suspende in culture medium [RPMI (Gibco-BRL, Gailthersburg, MD) containing 15% fetal bovine serum, 0.02 mM 2- mercaptoethanol], at a concentration of 2.5 x 106 cells/ml and then plated in 96 well plate (0.2 ml aliquots in each well). Test compound

were dissolve DMSO and then diluted with the culture medium such that the final DMSO concentration was 5%. 20 gl aliquots of test solution or only medium with DMSO (control) were added to each well.

The cells were incubated for 30 min., at 37 °C. LPS (Sigma, St. Louis, MO) was added to the wells at a final concentration of 0.5 gg/ml, and cells were incubated for an additional 2 h. At the end of the incubation period, culture supernatants were collecte and the amount of TNF-a present was determined using an ELISA assay as described below.

(b) ELISA Assav: The amount of human TNF-a present was determined by a specific trapping ELISA assay using two anti-TNF-a antibodies (2TNF-H22 and 2TNF-H34) described in Reimund, J. M., et al. GUT. Vol. 39 (5), 684-689 (1996).

Polystyrene 96-well plates were coated with 50 gel per well of antibody 2TNF-H22 in PBS (10, ug/ml) and incubated in a humidifie chamber at 4 °C overnight. The plates were washed with PBS and then blocked with 5% nonfat-dry milk in PBS for 1 hour at room temperature and washed with 0.1% BSA (bovine serum albumin) in PBS.

TNF standards were prepared from a stock solution of human recombinant TNF-α (R&D Systems, Minneapolis, MN). The concentration of the standards in the assay began at 10 ng/ml followed by 6 half log serial dilution's.

25 Rl aliquots of the above culture supernatants or TNF standards or only medium (control) were mixed with 25 ptl aliquots of biotinylated monoclonal antibody 2TNF-H34 (2 µg/ml in PBS containing 0.1% BSA) and then added to each well. The samples were incubated for 2 h at room temperature with gentle

shaking and then washed 3 times with 0.1% BSA in PBS. 50 gel of peroxidase-streptavidin (Zymed, S. San Francisco, CA) solution containing 0.416, ug/ml of peroxidase-streptavidin and 0.1% BSA in PBS was added to each well. The samples were incubated for an additional 1 h at room temperature and then washed 4 times with 0.1% BSA in PBS.

50 O-phenylenediaminesolution(1µg/mlO-phenylene-diamineandof 0.03 % hydrogen peroxide in 0.2M citrate buffer pH 4.5) was added to each well and the samples were incubated in the dark for 30 min., at room temperature. Optical density of the sample and the reference were read at 450 nm and 650 nm, respectively. TNF-α levels were determined from a graph relating the optical density at 450 nm to the concentration used.

The IC50 value was defined as the concentration of the test compound corresponding to half-maximal reduction in 450 nm absorbance. CPD # ICso, nM CPD # IC50, nM 2 0.46 106 1100 5 0.12 108 8830 9 0.3 112 241 Example 22 Inhibition of LPS-Induced TNF-α Production In Mice.... In Vivo Assa The ability of the compound of this invention to inhibit the TNF-α release, in vivo, was determined using a minor modification of the methods described in described in Zanetti, G.; Heumann, D. , et. al.,

"Cytokine production after intravenous or peritoneal Gram-negative bacterial challenge in mice,"J. Immunol., 148,1890, (1992) and Sekut, L., Menius, J. A., et. al., "Evaluation of the significance of elevated levels of systemic and localized tumor necrosis factor in different animal models of inflammation,"J. Lab. Clin. Med., 124,813, (1994).

Female BALB/c mice weighing 18-21 grams (harles River, Hollister, CA) were acclimate for one week. Groups containing 8 mice each were dosed orally either with the test compound dissolve in an aqueous vehicle containing 0.9% sodium chloride, 0.5% sodium carboxymethyl-cellulose, 0.4% polysorbate 80,0.9% benzyl alcohol (CMC vehicle) or only vehicle (control group). After 30 min., the mice were injecte intraperitoneally with 20 gag of LPS (Sigma, St. Louis, MO).

After 1.5 h, the mice were sacrifice bye02 inhalation and blood was harvested by cardiocentesis. Blood was clarifie by centrifugation at 15,600 X g for 5 min., and sera were transferred to clean tubes and frozen at-20°C until analyzed for TNF-a by ELISA assay (Biosource International, Camarillo, CA) following the manufacturer's protocol.

The TNF-a inhibitory activity of test materials, i. e., the measure of the TNF-a content in the test group relative to the vehicle treated group (control group) at 30 mg was: CPD % Inhibition 2 75% 3 56% 6 68% 101 86

The foregoing invention has been described in some detail by way of illustration and example, for purposes of clarity and understanding.

It will be obvious to one of skill in the art that changes and modifications may be practiced within the scope of the appende claims.

Therefore, it is to be understood that the above description is intended to be illustrative and not restrictive. The scope of the invention should, therefore, be determined not with reference to the above description, but should instead be determined with reference to the following appende claims, along with the full scope of equivalents to which such claims are entitled.

All patents, patent applications and publications cited in this application are hereby incorporated by reference in their entirety for all purposes to the same extent as if each individual patent, patent application or publication were so individually denoted.