CROSS-REFERENCE TO RELATED APPLICATIONS 0001 This application claims the benefit under 35 U.S.C. 119(e) of U.S. Provisional Applications Ser. No. 60/062,548 filed Oct. 20, 1997, Ser. No. 60/075,515 filed Feb. 20, 1998 and Ser. No. 60/096,916 filed Aug. 18, 1998.

FIELD OF THE INVENTION 0002 This invention relates to compounds that inhibit p38 MAP kinase, pharmaceutical compositions containing them, methods for their use, and methods for preparing these compounds.

BACKGROUND INFORMATION AND RELATED DISCLOSURES 0003 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 ((see., 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 Network 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 ((see., 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 ((see., Abraham, E.; et. al. JAMA. 277(19):1531-1538, (1997), adult respiratory distress syndrome, asthma ((see., Shah, A.; et. al. Clin. & Exp. Allergy 1038-1044, (1995) and Lassalle, P., et. al. Clin. & Exp. Immunol. 94(1): 105-110, (1993)), bone resorption diseases, fever ((see., 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. 0004 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. 0005 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 ((see., Lee, J. C., et al. Nature 372 (6508): 739-46, (1994)). Compounds 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. 0006 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.

SUMMARY OF THE INVENTION 0007 In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I): 2

0008 wherein: 0009 R1 is heteroaryl; 0010 - - - - - - represents a bond between either B and CR1 or Q and CR1 such that: 0011 (i) when - - - - - - is between Q and CR1 then: 0012 B is nitrogen; 0013 R2 is aryl; and 0014 Q is CR wherein: 0015 R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, heteroalkyl, acyl, heterocyclyl, heterocyclylalkyl, heterocyclylcarbonyl, nitro, cyano, amino, monosubstituted amino, disubstituted amino, acylamino, sulfonylamino, OR5 (where R5 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), COOR7 (where R7 is hydrogen or alkyl) or CONRR (where R and R independently represent hydrogen, alkyl or heteroalkyl); and 0016 (ii) when - - - - - - is between B and CR1 then: 0017 B is carbon; 0018 R2 is aryl or heteroaryl; and 0019 Q is NR4, O, or S wherein: 0020 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), SO2R (where R is alkyl, amino, monosubstituted amino or disubstituted amino), CONRR (where R and R independently represent hydrogen, alkyl or heteroalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0021 Z is cyano; 0022 COOR7 where R7 is hydrogen or alkyl; 0023 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 attached form a heterocycle; 0024 C(NR10)(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 0025 COR13 where R13 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and 3

0026 where: 0027 R6 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, halo, cyano, nitro, amino, monosubstituted amino, disubstituted amino, COOR14, -(alkylene)-COOR14 (where R14 is hydrogen or alkyl), CONR15R16 (where R15 and R16 independently represent hydrogen or alkyl, or and R16 together with the nitrogen atom to which they are attached 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), OR8 (where R18 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 0028 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), CONR21R22 (where R21 and R22 independently represent hydrogen, alkyl or heteroalkyl, or R21 and R22 together with the nitrogen atom to which they are attached form a heterocycle), 0029 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: 0030 Z is cyano; 0031 COOR24 where R24 is hydrogen or alkyl; 0032 CONR25R26 where R25 and R26 independently represent hydrogen or alkyl, or R25 and R26 together with the nitrogen atom to which they are attached form a heterocycle; 0033 C(NR27)(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 0034 COR30 where R30 is alkyl, heteroalkyl, heterocyclylalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl; and 0035 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. 0036 In a second aspect, this invention provides compounds selected from the group of compounds represented by Formula (IIa): 4

0037 wherein: 0038 One of Z1 and Z2 is nitrogen and the other is CR6 wherein R6 is hydrogen, alkyl, or alkoxy; or both Z1 and Z2 are nitrogen such that: 0039 (a) when Z1 or Z2 is nitrogen and the other is CR6 then: 0040 (i) when Y is halo, then QR is NHC(R1)CH(R2) or NC(CH3)(R1); 0041 (ii) when Y is C(R2)C(R1)OX (where X is p-CH3C6H4SO2, CH3SO2, or CF3SO2), then QR is nitro or amino; and 0042 (iii) when Y is C(O)R2, then QR is NHC(O)R1, OCH2CO2R, or SCH2R1 where: 0043 R is alkyl; 0044 R1 is heteroaryl; and 0045 R2 is aryl or heteroaryl; and 0046 (b) when Z1 and Z2 both are nitrogen then: 0047 Y is halo and QR is NHC(R )CH(R2) where R1 and R2 are as defined above; and 0048 R3 is hydrogen, alkyl, halo, or alkoxy. 0049 In a third aspect, this invention provides compounds selected from the group of compounds represented by Formula (IIb): 5

0050 wherein: 0051 Z3 is nitrogen and Z4 is CR3 wherein R3 is hydrogen, alkyl, or alkoxy; or Z is nitrogen and Z3 is CH; such that: 0052 (a) when Y is hydrogen, then QR is NHNC(R1)CH2(R2); and 0053 (b) when Y is C(O)R2, then QR is OCH2CO2R or SCH2R1 where: 0054 R is alkyl; 0055 R1 is heteroaryl; and 0056 R2 is aryl or heteroaryl; and 0057 R6 is hydrogen, alkyl, halo, or alkoxy. 0058 In a fourth 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. 0059 In a fifth aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a p38 MAP kinase inhibitor, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt.

DETAILED DESCRIPTION OF THE INVENTION

Definitions 0060 Unless otherwise stated, the following terms used in the specification and claims have the meanings given below: 0061 Alkyl means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like. 0062 Cycloalky means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like. 0063 Alkylene means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like. 0064 Alkenyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like. 0065 Alkenylene means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, propenylene, and the like. 0066 Alkynyl means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one triple bond, e.g., ethynyl, propynyl, and the like. 0067 Alkoxy means a radical OR where R is alkyl as defined above, e.g., methoxy, ethoxy, propoxy, 2-propoxy, the like. 0068 Acyl means a radical C(O)R where R is hydrogen, alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaryl or heteroaralkyl, e.g., acetyl, benzoyl, thenoyl, and the like. 0069 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. 0070 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. 0071 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. 0072 Halo means fluoro, chloro, bromo, or iodo, preferably fluoro and chloro. 0073 Haloalkyl means alkyl substituted with one or more same or different halo atoms, e.g., CH2Cl, CF3, CH2CF3, CH2CCl3, and the like. 0074 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. 0075 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 include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl) amino, methylbenzylamino, and the like. 0076 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), CONRR and -(alkylene)-CONRR (where R and R are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof. 0077 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 CONRR (where R and R are independently selected from hydrogen or alkyl). 0078 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, -(alkylene)-COZ (where Z is amino, alkylamino, or dialkylamino) 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), NRaC(O) Rb where Ra is 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), CONRR and -(alkylene)-CONRR (where R and R are independently selected from hydrogen, alkyl, cycloalkyl or cycloalkylalkyl). More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrimidinyl, thiophen-2-yl, quinolyl, benzopyranyl, thiazolyl, imidazolyl and derivatives thereof. 0079 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 CONRR (where R and R are independently selected from hydrogen or alkyl). 0080 Heteroalkyl means an alkyl, alkenyl, alkynyl or cycloalkyl radical as defined above, carrying one or two substituents selected from NRaRb, ORC, S(O)nRd or SO3X wherein n is an integer from 0 to 2, X is an alkali metal, Ra is 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, Rc is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, hydroxyalkyl, alkoxyalkyl, aminoalkyl, alkylaminoalkyl, 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 dialkylaminoalkyl). Representative examples include, but are not limited to, 2-methoxyethyl, phenoxymethyl, 2-aminoethyl, 2-dimethylaminoethyl, 2-hydroxyethoxy, 2-dimethylaminoethoxy, and the like. 0081 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 replaced 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, alkylamninoalkyl, 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), CONRR or -(alkylene)-CONRR (where R and R are independently selected from hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl or optionally substituted phenylalkyl). More specifically the term heterocycle includes, but is not limited to, tetrahydropyranyl, pyrrolidine, piperidine, piperazine, homopiperazine, morpholine, thiomorpholine, azepine, and derivatives thereof. 0082 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 CONRR (where R and R are independently selected from hydrogen or alkyl). 0083 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 include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3hydroxybutyl, 4hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3hydroxypropyl, preferably 2-hydroxyethyl, 2,3dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl. 0084 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. 0085 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 include, but are not limited to, 2-methylaminoethyl, 3-ethylaminopropyl, 1-(methylaminomethyl)-2-methylpropyl, and the like. 0086 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 include, but are not limited to, 2-dimethylaminoethyl, 2-dimethylaminopropyl, 1-(dimethylamino-methyl)-2-methylpropyl, and the like. 0087 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. 0088 Cycloalkylalkyl means a radical RaRb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like. 0089 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. 0090 Heteroaralkyl means a radical RaRb where Ra is -n alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like. 0091 Heterocyclylalkyl means a radical RaRb where Ra is 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. 0092 Optional or optionally means that the subsequently described event or circumstance may but need not occur, and that the description includes 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 includes 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. 0093 Amino protecting group refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl, benzyloxycarbonyl (CBZ), tert-butoxycarbonyl (Boc), trifluoroacetyl, and the like. 0094 The compounds of this invention may possess one or more asymmetric centers; such compounds 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). 0095 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 includes 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 includes both one and more than one such excipient. 0096 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: 0097 (1) acid addition salts, formed with inorganic acids such as hydrochloric acid, 5-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, 4methylbicyclo2.2.2-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 0098 (2) salts formed when an acidic proton present in the parent compound either is replaced 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. 0099 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 compounds 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 include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like. 0100 Treating or treatment of a disease includes: 0101 (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, 0102 (2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or 0103 (3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms. 0104 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.

NOMENCLATURE 0105 The nomenclature used in this application is generally based on the IUPAC recommendations, for example: 6

0106 where Q is NH, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine. 7

0107 where Q is NH, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 3-phenyl-2-(pyridin-4-yl)-1H-pyrrolo3,2-cpyridine. 8

0108 where Q is NH, R1 is 4-pyridyl, R2 is phenyl and R3 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo3,2-cpyridazine. 9

0109 where Q is NH, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo3,2-dpyrimidine. 10

0110 where Q is NH, R is 4-pyridyl, R2 is phenyl and R6 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine. 11

0111 where R1 is 4-pyridyl, R2 is phenyl and R3 and R are hydrogen, is named as 1-phenyl-2-(pyridin-4-yl)-1H-pyrrolo2,3-bpyridine. 12

0112 where R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 1-phenyl-2-(pyridin-4-yl)-1H-pyrrolo2,3-cpyridine. 13

0113 where R1 is 4-pyridyl, R2 is phenyl and R6 is hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-7H-pyrrolo2,3-cpyridazine. 14

0114 where Q is NH, R1 is 4-pyridyl, R2 is phenyl and R3 and R6 are hydrogen, is named as 7-phenyl-6-(pyridin-4-yl)-7H-pyrrolo2,3-dpyrimidine. 1I. Compounds 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:

CPDMass Spec.R1R2R4R6M.Pt. C.m/e14-pyridyl4-fluorophenylhydroxyhydrogen225-22824-pyridyl4-fluorophenylmethoxyhydrogen168-171.534-pyridyl4-fluorophenyl2-(morpholin-4-yl)ethoxyhydrogen139-14144-pyridyl4-fluorophenyl2-(piperidin-1-yl)ethoxyhydrogen95.9-98.754-pyridyl4-fluorophenyl2-(pyrrolidin-1-yl)ethoxyhydrogen123-12964-pyridyl4-fluorophenylhydrogenhydrogen>28574-pyridyl4-fluorophenylethylhydrogen204-20684-pyridyl4-fluorophenyl2-(morpholin-4-yl)ethylhydrogen171.2-17394-pyridyl4-fluorophenyl2-(piperidin-1-yl)ethylhydrogen148.1-153.3104-pyridyl4-fluorophenyl3-dimethylaminopropylhydrogen375114-pyridyl4-fluorophenyl2-(1-methylpyrrolidin-2-yl)ethylhydrogen401124-pyridyl4-fluorophenyl3-hydroxypropylhydrogen348134-pyridyl4-fluorophenyl3-(1-methylpiperazin-4-yl)propylhydrogen430144-pyridyl4-fluorophenyl3-(trimethylamino)propyl.HCl salthydrogen390154-pyridyl4-fluorophenyl2-(RS)-(dimethylaminomethyl)propylhydrogen389164-pyridyl4-fluorophenyl3-cyanopropylhydrogen357174-pyridyl4-fluorophenyl2-aminocarbonylethylhydrogen361184-pyridyl4-fluorophenylethyl.dihydrochloridehydrogen>285194-pyridyl4-fluorophenyldimethylaminocarbonylmethyl.TFA salt.hydrogen375204-pyridyl4-fluorophenylmethylmethoxyaminocarbonylmethyl.TFAhydrogen391salt.214-pyridyl4-fluorophenylCH2COCH2CO2CH3.TFA salt.hydrogen404224-pyridyl4-fluorophenylCH2COCH3.TFA salt.hydrogen346234-pyridyl4-fluorophenyl(CH2)3NH(CH2)2NH2.3 TFA salt.hydrogen390244-pyridyl4-fluorophenyl3-(3-aminocarbonylpiperidin-1-yl)propylhydrogen458254-pyridyl4-fluorophenyl3-(piperidin-1-yl)propylhydrogen415264-pyridyl4-fluorophenyl3-(piperazin-1-yl)propyl.3 TFA salt.hydrogen416274-pyridyl4-fluorophenyl3-(homopiperazin-1-yl)propyl.3 TFA salt.hydrogen430284-pyridyl4-fluorophenyl3-hydroxylaminopropyl.2 TFA salt.hydrogen363294-pyridyl4-fluorophenyl3-(morpholin-4-yl)propyl.2 TFA salt.hydrogen417304-pyridyl4-fluorophenyl3-(4-hydroxypiperidin-1-yl)propyl.2 TFAhydrogen431salt.314-pyridyl4-fluorophenyl3-imidazol-1-ylpropyl.3 TFA salthydrogen398324-pyridyl4-fluorophenyl3-aminopropyl.2 TFA salthydrogen347334-pyridyl4-fluorophenyl3-(2-aminocarbonylpyrrolidin-1-yl)propyl.2hydrogenTFA salt344-pyridyl4-fluorophenyl3-3-(2-hydroxyethyl)piperidin-1-yl-propyl.hydrogen4592 TFA salt354-pyridyl4-fluorophenyl3-2-(hydroxymethyl)piperidin-1-yl-propyl.hydrogen4452 TFA salt364-pyridyl4-fluorophenyl3-(pyrrolidin-1-yl)propyl.2 TFA salthydrogen401374-pyridyl4-fluorophenyl3-(3-hydroxypyrrolidin-1-yl)propyl.hydrogen4312 TFA salt384-pyridyl4-fluorophenyl3-tris(hydroxymethyl)methylamino-hydrogen451propyl.2 TFA salt394-pyridyl4-fluorophenyl3-3-(hydroxymethyl)piperidin-1-yl)-propyl.hydrogen4452 TFA salt404-pyridyl4-fluorophenyl3-(5-aminocarbonylimidazol-4-yl)-hydrogen456aminopropyl.2 TFA salt414-pyridyl4-fluorophenyl3-3-hydroxypropylaminopropyl.2 TFA salthydrogen405424-pyridyl4-fluorophenyl3-(piperizin-1-ylethyl)aminopropyl.2 TFAhydrogen459salt434-pyridyl4-fluorophenyl2-methoxyethyl.2 HCl salthydrogen54-59444-pyridyl4-fluorophenylmethyl.HCl salthydrogen219-220454-pyridyl4-fluorophenyl3-(3-aminopiperidin-1-yl)propyl.3 TFA salthydrogen430464-pyridyl4-fluorophenyl3-(3-hydroxypyrrolidin-1-yl)propyl.2 TFAhydrogen417salt474-pyridyl4-fluorophenyl3-(tetrahydropyran-2-ylmethyl)aminopropylhydrogen431.2 TFA salt484-pyridyl4-fluorophenyl3-(2,6-dimethylmorpholin-4-yl)propyl.2hydrogen445TFA salt494-pyridyl4-fluorophenylaminocarbonylmethyl.TFA salthydrogen347504-pyridyl4-fluorophenyl(CH2)2SO3Na salthydrogen398514-pyridyl4-fluorophenyl(CH2)2CH(SO3)(CH2)3SO3.2 Na salthydrogen534524-pyridyl4-fluorophenylcarboxymethyl.TFA salthydrogen348534-pyridyl4-fluorophenyl4-(morpholin-4-yl)butyl.2 TFA salthydrogen431544-pyridyl4-fluorophenyl4-methylaminobutyl.2 TFA salthydrogen554-pyridyl4-fluorophenyl4-(pyrrolidin-1-yl)butyl.2 TFA salthydrogen415564-pyridyl4-fluorophenyl4-(piperidin-1-yl)butyl.2 TFA salthydrogen429574-pyridyl4-fluorophenyl2-hydroxyethyl.2 HCl salthydrogen232.8-237.9584-pyridyl4-fluorophenyl(CH2)3SO3Na salt.TFA salthydrogen412594-pyridyl4-fluorophenylcarboxymethylaminocarbonylmethyl.HClhydrogen405604-pyridyl4-fluorophenylcyanomethylhydrogen233.1-233.7614-pyridyl4-fluorophenyl2-(pyrrolidin-1-yl)ethylhydrogen148.1-153.3624-pyridyl4-fluorophenyl3-(bis(2-hydroxyethyl)aminopropyl.2 TFAhydrogen435salt634-pyridyl4-fluorophenyl3-(cyanomethylamino)propyl.2 TFA salthydrogen386644-pyridyl4-fluorophenyl2-aminoethyl.2 TFA salthydrogen333654-pyridyl4-fluorophenyl4-aminobutyl.2 TFA salthydrogen361664-pyridyl4-fluorophenyl2-(4-methylpiperazin-1-yl)ethyl.3 TFA salthydrogen416674-pyridyl4-fluorophenyl2-imidazol-1-ylethyl.2 TFA salthydrogen384684-pyridyl4-fluorophenyl2-cyanoethylhydrogen171.3-172.5694-pyridyl4-fluorophenylmethylsulfonylhydrogen206.6-207.1704-pyridyl4-fluorophenyl1-(hydroxymethyl)propylhydrogen176.6-178.2714-pyridyl4-fluorophenyl4-cyanobutyl.TFAhydrogen371724-pyridyl4-fluorophenyl3-guanidinopropyl.2 TFAhydrogen389734-pyridyl4-fluorophenyl2-guanidinoethyl.2 TFAhydrogen375744-pyridyl4-fluorophenyl3-(4-methylimidazol-1-yl)propyl.2 TFAhydrogen754-pyridyl4-fluorophenyl3-(2-nitroimidazol-1-yl)propyl.2 HClhydrogen764-pyridyl4-fluorophenyl3-(2-methylimidazol-1-yl)propyl.2 TFAhydrogen774-pyridyl4-fluorophenylhydrogenmethoxy244784-pyridyl4-fluorophenyl3-N,N-bis(pyridin-3-ylmethyl)aminopropylhydrogen794-pyridyl4-fluorophenyl(CH2)3N(CH2)3N(CH3)22hydrogen

0115

2II. Compounds 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:

CPDMassR1R3R2R4R6M.Pt. C.Spec.804-pyridylhydrogen3-chloro-4-fluoro-hydrogenhydrogen293.5-296.5phenyl814-pyridylhydrogen3-chlorophenylhydrogenhydrogen>280824-pyridylhydrogen3-trifluoromethyl-hydrogenhydrogen226.2-226.9phenyl834-pyridylhydrogen3-methoxyphenylhydrogenhydrogen240.4-240.6844-pyridylhydrogen2-methylphenylhydrogenhydrogen>300854-pyridylhydrogen2-methoxyphenylhydrogenhydrogen>300864-pyridylhydrogen3-trifluoromethyl-methylhydrogen.HCl220-252phenyl874-pyridylhydrogen3-chloro-4-fluoro-methylhydrogen.HCl220-230phenyl884-pyridylhydrogen4-fluorophenylmethylchloro.HCl250-252894-pyridylhydrogen4-fluorophenylhydrogenethyl.2 HCl195-199904-pyridylhydrogen4-fluorophenylhydrogenmethoxy.2244HCl914-pyridyl6-chloro4-fluorophenylhydrogenhydrogen229.5-231.2924-pyridyl6-trifluoro-4-fluorophenyl2-morpholin-4-hydrogen126.4-128.2methylylethoxy932-(2-hydroxyethyl-hydrogen4-fluorophenylhydrogenhydrogen.HCl349amino)-4-pyridyl942-HO(CH2)2O(CH2)2hydrogen4-fluorophenylhydrogenhydrogen.HCl393NH-4-pyridyl952-(2-methylamino-hydrogen4-fluorophenylhydrogenhydrogen.HCl379ethylamino)-4-pyridyl962-(3-methoxypropyl-hydrogen4-fluorophenylhydrogenhydrogen.HCl393amino)-4-pyridyl972-n-propylamino-4-hydrogen4-fluorophenylhydrogenhydrogen.HCl361pyridyl982-(3-hydroxypropyl-hydrogen4-fluorophenylhydrogenhydrogen.HCl363amino)-4-pyridyl992-methylamino-4-hydrogen4-fluorophenylhydrogenhydrogen.HCl320pyridyl1002-acetylamino-4-hydrogen4-fluorophenylhydrogen.HClhydrogen347pyridyl

0116

3III. Compounds 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 are as defined below are:

CPD R1R2M.Pt. C.1014-pyridyl4-fluorophenyl141-1431022-chloropyrimidin-4-yl4-fluorophenyl224.8-225.21032-aminopyrimidin-4-yl4-fluorophenyl252.9-253.71042-methylthiopyrimidin-4-yl4-fluorophenyl182.5-183.9

0117

4IV. Compounds 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 R1R2R4M.Pt. C.1054-pyridyl4-fluorophenylhydrogen256-257

0118

5V. Compounds 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 is:

CPDMassR1R2R4Spec. m/e1064-pyridyl4-fluorophenylhydrogen1074-pyridyl4-fluorophenylhydrogen.HCl salt1084-pyridyl4-fluorophenyl3-cyanopropyl3581094-pyridyl4-fluorophenyl3-(imidazol-1-yl)propyl3991104-pyridyl4-fluorophenylmethyl.HCl salt3051114-pyridyl4-fluorophenylethyl.HCl salt3181122-(2-hydroxyethyl)amino-4-4-fluorophenylhydrogen.HCl salt350pyridyl1132-(2-aminoethyl)amino-4-pyridyl4-fluorophenylhydrogen.HCl salt3491142-(3-hydroxypropyl)amino-4-4-fluorophenylhydrogen.HCl salt364pyridyl1152-methylamino-4-pyridyl4-fluorophenylhydrogen.HCl salt3201162-bromo-4-pyridyl4-fluorophenylhydrogen.HCl salt3691172-methoxy-4-pyridyl4-fluorophenylhydrogen.HCl salt3211182-(3-aminopropyl)amino-4-4-fluorophenylhydrogen.HCl salt363pyridyl1192-hydroxylamino-4-pyridyl4-fluorophenylhydrogen.HCl salt3221202-carboxymethylamino-4-pyridyl4-fluorophenylhydrogen.HCl salt3641214-pyridyl4-fluorophenyl3-(2-nitroimidazol-1-yl)propyl.HCl salt4441224-pyridyl4-fluorophenyl3-(4-methylimidazol-1-yl)propyl.HCl salt4131234-pyridyl4-fluorophenyl3-(4-methylpiperazin-1-yl)propyl.HCl salt4311244-pyridyl4-fluorophenyl3-(morpholin-4-yl)propyl.HCl salt4181254-pyridyl4-fluorophenyl3-methylaminopropyl.HCl salt3621264-pyridyl4-fluorophenyl3-(4-nitroimidazol-1-yl)propyl.HCl salt4441272-acetylamino-4-pyridyl4-fluorophenylhydrogen.HCl348

0119

6VI. Compounds 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 is:

CPDMass Spec.R1R2R6R4m/e1282-methylamino-4-pyridyl4-fluorophenyl6-methylaminohydrogen.2 HCl3491292-imidazol-1-ylmethyl-4-fluorophenylhydrogenhydrogen.2 HCl414carbonylamino-4-pyridyl1302-dimethylaminomethyl-4-fluorophenylhydrogenhydrogen.2 HCl391carbonylamino-4-pyridyl1312-methylaminomethyl-4-fluorophenylhydrogenhydrogen.2 HCl377carbonylamino-4-pyridyl1322-piperidin-1-ylmethyl-4-fluorophenylhydrogenhydrogen.2 HCl431carbonylamino-4-pyridyl1332-(4-methylpiperazin-1-yl-4-fluorophenylhydrogenhydrogen.2 HCl446methylcarbonylamino-4-pyridyl1344-pyridyl4-fluorophenyl6-dimethylaminohydrogen.2 HCl3341354-pyridyl4-fluorophenyl6-methoxyhydrogen.HCl3211364-pyridyl4-fluorophenyl6-methylthiohydrogen.HCl3371372-(2-methylthioethylamino)-3-chlorophenylhydrogenhydrogen.2 HCl3964-pyridyl1384-pyridyl4-fluorophenyl6-acetylaminohydrogen.HCl3481392-(2-hydroxyethylamino)-4-4-fluorophenyl6-methylaminohydrogen.2 HCl379pyridyl1402-acetylamino-4-pyridyl4-fluorophenyl6-acetylaminohydrogen.HCl4051412-methoxymethylcarbonyl-4-fluorophenylhydrogenhydrogen.HCl378amino-4-pyridyl1422-(2-dimethylaminoethyl-4-fluorophenylhydrogenhydrogen.2 HCl405carbonylamino)-4-pyridyl1432-chloro-4-pyridyl3-chlorophenylhydrogenhydrogen.HCl3411442-chloro-4-pyridyl4-fluorophenyl6-chlorohydrogen.HCl3591452-(2-hydroxyethylamino)-4-4-fluorophenyl6-(2-hydroxyethyl-hydrogen.2 HCl409pyridylamino)1462-(3-hydroxypropylamino)-4-4-fluorophenyl6-(3-hydroxypropyl-hydrogen.2 HCl437pyridylamino)1472-(4-hydroxybutylamino)-4-4-fluorophenyl6-(4-hydroxybutyl-hydrogen.2 HCl466pyridylamino)1482-(2-methoxyethylamino)-4-4-fluorophenyl6-(2-methoxyethyl-hydrogen.2 HCl437pyridylamino)1492-(3-methoxypropylamino)-4-4-fluorophenyl6-(3-methoxypropyl-hydrogen.2 HCl465pyridylamino)1502-(3-aminopropylamino)-4-4-fluorophenyl6-(3-aminopropyl-hydrogen.4 HCl435pyridylamino)

0120

7VII. Compounds of Formula (I) where B is nitrogen, Q is CH,R6 is hydrogen,

is a group of formula (S),and the other groups are as defined below are:

CPD R1R2R3M.Pt. C.1514-fluorophenyl4-pyridyl5-methyl202.1-206

0121

8VIII. Compounds 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 are:

CPD R1R2Mass Spec. m/e1524-pyridyl4-fluorophenyl290

PREFERRED EMBODIMENTS 0122 While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred. For example, 0123 A preferred group of compounds is that wherein - - - - - - is between B and CR1. 0124 Within this group, more preferred groups are as follows: 0125 I. One more preferred group of compounds is that wherein: 0126 Q is NR4; and 31

0127 Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein: 0128 (A) R2 is aryl; 0129 R3 is at the 7-position and is hydrogen, alkyl, halo or heteroalkyl, more preferably hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl, most preferably hydrogen; and 0130 R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen. 0131 Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein: 0132 R1 is a 4-pyridyl or 4-pyrimnidinyl ring optionally substituted with a substituent selected from heteroalkyl, NRR (where R and R are independently of each other hydrogen, alkyl, heterocyclylalkyl or heteroalkyl), NaC(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 R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy, most preferably 2-acetylamino-4-pyridyl or 2-(2-hydroxyethylamino)-4-pyridyl; and 0133 R2 is 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. 0134 Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein: 0135 R4 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0136 Z is COOR7 where R7 is alkyl; 0137 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 attached form a heterocycle; or 0138 C(NR10)(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; 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, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl. 0139 (B) Another even more preferred group of compounds is that wherein: 0140 R1 is a heteroaryl ring substituted with NRR (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and R is heterocyclylalkyl or heteroalkyl), preferably a 4-pyridyl or 4-pyrimidinyl ring substituted at the 2-position with NRR (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and R is heterocyclylalkyl or heteroalkyl), more preferably 2-hydroxyethylamino-4-pyridyl, 2-dimethylaminoethylamino-4-pyridyl, or 2-methylaminoethylamino-4-pyridyl; and 0141 R2isaryl. 0142 Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein: 0143 R is 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; 0144 R3 is at the 7-position and is hydrogen, alkyl, halo or heteroalkyl, more preferably hydrogen, methyl, chloro, fluoro, 2-hydroxyethyl, 2-aminoethyl or 2-dimethylaminoethyl, most preferably hydrogen; and 0145 R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen. 0146 Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein: 0147 R4 is hydrogen, alkyl, heteroalkyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0148 Z is COOR7 where R7 is alkyl; 0149 CONR8R9 where R5 is hydrogen or alkyl, R9 is alkoxy or (alkylene)-COOR7, or R8 and R9 together with the nitrogen atom to which they are attached form a heterocycle; or 0150 C(NR10)(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; preferably hydrogen, methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, 2-aminoethyl, 3-aminopropyl, 2-methylaminoethyl, 3-methylaminopropyl, 2-dimethvlaminoethyl, 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, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl. 0151 II. A second more preferred group of compounds is that wherein: 0152 Q is NR4; and 32

0153 Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein: 0154 (A) R is at the 6-position and is selected from hydrogen, alkyl, alkoxy, 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, 2-hydroxyethylamino, or acetylamino, most preferably hydrogen. 0155 Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein: 0156 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, 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 R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and 0157 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. 0158 Within these preferred, more preferred and particularly preferred groups, an even more preferred group of compounds is that wherein: 0159 R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0160 Z is COOR7 where R7 is alkyl; 0161 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 attached form a heterocycle; or 0162 C(NR10)(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; 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, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl. 0163 Another even more preferred group of compounds is that wherein: 0164 (B) R is a heteroaryl ring substituted with NRR (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and R is heterocyclylalkyl or heteroalkyl), preferably a 4-pyridyl or 4-pyrinidinyl ring substituted at the 2-position with NRR (where R is hydrogen, alkyl, heterocyclylalkyl or heteroalkyl and R is heterocyclylalkyl or heteroalkyl), preferably 2-hydroxyethylamino-4-pyridyl, 2-dimethylaminoethylamino-4-pyridyl, or 2-methylaminoethylamino-4-pyridyl; and 0165 R is aryl. 0166 Within these preferred, more preferred and even more preferred groups, a particularly preferred group of compounds is that wherein: 0167 R4 is hydrogen, alkyl, cycloalkyl, heteroalkyl, acyl, heterocyclylalkyl, -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0168 Z is COOR7 where R7 is alkyl; 0169 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 attached form a heterocycle; or 0170 C(NR10)(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; 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, more preferably hydrogen, methyl, 2-(morpholin-4-yl)ethyl, or 2-(piperidin-1-yl)ethyl; and 0171 R6 is at the 6-position of ring (W) and is selected from hydrogen, alkyl, alkoxy, 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. 0172 Within these preferred and more preferred groups and particularly preferred groups, an even more preferred group of compounds is that wherein: 0173 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 rmethoxy, most preferably 4-fluorophenyl. 0174 III. A third more preferred group of compounds is that wherein: 0175 Q is O; and 33

0176 Within these preferred and more preferred group of compounds, an even more preferred group of compounds is that wherein: 0177 R3 is at the 7-position and is hydrogen, alkyl, cycloalkyl, heteroalkyl, halo, heterocyclylalkyl, OR19 (where R19 is hydrogen, alkyl, heteroalkyl or heterocyclylalkyl), -(alkylene)-Z or -(alkylene)-CO-(alkylene)-Z wherein: 0178 Z is cyano; 0179 COOR24 where R24 is hydrogen or alkyl; 0180 CONR25R26 where R25 and R26 independently represent hydrogen or alkyl or and R26 together with the nitrogen atom to which they are attached form a heterocycle; 0181 C(NR27)(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 0182 COR30 where R30 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-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, more preferably hydrogen, hydroxy, methoxy, 2-(morpholin-4-yl)ethyl, 2-(morpholin-4-yl)ethoxy or 2-(piperidin-1-yl)ethyl; and 0183 R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen. 0184 Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein: 0185 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)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 R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and 0186 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. 0187 IV. A fourth more preferred group of compounds is that wherein: 0188 Q is O; and 34

0189 Within these preferred and more preferred groups, an even more preferred group of compounds is that wherein: 0190 R6 is hydrogen, alkyl, alkoxy or halo, preferably hydrogen, methyl, methoxy, fluoro or chloro, most preferably hydrogen. 0191 Within these preferred and more preferred groups, particularly preferred group of compounds is that wherein: 0192 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)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, alkylamnino, 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 R1 is a 4-pyridyl ring optionally substituted at the 2-position with a substituent selected from amino, acetylamino, methylamino, dimethylamino, methylsulfonylamino, 2-hydroxyethyl, 2-hydroxyethylamino, 3-hydroxypropylamino, 2-aminoethylamino, 2-aminoethyl, 3-aminopropyl, 2-dimethylaminoethyl, methoxy, 2-hydroxyethoxy or 2-dimethylaminoethoxy; and 0193 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. 0194 Exemplary particularly preferred compounds are: 0195 3-(4-Fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine. 0196 3-(4-Fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine. 0197 3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine. 0198 3-(4-Fluorophenyl)-2-2-(2-hydroxyethylamino)pyridin-4-yl-1H-pyrrolo3,2-bpyridine. 0199 3-(4-Fluorophenyl)-1-2-(piperidin-1-yl)ethoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-b-pyridine. 0200 3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1-2-(morpholin-4-yl)ethoxy-1H-pyrrolo3,2-b-pyridine. 0201 3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1-2-(morpholin-4-yl)ethyl-1H-pyrrolo3,2-b-pyridine. 0202 3-(4-Fluorophenyl)-1-2-(piperidin-1-yl)ethyl-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine. 0203 7-(4-Fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine. 0204 6-(2-Acetylarinopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine.

GENERAL SYNTHETIC SCHEME 0205 Compounds of this invention can be made by the methods depicted in the reaction schemes shown below. 0206 The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Lancaster (Windham, N.H., 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 Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, 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 compounds 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. 0207 The starting materials and the intermediates of the reaction may be isolated and purified 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 pnysical constants and spectral data.

Preparation of compounds of Formula (I) 0208 Schemes A-M describe methods to synthesize compounds of Formula (I). 35

0209 Reaction 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 -keto-acetonitrile intermediate of formula 3 ((see., Ivan Lantos, I. et al. J. Org. Chem. 53, 4223-4227 (1988)). Alternatively, the reaction can be carried out in the presence of lithium diisopropylamide or lithium hexamethyldisilazane in tetrahydrofuran. 0210 In general, compounds 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-pyrimidinecarboxylic acid, 4-pyrimidinecarboxylic acid, 2-pyrazinecarboxylic acid under standard esterification reaction conditions. 0211 Compounds of formula 2 such as 2-phenylacetonitrile, 4-fluorophenylacetonitrile, pyridylacetonitrile, and the like are commercially available. 0212 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 R1COONa with a Grignard reagent of formula R2CH2MgX (where X is halo). 0213 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 reaction 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. 0214 Compounds 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). 0215 Compounds 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 Turner 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). 0216 Cyclization of the enamine 7 or 8 provides the 1H-pyrrolo3,2-bpyridine or the 1H-pyrrolo3,2-cpyridine of Formula (I), respectively. The cyclization reaction 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 Dabco and in an inert organic solvent such as dimethylformamide ((see., Chen, C. et al. J. Org. Chem., 62, 2676-2677 (1997) and Sakamoto, T. et al. Synthesis, 215 (1990)). 0217 A compound of Formula (I) can be converted, if desired, to other compounds of Formula (I). For example, 0218 (i) A 1H-pyrrolo-3,2-bpyridine or a 1H-pyrrolo-3,2-cpyridine of 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 reaction conditions such as halo (preferably chloro). The reaction 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. 0219 (ii) A 1H-pyrrolo3,2-blpyridine or a 1H-pyrrolo-3,2-cpyridine of Formula (I) can be substituted at the 7-position (R37-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 pyrrolo3,2-bpyridine/pyrrolo-3,2-cpyridine ring. Treatment of the 7-lithio species with an electrophile such as alkyl disulfide, iodine, dimethylformamide, carbon dioxide will give a corresponding pyrrolo3,2-bpyridine/pyrrolo3,2-cpyridine of Formula (I) substituted at the 7-position with an iodo, formyl or carboxy group respectively ((see Gharpure, M.; et al. Synthesis, 12, 1079-82 (1991)). 36

0220 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-pyrrolo3,2-bpyridine 12 or 1H-pyrrolo3,2-cpyridine 13 respectively, by proceeding as described in Scheme A above. The condensation reaction is carried out in the presence of a suitable base such as sodium hydride and in an aprotic solvent e.g., tetrahydrofuran or dimethylformamide. 0221 Bromination of 12 or 13 with bromine in dimethylformamide gives the corresponding 3-bromo derivative which upon treatment with boronic acid of formula R2B(OH)2 (where R2 is as defined in the Summary of the Invention) under Suzuki coupling reaction conditions ((see., Miyaura, N. Chem. Commun., 866, (1979)) gives 1H-pyrrolo3,2-bpyridine or 1H-pyrrolo3,2-cpyridine of Formula (I) respectively. 0222 A 1H-pyrrolo3,2-bpyridine or 1H-pyrrolo3,2-cpyridine of Formula (I) where R3, R4 and R6 are hydrogen can be converted to the corresponding 1H-pyrrolo3,2-bpyridine or 1H-pyrrolo3,2-cpyridine of Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above. 37

0223 Reaction of a 4-aminopyridine of formula 14 where PG is an ortho-directing amino protecting group such as tert-butoxycarbonyl, pivaloyl or benzoyl, preferably pivaloyl, with a 10 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 reaction 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 ((see., Sugasawa, T. et al. J. Am. Chem. Soc. 4842-4851 (1978)). 4-Aminopyridine is commercially available. 0224 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 reaction conditions. Suitable acids are inorganic acids such as hydrochloric acid. 0225 Compounds 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. 0226 The 4-amido-3-acylpyridine 19 is converted to the 1H-pyrrolo3,2-cpyridine of Formula (I) (R4 is hydrogen) by following the procedure described in Furstner, A et al., J. Org. Chem., 59, 5215-5229, (1994). 0227 A compound of Formula (I) where R4 is hydrogen can be converted to other compounds of Formula (I) where R4 is not hydrogen as described in Scheme A above. 38

0228 Reaction of a ketone of formula 4 with a 2-chloro-3-nitropyridine 20 or a 3-chloro-4-nitropyridine 21 under nucleophilic substitution reaction conditions gives an -(3-nitro-2-pyridyl)ketone of formula 22 or -(4-nitro-3-pyridyl)ketone of formula 23 respectively. The reaction 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. 0229 Compounds 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. Compounds 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. 0230 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-1H-pyrrolo3,2-bpyridine or 1-hydroxy-1H-pyrrolo3,2-cpyridine (I) (R5H), respectively. The triflate reaction is carried out by reaction 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 reaction 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 reaction conditions. 0231 Alternatively, the 1-hydroxy-1H-pyrrolo3,2-bpyridine and 1-hydroxy-1H-pyrrolo3,2-cpyridine (I) can be prepared directly from 22 and 23 respectively, under the same ring cyclization reaction conditions without proceeding through the triflate intermediate. 0232 A compound of Formula (I) where R5 is hydrogen can be converted its corresponding compounds of Formula (I) where R5 is other than hydrogen by reacting it with an alkylating agent R5Y, as described in Scheme A above. 39

0233 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 reaction conditions gives a 2-ketopyridine of formula 29. The reaction 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. 0234 Removal of the O-protecting group in 29 gives a 2-keto-3-hydroxypyridine of formula 30. The reaction 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 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). 0235 Reaction 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-carboxyfuro3,2-bpyridine of formula 32 gives furo3,2-bpyridine of formula 33 ((see., Shiotani, S., and Moriata, H. J. Heterocyclic Chem., 23, 665 (1986)) 0236 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 R1X (where X is chloro, bromo or iodo) then provides furo3,2-bpyridine of Formula (I). The reaction 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. 0237 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 furo3,2-cpyridine of Formula (I). 40

0238 Reaction 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 reaction 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 ((see., 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)). 0239 Nucleophilic substitution of the fluoro group in 36 by a thiol reagent of formula 37 gives a compound of formula 38. The reaction 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). 0240 Cyclization of 38 to thieno3,2-bpyridine 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. 0241 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 thieno3,2-cpyridine of Formula (I) by proceeding as described in Scheme F above. 41

0242 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 reaction 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-pyrrolo3,2-cpyridazine of Formula (I) by proceeding as described in Scheme A above. 0243 Compounds 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 reaction conditions described in Yakugaku Zasshi, 85, 344 (1965). 0244 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 Klinge, D. E., Recueil des travaus chimiques des Pays-Bas, 93(8), 236-239, (1974). 42

0245 Condensation of a compound of formula 4 with hydrazine gives a hydrazone of formula 41. The reaction 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. Reaction of 41 with a pyrimidine of formula 42 provides a compound of formula 43 which is then converted to 5H-pyrrolo3,2-dpyrimidine of Formula (I) by heating 43 in high boiling solvent such as diethylene glycol. 0246 A 5H-pyrrolo-3,2-dpyrimidine of Formula (I) where R3, R4 and R6 are hydrogen can be converted to the corresponding 5H-pyrrolo3,2-dpyrimidine of Formula (I) where R3, R4 and R6 are other than hydrogen, if desired, by following the procedures described in Scheme A above. 43

0247 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 ((see, J. C. S. Perkin I, 1361-1363, (1976)). Suitable solvents for the reaction are aromatic hydrocarbons such as toluene. Compounds 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 ((see., Euro. J. Med. Chem., 24(3), 249-57 (1989) and J. Heterocyclic Chem., 11, 697-701, (1974)). 0248 Conversion of 46 to a 5H-pyrrolo2,3-bpyrazine of Formula (I) where R4 is hydrogen is achieved by heating 46 in high boiling solvent such as diethylene glycol. For other suitable cyclization reaction conditions see R. J. Sundberg, Indoles, Academic Press, San Diego, Calif., 1996, p 55. 0249 A compound of Formula (I) where R4 is hydrogen can be converted to other compounds of Formula (I) where R4 is not hydrogen as described in Scheme A above. 44

0250 Reaction 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 R2ZnX under the reaction 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). 0251 Nucleophilic substitution of the halo group in 48 by ethyl glycolate or a thiol reagent of formula R1CH2SH gives a compound of formula 49 or 50 respectively. The reaction 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 furo2,3-bpyrazine or a thieno2,3-bpyrazine of Formula (I) respectively, by proceeding as described in Scheme E or F above. 0252 Substituting 2-chloro-3-pyrazinecarbonyl chloride 47 with 5-chloro-4-pyrimidinecarbonyl chloride (see., U.S. Pat. No. 4,110,450) and following the procedures described above gives furo3,2-dpyrimidine or a thieno3,2-dpyrimidine of Formula (I), respectively. 45

0253 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 reaction are aromatic hydrocarbons such as toluene. 0254 Compounds 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-hydrazinopyridine can be prepared by heating 2,3-chloropyridine with hydrazine under conditions well known in the art ((see., Euro. J. Med. Chem., 24(3), 249-57 (1989)). Compounds of formula 52 such as 2-, 3-, 4-acetylpyridine, 2-acetylpyrazine are commercially available. 0255 Conversion of 53 to a 1H-pyrrolo2,3-bpyridine of formula 54 is achieved by heating 53 in high boiling solvent such as diethylene glycol. For other suitable cyclization reaction conditions see., R. J. Sundberg, Indoles, Academic Press, San Diego, Calif., 1996, p 55. 0256 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 R2 is as defined in the Summary of the Invention and X is a halo group) under the reaction 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). 0257 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, Calif., 1996, p 105-118. 0258 Substituting 2-hydrazinopyridine 51 with 4-hydrazinopyrimidine, 3-hydrazinopyridazine or 2-hydrazinopyrazine and following the procedure described above gives 7H-pyrrolo2,3-dpyrimidine, 7H-pyrrolo2,3-cpyridazine or 5H-pyrrolo2,3-bpyrazine respectively. 0259 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. 46

0260 Reaction 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 reaction 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). Compounds of formula 56 such as aniline, 4-fluoroaniline, 4-methylaniline are commercially available. 0261 Coupling of 57 with an alkyne of formula 58 gives 3-alkynyl-2-aminopyridine of formula 59 which is then cyclized to 1H-pyrrolo2,3-bpyridine of formula (). The alkynyl coupling reaction is carried under the reaction conditions such as those described in de Souza, P. T., Quim. Nova, 19(4), 377 (1996). The cyclization reaction is carried out in the presence of a palladium (II) catalyst and in an inert organic solvent such as acetonitrile or tetrahydrofuran ((see., Iritani, K. et al. Tet. Lett., 29(15), 1799 (1988)). 0262 Compounds of formula 58 such as 2-ethynylpyridine, 4-ethynylpyridine can be prepared by the procedure described in Yashima, E. et al., Japan Chirality, 9(5/6), 593-600 (1997). 47

0263 Reaction 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 R1COX (where R 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 pyrrolo2,3-cpyridine of formula 63. Conversion of 60 to 63 is carried out under the reaction 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 0264 Compounds 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: 0265 (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 reaction 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. 0266 (ii) Compounds of Formula (I) where R 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). 0267 (iii) Compounds of Formula (I) where R6 is cyano can be prepared by reacting the corresponding compound of Formula (I) where R6 is 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). 0268 (iv) Compounds of Formula (I) where R6 is alkyl can be prepared by reacting the corresponding compound of Formula (I) where R6 is chloro or bromo with alkyllithium or an alkyltin reagent in the presence of a palladium catalyst. 0269 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). 0270 Preparation of 7-(4-fluorophenyl)-6-2-(3-hydroxypropylamino)pyridin-4-yl-5H-pyrrolo2,3-bpyrazine from 7-(4-fluorophenyl)-642-bromopyridin-4-yl-5H-pyrrolo2,3-bpyrazine is described in Example 12.

UTILITY, TESTING, AND ADMINISTRATION

Utility 0271 The compounds of Formula (I) are p38 MAP kinase and JNK inhibitors and therefore compounds 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 colitis, pyresis, Alzheimer's and Parkinson's diseases.

Testing 0272 The ability of the compounds of Formula (I) to inhibit p38 MAP kinase was demonstrated by the in vitro assay described in Example 20. The ability of the compounds of Formula (I) to inhibit the release of TNF was demonstrated by the in vitro and the in vivo assays described in detail in Examples 21 and 22, respectively.

Administration and Pharmaceutical Compositions 0273 In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted 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 numerous 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. 0274 Therapeutically effective amounts of compounds 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. 0275 In general, compounds 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 tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions. 0276 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 tablets, 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 supported 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 dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability. 0277 The compositions are comprised 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. 0278 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. 0279 Compressed 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. 0280 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). 0281 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.

EXAMPLES 0282 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-pyrrolo3,2-bpyridine (following Scheme A) 0283

0284 Step 1 0285 Sodium metal (5.06 g, 210 mmol) was dissolved in absolute ethanol (150 ml) and then a solution of methyl isonicotinate (20.55 g, 150 mmol) and 4-fluorophenylacetonitrile (20.25 g, 150 mmol) in absolute ethanol (50 ml) was added in one portion. The reaction mixture was heated at reflux for 3 h and then cooled to room temperature. The reaction mixture was poured into ice water (300 ml) and the pH was adjusted to pH3 with 10% hydrochloric acid. The yellow precipitate was filtered and dried in vacuo to give 24 g of cyano ketone. This material was suspended in 48% hydrobromic acid (90 ml) and heated at reflux. After 8 h, the reaction mixture was cooled to room temperature and carefully poured into ice water (300 ml). The pH was adjusted to pH7-8 with ammonium hydroxide. The product was extracted into ethyl acetate and the combined 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. 0286 Step 2 0287 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 reaction 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 collected by vacuum filtration to give (2-chloropyridin-3-yl)-2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinylamine (5.0 g) as a tan solid. The filtrate was concentrated in vacuo and purified by flash column chromatography (50%-80% ethyl acetate:hexanes gradient) to give additional 1.50 g of product. 0288 Step 3 0289 To a solution of (2-chloropyridin-3-yl)-2-(4-fluorophenyl)-1-(pyridin-4-yl)-vinylamine (6.0 g, 18.5 immol) and DABCCO (6.2 g, 55 mmol) in dimethylformamide (75 ml) was added bis(triphenylphosphine)palladium(II) chloride (650 mg, 0.926 mmol) and the reaction mixture was heated at 120 C. under an argon atmosphere. After 4 h, 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-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine as a pale yellow solid (5.27 g).

Example 2

Synthesis of 1-Ethyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (following Scheme A) 0290

0291 To a solution of 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (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 l, 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 MgSO4 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-pyrrolo3,2-bpyridine as a white solid.

Example 3

Synthesis of 3-(4-Fluorophenyl)-2-(pyridin-4-yl)-1H-pyrrolo3,2-cpyridine (following Scheme C) 0292

0293 Step 1 0294 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 reaction mixture was stirred at 0 C. for 5 h, 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 reaction 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 purified by flash chromatography (10% ethyl acetate/ hexanes gradient) to afford N-3-(4-fluorobenzoyl)-pyridin-4-yl-2,2-dimethylpropanamide (10 g). 0295 Step 2 0296 A solution of N-3-(4-fluorobenzoyl)pyridin-4-yl-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 reaction 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 purified by flash chromatography (5% methanol/methylene chloride gradient) to afford 4-amino-3-(4-fluorobenzoyl)pyridine (1.58 g). 0297 Step 3 0298 4-amino-3-(4-fluorobenzoyl)pyridine (1.5 g, 7.0 mmol) was suspended in methylene chloride (90 ml) and pyridine (2.24, 28 mmol). The reaction mixture was cooled to 0 C. and isonicotinoyl chloride (1.4 g, 7.6 mmol) was added. The reaction 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). 0299 Step 4 0300 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 nmnol) and pyridine (0.62 ml, 8.0 mmol) in ethylene glycol dimethyl ether (50 ml) was refluxed for 1 h. The reaction mixture was cooled to room temperature, diluted with ethyl acetate and a solution of 5% sodium bicarbonate was added. The reaction 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) 1H-pyrrolo3,2-cpyridine as a solid (30 mg).

Example 4

Synthesis of 3-(4-Fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (following Scheme D) 0301

0302 Step 1 0303 To a solution of 2-(4-fluorophenyl)-1-(pyridin-4-yl)ethanone (4.0 g, 18.6 mmol) prepared as described in Example 1 above and 2-chloro-3-nitropyridine (6.50 g, 41.13 mmol) in dimethylformamide (50 ml) at 0 C. was added sodium hydride (1.65 g, 41 mmol, 60% in oil) under an argon atmosphere. The reaction mixture was warmed to room temperature and stirred for an hour. The reaction mixture was quenched with water and the product was extracted into ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4 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)-1-(pyridin-4-yl)ethanone as a brown oil (4.08 g). 0304 Step 2 0305 A solution of gave 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(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 C. After 1 h, the reaction mixture was poured into water (50 ml) and the product was extracted into dichloromethane. The combined organic extracts were washed with saturated sodium bicarbonate solution and brine and dried over MgSO4. Concentration in vacuo gave a brown oil which was purified by flash column chromatography (50%-60% ethyl acetate/ hexanes gradient) to give the trifluoromethanesulfonic acid 2-(4-fluorophenyl)-2-(3-nitropyridin-2-yl)-1-(pyridin-4-yl)vinyl ester as a light tan oil (1.56 g). 0306 Step 3 0307 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 reaction 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 (CH2Cl2-95% CH2Cl2/MeOH gradient) gave 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine as a tan solid (700 mg).

Example 5

Synthesis of 3-(4-Fluorophenyl)-1-methoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (following Scheme D) 0308

0309 A solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4yl)-1H-pyrrolo3,2-bpyridine (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 reaction was warmed to room temperature and stirred -overnight. The solvent was removed in vacuo and the residue was purified by flash column chromatography (50%-100% ethyl acetate/ hexanes gradient) to 3-(4-fluorophenyl)-1-methoxy-2-(pyridin-4-yl)1H-pyrrolo3,2-bpyridine 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-pyrrolo3,2-bpyridine (following Scheme D) 0310

0311 To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-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 reaction mixture was stirred overnight and quenched with 10% HCl (2 ml). The pH was adjusted to pH8-9 by the addition of saturated sodium bicarbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified 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-yl)ethoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (180 mg) which recrystallized from hexanes/ethyl acetate to give a white solid.

Example 7

Synthesis of 3-(4-Fluorophenyl)-1-2-(piperidin-1-yl)ethoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (following Scheme D) 0312

0313 To a solution of 3-(4-fluorophenyl)-1-hydroxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine (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 reaction mixture was stirred overnight and quenched with water (2 ml). The pH was adjusted to pH11-12 by the addition of saturated sodium carbonate solution and the product was extracted into ethyl acetate. The combined extracts were dried over anhydrous MgSO4 and concentrated in vacuo to give an oil. Purified by flash column chromatography (50%-80% ethyl acetate/hexanes, followed by 95/5% methylene chloride/methanol gradient) gave 3-(4-fluorophenyl)-1-2-(piperidin-1-yl)ethoxy-2-(pyridin-4-yl)-1H-pyrrolo3,2-bpyridine as a yellow solid (182 mg). 0314 Proceeding as described above but substituting 2-chloroethylpiperidine hydrochloride with 2-chloroethylpyrrolidine hydrochloride gave 3-(4-fluorophenyl)-2-(pyridin-4-yl)-1-2-(pyrrolidin-1-yl)ethoxy-1H-pyrrolo3,2-bpyridine.

Example 8

Synthesis of 7-(4-Fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine (following Scheme I) 0315

0316 Step 1 0317 To a solution of chloropyrazine (11.5 g, 0.1 mmol) in absolute ethanol (50 ml) was added anhydrous hydrazine (16 ml, 0.5 mmol) and the reaction 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). 0318 Step 2 0319 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 reaction mixture was refluxed with azeotropic removal of water. After 2.5 h, the reaction mixture was concentrated in vacuo to give pyrazinylhydrazone (8.8 g) which was used in the next step without further purification. 0320 Step 3 0321 The pyrazinylhydrazone (8.8 g) was suspended in diethylene glycol (75 ml) and the reaction mixture was heated at reflux. After 1.5 h, the reaction 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-pyrrolo2,3-bpyrazine as a solid (1.1 g).

Example 9

Synthesis of 1-(3-Chloropropyl)-7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine 0322

0323 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-pyrrolo2,3-bpyrazine (0.75 g, 2.58 mmol) followed by I-bromo-3-chloropropane (4.05 g, 25.8 mmol). The reaction 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 purified by flash chromatography on silica gel, elating with ethyl acetate, to give 1-(3-chloropropyl)-7-(4-fluorophenyl)-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazineas a solid (0.375 g).

Example 10

Synthesis of 7-(4-Fluorophenyl)-1-3-(4-methyimidazol-1-yl)propyl-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine 0324

0325 To a solution of 1-(3-chloropropyl)-3-(4-fluorophenyl)-2-(pyrindin-4-yl)-5H-pyrrolo2,3-bpyrazine (0.050 g, 0.14 mmol) in dimethylformamide was added 4-methylimidazole (0.046 g, 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 purified by reverse phase chromatography to yield pure 3-(4-fluorophenyD-1-3-(4-methyimidazol-1-yl)propyl-6-(pyridin-4-yl)-5H-pyrrolo2,3-bpyrazine(0.039 g).

Example 11

Synthesis of 6-(2-Bromopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine 0326

0327 Step 1 0328 2-Chloropyridine-4-carboxylic acid (15.5 g, 98 mmol) was suspended in methanol (175 ml) and anhydrous hydrogen chloride gas was slowly bubbled through the reaction 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 reaction 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 neutral. 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. 0329 Step 2 0330 4-Fluorophenylacetonitrile (11.13 g, 82 mmol) was dissolved in absolute ethanol (100 ml) and sodium ethoxide (21 wt % 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 absolute ethanol (100 ml) was then added to the reaction over 3-5 min. The reaction mixture was then refluxed for 2 h during which time the color turned to dark brown. The reaction mixture was concentrated in vacuo and water (100 ml) was added to the resulting residue. The pH of the reaction mixture was adjusted to 3 using 10% hydrochloric acid. The product was extracted with ethyl acetate and the combined 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). 0331 Step 3 0332 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 reaction mixture was heated at reflux in an oil bath at 135 C. After 4 h, the reaction 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 reaction mixture was neutral. The reaction 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 purified 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). 0333 Step 4 0334 Hydrazinopyrazine (0.71 g, 6.4 mmol) and 1-(2-bromopyridin4-yl)-2-(4-fluorophenyl) ethanone (1.9 g, 6.4 mrmol) were suspended in benzene (30 ml) and p-toluenesulfonic acid monohydrate (0.02 g) was added. The reaction mixture was then refluxed with azeotropic removal of water via Dean Stark trap. The benzene was then removed in vacuo to give the crude N-1-(3-bromopyridin-4-yl)-2-(4-fluorophenyl)ethylidene-N-pyrazin-2-ylhydrazineas a yellow semi-solid which was used without further purification (2.4 g). 0335 Step 5 0336 N-1-(3-Bromopyridin-4-yl)-2-(4-fluorophenyl)ethylidene-N-pyrazin-2-ylhydrazine(2.4 g, 6.2 mmol) was suspended in di(ethylene glycol) (30 ml) and heated in an oil bath at 250 C. After 1 h, the reaction mixture was allowed to cool and then poured into a separatory funnel containing water (50 ml). The reaction mixture was then extracted with diethyl ether. The ether extracts were combined, 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-pyrrolo2,3-bpyrazine as a tan solid (0.650 g). 0337 Example 12

Synthesis of the 7-(4-Fluorophenyl)-6-2-(3-hydroxypropylamino)pyridin-4-yl-5H-pyrrolo2,3-bpyrazine hydrochloride salt 0338

0339 Step 1 0340 6-(2-Bromopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine(0.05 g, 0.135 mmol) was dissolved in 3-amino-1-propanol (0.5 ml, 6.5 mmol) and the reaction mixture was heated in a sealed vial at 110 C. After 20 h, the reaction mixture was purified by reverse phase chromatography to yield the 7-(4-fluorophenyl)-6-2-(3-hydroxypropylamino)pyridin-4-yl-5H-pyrrolo2,3-bpyrazine trifluoroacetate salt as a yellow oil (0.018 g). 0341 Step 2 0342 7-(4-Fluorophenyl)-6-2-(3-hydroxypropylamino)pyridin-4-yl-5H-pyrrolo-5 2,3-bpyrazine 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 nitrogen gas and the resulting yellow solid was dried in vacuo to 7-(4-fluorophenyl)-6-2-(3-hydroxypropylamino)pyridin-4-yl -5H-pyrrolo2,3-bpyrazine hydrochloride salt (0.019 g).

Example 13

Synthesis of the 3-(4-Fluorophenyl)-2-(pyridin-4-yl)-furo3,2-bpyridine (following Scheme E) 0343

0344 Step 1 0345 3-Hydroxypicolinic acid (12.5 g, 900 mmol) was suspended in a mixture of ethanol (300 ml) and benzene (100 ml). Sulfuric acid (5 ml) was added and the reaction mixture was heated at reflux with azeotropic removal of water via Dean Stark trap. After the reaction was complete, the organics were removed in vacuo. The residue was dissolved 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). 0346 Step 2 0347 A mixture of ethyl 3-hydroxypicolinate (15 g, 900 mmol), tributylsilyl chloride (16.23 g, 110 mnmol), 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). 0348 Step 3 0349 A solution of ethyl 3-(tributylsilyloxy)picolinate (19 g, 35 mmol) in tetrahydrofuran (100 ml) was cooled to 0 C. and 4-fluorophenylmagnesium chloride (52 ml, 1.0 M in tetrahydrofuran) was added dropwise. After 30 min., the reaction mixture was quenched with water and the product was extracted with ethyl acetate. The organic layer 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). 0350 Step 4 0351 A solution of 2-(4-fluorobenzoyl)-3-(tributylsilyloxy)pyrdine (3.75 g, 11.3 mmol) in tetrahydrofuran (17 ml) was cooled to 0 C. and tetrabutylammonium fluoride (17 ml, 1.0 M in tetrahydrofuran) was added. After 2 h, the reaction 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 purified on a silica gel column using ethyl acetate-hexane (2:8) as the eluant to give 2-(4-fluorobenzoyl)-3-hydroxypyridine (2.2 g). 0352 Step 5 0353 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-yloxyacetate (3.5 g) which was used in the next step without further purification. 0354 Step 6 0355 Sodium ethoxide (1.51 g. 22.6 mmol) was suspended in toluene (25 ml) and ethyl 2-2-(4-fluorobenzoyl)pyridin-3-yloxyacetate (3.5 g, 11.5 mmol) was added. The reaction was heated at reflux under an argon atmosphere. After 12 h, the reaction mixture was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid to give 2-carboxy-3-(4-fluorophenyl)-furc3,2-bpyridine as a solid (1.8 g). 0356 Step 7 0357 A mixture of 2-carboxy-3-(4-fluorophenyl)-furo3,2-bpyridine (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 reaction was cooled to room temperature and the product was extracted into water. The aqueous layer was acidified with hydrochloric acid and acetic acid. The product was filtered and dissolved 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)-furo3,2-bpyridine as a solid (0.85 g). 0358 Step 8 0359 A solution of 3-(4-fluorophenyl)-furo3,2-bpyridine (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 reaction mixture was allowed to warm to room temperature. After 1.5 h, the reaction mixture was re-cooled to 78 C. and n-tributyltin chloride (0.5 ml, 1.84 mmol) was added. The reaction 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)-furo3,2-bpyridine (0.72 g). 0360 Step 9 0361 A mixture of 3-(4-fluorophenyl)-2-(n-tributyltin)-furo3,2-bpyridine (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 reaction mixture was cooled to room temperature and purified by flash chromatography using hexanes, followed by ethyl acetate-hexanes (5: 95) as the eluant to give 3-(4-fluorophenyl)-2-(pyridin-4-yl)-furo-3,2-bpyridine. Recrystallized 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)-pyrrolo3,2-bpyridine 0362

0363 Step 1 0364 2,2,6,6-Tetramethylpiperidine (1.76 ml, 10.40 mmol) was dissolved in tetrahydrofuran (39 ml) and placed under an atmosphere of nitrogen. The solution was cooled to 78 C. 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 reaction mixture was warmed to 10 C. for 30 min., then re-cooled to 78 C. A solution of 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-2-(pyridin-4-yl)-pyrrolo3,2-bpyridine (0.965 g, 2.47 mmol) in tetrahydrofuran (32 ml) was cooled to 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 reaction 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 purified by flash chromatography using 20% acetone/hexanes as the eluant to give 1-tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo3,2-bpyridine. MS: 435 (M). 0365 Step 2 0366 1-Tert-butoxycarbonyl-3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo3,2-bpyridine (29 mg, 0.064 mmol was dissolved 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 over anhydrous magnesium sulfate, and concentrated in vacuo to give 3-(4-fluorophenyl)-7-methylthio-2-(pyridin-4-yl)-pyrrolo3,2-bpyridine.

Example 15

Synthesis of the 2-(2-Chloropyrimidin-4-yl)-3-(4-fluorophenyl)-furo3,2-bpyridine (following Scheme E) 0367

0368 A mixture of 3-(4-fluorophenyl)-2-(n-tributyltin)-furo3,2-bpyridine (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 reaction 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 purified by flash chromatography using 80% ethyl acetate-hexanes as the eluant to give 2-(2-chloropyrimidin-4-yl)-3-(4-fluorophenyl)-furo3,2-bpyridine.

Example 16

Synthesis of the 2-(2-Aminopyrimidin-4-yl)3-(4-fluorophenyl)-furo3,2-bpyridine (following Scheme E) 0369

0370 2-(2-Chloropyrimidin-4-yl)-3-(4-fluorophenyl)-furo3,2-bpyridine (0.15 g) was dissolved in ethanol (10 ml) and ammonia was bubbled through the solution until it was saturated. The reaction mixture was heated in a sealed tube at 100 C. After 12 h, the solvent was removed in vacuo and the residue was purified by flash chromatography using 50% ethyl acetate-hexanes as the eluant to give 2-(2-aminopyrimidin-4-yl)-3-(4-fluorophenyl)-furo3,2-bpyridine (0.70 g) as a solid.

Example 17

Synthesis of 1-(4-Fluorophenyl)-4-methyl-2-(pyridin-4-yl)-1H-pyrrolo2,3-bpyridine 0371

0372 Step 1 0373 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 reaction mixture was refluxed under argon atmosphere. After 4 days, the reaction mixture was cooled to room temperature and the organics were removed in vacuo. The residue was purified by flash chromatography using 50% ethyl acetate-hexanes, followed by ethyl acetate as the eluant to (3-bromo-5-methylpyridin-2-yl)-(1-pyridin-4-ylethylidene)amine (4.29 g) as an oil. 0374 Step 2 0375 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) and, bis-dichlorotriphenylphosphine palladium (0.52 g, 0.73 mmol). The reaction mixture was heated at 120 C. under argon atmosphere. After 1.5 days, the reaction mixture was cooled into room temperature and poured into 10% hydrochloric acid (100 ml). The solution was filtered through Celite 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)-1H-pyrrolo2,3-bpyridine (1.57 g) as a brown solid. 0376 Step 3 0377 To a solution of 4-methyl-2-(pyridin-4-yl)-1H-pyrrolo2,3-bpyridine (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 reaction mixture was heated to 180 C. under argon. After 24 h, the reaction mixture was cooled and poured into 10% hydrochloric acid (50 ml). The solution was filtered through Celite and the filtrate was neutralized to pH 7 with 10% sodium hydroxide. The solid was filtered off, dissolved in 80% methanol:methylene chloride and purified by preparatory thin layer chromatography to give 1-(4-fluorophenyl)-4-methyl-2-(pyridin-4-yl)-1H-pyrrolo2,3-bpyridine (0.03 g) as a tan solid.

Example 18

Synthesis of the 6-2-(Acetylamino)pyridin-4-yl-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine hydrochloride salt 0378

0379 Step 1 0380 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 reaction. Once the reaction 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 reaction was stirred for 1 h and was used in the next step. 0381 Step 2 0382 Sodium hydride (8.6 g, 220 mmol, 60% dispersion in mineral oil) was washed twice with hexane (50 ml) and suspended 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 reaction was cooled in an ice-bath and 4-fluorobenzylmagnesium chloride (100 ml, 200 mmol) was added. After stirring overnight, the reaction 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 purified by flash chromatography using 25% ethyl acetate-hexanes as the eluant to 1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethanone (14 g). 0383 Step 3 0384 Hydrazinopyrazine (6.2 g, 57 mmol) and 1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethanone (14 g, 57 mmol) were suspended in benzene (250 ml) and p-toluenesulfonic acid monohydrate (0.68 g) was added. The reaction 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 reaction mixture was heated at reflux. After 2 h, the reaction 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-pyrrolo2,3-bpyrazine (4.9 g) as a solid. 0385 Step 4 0386 6-(2-Chloropyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine (0.5 g, 1.5 mmol) was dissolved 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 reaction vessel was sealed with O-ring screw cap. The reaction mixture was heated for 72 h in a sand bath at 150 C. The reaction 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 purified by reverse phase HPLC to give 6-(2-aminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine trifluoroacetate salt (0.1 g) as a yellow solid. 0387 Step 5 0388 6-(2-Aminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine trifluoroacetate salt (0.085 g, 0.28 mmol) was dissolved 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 reaction 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-pyrrolo2,3-bpyrazine 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-acetylaminopyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo2,3-bpyrazine hydrochloride salt (0.0.44 g) as a yellow solid.

Example 19 0389 The following are representative pharmaceutical formulations containing a compound of Formula (I).

Tablet formulation 0390 The following ingredients are mixed intimately and pressed into single scored tablets. 9IngredientQuantity per tablet, mgcompound of this invention400cornstarch50croscarmellose sodium25lactose120magnesium stearate5

Capsule formulation 0391 The following ingredients are mixed intimately and loaded into a hard-shell gelatin capsule. 10IngredientQuantity per capsule, mgcompound of this invention200lactose, spray-dried148magnesium stearate2

Suspension formulation 0392 The following ingredients are mixed to form a suspension for oral administration. 11IngredientAmountcompound of this invention1.0gfumaric acid0.5gsodium chloride2.0gmethyl paraben0.15gpropyl paraben0.05ggranulated sugar25.5gsorbitol (70% solution)12.85gVeegum K (Vanderbilt Co.)1.0gflavoring0.035mlcolorings0.5mgdistilled waterq.s. to 100ml

Injectable formulation 0393 The following ingredients are mixed to form an injectable formulation. 12IngredientAmountcompound of this invention0.2 gsodium acetate buffer solution, 0.4M2.0 mlHCl (1N) or NaOH (1N)q.s. to suitable pHwater (distilled, sterile)q.s. to 20 ml

0394 All of the above ingredients, except water, are combined 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.

Suppository formulation 0395 A suppository of total weight 2.5 g is prepared by mixing the compound of the invention with Witepsol H-15 (triglycerides of saturated vegetable fatty acid; Riches-Nelson, Inc., New York), and has the following composition: 13compound of the invention500 mgWitepsol H-15balance

Example 20

Inhibition Of p-38 (MAP) Kinase . . . In Vitro Assay 0396 The p-38 MAP kinase inhibitory activity of compounds of this invention in vitro was determined by measuring the transfer of the -phosphate from -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). 0397 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 purified by affinity chromatography using a Nickel column. 0398 The phosphorylated p38 MAP kinase was diluted in kinase buffer (20 mM 3-(N-morpholino)propanesulfonic acid, pH 7.2, 25 mM -glycerol phosphate, 5 mM ethylene glycol-bis(beta-aminoethyl ether)-N,N,N,N-tetraacetic acid, 1 mM sodium vanadate, 1 mM dithiothreitol, 40 mM magnesium chloride). Test compound dissolved in DMSO or only DMSO (control) was added and the samples were incubated for 10 min. at 30 C. The kinase reaction was initiated by the addition of a substrate cocktail containing MBP and -33P-ATP. After incubating for an additional 20 min. at 30 C., the reaction was terminated by adding 0.75% phosphoric acid. The phosphorylated MBP was then separated from the residual -33P-ATP using a phosphocellulose membrane (Millipore, Bedfrod, Mass.) and quantitated using a scintillation counter (Packard, Meriden, Conn.). 0399 The p-38 inhibitory activities (expressed as IC50, the concentration causing 50% inhibition of the p-38 enzyme being assayed) of some compounds of the invention is: 14CPD IC50, nMCPD IC50, nM2681061203221108747524611234.410185.5

Example 21

Inhibition of LPS -Induced TNF- Production In THP1 Cells . . . In Vitro Assay 0400 The ability of the compounds of this invention to inhibit the TNF- 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). 0401 (a) Induction of TNF biosynthesis: 0402 THP-1 cells were suspended in culture medium RPMI (Gibco-BRL, Gailthersburg, Md.) containing 15% fetal bovine serum, 0.02 mM 2-mercaptoethanol, at a concentration of 2.5106 cells/ml and then plated in 96 well plate (0.2 ml aliquots in each well). Test compounds were dissolved DMSO and then diluted with the culture medium such that the final DMSO concentration was 5%. 20 l 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 collected and the amount of TNF- present was determined using an ELISA assay as described below. 0403 (b) ELISA Assay: 0404 The amount of human TNF- present was determined by a specific trapping ELISA assay using two anti-TNF- antibodies (2TNF-H22 and 2TNF-H34) described in Reimund, J. M., et al. GUT. Vol. 39(5), 684-689 (1996). 0405 Polystyrene 96-well plates were coated with 50 l per well of antibody 2TNF-H22 in PBS (10 g/ml) and incubated in a humidified 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. 0406 TNF-standards were prepared from a stock solution of human recombinant TNF- (R&D Systems, Minneapolis, Minn.). The concentration of the standards in the assay began at 10 ng/ml followed by 6 half log serial dilution's. 0407 25 l aliquots of the above culture supernatants or TNF standards or only medium (control) were mixed with 25 l aliquots of biotinylated monoclonal antibody 2TNF-H34 (2 g/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 l of peroxidase-streptavidin (Zymed, S. San Francisco, Calif.) solution containing 0.416 g/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 l of O-phenylenediamine solution (1 g/ml O-phenylenediamine and 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- levels were determined from a graph relating the optical density at 450 nm to the concentration used. 0408 The IC50 value was defined as the concentration of the test compound corresponding to half-maximal reduction in 450 nm absorbance. 15CPD IC50, nMCPD IC50, nM20.46106110050.12108883090.3112241

Example 22

Inhibition of LPS-Induced TNF- Production In Mice . . . In Vivo Assay 0409 The ability of the compounds of this invention to inhibit the TNF- 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). 0410 Female BALB/c mice weighing 18-21 grams (Charles River, Hollister, Calif.) were acclimated for one week. Groups containing 8 mice each were dosed orally either with the test compounds dissolved 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 injected intraperitoneally with 20 gg of LPS (Sigma, St. Louis, Mo.). After 1.5 h, the mice were sacrificed by CO2 inhalation and blood was harvested by cardiocentesis. Blood was clarified by centrifugation at 15,600g for 5 min., and sera were transferred to clean tubes and frozen at 20 C. until analyzed for TNF- by ELISA assay (Biosource International, Camarillo, Calif.) following the manufacturer's protocol. 0411 The TNF- inhibitory activity of test materials, i.e., the measure of the TNF- content in the test group relative to the vehicle treated group (control group) at 30 mg was: 16CPD % Inhibition275%356%668%10186

0412 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 appended 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 appended claims, along with the full scope of equivalents to which such claims are entitled. 0413 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.