MXPA01009038A

MXPA01009038A - 4-OXO-4,7-DIHYDRO-THIENO[2,3-b]PYRIDINE-5-CARBOXAMIDES AS ANTIVIRAL AGENTS

Info

Publication number: MXPA01009038A
Application number: MXPA/A/2001/009038A
Authority: MX
Inventors: Mark E Schnute; Michele M Cudahy; Allen Scott
Original assignee: Pharmacia&Ampupjohn Company
Priority date: 1999-03-09
Filing date: 2001-09-07
Publication date: 2002-05-09

Abstract

The invention provides a compound of formula (I), wherein R1, R2, R3, and R4 have any of the values defined in the specification, or a pharmaceutically acceptable salt thereof, as well as processes and intermediates useful for preparing such compounds or salts, and methods of preventing or treating a herpesvirus infection using such compounds or salts.

Description

4-OXO-4, 7-DIHYDRO-TIENO [2, 3-b] PIRIDIN-5-CARBOXAMIDAS AS ANTIVIRAL AGENTS FIELD OF THE INVENTION The present invention provides 4-oxo-4,7-dihydro-thieno [2,3-b] pyridine-5-carboxamide derivatives, more specifically 5-benzylaminocarbonyl-4-oxo-4, 7- derivatives dihydro-thieno [2, 3-b] pyridine of the formula (I), which are useful as antiviral agents (for example, as agents against viruses of the herpes family).

BACKGROUND OF THE INVENTION Herpes viruses comprise a large family of DNA viruses with double chain. They are also a source of most common viral diseases in man. Eight of the herpes viruses, herpes simplex virus types 1 and 2 (HSV-1 and HSV-2), varicella zoster virus (VZV), human cytomegalovirus (HCMV), epstein-Barr virus (EBV) and the viruses of Human herpes 6, 7 and 8 (HHV-6, HHV-7 and HHV-8), have been shown to infect humans. HSV-1 and HSV-2 cause hertpetic lesions on the lips and genitals, respectively. Occasionally they also cause eye infections and encephalitis. HCMV causes birth defects in infants and a variety of diseases in immunocompromised patients such as for example retinitis, pneumonia and gastrointestinal diseases. VZV is the agent that provokes chickenpox and shingles. EBV causes mononucleosis infectious. This can also cause lymphomas in immunocompromised patients and has been associated with Burkitt's lymphoma, nasopharyngeal carcinoma and Hodgkins disease. HHV-ß is the provocative agent of roseola and may be associated with multiple sclerosis and chronic fatigue syndrome. The association of the disease with HHV-7 is not clear, although it may be involved in some cases of roseola. HHV-8 has been associated with Kaposi's sarcoma, lymphomas based on body cavities and multiple myeloma.

EXPOSURE OF THE INFORMATION JP 8301849 discloses a series of compounds that can generically include the compounds of the formula I, wherein R 1 is halo and R 2 is hydrogen. The compounds are reported to be tachykinin inhibitors. No antiviral activity is reported for the compounds. WO 97/40846 discloses a pharmaceutical product comprising an agonist for the LH-releasing hormone and an antagonist for the LH-releasing hormone. Antagonists for the exposed LH-releasing hormone include a series of bicyclic compounds that can generically include iodopir-idines of the formula I. Antagonists for the LH-releasing hormone are not reported to possess any viral activity. EP 443568 discloses fused thiophene derivatives that are reported to have antagonist activity for angiotensin II and an anti-hypertensive activity. JP 9208496 and WO 95/28405 disclose antagonists for thienopyridine LH-RH. WO 92/03427 and JP 7076586 disclose thienopyridine compounds which are reported to be useful as resorption inhibitors for the treatment of osteoporosis. US 4,767,766 discloses thienopyridine compounds that are reported to be useful as inhibitors of 5-1 ipoxygenase.

DE 4227747 discloses thienopyridine compounds that are reported to be useful as herbicides. EP 505058 discloses thienopyridine compounds that are reported to possess immunoregulation and activity to inhibit bone absorption. WO 96/18616 and WO 96/18617 generically disclose a series of 2-acylamino-pyridines which may include 6- (acylamino) thienopyridines. Voelter et al. Z Na t urfors ch. 1997, 419-426 expose the preparation and quiropic properties of seven 2-chloro-7-cyclopropyl-4-oxo-4,7-dihydrothien [2, 3-b] pyridine-5-carboxamides specific. No biological activity is reported for the compounds. Additionally, there have been many reports of 3-carboxy-ienopyridines and thienopyridinones that possess antimicrobial activity against gram-positive or gram-negative bacteria. The corresponding thienopyridine and the thienopyridine esters have been exposed as intermediates for the synthesis of these acids.

BRIEF DESCRIPTION OF THE INVENTION The present invention provides a compound of the formula I: or a pharmaceutically acceptable salt thereof wherein R1 is Cl, Br, CN, N02, or F; R¿ is H, R- NR7RE SO, R, or OR9; RJ is H, halo, aryl, S (0) mR6 (C = 0) R6 (C = 0) OR9, (g) cyano, (h) het, in each carbon atom, (i) OR10, (j) Ohet, (k) NR7R8 (1) SR10, (m) Shet, (n) NHCOR12, (o) NHS02R12, or (P) C? Alkyl? 1-7 which may be partially unsaturated and is optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR7R8, halo, (C = 0) C? _7 alkyl or SOmR9; R 'is (a) H, (b) halo, (c) C? _4 alkyl, or (d) R4 together with R3 form a carbocyclic or het, any of which may be optionally substituted by NR7R8, by alkyl of C? -7 which can be optionally substituted by OR14, or by het, where het is linked by a carbon atom; R- is (a) (CH2CH20) iR 1l0u, (b) het, wherein het is bonded by a carbon atom, (c) aryl, (d) C 1 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR7R8, R11, SOmR9 and C2_4 Oalkyl which may be further substituted by het, OR10 or NR7R8, or (e) C3-g cycloalkyl which may be partially unsaturated and substituted optionally by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9 and C7_7alkyl optionally substituted by R11, NR, 7pR8, or SOmR; R6 is (a) alkyl of C? _7, (b) NR7R8, (c) aryl, or (d) het, wherein het is attached by a carbon atom; R7 and R8 are independently (a) H, (b) aryl, (c) C? -7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR10R10, R11, SOmR9 , CONR10R10 and halo, or, (d) R7 and R8 together with the nitrogen atom to which they are attached form a het; R9 is (a) aryl, (b) het, (c) C3_8 cycloalkyl, or (d) C7_7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR , ?? tR.?o R 1J1 SH, CONR, 1i0? tR, 1J0 and halo; (a) H, or (b) C 1 _ 7 alkyl optionally substituted by OH; R11 is (a) OR10, (b) Ohet, (c) Oaryl, (d) C02R10, (e) het, (f) aryl, or (g) CN; R12 is (a) H, (b) het, (c) aryl, (d) C3_8 cycloalkyl, or (e) C7_7 alkyl optionally substituted by NR7R8 or R11; R13 is (a) (P = 0) (OR14) 2, (b) CO (CH2) nCON (CH3) - (CH2) nS03 ~ M +, (c) an amino acid, (d) C (= 0) aryl, or (e) C (= 0) C? -7 alkyl optionally substituted by NR7R8, aryl, het, C02H, or (a) H, or (b) C? _7 alkyl; each i is independently 2, 3 or 4; each n is independently 1, 2, 3, 4 or 5; each m is independently 0, 1 or 2; M is sodium, potassium or lithium; wherein any aryl is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, C02R14, CF3, alkoxy, C? _6, and C _. 6 alkyl which may be further substituted by one to three SR14, NR14R, OR, het or C02R14; and wherein any het is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, phenyl, C02R14, CF3, C? _6 alkoxy, oxo, oxime, and C? -6 alkyl which is they can additionally be replaced by one to three SR14, NR14R14, OR14 or C02R14. In another aspect, the present invention also provides: a pharmaceutical composition comprising a compound of formula I or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient (the composition preferably comprises an effective antiviral amount of the compound or salt); a method for treating or preventing a herpesviral infection, comprising administering to a mammal (e.g., a human) in need of this treatment, a compound of the formula (I) or a pharmaceutically acceptable salt thereof; a compound of the formula (I) or a pharmaceutically acceptable salt thereof for use in medical treatment (e.g., treatment or prevention of an infection, herpesviral); the use of a compound of the formula (I) or a pharmaceutically acceptable salt thereof for preparing a medicament for treating or preventing a herpesviral infection in a mammal (e.g., a human); and a method for inhibiting a viral DNA polymerase, comprising contacting (i n vi t ro or i n vi ve) the polymerase with an effective inhibitory amount of a compound of the formula I or a pharmaceutically acceptable salt thereof. The invention also provides novel intermediates and processes disclosed herein that are useful for preparing the compounds of formula I. The compounds of formula I have 4-substituted benzylaminocarbonyl unsubstituted substituent in the 5-position of the thieno [2,3-b] pyridine ring system. It has been found that this substitution pattern provides the compounds with significantly improved viral activity compared to the thienopyridines lacking this substitution.

DETAILED DESCRIPTION OF THE INVENTION The following definitions are used, unless otherwise described: halo is fluorine, chlorine, bromine or iodine. Alkyl, alkoxy, etc. denote both straight and branched groups; although the reference to an individual radical such as for example "propyl" embraces only the straight chain radical, a branched chain isomer such as "isopropyl" specifically referred to. When alkyl may be partially unsaturated, the alkyl chain may comprise one or more (eg, 1, 2, 3 or 4) double or triple bonds in the chain. Aryl denotes a phenyl radical or an ortho-fused bicyclic carbocyclic radical having approximately nine to ten ring atoms in which at least one ring is aromatic. Het is a saturated or unsaturated heterocyclic ring of four (4), five (5), six (6) or seven (7) members having 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxy, thio, sulfinyl , sulfonyl and nitrogen, which is optionally fused to a benzene ring or any bicyclic heteocycle group. Het includes "heteroaryl" encompassing a radical linked by a carbon ring of a monocyclic aromatic ring containing five or six ring atoms consisting of carbon and 1, 2, 3 or 4 heteroatoms each selected from the group consisting of oxy, peroxide-free thio and N (X) wherein X is absent or is H, 0, C, C-.alkyl, phenyl or benzyl, as well as a radical of an ortho-fused bicyclic heterocycle of about eight to ten atoms in the ring derived therefrom, in particular a benz-derivate or a derivative by fusing a propylene, trimethylene or a tetramethylene diradical of the same. When R 4 together with R 3 form a carbocyclic, R 4 and R 3 together can be a 3, 4, 5 or 6 membered saturated or unsaturated carbon chain. "Amino Acid" includes a natural amino acid residue (eg, Ala, Arg, Asn, Asp, Cys, Glu, Gln, Gly, His, Hyl, Hyp, Lie, Leu, Lys, Met, Phe, Pro, Ser, Thr, Trp, Tyr and Val) in the D or L form, as well as non-natural amino acids (for example, phosphoserine, fos fot reonin, fos fot iros ina, hydroxyproline, gamma-carboxiglut amato, hipuric acid, oct ahydroindol acid - 2-carboxy 1, statin, acid 1, 2, 3, 4, - tet rahidroisoquinolin-3-carboxylic acid, penicillamine, ornithine, citrulline, oc-met il-alanine, para-benzoi 1 phenylalanine, phenylglycine, propargi glycine , sarcosine and ter-but ilglycine). Conveniently, an amino acid can be attached to the remainder of a compound of formula I through the carboxy terminus, the amino terminus or through any other convenient point of attachment, such as, for example, through the sulfur of cysteine. In particular, an amino acid may be conveniently linked to the remainder of a compound of formula I through the carboxy terminus. It will be appreciated by those skilled in the art that the compounds of the invention, which have a chiral center, can exist in optically active and racemic forms and can be isolated therefrom. Some compounds may exhibit polymorphism. It should be understood that the present invention encompasses any racemic, optically-active, polymorphic, tautomeric, or stereoisomeric or mixture thereof form of a compound of the invention, which possesses the useful properties described herein, is well known in the art how to prepare the optically active forms (for example, by resolution of the racemic form by recrystallization techniques, by synthesis of the optically-active starting materials, by chiral synthesis or by chromatographic separation using a chiral stationary phase) and how to determine viral activity using the standard tests described herein or using other similar tests that are well known in the art. In particular, it should be understood that the compounds of the formula I, wherein R2 is hydrogen, can exist in the corresponding tautomeric "enol" form and that these tautomers are included as compounds of the invention. The content of carbon atoms of various hydrocarbon-containing entities is indicated by a prefix designating the minimum and maximum number of carbon atoms in the entity, ie, the prefix Cj indicates an entity of the integer "i" to the whole number "j" of carbon atoms, inclusive.

Thus, for example, C?-7 alkyl refers to alkyl of one to seven carbon atoms, inclusive. The compounds of the present invention are generally referred to in accordance with the IUPAC or CAS nomenclature system. Abbreviations that are well known to one of ordinary skill in the art can be used (eg, "Ph" for phenyl, "Me" for methyl, "Et" for ethyl "," h "for hour or hours and" rt "for room temperature,).

The specific and preferred values listed below for the radicals, substituents, and variations are for illustration only; they do not exclude other values defined within the variations defined for the radicals and substituents. The compounds of the invention include the compounds of the formula I having any combination of values, specific values, more specific values and preferred values described herein. Specifically, C?-Alkyl can be methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, pentyl, 3-pentyl, hexyl or heptyl; C3-s cycloalkyl may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or cyclooctyl; C.sub.7 alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, 1-methexyhexyloxy or heptyloxy; C (= 0) C? -7 alkyl can be acetyl, propanoyl, butanoyl, pentanoyl, 4-met ilpent anoyl, hexanoyl or heptanoyl; aryl can be phenyl, indenyl or naphthyl; het can be pyrrolidinyl, piperidinyl, morpholinyl, thiomorpholinyl or heteroaryl; and heteroaryl can be furyl, imidazolyl, triazolyl, triazinyl, oxazoyl, isoxazoyl, thiazolyl, isothiazolyl, pyrazolyl, pyrrolyl, pyrazinyl, tetrazolyl, pyridyl, (or its N-oxide), thienyl, pyrimidinyl (or its N-oxide), indolyl , isoquinolyl (or its N-oxide) or quinolyl (or its N-oxide). When alkyl of C? _7 is partially unsaturated, it can specifically be vinyl, allyl, 1-propenyl, 2-propenyl, 1-butenyl, 2-butenyl, 3-butenyl, 1, 3-butadienyl, 1-pentenyl, 2-pentenyl , 3-pentenyl, 4-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, 4-hexenyl, 5-hexenyl, ethynyl, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl , 1-pentynyl, 2-pentynyl, 3-pentynyl, 4-pentynyl, 5-hexen-1-ynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl or 5-hexynyl. A specific value for Het is a saturated or unsaturated ring of five (5), six (6) or seven (7) members containing 1, 2, 3 or 4 heteroatoms selected from the group consisting of oxy thio, sulfinyl, sulfonyl, and nitrogen, without peroxide; as well as a radical of an ionado bicyclic heterocycle ortofus of about eight to twelve ring atoms derived therefrom, particularly benz-derivative or one derived by fusing a propylene, trimethylene, tetramethylene or another diradical monocyclic het thereof. A specific value for R1 is F, Cl or Br. A more specific value for R1 is Cl. A specific value for R2 is H. A specific value for R2 is R5, NR7R8, S02R9 or 0R- A specific value for R is R "A more specific value for R is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, carboxymethyl, (C 1 7 alkoxy) carbonyl 1-methyl, 2-hydroxyethyl, 2- (2-methoxyethoxy) ethyl, 3 - (2-tetrahydropyranyloxy) propyl, 2 -morfolinoet yl, 2- (diet ylamino) ethyl, 2 - (dimeth ylamino) et i I, 2-piperidinoet yl, 3-piperidinopropyl, 2- (l-methylpyrrolidin-2-yl ) ethyl, 2 (diisopropylamino) ethyl, 2-pyrrolidin-l-yl-ethyl, 3- (dimethylamino) propyl, benzyl, 3-f luorobencilo, 3-phenylpropyl, 2-tetrahidrofuranilmet yl, 2-pirrolidinoet yl, 3-piridilmet yl or vinyl. A more specific value for R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, 2- (diethylamino) ethyl or 2- (dimethylamino) ethyl. A specific value for R3 is H, halo, S (0) mR < (C = 0) R *; C = 0) OR cyano C alquilo _7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents of the R 11 group, OR13, SR10, SR13, NR7R8, halo, (C = 0) C? - alkyl? , and SOmR9. A specific value for R3 is Ci- alkyl, which may be partially unsaturated and is optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR7R8, halo, (C = 0) C1-7 alkyl, and SOmR9. A specific value for R3 is C7_7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR R8, halo, (C = 0) C1-7 alkyl , and SOmR9. A specific value for R3 is C alquilo _ alkyl which may be partially unsaturated and is replaced by one or more substituents of the group OR10, het and NR7R8. A specific value for R3 is (Z or E) -CH = CH (CH2) nRa or -C = C (CH2) nRa where Ra is R11, OR13, SR10, SR13, NR7R8, halo, (C = 0) alkyl of C1-7 or SOmR9. A more specific value for R3 is bromine, iodine, 3-hydroxy-1-propynyl, 3-methoxy-1-propyne, 4-hydroxy-1-butyl, 3-hydroxypropyl, cyano, 4, 4-di ( methoxycarbonyl) -1-butyl inyl, 4-hydroxybutyl, 3- (3-carboxypropanoyloxy) -ltpropynyl, 3- (morpholinoacetoxy) -l-propynyl, 3- (2-amino-3 -methylbutanoi loxi) -1-propinyl ot iomor folinomet ilo, N [2- (4-hydroxyphenyl) -2-hydroxyethyl] -N- (methyl) aminomethyl, morpholinocarbonyl, 3- [3- (mor fol inome ti 1) benzoyloxy] -1- propinyl. A more specific value for R3 is iodine, 3-hydroxy-1-propynyl, 4-hydroxy-1-butyl, 3-hydroxypropyl, morpholinimethyl, N- [2- (4-hydroxyphenyl) -2-hydroxyethyl] -N- (methyl) aminomethyl or 4-hydroxybutyl ilo. A specific value for R3 is 3-hydroxy-1-propynyl, morphinomethyl, N- [2- (4-hydroxy phenyl) -2-hydroxyethyl] -N- (meth il) aminomethyl or 3-hydroxypropyl. A specific value for R5 is (CH2CH20) iR10. A specific value for R5 is C7_7alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR7R8, R11, SOmR9, and C2_4alkyl, which may be optionally substituted by het. , OR10 or NR7R8; wherein R9 and R10 have any of the values defined herein; and wherein R7 and R8 are independently (a) H, (b) aryl, or (c) C1-7alkyl and may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR10R10, R11, SOmR9, CONR10R10 and halo; Y (a) OR10, (b) Ohet, (c) Oaril, (d) C02R10, or (e) CN. A specific value for R5 is C alquilo-alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR7R8, R11, SOmR9, and C2- Oalkyl, which may be further substituted by het, OR10 or NR7R8. A specific value for R5 is Ci-7 alkyl, which may be partially unsaturated and is optionally substituted by one or more aryl or het. A more specific value for R5 is C1-7 alkyl. The invention also specifically provides a compound of formula III: or a pharmaceutically acceptable salt thereof wherein R 'is H, - (CH2CH20) nH, - (CH2CH20) nCH3, S02R 3 ° 5 ° or COR35, C? _7 alkyl which may be partially unsaturated and is substituted optionally by R36, C2-7 alkyl which may be partially unsaturated and is optionally substituted by R33, or C3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by R36, R33 or R34; each R23 and R24 is independently H, halo, aryl, S (0) mR, 30, COR, 3J0U, cyano, het, CF3, OR¿y, ORJi, SR 29 SR31, NR25R26, CH (OR29) R27, C02R29, CH (C02R29) 2, NHCOR27, or, NHS (0) 2R27 or C _ _ 7 alkyl which may be partially unsaturated and is optionally substituted by R28; each R25 and R26 is independently H or C? -7 alkyl; R 27 is C 1-7 alkyl optionally substituted by R 36 or C 2-7 alkyl optionally substituted by R 3 ~ 3 R 28 is cyano, halo, CF, aryl, het, C (= 0) alkyl of C? -7, C02 alkyl of C? -7, OR29, OR ^ 9,, 27 29 OR32, 29 SR SR 31 SR 32 NR25R26. CH (OR, 2 / s) R 'C02R' CH (C02R 29y). 2 Rz is H or C? _7 alkyl. R 30 is C?-7 alkyl, R "25Rr, 2" 6, aryl or het; R31 is C2-7 alkyl substituted by OH; RJZ is (P = 0) (OR, 2 ^ 9) 2, CO (CH2) nCON (CH3) - (CH2) nS03"M +, an amino acid, C (= 0) aryl or C (= 0) C-alkyl Β-7 optionally substituted by NR 25 R 26, aryl, het, carboxy or O (CH 2) n C02 R 29, R 33 is hydroxy or NR 25 R 26, R 34 is C 1 alkyl optionally substituted R 33 R, 35 is C? _7 alkyl, aryl or het; R36 is C02H or C02alkyl of C? _7 each n is independently 1, 2, 3, 4 or 5; each m is independently 0, 1 or 2; M is a pharmaceutically acceptable cation (eg, sodium, potassium or lithium); wherein any aryl or het is optionally substituted with one or more substituents (e.g., (1, 2, 3, 4 or 5) independently selected from the group consisting of halo, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, carboxy, OR27, phenyl, phenoxy, (C? -7) alkoxycarbonyl, SR31 and C? _7 alkyl optionally substituted with one or more substituents independently selected from the group consisting of cyano, aryl, mercapto, het, R36, OR27, SR27 and SR31 wherein phenyl or phenoxy is optionally substituted with one or more substituents independently selected from cyano, halo, trifluoromethyl, trifluoromethoxy, carboxy, het, OR31 and R27 The preferred compounds are compounds of formula III as described above, with the proviso that when R21 is Cl and R22 is H, R23 is different from CH2OH.A specific value for R21 is Cl.Another specific value for R21 is CN or N02.A specific value for R22 is H, - (CH2CH20) nH, - (CH2CH20) nCH3, S02R35, COR35, C? -7 alkyl which may be partially unsaturated and optionally substituted by R36, C2-7 alkyl which may be partially unsaturated and is optionally substituted by R33 or C3_8 cycloalkyl which may be partially unsaturated and optionally substituted by R 3 ~ 6 R, 3: 3 R, 34 Another specific value for R 22 is C 1 _ 7 alkyl which may be partially unsaturated and is optionally substituted by R 36, C 2-7 alkyl which may be partially unsaturated and is replaced by R 33 or C3_8 cycloalkyl which may be partially unsaturated and is optionally substituted by R, R or R34. Another specific value for R22 is C? -7 alkyl which may be substituted by R36. Another specific value for R22 is C2_7 alkyl which is partially unsaturated and is replaced by R33. A specific value for each R23 is independently H, halo, aryl, S (0) mR30, COR30, cyano, het, CF3, OR29, OR31, SR29, SR31, NR25R26, CH (OR29) R27, C02R29, CH (COOR29) 2, NHCOR27 or NHS (0) 2R27 or C1-7 alkyl which may be partially unsaturated and is optionally substituted by R28; Another specific value for each R23 is independently halo, S (0) mR30, COR30, cyano, het or C? _7 alkyl which may be partially unsaturated and is optionally substituted by R28 with the proviso that at least one R23 and R24 is hydrogen. Another specific value for each R 23 is independently Ci-7 alkyl optionally substituted by R28 with the proviso that at least one R23 and R24 is hydrogen. Another specific value for each R 3 is independently C 1 -C 7 partially unsaturated alkyl and is optionally substituted by R 28 with the proviso that at least one R 23 and R 24 is hydrogen. Another specific value for each R 23 is independently (Z E) -CH = CH (CH 2) n R 28 O C = C (CH 2) n R with the condi tion that at least an R 23 R, 24 is hydrogen. A more specific value for R22 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, carboxymethyl, (C7_7 alkoxy) carbonylmethyl, 2-hydroxyethyl, 2- (2-methoxyethoxy) and yl, 3- (2-tetrahydropyranyloxy) propyl, 2-morpholinoethyl, 2- (diethylamino) ethyl, 2- (dimethylamino) ethyl, 2-piperidinoetyl, 3-piperidinopropyl, 2- (1-methylpyrrolidin-2-yl) ethyl , 2- (diisopropylamino) ethyl, 2-pyrrolidin-1-ylethyl, 3- (dimethylamino) propyl or vinyl. Another more specific value for R22 is methyl, ethyl, isopropyl, 2-hydroxyethyl, 2- (diethylamino) ethyl or 2 - (dimethylamino) ethyl. Another more specific value for R22 is methyl or 2- (dimethylamino) ethyl.

. Another more specific value for R is independently 3-hydroxy-1-propynyl, or 3-hydroxypropyl when R24 is hydrogen. A specific compound of the formula I is a compound wherein R21 is Cl; R22 is - (CH2CH20) nH, - (CH2CH20) nCH3, S02R35, COR35, C1-7alkyl which may be partially unsaturated and is optionally substituted by R36, C2_7alkyl which may be partially unsaturated and is optionally substituted by R33 or C3_8 cycloalkyl which may be partially unsaturated and is optionally substituted by R36, R33 or R34; each R23 and R24 is independently C7_7 alkyl which may be partially unsaturated and is optionally substituted by R28 with the proviso that at least one R23 and R24 is hydrogen; and R28 is cyano, C1-7 alkanoyl, OR29, NR25R26, OR31, OR32, pyrrolidino, piperidino, morpholino, thiomorpholino; (CH2) nOR29, (CH2) nOR32, (CH2) nSR29, CH (OR29) R27, (CH2) nCN, C? _7C02R29 alkyl or CH (COOR29) 2; or a pharmaceutically acceptable salt thereof. A specific compound of formula I or III is a compound wherein any aryl or het is optionally substituted with one or two substituents selected from the group consisting of halo, cyano, het, trifluoromethyl, trifluoromethoxy, hydroxyC1-7 alkoxy, and C? _7 alkyl; or a pharmaceutically acceptable salt thereof. The preferred compounds of the formulas I and III exclude the compounds specifically or generically exposed in the references cited herein. A preferred compound of the formula I excludes a compound of the formula I wherein R is halo when R2 is hydrogen. A preferred compound of the formula III excludes a compound of the formula I wherein R21 is halo when R22 is hydrogen. These excluded compounds of formula I and formula III can be included in or can be included in the pharmaceutical compositions and methods described herein. The following diagrams A-L describe the preparation of the compounds of the present invention. All starting materials are prepared by the procedures described in these diagrams or by analogous procedures thereto, which could be well known to someone with ordinary experience in organic chemistry. All of the final compounds of the present invention are prepared by the methods described in these diagrams, by analogous methods thereof or by methods that are known to one of ordinary skill in organic chemistry. All the variables used in the diagrams are as defined below or as in the claims.

Diagram A 2-aminothiophenes of the formula A-1 are optionally substituted by reduction of the corresponding nitro A-2 compounds. The compounds of the formula A-1 are then heated with diethyl ether ammonium malonate followed by thermolysis in diphenylether to provide the esters of the formula A-4. The esters are converted to the amides of the formula A-6 by direct aminolysis with a benzylamine optionally substituted at 190 ° C or by hydrolysis for the acids of the formula A-5 followed by the treatment with carbonyldiimidazole and the amine. The compounds of the formula A-6 are treated with an alkyl halide optionally substituted in the presence of potassium carbonate to provide the N-alkylated amides of the formula A-1.

A-ß Diagram B Compound B-1 (5-nitro-2-thiophenesulfonyl chloride) is treated with an amine to provide the nitro compounds of the formula B-2. The compounds of the formula B-2 are transformed as in Diagram A to provide the analogous amides for A-6 and A-7.

OzS, ^ - € sk RzNH Cl ^ NOj R2N02S- ^ S '' N02 B-1 B-2 Diagram C The compounds of the formula C-1 wherein R is H or alkyl are halogenated to provide the compounds of the formula C-2. The compounds of the formula C-2 are transformed as in Diagram A to provide the analogous amides for A-6 and A-7.

C-1 C-2 Diagram D The palladium-copper-mediated coupling of D-1 (where X = Br or I) with an alkane leads to the compounds of the formula D-2. The compounds of the formula D-2 are hydrogenated using palladium on carbon as the catalyst to provide the saturated compounds D-4. The compounds D-2 and D-4 are treated with an alkyl halide optionally substituted to provide the N-alkylated compounds D-3 and D-5.

Diagram E The compound E-1 is treated with copper cyanide (I) to provide the cyano compound E-2.

E-1 e * Diagram F The compounds of the formula F-1 are treated with an alkyl halide optionally substituted in the presence of potassium carbonate to give the N-alkylated esters of the formula F-2. The esters are converted to the amides of the formula A-7 by direct aminolysis with a substituted benzylamine or by hydrolysis for the acids of the formula F-3 followed by the treatment with carbonyldiimidazole and the amine.

F-3 Diagram G The palladium-copper-mediated coupling of G-1 (where R = Br or I) with an alkin leads to the compounds of the formula D-3. The compounds D-3 are hydrogenated using palladium on carbon as the catalyst to provide the saturated compounds of the formula D-5.

D-6 Diagram H The compounds of the formula H-1 are treated with an acylating agent to provide the compounds of the formula H-2 wherein A is either an alkyl or arylalkyl substituent and X is a halogen (Br, Cl or I). The halide is then displaced by an amine to provide the compounds of formula H-3.

H-3 Diagram I Compounds of formula 1-4 bearing a 2-alkylamino substitution are prepared by palladium-catalyzed carboxylation of 2-iodot-ienopyr idin E-1 to provide the corresponding 2-methyl ester 1-1. Reduction of 1-1 with LiAlH4 yields the 2-hydroxymethyl derivative 1-2 which can then be treated with an alkyl halide optionally substituted in the presence of potassium carbonate to provide N-alkylpyridones of formula 1-3. Activation of the alcohol with methanesulfonyl chloride followed by displacement with a primary or secondary amine provides the compounds of formula 1-4. 1-2 R - H W l 1-3 R a Alkyl Diagram J N- (4-chlorobenzyl) -4-hydroxynthene [2,5-3-b] pyridine-S-carboxamide (A-6 where R = H) is subjected to Mannich reaction by heating with morpholine and formaldehyde in acid acetic acid / ethanol to provide the 2-morpholinometyl derivative J-1. The compound J-1 is then treated with an alkyl halide optionally substituted in the presence of potassium carbonate or with an alcohol optionally substituted under Mitsunobu conditions to provide thienopyridones of the general formula J-2.

A-ß (RH) r- J-1 R'-H-, r L * ~ j-2 R * m optionally substituted alkyl Diagram K 2-yodot ienopyr idin-5-carboxamide is applied to carbon monoxide insertion Palladium catalyzed with trapping by an amine to provide 2-carboxamides of the general formula Kl. Compounds K-1 are then treated with an alkyl halide optionally substituted in the presence of potassium carbonate to provide thienopyridones of the formula K-2.

E-1 K-1 K "H C K" 2 * "alkyl optionally substituted Diagram L Aminomet ilenmalonate L-2 is prepared as described in German patent 2447477 (1976) from 2-aminociofen-3-carboxylate or tert-butyl (Ll) (M. Gutschow and U. Neumann, J. Med. Chem. 1998, 41, 1729-1740) by reacting it with ethoxymethylethyl malonate. Intermediate L-2 is then alkylated in nitrogen by reaction with iodomethane in the presence of potassium carbonate which provides L-3. Subsequently, L-3 is subjected to a Mannich reaction with 4-methylene morpholinium chloride (Dimmock, JR, et al., Eur. J. Med. Chem. 1989, 24, 379-383) to provide the morpholinometyl L intermediate. -4. The thieno [2, 3-b] pyridone L-5 is then prepared by heating the compound L-4 in a mixture of Eaton's reagent. The ester L-5 is then treated with a benzylamine (for example, -chlorobenzylamine, 4-bromobenzylamine or 4-f luorobenzylamine) at high temperature to provide the correding amides of the general formula L-7 or the ester L-5 can be saponifying to provide the L-6 acid which is then coupled with a benzylamine to provide the amides of the general formula L-7.

L-7 L-5 R - Et L-6 R - H Diagram M The compounds of this invention wherein, R2 is (a) R5; (b) NR7R8; or (c) OR9 in such a way that R5 is (a) het, where het is bonded by carbon; (b) aryl; (c) C3_8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9 and C alquilo_alkyl optionally substituted by R11, NR7R8 and SOraR9; or (d) tert-butyl, are prepared as exemplified in Diagram M. Intermediates carrying the ring system 4-oxo-4,7-dihydrothieno [2,3-b] pyridine are prepared in an analogous manner to the previous one in the literature (MM El-Abedelah, MZ Nazer, SF Okasha, M. Calas, J. Bompart, P. Mion Eur. J. Med. Chem. 1998, 33, 33-42; and MM El-Abedelah , SS Sabri, AA Al-Ashqar Hetrocicles 1997, 45, 255-264). 2-Bromo-5-chloro-4-thiophenecarboxylic acid (Ml) (prepared as described by S. 01, H. Nagaya, N. Inatormoi, M. Nakao, H. Yukimasa WO-97/11705, 1997) activated with 1,1'-carbonyldiimidazole and then treated with ethyl trimethylsilyl malonate in the presence of DBU to provide 3-ketoester M-2. The reflux compound M-2 in acetic anhydride and triethyl orthoformate provides the enol ether M-3. The compound M-3 is then contacted with a nitrogen atom containing the compound of the formula RNH2 wherein R can be enunciatively: the one defined from above R2 (for example, cyclopropylamine, tert-butylamine, aniline, -furylamine, 4-aminomorpholine, l-amino-4-methylpiperazine or O-ethylhydroxylamine) to provide a compound of the formula M-4. The reaction can be conveniently carried out in ethanol. The resulting enamines M-4 are then cyclized by heating with sodium hydride (or other suitable base) in tetrahydrofuran to provide the thieno [2,3-b] pyridine-5-carboxyyl esters of the formula M-5. The M-5 esters are heated in the presence of a substituted benzylamine (e.g., 4-chlorobenzylamine) and iodine to provide the correding carboxamides of the formula M-6. Alternatively, the carboxamides of the formula M-6 are prepared in such a way that the M-5 esters are saponified in the presence of aqueous sodium hydroxide which provides the correding acidic carboxylic which is then coupled with a substituted benzylamine in the presence of 1.1 '-carbonyldiimidazole. The compounds of the formula M-6 are converted to the derivatives in a manner analogous to that described in the diagrams G and K. Specifically, the compounds of the formula M-6 are coupled with propargyl alcohol in the presence of Pd (PPh3) 2C12 , Cul, and diethylamine to provide the compounds of the formula M-7. Saturation of the alkynyl functional group present in M-7 by hydrogenation over a palladium catalyst provides the compounds of the formula M-8.

M-l M-2 M-3 Y - OCHxCHj M-4 Y- NHR '? xr ?? x Br "~ T irc? 2Et M-6 R M-7 M-8 Diagram N Alternatively, a subset of the compounds carrying the definition R2 in Diagram M where R3 is CH2NR7R8 are prepared as exemplified in Diagram N. 3-Bromo-2-chlorothiophene is metallized (Nl) ) (prepared as described by JJ Baldwin, JM Hoffman, JH Jones, CS Rooney, AM Smith US 5,276,025; 1994) with lithium diisopropylamide in tetrahydrofuran followed by quenching with N, N-dimethylformamide to provide the carboxaldehyde N-2. Reductive amination of N-2 by treatment with an amine (eg, morpholine), acetic acid, and sodium triacetoxyborohydride provides thiophene N-3. The metallation of compound N-3 with n-BuLi followed by trapping with carbon dioxide provides the carboxylic acid N-4. The N-4 acid is activated with 1,1'-carbonyldi imidazole and then treated with ethyl trimethylsilyl malonate in the presence of DBU to provide the 3-ketoester N-5. The compound in N-5 reflux in acetic anhydride and triethyl orthoformate provides the enol ether N-6. The compound N-6 is then contacted with nitrogen containing the compound of the formula RNH2 wherein R can be enunciatively the definition R2 above (eg, cyclopropylamine, tert-butylamin, aniline, 3-furylamine, 4 - aminomor folin, 1-amino-4-methylpiperazine or o-et i lhydroxylamine) to provide a compound of the formula N-7. The reaction can be conveniently carried out in ethanol. The resulting N-7 enamines are then cyclized by heating with sodium hydride (or other suitable base) in tetrahydrofuran to provide the [2, 3-b] pyridine-5-carboxylic esters of the formula N-8. The N-8 esters are heated in the presence of a substituted benzylamine (e.g., 4-chlorobenzylamine) to provide the corresponding carboxamides of the formula N-9. Alternatively, the carboxamides of the formula N-9 are prepared in such a way that the N-8 esters are saponified in the presence of aqueous sodium hydroxide which provides the corresponding carboxylic acid which is then coupled with a substituted benzylamine in the presence of 1.1. '-carbonyldiimidazole.

N-9 The invention also provides the processes and intermediates described herein that are useful for preparing the compounds of the invention. For example, the invention provides a method for preparing a compound of formula L-7: L-7 wherein R is Cx-4 alkyl; and X is Cl, Br, CN, N02 or F, comprising steps 1-6 described below. (1) reacting an amine of the formula L-1: L-l with an alkoxymethyl malonate of the formula R '0CH = CH (C02W) 2 wherein R' is C 1 alkyl - and each W is independently selected from C 1 4 alkyl, to provide a compound of the formula L -2: The reaction can be conveniently carried out by heating a solution of the compound L-1 with the alkoxymethylene malonate or an equivalent thereof. (2) alkylating the compound of the formula L-2 to provide a corresponding compound of the formula L-3: wherein R is C? _4 alkyl. The reaction can be conveniently carried out by contacting the compound of the formula L-2 with an iodoalkane of the formula I-R in the presence of a suitable base (for example, an alkali metal carbonate). (3) reacting the compound of the formula L-3 with a 4-methynmorpholinium salt to provide a compound of the formula L-4: L-4 The reaction can be conveniently carried out by contacting the ester with a salt of 4-met i lenmor fol inio or with a combination of reactants that generates a salt of 4-me t i lenomor folinio in si tu. (4) cyclize the compound of the formula L-4 under suitable conditions to provide a bicyclic ester of the formula L-5: The cyclization can be conveniently carried out by contacting a compound of the formula L-4 with a mixture of phosphorus pentoxide and methanesulfonic acid. (5) hydrolyze the L-5 ester to provide a carboxylic acid of the formula L-6: Suitable conditions for converting an ester to a corresponding carboxylic acid are well known in the art. The reaction can be carried out under any suitable conditions. (6) reacting the carboxylic acid of the formula L-6 with a 4-substituted benzylamine to provide the compound of the formula L-7. Suitable conditions for preparing an amide of a corresponding carboxylic acid are well known in the art. The reaction can be carried out under any suitable conditions. For example, the reaction can be conveniently carried out by activating the carboxylic acid with a suitable activating agent, and by treating the resulting activated acid with the 4-substituted benzylamine necessary to provide the compound of the formula L-7. The invention also provides a method for preparing a compound of the formula (I) wherein R1-R4 have any of the values, specific values or preferred values described herein, which comprises reacting a corresponding carboxylic acid of the formula (II) ): with a benzylamine of the formula wherein X is Cl, Br, CN, N02 or F, under suitable conditions to provide the compound of the formula (I). Suitable conditions for preparing an amide of a corresponding carboxylic acid are well known in the art. The reaction can be carried out under any suitable conditions. For example, the reaction can be conveniently carried out by activating the carboxylic acid with a suitable activating agent, and by treating the activated acid with the 4-substituted benzylamine necessary to provide the compound of the formula (I). Suitable amines include 4-chlorobenzylamine, 4-f luorobenzylamine, 4-bromobenzylamine, 4-cyanobenzylamine and 4-nitro-robenzylamine. In cases where the compounds are sufficiently basic or acidic to form stable non-toxic acid or basic salts, administration of the compounds as salts may be adequate. Examples of pharmaceutically acceptable salts are organic acid addition salts formed with acids that form an acceptable physiological anion, for example, tosylate, methanesulfonate, acetate, citrate, malonate, tartrate, succinate, benzoate, ascorbate, α-ketoglutarate and α-glycerophosphate . Suitable inorganic salts can also be formed, including hydrochloride, hydrobromide, sulfate, nitrate, bicarbonate and carbonate salts. Pharmaceutically acceptable salts can be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suitable acid which provides a physiologically acceptable anion. Alkali metal salts (eg, sodium, potassium or lithium) or alkaline earth metal (eg calcium) carboxylic acids can also be produced. The compounds of the present invention can be conveniently administered in a pharmaceutical composition containing the compound in combination with a suitable excipient, the composition being useful for combating viral infections. Pharmaceutical compositions containing a compound suitable for antiviral use are prepared by methods and contain excipients that are well known in the art. A generally recognized compendium of these methods and ingredients is Remington's Pharmaceutical 1 Sciences by W. W. Martin (Mark Publ. Co., 15th Ed., 1975). The compounds and compositions of the present invention may be administered parenterally (for example, by intravenous, intraperitoneal or intramuscular injection), topically, orally or rectally, depending on whether the preparation is used to treat internal or external viral infections. For an oral therapeutic administration, the active compound can be combined with one or more excipients and can be used in the form of ingestible tablets, buccal tablets, troches, capsules, elixirs, suspensions, syrups, wafers and the like. These compositions and preparations should contain at least 0.1% of the active compound. The percentage of the compositions and preparations can, of course, be varied and conveniently be between about 2 and 60% by weight of a given unit dosage form. The amount of the active compound in these therapeutically useful compositions is such that an effective dose level will be obtained. Tablets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch or gelatin; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid the like; a lubricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose or aspartame or a flavoring agent such as peppermint, wintergreen oil, or cherry flavoring may be added. When the unit dosage form is a capsule, it may contain, in addition to the materials of the above type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dose form. For example, tablets, pills or capsules may be coated with gelatin, wax, shellac or sugar and the like. A syrup or elixir may contain the active compound, sucrose or fructose as a sweetening agent, methyl and propylarabines as preservatives, a dye and a flavoring such as cherry or orange flavor. Of course, any material used to prepare any unit dosage form must be pharmaceutically acceptable and practically non-toxic in the amounts employed. In addition, the active compound can be incorporated into sustained release preparations and devices.

The compounds or compositions may also be administered intravenously or intraperitoneally by infusion or injection. The solutions of the active compound or its salts can be prepared in water, optionally mixed with a non-toxic surfactant. The dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin and mixtures thereof and in oils. Under normal conditions of storage and use, these preparations contain a preservative to prevent the development of microorganisms. The pharmaceutical dosage forms suitable for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of injectable or infusible solutions or dispersions, optionally encapsulated in liposomes. . In all cases, the ultimate dosage form must be sterile, fluid and stable under the conditions of manufacture and storage. The carrier or liquid carrier may be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols and the like), vegetable oils, non-toxic glyceryl esters and suitable mixtures thereof. The proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants. The prevention of the action of microorganisms can be caused by various antibacterial and antifungal agents, for example, parabens, chlorobutanoi, phenol, sorbic acid, thimerosal and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars, buffers or sodium chloride. Prolonged absorption of the injectable compositions can be caused by the use in the compositions of agents for delaying absorption, for example, aluminum monostearate and gelatin. Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in the appropriate solvent with several of the other ingredients listed above, as required, followed by filter sterilization. In the case of sterile powders for the preparation of sterile injectable solutions, the preferred methods of preparation are vacuum drying and lyophilization techniques, which provide a powder of the active ingredient plus any additional desired ingredients present in the previously sterile filtered solutions. For topical administration, the compounds herein can be applied in pure form, that is, when they are liquid. However, in general it will be desirable to administer them to the skin as compositions or formulations, in combination with a dermatologically acceptable carrier, which may be a solid or a liquid. Useful solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina and the like. Useful liquid carriers include water, alcohols or glycols or water-alcohol / glycol combinations, in which the compounds herein can be dissolved or dispersed at effective levels, optionally with the aid of non-toxic surfactants. Adjuvants such as fragrances and additional antimicrobial agents can be added to optimize the properties for a particular use. The resulting liquid compositions can be applied from absorbent pads, used for impregnated bandages and other cures, or can be spread over the affected area using pump or aerosol type sprinklers. Thickeners such as synthetic polymers, fatty acids, fatty acid salts and esters, fatty alcohols, modified celluloses or mineral materials modified with liquid carriers can be used to form pastes, gels, ointments, spreadable soaps and the like, for the application directly to the user's skin. Examples of useful dermatological compositions which can be used to deliver the compounds of formula I to the skin are known in the art.; for example, see Jacquet et al. (U.S. Patent No. 4,608,392), Geria (U.S. Patent No. 4,992,478), Smith et al. (U.S. Patent No. 4,559,157) and Wortzman (U.S. Patent No. 4, 820, 508). Useful doses of the compounds of the formula I can be determined by comparing their activity in vitro and in vivo in animal models. Methods for the extrapolation of effective doses in mice and other animals to humans are known in the art; for example, see U.S. Patent No. 4,938,949.

The compound is conveniently administered in unit dosage form; for example, containing from 5 to 1000 mg, conveniently from 10 to 750 mg, more conveniently, from 50 to 500 mg of the active ingredient per unit dosage form. The desired dose may be conveniently presented in a single dose or as divided doses administered at suitable intervals, for example, as two, three, four or more sub-doses per day. The sub-dose itself can be further divided, for example, into several approximately separate administrations; such as multiple inhalations from an insufflator or by applying a plurality of drops to the eye. For internal infections, the compositions can be administered orally or parenterally at dose levels, calculated as the free base, of from about 0.1 to 300 mg / kg, preferably from 1.0 to 30 mg / kg of body weight of the mammal and can be used in man in a unit dose form, administered one to four times daily in the amount of 1 to 1000 mg per unit dose. For parenteral administration or for administration as drops, such as for eye infections, the compounds are presented in aqueous solution in a concentration between about 0.1 and 10%, more preferably between about 0.1 and 7%. The solution may contain other ingredients, such as emulsifiers, antioxidants or buffers. In general, the concentration of the compounds of the formula I in a liquid composition, such as a lotion, will be between about 0.1-25% by weight, preferably between about 0.5 and 10% by weight. The concentration in a semi-solid or solid composition such as a gel or a powder will be between about 0.1 and 5% by weight, preferably between about 0.5 and 2.5% by weight. The exact regimen for administration of the compounds and compositions set forth herein will necessarily depend on the needs of the individual subject being treated, the type of treatment and, of course, the judgment of the attending physician. The antiviral activity of a compound of the invention can be determined using pharmacological models that are well known in the art, or using Test A described below.

The compounds of the formula (I) and the pharmaceutically acceptable salts thereof are useful as antiviral agents. In this way, they are useful to combat viral infections in animals, including humans. In general, the compounds are active against herpes viruses and are particularly useful against varicella zoster virus, Epstein-Barr virus, herpes simplex virus, human herpes virus type 8 (HHV-8) and cytomegalorivus (CMV). . While many of the compounds of the present invention have shown activity against CMV polymerase, these compounds can be active against cytomegalovirus by this or another mechanism of action. Thus, the following description of this activity of the compounds against the CMV polymerase is not intended to limit the present invention to a specific mechanism of action.

Test A The HCMV polymerase assay is performed using a scintillation proximity assay (SPA) as described in various references, such as N.D.

Cook, et al., Pharmaceutical Manufacturing International, pages 49-53 (1992); K. Takeguchi, Laboratory Practice, granted in September (1992); U.S. Patent No. 5,568,649 (1986); which are incorporated herein by reference. The reactions are carried out in 96-well plates. This analysis was conducted in 100 μl volume with 5.4 mM HEPES (pH 7.5), 11.7 mM KCl, 4.5 mM MgCl 2, 0.36 mg / ml BSA, and 90 nM 3 H-dTTP. The analyzes were run with and without CHAPS, (3 - [(3-colamidopropyl) -dimethylammonium] -1-propan-sulfonate) at a final concentration of 2 mM. The HCMV polymerase is diluted in enzyme dilution buffer containing 50% glycerol, 250 mM NaCl, 10 mM HEPES (pH 7.5), 100 μg / ml BSA, and 0.01% sodium azide. The HCMV polymerase, which is expressed in SF-9 cells infected with recombinant baculoviruses and purified according to literature procedures, is added to 10% (or 10 μl) of the final reaction volume, i.e., 100 μl. The compounds are diluted in 50% DMSO and 10 μl is added to each well. The control cavities contain an equivalent concentration of DMSO. Unless otherwise noted, the reactions are initiated by the addition of the biotinylated poly (dA) -oligo (dT) 6 nM primer / primer to the reaction mixtures containing the enzyme, substrate and the compounds of interest. The plates are incubated in a H20 bath at 25 ° C or 37 ° C and are terminated by the addition of 40 μl / reaction of 0.5 M EDTA (pH 8) per well. The reactions are completed within the time frame during which the incorporation of the substrate is linear and varies depending on the enzyme and conditions used, ie 30 min. for the HCMV polymerase. Ten μl of streptavidin-SPA beads (20 mg / ml in PBS / 10% glycerol) are added after the reaction is complete. The plates are incubated 10 min. at 37 ° C, then equilibrated at room temperature, and counted in a Packard Topcount. Linear regressions are performed and the IC5o's are calculated using computer software. A modified version of the HCMV polymerase assay is performed as described above, although with the following changes: The compounds are diluted in 100% DMSO until the final dilution in the assay buffer. In the above analysis, the compounds are diluted in 50% DMSO. 4.5 mM dithioterotol (DTT) is added to the polymerase buffer. A batch of CMV polymerase is also used, which appears to be more active resulting in a faster polymerase reaction. The test results of representative compounds of formula I in this analysis are shown in Table 1. In Table 1, the term "nd" refers to undetermined activity data.

Table 1. Biological data polymerase ICj_ (μM) Example HCMV HSV VZV 1 28.9 nd nd 2 6.3 nd nd 3 15.9 nd nd 4 10.8 nd nd 5 2.5 0.88 0.60 6 5.8 nd nd 7 8.0 nd nd 8 11 0.91 0.55 9 12.5 nd nd 10 34.3 nd nd 11 18.8 nd nd 12 11.0 nd nd 13 9.0 nd nd 14 1.8 nd nd 15 4.7 22 1.9 16 0.67 nd nd 17 0.92 0.89 0.28 18 1.7 0.95 039 19 0.86 nd nd 20 0.18 nd nd 21 < 0.78 nd nd 22 0.81 nd nd 23 2.9 nd nd 24 1.0 nd nd 25 0.4 0.45 0.46 26 14.2 nd nd 27 4.2 nd nd 28 2.4 nd nd 29 6.5 nd nd 30 28.2 nd nd 31 15.4 nd nd 32 > 50.0 nd nd 33 22.4 nd nd 34 > 20.0 nd nd 35 18.5 nd nd 36 1.8 1.2 0.77 nd = not determined Table 1. Biological data (continued) polymerase ic *, (μM) Example HCMV HSV VZV 37 nd nd nd 38 2.6 nd nd 39 < 0.31 nd nd 40 < 0.31 nd nd 41 3.4 nd nd 42 1.9 nd nd 43 1.9 nd nd 44 4.7 nd nd 45 2.6 nd nd 46 3.8 nd nd 47 > 20.0 nd nd 48 19.0 nd nd 49 3-2 nd nd 50 3.8 nd nd 51 12 nd nd 52 1.5 nd nd 53 4.0 nd nd 54 22 nd nd 55 5.0 nd nd nd = not determined DESCRIPTION OF THE PREFERRED MODALITIES EXAMPLE 1. N- (4-Chlorobenz 1) -4-hydroxythieno [2,3-b] pyridine-5-carboxamide OH O aí tic. A mixture of 4-hydroxy-thieno [2,3-b] pi-idin-ethyl-carboxylate (J. Heterocyclic Chem. 1977, 14-07) (0.447 g) and 4-c-lorobenzyl (2.43 mL) was stirred at 190 ° C for 1 h. . The reaction was then allowed to cool to rt and diluted with toluene (5 mL). The resulting precipitate was removed by filtration and washed with toluene followed by hexanes to give an off white solid. This material was recrystallized from acetic acid / water then with ethanol to give 0.285 g (45%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 238-240 ° C; XH NMR (300 MHz, DMSO-d6) d 13. 37, 10.56, 8.71, 7.43-7.34, 4.54; 13 C NMR (75 MHz, TFA) d 169.0, 167.1, 153.6, 139.5, 134.7, 133.2, 128.8, 128.8, 127.8, 127.6, 107.9, 43.8; IR (heating) 2785, 2753, 2694, 2672, 2317, 1996, 1668, 1541, 1498, 1432, 1398, 1348, 803, 700, 610 cm-1; MS (ESI-) m / z 317 (M-H) -; Analysis found: C, 56.30; H, 3.61; N, 8.72; Cl, 11.08; S, 9.98.

EXAMPLE 2. N- (4-Chlorobenz 1) -4-hydroxy-2-iodothieno [2, 3-b] pyridine-5-carboxamide Mercuric oxide (7.10 g) and iodine (8.32 g) are added in portions to a solution of ethyl 4-hydroxythieno [2, 3-b] pyridine-5-carboxylate (J. Heteroeyelie Chem. 1977, 14, 807) ( 5.22 g) in CHC13 (90 mL). The reaction was stirred at rt for 18 h. The reaction mixture was filtered, and the solid was washed with CHC13 (400 mL). The organic layer was washed with H20 (200 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting orange solid was purified by column chromatography (CH2C12: heptane, 1: 1). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 2.95 g (36%) of 4-hydroxy-2-yodot-ieno [2, 3-b] pyridine-5-carboxylic acid ethyl ester as a pale yellow solid. 4-Hydroxy-2-yodot ieno [2, 3-b] pyridine-5-carboxylic acid ethyl ester (2.64 g) was suspended in 10% NaOH (21 mL) and heated to reflux. The reaction was stirred at reflux for 1 h and then cooled to rt. The reaction mixture was poured into H20 (80 mL). Concentrated HCl was added until a precipitate formed, and 2,272 g (94%) of 4-hydroxy-2-iodot-ieno [2,3-b] pyridine-5-carboxylic acid was isolated as a white solid. Carbonyldiimidazole (1.34 g) was added to a solution of 4-hydroxy-2-yodothieno [2,3-b] pyridine-5-carboxylic acid (2.041 g) in DMF (58 mL). The reaction was heated to 60 ° C and stirred for 18 h. The reaction mixture was cooled to rt, and 4-chlorobenzylamine (1.01 L, 8.27) was added. The reaction was stirred at rt for 7 h. The reaction mixture was emptied into 20% aqueous HOAC (180 L), and the resulting white solid was removed by filtration. This material was recrystallized from methanol then with toluene to provide 2.095 g (74%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 231-232 (dec) ° C; l NMR (300 MHz, DMSO-d6) d 13.27, 10.43, 8.69, 7.63, 7.41-7.33, 4.53; 13 C NMR (75 MHz, DMSO-d 6) d 165.0, 142.1, 139.0, 133.1, 131.9, 131.2, 129.6, 128.8, 113.9, 74.5, 41.9; IR (trend) 3172, 3060, 2993, 2923, 2908, 2841, 1639, 1588, 1537, 1509, 1497, 1473, 1293, 802, 785, cm "1; MS (ESI-) for m / z 443 (MH ) "; Analysis found: C, 40.75; H, 2.41; N, 6.44; Cl, 7.81; S, 7.01.

EXAMPLE 3. N- (4-Chlorobenzyl) -4-hydroxy-2- (4-morpholinyl sulfonyl) has [2,3-b] pyridine-5-carboxamide Morpholine (1.69 mL) was dissolved in CH2C12 (40 mL). Triethylamine (6.8 mL) was added and the reaction was cooled to 0 ° C. A solution of 5-nitro-2-thiophenesulfonyl chloride (3.69 g) in CH2C12 (25 mL) was then added dropwise. The reaction was stirred at 0 ° C for 15 min. and then at room temperature for 30 min. The reaction mixture was concentrated in vacuo, and the resulting brown solid was purified by column chromatography (CH2C12). The homogeneous fractions by TLC were combined and concentrated in vacuo to give 3.52 g (78%) of 2-mor folinosul foni-5-nit rot iofen as a yellow solid. 2-mor folinosulfonyl-5-nitrothiophene (3.40 g) and concentrated HCl (27 mL) were combined and heated to 40 ° C. SnCl2"2H20 (7.72 g) was added in portions while maintaining the reaction temperature between 40-45 ° C using an ice bath. After the addition was complete, the reaction was stirred at 40 ° C for 1 h. The reaction mixture was cooled to room temperature, diluted with H20 (100 mL), and the solution adjusted to pH 11 with NH40H. The aqueous layer was extracted with ethyl acetate (3 x 250 mL). The combined organic layers were dried with MgSO 4, filtered, and concentrated in vacuo to provide 2.83 g of 2-amino-5-mor phos inosul-onyl-thiophene as a brown solid. 2-Amino-5-morpholinosulfonylthiophene (2.12 g) and • diethylethoxymethylene malonate (1.73 mL) were combined and heated to 135 ° C. The reaction was stirred at 135 ° C for 1 h. The reaction was then cooled for several minutes and diluted with heptane. The product was obtained as oil, such that the mixture was concentrated in vacuo and the residue was purified by column chromatography (CH2C12: CH30H, 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 1.89 g (53%) of the intermediate malonate as a brown oil. This material was combined with diphenylether (5 mL). The reaction mixture was degassed and then heated to reflux. The reaction was stirred at reflux for 1 h. The reaction mixture was allowed to cool for several minutes and was diluted with heptane. The resulting tan solid was extracted by filtration and purified by column chromatography (CH2C12, CH2C12: CH30H, 98: 2) '. The homogeneous fractions by TLC were combined and concentrated in vacuo to yield 0.537 g (43%) of 4-hydroxy-2-morpholinosulfonyl-thieno [2,3-b] pyroindin-5-carboxylic acid ethyl ester, as a brown solid. Clear. A mixture of 4-hydroxy-2-morpholinosul-fonyl-thieno [2,3-b] pi idin-5-carboxylic acid ethyl ester (0.503 g) and 4-chlorobenzylamine (1.64 mL) was stirred at 190 ° C. for 1 h. The reaction was then allowed to cool to rt and diluted with toluene. The resulting precipitate was removed by filtration and washed with toluene followed by hexanes to give a tan solid. This material was recrystallized from acetic acid / water then with ethanol to provide 0.240 g (38%) of the title compound as a tan solid. The physical characteristics are as follows: P.f. > 300 ° C; H NMR (300 MHz, DMS0-d6) d 13.45, 10.29, 8.86, 7.81, 7.42-7.33, 4.55, 3.68, 3.02; 13 C NMR (75 MHz, DMS0-d 6) d 173.7, 164.5, 151.8, 144.3, 138.9, 131.9, 130.8, 129.6, 129.1, 128.8, 128.1, 114.7, 65.7, 46.3, 41.9; IR (heating) 3156, 1648, 1598, 1536, 1500, 1491, 1352, 1340, 1334, 1260, 1155, 1115, 1076, 945, 733 cm-i; MS (FAB) m / z 468 (MH +); HRMS (FAB) found 468.0458; Analysis found: C, 48.69; H, 4.10; N, 891; Cl, 7.51; S, 13.76.EXAMPLE 4. 2-Bromo-N- (4-chlorobenzyl) -4-hydroxy thieno [2,3-b] pyridin-5-carboxamide OH O * * A To a solution of ethyl 4-hydroxyethyl [2, 3-b] pyridine-5-carboxylate (J. Heteroeyelie Chem. 1977, 14, 807) (1.00 g) in CHC13 (26 mL) Bromine (0.23 mL) was added dropwise. The reaction was stirred at rt for 2 h. The reaction mixture was poured into 2N HCl (30 mL) and the aqueous layer was extracted with CHC13 (3 x 30 mL). The combined organic layers were washed with H20 (100 mL), dried with MgSO4, filtered and concentrated in vacuo to provide 0.840 g (62%) of the bromide as a yellow solid. This material (0.757 g) was suspended in 10% aqueous NaOH (7 mL) and heated to reflux. The reaction was stirred at reflux for 1 h. The reaction mixture was cooled to rt, and H20 (26 mL) was added. Concentrated HCl was added until a precipitate formed. The precipitate was removed by filtration to provide 0.597 (87%) of the acid as a brown solid. Carbonyldiimidazole (0.530 g) was added to a solution of 2-bromo-4-hydroxy-t-ene- [2,3-b] pyridine-5-carboxylic acid (0.597 g) in DMF (20 mL). The reaction was heated to 60 ° C and stirred for 18 h. The reaction mixture was cooled to rt, and 4-chlorobenzylamine (1.01 mL) was added. The reaction was stirred at rt for 7 h. The reaction mixture was drained in 20% aqueous HOAc (180 mL), and the resulting white solid was removed by filtration. This material was recrystallized from methanol then with toluene to provide 2.095 g (74%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 234-236 ° C; XH NMR (300 MHz, DMS0-d6) d 13.25, 10.41, 8.74, 7.52, 7.41-7.33, 4.53; 13 C NMR (75 MHz, TFA) d 167.7, 166.9, 153.9, 139.1, 134.7, 133.2, 129.0, 128.9, 128.1, 122.3, 116.7, 108.6, 43.8; GO (trend) 3187, 3098, 3074, 3024, 2927, 2842, 1645, 1592, 1541, 1503, 1338, 1287, 916, 792, 689 cm "1; (ESI-) m / z 397 (M-H) "Found Analysis: C, 45.03; H, 2.73; N, 6.98; Br, 19.72; Cl, 8.70; S, 7.96.

EXAMPLE 5. N- (4-Chlorobenz 1) -4-hydroxy-2- (3-hydroxy-1-propy1) thieno [2, 3-b] pyridine-5-carboxamide A suspension of N- (4-chlorobenzyl) -4-hydroxy-2-iodot-ieno [2, 3-b] pi-ridin-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) was added. added copper iodide (0.128 g) and Pd (PPh3) 2Cl2 (0.032 g) followed by the addition of propargyl alcohol (0.16 mL). The reaction was stirred at rt for 3 d. The reaction mixture was partitioned between H20 (100 mL) and ethyl acetate (100 mL). The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were washed with a saturated solution with aqueous NH 4 Cl, dried with MgSO 4, filtered, and concentrated in vacuo. The resulting orange solid was purified by column chromatography (CH2C12: CH30H; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a pale orange solid which was recrystallized from CH2C12 / CH30H to give 0.165 g (20%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 233-236 ° C; XH NMR (300 MHz, DMS0-d6) d 13.32, . 41 75 7.49 7.41-7.33 5.44 4.53 4.34 13, NMR (75 MHz, DMS0-d6) d 172.8, 164.9, 148.8, 143.0, 131.9, 130.9, 129.6, 128.8, 126.8, 117.1, 114.2, 96.4, 76.6, 50.0, 41.9; IR (trend) 3239, 3107, 2944, 2888, 2872, 2239, 1650, 1581, 1550, 1513, 1345, 1312, 1041, 819, 790 cm "1; MS (ESI-) for 371 (MH) -; found: C, 57.87; H, 3.58; N, 7.59; Cl, 9.38; S, 8.48.

EXAMPLE 6. N- (4-Chlorobenz 1) -4-hydroxy-2- (3-methoxy-1-propynyl) thieno [2,3-b] pyridine-5-carboxamide To a suspension of N- (-chlorobenzyl) -4-hydroxy-2-yodothieno [2, 3-b] pyridine-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) was added iodide. copper (0.128 g), and Pd (PPh3) 2Cl2 (0.079 g) followed by the addition of methyl propargyl ether (0.27 mL). The reaction was stirred at rt for 18 h. The reaction mixture was partitioned between H20 (100 mL) and CH2C12 (100 mL). The organic layer was removed, and the aqueous layer was extracted with CH2C12 (3 x 100 mL). The combined organic layers were washed with a saturated solution with aqueous NH 4 Cl (200 mL), dried with MgSO 4, filtered, and concentrated in vacuo. The resulting brown oil was purified by column chromatography (CH2C12: CH30H; 98: 2). The resulting impure material was repurified by column chromatography (heptane: 2-propanol, 10: 1; CH2C12: CH30H, 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 0.260 g (30%) of the title compound as an off-white solid.

The physical characteristics are as follows: P.f. 215-218 ° C; XH NMR (300 MHz, DMSO-d6) d 13.33, 10.40, 8.76, 7.56, 7.41-7.33, 4.55, 3.33; 13 C NMR (75 MHz, DMSO-de) d 164.8, 143.1, 139.0, 131.9, 129.6, 128.8, 127.6, 116.4, 114.2, 92.5, 78.7, 60.0, 57.7, 41.9; IR (trend) 3176, 3074, 3016, 2924, 2859, 2822, 2320, 2218, 1640, 1587, 1534, 1512, 1353, 1097, 783 cm "1; MS (ESI-) for m / z 385 (MH) "; Analysis found: C, 58.84; H, 4.09; N, 7.28; Cl, 9.16; S, 8.32.

EXAMPLE 7. N- (4-Chlorobenz 1) -4-hydroxy-2- (4-hydroxy-1-butynyl) thieno [2, 3-b] pyridin-5-carboxamide A suspension of N- (4-chlorobenz 1) -4-hydroxy-2-iodot-ieno [2, 3-b] pyridin-5-carboxamide (Example No. 2) (1.00 g) in diethylamine (28 mL) was added. added copper iodide (0.128 g) and Pd (P? h3) 2Cl2 (0.032 g) followed by the addition of 3-butin-1-ol (0.20 mL). The reaction was stirred at rt for 18. The reaction mixture was partitioned between H20 (100 mL) and ethyl acetate (100 mL). The organic layer was removed and the aqueous layer was extracted with ethyl acetate (2 x 100 mL). The combined organic layers were dried with MgSO 4, filtered and concentrated in vacuo. The resulting brown oil was purified by column chromatography (CH2C12: CH30H; 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a brown solid. This material was dissolved in DMF (15 mL) and 2N HCl was added until a precipitate formed. The resulting tan solid was purified by column chromatography (CH2C12: CH3OH; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 0.183 g (21%) of the title compound as a yellow crystalline solid. The physical characteristics are as follows: P.f. 242-246 ° C; XH NMR (300 MHz, DMSO-d6) d 13.31, 10.43, 8.73, 7.41-7.33, 4.95, 4.54, 3.59, 2.62; IR (trend) 2934, 2915, 2845, 2771, 2352, 2.327, 2224, 1965, 1920, 1662, 1646, 1587, 1538, 1515, 1500 cm "1; MS (ESI-) for m / z 385 (MH) " Analysis found: C, 58.61; H, 4.05; N, 7.18; Cl, 9.02; S, 8.11.

EXAMPLE 8. N- (4-Cyclohexene 1) -4-hydroxy-2- (3-hydroxypropyl) thieno [2, 3b] pyridin-5-caboxamide A solution of N- (4-chlorobenzyl) -4-hydroxy-2- (3-hydroxy-1-propynyl) -thieno [2, 3b] pyridine-5-carboxamide (Example No. 5) (0.300 g) in 1 / 1 CH2C12 / CH30H (70 mL) was hydrogenated over 10% Pd / C (90 mg) at 35 psi. After 3 h, an additional 90 mg of 10% Pd / C was added, and the solution was hydrogenated at 35 psi for 1 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting pale orange solid was purified by column chromatography (CH2C12: CH3OH; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to give an off white solid which was recrystallized from ethanol to give 0.083 g (27%) of the title compound as a white crystalline solid. The physical characteristics are as follows: P.f. 185-186 ° C; XH NMR (300 MHz, DMSO-d6) d 13. 29, 10.61, 8.64, 7.42-7.33, 7.11, 4.54, 3.45, 2.87, 1.80; 13 C NMR (75 MHz, DMSO-d 6) d 173.1, 165.2, 147.3, 141.3, 140.5, 139.1, 131.9, 129.6, 128.8, 118.7, 113.8, 60.0, 41.9, 34.3, 26.5; IR (trend) 3224, 2929, 2886, 2846, 2817, 2750, 2327, 1906, 1657, 1604, 1541, 1489, 1470, 802, 698 cm "1; MS (ESI-) for m / z 376 (MH) "; Analysis found: C, 57.06; H, 4.50; N, 7.40; Cl, 9.25; S, 8.35.

EXAMPLE 9. N- (4-Chlorobenz-1) -2-cyano-4-hydroxy-thieno [2,3-b] pyridin-5 -carboxamide OH O-? FY ,, To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-iodot-ieno [2, 3-b] pyridin-5-carboxamide (Example No. 2) (0.500 g) in pyridine (5 mL) was added CuCN (0.201 g). The reaction was heated to reflux and stirred for 18 h. The reaction mixture was purified by column chromatography (CH2C12: CH3OH; 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a pale yellow solid which was recrystallized from methanol to give 0.100 g (26%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 274-276 ° C (dec); XH NMR (300 MHz, DMSO-d6) d 13.30, 10.24, 8.68, 8.28, 7.41-7.33, 4.54; 13 C NMR (75 MHz, DMSO-d 6) d 173.1, 164.5, 152.1, 144.4, 138.8, 135.2, 131.9, 129.6, 128.8, 114.5, 103.4, 42.0; IR (trend) 3306, 3097, 3003, 2921, 2844, 2220, 1638, 1587, 1524, 1484, 1398, 1342, 1298, 884, 791 cm "1; HRMS (El) found 343.1082; Analysis found: C, 55.31; H, 2.88; N, 12.02; Cl, 9.95; S, 9.04.

EXAMPLE 10. 2- [3- (5-. {[[(4-chlorobenz 1) amino] carbonyl] -4-hydroxythieno [2, 3-b] pindin-2-yl) -2-propini 1] dimethyl malonate To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-iodot-ieno [2, 3-b] pi-ridin-5-carboxamide (Example No. 2) (0.500 g) in diethylamine (14 mL) and DMF (1.5 mL) was added copper iodide (0.064 g) and Pd (PPh3) 2Cl2 (0.039 g) followed by the addition of dimethyl propargyl malonate (0.24 mL). The reaction was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The resulting orange solid was purified by column chromatography (CH2Cl2: CH3OH; 98: 2). The homogeneous fractions by TLC was combined and concentrated in vacuo to give an orange solid which was recrystallized twice from methanol to give 0.267 g (49%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 197-198 ° C; XH NMR (300 MHz, DMSO-d6 d 13.30, 10.40, 8.74, 7.41-7.33, 4.54, 3.94, 3.71, 3.01; 13C NMR (75 MHz, DMSO-d6) d 168.5, 139.0, 131.9, 129.6, 128.8, 126.6 , 93.2, 74.8, 53.2, 50.3, 41.9, 19.6, IR (trend) 2353, 2327, 2229, 1738, 1663, 1646, 1593, 1568, 1540, 1516, 1491, 1435, 1347, 1286, 1240 cm "1; MS (FAB) m / z 487 (MH +, 99), 973 (7), 490 (12), 489 (43), 488 (37), 487 (99), 486 (21), 346 (27), 140 (13), 127 (14), 125 (41); HRMS (FAB) found 487.0714; Analysis found: C, 56.46; H, 3.80; N, 5.74; Cl, 7.32; S, 6.55 (corrected for 3.10% of H20).

EXAMPLE 11. 2-Bromo-N- (4-chlorobenzyl) -7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide A mixture of 2-bromo-7 -et i 1-4 -oxo-4,7-dihydro-ieno [2, 3-b] pi-ridin-5-carboxylic acid ethyl ester (Eur. J. Med. Chem. 1987, 22 , 139) (0.500 g) and 4-chlorobenzylamine (1.84 mL) was stirred at 190 ° C for 1 h. The reaction was then allowed to cool to rt and diluted with toluene. The resulting precipitate was removed by filtration and washed with toluene followed by hexanes to give a tan solid. This material was recrystallized from acetic acid / water then with ethanol to provide 0.379 g (59%) of the title compound as a white crystalline solid. The physical characteristics are as follows: P.f. 196-197 ° C; XH NMR (300 MHz, DMSO-d6) d 10.43, 8.76, 7.60, 7.41-7.33, 4.54, 4.30, 1.43; 13 C NMR (75 MHz, DMSO-d 6) d 171.4, 164.4, 150.2, 144.8, 139.0, 132.3, 131.9, 129.6, 128.8, 126.2, 115.5, 108.3, 52.3, 41.9, 14.3; IR (heating) 3083, 3043, 1441, 1416, 1411, 1232, 801 cm "1; MS (ESI +) m / z 426 (M + H) +; Analysis found: C, 48.01; H, 3.59; N, 6.54; Br, 18.43; Cl, 8.20; S, 7.35.

EXAMPLE 12. N- (4-Chlorobenz 1) -7 -et i 1-4 -oxo-4,7-dihydrothieno [2, 3b] pyridine-5-carboxamide A mixture of ethyl 7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylate (Eur. J. Med. Chem. 1987, 22, 139) (0.447 g. ) and 4-chlorobenzylamine (2.42 mL) was stirred at 190 ° C for 1 h. The reaction was then allowed to cool to rt and diluted with toluene. The resulting precipitate was removed by filtration and washed with toluene followed by hexanes to give a pale yellow solid. This material was recrystallized from acetic acid / water then with ethanol to provide 0.312 g (45%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 183-184 ° C; XH NMR (300 MHz, DMSO-d6) d 10.57, 8.78, 7.53, 7.46, 7.41-7.33, 4.55, 4.35, 1.45; 13 C NMR (75 MHz, DMSO-d 6) d 172.8, 164.8, 150.3, 144.9, 139.1, 132.0, 131.9, 129.6, 128.8, 123.3, 121.9, 115.0, 52.2, 41.9, 14.3; IR (heating) 3075, 1658, 1599, 1543, 1517, 1492, 1419, 1408, 1229, 1084, 1015, 808, 801, 714, 610 cm "1; MS (ESI +) m / z 347 (M + H) +, Analysis found: C, 58.62, H, 4.48, N, 8.07, Cl, 10.10, S, 9.12.

EXAMPLE 13. N- (4-Chlorobenz 1) -7-yl-2-iodo-4-OXO-4,7-dihydrothieno [2, 3b] pyridine-5-carboxamide Carbonyldiimidazole (0.290 g) was added to a solution of 7-ethyl-2-yl-2-oxido-4,7-dihydro-ieno acid [2]., 3-b] pyridine-5-carboxylic acid (Eur. J. Med. Chem. 1987, 22, 139) (0.520 g) in DMF (13 mL). The reaction was heated to 60 ° C and stirred for 18 h. The reaction mixture was cooled to rt, and 4-chlorobenzylamine (0.22 mL) was added. The reaction was stirred at rt for 7 h. The reaction mixture was drained in 20% aqueous HOAc (50 mL), and the resulting off-white solid was removed by filtration. This material was recrystallized twice from methanol to provide 0.372 g (53%) of the title compound as an off-white, crystalline solid. The physical characteristics are as follows: P.f. 214-218 ° C; XH NMR (300 MHz, DMSO-d6) d 10.45, 8.72, 7.71, 7.41-7.33, 7.53, 4.30, 1.42; 13 C NMR (75 MHz, TFA) d 166.4, 165.9, 158.7, 141.5, 134.9, 133.1, 131.0, 129.7, 129.1, 129.0, 110.2, 108.8, 77.4, 56.0, 44.0, 12.4; IR (trend) 1654, 1590, 1541, 1511, 1489, 1431, 1408, 1295, 1217, 1086, 1014, 851, 800, 794, 707, cm "1; MS (ESI +) m / z 473 (M + H ) +; Analysis found: C, 42.80, H, 3.00, N, 5.82, Cl, 7.51, S, 6.85.

EXAMPLE 14. N- (4-Chlorobenz 1) -7-ethyl-2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide To a suspension of N- (4-chlorobenzyl) -7-yt-yl-2-iodo-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide (Example No. 12) (0.267 g) in diethylamine (14 mL) was added copper iodide (0.032 g) and Pd (PPh3) 2Cl2 (0.009 g) followed by the addition of propargyl alcohol (39 μL). The reaction was stirred at rt for 18 h. The diethylamine was removed in vacuo, and the resulting residue was partitioned between H20 (25 mL) and CH2C12 (25 mL). The organic layer was removed, and the aqueous layer was extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried with MgSO4, and concentrated in vacuo. The resulting orange solid was purified by column chromatography (CH2Cl2: CH3OH, 98: 2). The homogeneous fractions by TLC was combined and concentrated in vacuo to provide 0.158 g (70%) of the title compound as a crystalline, yellow solid. The characteristics are as follows: P.f. 217-219 ° C; XH NMR (300 MHz, DMSO-d6) d 10.41, 8.79, 7.53, 7.41-7.33, 5.47, 4.54, 4.36, 4.29, 144; 13 C NMR (75 MHz, DMSO-d 6) d 172.3, 164.4, 149.7, 145.5, 138.9, 131.9, 131.5, 129.6. 128.8, 128.0, 116.9, 115.6, 96.9, 76.2, 52.4, 50.0, 41.9, 14.2; IR (trend) 3390, 2478, 2339, 2284, 2040, 1915, 1655, 1591, 1544, 1502, 1300, 1224, 1029, 1015, 795, cm "1; MS (ESI +) m / z 399 (M + H ) +; Analysis found: C, 59.42; H, 4.35; N, 6.88; Cl, 8.85; S, 7.98.

EXAMPLE 15. N- (4-Chlorobenz 1) -7-ethyl-2- (4-hydroxy-1-butynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pi ridin-5-carboxamide To a suspension of 2-bromo-N- (4-chlorobenzyl) -7-ethyl-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide (Example No. 11) ( 0.500 g) in diethylamine (12 mL) was added copper iodide (0.067 g) and Pd (PPh3) 2Cl2 (0.041 g) followed by the addition of 3-butin-l-ol (0.11 mL). The reaction was stirred at rt for 3 d. The diethylamine was removed in vacuo and the resulting residue was partitioned between H20 (50 mL) and CH2C12 (50 mL). The organic layer was removed, and the aqueous layer was extracted with CH C12 (3 x 50 mL). The combined organic layers were washed with a solution saturated with NH C1 (50 mL), dried over MgSO4, filtered, and concentrated in vacuo. The resulting orange solid was purified by column chromatography (CH2C12: CH30H, 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo. The resulting yellow solid was recrystallized from methanol to provide 0.312 g (64%) of the title compound as a pale yellow, crystalline solid. The physical characteristics are as follows: P.f. 158-162 ° C; 1 H NMR (300 MHz, DMSO-d 6) d 10.43, 8.78, 7.48, 7.41-7.33, 4.96, 4.55, 4.31, 3.60, 2.63, 1.43; 13 C NMR (75 MHz, DMSO-d 6) d 172.2, 164.4, 149.2, 145.3, 139.0, 131.9, 131.5, 129.6, 128.8, 127.1, 117.9, 115.5, 96.4, 73.5, 59.8, 52.4, 24.1, 14.2; IR (trend) 3050, 2223, 1921, 1653, 1593, 1549, 1545, 1502, 1389, 1298, 1230, 1092, 1058, 799, 725 cm "1; HRMS (El) found 414.0800; Analysis found: C, 60.70; H, 4.56; N, 6.77; Cl, 8.43; S, 7.59 (corrected for 0.75% H20).

EXAMPLE 16. N- (4-Chlorobenz 1) -7-ethyl-2- (3-hydroxypropyl) -4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide A solution of N- (4-chlorobenz 1) -7 -et i 1-2- (3-hydroxy-l-propynyl) -4 -oxo-4,7-dihydro-ieno [2, 3-b] pyridin-5 -carboxamide (Example No. 14) (0.197 g) in 1/1 CH2C12 / CH30H (50 mL) was hydrogenated over 10% Pd / C (59 mg) at 35 psi for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting yellow solid was purified by column chromatography (CH2C12, CH2C12: CH3OH; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 0.114 g (57%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 144-146 ° C; ÍH NMR (300 MHz, DMSO-d6) d 10.62, 8.72, 7.41-7.33, 7.20, 4.56, 4.55, 4.31, 3.47, 2.90, 1.80, 1.44; 13 C NMR (75 MHz, DMSO-ds) d 172.3, 164.8, 148.6, 144.2, 140.5, 139.1, 132.1, 131.8, 129.6, 128.8, 120.0, 115.1, 60.0, 52.1, 41.9, 34.3, 26.5, 14.4; IR (trend) 1491, 1299, 1230, 1092, 801, 708 cm "1; MS (ESI-) for m / z 403 (M-H)"; Analysis found: C, 59.61; H, N, 6.75; Cl, 8.51; S, 7.61.

EXAMPLE 17. N- (4-Chlorobenz 1) -7- (2-hydroxyethyl) -2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine 5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (3-hydroxy-1-propynyl) thieno [2,3-b] pyridine-5-carboxamide (Example No. 5) (0.250 g) DMF (3 mL) was added K2C03 (0.278 g) and 2-bromoethanol (0.14 mL). The reaction was heated to 100 ° C and stirred for 18 h. The reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between H20 (50 mL) and CH2C12 (50 mL). The aqueous layer was extracted with CH2C12 (3 x 50 mL). The combined organic layers were dried with MgSO 4, filtered, and concentrated in vacuo to provide a small amount of the starting material. The desired product was precipitated from the aqueous layer as a tan solid. This material was recrystallized from methanol to provide 0.100 g (36%) of the title compound as a tan crystalline crystalline solid. The physical characteristics are as follows: P.f. 231-234 ° C (dec); XH NMR (300 MHz, DMSO-d6) d 10.43, 8.70, 7.56, 7.42-7.33, 5.46, 5.16, 4.55, 4.36, 4.31, 3.82; 13 C NMR (75 MHz, DMSO-d 6) d 174.4, 167.0, 152.9, 149.0, 114.3, 134.2, 133.2, 132.8, 132.0, 131.2, 130.1, 119.1, 117.3, 99.1, 78.5, 62.1, 52.3, 44.2; IR (trend) 3381, 3228, 2395, 2218, 1905, 1646, 1591, 1555, 1505, 1341, 1079, 1026, 848, 800, 602 cm "1; HRMS (El) found 416.0596; Analysis found: C, 56.62; H, 3.99; N, 6.52; Cl, 8.35; S, 7.52.

EXAMPLE 18. N- (4-Chlorobenzyl) -7- [2- (diethylamino) ethyl] -2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] hydrochloride ] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (3-hydroxy-1-propynyl) thieno [2, 3-b] pyridine-5-carboxamide (Example No. 5) (0.300 g) DMF (4 mL) was added K2C03 (0.334 g) and 2-bromo-N, N-diethylethylamine hydrobromide (0.420 g). The reaction was heated to 90 ° C. After 4.5 h, an additional 0.111 g of K2C03 was added and the reaction was stirred at 90 ° C for 3 d. An additional 0.210 g of 2-bromo-N, N-diethylamine hydrobromide and 0.111 g of K2C03 were added and the reaction is for 5 h. additional The reaction mixture was added to H20 and then concentrated in vacuo. The resulting brown solid was purified by column chromatography (CH2C12: CH30H; 98: 2, 95: 5). The resulting yellow solid was dissolved in methanolic HCl and concentrated in vacuo. The salt was recrystallized twice from ethanol to provide 0.080 g (20%) of the title compound as a pale yellow solid. The physical characteristics are as follows: P.f. 212-214 ° C (dec); H NMR (300 MHz, DMSO-d6) d 10.84, 10.36, 8.89, 7.58, 7.42-7.33, 5.50, 4.77, 4.56, 4.36, 3.60-3.54, 3.27-3.17, 1.26; 13C NMR (75 MHz, DMSOd6) d 172.5, 164.2, 150.3, 146.7, 138.9, 131.9, 131.6, 129.6, 128.8, 127.9, 117.0, 115.8, 97.1, 76.1, 51.0, 50.0, 48.5, 47.1, 42.0, 40.8, 8.9; IR (trend) 3295, 3290, 2459, 2352, 2342, 1920, 1666, 1595, 1550, 1503, 1457, 1356, 1229, 1031, 798 cm "1; MS (FAB) m / z 472 (MH +); HRMS (FAB) found 472.1470; Analysis found: C, 55.19; H, 5.32; N, 8.05; Cl, 13.74; S, 6.11.

EXAMPLE 19. Acid 2 - [5-. { [(4-chlorobenzyl amino] carbonyl.] -2- (3-hydroxy-l-propynyl) -4-oxothieno [2,3-b] pyridin-7 (4H) -yl] -acetic To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (3-hydroxy-1-propynyl) -thieno [2, 3-b] pyridine-5-carboxamide (Example No. 5) (0.250 g ) in DMF (3 mL) was added K2CO3 (0.278 g) and bromoacetic acid (0.279 g). The reaction was heated to 100 ° C and stirred for 18 h. An additional 0.200 g of bromoacetic acid was added and the reaction was stirred for 18 h. additional The reaction mixture was concentrated in vacuo, and the resulting residue was dissolved in 10% NaOH and washed with CH2C12. The aqueous layer was acidified with concentrated HCl and the resulting precipitate was filtered. This material was recrystallized 3 times from methanol to provide 0.068 g (24%) of the title compound as a tan solid. The physical characteristics are as follows: P.f. 230-235 ° C (dec); XH NMR (300 MHz, DMSO-d6) d 13.85, 10.34, 8.83, 7.57, 7.42-7.33, 5.48, 5.45, 4.56, 4.34; 13 C NMR (75 MHz, DMSO-d 6) d 172.4, 168.5, 164.2, 150.9, 147.3, 138.9, 131.9, 131.1, 129.6, 128.9, 127.8, 116.9, 115.5, 97.0, 76.0, 57.0, 50.0, 42.0; IR (trend) 3362, 3279, 2342, 2223, 1726, 1639, 1581, 1551, 1505, 1416, 1243, 1222, 1208, 1027, 801 cm "1; MS (FAB) m / z (relative intensity) 431 ( MH +, 99), 433 (39), 432 (26), 431 (99), 290 (20), 125 (34), 121 (21), 119 (13), 81 (11), 63 (23), 49 (24); HRMS (FAB) found 431.0474; Analysis found: C, 52.52; H, 3.33; N, 6.08; Cl, 9.90; S, 7.10.

EXAMPLE 20. N- (4-chlorobenz 1) -7-ethyl-2- (4-hydroxybutyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide A solution of N- (4-chlorobenzyl) -7 -et i 1-2 • (4-hydroxy-l-butynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (Example No. 15) (0.257 g) in 1/1 CH2C12 / CH30H (50 mL) was hydrogenated over 10% Pd / C (75 mg) at 35 psi for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was purified by column chromatography (CH2C12: CH30H; 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give 0.209 g (81%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 136-139 ° C; 1 H NMR (300 MHz, DMSO-d 6) d 10.60, 8.72, 7.41-7.33, 7.20, 4.55, 4.42, 4.31, 3.44, 2.88, 1.69, 1.49, 1.44; 13 C NMR (75 MHz, DMSO-d 6) d 172.3, 164.8, 148.6, 144.1, 140.7, 139.1, 132.1, 131.8, 129.6, 128.8, 120.0, 115.1, 60.7, 52.1, 41.9, 32.2, 29.7, 27.8, 14.4; IR (trend) 3052, 2934, 1920, 1653, 1593, 1550, 1506, 1390, 1304, 1231, 1092, 1052, 801, 725, 710 cm "1; MS (ESI-) for m / z 417 (MH) "; Analysis found: C, 60.26; H, 5.51; N, 6.73; Cl, 8.25; S, 7.43.

EXAMPLE 21. N- (4-chlorobenz 1) -7- (2-hydroxyethyl) -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (3-hydroxypropyl) -thieno- [2, 3-b] pyridine-5-carboxamide (Example No. 8) (0.330 g) in DMF (5 mL) K2CO3 (0.363 g) and 2-bromoethanol (0.19 mL) were added. The reaction was heated to 100 ° C and stirred for 18 h. An additional 0.19 mL of 2-bromoethanol was added and stirring was continued for 18 h. An additional 0.19 mL of 2-bromoethanol and 0.363 g of K2CO3 were added. After 5 h, 35 mg of NaH was added (dispersion in 60% oil). The reaction was stirred for 1 h. The reaction mixture was cooled to rt and concentrated in vacuo. The residue was suspended in CH2C12 and H20. The resulting off-white precipitate was removed by filtration and purified by column chromatography (CH2C12: CH3OH; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 0.145 g (39%) of the title compound as a white solid.

The physical characteristics are as follows: P.f. 174-178 ° C; XH NMR (300 MHz, DMSO-d6) d 10.62, 8.63, 7.41-7.33, 7.19, 5.14, 4.58-4.53, 4.29, 3.81, 3.47, 2.90, 1.79; 13 C NMR (75 MHz, DMSO-d 6) d 172.4, 164.9, 149.2, 145.5, 140.2, 139.1, 132.0, 131.9, 129.6, 128.8, 119.9, 114.4, 60.0, 59.4, 58.7, 41.9, 34.3, 26.4; IR (trend) 3282, 3265, 2480, 1657, 1648, 1599, 1550, 1524, 1493, 1304, 1220, 1090, 1057, 1014, 798 cm "1; MS (ESI-) for m / z 419 (MH) Analysis found: C, 56.84; H, 5.01; N, 6.53; Cl, 8.33; S, 7.47.

EXAMPLE 22. N- (4-Chlorobenzyl) -7- [2- (diethylamino) ethyl] -2- (3-hydroxypropyl) -oxo-4,7-dihydro-ieno [2, 3-b] pyridine hydrochloride 5-carboxamide To a solution of N- (4-chlorobenz 1) -4-hydroxy-2- (3-hydroxypropyl) thieno [2,3-b] pyridine-5-carboxy-ida (Example No. 8) (0.300 g) in DMF (4%). mL) were added K2C03 (0.550 g) and 2-bromo-N, N-diethylethylamine hydrobromide (0.623 g). The reaction was heated to 90 ° C and stirred for 3 d. An additional 0.220 g of K2C03 and 0.415 g of 2-bromo-N, N-diethylethylamine hydrobromide were added. The reaction was stirred at 90 ° C for 6 h. The reaction mixture was concentrated in vacuo, and the resulting residue was partitioned between CH2C12 (25 mL) and H20 (25 mL). The aqueous layer was extracted with CH2C12 (3 x 25 mL). The combined organic layers were dried with MgSO, filtered and concentrated in vacuo. The resulting yellow oil was purified by column chromatography (CH2C12: CH3OH; 98: 2, 95: 5). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a yellow oil. This material was dissolved in methanolic HCl and then concentrated in vacuo. The residue was recrystallized twice from ethyl acetate / methanol to provide 0.078 g (19%) of the title compound as an off-white, crystalline solid. The physical characteristics are as follows: P.f. 111-114 ° C; XH NMR (300 MHz, DMSO-d6) d 10.93, 10.53, 8.82, 7.42-7.33, 7.21, 4.76, 4.56, 3.55, 3.42, 3.22, 2.92, 1.83, 1.28; 13C NMR (75 MHz, DMSO-d6) d 172.5, 164.6, 149.0, 145.5, 140.6, 139.1, 132.1, 131.9, 129.6, 128.8, 120.2, 115.4, 60.0, 50.7, 48.7, 47.2 ,. 41.9, 34.4, 26.5, 8.9; IR (trend) 2350, 2350, 2338, 2329, 2250, 1941, 1656, 1596, 1537, 1507, 1489, 1459, 1451, 1011, 799 cm "1; MS (FAB) m / z 476 (MH); HRMS; (FAB) found 476.1792; Analysis found: C, 55.44; H, 6.27; N, 8.01; Cl, 13.90; S, 6.24 (corrected for 6.35% H? O).

EXAMPLE 23. N- (4-chlorobenz 1) -2-iodo-7-methyl-4-oxo-4,7-dihydrothieno [2, 3b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-yodot i eno [2,3-b] pyridin-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) was they added K2C03 (1.76 g) and iodomethane (0.79 mL). The reaction was heated to 90 ° C and stirred for 18 h. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between H20 (100 mL) and CH2C12 (200 mL). The aqueous layer was extracted with CH2C12 (3 x 150 mL). The combined organic layers were dried with MgSO 4, filtered and concentrated in vacuo. The resulting off-white solid was recrystallized from ethanol to provide 1.78 g (92%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 236-237 ° C; XH NMR (300 MHz, DMSO-d6) d 10.45, 8.69, 7.71, 7.41-7.32, 4.54, 3.93; 13 C NMR (75 MHz, DMSO-d 6) d 171.1, 164.5, 154.8, 145.9, 139.0, 133.2, 132.5, 131.9, 129.6, 128.8, 115.0, 73.5, 43.5, 41.9; IR (trend) 3042, 1916, 1648, 1595, 1545, 1514, 1492, 1426, 1361, 1340, 1305, 1242, 1172, 1123, 798 cm "1; MS (ESI +) for m / z 459 (M + H) +; Analysis found: C, 41.65; H, 2.63; N, 6.17; Cl, 7.76; S, 6.96.

EXAMPLE 24. N- (4-Chlorobenz 1) -2 - (3-hydroxy-1-propynyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide To a suspension of N- (4-chlorobenzyl) -2-iodo-7-methyl-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide (Example No. 23) ( 1632 g) in diethylamine (40 mL) was added copper iodide (0.210 g) and Pd (PPh3) 2Cl2 (0.125 g) followed by the addition of propargyl alcohol (0.29 mL). The reaction was stirred at rt for 18 h. The diethylamine was removed in vacuo and the resulting solid coffee was purified by column chromatography (CH2C12: CH3OH; 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give an orange solid which was recrystallized from ethanol to provide 1.06 g (77%) of the title compound as a yellow solid. The physical characteristics are as follows: P.f. 206-208 ° C; XH NMR (300 MHz, DMSO-d6) d 10.42, 8.76, 7.57, 7.41-7.33, 5.47, 4.55, 4.37, 3.95; 13 C NMR (75 MHz, DMSO-d 6) d 172.2, 164.4, 151.0, 146.8, 138.9, 131.9, 130.9, 129.6, 128.8, 128.0, 116.9, 115.2, 96.8, 76.2, 50.0, 43.6, 41.9; IR (trend) 3378, 3222, 3058, 1651, 1593, 1550, 1544, 1509, 1410, 1349, 1305, 1243, 1026, 799, 714 cm "1; MS (FAB) m / z 387 (MH +); HRMS (FAB) found 387.0558; Analysis found: C, 58.79; H, 3.99; N, 7.28; Cl, 9.26; S, 7.98 (corrected for 1.53% of H20).

EXAMPLE 25. N- (-Clorobenz 1) -2- (3-hydroxypropyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pindin-5 -carboxamide HQ O Q ^ tf Mjßfr A solution of N- (4-chlorobenzyl) -2- (3-hydroxy-1-prcpinyl) -7-methyl-4-cxo-4,7-dihydroxy-dihydroxy-2-dihydroxybenzoate. carboxamide (Example No. 24) (0.520 g) in 1/1 CH2Cl2 / ethanol (160 mL) was hydrogenated over 10% Pd / C (0.156 q) at 35 psi for 2 h. The reaction mixture was filtered through a pad of celite and the filtrate was concentrated in vacuo. The resulting pale yellow solid was purified by column chromatography (CH2C12: CH3OH; 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a pale yellow solid (this material contained a small amount of partially reduced product). This material was dissolved in ethanol (100 mL) and hydrogen on 10% Pd / C (0.156 g) at 35 psi for 1 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting off-white solid was recrystallized from ethanol to provide 0.211 g (40%) of the desired product as a white solid. The physical characteristics are like siaue: P.f. 197-198 ° C; XH NMR (300 MHz, DMSO-d6) d 10.61, 8.69, 7.41-7.33, 7.21, 4.58-4.53, 3.95, 3.47, 2.91, 1.80; 13 C NMR (75 MHz, DMSO-d 6) d 172.2, 164.9, 149.8, 145.5, 140.6, 139.1, 131.8, 131.5, 129.6, 128.8, 120.0, 114.7, 60.0, 43.4, 41.9, 34.4, 26.5; IR (trend) 3052, 1921, 1653, 1596, 1557, 1512, 1489, 1429, 1305, 1242, 1091, 1032, 801, 727, 712 cm "1; HRMS (FAB) found 391.0904; Analysis found: C, 57.42; H, 4.78; N, 7.03; Cl, 8.78; S, 8.13.

EXAMPLE 26. N- (4-Chlorobenzyl) -2-iodo-7-isopropyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-yodothieno [2, 3-b] pyridine-5-carboxamide (Example No. 2) (2.00 g) in DMF (14 mL) was added K2C03 (1.76 g) and 2-bromopropane (1.19 mL). The reaction was heated to 90 ° C and stirred for 18 h. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between H20 (100 mL) and CH2C12 (200 mL). The aqueous layer was extracted with CH2C12 (3 x 150 mL). The combined organic layers were dried with MgSO4, filtered and concentrated in vacuo. The resulting yellow solid was purified by column chromatography (CH2C12, CH2C12: CH3OH; 99: 1). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a yellow solid. This material was recrystallized from ethanol then with methanol to give 0.808 g (39%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 173-180 ° C; 1ti NMR (300 MHz, DMSO-d6) d 10.45, 8.65, 7.71, 7.41-7.33, 4.54, 4.49, 1.56; 13 C NMR (75 MHz, DMSO-d 6) d 171.2, 164.4, 153.6, 140.5, 139.0, 133.9, 132.5, 131.9, 129.7, 128.8, 115.5, 73.8, 59.5, 42.0, 21.4; IR (trend) 2975, 1905, 1661, 1587, 1280, 1223, 1209, 1193, 794 cm "1; MS (ESI +) for m / z 487 (M + H) +; Analysis found: C, 44.36; H, 3.21; N, 5.76; Cl, 7.31; S, 6.55.

EXAMPLE 27. N- (4-Chlorobenz 1) -2 - (3-hydroxy-1-propynyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide To a suspension of N- (4-chlorobenzyl) -2-iodo-7-isopropyl-4-oxo-4,7-dihydro-thieno [2,3-b] pyridine-5-carboxamide (Example No. 26) ( 0.717 g) in diethylamine (20 mL) was added copper iodide (0.084 g) and Pd (PPh3) 2Cl2 (0.052 g) followed by the addition of propargyl alcohol (0.12 mL). The reaction was stirred at rt for 18 h. The diethylamine was removed in vacuo and the resulting brown solid was purified by column chromatography (CH2C12: CH3OH, 98: 2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give an orange solid which was recrystallized from ethanol then with methanol to provide 0.281 g (46%) of the title compound as a yellow crystalline solid. The physical characteristics are as follows: P.f. 190-196 ° C; XH NMR (300 MHz, DMSO-d6) d 10.42, 8.71, 7.56, 7.41-7.33, 5.47, 4.54, 4.51, 4.37, 3.95, 1.57; 13C NMR (75 MHz, DMSO-d6) d 172.2, 164.3, 149.7, 141.2, 140.6, 138.9, 131.9, 131.6, 129.7, 128.8, 128.0, 123.3, 121.8, 116.9, 115.7, 96.9, 76.1, 59.5, 50.0, 42.0 , 21.4; IR (trend) 3450, 2320, 2229, 2059, 1908, 1657, 1591, 1550, 1500, 1291, 1218, 1203, 1045, 803, 795 cm "1; MS (ESI +) for m / z 415 (M + H) +, Analysis found: C, 60.47, H, 4.50, N, 6.55, Cl, 8.47, S, 7.73.

EXAMPLE 28. N- (4-Chlorobenz 1) -2 - (3-hydroxypropyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide A solution of N- (4-chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (Example No. 27) (0.225 g) in ethanol (50 mL) was hydrogenated over 10% Pd / C (68 mg) at 35 psi for 2 h. The reaction mixture was filtered through a pad of celite, and the filtrate was concentrated in vacuo. The resulting pale yellow solid was recrystallized from ethyl acetate / heptane to give 0.104 g (46%) of the desired product as an off-white solid. The physical characteristics are as follows: P.f. 84-92 ° C; 1ti NMR (300 MHz, DMSO-d6) d 10.61, 8.66, 7.41-7.33, 7.21, 4.594.50, 3.47, 2.91, 1.80, 1.57; 13 C NMR (75 MHz, DMSO-d 6) d 172.2, 164.8, 148.6, 140.4, 140.0, 139.1, 132.2, 131.9, 129.7, 128.8, 120.0, 115.1, 60.0, 59.0, 41.9, 34.3, 26.4, 21.5; IR (trend) 3491, 1660, 1594, 1538, 1504, 1465, 1448, 1349, 1325, 1294, 1216, 1090, 1060, 1012, 798 cm "1; MS (FAB) m / z 419 (MH +); HRMS (FAB) found 419.1172; Found analysis: C, 60.06; H, 5.52; N, 6.58; Cl, 8.27; S, 7.57.

EXAMPLE 29. Acid 4 -. { [3- (5- { [(4-chlorobenzyl) amino] carbonyl.} - 7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-2-yl) -2 -propinil] oxy} -4-oxobutanoic To a solution of N- (4-chlorobenzyl) -7-ethyl-2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide ( Example No. 14) (0.200 g) in pyridine (10 mL) was added succinic anhydride (0.639 g). The reaction was stirred at rt for 18 h then at 40 ° C for 1 h. The reaction mixture was concentrated in vacuo. The residue was suspended in H20 (25 mL) and stirred for 1 h. A whitish solid was removed by filtration and recrystallized from ethanol to give 0.210 g (84%) of the title compound as a pale yellow, crystalline solid.

The physical characteristics are as follows: P.f. 180-182 ° C; 1ti NMR (300 MHz, DMSO-d6) d 12. 27, 10.38, 8.80, 7.65, 7.417.33, 5.02, 4.54, 4.31, 2. 62-2.50, 1.44; 13C NMR (75 MHz, DMSO-d6) d 173.7, 172.3, 172.0, 164.3, 150.1, 145.6, 138.9, 131.9, 131. 4, 129.6, 129.3, 128.8, 115.7, 91.0, 78.2, 52.8, 52. 4, 42.0, 29.1, 29.0, 14.2; IR (trend) 2233, 1927, 1728, 1698, 1651, 1590, 1546, 1503, 1348, 1325, 1307, 1230, 1211, 1172, 801 cm "1; MS (ESI-) for m / z 499 (M-H) - Analysis Found: C, 57.27; H, 4.40; N, . 64; Cl, 7.04; S, 6.35.

EXAMPLE 30. 3- (5- { [(4-chlorobenz 1) amino] carbonyl.} - 7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-2-yl. ) -2-propynyl 2 - (4 -mor folinyl) acet ato To a suspension of N- (4-chlorobenzyl) -7-ethyl-2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide ( Example No. 14) (0.300 g) in CH2C12 (3 mL) at 0 ° C was added pyridine (67 pL) followed by the dropwise addition of bromoacetyl bromide (72, μL). The reaction was allowed to warm to rt. After stirring for 2 h at rt, an additional 67 μL of pyridine and 72 μL of bromoacetyl bromide were added. The reaction was stirred at rt for 30 min. The reaction mixture was diluted with CH2C12 (25 mL) and extracted with H2O (2 x 25 mL). The organic layer was dried with MgSO 4, filtered, and concentrated in vacuo. The resulting yellow solid was recrystallized from methanol to provide 0.314 g (80%) of the bromide. This material (0.250 g) was dissolved in acetonitrile (5 mL) and CH2C12 (2 mL). Morpholine (0.10 mL) was added and the reaction was stirred at rt for 1 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in CH2C12 (70 mL) and washed with H20 (2 x 70 L) and brine (70 mL), dried with MgSO4, filtered, and concentrated in vacuo. The resulting yellow solid was recrystallized from methanol to provide 0.183 g (72%) of the title compound as a pale yellow, crystalline solid. The physical characteristics are as follows: P.f. 168-170 ° C; ? H NMR (300 MHz, DMSO-d6) d 10.45, 8.67, 7.69, 7.33-7.27, 4.99, 4.63, 4.16, 3.78, 3.33, 1.60; 13C NMR (75 MHz, CDC13) d 172.8, 168.8, 164.6, 149.6, 144.1, 137.2, 132.9, 131.8, 129.7, 129.0, 128.7, 116.3, 116.0, 89.1, 78.7, 66.5, 59.0, 53.1, 52.8, 52.4, 42.6 , 14.1; IR (trend) 2229, 1921, 1730, 1655, 1596, 1543, 1500, 1348, 1228, 1192, 1175, 1133, 1112, 1011, 799 cm "1; MS (ESI +) for m / z 528 (M + H) +; Analysis found: C, 59.07; H, 4.90; N, 7.86; Cl, 6.72; S, 6.08.

EXAMPLE 31. 3- (5- ([(4-Chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-dihydrothieno [2, 3-b] 2-amino-3-methylbutanoate hydrochloride. ] pyridin-2-yl) -2-propynyl To a solution of N- (4-chlorobenzyl) -7-ethyl-2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide ( Example No. 14) (0.400 g) in pyridine (16 mL) were added EDC (0.288 g), DMAP (0.020 g), and N-Boc valine (0.326 g). The reaction was stirred at rt for 3 d. The reaction mixture was concentrated in vacuo. The residue was dissolved in CH2C12 (80 mL), washed with H20 (40 mL) and brine (40 mL), dried with MgSO4, filtered, and concentrated in vacuo.

The resulting yellow solid was recrystallized from ethanol to provide 0.492 g (82%) of the Boc-protected compound. This material (0.303 g) was dissolved in CH2C12 (6 mL) and cooled to 0 ° C. Trifluoroacetic acid (6 mL) was added, and the reaction was stirred at 0 ° C for 1 h. The reaction mixture was concentrated in vacuo. The resulting residue was dissolved in CH2C12 (60 mL), washed with NaHCO3 (60 mL) and H20 (60 mL), dried with MgSO4, filtered and concentrated in vacuo The resulting white solid was recrystallized from ethanol provide 0.128 g (51%) of the free amine as a white crystalline solid.The amine (0.105g) was dissolved in methanolic HCl (4 mL) and concentrated in vacuo.The resulting residue was recrystallized from methanol / ethyl acetate. ethyl to give 0.092 g (81%) of the title compound as a white solid.The physical characteristics are as follows: Mp 171-172 ° C; 1ti NMR (300 MHz, DMSO-d6) d 10.36, 8.81, 8.52, 7.66, 7.42-7.33, 5.22, 4.55, 4.33, 4.02, 2.22, 1.44, 1.01; 13C NMR (75 MHz, DMSO-d6) d 172.3, 169.0, 164.2, 150.3, 145.8, 138.9, 131.9, 131.3, 129.6, 129.5, 128.8, 115.7, 115.3, 90.1, 79.0, 57.6, 54.1, 52.5, 42.0, 30.0 , 18.7, 18.0, 14.2; IR (trend) 3047, 2968, 2935, 2914, 2879, 2226, 1931, 1754, 1649, 1594, 1544, 1502, 1232, 1212, 803 cm "1; MS (FAB) m / z 500 (MH +); HRMS (FAB) found 500.1408; Analysis found: C. 54.10; H, 5.06; N, 7.55; Cl, 12.77; S, 5.81.

EXAMPLE 32. 3- (4 -mor fol ini lmet i 1) 3- (5- {[[(4-Chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-benzoate. dihydrothieno [2,3-b] pyridin-2-yl) -2-propynyl To a solution of N- (4-chlorobenzyl) -7-ytl-2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (Example No. 14) (0.956 g) in CH2C12 (15 mL) and triethylamine (0.73 mL) was added 3-chlorome-t-benzene chloride (0.74 mL). The reaction was stirred at rt for 18 h. The reaction mixture was concentrated in vacuo. The resulting residue was partitioned between H20 (80 mL) and CH2C12 (80 mL). The aqueous layer was extracted with CH2C12 (3 x 80 mL). The combined organic layers were dried with MgSO 4, filtered, and concentrated in vacuo. The resulting yellow oil was purified by column chromatography (CH2C12, CH2C12: CH3OH, 98: 2). The resulting yellow solid was recrystallized from ethyl acetate to give 0.797 g (61%) of the chloride as a pale yellow solid. This material (0.400 g) was suspended in DMF (6 mL), and K2C03 (0. 300 g) and morpholine (0.19 mL) were added. The reaction was heated to 90 ° C and stirred for 2 h. The reaction mixture was cooled to rt and concentrated in vacuo. The resulting residue was partitioned between H20 (80 mL) and CH2C12 (80 mL). Brine (50 mL) was added to separate the emulsion that formed. The aqueous layer was extracted with CH2C12 (3 x 80 L). The combined organic layers were dried with MgSO, filtered, and concentrated in vacuo. The resulting pale yellow solid was recrystallized from ethanol to provide 0.346 g (79%) of the title compound as a pale yellow solid. The physical characteristics are as follows: P.f. 147-150 ° C; 1ti NMR (300 MHz, DMS0-d6) d 10.38, 8.80, 7.95-7.89, 7.69, 7.64, 7.52, 7.41-7.33, 5.29, 4.55, 4.323.59-3.54, 2.36, 1.44; 13C NMR (75 MHz, DMS0-d6) d 172.3, 165.5, 164.3, 150.2, 145.7, 138.9, 134.9, 131.9, 131.4, 131.4, 130.2, 129.6, 129.5, 129.4, 128.8, 128.7, 115.7, 115.6, 91.0, 78.5, 66.6 , 62.2, 53.5, 52.4, 41.9, 14.1; IR (trend) 2228, 1926, 1726, 1651, 1591, 1542, 1500, 1300, 1278, 1248, 1189, 1118, 1081, 800, 743 cm "1; MS (ESI +) for m / z 604 (M + H) Analysis found: C, 63.41; H, 4.89; N, Cl 5.97 5.32 EXAMPLE 33. 5 -. { [(-chlorobenz 1) amino] carbonyl} Methyl-2-hydroxyethyl [2, 3-b] pyridin-2-carboxylate OH O CHjO. ? ft k Cl To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-yodothieno [2, 3-b] pyridin-5-carboxamide (2.61 g) from Example No. 2 in DMF (33 mL) was added triethylamine ( 1.6 L), methanol (9.5 mL), Pd (0Ac) 2 (0.132 g), and dppp (0.242 g). Carbon monoxide was bubbled through the solution and the reaction was heated to 70 ° C. The reaction was stirred at 70 ° C for 18 h. The reaction mixture was cooled to rt, and water (25 mL) and 2 N HCl (25 mL) were added. The resulting precipitate was removed by filtration and purified by column chromatography (CH2C12; CH2Cl2 / methanol, 99/1; 98/2). A mixture of the starting material and the desired product was isolated as a yellow solid. This material was resubmitted to the above reaction conditions. The reaction was stirred at 70 ° C for 18 h. The reaction was cooled to rt and water (25 mL) and 2 N HCl (25 mL) were added. The resulting orange solid was removed by filtration and purified by column chromatography (CH2C12; CH2Cl2 / methanol, 99/1; 98/2). The homogeneous fractions by TLC were combined and concentrated in vacuo to give a pale yellow solid which was recrystallized from methanol to provide 1337 g (60%) of the title compound as a pale yellow, crystalline solid. The physical characteristics are as follows: P.f. 238-240 ° C; XH NMR (300 MHz, DMSO-d6) d 13.45, 10.30, 8.80, 7.96, 7.41- 7.33, 4.55, 3.87; 13 C NMR (75 MHz, DMSO-d 6) d 173.3, 164.1, 161.7, 151.4, 143.5, 138.5, 131.4, 130.6, 129.1, 128.3, 127.9, 126.4, 114.0, 52.7, 41.4; IR (trend) 2944, 2350 (w), 1729, 1645, 1595, 1549, 1543, 1485, 1478, 1433, 1284, 1238, 1175, 800, 751 c "1; MS (ESI-) for m / z 375 (MH) ~ .. Analysis found (corrected for 3.64% of H20): C, 54.03; H, 3.38; N, 7.39; Cl, 9.41; S, 8.52.

EXAMPLE 34. N- (4-Chlorobenz 1) -4-hydroxy-2- (hydroxymethyl) thieno [2, 3b] pyridine-5-carboxamide.

It dissolved 5 -. { [(4-chlorobenzyl) amino] carbonyl} Methyl-4-hydroxyethyl [2, 3-b] pyridine-2-carboxylate (0.506 g) from Example No. 33 in THF (100 mL) with heating and then the reaction was cooled in an ice bath. To this solution was added a 1.0 M solution of LiAlH4 in THF (2.4 mL). The reaction was allowed to warm to room temperature and was stirred for 2.5 h. The reaction was quenched with water (1 mL), 10% NaOH (1 mL), and H20 (1 mL). The aluminum salts were removed by filtration and the filtrate was concentrated in vacuo. The resulting yellow oil was purified by column chromatography (CH2Cl2 / methanol, 98/2; 95/5). The homogeneous fractions by TLC were combined and concentrated in vacuo to provide 0.254 g (54%) of the title compound as a pale yellow solid. The physical characteristics are as follows: P.f. 205-210 ° C; ? H NMR (300 MHz, DMS0-d6) d 13. 34, 10.57, 8.66, 7.41-7.33, 7.22, 5.69, 4.68, 4.54; 13C NMR (75 MHz, DMS0-d6) d 172.4, 164.9, 148.5, 141.8, 141.4, 138.6, 131.4, 130.5, 129.2, 128.3, 117.3, 113.2, 58.5, 48.6, 41.4; IR (trend) 3007, 2917, 2854, 2319, 1903, 1647, 1593, 1568, 1538, 1511, 1493, 1353, 1298, 1123, 789 cm "1; MS (ESI-) for m / z 347 (MH) " Analysis found: C, 54.86; H, 3.89; N, 7.86; Cl, 10.00; S, 9.01.

EXAMPLE 35. N- (4-Chlorobenz 1) -2 - (hydroxymethyl) -7-methyl-1-4 -oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (hydroxymethyl) thieno [2, 3-b] pyridine-5-carboxamide (0.955 g) of Example No. 34 in DMF (20 mL) was added potassium carbonate (0.567 g) followed by iodomethane (0.20 mL). The reaction was stirred at rt for 1 h. The reaction mixture was partitioned between water (50 mL) and CH2C12 (100 mL). The aqueous layer was extracted with CH C12 (100 mL). The organic layer was removed in vacuo and the insoluble material in the aqueous layer was removed by filtration. The resulting solid was recrystallized from ethanol to provide 0.825 g (83%) of the title compound as a white crystalline solid. The physical characteristics are as follows: P.f. 222-225 ° C; XH NMR (300 MHz, DMSO-d6) d 10.59, 8.70, 7.41-7.33, 7.30, 5.79, 4.72, 4.55, 3.96; 13 C NMR (75 MHz, DMSO-d 6) d 172.0, 164.4, 150.1, 145.2, 141.9, 138.6, 131.4, 130.7, 129.1, 128.3, 118.4, 114.3, 58.4, 42.9, 41.4; IR (trend) 3304, 2474, 1906, 1646, 1593, 1574, 1545, 1513, 1490, 1237, 1140, 1088, 1018, 800, 723 c "1; MS (ESI +) for m / z 363 (M + H) + Analysis found: C, 56.15, H, 4.09, N, 7.60, Cl, 9.70, S, 8.81.

EXAMPLE 36. N- (4-Chlorobenzyl) -7-methyl-2 - (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide To a solution of N- (4-chlorobenzyl) -2- (hydroxymethyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (0.250 g) of Example No In DMF (14 mL), DMAP (13 mg), 2,4,6-collidine (0.23 mL) and methanesulfonyl chloride (0.13 mL) were added. The reaction was stirred at rt for 1.5 h and then morpholine (0.60 mL, 6.9 mmol) was added. The reaction was stirred at rt for 18 h. The reaction mixture was poured into water (40 mL). The resulting off-white solid was removed by filtration and recrystallized from ethanol to provide 0.242 g (81%) of the title compound as a white crystalline solid.

The characteristics . physical are as follows: P.f. 230-236 ° C; lti NMR (300 MHz, DMSO-d6) d 10.59, 8.70, 7.41-7.32, 4.55, 3.96, 3.59, 2.45; 13 C NMR (75 MHz, CDC13) d 173.0, 165.0, 150.6, 144.5, 138.1, 137.4, 132.8, 131.6, 128.9, 128.7, 121.3, 115.8, 66.9, 57.7, 53.5, 43.1, 42.6; IR (trend) 2815, 1906, 1456, 1306, 1112, 865, 811, 806, 798, 729, cm "1; MS (ESI +) for m / z 432 (M + H) + Analysis found: C, 57.99; H, 5.20; N, 9.60; Cl, 8.23; S, 7.34.

EXAMPLE 37. N- (4-Chloro-benzyl) -7-met-il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide hydrochloride N- (4-chlorobenzyl) -7-met-il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide (1.50 g) was dissolved of Example No. 36 in methanolic HCl (50 mL) and concentrated in vacuo. The resulting off-white solid was recrystallized from meth anoi / ethanol to provide 1458 g (90%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 278-280 ° C (dec); XH NMR (300 MHz, DMSO-de) d 11.89, 10.47, 8.78, 7.76, 7.42-7.32, 4.66, 4.56, 4.05-3.90, 3.98, 3.85-3.73, 3.38-3.25, 3.18-3.02; 13 C NMR (DMSO-de) d 172.1, 164.0, 152.2, 146.1, 138.4, 131.3, 129.0, 128.6, 128.2, 124.9, 114.5, 63.1, 52.6, 50.2, 42.9, 41.6; IR (trend) 2464, 2464, 2432, 2414, 2389, 2244, 1666, 1601, 1552, 1510, 1235, 1117, 1080, 804, 795 c "1; MS (ESI +) m / z 432 (M + H) +, Analysis found: C, 53.82; H, 4.97; N, 8.95; Cl, 15.16; S, 6.84.

EXAMPLE 38. N- (4-Chlorobenzyl) -7-methyl-4-oxo-2- (4-thiomorpholinyl-methyl) -4,7-dihydrothieno [2,3-b] pi-ridin-5-carboxamide To a solution of N- (4-chlorobenzyl) -2- (hydroxymethyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (0.300 g) of Example No In DMF (16 mL), DMAP (16 mg), 2,4,6-collidine (0.27 mL) and methanesulfonyl chloride (0.16 mL) were added. The reaction mixture was stirred at room temperature for 2 h and then thiomorpholine (0.83 mL) was added. The mixture was stirred at room temperature for 3 d and then poured into water (50 mL). The resulting off-white solid was removed by filtration and recrystallized from ethanol to provide 0.222 g (60%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 215-218 ° C (dec); XH NMR (300 MHz, DMSO-d6) d 10.60, 8.70, 7.41-7.32, 4.55, 3.95, 2.74-2.72, 2.64-2.61; 13C NMR (CDC13) d 180.6, 172.6, 158.1, 152.1, 146.4, 145.0, 140.4, 139.3, 136.6, 136.3, 128.7, 123.3, 65.7, 62.5, 50.7, 50.2, 35.6; IR (trend) 2814, 1654, 1597, 1545, 1511, 1491, 1456, 1375, 1340, 1306, 1285, 1240, 1139, 801, 722 cm "1; HRMS (FAB) m / z 448.0915 (C2? H22ClN302S2 + H); Analysis found: C, 56.07; H, 5.03; N, 9.30; Cl, 7.79; S, 14.21.

EXAMPLE 39. N- (4-Chlorobenz 1) -2 - (((2-hydroxy-2- (4-hydroxyphenyl) ethyl) (methyl) amino) methyl) -7-methyl-4-oxo-4,7- dihydrothieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -2 - (hydroxymethyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide (0.300 g) of Example No. 35 in DMF (17 mL) were added DMAP (16 mg), 2,4,6-collidine (0.27 mL) and methanesulfonyl chloride (0.16 mL). The reaction mixture was stirred at room temperature for 1 h and then synephrine (1.39 g) was added. The mixture was stirred at room temperature for 18 h and then poured into water (50 mL). The resulting off-white solid was removed by filtration. The additional material was precipitated from the filtrate. The two batches of material were combined and purified by column chromatography (CH2C12, CH2Cl2 / methanol, 99/1; 98/2; 96/4) to provide 0.253 g (60%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 187 ° C; XH NMR (300 MHz, DMSO-d6) d 10.61, 9.23, 8.69, 7.41-7.32, 7.29, 7.12, 6.70, 4.95, 4.66-4.61, 4.55, 3.92, 3.83, 2.65-2.47, 2.30; 13C NMR (DMSO-d6) d 171. 8, 164.3, 156.1, 150.3, 145.0, 139.8, 138.5, 134. 9, 131.2, 130.4, 129.0, 128.2, 127.2, 119.7, 114.5, 114.1, 70.2, 64.6, 56.2, 42.6, 42.3, 41.3; IR (trend) 1641, 1595, 1543, 1514, 1493, 1455, 1343, 1307, 1267, 1256, 1234, 1035, 1014, 839, 803 c "1; MS (ESI +) m / z 512 (M + H) +; Analysis found: C, 60.90; H, 5.12; N, 8.15; Cl, 6.99; S, 6.26.

EXAMPLE 40. N- (4-Chlorobenz 1) -2- (((2-hydroxy-2-phenylethyl) (met yl) -amino) et il) -7-metyl-4-oxo-4,7-dihydrothien [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -2- (hydroxymethyl) -7-methyl-4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide (0.300 g) of Example No. 35 in DMF (17 mL) were added DMAP (16 mg), 2,4,6-collidine (0.27 mL) and methanesulfonyl chloride (0.16 mL). The reaction mixture was stirred at room temperature for 1 h and then α- (methylaminomethyl) benzyl alcohol (1.26 g) was added. The mixture was stirred at room temperature for 18 h and then poured into water (50 mL). The resulting off-white solid was removed by filtration and purified by column chromatography (CH2Cl2 / methanol, 99/1; 97/3) to provide 0.261 g (63%) of the title compound as a pale yellow solid. The physical characteristics are as follows: P. f. 184-187 ° C; ? H NMR (300 MHz, DMSO-d6) . 61, 8.69, 7.41-7.21, 5.17, 4.79-4.73, 4.55, 3.92, 3. 86, 2.69-2.50, 2.31; 13C NMR (DMSO-d6) d 171.8, 164. 3, 150.3, 145.0, 144.6, 139.6, 138.5, 131.2, 130.4, 129.0, 128.2, 127.7, 126.7, 126.1, 119.9, 114. 2, 70.5, 64.6, 56.2, 42.7, 42.2, 41.2; GO (trend) 1652, 1595, 1532, 1490, 1369, 1347, 1336, 1303, 1242, 1130, 1124, 1086, 803, 757, 697 cm "1; MS (ESI +) m / z 496 (M + H) +; Analysis found: C, 63.01; H, 5.40; N, 8.29; Cl, 7.03; S, 6.37.

EXAMPLE 41. N- (4-Chlorobenz 1) -4-hydroxy-2- (4-morpholinylmethyl) -thieno [2, 3-b] pyridine-5-carboxamide Formaldehyde (2.6 mL) was added to morpholine (2.7 mL) at 0 ° C. Ethanol (10 mL) is then added, followed by the addition of N- (4-chlorobenzyl) -4-hydroxytieno [2,3-b] pyridin-5-carboxamide (1.00 g) of the Example No. 1. Acetic acid (2 mL) was added and the reaction mixture was allowed to warm to rt and then refluxed for 18 h. Morpholine added (2.7 mL) and additional formaldehyde (2.6 mL) and the reaction was led to re fl ux for an additional 24 h.

The reaction mixture was allowed to cool to room temperature and then concentrated in vacuo. The residue was treated with 25% NaOH (20 mL). The aqueous layer was extracted with ethyl acetate (50 mL) then with CHC13 (60 mL). Methanol (30 mL) was added to the aqueous layer and extracted with CHC13 (2 x 60 mL). This procedure was repeated 3 times. The combined organic layers were dried with MgSO 4, filtered and concentrated in vacuo. The resulting brown solid was purified by column chromatography (CH2Cl2 / methanol, 98/2; 96/4) to give a tan solid which was recrystallized from ethyl acetate / Et20 to provide 0.718 g (55%) of the compound of the title as a whitish solid. The physical characteristics are as follows: P.f. 193-195 ° C; XH NMR (300 MHz, DMSO-d6) d 13.30, 10.59, 8.66, 7.41-7.33, 7.27, 4.54, 3.72, 3.58, 2.44; IR (trend) 2958, 2926, 2912, 2853, 2845, 2810, 1641, 1595, 1550, 1492, 1118, 866, 800, 791, 785 cm "1; MS (FAB) m / z 418 (MH +, 99) , 420 (42), 419 (33), 418 (99), 417 (19), 416 (17), 331 (17), 277 (13), 190 (11), 125 (21), 100 (22) HRMS (FAB) m / z 418.0996 (C20H2oClN3? 3S + H); Analysis found: C, 57.07; H, 5.02; N, 9.94; Cl, 8.45; S, 7.51.

Example 42. N- (4-Chlorobenz 1) -7-yt-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridine-5-carboxamide (418 mg) of Example No. 41 and potassium carbonate (152 mg) were suspended. ) in DMF (10 mL) and iodoethane (88 μL) was added to the mixture. The reaction mixture was allowed to stir at room temperature for 24 h. The resulting suspension was poured into water (25 mL), filtered and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid was purified by recrystallization from ethanol to provide 325 mg (73%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 194-196 ° C; XH NMR (300 MHz, DMSO-d6) d . 59, 8.73, 7.41-7.32, 4.54, 4.32, 3.75, 3.59, 2.46, 1.44; 13 C NMR (75 MHz, DMSO-d 6) d 171.9, 164.3, 149.3, 143.9, 138.6, 138.0, 131.4, 131.1, 129.1, 128.4, 120.6, 114.7, 66.2, 56.6, 53.0, 51.5, 41.4, 14.0; IR (trend) 2813, 1653, 1597, 1563, 1543, 1507, 1455, 1349, 1328, 1302, 1226, 1116, 867, 803, 795 cm "1; MS (ESI +) m / z 446 (100, (M + H) +), 447 (30), 448 (40); HRMS (FAB) m / z 446.1304 (C22H24C1N303S + H) Analysis found (C22H2.CIN3O3S): C, 59.16; H, 5.45; N, 9.40; Cl, 7.99; S, 7.21.

EXAMPLE 43. N- (4-Chlorobenz 1) -2 - (4-morpholinylmethyl) -4-oxo-7-propyl-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide N- (4-Chlorobenz 1) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2,3-b] pyridine-5-carboxamide (418 mg) from Example No. 41 and potassium carbonate (152) were suspended. mg) in DMF (10 mL) and 1-iodopropane (107 μL) was added to the mixture. The reaction mixture was allowed to stir at room temperature for 4. Additional 1-iodopropane (107 μL) was added and the mixture was heated at 60 ° C for 2 h. The mixture was allowed to cool to room temperature and was allowed to stand for 18 h. The resulting suspension was poured into water (25 mL), filtered and washed with water (5 ml.) followed by diethyl ether (5 ml.). The resulting crude solid was purified by recrystallization from ethanol to provide 335 mg (73%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 174-176 ° C; XH NMR (300 MHz, DMSO-d6) d 10.58, 8.71, 7.42-7.33, 4.54, 4.26, 3.74, 3.59, 2.45, 1.86, 0.90; 13 C NMR (75 MHz, DMSO-d 6) d 171.9, 164.3, 149.6, 144.4, 138.6, 137.9, 131.4, 131.1, 129.1, 128.3, 120.6, 114.4, 66.1, 57.6, 56.6, 52.9, 41.4, 21.6, 10.6; IR (trend) 2968, 1652, 1593, 1540, 1505, 1458, 1351, 1343, 1327, 1300, 1226, 808 cm "1; MS (ESI +) m / z 460 (100, (M + H) +), 461 (28), 462 (40); HRMS (FAB) m / z 460.1461 (C23H26ClN3? 3S + H) Analysis found (C23H-26CIN3O3S): C, 60.03; H, 5.76; N, 9.11; Cl, 7.75; S, 6.95.

EXAMPLE 44. N- (4-Chlorobenzyl) -7-isopropyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide N- (4-chlorobenz 1) -4-hydroxy-2- (4-morphylimethyl) -1) thieno [2,3-b] pi-ridin-5-carboxamide (418 mg) of Example No. 41 was suspended and potassium carbonate (152 mg) in DMF (10 mL) and 2-bromopropane (103 μL) was added to the mixture. The reaction mixture was stirred at room temperature for 4 h. Additional 2-bromopropane (103 μL) was added and the mixture was heated at 60 ° C for 20 h. The reaction mixture was allowed to cool to room temperature, poured into water (25 mL) and then extracted with EtOAc (3 x 25 mL). The organic layer was dried (Na2SO) and concentrated. The resulting crude solid was purified by recrystallization from ethanol to give 173 mg (38%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 191-195 ° C; 1 H NMR (300 MHz, DMSO-d 6) d 10.59, 8.67, 7.41-7.33, 4.60-4.53, 3.75, 3.59, 2.46, 1.55; 13C NMR (75 MHz, DMSO-d6) d 171.8, 164.3, 149.5, 139. 6, 138.6, 137.8, 131.7, 131.2, 129.2, 128.3, 120. 7, 11.8, 66.2, 58.3, 56.6, 53.0, 41.4, 21.1; IR (trend) 2968, 1662, 1593, 1541, 1503, 1409, 1342, 1331, 1295, 1218, 1144, 1112, 1014, 867, 800 cm "1; MS (ESI +) m / z 460 (100, (M + H) +), 461 (30), 462 (40); HRMS (FAB) m / z 460.1463 (C23H26ClN3? 3S + H) Analysis found (C23H26CIN3O3S): C, 59.92; H, 5.71; N, 9.08; Cl, 7.74; S, 7.01.

PREPARATION 1. Diethyl ester of N- (3-tert-butoxycarbonyl-thien-2-yl) -aminomet ionic acid The title compound was prepared from tert-butyl 2-aminothiophene-3-carboxylate as described in German Patent 2447477 (1976). A solution of tert-butyl 2-aminot iofen-3-carboxylate (14.0 g, obtained through a slight modification of the procedures employed by M. Gutschow and U. Neumann, J. Med. Chem. 1998, 41, 1729 -1740) and ethoxymethylene diethyl malonate (14.2 ml) in toluene (50 ml) was heated at about 100 ° C for about 24 hr. The solution was cooled slowly to about -20 ° C and filtered. The crystals were washed with cold toluene and dried in a vacuum oven at 30 ° C to provide a 79.5% yield of the title compound as pale yellow crystals. The physical characteristics are as follows: XH NMR (400 MHz, CDC13) d 8.2, 7.1, 6.6, 4.35, 4.25, 1.55, 1.39); 13C NMR (100 MHz, CDC13) d 166.63, 165.48, 163.36, 152.46, 149.86, 127.69, 115.98, 112.79, 97.22, 81.97, 60.76, 60.52, 28.37, 14.34, 14.32.

PREPARATION 2. N- (3-tert-butoxycarbonyl-tien-2-yl) -methylamino-met i lenma Ionic acid diethyl ester Iodomethane (3.0 ml) was added to a mixture of diethyl ester of N (3-tert-butoxycarbonyl-1-yl-2-yl) -aminomethylenic acid (15.0 g) of Preparation No. 1 and anhydrous potassium carbonate (8.4 g) in DMF (67 ml). The mixture was stirred vigorously at room temperature for approximately 20 hr. Water (150 ml) was added and the solution extracted with toluene (2 x 75 ml). The combined toluene layers were washed with water (2 x 150 ml) and the solvent was removed in vacuo to give 15.8 g of the title compound as a dark yellow oil. The physical characteristics are as follows: 1 H NMR (300 MHz, CDC13) d 7.5, 7.3, 7.2, 4.2, 3.96, 3.36, 1.55, 1.25; 13C NMR (75 MHz, CDC13) d 166.31, 160.57, 149.37, 128.14, 127.98, 121.42, 99.45, 81.85, 60.87, 60.21, 28.08, 14.27, 13.86.

PREPARATION 3. Diethyl ester of N- (3-tert-butoxycarbonyl-5-morpholinomethyl-thien-2-yl) -met i 1 aminomet i lenma Ionic A mixture of N- (3-tert-butoxycarbonyl-thien-2-yl) -methylaminomethylenemalonic acid diethyl ester (19.0 g) of Preparation No. 2 and 4-methylene morpholinium chloride (Dimmock, JR, et al. J Med. Chem. 1989, 24, 379-383) (13.4 g) in dry acetonitrile (50 ml) was heated to reflux for about 4 hr. The solution was then cooled in an ice bath and saturated aqueous sodium carbonate (98 ml) was slowly added. The solution was extracted three times with ethyl acetate (300 ml total) and the combined organic layers were then washed three times with water (600 ml total). The solvent was removed in vacuo to provide 23.0 g (96%) of the title compound as a brown oil. The physical characteristics are as follows: 1H NMR (400 MHz, CDC13) d 7.45, 7.06, 4.1, 3.70, 3.60, 3.34, 2.50, 1.54 and 1.2; 13C NMR (100 MHz, CDC13) d 166.44, 160.71, 149.45, 125.73, 99'.35, 81.86, 66.95, 60.85, 60.27, 57.79, 53.35, 28.16, 14.36, 13.98.

PREPARATION 4. 7 -Met i 1-2- (4-morphonomethyl) -4 -oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid ethyl ester Phosphorus pentoxide (1.20 g) was dissd in anhydrous methanesulfonic acid (7.2 ml) with heating at 50 ° C as necessary. The solution was cooled to room temperature and a diethyl ester solution of N- (3-tert-butoxycarbonyl-5-mor-folinomet-il-t-ene-2-yl) -methylaminomethenemalonic acid (2.00 g) of Preparation No. 3 in toluene (2 ml) was added with vigorous stirring. After approximately 30 min at room temperature the two-phase system was heated to 35 ° C and maintained for about 2 hr. With cooling with ice, saturated aqueous sodium carbonate (64 ml) was added very slowly with vigorous stirring. The mixture was extracted twice with methylene chloride (80 ml total). The snt was removed in vacuo to provide 1.10 g of tan crystals. The solid was recrystallized from ethyl acetate (16 ml) over the steam bath and the solution was slowly heated to 0-5 ° C overnight. The resulting tan crystals were filtered and washed with cold ethyl acetate. The product was dried in a vacuum oven at 30 ° C overnight to provide 0.58 g (42%) of the title compound. The physical characteristics are as follows:? H NMR (300 MHz, CDC13) d 8.24, 7.41, 4.36, 3.83, 3.72, 2.52, 1.39; 13C NMR (75 MHz, CDC13) d 170.71, 165.53, 149.69, 145.61, 136.96, 132.77, 122.18, 115.17, 66.85, 60.83, 57.63, 53.37, 42.70, 14. 31 PREPARATION 5. 7-Methyl-2- (4-morpholinomethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid CO.H Q ^ & < = » A mixture of ethyl 7 -met-il-2- (4-morpholinomethyl) -4 -oxo-4,7-dihydrothieno [2,3b] pyridine-5-carboxylate (0.50 g) of Preparation No. 4, ethanol (2.5 ml), water (2.5 ml) and 50% sodium hydroxide (0.56 ml) were refluxed for 30 min. The ethanol was removed by distillation in vacuo. The residue was extracted with methyl t-butyl ether and then the pH was lowered to about 4 with 6 M HCl. The mixture was cooled and 0 ° C and filtered by cold rinsing with cold water. The light brown solid was dried in a vacuum oven at 40 ° C for two days to provide 0.45 g (98%) of the title compound. The physical characteristics are as follows: XH NMR (400 MHz, D20) d 8.6, 7.68, 4.66, 4.00, 3.92, 3.38; 13C NMR (100 MHz, D20) d 174.00, 169.02, 155.00, 147.70, 129.53, 128.02, 127.41, 111.20, 64.17, 54.47, 51.75, 44.53.

PREPARATION 6. N- (4-chlorobenzyl) - 7 -met i 1 -2 • (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridin-5-carboxamide 7-Methyl-2- (4-morpholinomethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylic acid (1.09 g) was dissd from Preparation No. 5 and 1,1 'carbonyldiimidazole (0.86 g) in dry N, N-dimethylformamide (9.8 ml) and heated at 65-70 ° C for 3.5 hr. To the reaction mixture was added 4-chlorobenzylamine (0.44 ml) and the mixture was heated for about 1.5 hr at 65-70 ° C. The reaction mixture was diluted with water (6.5 ml) and cooled to about 0 ° C. The crude product was filtered cold, washed with cold water and dried at about 45 ° C in a vacuum oven overnight to provide 1.29 g (85%) of the title compound. ? ñ NMR (300 MHz, CDC12) d 10.61, 8.59, 7.41, 7.28, 4.61, 3.88, 3.72, 2.53.

EXAMPLE 45. N- (4-Fluorobenz 1) -7-met i 1 -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide A mixture of ethyl 7-met-il-2- (4-morphinylmethyl) -4 -oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxylate (0.300 g) of Preparation No 4 and 4-fluorobenzylamin (1.02 mL) was stirred at 175 ° C for 3 h. The reaction mixture was allowed to cool for several minutes and then diluted with toluene (15 mL).

The resulting off-white precipitate was removed by filtration and recrystallized from acetonitrile then with ethanol to give 0.184 g (50%) of the title compound as a white crystalline solid. The physical characteristics are as follows: P.f. 214-216 ° C; XH NMR (300 MHz, DMSO-d6) d . 57, 8.71, 7.39-7.34, 7.19-7.13, 4.54, 3.96, 3.75, 3.59, 2.45; 13C NMR (CDC13) d 173.0, 164.9, 163.6, 160.3, 150.6, 144.5, 138.1, 134.6, 134.5, 131.6, 129.3, 121.3, 115.7, 115.5, 115.2, 66.9, 57.7, 53.4, 43.0, 42.5; IR (trend) 2810, 1662, 1597, 1541, 1509, 1370, 1342, 1332, 1303, 1218, 1149, 1113, 820, 804, 797 cm "1; MS (ESI +) m / z 416 (M + H) +, Analysis found: C, 60.57; H, 5.43; N, 10.02; S, 7.49; F, 4.68.

EXAMPLE 46. N- (4-Bromobenz 1) -7-met i 1 -2 - (-morfo 1 inylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide Or HF * »> CH, 4-Bromobenzylamine (1.98 g) was suspended in CH2C12 (50 mL) and stirred with an aqueous solution of 10% NaOH solution (25 mL). The organic layer was removed and the aqueous layer was extracted with CH2C12 (2 x 25 mL). The combined organic layers were dried (MgSO4), filtered and concentrated in vacuo. Then ethyl 7-met il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxylate of Preparation No. 4 (0.300 g) was added. ) to the free amine and the mixture was stirred at 190 ° C for 1 h. The reaction mixture was allowed to cool for several minutes and then diluted with toluene (10 mL). The resulting pale yellow precipitate was removed by filtration and recrystallized from ethanol to provide 0.272 g (64%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 245-246 ° C; XH NMR (300 MHz, DMSO-d6) d 10.60, 8.70, 7.54, 7.35, 7.29, 4.53, 3.96, 3.75, 3.59, 2.45; 13 C NMR (CDC13) d 173.0, 165.0, 144.6, 137.9, 131.6, 129.3, 120.9, 115.7, 66.8, 57.6, 53.4, 43.1, 42.6; IR (trend) 2815, 1653, 1597, 1542, 1511, 1486, 1372, 1306, 1118, 1112, 1010, 865, 805, 798, 729 cm "1; MS (ESI +) m / z 476 (M + H ) + Analysis found: C, 52.64, H, 4.66, N, 8.76, Br, 16.56, S, 6.65.

EXAMPLE 47. N- (4-Chlorobenz 1) -4-hydroxy-2 • (4-morpholinylcarbonyl) -thieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2-yodothieno [2, 3-b] pyridin-5-carboxamide (2.00 g) from Example No. 2 in DMF (45 L) was added triethylamine ( 1.25 mL), morpholine (15.7 mL), Pd (OAc) 2 (0.101 g) and dppp (0.186 g). The reaction mixture was degassed by bubbling N2 through the solution for 15 minutes. Carbon monoxide was then bubbled through the solution and the reaction mixture was heated to 70 ° C and stirred for 18 h. The reaction mixture was allowed to cool to room temperature and water (25 mL) and 2 N HCl (75 mL) were added. The resulting green solid. it was removed by filtration and the filtrate was extracted with CH2C12 (4 x 100 mL). The combined organic layers were dried with MgSO 4, filtered and concentrated in vacuo. The resulting orange oil was purified by column chromatography (CH2C12; CH2C12 / met anoi, 98/2). The resulting pale yellow solid was recrystallized from acetonitrile to provide 0.648 g (33%) of the title compound as an off-white solid. The physical characteristics are as follows: P.f. 217-219 ° C; 1ti NMR (300 MHz, CDC13) d 8.72, 7.67, 7.31-7.25, 4.68, 3.86, 3.80; 13C NMR (CDCI3) d 165.8, 162.3, 142.1, 136.3, 133.2, 131.7, 128. 8, 128.7, 123.7, 66.7, 43.0; IR (trend) 2923, 2854, 2769, 2760, 1662, 1603, 1569, 1541, 1509, 1488, 1458, 1432, 1274, 1113, 791, cm "1; MS (ESI-) m / z 430 (M-H)". Analysis found: C, 55.47; H, 4.16; N, 9. 76; Cl, 8.29; S, 7.50.

EXAMPLE 48. N- (4-Chlorobenz 1) -7-met il-2 - (4-morpholine) Icarboni 1) -4 -oxo-4,7-dihydro-ieno [2,3-b] pyridine-5-carboxamide To a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (4-morphol inylca boni 1) -thieno [2,3-b] pyridine-5-carboxamide (0.527 g) of Example No. 47 in DMF (10 mL) was added potassium carbonate (0.337 g) followed by iodomethane (0.11 mL). The reaction mixture was stirred at room temperature for 1 h. The reaction mixture was then poured into water (25 mL). The resulting off-white solid was removed by filtration and recrystallized from acetonitrile to provide 0.448 g (82%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 244-245 ° C (dec); 1 NMR (300 MHz, CDC13) d 10.37, 8.66, 7.81, 7.34-7.28, 4.65, 3.94, 3.85, 3.77; 13 C NMR (CDCl 3) d 173.6, 164.4, 161.7, 152.0, 145.9, 137.1, 133.0, 132.4, 131.1, 129.0, 128.7, 124.5, 116.3, 66.7, 43.2, 42.7; IR (trend) 1655, 1607, 1550, 1525, 1488, 1451, 1428, 1303, 1273, 1253, 1133, 1114, 999, 802, 731 cm "1; MS (ESI +) m / z 446 (M + H ) +; Analysis found: C, 56.50; H, 4.52; N, 9.47; Cl, 7.96; S, 7.23, HRMS (FAB) m / z 466.1416 (C22H22F3N3? 3S + H) Analysis found: C, 56.70; , 4.83; N, 9.02; S, 6.70; F, 12.89.

EXAMPLE 49. 7-Benzl-N- (4-chlorobenz 1) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridine-5-carboxamide (418 mg) of Example No. 41 and potassium carbonate (152 mg) were suspended. ) in DMF (10 mL) and benzyl bromide (130 μL) was added to the mixture. The reaction mixture was allowed to stir at room temperature for 18 h. The resulting suspension was poured into water (10 mL), filtered and washed with water (5 mL) followed by diethyl ether (5 mL). The resulting crude solid was purified by recrystallization from ethanol to give 400 mg (79%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 225-226.5 ° C; XH NMR (300 MHz, DMSO-d6) d 10.56, 8.92, 7.43-7.32, 5.58, 4.54, 3.68, 3.55, 2.39; 13C NMR (75 MHz, DMSO-d6) d 172.0, 164.2, 149.7, 145.0, 138.5, 138.3, 134.2, 131.4, 131.3, 129.2, 129.0, 128.5, 128.3, 127.6, 120.4, 114.6, 66.1, 58.9, 56.5, 52.9 , 41.4; IR (trend) 1646, 1592, 1541, 1498, 1454, 1342, 1327, 1297, 1219, 1119, 1112, 868, 806, 740, 699 cm "1; MS (ESI +) m / z 508 (100, ( M + H) +), 509 (30), 510 (40) Analysis found (C2 H26C1N303S): C, 63.71; H, 5.22; N, 8.25; Cl, 7.13; S, 6.40.

EXAMPLE 50. N- (4-Chlorobenz 1) -7- (3-fluorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridine-5-carboxamide (418 mg) of Example No. 41 and potassium carbonate (152 mg) were suspended. ) in DMF (10 mL) and the mixture was added 3-fluorourocyclyl bromide (135 μL). The reaction mixture was allowed to stir at room temperature for 18 h. The resulting suspension was poured into water (10 mL), filtered and washed with water (5 L) followed by diethyl ether (5 mL). The resulting crude solid was purified by recrystallization from ethanol to provide 425 mg (81%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 214-215 ° C; 1ti NMR (300 MHz, DMSO-d6) d . 55, 8.93, 7.48-7.12, 5.60, 4.55, 3.69, 3.55, 2.39; 13C NMR (75 MHz, DMSO-d6) d 172.1, 164.2, 162.2 (d, J = 245 Hz), 149.6, 145.1, 138.4, 137.0, 131.4, 131.1, 129.2, 128.3, 123.6, 120.5, 115.5, 115.3, 114.8 , 114.7, 114.5, 66.1, 58.2, 56.5, 52.9, 41.4; IR (trend) 1649, 1593, 1543, 1502, 1492, 1453, 1327, 1299, 1266, 1258, 1213, 1118, 1112, 808, 788 cm "1; MS (ESI +) m / z 526 (100, (M + H) +), 527 (30), 528 (40) Analysis found (C27H25C1 FN303S): C, 61.42; H, N, 7.95; Cl, 6.70; S, 6.09.

EXAMPLE 51. N- (4-Cl-Orobenz-1) -2- (4-morpholinylmethyl) -4-oxo-7- (3-phenylpropyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridin-5-carboxamide (418 mg) of Example No. 41 and potassium carbonate (152 mg) were suspended. ) in DMF (10 mL) and 1-bromo-3-phenylpropane (167 μL) was added to the mixture. The reaction mixture was allowed to stir at room temperature for 72 h. The reaction mixture was poured into water (25 mL) and extracted with EtOAc (2 x 25 mL). The organic layer was dried (Na S04) and concentrated. The resulting crude solid was purified by recrystallization from ethanol to provide 277 mg (52%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 169-171 ° C; 1 H NMR (300 MHz, DMS0-d6) d 10.57, 8.70, 7.41-7.16, 4.54, 4.30, 3.73, 3.59, 2.67, 2.45, 2.17; 13C NMR (75 MHz, DMS0-d6) d 171.9, 164.3, 149.6, 144.4, 140.5, 138.6, 137.9, 131.4, 131.1, 129.1, 128.4, 128.3, 128.2, 126.0, 120.5, 114.5, 66.2, 56.6, 55.9, 52.9 , 41.4, 31.7, 29.7; IR (trend) 1665, 1595, 1539, 1505, 1330, 1301, 1221, 1117, 1111, 868, 808, 799, 750, 719, 703 cm "1; MS (ESI +) m / z 536 (100, (M + H) +), 537 (30), 538 (40) Analysis found (C29H30CIN3O3S): C, 64.74; H, 5.66; N, 7.80; Cl, 6.54; S, 5.93.

EXAMPLE 52. N- (4-chlorobenz 1) -2 - (4 -morfo-1 -inylmethyl) -4-oxo-7- (tetrahydro-2-furanylmethyl) -4,7-dihydrothieno [2, 3-b] ]? iridin-5-carboxamide N- (4-Chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridine-5-carboxamide (418 mg) of Example No. 41 and potassium carbonate (152 mg) were suspended. ) in DMF (10 mL) and tetrahydrofurfuryl bromide (125 uL) was added to the mixture. The reaction mixture was heated at 60 ° C for 4 h and then allowed to stand at room temperature for 18 h. The reaction mixture was poured into water (25 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was dried (Na2SO4) and concentrated. The resulting crude solid was purified by recrystallization from ethanol to give 15 mg (3%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 191-195 ° C; XH NMR (300 MHz, DMSO-d6) d 10.57, 8.67, 7.42-7.33, 4.54, 4.41-4.2, 3.83-3.72, 3.75, 3.70-3.60, 3.59, 2.07, 2.10-1.92, 1.90-1.75, 1.68-1.52; MS (ESI +) m / z 502 (100, (M + H) +), 503 (30), 504 (40). Analysis found (C25H28C1N304S): C, 59.46; H, 5.73; N, 8.19.

EXAMPLE 53. N- (4-Chlorobenz 1) -2 - (4-morpholinylmethyl) -4 -oxo-7- [2- (1-pyrrolidinyl) ethyl] -4,7-dihydrothieno [2,3-b] pindin - 5 -carboxamide 1,4-Diethyl azodicarboxylate (205 μL) was added to a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2,3-b] pyridine-5-carboxamide (418 mg) of Example No. 41, triphenylphosphine (341 mg) and 1- (2-hydroxyethyl) pyrrolidine (292 L) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and then emptied into 0.5 N aqueous NaOH solution (25 mL). The mixture was extracted with EtOAc (3 x 25 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (CH2Cl2 / meth anoi, 100/1; 50/1; 20/1; 10/1) followed by recrystallization from ethanol to provide 54 mg (11%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 178-180 ° C; XH NMR (300 MHz, DMSO-d6) d 10.57, 8.69, 7.42-7.33, 4.53, 4.38, 3.75, 3.59, 2.89, 2.51-2.45, 1.69-1.62; IR (trend) 1651, 1592, 1559, 1532, 1502, 1457, 1327, 1296, 1143, 1119, 1110, 868, 811, 806, 800 cm "1; MS (ESI +) m / z 515 (100, ( M + H) +), 516 (30), 517 (40) Analysis found (C26H3iClN403S): C, 60.48; H, 6.04; N, 10.72; Cl, 6.99; S, 6.25.

EXAMPLE 54. N- (4-Chlorobenz 1) -2 - (4-morpholino-methyl) -4-oxo-7- (3-pyridinylmethyl) -4,7-dihydro-thieno [2,3-b] pyridine-5-carboxamide. 1,4-Diethyl azodicarboxylate (205 μL) was added to a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2,3-b] pyridine-5-carboxamide (418) mg) of Example No. 41, triphenylphosphine (341 mg) and 3-pyridylmethanol (243 μL) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and then the resulting suspension was filtered. The crude product was purified by recrystallization from ethanol to provide 63 mg (12%) of the title compound as a white solid. The physical characteristics are as follows: P.f. 214-215 ° C; XH NMR (300 MHz, DMSO-d6) d 10.54, 8.97, 8.65, 8.57, 7.73, 7.44-7.33, 5.64, 4.55, 3.69, 3.55, 2.40; IR (trend) 1646, 1592, 1542, 1501, 1420, 1341, 1325, 1297, 1267, 1209, 1111, 865, 807, 794, 716 cm "1; MS (ESI +) for m / z 509 (100, (M + H) +), 510 (30), 511 (40) Analysis found (C26H25C1N403S): C, 61.20; H, 4.98; N, 10.92; Cl, 6.94; S, 6.26.

EXAMPLE 55. N- (4-Chlorobenz 1) -2 - (morpholinylmethyl) -4-oxo-7- (4-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide 1,4-Diethyl azodicarboxylate (205 μL) was added to a solution of N- (4-chlorobenzyl) -4-hydroxy-2- (4 -mor fol inimethyl i 1) thieno [2, 3-b] pyridine -5-carboxamide (418 mg) of Example No. 41, triphenylphosphine (341 mg) and 4 -pyr idylmet anoi (273 mg) in THF (10 mL). The reaction mixture was stirred at room temperature for 20 h and then emptied into 0.5 N aqueous NaOH solution (25 mL). The mixture was extracted with EtOAc (3 x 25 mL). The organic layer was dried (Na2SO4) and concentrated. The crude product was purified by column chromatography (CH2Cl2 / met anoi, 50/1; 20/1) followed by recrystallization from ethanol to provide 107 mg (21%) of the title compound as a white solid.

The physical characteristics are as follows: P.f. 208-210 ° C (dec); XH NMR (300 MHz, DMSO-de) d 10.55, 8.95, 8.56, 7.43-7.35, 7.34, 7.25, 5.67, 4.56, 3.68, 3.54, 2.39; IR (trend) 2812, 1648, 1593, 1550, 1543, 1500, 1416, 1345, 1328, 1229, 1117, 1111, 866, 805, 795 cm "1; MS (ESI +) for m / z 509 (100, ( M + H) +), 510 (30), 511 (40); HRMS (FAB) m / z 509.1424 (C 6H25C1N403S + H) Analysis found for C26H25C1N403S: C, 60.89; H, 5.03; N, 10.81; Ci, 7.04; S, 6.30. All publications, patents and patent documents cited are incorporated herein by reference, as if they were incorporated individually as a reference. The invention has been described with reference to various specific and preferred modalities and techniques. However, it should be understood that many variations and modifications may be made as long as they remain within the spirit and scope of the invention.

Claims

CLAIMS 1. A compound of the formula I or a pharmaceutically acceptable salt thereof wherein R1 is (a) Cl, (b) Br, (c) CN, (d) N02, or (e) F; R2 is (a) H, (b) R5, (c) NR7R8, (d) SO, R9, or (e) OR9; R; is (a) H, (b) halo, (c) aryl, (d) S (0) mR6 (e) (C = 0) Rb (f) (C = 0) 0R9, (g) cyano, (h) ) het, where het is linked by a carbon atom, (i) OR10, (j) Ohet, (k) NR7R8 (1) SR10, (m) Shet (n) NHCOR 1J2 (p) alkyl of 1-7 which may be partially unsaturated and is optionally substituted by one or more substituents of the group R11, OR13, SR10, SR13, NR7R8, halo, (C = 0) alkyl of d7 or SOraR9; R 4 is (a) H, (b) halo, (c) C 4 alkyl, or (d) R 4 together with R 3 form a carbocyclic or het, any of which may be optionally substituted by NR 7 R 8, by C alkyl. ? -7 which can be optionally substituted by OR14, or by het, where het is linked by a carbon atom;

R is (b) het, wherein het is bonded via a carbon atom, (c) aryl, (d) C? _7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consists of NR7R8, R11, SOmR9 and C2-4 O-alkyl which may be further substituted by het, OR10 or NR7R8, or (e) C3-8 cycloalkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of R11, NR7R8, SOmR9 and C? _7 alkyl optionally substituted by R11, NR7R8, or SOmR9; R6 is (a) alkyl of C? _7, (b) NR7R8, (c) aryl, or (d) het, wherein het is attached by a carbon atom; R 7 and R 8 are independently (a) H, (b) aryl, (c) C 1 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR 10 R 10, R 11, SO m R 9, CONR10R10 and halo, or, (d) R7 and R8 together with the nitrogen atom to which they are attached form a het; R9 is (a) aryl, (b) het, (c) C3-8 cycloalkyl, or (d) C7_7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of of NR10R10, R11, SH, CONR10R10 and halo; R10 is (a) H, or (b) C? -7 alkyl optionally substituted by OH; (b) Ohet, (c) Oar ilo, (e) het, (f) aryl, or (g) CN (a) H, (b) het, (c) aryl, (d) C3_8 cycloalkyl, or (e) C7_7 alkyl optionally substituted by NR7R8 or R11; R13 is (a) (P = 0) (OR14) 2, (b) CO (CH2) nCON (CH3) - (CH2) nS03"M +, (c) an amino acid, (d) C (= 0) aryl, or (e) C (= 0) C7_7 alkyl optionally substituted by NR7R8, aryl, het, C02H, or R14 is (a) H, or (b) C7_7 alkyl, each i is independently 2, 3 or 4, each n is independently 1, 2, 3, 4 or 5, each m is independently 0, 1 or 2, M is sodium, potassium or lithium, wherein any aryl is optionally substituted with one or more substituents selected from the group which consists of halo, OH, cyano, C02R14, CF3, C? -6 alkoxy, and C? _6 alkyl which can be further substituted by one to three SR14, NR14R14, OR14, het or C02R14; is optionally substituted with one or more substituents selected from the group consisting of halo, OH, cyano, phenyl, C02R14, CF3, C? -6 alkoxy, oxo, oxime, and C-. 6 alkyl which can be further substituted by one to three SR14, NR1 R14, OR14 or C02R14.
2. The compound according to claim 1 wherein R1 is F, Cl or Br.
3. The compound according to claim 1 wherein R1 is Cl.
4. The compound according to any of claims 1-3 wherein R2 is H.
5. The compound according to any of claims 1-3 wherein R2 is R5, NR7R8, S02R9 or OR9.
6. The compound according to claim 5 wherein R2 is R5 and R5 is C_7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents selected from a group consisting of NR R8, OR10, Ohet, Oaryl, C02R10 , CN, SOmR9 and O-alkyl of C2_, which may be further substituted by het, OR10 or NR7R8.
7. The compound according to claim 5 wherein R2 is R5 and R5 is C? _7 alkyl, which may be partially unsaturated and is optionally substituted by one or more aryl or het.
The compound according to claim 7 wherein R is C? _7 alkyl
9. The compound according to claim 1 wherein R 2 is methyl, ethyl, propyl, isopropyl, butyl, tert-butyl, carboxymethyl, (C 7 -alkoxy) carbonylmethyl, 2-hydroxyethyl, 2- (2-methoxyethoxy) -ethyl 3- (2-tet rahydropyranyloxy) propyl, 2-morpholinoethyl, 2- (diethylamino) ethyl, 2- (dimethylamino) ethyl, 2-piper idinoetheyl, 3-piperidinopropyl, 2- (1-met ilpyrrolidine) -2-i 1) et i lo, 2- (diisopropylamino) ethyl, 2-pyrrole idin-1-ylethyl, 3- (dimethylamino) pr.opril, benzyl, 3-f luorobenzyl, 3-phenylpropyl, 2- tet rahidrofuranilmet ilo, 2-pyrrolidinoetyl, 3-pyridylmethyl or vinyl.
10. The compound according to claim 1 wherein R2 is methyl, ethyl, isopropyl, 2-hydroxyethyl, 2- (diethylamino) ethyl or 2- (dimethylamino) et i lo.
11. The compound according to claim 1 wherein R3 is H, halo, S (0) mR6, (C = 0) R6, (C = 0) OR9, cyano or C? _ Alkyl, which may be partially unsaturated and substituted optionally by one or more substituents of the group R11, OR13, SR10, SR13, NR R8, halo, (C = 0) C? _7 alkyl, and SOmR9.
12. The compound according to claim 1 wherein R3 is C7_7 alkyl which may be partially unsaturated and is optionally substituted by one or more substituents of the group R11, OR13, SR10, SR, 13, NR'RB, halo, (C = 0) C alquilo-7 alkyl, and SOmR.
13. The compound according to the rei indication 1 wherein R3 is C? -7 alkyl which may be partially unsaturated and is replaced by one or more substituents of the group R11, 0R1J, SR,? IoU, SR, 1i3J, NR, 7'R , 0, halo, (C = 0) C? -7 alkyl, and SOmR9.
14. The compound according to claim 1 wherein R3 is C7_7 alkyl which may be partially unsaturated and is substituted by one or more substituents of the group OR10, het and NR7R8.
15. The compound according to claim 1 wherein R 3 is bromine, iodine, 3-hydroxy-1-propyne lo, 3-methoxy-1-propynyl, 4-hydroxy-1-butyl, 3-hydroxypropyl, cyano, 4, 4 - di (methoxy-carbonyl) -1-butynyl, 4-hydroxybutyl, 3- (3-carboxypropanoyloxy) -1-propynyl, 3- (morpholinoacetoxy) -1-propynyl, 3- (2-amino-3-ethoxybutanoyloxy) -1 -propynyl, ot iomor folinomethyl, N- [2- (4-hydroxyphenyl) -2-hydroxyethyl] -N- (methyl) aminomethyl, morpholinocarbonyl, 3- [3- (morpholinomethyl) benzoyloxy] -1-propynyl.
16. The compound according to claim 1 wherein R 3 is iodine, 3-hydroxy-1-propyne, 4-hydroxy-1-butynyl, 3-hydroxypropyl, morphomethyl, N- [2- (4-hydroxy phenyl) -2-hydroxiet i 1] -N- (met i 1) aminomet i lo or 4-hydroxybutyl.
17. The compound according to claim 1 wherein R 3 is 3-hydroxy-1-propynyl, morpholomethyl γ, N- [2- (4-hydroxyphenyl) -2-hydroxyethyl] -N- (methyl) aminomethyl or 3-hydroxypropyl.
18. The compound according to claim 1 which is: (1) N- (4-chlorobenzyl) -4-hydroxy-thieno [2,3-b] pyridin-5-carboxamide; (2) N- (4-Chlorobenzyl) -4-hydroxy-2-yodothieno [2, 3-b] pyridine-5-carboxamide; (3) N- (4-Chlorobenzyl) -4-hydroxy-2- (4-morpholinyl sulphonyl) thieno [2, 3-b] pyridine-5-carboxamide; (4) 2-Bromo-N- (4-chlorobenzyl) -4-hydroxy-thieno [2, 3-b] pyridine-5-carboxamide; (5) N- (4-Chlorobenzyl) -4-hydroxy-2- (3-hydroxy-1-propynyl) thieno [2, 3-b] pyridin-5-carboxamide; (6) N- (4-Chlorobenzyl) -4-hydroxy-2- (3-methoxy-1-propynyl) thieno [2, 3-b] pyridine-5-carboxamide; (7) N- (4-Chlorobenzyl) -4-hydroxy-2- (4-hydroxy-1-butynyl) thieno [2, 3-b] -pyridin-5-carboxamide; (8) N- (4-Chlorobenzyl) -4-hydroxy-2- (3-hydroxypropyl) thieno [2, 3-b] pyridin-5-carboxamide; (9) N- (4-Chlorobenzyl) -2-cyano-4-hydroxy-thieno [2, 3-b] pyridin-5-carboxamide; (10) 2- [3- (5-. {[[(4-chlorobenzyl) amino] -carbonyl} -4-hydroxythieno [2,3-b] pyridin-2-yl) -2-propynyl] malonate of dimethyl; (11) 2-Bromo-N- (4-chlorobenzyl) -7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (12) N- (4-Chlorobenzyl) -7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (13) N- (4-Chlorobenzyl) -7-ethyl-2-iodo-4-oxo-4,7-dihydrothieno [2, 3-b] -pyridine-5-carboxamide; (14) N- (4-Chlorobenzyl) -7-ethyl-2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (15) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxy-1-butynyl) -4-OXO-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (16) N- (4-Chlorobenzyl) -7-ethyl-2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (17) N- (4-Chlorobenzyl) -7- (2-hydroxyethyl) -2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5 -carboxamide; (18) N- (4-Chlorobenzyl) -7- [2- (diethylamino) -ethyl] -2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydro-ene [2, 3 -b] pyridin-5-carboxamide; (19) 2- [5-] acid. { [(4-chlorobenzyl) amino] carbonyl} -2- (3-hydroxy-1-propynyl) -4-oxothieno [2, 3-b] pyridin-7 (4H) -yl] acetic acid; (20) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxybutyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (21) N- (4-Chlorobenzyl) -7- (2-hydroxyethyl) -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (22) N- (4-Chlorobenzyl) -7- [2- (diethylamino) -ethyl] -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine- -carboxamide; (23) N- (-Clorobenzyl) -2-iodo-7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (24) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (25) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (26) N- (4-Chlorobenzyl) -2-iodo-7- isopropyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridin-5-carboxamide; (27) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (28) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (29) 4- acid. { [3- (5- { [(4-chlorobenzyl) amino] -carbonyl.} - 7-ethyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridin-2-yl) - 2-propynyl] oxy} -4-oxobutanoic; (30) 3- (5- {[[(4-chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-dihydrothieno [2, 3] 2- (4-morpholinyl) acetate. -b] pyridin-2-yl) -2-propynyl; (31) 3- (5-. {[[(4-Chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-dihydrothieno-2-amino-3-methobutanoate [2, 3] -b] pyridin-2-yl) -2-propynyl; (32) 3- (5- {[[(4-Chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-dihydrothieno 3- (4-morpholinylmethyl) benzoate [2, 3 -b] pyridin-2-yl) -2-propynyl; (33) Methyl-5-. { [4-chlorobenzyl) amino] carbonyl} -4-hydroxythienol [2, 3b] pyridin-2-carboxylate; (34) N- (4-Chlorobenzyl) -4-hydroxy-2- (hydroxymethyl) thieno [2, 3-b] pyridine-5-carboxamide; (35) N- (4-chlorobenzyl) -2- (hydroxymethyl) -7-methyl-4-oxo-4,7-dihydrothienol [2, 3-b] pyridine-5-carboxamide; (36) N- (4-chlorobenzyl) -7-met-il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothienol [2, 3-b] -pyridine-5-carboxamide; (37) N- (4-chlorobenzyl) -methyl-4-oxo-2- (4-thiomono-follinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (38) N- (4-chlorobenzyl) -2- (((2-hydroxy-2- (4-hydroxyphenyl) ethyl) - (methyl) amino) methyl) -7-methyl-4-oxo-4, 7- dihydrothieno [2, 3-b] pyridin-5-carboxamide; (39) N- (4-chlorobenzyl) -2 - (((2-hydroxy-2-phenylethyl) (methyl) amino) methyl) -7-met-il-4 -oxo-4,7-dihydrothieno [2, 3 -b] pyridine-5-carboxamide; (40) N- (4-chlorobenzyl) -4-hydroxy-2- (4-morpholinylmethyl) thieno [2, 3-b] pyridine-5-carboxamide; (41) N- (4-Chlorobenzyl) -7-ethyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (42) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-7-propyl-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (43) N- (4-Chlorobenzyl) -7-isopropyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (44) N- (4-Fluorobenzyl) -7-met-il-2- (4-morpholinylmethyl) -4 -oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (45) N- (4-bromobenzyl) -7-met i 1-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (46) N- (4-chlorobenzyl) -4-hydroxy-2- (4-morphol) icarboni 1) thieno [2, 3b] pyridine-5-carboxamide; (47) N- (4-chlorobenzyl) -7-methyl-2- (4-morpholinylcarbonyl) -4-oxo-4,7-dihydrothieno [2,3-b] pi-ridin-5-carboxamide; (48) 7-Benzyl-N- (4-chlorobenz 1) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (49) N- (4-Chlorobenzyl) -7- (3-f luorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (50) N- (4-Chlorobenzyl) -2- (4 -mor phinylmethyl) -4-OXO-7- (3-phenylpropyl) -4,7-dihydrothieno [2,3-b] pyridine- 5 - carboxamide; (51) N- (4-Chlorobenzyl) -2- (4-morphinylmethyl) -4-oxo-7- (tet rahydro-2-furanylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5 -carboxamide; (52) N- (4-Chlorobenzyl) -2- (4 -mornylmethylmethyl) -4-oxo-7- [2- (l-pyrrolidinyl) ethyl] -4,7-dihydrothieno [2,3-b] pi Ridin-5-carboxamide; (53) N - (4-C-robencyl) -2- (4 -mornylmethylmethyl) -4-OXO-7- (3-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridin-5- carboxamide; (54) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-OXO-7- (4-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; or a pharmaceutically acceptable salt thereof.
19. The compound according to claim 1 which is: (1) N- (4-chlorobenzyl) -7-ethyl-2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide; (2) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxy-1-butynyl) -4-OXO-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (3) N- (4-Chlorobenzyl) -7-ethyl-2- (3-hydroxypropyl) -4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide; (4) N- (-Clorobenzyl) -7- ("2-hydroxyethyl) -2- (3-hydroxy-1-propynyl) -4 -oxo-, 7-dihydrothieno [2,3-b] pyridine- 5 - carboxamide; (5) N- (4-Chlorobenzyl) -7- [2- (diethylamino) ethyl] -2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (6) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxybutyl) -4 -oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (7) N- (4-Chlorobenzyl) -7- (2-hydroxyethyl) -2- (3-hydroxypropyl) -4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide; (8) N- (4-Chlorobenzyl) -7- [2- (diethylamino) -ethyl] -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5 -carboxamide; (9) N- (4-Chlorobenzyl) -2-iodo-7-methyl-4-oxo-4,7-dihydro-ieno [2, 3-b] -pyridine-5-carboxamide; (10) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-methyl-4-oxo-, 7-dihydrothieno [2,3-b] pi-ridin-5-carboxamide; (11) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-methyl-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide; (12) N- (4-Chlorobenzyl) -2-iodo-7-isopropyl-4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide; (13) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (14) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-isopropyl-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide; (15) 4- acid. { [3- (5- { [(4-Chlorobenzyl) amino] -carbonyl.} - 7-ethyl-4-oxo-4,7-dihydro-thieno [2, 3-b] pyridin-2-yl ) -2-propinyl] oxy} -4-oxobutanoic; (16) 3- (5-. {[[(4-Chlorobenzyl) amino] carbonyl} -7-ethyl-4-oxo-4,7-dihydro-thieno 2- (4-morpholinyl) acetate [2 , 3-b] pyridin-2-yl) -2-propynyl; (17) 3- (5-. {[[(4-Chlorobenzyl) amino] carbonyl) -7-ethyl-4-oxo-4,7-dihydrothieno [2, 3-b] 2-amino-3-methylbutanoate pyridin-2-yl) -2-propynyl; (18) 3- (5-. {[[(4-chlorobenzyl) amino] carbonyl] 3- (4-morphinylmethyl) benzoate] -7-ethyl-1-4 -oxo-4,7-dihydrothieno [2] , 3-b] pyridin-2-yl) -2-propynyl; (19) N- (4-chlorobenzyl) -7-methyl-2- (4-mor-folinylmethyl) -4-oxo-4,7-dihydrothienol [2,3-b] pi-ridin-5-carboxamide; (20) N- (4-chlorobenzyl) -7-methyl-4-oxo-2- (4-thiomorpholyl-ylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (21) N- (4-chlorobenzyl) -2- (((2-hydroxy-2- (4-hydroxyphenyl) ethyl) (methyl) amino) methyl) -7-methyl-4-oxo-, 7-dihydrothieno [ 2, 3-b] pyridine-5-carboxamide; (22) N- (4-chlorobenzyl) -2- (((2-hydroxy-2-phenylethyl) (methyl) amino) methyl) -7-methyl-4-oxo-4,7-dihydrothieno [2, 3- b] pyridin-5-carboxamide; (23) N- (4-Chlorobenzyl) -7-yl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (24) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-7-propyl-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (25) N- (4-Chlorobenzyl) -7-isopropyl-2 - (4-orpholinylmethyl) -4 -oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (26) N- (4-Fluorobenzyl) -7-methyl-1- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (27) N- (4-bromobenzyl) -7-met i 1-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (28) 7-Benzyl-N- (4-chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (29) N- (4-Chlorobenzyl) -7- (3-fluorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-, 7-dihydrothieno [2, 3-b] pyridin-5-carboxamide; (30) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-OXO-7- (3-phenylpropyl) -4,7-dihydrothieno [2, 3-b] pyridin-5-carboxamide; (31) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-OXO-7- (tetrahydro-2-furaniylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5 -carboxamide; (32) N- (4-Chlorobenzyl) -2- (4 -mor fo lini lmet i 1) -4-OXO-7- [2- (1-pyrrolidinyl) ethyl] -4,7-dihydrothieno [2, 3 -b] pyridin-5-carboxamide; (33) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-7- (3-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (34) N- (4-Chlorobenzyl) -2- (4 -mornylmethylmethyl) -4-OXO-7- (4-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; or a pharmaceutically acceptable salt thereof.
20. The compound according to claim 1 which is: (1) N- (4-chlorobenzyl) -7-ethyl-2- (3-hydroxy-l-propynyl) -4 -oxo-4, -dihydro-thieno [2, 3 -b] pyridin-5-carboxamide; (2) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxy-1-butynyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (3) N- (4-Chlorobenzyl) -7-ethyl-2- (3-hydroxypropyl) -4-oxo-4,7-dihydro-thieno [2,3-b] pyridin-5-carboxamide; (4) N- (4-Chlorobenzyl) -7- (2-hydroxyethyl) -2- (3-hydroxy-1-propynyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pi ridin- 5-carboxamide; (5) N- (4-Chlorobenzyl) -7- [2- (diethylamino) ethyl] -2- (3-hydroxy-l-propynyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (6) N- (4-Chlorobenzyl) -7-ethyl-2- (4-hydroxybutyl) -4-oxo-4,7-dihydro-thieno [2, 3-b] pyridine-5-carboxamide; (7) N- (4-Chlorobenzyl) -7- (2-hydroxyethyl) -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (8) N- (4-Chlorobenzyl) -7- [2- (diethylamino) ethyl] -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5- carboxamide; (9) N- (4-Chlorobenzyl) -2-iodo-7-met i 1-4 -oxo-4,7-dihydrothieno [2, 3-b] -pyridine-5-carboxamide; (10) N- (4-Chlorobenzyl) -2- (3-hydroxy-l-propynyl) -7-methyl-4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (11) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-methyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (12) N- (4-Chlorobenzyl) -2-iodo-7-isopropyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (13) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-isopropyl-4-oxo-4,7-dihydrothieno [2, 3-b] pi-ridin-5-carboxamide; (14) N- (-Clorobenzyl) -2- (3-hydroxypropyl) -7-isopropyl-4-oxo-4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide; (15) N- (4-chlorobenzyl) -7-methyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (16) N- (4-chlorobenzyl) -7-methyl-4-oxo-2- (4-thiomorpholinylmethyl) -4,7-dihydro-ieno [2, 3-b] pyridine-5-carboxamide; (17) N- (4-chlorobenzyl) -2- (((2-hydroxy-2- (4-hydroxyphenyl) ethyl) - (methyl) amino) methyl) -7-methyl-4-oxo-4, 7- dihydrothieno [2, 3-b] pyridine-5-carboxamide; (18) N- (4-chlorobenzyl) -2 - (((2-hydroxy-2-phenylethyl) (methyl) amino) methyl) -7-met i 1-4 -oxo-4,7-dihydrothieno [2, 3-b ] pyridine-5-carboxamide; (19) N- (4-Chlorobenzyl) -7-ethyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (20) N- (4-Chlorobenzyl) -2- (4-morphinylmethyl) -4-oxo-7-propyl-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (21) N- (4-Chlorobenzyl) -7-i-sopropyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (22) N- (4-Fluorobenzyl) -7-met i 1-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (23) N- (4-bromobenzyl) -7-met i 1-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (24) 7-Benzyl-N- (4-chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridin-5-carboxamide; (25) N- (4-Chlorobenzyl) -7- (3-f-luorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pi-ridin-5-carboxamide; (26) N- (4-Chlorobenzyl) -2- (4 -mor folin lmethyl) -4-OXO-7- (tetrahydro-2-furanylmethyl) -4,7-dihydrothieno [2, 3-b] pyridine- 5-carboxamide; (27) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-7- [2- (l-pyrrolidinyl) ethyl] -4,7-dihydrothieno [2,3-b] pyridine -5-carboxamide; (28) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-OXO-7- (3-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (29) N- (4-Chlorobenzyl) -2- (4-morpholinylmethyl) -4-oxo-7- (4-pyridinylmethyl) -4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; or a pharmaceutically acceptable salt thereof.
21. The compound according to claim 1 which is: (1) N- (4-Chlorobenzyl) -7- [2- (diethylamino) -ethyl] -2- (3-hydroxypropyl) -4-oxo-4,7-dihydrothieno [ 2, 3-b] pyridine-5-carboxamide; (2) N- (4-Chlorobenzyl) -2- (3-hydroxy-1-propynyl) -7-methyl-4-oxo-4,7-dihydro-thieno [2,3-b] pyridin-5-carboxamide; (3) N- (4-Chlorobenzyl) -2- (3-hydroxypropyl) -7-methyl-4-oxo-4,7-dihydrothieno [2, 3-b] pyridine-5-carboxamide; (4) N- (4-chlorobenzyl) -7-met-il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (5) N- (4-chlorobenzyl) -2- (((2-hydroxy-2- (4-hydroxyphenyl) ethyl) (methyl) -amino) methyl) -7-methyl-4-oxo-4, 7- dihydrothieno [2, 3-b] pyridine-5-carboxamide; (6) N- (4-chlorobenzyl) -2- (((2-hydroxy-2-phenylethyl) (methyl) amino) methyl) -7-methyl-4-oxo-4,7-dihydrothieno [2, 3 b] pyridin-5-carboxamide; (7) N- (4-Chlorobenzyl) -7-ethyl-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; (8) N- (4-chlorobenzyl) -2- (4-morphinylmethyl) -4-oxo-7-propyl-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide; or a pharmaceutically acceptable salt thereof.
22. The compound N- (4-chlorobenzyl) -7-met-il-2- (4-morpholinylmethyl) -4-oxo-4,7-dihydrothieno [2,3-b] pyridine-5-carboxamide or a pharmaceutically acceptable salt of the same.
23. A compound of formula III or a pharmaceutically acceptable salt thereof wherein, R22 e s H, - (CH2CH20) nH, - (CH2 CH20) nCH3, S02 R3 5 or COR, 35, C 1 7 alkyl which may be partially unsaturated and is optionally substituted by R 36, C 2 7 alkyl which may be partially unsaturated and is optionally substituted by R 33, or C 3-8 cycloalkyl which may be partially unsaturated and is replaced optionally by R36, R33 or R34; each R23 and R24 is independently H, halo, aryl, S (0) mR30, COR30, cyano, het, CF3, OR29, OR31, SR29, SR31, NR 5R26, CH (OR29) R27, C02R29, CH (C02R29) 2 , NHCOR27, or, NHS (0) 2R27 or C1-7 alkyl which may be partially unsaturated and is optionally substituted by R28; each R25 and R26 is independently H or C? -7 alkyl; R, 2¿7 'is C7_7 alkyl optionally substituted by R36 or C2_7 alkyl optionally substituted by R 33 R 28 is cyano, halo, CF3, aryl, het, C (= 0) C 1 - 7 alkyl, C 0 2 alkyl of C 7 - 7? OR29, OR 31 % SR¿3, SR, 3J11, SR, 3J2% NR 250rR, 26D, CH (OR, 2"9,) R n2" 7, 29 ORJ, C02R CH (C02R29) 2; R29 is H or C? _ Alkyl; R30 is C? _7 alkyl, NR25R26, aryl or het; R31 is C2-7 alkyl substituted by OH; R32 is (P = 0) (OR29) 2, CO (CH2) nCON (CH3) - (CH2) nS03"M +, an amino acid, C (= 0) aryl or C (= 0) C7-7 alkyl optionally substituted by NR25R26, aryl, het, carboxy or O (CH2) nC02R29, R33 is hydroxy or NR25R26, R34 is optionally substituted C7_7 alkyl R33, R35 is C_7 alkyl, aryl or het R36 is C02H or C02alkyl of C _.- 7 each n is independently 1, 2, 3, 4 or 5, each m is independently 0, 1 or 2, M is a pharmaceutically acceptable cation (eg, sodium, potassium or lithium), where any aryl or het is optionally substituted with one or more substituents (eg, (1, 2, 3, 4 or 5) independently selected from the group consisting of halo, cyano, trifluoromethyl, trifluoromethoxy, hydroxy, carboxy, OR27, phenyl, phenoxy , (C 1 -) alkoxycarbonyl, SR 31 and C 7 optionally substituted with one or more substituents independently selected from the group consisting of cyano, aryl, mercapto, het, R36, OR27, SR27 and SR31; wherein phenyl or phenoxy is optionally substituted with one or more substituents independently selected from cyano, halo, trifluoromethyl, trifluoromethoxy, carboxy, het, OR31 and
24. A pharmaceutical composition comprising a compound according to any of claims 1 to 23 and a pharmaceutically acceptable excipient.
25. A compound according to any of claims 1 to 23 for use in medical treatment.
26. The compound according to claim 25 wherein the treatment is the treatment or prevention of a herpesviral infection.
27. The compound according to claim 26 wherein the herpesviral infection is herpes simplex virus type 1, 2, 6, 7 or 8, varicella zoster virus, human cytomegalovirus or Epstein-Barr virus.
28. The compound according to claim 26 wherein the herpesviral infection is herpes simplex virus type 1, herpes simplex virus type 2, varicella zoster virus, human cytomegalovirus, Epstein-Barr virus, human herpes virus 7 or human herpes virus 8 .
29. The compound according to claim 26 wherein the herpesviral infection is human cytomegalovirus.
30. The use of a compound according to any of claims 1 to 23 for preparing a medicament for treating or preventing a herpesviral infection in a mammal.
31. The use of a compound according to any of claims 1 to 23 for preparing a medicament for inhibiting a viral DNA polymerase in a mammal.
32. A method for preparing a compound of the formula L-7: L-7 wherein R is C? _4 alkyl; and X is Cl, Br, CN, N02 or F, which comprises: reacting an amine of the formula L-1: L-l with an alkoxymethylene malonate of the formula R 1 OCH = CH (C02) 2 wherein R 'is C 1 alkyl and each is independently selected from C 1 - alkyl, to provide a compound of the formula L-2: alkylating the compound of the formula L-2 to provide a corresponding compound of the formula L-3: wherein R is C 4 alkyl; reacting the compound of the formula L-3 with a 4-methylenemorpholinium salt to provide a compound of the formula L-4: L-4 cyclize the compound of the formula L-4 to provide a bicyclic ester of the formula L-5: hydrolyzing the L-5 ester to provide a carboxylic acid of the formula L-6: reacting the carboxylic acid of the formula L-6 with a benzylamine of the formula: wherein X is Cl, Br, CN, N02 or F, to provide the compound of the formula L-7.
33. The method according to claim 32 wherein is ethyl, R is methyl and X is Cl.
34. A compound of the formula L-3 wherein R is H or C? _4 alkyl and each is independently selected from C? _ alkyl.
35. A compound of the formula L-4 L- * where R is C? -4 alkyl and each se. independently selects C? -4 alkyl.
36 A compound of the formula L-5 wherein R is C 4 alkyl and W is H or C 1 alkyl
37. The compound according to claim 34, 35 or 36 wherein R is methyl and is ethyl.
38. the compound: (1) diethyl ester of N- (3-tert-butoxycarbonyl-thien-2-yl) methylaminomethyl ionic acid; (2) Diethyl ester of N- (3-tert-butoxycarbonyl-5-morpholinomethyl-t-ene-2-yl) methylaminomethyl ionic acid; (3) 7-methyl-2- (4-morpholinomethyl) -4-OXO-4,7-dihydro-ieno [2, 3b] pyridine-5-carboxylate or ethyl; or (4) 7-met il-2- (4-morpholinomethyl) -4 -oxo-4,7-dihydrothieno [2,3-pyridine-5-carboxylic acid.
39. A method for preparing a compound of the formula I: I wherein R1-R4 have the values described in claim 1, which comprises reacting a corresponding carboxylic acid of the formula (II): with a benzylamine of the formula wherein X is Cl, Br, CN, N02 or F, to provide the compound of the formula (I).