Ortho-anthranilamide derivatives as anti-coagulants

[0003] This application is division of Ser. Nos. 09/187,459, Nov. 5, 1998, U.S. Pat. No. 6,140,351, which is a continuation-in-part of U.S. patent application, Ser. No. 08/994,284, filed Dec. 19, 1997, abandoned, which is incorporated by reference in full herein.

[0004] The present invention is directed to ortho-anthranilamide derivatives and their pharmaceutically acceptable salts, which inhibit the enzyme, factor Xa, thereby being useful as anti-coagulants. It also relates to pharmaceutical compositions containing the derivatives or their pharmaceutically acceptable salts, and methods of their use.

[0005] Factor Xa is a member of the trypsin-like serine protease class of enzymes. A one-to-one binding of factors Xa and Va with calcium ions and phospholipid forms the prothrombinase complex which converts prothrombin to thrombin. Thrombin, in turn, converts fibrinogen to fibrin which polymerizes to form insoluble fibrin.

[0006] In the coagulation cascade, the prothrombinase complex is the convergent point of the intrinsic (surface activated) and extrinsic (vessel injury-tissue factor) pathways (Biochemistry(1991), Vol. 30, p. 10363; and Cell(1988), Vol. 53, pp. 505-518). The model of the coagulation cascade has been refined further with the discovery of the mode of action of tissue factor pathway inhibitor (TFPI) (Seminars in Hematology(1992), Vol. 29, pp. 159-161). TFPI is a circulating multi-domain serine protease inhibitor with three Kunitz-type domains which competes with factor Va for free factor Xa. Once formed, the binary complex of factor Xa and TFPI becomes a potent inhibitor of the factor VIIa and tissue factor complex.

[0007] Factor Xa can be activated by two distinct complexes, by tissue factor-VIIa complex on the “Xa burst” pathway and by the factor IXa-VIIIa complex (TENase) of the “sustained Xa” pathway in the coagulation cascade. After vessel injury, the “Xa burst” pathway is activated via tissue factor (TF). Up regulation of the coagulation cascade occurs via increased factor Xa production via the “sustained Xa” pathway. Down regulation of the coagulation cascade occurs with the formation of the factor Xa-TFPI complex, which not only removes factor Xa but also inhibits further factor formation via the “Xa burst” pathway. Therefore, the coagulation cascade is naturally regulated by factor Xa.

[0008] The primary advantage of inhibiting factor Xa over thrombin in order to prevent coagulation is the focal role of factor Xa versus the multiple functions of thrombin. Thrombin not only catalyzes the conversion of fibrinogen to fibrin, factor VIII to VIIIA, factor V to Va, and factor XI to XIa, but also activates platelets, is a monocyte chemotactic factor, and mitogen for lymphocytes and smooth muscle cells. Thrombin activates protein C, the in vivo anti-coagulant inactivator of factors Va and VIIIa, when bound to thrombomodulin. In circulation, thrombin is rapidly inactivated by antithrombin IIII (ATIII) and heparin cofactor II (HCII) in a reaction which is catalyzed by heparin or other proteoglycan-associated glycosaminoglycans, whereas thrombin in tissues is inactivated by the protease, nexin. Thrombin carries out its multiple cellular activation functions through a unique “tethered ligand” thrombin receptor (Cell(1991), Vol. 64, p. 1057), which requires the same anionic binding site and active site used in fibrinogen binding and cleavage and by thrombomodulin binding and protein C activation. Thus, a diverse group of in vivo molecular targets compete to bind thrombin and the subsequent proteolytic events will have very different physiological consequences depending upon which cell type and which receptor, modulator, substrate or inhibitor binds thrombin.

[0009] Published data with the proteins antistasin and tick anti-coagulant peptide (TAP) demonstrate that factor Xa inhibitors are efficacious anti-coagulants (Thrombosis and Haemostasis(1992), Vol. 67, pp. 371-376; and Science(1990), Vol. 248, pp. 593-596).

[0010] The active site of factor Xa can be blocked by either a mechanism-based or a tight binding inhibitor (a tight binding inhibitor differs from a mechanism-based inhibitor by the lack of a covalent link between the enzyme and the inhibitor). Two types of mechanism-based inhibitors are known, reversible and irreversible, which are distinguished by ease of hydrolysis of the enzyme-inhibitor link (Thrombosis Res(1992), Vol. 67, pp. 221-231; and Trends Pharmacol. Sci. (1987), Vol. 8, pp. 303-307). A series of guanidino compounds are examples of tight-binding inhibitors (Thrombosis Res. (1980), Vol. 19, pp. 339-349). Arylsulfonyl-arginine-piperidine-carboxylic acid derivatives have also been shown to be tight-binding inhibitors of thrombin (Biochem. (1984), Vol. 23, pp. 85-90), as well as a series of arylamidine-containing compounds, including 3-amidinophenylaryl derivatives (Thrombosis Res. (1983), Vol. 29, pp. 635-642) and bis(amidino)benzyl cycloketones (Thrombosis Res. (1980), Vol. 17, pp. 545-548). However, these compounds demonstrate poor selectivity for factor Xa.

[0011] European Published Patent Application 0 540 051 (Nagahara et al) describes aromatic amidine derivatives. These derivatives are stated to be capable of showing a strong anticoagulant effect through reversible inhibition of factor Xa.

[0012] The synthesis of α,α′-bis(amidinobenzylidene)cycloalkanones and α,α′-bis(amidino-benzyl)cycloalkanones is described in Pharmazie(1977), Vol. 32, No. 3, pp. 141-145. These compounds are disclosed as being serine protease inhibitors.

[0013] U.S. Pat. No. 5,612,363 (Mohan et al.) describes N,N-di(aryl) cyclic urea derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.

[0014] U.S. Pat. No. 5,633,381 (Dallas et al.) describes (Z,Z), (Z,E) and (E,Z) isomers of substituted bis(phenylmethylene)cycloketones. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.

[0015] U.S. Pat. No. 5,691,364 (Buckman et al.) describes benzamidine derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.

[0016] PCT Published Patent Application WO/97/21437 (Arnaiz et al) describes naphthyl-substituted benzimidazole derivatives. These compounds are disclosed as being factor Xa inhibitors, thereby being useful as anticoagulants.

[0017] PCT Published Patent Application WO/97129067 (Kochanny et al.) describes benzamidine derivatives that are substituted by amino acid and hydroxy acid derivatives. These compounds are stated to be factor Xa inhibitors, thereby being useful as anticoagulants.

[0018] PCT Published Patent Applications WO/96/10022 (Faull et al.), W097/29104 (Faull et al.), and WO/97/28129 describe aminoheterocyclic compounds which are disclosed as being factor Xa inhibitors, thereby being useful as antithrombotics and anticoagulants.

[0019] The above references, published patent applications and U.S. patents are herein incorporated in full by reference.

[0020] This invention is directed to compounds or their pharmaceutically acceptable salts which inhibit human factor Xa and are therefore useful as pharmacological agents for the treatment of disease-states characterized by thrombotic activity, i.e., as anti-coagulants.

[0021] Accordingly, in one aspect, this invention provides compounds of formula (III):

[0022] wherein

[0023] m is 1 to 3;

[0024] n is 1 to 5;

[0025] is an aryl or a heterocyclic ring substituted by R²and one or more R¹groups;

[0026] is an aryl or a heterocyclic ring substituted by one or more R⁴groups;

[0027] D and E are independently a linker selected from the group consisting of —N(R⁵)—C(X)—; —R⁸—N(R⁵)—C(X)—; —N(R⁵)—C(X)—R⁸—; —R⁸—N(R⁵)—C(X)—R⁸—; —N(R⁵)—S(O)_p—; —R⁸—N(R⁵)—S(O)_p—; —N(R⁵)—S(O)_p—R⁸—; and —R⁸—N(R⁵)—S(O)_p—R⁸— (where p is 0 to 2; X is oxygen, sulfur or H₂) where D and E can be attached to the B ring having the R¹and R²substituents by either terminus of the selected linker;

[0028] each R¹is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵—S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R⁵)R⁶, —O—C(O)R⁵, —N(R⁵)—CH(R¹²)—C(O)OR⁵, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶) or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶);

[0029] R²is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —C(R)H—R⁸—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—(R⁸—O)_t—R¹⁹(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)R¹⁹, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2), —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2), or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0030] R³is aryl or heterocyclyl both substituted by one or more R¹⁴substituents independently selected from the group consisting of hydrogen, alkyl, halo, formyl, acetyl, cyano, —R⁸—CN, —N(R¹⁰)R¹¹, —R⁸—N(R¹⁰)R¹¹, —R⁸—N^⊕(R⁹)(R¹⁶)₂, —C(O)OR⁵, —R⁸—C(O)OR⁵, —OR⁵, —R⁸—OR⁵, —C(R⁷)H—O—R¹⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —R⁸—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —R⁸—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰, —C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—O—N(R⁵)R⁶, heterocyclyl (wherein the heterocyclyl radical is not attached to the rest of the molecule through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), and heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen ring and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0031] each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, or —R⁸—N(R⁵)R⁶;

[0032] each R⁵and R⁶is independently hydrogen, alkyl, aryl or aralkyl;

[0033] each R⁷is independently hydrogen or alkyl;

[0034] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0035] each R⁹is independently alkyl, aryl or aralkyl;

[0036] each R¹⁰and R¹¹is independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R —C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0037] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0038] R¹²is a side chain of an α-amino acid;

[0039] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0040] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;

[0041] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁵or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶); or

[0042] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6);

[0043] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶;

[0044] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂; and

[0045] each R¹⁹is cycloalkyl, haloalkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0046] as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof.

[0047] In another aspect, this invention provides compounds of formula (I):

[0048] A is ═CH— or ═N—;

[0049] m is 1 to 3;

[0050] n is 1 to 4;

[0051] D is —N(R⁵)—C(Z)— or —N(R⁵)—S(O)_p— (where p is 0 to 2; Z is oxygen, sulfur or H₂; and the nitrogen atom is directly bonded to the phenyl ring having the R¹and R²substituents);

[0052] E is —C(Z)—N(R⁵)— or —S(O)_p—N(R⁵)— (where p is 0 to 2; Z is oxygen, sulfur or H₂; and the nitrogen atom can be bonded to the phenyl ring having the R¹and the R²substituents or to the aromatic ring having the R⁴substituent);

[0053] each R¹is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R⁵)R⁶, —O—C(O)R⁵, or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0054] or two adjacent R¹'s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring wherein the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl and aralkyl;

[0055] R²is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —OC(O)—R⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —C(R⁷)H—R⁸—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—(R⁸—O)_t—R¹⁹(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)R¹⁹, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2), —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2), or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0056] R³is a radical of formula (i):

[0057] where:

[0058] r is 1 or 2;

[0059] R¹³is hydrogen, alkyl, halo, haloalkyl, —N(R⁵)R⁶, —C(R⁷)H—N(R⁵)R⁶, —OR⁵, —R⁸—OR⁵, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and

[0060] each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, —R⁸—CN, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —C(R⁷)H—R⁸—N^⊕(R⁹)(R¹⁶)₂, —C(O)OR⁵, —C(R⁷)H—C(O)OR⁵, —C(R⁷)H—R⁸—C(O)OR⁵, —OR⁵, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—O—R¹⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—C(O)N(R⁵)R⁶, —C(R⁷)H—R⁸—C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰, —C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—C(NR ⁷)—N(R⁵)R⁶, —C(R⁷)H—O—N(R⁵)R⁶, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0061] or R³is a radical of the formula (ii):

[0062] where v is 1 to 4;

[0063] R¹³is as defined above for formula (i); and

[0064] R¹⁴is as defined above for formula (i);

[0065] each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, or —R⁸—N(R⁵)R⁶;

[0066] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0067] each R⁷is independently hydrogen or alkyl;

[0068] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0069] each R⁹is independently alkyl, aryl or aralkyl;

[0070] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁶(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0071] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵—C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0072] R¹²is a side chain of an α-amino acid;

[0073] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0074] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;

[0075] each R⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁵—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶); or

[0076] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6);

[0077] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶or R⁸—C(O)—N(R⁵)R⁶;

[0078] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂; and

[0079] each R⁹is cycloalkyl, haloalkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0080] as a single stereoisomer or a mixture thereof; or a pharmaceutically acceptable salt thereof; provided that when A is ═CH—, m is 1, n is 1, D is —N(H)—C(O)— (where the nitrogen atom is directly bonded to the phenyl ring having the R¹and R²substituents), E is —C(O)—N(H)— (where the nitrogen atom is directly bonded to the phenyl ring having the R⁴substituent), R¹is hydrogen and R²is in the 5-position and is methyl, R⁴is in the 4-position and is fluoro, R³can not be a radical of formula (ii) where v is 1, R¹⁴is hydrogen, and R¹³is chloro.

[0081] In another aspect, this invention provides compositions useful in treating a human having a disease-state characterized by thrombotic activity, which composition comprises a therapeutically effective amount of a compound of the invention as described above, without the proviso, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0082] In another aspect, this invention provides a method of treating a human having a disease-state characterized by thrombotic activity, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above, without the proviso.

[0083] In another aspect, this invention provides a method of treating a human having a disease-state alleviated by the inhibition of factor Xa, which method comprises administering to a human in need thereof a therapeutically effective amount of a compound of the invention as described above, without the proviso.

[0084] In another aspect, this invention provides a method of inhibiting human factor Xa in vitro by the administration of a compound of the invention, without the proviso.

[0085] As used in the specification and appended claims, unless specified to the contrary, the following terms have the meaning indicated:

[0086] “Alkyl” refers to a straight or branched hydrocarbon chain radical consisting solely of carbon and hydrogen atoms, containing no unsaturation, having from one to six carbon atoms, and which is attached to the rest of the molecule by a single bond, e.g., methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, n-pentyl, 1,1-dimethylethyl (t-butyl), and the like.

[0087] “Alkoxy” refers to a radical of the formula —OR_awhere R_ais an alkyl radical as defined above, e.g., methoxy, ethoxy, propoxy, and the like.

[0088] “Alkoxyalkyl” refers to a radical of the formula —R_a—OR_awhere each R_ais independently an alkyl radical as defined above, e.g., 2-methoxyethyl, methoxymethyl, 3-ethoxypropyl, and the like.

[0089] “Alkylene chain” refers to straight or branched chain divalent radical consisting solely of carbon and hydrogen atoms, containing no unsaturation and having from one to six carbon atoms, e.g., methylene, ethylene, propylene, n-butylene and the like.

[0090] “Alkylidene chain” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms, having from two to six carbon atoms, wherein the unsaturation is present only as double bonds and wherein a double bond can exist between the first carbon of the chain and the rest of the molecule, e.g., ethylidene, propylidene, n-butylidene, and the like.

[0091] “Alkylidyne chain” refers to a straight or branched chain unsaturated divalent radical consisting solely of carbon and hydrogen atoms having from two to six carbon atoms, wherein the unsaturation is present only as triple bonds and wherein a triple bond can exist between the first carbon of the chain and the carbon atom of the rest of the molecule to which it is attached, e.g., propylid-2-ynyl, n-butylid-1-ynyl, and the like.

[0092] “Amino” refers to the —NH₂radical.

[0093] “Aminocarbonyl” refers to the —C(O)NH₂radical.

[0094] “Aryl” refers to a phenyl or naphthyl radical. Unless otherwise indicated, the term “aryl” refers to phenyl or naphthyl radicals which are optionally substituted by alkyl, halo, —OR⁵(where R⁵is hydrogen, alkyl, aryl or aralkyl).

[0095] “Aralkyl” refers to a radical of the formula —R_aR_bwhere R_ais an alkyl radical, as defined above, substituted by R_b, an aryl radical, as defined above, e.g., benzyl.

[0096] “α-Amino Acids” refer to naturally occurring and commercially available amino acids and optical isomers thereof. Typical natural and commercially available amino acids are glycine, alanine, serine, homoserine, threonine, valine, norvaline, leucine, isoleucine, norleucine, aspartic acid, glutamic acid, lysine, ornithine, histidine, arginine, cysteine, homocysteine, methionine, phenylalanine, homophenylalanine, phenylglycine, ortho-tyrosine, meta-tyrosine, para-tyrosine, tryptophan, glutamine, asparagine, proline and hydroxyproline. A “side chain of an α-amino acid” refers to the radical found on the α-carbon of an α-amino acid as defined above, for example, hydrogen (for glycine), methyl (for alanine), benzyl (for phenylalanine), and the like.

[0097] “Cycloalkyl” refers to a 3- to 7-membered monocyclic cyclic radical which is saturated, and which consists solely of carbon and hydrogen atoms, e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like.

[0098] “DMF” refers to N,N-dimethylformamide.

[0099] “DMSO” refers to dimethylsulfoxide.

[0100] “Dialkylamino” refers to a radical of the formula —N(R_a)R_awhere each R_ais independently an alkyl radical as defined above, e.g., dimethylamino, diethylamino, (isopropyl)(ethyl)amino, and the like.

[0101] “Dialkylaminocarbonyl” refers to a radical of the formula —C(O)N(R_a)R_awhere each R_ais independently an alkyl radical as defined above, e.g., (dimethylamino)carbonyl, (diethylamino)carbonyl, ((isopropyl)(ethyl)amino)carbonyl, and the like.

[0102] “Halo” refers to bromo, chloro, iodo or fluoro.

[0103] “Haloalkyl” refers to an alkyl radical, as defined above, that is substituted by one or more halo radicals, as defined above, e.g., trifluoromethyl, difluoromethyl, trichloromethyl, 2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, 3-bromo-2-fluoropropyl, 1-bromomethyl-2-bromoethyl, and the like. “Heterocyclic ring” refers to a stable 3- to 15-membered ring radical which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, phosphorus, oxygen and sulfur. For purposes of this invention, the heterocyclic ring radical may be a monocyclic, bicyclic or tricyclic ring system, which may include fused or bridged ring systems, and the nitrogen, phosphorus, carbon or sulfur atoms in the heterocyclic ring radical may be optionally oxidized to various oxidation states. In addition, the nitrogen atom may be optionally quaternized; and the ring radical may be partially or fully saturated or aromatic. Examples of such heterocyclic ring radicals include, but are not limited to, azetidinyl, acridinyl, benzodioxolyl, benzodioxanyl, benzofuranyl, carbazoyl, cinnolinyl, dioxolanyl, indolizinyl, naphthyridinyl, perhydroazepinyl, phenazinyl, phenothiazinyl, phenoxazinyl, phthalazinyl, pteridinyl, purinyl, quinazolinyl, quinoxalinyl, quinolinyl, isoquinolinyl, tetrazoyl, tetrahydroisoquinolyl, piperidinyl, piperazinyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, 2-oxoazepinyl, azepinyl, pyrrolyl, 4-piperidonyl, pyrrolidinyl, pyrazolyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, dihydropyridinyl, tetrahydropyridinyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, triazolyl, indanyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiazolyl, thiazolinyl, thiazolidinyl, isothiazolyl, quinuclidinyl, isothiazolidinyl, indolyl, isoindolyl, indolinyl, isoindolinyl, octahydroindolyl, octahydroisoindolyl, quinolyl, isoquinolyl, decahydroisoquinolyl, benzimidazolyl, thiadiazolyl, benzopyranyl, benzothiazolyl, benzoxazolyl, furyl, tetrahydrofuryl, tetrahydropyranyl, thienyl, benzothienyl, thiamorpholinyl, thiamorpholinyl sulfoxide, thiamorpholinyl sulfone, dioxaphospholanyl and oxadiazolyl. For those compounds where two adjacent R¹'s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring, the most preferred heterocyclic ring is the dioxolane ring (with the phenyl ring forms a benzodioxole ring).

[0104] “Heterocyclyl” refers to a heterocyclic ring radical as defined above, except that the heterocyclyl ring radical may be attached to the main structure at any heteroatom or carbon atom that results in the creation of a stable structure.

[0105] “Heterocyclylalkyl” refers to a radical of the formula —R_a—R_cwhere R_ais an alkyl radical as defined above and R_cis a heterocyclyl ring radical as defined above, for example, (4-methylpiperazin-1-yl)methyl, (morpholin-4-yl)methyl, 2-(oxazolin-2-yl)ethyl, and the like. “N-heterocyclic ring” refers to those heterocyclic ring radicals defined above which contain at least one nitrogen. The N-heterocyclic ring radical is attached to the main structure through a nitrogen atom in the ring. Examples include, but are not limited to, 4-methylpiperazin-1-yl, pyrrolidin-1-yl, morpholin-4-yl, oxazolin-2-yl, and the like. The N-heterocyclic ring may contain up to three additional hetero atoms. Examples include tetrazolyl, triazolyl, thiomorpholinyl, oxazinyl, and the like.

[0106] “HPLC” refers to high pressure liquid chromatography.

[0107] “Monoalkylamino” refers to a radical of the formula —N(H)R_awhere R_ais an alkyl radical as defined above, e.g., methylamino, ethylamino, (t-butyl)amino, and the like.

[0108] “Monoalkylaminocarbonyl” refers to a radical of the formula —C(O)N(H)R_awhere R_ais an alkyl radical as defined above, e.g., (methylamino)carbonyl, (ethylamino)carbonyl, ((t-butyl)amino)carbonyl, and the like.

[0109] “Optional” or “optionally” means that the subsequently described event of circumstances may or may not occur, and that the description includes instances where said event or circumstance occurs and instances in which it does not. For example, “optionally substituted aryl” means that the aryl radical may or may not be substituted and that the description includes both substituted aryl radicals and aryl radicals having no substitution.

[0110] “Pharmaceutically acceptable salt” includes both acid and base addition salts.

[0111] “Pharmaceutically acceptable acid addition salt” refers to those salts which retain the biological effectiveness and properties of the free bases, which are not biologically or otherwise undesirable, and which are formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like, and organic acids such as acetic acid, trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, and the like.

[0112] “Pharmaceutically acceptable base addition salt” refers to those salts which retain the biological effectiveness and properties of the free acids, which are not biologically or otherwise undesirable. These salts are prepared from addition of an inorganic base or an organic base to the free acid. Salts derived from inorganic bases include, but are not limited to, the sodium, potassium, lithium, ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminum salts and the like. Preferred inorganic salts are the ammonium, sodium, potassium, calcium, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-dimethylaminoethanol, 2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydrabamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purines, piperazine, piperidine, N-ethylpiperidine, polyamine resins and the like. Particularly preferred organic bases are isopropylamine, diethylamine, ethanolamine, trimethylamine, dicyclohexylamine, choline and caffeine. “Therapeutically effective amount” refers to that amount of a compound of the invention which, when administered to a human in need thereof, is sufficient to effect treatment, as defined below, for disease-states characterized by thrombotic activity. The amount of a compound of the invention which constitutes a “therapeutically effective amount” will vary depending on the compound, the disease-state and its severity, and the age of the human to be treated, but can be determined routinely by one of ordinary skill in the art having regard to his own knowledge and to this disclosure.

[0113] “THF” refers to tetrahydrofuran.

[0114] “Treating” or “treatment” as used herein covers the treatment of a disease-state in a human, which disease-state is characterized by thrombotic activity, and includes:

[0115] (i) preventing the disease-state from occurring in a human, in particular, when such human is predisposed to the disease-state but has not yet been diagnosed as having it;

[0116] (ii) inhibiting the disease-state, ie., arresting its development; or

[0117] (iii) relieving the disease-state, i.e., causing regression of the disease-state.

[0118] The yield of each of the reactions described herein is expressed as a percentage of the theoretical yield.

[0119] For purposes of this invention, in the substituent “—R⁸—OR⁵”, the “—OR⁵” group may be attached to any carbon in the alkylene, alkylidene or alkylidyne chain.

[0120] Some of the compounds of the invention may have imino, amino, oxo or hydroxy substituents off aromatic heterocyclic ring systems. For purposes of this disclosure, it is understood that such imino, amino, oxo or hydroxy substituents may exist in their corresponding tautomeric form, i.e., amino, imino, hydroxy or oxo, respectively.

[0121] For purposes of this invention, unless otherwise indicated, the linker moieties between the B ring and the C ring (“E”) and between the B ring and the R³moiety (“D”) may be independently attached to the B ring on either end of the linker.

[0122] For purposes of this invention, the quaternary salts represented by “—N^⊕(R⁹(R¹⁶)²” include aromatic rings wherein both R¹⁶'s together with the nitrogen to which they are attached form an aromatic ring and it is understood that R⁹is not present.

[0123] The compounds of the invention, or their pharmaceutically acceptable salts, may have asymmetric carbon atoms, oxidized sulfur atoms or quaternized nitrogen atoms in their structure. The compounds of the invention and their pharmaceutically acceptable salts may therefore exist as single stereoisomers, racemates, and as mixtures of enantiomers and diastereomers. The compounds may also exist as geometric isomers. All such single stereoisomers, racemates and mixtures thereof, and geometric isomers are intended to be within the scope of this invention. Methods for the preparation and/or separation and isolation of single stereoisomers from racemic mixtures or non-racemic mixtures of stereoisomers are well known in the art.

[0124] The nomenclature used herein is a modified form of the I.U.P.A.C. system wherein the compounds of the invention are named as derivatives of benzamide. For example, a compound of the invention selected from formula (I) where A is —N—; m is 1; n is 1; E is —C(O)—N(H)— where the nitrogen atom is bonded to pyridine ring; D is —N(H)—C(O)— where the nitrogen atom is bonded to the phenyl ring; R¹is in the 5-position and is chloro; R²is in the 3-position and is —N(R¹⁰)R¹¹where R¹⁰and R¹¹together with nitrogen to which they are attached form a morpholin-4-yl ring; R⁴is in the 5-position and is chloro; and R³is selected from formula (i):

[0125] where R¹³is chloro, r is 1 and R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R⁷is hydrogen, R¹⁰is methyl and R¹¹is 1-methylpiperidin-4-yl; i.e., a compound of the following formula (with position numbers indicated):

[0126] is named herein as N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.

[0127] For purposes of this specification, parenthesis are used to denote substituents of a main atom. For example, —C(R⁷)H—N(R¹⁰)R¹¹refers to the radical:

[0128] Carbonyl and thiocarbonyl groups are indicated as —C(O)— and —C(S)—, respectively, and optionally substituted imino radicals are indicated as ═N(R¹⁷).

[0129] Substituents having repeating sections are indicated by brackets (or parenthesis) and the repeating integer. For example, the substituent —C(R⁷)H—R⁸—(R⁸—O)_t—R⁵where t is 3 refers to the the substituent —C(R⁷)H—R⁸—R⁸—O—R⁸—O—R⁸—O—R⁵.

[0130] The compounds of the invention are inhibitors of the serine protease, factor Xa, and are therefore useful in disease-states characterized by thrombotic activity based on factor Xa's role in the coagulation cascade (see Background of the Invention above). Primarily, the compounds of the invention are useful as anti-coagulants. A primary indication for the compounds is prophylaxis for long term risk following myocardial infarction. Additional indications are prophylaxis of deep vein thrombosis (DVT) following orthopedic surgery or prophylaxis of selected patients following a transient ischemic attack. The compounds of the invention may also be useful for indications in which coumarin is currently used, such as for DVT or other types of surgical intervention such as coronary artery bypass graft and percutaneous transluminal coronary angioplasty. The compounds are also useful for the treatment of thrombotic complications associated with acute promyelocytic leukemia, diabetes, multiple myelomas, disseminated intravascular coagulation associated with septic shock, purpura fulminanas associated infection, adult respiratory distress syndrome, unstable angina, and thrombotic complications associated with aortic valve or vascular prosthesis. The compounds are also useful for prophylaxis for thrombotic diseases, in particular in patients who have a high risk of developing such disease.

[0131] In addition, the compounds of the invention are useful as in vitro diagnostic reagents for selectively inhibiting factor Xa without inhibiting other components of the coagulation cascade.

[0132] The primary bioassays used to demonstrate the inhibitory effect of the compounds of the invention on factor Xa are simple chromogenic assays involving only serine protease, the compound of the invention to be tested, substrate and buffer (see, e.g., Thrombosis Res. (1979), Vol. 16, pp. 245-254). For example, four tissue human serine proteases can be used in the primary bioassay, free factor Xa, prothrombinase, thrombin (IIa) and tissue plasminogen activator (tPA). The assay for tPA has been successfully used before to demonstrate undesired side effects in the inhibition of the fibrinolytic process (see, e.g., J. Med. Chem. (1993), Vol. 36, pp. 314-319).

[0133] Another bioassay useful in demonstrating the utility of the compounds of the invention in inhibiting factor Xa demonstrates the potency of the compounds against free factor Xa in citrated plasma. For example, the anticoagulant efficacy of the compounds of the invention will be tested using either the prothrombin time (PT), or activated partial thromboplastin time (aPTT) while selectivity of the compounds is checked with the thrombin clotting time (TCT) assay. Correlation of the K_iin the primary enzyme assay with the K_ifor free factor Xa in citrated plasma will screen against compounds which interact with or are inactivated by other plasma components. Correlation of the K_iwith the extension of the PT is a necessary in vitro demonstration that potency in the free factor Xa inhibition assay translates into potency in a clinical coagulation assay. In addition, extension of the PT in citrated plasma can be used to measure duration of action in subsequent pharmacodynamic studies.

[0134] For further information on assays to demonstrate the activity of the compounds of the invention, see R. Lottenberg et al., Methods in Enzymology(1981), Vol. 80, pp. 341-361, and H. Ohno et al., Thrombosis Research(1980), Vol. 19, pp. 579-588.

[0135] Administration of the compounds of the invention, or their pharmaceutically acceptable salts, in pure form or in an appropriate pharmaceutical composition, can be carried out via any of the accepted modes of administration or agents for serving similar utilities. Thus, administration can be, for example, orally, nasally, parenterally, topically, transdermally, or rectally, in the form of solid, semi-solid, lyophilized powder, or liquid dosage forms, such as for example, tablets, suppositories, pills, soft elastic and hard gelatin capsules, powders, solutions, suspensions, or aerosols, or the like, preferably in unit dosage forms suitable for simple administration of precise dosages. The compositions will include a conventional pharmaceutical carrier or excipient and a compound of the invention as the/an active agent, and, in addition, may include other medicinal agents, pharmaceutical agents, carriers, adjuvants, etc.

[0136] Generally, depending on the intended mode of administration, the pharmaceutically acceptable compositions will contain about 1% to about 99% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, and 99% to 1% by weight of a suitable pharmaceutical excipient. Preferably, the composition will be about 5% to 75% by weight of a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, with the rest being suitable pharmaceutical excipients.

[0137] The preferred route of administration is oral, using a convenient daily dosage regimen which can be adjusted according to the degree of severity of the disease-state to be treated. For such oral administration, a pharmaceutically acceptable composition containing a compound(s) of the invention, or a pharmaceutically acceptable salt thereof, is formed by the incorporation of any of the normally employed excipients, such as, for example, pharmaceutical grades of mannitol, lactose, starch, pregelatinized starch, magnesium stearate, sodium saccharin, talcum, cellulose ether derivatives, glucose, gelatin, sucrose, citrate, propyl gallate, and the like. Such compositions take the form of solutions, suspensions, tablets, pills, capsules, powders, sustained release formulations and the like.

[0138] Preferably such compositions will take the form of capsule, caplet or tablet and therefore will also contain a diluent such as lactose, sucrose, dicalcium phosphate, and the like; a disintegrant such as croscarmellose sodium or derivatives thereof; a lubricant such as magnesium stearate and the like; and a binder such as starch, gum acacia, polyvinylpyrrolidone, gelatin, cellulose ether derivatives, and the like.

[0139] The compounds of the invention, or their pharmaceutically acceptable salts, may also be formulated into a suppository using, for example, about 0.5% to about 50% active ingredient disposed in a carrier that slowly dissolves within the body, e.g., polyoxyethylene glycols and polyethylene glycols (PEG), e.g., PEG 1000 (96%) and PEG 4000 (4%).

[0140] Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, etc., a compound(s) of the invention (about 0.5% to about 20%), or a pharmaceutically acceptable salt thereof, and optional pharmaceutical adjuvants in a carrier, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol and the like, to thereby form a solution or suspension.

[0141] If desired, a pharmaceutical composition of the invention may also contain minor amounts of auxiliary substances such as wetting or emulsifying agents, pH buffering agents, antioxidants, and the like, such as, for example, citric acid, sorbitan monolaurate, triethanolamine oleate, butylated hydroxytoluene, etc.

[0142] Actual methods of preparing such dosage forms are known, or will be apparent, to those skilled in this art; for example, see Remington's Pharmaceutical Sciences, 18th Ed., (Mack Publishing Company, Easton, Pa., 1990). The composition to be administered will, in any event, contain a therapeutically effective amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, for treatment of a disease-state alleviated by the inhibition of factor Xa in accordance with the teachings of this invention.

[0143] The compounds of the invention, or their pharmaceutically acceptable salts, are administered in a therapeutically effective amount which will vary depending upon a variety of factors including the activity of the specific compound employed; the metabolic stability and length of action of the compound; the age, body weight, general health, sex, and diet of the patient; the mode and time of administration; the rate of excretion; the drug combination; the severity of the particular disease-states; and the host undergoing therapy. Generally, a therapeutically effective daily dose is from about 0.14 mg to about 14.3 mg/kg of body weight per day of a compound of the invention, or a pharmaceutically acceptable salt thereof; preferably, from about 0.7 mg to about 10 mg/kg of body weight per day; and most preferably, from about 1.4 mg to about 7.2 mg/kg of body weight per day. For example, for administration to a 70 kg person, the dosage range would be from about 10 mg to about 1.0 gram per day of a compound of the invention, or a pharmaceutically acceptable salt thereof, preferably from about 50 mg to about 700 mg per day, and most preferably from about 100 mg to about 500 mg per day.

[0144] Of the compounds disclosed in the Summary of the Invention, certain compounds are preferred.

[0145] The most preferred compounds of the invention are those compounds selected from formula (Ill) having the formula (I):

[0146] A is ═CH— or ═N—;

[0147] m is 1 to 3;

[0148] n is 1 to 4;

[0149] D is —N(R⁵)—C(Z)— or —N(R⁵)—S(O)_p— (where p is 0 to 2; Z is oxygen, sulfur or H₂; and the nitrogen atom is directly bonded to the phenyl ring having the R¹and R²substituents);

[0150] E is —C(Z)—N(R⁵)— or —S(O)_p—N(R⁵)— (where p is 0 to 2; Z is oxygen, sulfur or H₂; and the nitrogen atom can be bonded to the phenyl ring having the R¹and the R²substituents or to the aromatic ring having the R⁴substituent);

[0151] each R¹is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R⁵)R⁶, —O—C(O)R⁵, or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0152] or two adjacent R¹'s together with the carbons to which they are attached form a heterocyclic ring fused to the phenyl ring wherein the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl and aralkyl;

[0153] R²is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —OC(O)—R⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —C(R⁷)H—R⁸—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, —O—R⁸—N(R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—(R⁸—O)_t—R¹⁹(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)R¹⁹, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2), —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2), or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0154] R³is a radical of formula (i):

[0155] where:

[0156] r is 1 or 2;

[0157] R¹³is hydrogen, alkyl, halo, haloalkyl, —N(R⁵)R⁶, —C(R⁷)H—N(R⁵)R⁶, —OR⁵, —R⁸—OR⁵, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and

[0158] each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, —R⁸—CN, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —C(R⁷)H—R⁸—N^⊕(R⁹)(R¹⁶)₂, —C(O)OR⁵, —C(R⁷)H—C(O)OR⁵, —C(R⁷)H—R⁸—C(O)OR⁵, —OR⁵, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—O—R¹⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—C(O)N(R⁵)R⁶, —C(R⁷)H—R⁸—C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵₁, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰, —C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—O—N(R⁵)R⁶, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0159] or R³is a radical of the formula (ii):

[0160] where v is 1 to 4;

[0161] R¹³is as defined above for formula (i); and

[0162] R¹⁴is as defined above for formula (i);

[0163] each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, or —R⁸—N(R⁵)R⁶;

[0164] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0165] each R⁷is independently hydrogen or alkyl;

[0166] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0167] each R⁹is independently alkyl, aryl or aralkyl;

[0168] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0169] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0170] R¹²is a side chain of an α-amino acid;

[0171] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and—C(O)N(R⁵)R⁶);

[0172] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl;

[0173] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶); or

[0174] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6);

[0175] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶;

[0176] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂; and

[0177] each R¹⁹is cycloalkyl, haloalkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —R⁸—C(O)N(R⁵)R⁶, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶).

[0178] Of these compounds, a preferred group of compounds are those compounds wherein:

[0179] A is ═N—;

[0180] m is 1 to 3;

[0181] n is 1 to 4;

[0182] D is —N(R⁵)—C(Z)— (where Z is oxygen, sulfur or H₂, and R⁵is hydrogen or alkyl);

[0183] E is —C(Z)—N(R⁵)— (where Z is oxygen, sulfur or H₂, R⁵is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);

[0184] R¹is halo or haloalkyl;

[0185] R²is —N(R⁵)R¹¹, —O—R⁸—S(O)_p—R⁹(where p is 0), —O—R⁸—C(O)OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1) or —O—R⁸—N(R¹⁰)R¹¹where:

[0186] each R⁵is independently hydrogen or alkyl;

[0187] each R⁸is independently a straight or branched alkylene chain;

[0188] R⁹is alkyl; and

[0189] R¹⁰and R¹¹are each independently hydrogen, alkyl, or —R⁸—O—R⁵(where R⁸is a straight or branched alkylene chain and R⁵is hydrogen or alkyl);

[0190] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl;

[0191] R³is a radical of the formula (i):

[0192] where r is 1;

[0193] R¹³is halo; and

[0194] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0195] R⁷is hydrogen; and

[0196] R¹⁰and R¹¹together with the nitrogen to which they are attached form piperazinyl optionally substituted by one or more substituents selected from the group consisting of alkyl and —C(O)R⁵; and

[0197] R⁴is hydrogen or halo.

[0198] Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:

[0199] m is 1;

[0200] n is 1;

[0201] D is —N(H)—C(O)—;

[0202] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0203] R¹is halo in the 5-position;

[0204] R²is —N(R¹⁰)R¹¹, —O—R⁸—S(O)_p—R⁹(where p is 0), —O—R⁸—C(O)OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1) or —O—R⁸—N(R¹⁰)R¹¹where:

[0205] each R⁵is independently hydrogen, methyl or ethyl;

[0206] each R⁸is independently a methylene, ethylene or propylene chain;

[0207] R⁹is methyl or ethyl; and

[0208] R¹⁰and R¹¹are each independently hydrogen, methyl, ethyl, or —R⁸—O—R⁵(where R⁸is ethylene and R⁵is hydrogen, methyl or ethyl); or

[0209] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl;

[0210] R³is a radical of the formula (i):

[0211] where r is 1;

[0212] R¹³is chloro; and

[0213] R¹⁴is in the 4-position and is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0214] R⁷is hydrogen; and

[0215] R¹⁰and R¹¹together with the nitrogen to which they are attached form piperazinyl optionally substituted by methyl or ethyl; and

[0216] R⁴is hydrogen, bromo or chloro in the 5-position.

[0217] Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:

[0218] R¹is chloro;

[0219] R²is —O—R⁸—S(O)_p—R⁹(where p is 0), —O—R⁸—C(O)OR⁵or —O—(R⁸—O)_t—R⁵(where t is 1 or 2) where:

[0220] each R⁵is independently hydrogen, methyl or ethyl;

[0221] each R⁸is independently a methylene, ethylene or propylene chain; and

[0222] R⁹is methyl or ethyl.

[0223] Of this class of compounds, more preferred compounds are those compounds selected from the group consisting of:

[0224] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(methylthio)methoxy-5-chlorobenzamide;

[0225] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;

[0226] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

[0227] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide; and

[0228] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-ethoxyethoxy)-5-chlorobenzamide;

[0229] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide, and

[0230] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide.

[0231] Of this subgroup of compounds, another preferred class of compounds are those compounds wherein:

[0232] R¹is chloro; and

[0233] R²is —N(R¹⁰)R¹¹or —O—R⁸—N(R¹⁰)R¹¹where:

[0234] R⁸is a methylene, ethylene or propylene chain; and

[0235] R¹⁰and R¹¹are each independently hydrogen, methyl, ethyl, or —R⁸—O—R⁵(where R⁸is ethylene and R⁵is hydrogen, methyl or ethyl).

[0236] Of this class of compounds, preferred compounds are selected from the group consisting of:

[0237] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

[0238] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(N′-methyl-N′-(2-hydroxyethyl)amino)propoxy)-5-chlorobenzamide; and

[0239] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-amino-5-chlorobenzamide.

[0240] Of this subgroup of compounds, another preferred class of compounds are those compounds wherein:

[0241] R¹is chloro;

[0242] R²is —N(R¹⁰)R¹¹or —O—R⁸—N(R¹⁰)R¹¹where:

[0243] R⁸is methylene, ethylene or propylene; and

[0244] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to one additional hetero atoms, where the N-heterocyclic ring is optionally substituted by alkyl and is selected from the group consisting of morpholinyl, piperazinyl, pyrrolidinyl or imidazolyl.

[0245] Of this class of compounds, preferred compounds are selected from the group consisting of:

[0246] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0247] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

[0248] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-morpholinylpropoxy)-5-chlorobenzamide;

[0249] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

[0250] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

[0251] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide; and

[0252] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.

[0253] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0254] A is ═N—;

[0255] m is 1 to 3;

[0256] n is 1 to 4;

[0257] D is —N(R⁵)—C(Z)— (where Z is oxygen, sulfur or H₂, and R⁵is hydrogen or alkyl);

[0258] E is —C(Z)—N(R⁵)— (where Z is oxygen, sulfur or H₂, R⁵is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);

[0259] R¹is halo or haloalkyl;

[0260] R²is hydrogen, haloalkyl, or —OR⁵where R⁵is hydrogen or alkyl;

[0261] R³is a radical of the formula (i):

[0262] where r is 1;

[0263] R¹³is halo; and

[0264] each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, cyano, —R⁸—CN, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —C(R⁷)H—R⁸—N^⊕(R⁹)(R¹⁶)₂, —C(O)OR⁵, —C(R⁷)H—C(O)OR⁵, —C(R⁷)H—R⁸—C(O)OR⁵, —OR⁵, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—O—R¹⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—C(O)N(R⁵)R⁶, —C(R⁷)H—R⁸—C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—R⁸—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—N(R⁵)—R⁸-[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰, —C(NR¹⁷)—N(R⁵)R⁶, —C(R⁷)H—C(NR¹⁷)—N(R⁵)R⁶₁, —C(R⁷)H—O—N(R⁵)R⁶, heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (wherein the heterocyclyl radical is not attached to the alkyl radical through a nitrogen atom and is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶); where

[0265] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0266] each R⁷is independently hydrogen or alkyl;

[0267] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0268] each R⁹is independently alkyl, aryl or aralkyl;

[0269] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0270] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0271] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0272] each R⁹is independently alkyl, aryl or aralkyl;

[0273] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵—N(R⁵)R⁶, —R⁸—N(R⁵)R⁶₁, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0274] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0275] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0276] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

[0277] each R⁵is hydrogen, alkyl, aryl or aralkyl; and

[0278] R⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂;

[0279] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0280] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0281] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0282] each R⁹is independently alkyl, aryl or aralkyl;

[0283] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶, where

[0284] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0285] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0286] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0287] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0288] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain; or

[0289] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6), where

[0290] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0291] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0292] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶, where

[0293] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0294] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0295] and R⁴is hydrogen or halo.

[0296] Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:

[0297] m is 1;

[0298] n is 1;

[0299] D is —N(H)—C(O)—;

[0300] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0301] R²is hydrogen, haloalkyl, or —OR⁵where R⁵is hydrogen or alkyl;

[0302] R³is a radical of the formula (i):

[0303] where r is 1;

[0304] R¹³is halo; and

[0305] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0306] R⁷is hydrogen;

[0307] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹, (where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0308] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0309] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0310] each R⁹is independently alkyl, aryl or aralkyl;

[0311] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0312] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0313] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0314] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

[0315] each R⁵is hydrogen, alkyl, aryl or aralkyl; and

[0316] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂;

[0317] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0318] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0319] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0320] each R⁹is independently alkyl, aryl or aralkyl;

[0321] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵₁—R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶where

[0322] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0323] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0324] and R⁴is in the 5-position.

[0325] Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:

[0326] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵₁—C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0327] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0328] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0329] each R⁹is independently alkyl, aryl or aralkyl;

[0330] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl —OR⁵, —R⁸OR⁵—C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶) where

[0331] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0332] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0333] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

[0334] each R⁵is independently hydrogen, alkyl, aryl or aralkyl; and

[0335] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂.

[0336] Of this class of compounds, a preferred subclass of compounds are those compounds wherein:

[0337] R¹⁰is hydrogen, alkyl, or —R⁸—OR⁵; and

[0338] R¹¹is hydrogen, alkyl or —R⁸—OR⁵;

[0339] where each R⁸is independently a straight or branched alkylene chain, and each R⁵is hydrogen or alkyl.

[0340] Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:

[0341] N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0342] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0343] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0344] N-(5-chloropyridin-2-yl)-2-[((4-((N′, N′-di(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0345] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0346] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0347] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0348] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2,2-dimethyl-2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0349] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-ethoxy-5-chlorobenzamide;

[0350] N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0351] N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0352] N-(5-chloropyridin-2-yl)-2-[((4-(amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0353] N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0354] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0355] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1-methylethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0356] N-(5-chloropyridin-2-yl)-2-[((4-(ethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0357] N-(5-chloropyridin-2-yl)-2-[((4-(diethylamino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0358] Of this class of compounds, another preferred subclass of compounds are those compounds wherein:

[0359] R¹⁰is hydrogen, alkyl, or —R⁸—N(R⁵)R⁶, and

[0360] R¹¹is —S(O)_p—R¹⁵(where p is 0 to 2) or —R⁸—N(R⁵)R⁶where:

[0361] R⁵and R⁶are independently hydrogen or alkyl;

[0362] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain; and

[0363] R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶) where

[0364] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0365] each R³is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0366] Of this subclass of compounds, preferred compounds are selected from the group consisting of:

[0367] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0368] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0369] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0370] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(methyl)sulfonyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0371] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0372] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((3,5-dimethylisoxazol4-yl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0373] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0374] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((2-(4-hydroxypiperidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0375] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((2-(pyrrolidin-1-yl)ethyl)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0376] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0377] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-aminoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0378] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(4-(dimethylamino)but-3-yn-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0379] Of this class of compounds, another preferred subclass of compound are those compounds wherein:

[0380] R¹⁰is hydrogen, alkyl or —R⁸—OR⁵; and

[0381] R¹¹is formyl, cyano, —C(O)—R⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R⁵, —R⁸—N(R⁵)—P(O)(OR⁵)₂, or —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, where:

[0382] each R⁵is hydrogen or alkyl;

[0383] R⁸is a straight or branched alkylene chain;

[0384] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶) where

[0385] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0386] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain; and

[0387] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂.

[0388] Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:

[0389] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0390] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-carboxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0391] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((4-(2-hydroxyethyl)piperazin-1-yl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0392] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(morpholin-4-yl)ethyl)thioureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0393] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(((4-hydroxypiperidin-1-yl)methyl)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0394] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0395] N-(5-chloropyridin-2-yl)-2-[((4-(N′-methylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0396] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-hydroxyethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0397] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0398] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(acetoxy)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0399] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0400] N-(5-chloropyridin-2-yl)-2-[((4-((N″-(2-(chloro)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0401] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(((2-hydroxyphenyl)carbonyl)oxy)ethyl)ureido)-methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0402] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-cyanoamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0403] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-((fluoromethylcarbonyl)amino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0404] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((2-aminoethoxy)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0405] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((methylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0406] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-((phenylthio)carbonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0407] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-nitro-1-(methylamino)ethenyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0408] N-(5-chloropyridin-2-yl)-2-[((4-(((2-dimethylphosphoramidoethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0409] Of the class of compounds, another preferred subclass of compounds are those compounds wherein:

[0410] R¹⁰is hydrogen, alkyl, haloalkyl, or —R⁸—OR⁵;

[0411] R¹¹is cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0412] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0413] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0414] each R⁹is independently alkyl, aryl or aralkyl;

[0415] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶) where

[0416] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0417] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0418] Of this subclass of compounds, preferred compounds are selected from the group consisting of:

[0419] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2yl)carbonyl)amino]-5-chlorobenzamide;

[0420] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino) methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0421] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0422] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-hydroxycyclohexyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0423] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(pyridin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0424] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0425] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0426] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0427] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(thiazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0428] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-(oxo)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0429] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(pyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0430] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0431] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0432] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0433] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(t-butyl)-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0434] N-(5-chloropyridin-2-yl)-2-[((4-(((thiazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0435] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-methoxyethyl)-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0436] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(oxazol-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0437] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0438] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(dihydro-4(H)-1,3-oxazin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0439] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(5-methyloxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0440] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0441] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(tetrazol-5-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0442] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(4-methyloxazolin-2-yl)amino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0443] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(pyrazol-3-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0444] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2,2,2-trifluoroethyl)-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0445] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(4-(ethoxycarbonyl)oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0446] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0447] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1,2,4-triazol-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0448] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0449] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0450] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-amino-6-methylpyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0451] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((1,2,4-oxadiazol-3-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0452] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-(imidazol4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0453] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3,4,5,6-tetrahydropyridin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0454] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-chloropyrimidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0455] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-((imidazol-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0456] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0457] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-aminopyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0458] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(4-(methylamino)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0459] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((3-(methoxymethyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0460] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((3-((methylthio)methyl)-1,2,4-oxadiazol-5-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0461] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1,3,2-dioxaphospholan-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0462] Of the subgroup of compounds, another preferred class of compounds are those compounds wherein:

[0463] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁾—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0464] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0465] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0466] each R⁹is independently alkyl, aryl or aralkyl;

[0467] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶where

[0468] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0469] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0470] Of this class of compounds, a preferred subclass of compounds are those compounds wherein the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, and nitro.

[0471] Of this subclass of compounds, preferred compounds are selected from the group consisting of:

[0472] N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dihydropyrazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0473] N-(5-chloropyridin-2-yl)-2-[((4-((imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0474] N-(5-chloropyridin-2-yl)-2-[((4-((morpholin-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0475] N-(5-chloropyridin-2-yl)-2-[((4-((pyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0476] N-(5-chloropyridin-2-yl)-2-[((4-((hydantoin-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0477] N-(5-chloropyridin-2-yl)-2-[((4-((1,4,5,6-tetrahydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0478] N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0479] N-(5-chloropyridin-2-yl)-2-[((4-((pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0480] N-(5-chloropyridin-2-yl)-2-[((4-((2,3,4,5,6,7-hexahydro-3,7-dimethyl-2,6-dioxo-1H-purin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0481] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0482] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0483] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0484] N-(pyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0485] N-(5-bromopyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0486] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0487] N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0488] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0489] N-(5-chloropyridin-2-yl)-2-[((4-((5-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0490] N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0491] N-(5-chloropyridin-2-yl)-2-[((4-((2,4-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0492] N-(5-chloropyridin-2-yl)-2-[((4-((2,5-dimethylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0493] N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0494] N-(5-chloropyridin-2-yl)-2-[((4-((4,5-dichloroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0495] N-(5-chloropyridin-2-yl)-2-[((4-((2-(chloromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0496] N-(5-chloropyridin-2-yl)-2-[((4-((2-(fluoromethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0497] Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by one or more substituents selected from the group consisting of alkyl, nitro, —R⁸—CN, —OR⁵, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0498] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0499] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0500] each R⁹is independently alkyl, aryl or aralkyl.

[0501] Of this subclass of compounds, preferred compounds are those compounds selected from the group consisting of:

[0502] N-(5-chloropyridin-2-yl)-2-[((4-((4-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0503] N-(5-chloropyridin-2-yl)-2-[((4-((5-(hydroxymethyl)imidazol-1-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0504] N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxymethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0505] N-(5-chloropyridin-2-yl)-2-[((4-((2-(hydroxymethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0506] N-(5-chloropyridin-2-yl)-2-[((4-((4-formylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0507] N-(5-chloropyridin-2-yl)-2-[((4-((2-(N′-amino-N′-methylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0508] N-(5-chloropyridin-2-yl)-2-[((4-((4-hydroxypiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0509] N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylthio)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0510] N-(5-chloropyridin-2-yl)-2-[((4-((4-(methylsulfonyl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0511] N-(5-chloropyridin-2-yl)-2-[((4-((2-methyl-4-nitroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0512] N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanomethyl)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0513] N-(5-chloropyridin-2-yl)-2-[((4-((4-(pyrimidin-2-yl)piperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0514] Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by one or more substituents selected from the group consisting of alkyl, oxo, ═N(R¹⁷), —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —(R⁸—O)_tR⁵, and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0515] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0516] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0517] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, or —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, —R⁸—C(O)—N(R⁵)R⁶where

[0518] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0519] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0520] Of this subclass of compounds, preferred compounds are those wherein the N-heterocylic ring is substituted by ═N(R¹⁷) and is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, and —(R⁸—O)_t—R⁵, where

[0521] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0522] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0523] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶where

[0524] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0525] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0526] Of these compounds, preferred compounds are selected from the group consisting of:

[0527] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0528] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0529] N-(5-chloropyridin-2-yl)-2-[((4-((2-ethylimino-5,5-(dimethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0530] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0531] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(R)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0532] N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0533] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5-(methoxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0534] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0535] N-(5-chloropyridin-2-yl)-2-[((4-((trans-4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0536] N-(5-chloropyridin-2-yl)-2-[((4-((cis-4,5-dimethyl-2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0537] N-(5-chloropyridin-2-yl)-2-[((4-((3-methyl-2-imino-2,3-dihydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0538] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0539] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1,2-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0540] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-(hydroxymethyl)tetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0541] N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrothiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0542] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-4-oxoimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0543] N-(5-chloropyridin-2-yl)-2-[((4-((tetrahydro-2-imino-2H-pyrimidin-1-ylpyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0544] N-(5-chloropyridin-2-yl)-2-[((4-((2-(methoxycarbonylamino)imidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0545] N-(5-chloropyridin-2-yl)-2-[((4-((2-(cyanoimino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0546] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-3-((phenylamino)carbonyl)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0547] N-(5-chloropyridin-2-yl)-2-[((4-((cis-4,5-dimethoxy-2-iminotetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0548] N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-4-imino-1,4-dihydropyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0549] N-(5-chloropyridin-2-yl)-2-[((4-((2-((2-hydroxyethyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0550] N-(5-chloropyridin-2-yl)-2-[((4-((2-iminopiperidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0551] N-(5-chloropyridin-2-yl)-2-[((4-((4-imino-1(4H)-pyridinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0552] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-1(2H)-pyridin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0553] N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylimino)pyrrolidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0554] N-(5-chloropyridin-2-yl)-2-[((4-((2-(((aminocarbonyl)methyl)imino)tetrahydroimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0555] Of the class of compounds, another preferred subclass of compounds are those compounds wherein the N-heterocylic ring is substituted by —N(R⁵)R⁶and optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, —N(R⁵)R⁶, —OR⁵, and —C(O)N(R⁵)R⁶, where R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl.

[0556] Of this subclass of compounds, preferred compounds are selected from the group consisting of:

[0557] N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0558] N-(5-chloropyridin-2-yl)-2-[((4-((5-aminotetrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0559] N-(5-chloropyridin-2-yl)-2-[((4-((3-amino-1,2,4-triazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0560] N-(5-chloropyridin-2-yl)-2-[((4-((3,5-diamino-4H-1,2,4-triazol-4-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0561] N-(5-chloropyridin-2-yl)-2-[((4-((4-amino-5-(aminocarbonyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0562] N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0563] N-(5-chloropyridin-2-yl)-2-[((4-((2,6-diaminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0564] N-(5-chlorbpyridin-2-yl)-2-[((4-((5-amino-2-oxo-2H-pyrimidin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0565] N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0566] N-(5-chloropyridin-2-yl)-2-[((4-((6-aminopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0567] N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-9-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0568] N-(5-chloropyridin-2-yl)-2-[((4-((2-amino-6-oxopurin-7-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0569] N-(5-chloropyridin-2-yl)-2-[((4-((5-(dimethylamino)-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0570] N-(5-chloropyridin-2-yl)-2-[((4-((5-amino-1,2,4-oxadiazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0571] N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0572] N-(5-chloropyridin-2-yl)-2-[((4-((2,4-diamino-6-hydroxypyrimidin-5-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0573] N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0574] N-(5-chloropyridin-2-yl)-2-[((4-((2-(1-methylethyl)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0575] N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0576] N-(5-chloropyridin-2-yl)-2-[((4-((3-dimethylamino-5-methylpyrazol-2-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0577] Of the group of compounds described above, another preferred subgroup of compounds are those compounds wherein:

[0578] each R¹⁴is independently alkyl, —R⁸—CN, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N^⊕(R⁹)(R¹⁶)₂, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—O—R¹⁵, —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹, —C(R⁷)H—O—N(R⁵)R⁶, or heterocyclyl (wherein the heterocyclyl radical is not attached to the radical of formula (i) through a nitrogen atom and is optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), where

[0579] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0580] each R⁷is independently hydrogen or alkyl;

[0581] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0582] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R^8—OR5, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0583] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0584] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0585] each R⁹is independently alkyl, aryl or aralkyl;

[0586] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R⁸—OR ⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0587] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0588] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0589] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

[0590] each R⁵is hydrogen, alkyl, aryl or aralkyl; and

[0591] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂;

[0592] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0593] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0594] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0595] each R⁹is independently alkyl, aryl or aralkyl;

[0596] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R^—OR5, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶, where

[0597] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0598] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0599] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), where

[0600] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0601] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain; or

[0602] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6), where

[0603] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0604] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0605] Of this subgroup of compounds, preferred compounds are selected from the group consisting of:

[0606] N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide,

[0607] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(hydroxyethoxy)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0608] N-(5-chloropyridin-2-yl)-2-[((4-((methylsulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0609] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0610] N-(5-chloropyridin-2-yl)-2-[((4-(((2-hydroxyethyl)sulfinyl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0611] N-(5-chloropyridin-2-yl)-2-[((4-((pyridinium-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0612] N-(5-chloropyridin-2-yl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0613] N-(5-chloropyridin-2-yl)-2-[((4-cyanomethyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0614] N-(5-chloropyridin-2-yl)-2-[((4-(2-methylaminoethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0615] N-(5-chloropyridin-2-yl)-2-[((4-(hydroxy)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0616] N-(5-chloropyridin-2-yl)-2-[((4-(((imidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0617] N-(5-chloropyridin-2-yl)-2-[((4-((imidazolin-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0618] N-(5-chloropyridin-2-yl)-2-[((4-(((5-hydroxymethyl-1-methylimidazol-2-yl)thio)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0619] N-(5-chloropyridin-2-yl)-2-[((4-(((diethylamino)oxy)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0620] N-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0621] Of the group of compounds described above, another preferred subgroup of compounds are those compounds wherein:

[0622] each R¹⁴is independently —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰, or —C(R⁷)H—C(NR¹⁷)—N(R⁵)R⁶, where

[0623] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0624] each R⁷is independently hydrogen or alkyl;

[0625] each R⁹is independently alkyl, aryl or aralkyl;

[0626] R¹⁰and R¹¹are each independently hydrogen, alkyl, haloalkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R⁵(where p is 0 to 2), —N(R⁵)R⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸—N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R^—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁵and —C(O)N(R⁵)R⁶), where

[0627] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0628] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0629] each R⁹is independently alkyl, aryl or aralkyl;

[0630] each R¹⁵is independently alkyl, cycloalkyl, haloalkyl, aryl, aralkyl, —R^{—O—C(O)—R5}, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0631] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0632] each R³is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0633] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl, where

[0634] each R⁵is hydrogen, alkyl, aryl or aralkyl; and

[0635] R¹⁸is hydrogen, alkyl, aryl, aralkyl, cyano, —C(O)OR⁵, or —NO₂;

[0636] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), where

[0637] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0638] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0639] each R⁹is independently alkyl, aryl or aralkyl;

[0640] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶, where

[0641] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0642] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain;

[0643] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶, where

[0644] R⁵and R⁶are independently each hydrogen, alkyl, aryl or aralkyl, and

[0645] each R⁸is independently a straight or branched alkylene, alkylidene or alkylidyne chain.

[0646] Of this subgroup of compounds, preferred compounds are selected from the group consisting of:

[0647] N-(5-chloropyridin-2-yl)-2-[((4-(((amidino)(methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0648] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1-iminoethyl)—N′-methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0649] N-(5-chloropyridin-2-yl)-2-[((4-(N′,N″-dimethyl-N′″-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0650] N-(5-chloropyridin-2-yl)-2-[((4-(N′-methyl-N″-hydroxyguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0651] N-(5-chloropyridin-2-yl)-2-[((4-(N′-methyl-N″-(2-aminoethyl)—N′″-cyanoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0652] N-(5-chloropyridin-2-yl)-2-[((4-(N′-methyl-N″-aminoguanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0653] N-(5-chloropyridin-2-yl)-2-[((4-(N′,N″-dimethyl-N′″-(aminocarbonyl)guanidino)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0654] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(imino(phenyl)methyl)amino) methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0655] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1-imino-2-(aminocarbonyl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0656] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0657] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(imino(pyridin-4-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0658] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(imino(thiophen-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0659] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(imino(pyrazin-2-yl)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0660] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(cyclopropyl(imino)methyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0661] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(3-cyano-1-iminopropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0662] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-imino-4,4,4-trifluorobutyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[0663] N-(5-chloropyridin-2-yl)-2-[((4-(2-amino-2-(hydroxyimino)ethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0664] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0665] A is ═N—;

[0666] m is 1;

[0667] n is 1;

[0668] D is —N(H)—C(O)—;

[0669] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0670] R²is —N(R¹⁰)R¹¹where:

[0671] R¹⁰and R¹¹are each independently hydrogen, alkyl or —R⁸—O—R⁵where R⁸is an alkylene chain, and R⁵is hydrogen or alkyl; or

[0672] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and —C(O)OR⁵where R⁵is hydrogen or alkyl;

[0673] R³is a radical of the formula (i):

[0674] where r is 1;

[0675] R¹³is halo; and

[0676] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹or —C(R⁷)H—N(R⁵)—R⁸-[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 3) where:

[0677] each R⁵is independently hydrogen or alkyl;

[0678] R⁷is hydrogen;

[0679] R⁸is a straight or branched alkylene chain;

[0680] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), where:

[0681] each R⁵and R⁶is independently hydrogen or alkyl;

[0682] each R⁸is independently a straight or branched alkylene chain; and

[0683] each R¹⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵);

[0684] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, ═N(R¹⁷), —OR⁵, —R⁸—OR⁵, and —N(R⁵)R⁶; where

[0685] each R⁵and R⁶is independently hydrogen or alkyl;

[0686] R⁸is a straight or branched alkylene chain; and

[0687] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶;

[0688] and R⁴is in the 5-position and is hydrogen or halo.

[0689] Of this group of compound, a preferred subgroup of compounds are those compounds wherein:

[0690] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0691] R¹⁰and R¹¹are each independently hydrogen, alkyl or —R⁸—O—R⁵where R⁸is an alkylene chain, and R⁵is hydrogen or alkyl.

[0692] Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:

[0693] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0694] R⁷is hydrogen;

[0695] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵); where:

[0696] each R⁵and R⁶is hydrogen or alkyl;

[0697] each R⁸is independently a straight or branched alkylene chain; and

[0698] each R¹⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵);

[0699] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, ═N(R¹⁷), —OR⁵, —R⁸—OR⁵, and —N(R⁵)R⁶; where:

[0700] each R⁵is hydrogen or alkyl;

[0701] R⁸is straight or branched alkylene chain; and

[0702] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶.

[0703] Of this class of compounds, preferred compounds are selected from the group consisting of.

[0704] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

[0705] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide;

[0706] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(dimethyl)amino-5-chlorobenzamide; and

[0707] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(di(2-methoxyethyl)amino)-5-chlorobenzamide.

[0708] Of this group of compounds, another preferred subgroup of compounds are those compounds wherein:

[0709] R²is —N(R¹⁰)R¹¹where:

[0710] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and —C(O)OR⁵where R⁵is hydrogen or alkyl.

[0711] Of this subgroup of compounds, preferred compounds are selected from the group consisting of:

[0712] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0713] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0714] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0715] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0716] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(morpholin-4-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0717] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0718] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3-(dimethylamino)propyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0719] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0720] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-methoxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0721] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methylsulfonyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0722] N-(5-chloropyridin-2-yl)-2-[((4-((N″-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0723] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

[0724] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-methylpiperazin-1-yl)-5-chlorobenzamide;

[0725] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(pyrrolidin-1-yl)-5-chlorobenzamide;

[0726] N-(5-chloropyridin-2-yl)-2-[((4-((N′-(1-methylethyl)-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0727] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(ethoxycarbonyl)piperidin-1-yl)-5-chlorobenzamide;

[0728] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-(carboxy)piperidin-1-yl)-5-chlorobenzamide;

[0729] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0730] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-ethylureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(4-ethylpiperazin-1-yl)-5-chlorobenzamide;

[0731] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0732] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0733] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-trifluoromethyl-5-(methoxycarbonyl)pyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0734] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(4-trifluoromethyl-5-carboxypyrimidin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0735] N-(5-chloropyridin-2-yl)-2-[((4-((2-iminotetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide; and

[0736] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(tetrazol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide.

[0737] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0738] A is ═N—;

[0739] m is 1;

[0740] n is 1;

[0741] D is —N(H)—C(O)—;

[0742] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0743] R²is —O—(R⁸—O)_t—R⁵(where t is 1 to 3) or —O—(R⁸—O)_t—R¹⁹where R⁵is hydrogen or alkyl, each R⁸is independently a straight or branched alkylene chain, and R¹⁹is heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, or haloalkyl);

[0744] R³is a radical of the formula (i):

[0745]

[0746] where r is 1;

[0747] R¹³is halo; and

[0748] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0749] R⁷is hydrogen;

[0750] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵); where:

[0751] each R⁵and R⁶is hydrogen or alkyl;

[0752] each R⁸is independently a straight or branched alkylene chain; and

[0753] each R⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵);

[0754] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, ═N(R¹⁷), —OR⁵, —R⁸—OR⁵, and —N(R⁵)R⁶; where

[0755] each R⁵is hydrogen or alkyl;

[0756] R⁵is straight or branched alkylene chain; and

[0757] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶; and

[0758] R⁴is in the 5-position and is hydrogen or halo.

[0759] Of this group of compounds, preferred compounds are selected from the group consisting of:

[0760] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(dimethylamino)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

[0761] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

[0762] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

[0763] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxyethoxy)-5-chlorobenzamide;

[0764] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide;

[0765] N-(5-chloropyridin-2-yl)-2-[((4-((N′-ethyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

[0766] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

[0767] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide;

[0768] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide; and

[0769] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyridin-3-yloxy)propoxy)-5-chlorobenzamide.

[0770] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0771] A is ═N—;

[0772] m is 1;

[0773] n is 1;

[0774] D is —N(H)—C(O)—;

[0775] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0776] R²is —O—R⁸—N(R¹⁰)R¹¹where:

[0777] R⁸is a straight or branched alkylene chain; and

[0778] R¹⁰and R¹¹are each independently hydrogen, alkyl or —R⁸—O—R⁵where R⁸is an alkylene chain, and R⁵is hydrogen or alkyl; or

[0779] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and —C(O)OR⁵where R⁵is hydrogen or alkyl;

[0780] R³is a radical of the formula (i):

[0781] where r is 1;

[0782] R¹³is halo; and

[0783] R¹⁴is —C(R⁷)H—N(R^10)R11where:

[0784] R⁷is hydrogen;

[0785] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), where:

[0786] each R⁵and R⁶is hydrogen or alkyl;

[0787] each R⁸is independently a straight or branched alkylene chain; and

[0788] each R¹⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵); and

[0789] R⁴is in the 5-position and is hydrogen or halo.

[0790] Of this group of compounds, preferred compounds are selected from the group consisting of:

[0791] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;

[0792] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

[0793] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;

[0794] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;

[0795] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(imidazol-1-yl)propoxy)-5-chlorobenzamide;

[0796] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;

[0797] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(imidazol-1-yl)ethoxy)-5-chlorobenzamide;

[0798] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(pyrrolidin-1-yl)ethoxy)-5-chlorobenzamide;

[0799] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(4-ethylpiperazin-1-yl)propoxy)-5-chlorobenzamide; and

[0800] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-aminoethoxy)-5-chlorobenzamide.

[0801] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0802] A is ═N—;

[0803] m is 1;

[0804] n is 1;

[0805] D is —N(H)—C(O)—;

[0806] E is —C(O)—N(H)— (where the nitrogen is bonded to the 2-position of the pyridinyl ring);

[0807] R²is —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, or —O—R⁸—CH(OH)—CH₂—OR⁵where

[0808] each R⁵is hydrogen or alkyl;

[0809] R⁸is a straight or branched alkylene chain; and

[0810] R¹⁰and R¹¹are each independently hydrogen, alkyl or —R⁸—O—R⁵where R⁸is an alkylene chain, and R⁵is hydrogen or alkyl; or

[0811] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl and —C(O)OR⁵where R⁵is hydrogen or alkyl;

[0812] R³is a radical of the formula (i):

[0813] where r is 1;

[0814] R¹³is halo; and

[0815] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹or —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰)R¹¹where:

[0816] R⁵is hydrogen or alkyl;

[0817] R⁷is hydrogen;

[0818] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵); where:

[0819] each R⁵and R⁶is hydrogen or alkyl;

[0820] each R⁸is independently a straight or branched alkylene chain; and

[0821] each R¹⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵); and

[0822] R⁴is in the 5-position and is hydrogen or halo.

[0823] Of this group of compounds, preferred compounds are selected from the group consisting of:

[0824] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-acetoxyethoxy)-5-chlorobenzamide;

[0825] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

[0826] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-((dimethylamino)sulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide;

[0827] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(imidazol-1-yl)propoxy)-5-chlorobenzamide; and

[0828] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-methoxypropoxy)-5-chlorobenzamide.

[0829] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0830] A is ═N—;

[0831] m is 1 to 3;

[0832] n is 1;

[0833] D is —N(R⁵)—C(Z)— (where Z is oxygen and R⁵is hydrogen or alkyl);

[0834] E is —C(Z)—N(R⁵)— (where Z is oxygen, R⁵is hydrogen or alkyl, and the nitrogen is attached to the pyridinyl ring);

[0835] each R¹is independently hydrogen, halo or —OR⁵;

[0836] or two adjacent R¹'s together with the carbons to which they are attached form a dioxole ring fused to the phenyl ring wherein the dioxole ring is optionally substituted by alkyl;

[0837] R²is hydrogen;

[0838] R³is a radical of the formula (i):

[0839] where r is 1;

[0840] R¹³is halo; and

[0841] R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0842] R⁷is hydrogen; and

[0843] R¹⁰and R¹¹are each independently hydrogen, alkyl, formyl, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, haloalkyl, oxo, —OR⁵, and —C(O)OR⁵); where:

[0844] each R⁵and R⁶is hydrogen or alkyl;

[0845] each R⁸is independently a straight or branched alkylene chain; and

[0846] each R¹⁵is alkyl, —R⁸—OR⁵, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by —R⁸—OR⁵), or heterocyclylalkyl (optionally substituted by —OR⁵); and

[0847] R⁴is in the 5-position and is hydrogen or halo.

[0848] Of this group of compounds, preferred compounds are selected from the group consisting of:

[0849] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3,4,5-trimethoxybenzamide;

[0850] 5(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole;

[0851] 5(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole; and

[0852] 5(N-(5-chloropyridin-2-yl)amino)carbonyl-6-[4-((N′-(2-methoxyethyl)-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl]amino-1,3-benzodioxole.

[0853] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[0854] A is —CH—;

[0855] m is 1;

[0856] n is 1;

[0857] D is —N(R⁵)—C(Z)— (where Z is oxygen and R⁵is hydrogen or alkyl);

[0858] E is —C(Z)—N(R⁵)— (where Z is oxygen, R⁵is hydrogen or alkyl, and the nitrogen is attached to the phenyl ring having the R⁴substituent);

[0859] R¹is alkyl or halo;

[0860] R²is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R^10)R11, —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—OR⁵; O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶where p is 0 to 2), —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2), —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[0861] R³is a radical of formula (i):

[0862] where:

[0863] r is 1 or 2;

[0864] R¹³is hydrogen, alkyl, halo, haloalkyl, —N(R⁵)R⁶, —C(R⁷)H—N(R⁵)R⁶, —OR⁵, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and

[0865] each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —N(R⁵)—R⁸—C(O)OR⁵, —C(R⁷)H—N(R⁵)—R⁸—C(O)OR⁵, —C(O)OR⁵, —OR⁵, —C(R⁷)H—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R¹⁰—O)R¹¹, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, or —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰;

[0866] R⁴is halo;

[0867] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[0868] R⁷is hydrogen or alkyl;

[0869] each R⁸is independently a straight or branched alkylene or alkylidene chain;

[0870] each R⁹is independently alkyl, aryl or aralkyl;

[0871] R¹⁰and R¹¹are each independently hydrogen, alkyl, aryl, aralkyl, formyl, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵₁, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0872] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6);

[0873] R¹²is a side chain of an α-amino acid;

[0874] each R¹⁵is independently alkyl, haloalkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0875] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

[0876] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), or

[0877] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)^t—R⁵(where t is 1 to 6).

[0878] Of this group of compounds, a preferred subgroup of compounds are those compounds wherein:

[0879] D is —N(H)—C(O)—;

[0880] E is —C(O)—N(H)—;

[0881] R¹is halo;

[0882] R²is hydrogen, —OR⁵, —N(R¹⁰)R¹¹, —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵or —O—R⁸—C(O)OR⁵where:

[0883] each R⁵is hydrogen or alkyl;

[0884] each R⁸is independently a straight or branched alkylene chain;

[0885] R⁹is alkyl;

[0886] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms;

[0887] R³is a radical of formula (i):

[0888] where:

[0889] r is 1;

[0890] R¹³is halo; and

[0891] R¹⁴is in the 4-position and is —C(R⁷)H—N(R¹⁰)R¹¹where:

[0892] R⁷is hydrogen or alkyl; and

[0893] R¹⁰and R¹¹are each independently hydrogen, alkyl, —R⁸—OR⁵or heterocyclyl;

[0894] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a piperazine ring optionally substituted by alkyl; and

[0895] R⁴is chloro.

[0896] Of this subgroup of compounds, preferred compounds are selected from the group consisting of:

[0897] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[0898] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[0899] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-fluorobenzamide;

[0900] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxy-5-chlorobenzamide;

[0901] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((acetoxy)ethoxy)-5-chlorobenzamide;

[0902] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(morpholin-4-yl)ethoxy)-5-chlorobenzamide;

[0903] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-((methylthio)methoxy)-5-chlorobenzamide;

[0904] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(3-(morpholin-4-yl)propoxy)-5-chlorobenzamide;

[0905] N-(4-chlorophenyl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[0906] N-(4-chlorophenyl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide; and

[0907] N-(4-chlorophenyl)-2-[((4-((N′-methyl-N′-(oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[0908] Of the group of compounds described above, another preferred subgroup of compounds are those compounds wherein:

[0909] D is —N(H)—C(O)—;

[0910] E is —C(O)—N(H)—;

[0911] R¹is methyl or chloro;

[0912] R²is hydrogen or —OR⁵;

[0913] R³is a radical of formula (i):

[0914] where:

[0915] r is 1 or 2;

[0916] R¹³is alkyl, halo, OR⁵(where R⁵is alkyl) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by alkyl); and

[0917] each R¹⁴is independently hydrogen, alkyl, halo, formyl, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —C(O)OR⁵, —C(R⁷)H—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, or —C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6);

[0918] R⁴is halo;

[0919] R⁵and R⁶are each independently hydrogen or alkyl;

[0920] each R⁷is independently hydrogen or alkyl;

[0921] each R⁸is independently a straight or branched alkylene chain;

[0922] R⁹is alkyl;

[0923] R¹⁰and R¹¹are each independently hydrogen, alkyl, aryl, aralkyl, formyl, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[0924] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, —N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)R⁵, and —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6);

[0925] R¹⁵is alkyl, haloalkyl, aryl, aralkyl, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[0926] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

[0927] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), or

[0928] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6).

[0929] Of this subgroup of compounds, a preferred class of compounds are those compounds wherein:

[0930] R³is a radical of formula (i):

[0931] where:

[0932] r is 1 or 2;

[0933] R¹³is halo, alkyl or 4-methylpiperazin-1-yl, and

[0934] each R¹⁴is independently hydrogen or —C(R⁷)H—N(R¹⁰)R¹¹where:

[0935] R⁷is hydrogen or alkyl;

[0936] R¹⁰and R¹¹are each independently hydrogen, alkyl, aryl, aralkyl, formyl, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶) where:

[0937] each R⁵and R⁶are independently hydrogen or alkyl;

[0938] each R⁸is independently a straight or branched alkylene chain; and

[0939] each R¹⁵is alkyl, haloalkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶).

[0940] Of this class of compounds, preferred compounds are selected from the group consisting of:

[0941] N-(4-chlorophenyl)-2-[((3-methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0942] N-(4-chlorophenyl)-2-[((3-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0943] N-(4-chlorophenyl)-2-[((5-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0944] N-(4-chlorophenyl)-2-[((3-chloro-5-(N′-methyl-N′-(2-hydroxyethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0945] N-(4-chlorophenyl)-2-[((3-chloro-5-(N′-methyl-N′-(ethoxycarbonylmethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0946] N-(4-chlorophenyl)-2-[((3-chloro-5-(N′-methyl-N′-(carboxymethyl)amino)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0947] N-(4-chlorophenyl)-2-[((3-chloro-5-(N′,N′-di(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0948] N-(4-chlorophenyl)-2-[((3-chloro-5-(((N′-(3-dimethylaminophenyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0949] N-(4-chlorophenyl)-2-[((3-chloro-4,5-di((n-propyl)aminomethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0950] N-(4-chlorophenyl)-2-[((3-chloro-5-((N′-methyl-N′-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0951] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0952] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(ethoxycarbonylmethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0953] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2-dimethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0954] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-(3-(imidazol-1-yl)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0955] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(3-(dimethylamino)propyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0956] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-(2-methylpropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0957] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(1-methylpiperidin-4-yl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0958] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0959] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-hydroxyamino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0960] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2-diethylaminoethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0961] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-(2-hydroxyethyl)l-N′-(2-(morpholin-4-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and

[0962] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2-(pyrrolidin-1-yl)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

[0963] Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:

[0964] R³is a radical of formula (i):

[0965] where:

[0966] r is 1 or 2;

[0967] R¹³is halo or alkyl, and

[0968] each R¹⁴is independently hydrogen, alkyl or —C(R⁷)H—N(R¹⁰)R¹¹where:

[0969] R⁷is hydrogen or alkyl; and

[0970] R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, oxo, —N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)R⁵, and —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6) where

[0971] each R⁵is hydrogen or alkyl; and

[0972] R⁸is a straight or branched alkylene chain.

[0973] Of this class of compounds, preferred compounds are selected from the group consisting of:

[0974] N-(4-chlorophenyl)-2-[((4-methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0975] N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(carboxymethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0976] N-(4-chlorophenyl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0977] N-(4-chlorophenyl)-2-[((5-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0978] N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(ethoxycarbonylmethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0979] N-(4-chlorophenyl)-2-[((3-chloro-5-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0980] N-(4-chlorophenyl)-2-[((3-chloro-5-(morpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0981] N-(4-chlorophenyl)-2-[((3-chloro-5-(1-(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0982] N-(4-chlorophenyl)-2-[((3-chloro-5-((4-(((2-(2-methoxyethoxy)ethoxy)methyl)carbonyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0983] N-(4-chlorophenyl)-2-[((4-(morpholin-4-yl)methyl-3-chlorothiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0984] N-(4-chlorophenyl)-2-[((3-chloro-5-(1,1,4-tri(oxo)thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0985] N-(4-chlorophenyl)-2-[((3-chloro-4-(thiomorpholin-4-yl)methylthiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0986] N-(4-chlorophenyl)-2-[((3-chloro-5-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0987] N-(4-chlorophenyl)-2-[((3-chloro-5-methyl-4-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0988] N-(4-chlorophenyl)-2-[((3-chloro-4-methyl-5-((4-methylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0989] N-(4-chlorophenyl)-2-[((3-chloro-4-((4H-1,2,4-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0990] N-(4-chlorophenyl)-2-[((3-chloro-4-((imidazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0991] N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0992] N-(4-chlorophenyl)-2-[((3-chloro-4-((tetrazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0993] N-(4-chlorophenyl)-2-[((3-chloro-4-((pyrazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0994] N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0995] N-(4-chlorophenyl)-2-[((3-chloro-4-((4-(2-(2-hydroxyethoxy)ethyl)piperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0996] N-(4-chlorophenyl)-2-[((3-chloro-4-((1,2,3-triazol-2-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0997] N-(4-chlorophenyl)-2-[((3-chloro-4-((4-ethylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0998] N-(4-chlorophenyl)-2-[((3-chloro-4-((4-oxomorpholin-4-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[0999] N-(4-chlorophenyl)-2-[((3-chloro-4-((4-acetylpiperazin-1-yl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and

[1000] N-(4-chlorophenyl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[1001] Of this subgroup of compounds described above, another preferred class of compounds are those compounds wherein:

[1002] R³is a radical of formula (i):

[1003] where:

[1004] r is 1 or 2;

[1005] R¹³is halo or alkyl, and

[1006] each R¹⁴is independently —C(R⁷)H—S(O)_p—R¹⁵where:

[1007] p is 0 to 2;

[1008] R⁷is hydrogen or alkyl; and

[1009] R¹⁵is alkyl, —R⁸—N(R⁵)R⁶or —R⁸—C(O)OR⁵where:

[1010] R⁵and R⁶are each independently hydrogen or alkyl; and

[1011] each R⁸is independently a straight or branched alkylene chain.

[1012] Of this class of compounds, preferred compounds are selected from the group consisting of:

[1013] N-(4-chlorophenyl)-2-[((3-chloro-5-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1014] N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1015] N-(4-chlorophenyl)-2-[((3-chloro-5-(((methoxycarbonylmethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1016] N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1017] N-(4-chlorophenyl)-2-[((3-chloro-5-(((carboxymethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1018] N-(4-chlorophenyl)-2-[((3-chloro-5-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1019] N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1020] N-(4-chlorophenyl)-2-[((3-chloro-5-(((2-(dimethylamino)ethyl)sulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1021] N-(4-chlorophenyl)-2-[((3-chloro-4-((methylthio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1022] N-(4-chlorophenyl)-2-[((3-chloro-4-(((methoxycarbonylmethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1023] N-(4-chlorophenyl)-2-[((3-chloro-4-(((2-(dimethylamino)ethyl)thio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1024] N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfonyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and

[1025] N-(4-chlorophenyl)-2-[((3-chloro-4-((methylsulfinyl)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

[1026] Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:

[1027] R³is a radical of formula (i):

[1028] where:

[1029] r is 1 or 2;

[1030] R¹³is halo or alkyl, and

[1031] each R¹⁴is independently formyl, —N(R¹⁰)R¹¹, —C(O)OR⁵, —C(R⁷)H—OR⁵or —C(O)N(R⁵)R⁶where

[1032] R⁵and R⁶are each independently hydrogen or alkyl;

[1033] R⁷is hydrogen or alkyl; and

[1034] R¹⁰and R¹¹are independently hydrogen or alkyl.

[1035] Of this class of compounds, preferred compounds are selected from the group consisting of:

[1036] N-(4-chlorophenyl)-2-[((3-chloro-5-carboxythiophen-2-yl)carbonyl)amino]-5-chlorobenzamide; and

[1037] N-(4-chlorophenyl)-2-[((3-chloro-4-(hydroxymethyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide.

[1038] Of the subgroup of compounds described above, another preferred class of compounds are those compounds wherein:

[1039] R³is a radical of formula (i):

[1040] where:

[1041] r is 1 or 2;

[1042] R¹³is alkyl, halo or —OR⁵(where R⁵is alkyl), and

[1043] each R¹⁴is independently hydrogen, halo, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —S(O)_p—R¹⁵, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵, or —C(R⁷)H—N(R⁵)—R⁸-[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6) where:

[1044] R⁵and R⁶are independently hydrogen or alkyl;

[1045] R⁷is hydrogen or alkyl;

[1046] each R⁸is independently a straight or branched alkylene chain;

[1047] R¹⁰and R¹¹are independently hydrogen, alkyl or —R⁸—OR⁵where R⁸is a straight or branched alkylene chain and R⁵is hydrogen or alkyl; and

[1048] R¹⁵is alkyl or —N(R⁵)R⁶; and

[1049] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), or

[1050] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6).

[1051] Of this class of compounds, preferred compounds are selected from the group consisting of:

[1052] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′,N′-dimethyl-N′-(2-hydroxyethyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1053] N-(4-chlorophenyl)-2-[((3-chloro-4-((((2-hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1054] N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-methoxyethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1055] N-(4-chlorophenyl)-2-[((3-chloro-4-((2-(2-(2-methoxyethoxy)ethoxy)ethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1056] N-(4-chlorophenyl)-2-[((3-chloro-4-((2-methoxyethoxy)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1057] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′,N′-dimethyl-N′-(3-hydroxypropyl)ammonio)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1058] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2,3-dihydroxypropyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1059] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2,3,4,5,6-pentahydroxyhexyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1060] N-(4-chlorophenyl)-2-[((3-chloro-4-((N′-methyl-N′-(2-(hydroxyethoxy)ethyl)amino)methyl)thiophen-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1061] N-(4-chlorophenyl)-2-[((3-chloro-4-(methylsulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

[1062] N-(4-chlorophenyl)-2-[((3-chlorothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

[1063] N-(4-chlorophenyl)-2-[((3-bromothiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

[1064] N-(4-chlorophenyl)-2-[((3-chloro-4-((1-methylethyl)sulfonyl)thiophen-2-yl)carbonyl)amino]-5-methylbenzamide;

[1065] N-(4-chlorophenyl)-2-[((4-(methylamino)sulfonyl-3-methylthiophen-2-yl)carbonyl)amino]-5-methylbenzamide; and

[1066] N-(4-chlorophenyl)-2-[((3-methoxythiophen-2-yl)carbonyl)amino]-5-methylbenzamide.

[1067] Of the compounds of formula (I) described above, another preferred group of compounds are those compounds of formula (I) wherein:

[1068] A is —CH— or ═N—;

[1069] m is 1 to 3;

[1070] n is 1 to 4;

[1071] D is —N(H)—C(O)— or —N(H)—CH₂—;

[1072] E is —C(O)—N(H)—; (where the nitrogen atom is bonded to the aromatic ring containing the R⁴substituent);

[1073] each R¹is independently hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R⁵)R⁶, —O—C(O)R⁵, or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[1074] R²is hydrogen, alkyl, aryl, aralkyl, halo, haloalkyl, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —OC(O)—R⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—OR⁵; —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2), —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2), or —N(R⁵)—CH(R¹²)—C(O)OR⁵;

[1075] R³is a radical of formula (ii):

[1076] where v is 1 to 4;

[1077] R¹³is hydrogen, alkyl, halo, haloalkyl, —N(R⁵)R⁶, —C(R⁷)H—N(R⁵)R⁶, —OR⁶, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2) or heterocyclylalkyl (where the heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, aralkyl, nitro and cyano); and

[1078] each R¹⁴is independently hydrogen, alkyl, halo, formyl, acetyl, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—N^⊕(R⁹)(R¹⁶)₂, —N(R⁵)—R⁸—C(O)OR⁵, —C(R^)H—N(R5)—R⁸—C(O)OR⁵, —C(O)OR⁵, —OR⁵, —C(R⁷)H—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —C(R⁷)H—S(O)_p—R¹⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶(where p is 0 to 2), —C(O)N(R⁵)R⁶, —C(R⁷)H—N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —C(R⁷)H—O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—R⁸—CH(OH)—CH₂—OR⁵, —C(R⁷)H—O—R⁸—CH(OH)—CH₂—OR⁵—C(R⁷)H—N(R⁵)—R⁸—[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —C(R⁷)H—N(R⁵)—S(O)₂—N(R⁵)R⁶, —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—N(R¹⁰)R¹¹, or —C(R⁷)H—N(R¹⁰)—C(NR¹⁷)—R¹⁰;

[1079] each R⁴is independently hydrogen, alkyl, halo, haloalkyl, cyano, nitro, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, or —R⁸—N(R⁵)R⁶;

[1080] R⁵and R⁶are each independently hydrogen, alkyl, aryl or aralkyl;

[1081] each R⁷is independently hydrogen or alkyl;

[1082] each R⁸is independently a straight or branched alkylene or alkylidene chain;

[1083] each R⁹is independently alkyl, aryl or aralkyl;

[1084] R¹⁰and R¹¹are each independently hydrogen, alkyl, aryl, aralkyl, formyl, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, —C(S)NH₂, —C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶);

[1085] or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵—C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸—O)_t—R⁵(where t is 1 to 6);

[1086] R¹²is a side chain of an α-amino acid;

[1087] R¹⁵is alkyl, haloalkyl, aryl, aralkyl, —R⁸—OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶);

[1088] or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocyclic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, amino, monoalkylamino, dialkylamino, —OR⁵, —C(O)OR⁵, aminocarbonyl, monoalkylaminocarbonyl, and dialkylaminocarbonyl; and

[1089] each R¹⁶is independently alkyl, aryl, aralkyl, —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), or

[1090] both R¹⁶'s together with the nitrogen to which they are attached (and wherein the R⁹substituent is not present) form an aromatic N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), and —(R⁸)_t—R⁵(where t is 1 to 6); and

[1091] each R¹⁷is independently hydrogen, alkyl, aryl, aralkyl, cyano, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —C(O)—N(R⁵)R⁶, or —R⁸—C(O)—N(R⁵)R⁶.

[1092] Of this group of compounds, preferred compounds are selected from the group consisting of:

[1093] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1094] N-(pyridin-3-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1095] N-(pyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1096] N-(4-methoxyphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1097] N-(3-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1098] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1099] N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1100] N-(5-chloropyridin-2-yl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1101] N-(3-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1102] N-(3-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1103] N-(4-chloro-2-methylphenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1104] N-(4-cyanophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1105] N-(4-fluorophenyl)-2-[((benzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1106] N-(4-fluorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1107] N-(4-chlorophenyl)-2-[((3-methoxybenzo[b]thien-2-yl)carbonyl)amino]-5-methylbenzamide;

[1108] N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;

[1109] N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-methoxybenzamide;

[1110] N-(4-bromophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1111] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

[1112] N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(pyrrolidin-1-yl)methylbenzamide;

[1113] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(trifluoromethyl)benzamide;

[1114] N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(dimethylamino)benzamide;

[1115] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(4-methylpiperazin-1-yl)benzamide;

[1116] N-(4-fluorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-(amino)methylbenzamide;

[1117] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxybenzamide;

[1118] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dimethoxybenzamide;

[1119] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide;

[1120] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-fluorobenzamide;

[1121] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-chlorobenzamide;

[1122] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

[1123] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;

[1124] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluorobenzamide;

[1125] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-chlorobenzamide;

[1126] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxybenzamide;

[1127] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-6-fluorobenzamide;

[1128] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxybenzamide;

[1129] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-methylbenzamide;

[1130] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-(ethoxycarbonyl)methoxybenzamide;

[1131] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dihydroxybenzamide;

[1132] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-dimethoxybenzamide;

[1133] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]benzamide;

[1134] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-aminobenzamide;

[1135] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-methyl-5-chlorobenzamide;

[1136] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1137] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methylbenzamide;

[1138] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-methyl-5-chlorobenzamide;

[1139] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-fluoro-5-chlorobenzamide;

[1140] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-3-hydroxy-5-chlorobenzamide;

[1141] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4,5-difluorobenzamide;

[1142] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(N′-methyl-N′-(3-(dimethylamino)propylamino-5-fluorobenzamide;

[1143] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-(4-methylpiperazin-1-yl)-5-fluorobenzamide;

[1144] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-4-((3-(4-methylpiperazin-1-yl)propyl)amino)-5-fluorobenzamide;

[1145] N-(4-chlorophenyl)-2-[((3-chloro-6-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1146] N-(4-chlorophenyl)-2-[((3-methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1147] N-(4-chlorophenyl)-2-[((3-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1148] N-(4-chlorophenyl)-2-[((3-chloro-6-(dimethylamino)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1149] N-(4-chlorophenyl)-2-[((3-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1150] N-(4-chlorophenyl)-2-[((3-chloro-6-(4-methylpiperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1151] N-(4-chlorophenyl)-2-[((3-chloro-6-(4-(carboxymethyl)piperazin-1-yl)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1152] N-(4-chlorophenyl)-2-[((3-chloro-6-((methoxycarbonyl)methylthio)methylbenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1153] N-(4-chlorophenyl)-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-chlorobenzamide;

[1154] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N′-methyl-N′-(ethoxycarbonyl)methylamino)benzamide;

[1155] N-(5-chloropyridin-2-yl)-2-[((4-(N′-methyl-N′-(2-(dimethylamino)ethyl)amino)-3-chlorothiophen-2-yl)carbonyl)amino]-3-chloro-5-(N′-methyl-N′-(ethoxycarbonyl)methylamino)benzamide;

[1156] N-phenyl-2-[((3-chlorobenzo[b]thien-2-yl)carbonyl)amino]-5-hydroxy-4-((1,1-dimethylethyl)carbonyl)oxybenzamide; and

[1157] N′-(4-chlorophenyl)-2-((3-methylbenzo[b]thien-2yl)methyl)amino-5-benzamide.

[1158] Of the compounds disclosed above, the following compounds are the most preferred compounds of the invention:

[1159] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(morpholin-4-yl)-5-chlorobenzamide;

[1160] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2,3-dihydroxypropyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1161] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(2-hydroxyethyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1162] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1163] N-(5-chloropyridin-2-yl)-2-[((4-((4-methylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-methoxyethoxy)-5-chlorobenzamide,

[1164] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N″-(2-(pyrrolidin-1-yl)ethyl)ureido)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1165] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-oxazolin-2-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1166] N-(5-chloropyridin-2-yl)-2-[((4-((4-ethylpiperazin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-(2-methoxyethoxy)ethoxy)-5-chlorobenzamide,

[1167] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(methylsulfonyl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-(2-hydroxy-3-(pyrrolidin-1-yl)propoxy)-5-chlorobenzamide,

[1168] N-(5-chloropyridin-2-yl)-2-[((4-((2-aminoimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,

[1169] N-(5-chloropyridin-2-yl)-2-[((4-(chloromethyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1170] N-(5-chloropyridin-2-yl)-2-[((4-((methylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide

[1171] N-(5-chloropyridin-2-yl)-2-[((4-((2-imino-5(S)-methyltetrahydrooxazol-3-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide,

[1172] N-(5-chloropyridin-2-yl)-2-[((4-((dimethylamino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1173] N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1174] N-(5-chloropyridin-2-yl)-2-[((4-((2-methylimidazolin-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1175] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(3,4-dihydro-2H-pyrrol-5-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1176] N-(5-chloropyridin-2-yl)-2-[((4-((2-(methylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1177] N-(5-chloropyridin-2-yl)-2-[((4-(imidazolin-2-yl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide;

[1178] N-(5-chloropyridin-2-yl)-2-[((4-((N′-methyl-N′-(pyridin-4-yl)amino)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide; and

[1179] N-(5-chloropyridin-2-yl)-2-[((4-((2-(ethylamino)imidazol-1-yl)methyl)-3-chlorothiophen-2-yl)carbonyl)amino]-3-methoxy-5-chlorobenzamide.

[1180] It is understood that in the following description, combinations of substituents and/or variables on the depicted formulae are permissible only if such combinations result in stable compounds.

[1181] For purposes of illustration only and unless otherwise indicated, the following Reaction Schemes are directed to the preparation of the compounds of the invention as set forth above in the Summary of the Invention as compounds of formula (I). In particular, for purposes of illustration only and unless otherwise indicated, the compounds prepared in the following Reaction Schemes are compounds of formula (I) wherein D is —N(R⁵)—C(O)— (where the nitrogen is bonded to the phenyl ring having the R¹and R²substituents), and E is —C(O)—N(R⁵)— (where the nitrogen is bonded at the 2-position of the pyridinyl (if A is ═N—) or to the phenyl (if A is ═CH—) having the R⁴substituent) and R³is a radical of the formula (i):

[1182] where each R¹³and each R¹⁴are as described in each following Reaction Scheme. It is understood that the other compounds of the invention may be prepared by similar methods as described herein.

[1183] Compounds of formula (Ia) are compounds of the invention wherein R¹³is chloro and the R¹⁴substituent is in the 4-position of the thienyl radical. These compounds are prepared as described below in Reaction Scheme 1 where A is ═CH— or ═N—, each R^1ais independently hydrogen, alkyl, aryl, aralkyl, halo, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —O—C(O)—R⁵, —C(O)N(R⁵)R⁶, —N(R⁵)R⁶; R^2ais hydrogen, alkyl, aryl, aralkyl, halo, cyano, —OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —C(O)OR⁵, —C(O)N(R⁵)R⁶, —N(R¹⁰)R¹¹, —C(R⁷)H—N(R¹⁰)R¹¹, —C(R⁷)H—R⁸—N(R¹⁰)R¹¹, —C(R⁷)H—OR⁵, —C(R⁷)H—R⁸—OR⁵, —C(R⁷)H—S(O)_p—R⁹where p is 0 to 2), —C(R⁷)H—R⁸—S(O)_p—R⁹(where p is 0 to 2), —O—R⁸—S(O)_p—R⁹(where p is 0 to 2), —C(R⁷)H—N(R⁵)R⁶, —C(R⁷)H—R⁸—N(R⁵)R⁶, —O—R⁸—CH(OH)—CH₂—N(R¹⁰)R¹¹, —O—R⁸—N(R¹⁰)R¹¹, —O—R⁸—O—C(O)R⁵, —O—R⁸—CH(OH)—CH₂—OR⁵, —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —O—(R⁸—O)_t—R¹⁹(where t is 1 to 6), —O—R⁸—C(O)R⁵, —O—R⁸—C(O)R¹⁹, —O—R⁸—C(O)OR⁵, —N(R⁵)—R⁸—N(R¹⁰)R¹¹, —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0 to 2), or —S(O)_p—R⁸—C(O)OR⁵(where p is 0 to 2); each R⁴is independently hydrogen, alkyl, halo, cyano, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, —C(O)N(R⁵)R⁶, or —R⁸—N(R⁵)R⁶; each R⁵and R⁶is as described above in the Summary of the Invention for compounds of formula (I); R^5ais hydrogen; R⁷is hydrogen or alkyl; each R⁸and R⁹are as described above in the Summary of the Invention for compounds of formula (I); each R¹⁰and R¹¹is independently hydrogen, alkyl, aryl, aralkyl, formyl, cyano, —R⁸—CN, —OR⁵, —R⁸—OR⁵, —S(O)_p—R¹⁵(where p is 0 to 2), —R⁸—S(O)_p—R¹⁵(where p is 0 to 2), —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, —C(O)—R¹⁵, —C(O)NH₂, R⁸—C(O)NH₂, —C(S)NH₂, —C(O)—S—R⁵, —C(O)—N(R⁵)R¹⁵, —R⁸—C(O)—N(R⁵)R¹⁵, —C(S)—N(R⁵)R¹⁵, —R⁸—N(R⁵)—C(O)H, —R⁸N(R⁵)—C(O)R¹⁵, —C(O)O—R⁸—N(R⁵)R⁶, —C(N(R⁵)R⁶)═C(R¹⁸)R¹⁰, —R⁸—N(R⁵)—P(O)(OR⁵)₂, cycloalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, halo and —OR⁵), heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶and —C(O)N(R⁵)R⁶), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, —OR⁵, —R⁸—OR⁵, —C(O)OR⁵, —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —N(R⁵)R⁶and —C(O)N(R⁵)R⁶); or R¹⁰and R¹¹together with the nitrogen to which they are attached form a N-heterocyclic ring containing zero to three additional hetero atoms, where the heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R¹⁷), —OR⁵, —C(O)OR⁵, —R⁸—C(O)OR⁵, —N(R⁵)R⁶, —R⁸—N(R⁵)R⁶, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R⁵)R⁶, —N(R⁵)—N(R⁵)R⁶, —C(O)R⁵, —C(O)—(R⁸—O)_t—R⁵(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R⁸—O)_t—R⁵(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶, and —C(O)N(R⁵)R⁶); R^14ais cyano, —N(R¹⁰)R¹¹, —N^⊕—(R⁹)(R¹⁶)₂, —N(R⁵)—R⁸C(O)OR⁵, —S—R¹⁵, —S—R⁸—C(O)R⁵, —S—R⁸—N(R⁵)R⁶, —N(R⁵)—(R⁸—O)_t—R⁵(where t is 1 to 6), —N(R⁵)—R⁸-[CH(OH)]_t—CH₂—OR⁵(where t is 1 to 6), —S—R⁸—OR¹⁵; or R^14ais heterocyclyl wherein the heterocyclic ring is optionally substituted by alkyl, aryl, aralkyl, oxo, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶; where each R¹⁵and R¹⁶are as described above in the Summary of the Invention for compounds of formula (I) except that neither can be or contain haloalkyl; R¹⁷is as described in the Summary of the Invention for compounds of formula (I); and X is chloro or bromo:

[1184] Compounds of formula (A), formula (C), and formula (H) are commercially available, for example, from Aldrich Co. Compounds of formula (F) are commercially available or may be prepared according to methods described herein.

[1185] In general, compounds of formula (Ia) are prepared by first reacting a compound of formula (A) in an aprotic solvent, for example, methylene chloride, at temperatures of between about −10° C. to about 10° C., preferably at 0° C., with a halogenating agent, for example, oxalyl chloride. The reaction mixture is allowed to warm to ambient temperature and stirred for about 8 to 20 hours, preferably for about 16 hours, to produce a compound of formula (B), which is isolated from the reaction mixture by standard techniques (such as removal of solvents).

[1186] The compound of formula (B) in an aprotic solvent, for example, methylene chloride, at temperatures of between about −10° C. to about 10° C., preferably at 0° C., is then treated with a compound of formula (C) in the presence of a base, for example, triethylamine. The reaction mixture is then stirred for about 20 to 30 minutes, preferably for about 20 minutes, at temperatures of between about −10° C. to about 10° C., preferably at 0° C., then warmed to ambient temperature, and stirred for about 1 to about 20 hours, preferably for about 16 hours. The compound of formula (D) is then isolated from the reaction mixture by standard isolation techniques, such as evaporation of solvents, extraction and concentration.

[1187] The compound of formula (D) is then reduced by treatment with a reducing agent, such as tin(II) chloride under standard reducing conditions to produce a compound of formula (E), which is isolated from the reaction mixture by standard techniques.

[1188] The compound of formula (E) in an aprotic solvent, for example, methylene chloride, at temperatures of between about −10° C. to about 10° C. , preferably at 0C, is then treated with a compound of formula (F) in the presence of a base, for example, pyridine. The compound of formula (G) is then isolated from the reaction mixture by standard isolation techniques, such as concentration and trituration with water.

[1189] The compound of formula (G) in an aprotic solvent, such as DMF, at temperatures of between about −10° C. to about 10° C. , preferably at 0° C., is then treated with a compound of formula (H). The reaction mixture is stirred for about 20 minutes to an hour, preferably for about 30 minutes, and then allowed to warm to ambient temperature. After stirring for about 6 to about 20 hours, preferably for about 7 hours, the compound of formula (Ia) is isolated from the reaction mixture by standard isolation techniques, such as filtration and purification by flash chromatography.

[1190] The compound of formula (H) may be present as an acid salt, wherein the corresponding free base is formed in situ by the addition of a base to the reaction mixture, or is treated with a base prior to the reaction with the compounds of formula (G) to form the free base.

[1191] Any unprotected amino substituent must be protected prior to Step 4 to avoid acylation. Any carboxy substituent must also be esterified prior to Step 1. The resulting compounds may be deprotected when needed by appropriate methods known to those skilled in the art to afford compounds having an unsubstituted amino or carboxy substituent thereon.

[1192] Compounds of the invention where D is —N(R⁵)—S(O)_p— (where p is 2) may be prepared by methods disclosed above by reacting a compound of formula (E) with the sulfonyl chloride of the substituted thiophene or benzothiophene radical.

[1193] Compounds of the invention where E is —N(R⁵)—S(O)_p— (where p is 2), can be formed by reacting a substituted benzene sulfonyl chloride with a compound of formula (C) and then proceeding with Steps 3-5 above.

[1194] Compounds of formula (E) where R^5ais hydrogen may be reacted with an appropriate alkylating agent prior to Step 4 to produce compounds where R^5ais alkyl, aryl or aralkyl.

[1195] Compounds of the invention where R¹³is —S(O)_p—R⁸—N(R⁵)R⁶(where p is 0) may be prepared from the corresponding halo as described herein. Compounds where R¹³is heterocyclylalkyl may be made from substitution from the corresponding haloalkyl.

[1196] Compounds of formula (G) may be reacted with tertiary amines of the formula N(R⁹)(R¹⁶)₂where R⁹and R¹⁶are as described above in the Summary of the Invention for compounds of formula (I) by methods similar to those described above to prepare compounds of the invention wherein R^14ais —N^⊕(R⁹)(R¹⁶)₂.

[1197] Any unoxidized sulfur and nitrogen may be oxidized after the final step in Reaction Scheme 1 by methods known to those skilled in the art to produce the desired oxidized substituents.

[1198] Compounds of formula (Ia) where R^14acontains a —N(H)R¹⁰group may be reacted with a heterocyclic compound having a reactive halogen to form compounds where R^14acontains a —N(R¹⁰)R¹¹group wherein R¹¹is heterocyclyl.

[1199] Compounds of formula (Ia) where R^14acontains a secondary amino substituent may be reacted with an aldehyde in an aprotic solvent, such as acetonitrile, in the presence of a reducing agent such as sodium cyanoborohydride to form compounds wherein the amino substituent is further substituted by an alkyl or aralkyl group.

[1200] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰is hydrogen and R¹¹is —R⁸—OR⁵(where R⁵is hydrogen and R⁸is ethyl or propyl optionally substituted by alkyl or alkoxyalkyl) can be reacted with cyanogen bromide to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen to which they are attached form optionally substituted 2-iminooxazolidin-3-yl or optionally substituted tetrahydro-2-amino-1,3-oxazinyl.

[1201] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹¹is hydrogen and R¹⁰is alkyl, aryl or aralkyl can be reacted with a cyano halide under basic conditions to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)—CN, which can then be reacted with an azide in the presence of tributyl tin chloride in an aprotic solvent to form a compound of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹¹is tetrazolyl attached to the nitrogen through a carbon atom in the heterocyclic ring.

[1202] Compounds of formula (G) may be treated with an oxidizing agent to form the corresponding N-oxide when A is ═N—, and then treated with compounds of formula (H) to form other compounds of the invention where the pyridinyl ring is oxidized.

[1203] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰is hydrogen and R¹¹is —R⁸—N(R⁵)R⁶where R⁸is ethyl or propyl and at least one R⁵or R⁶is hydrogen may be further treated with an ortho ester under mild acidic conditions to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form an optionally substituted imidazolinyl. Other compounds of the invention may be similarly made. Such compounds wherein the imidazolinyl is substituted with an appropriate haloalkyl may be further treated with a compound of formula (H) in an aprotic solvent to form compounds wherein the imidazolinyl is substituted by the corresponding R^14agroup.

[1204] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form a 2-aminoimidazolyl in a protic solvent of the formula R⁵—OH may be further treated with a halogenating agent, such as N-chlorosuccinimide (NCS) in the presence of a strong acid to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰and R¹¹form a 2-iminoimidazolidinyl substituted at the 4— and 5-position with —OR⁵. Other compounds of the invention may be similarly made.

[1205] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰is hydrogen and R¹¹is —R⁸—N(R⁵)R⁶where either R⁵or R⁶is hydrogen may be further treated with phosphoryl chloride in the presence of a base, followed by treatment with a compound of the formula R⁵—OH to form compounds of the invention where R^14ais —C(R⁷)H—N(R⁵)—P(O)(OR⁵)₂.

[1206] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form 2-methylthioimidazolinyl may be further treated with N(R⁵)H—R⁸—OR⁵or with NH₂—R⁸—C(O)—N(R⁵)R⁶to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form a imidazolinyl substituted at the 2-position with —N(R⁵)—R⁸—OR⁵or with ═NR¹⁷where R¹⁷is —R⁸—C(O)—N(R⁵)R⁶, respectively.

[1207] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form a N-heterocyclic substituted with formyl may be treated under standard reducing conditions to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰and R¹¹together with the nitrogen form a N-heterocyclic substituted with hydroxymethyl. Other compounds of the invention may be similarly made.

[1208] Compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹where R¹⁰is alkyl and R¹¹is oxazolin-2-yl may be treated with compounds of the formula R⁵—C(O)OH to form compounds of the invention where R¹⁴is —N(R¹⁰)R¹¹where R¹⁰is alkyl and R¹¹is —C(O)—N(R⁵)R¹⁵where R⁵hydrogen and R⁵is —R⁸—O—C(O)R⁵where R⁸is ethyl.

[1209] Other compounds of formula (Ia) may be prepared according to the methods described herein according to methods known to those skilled in the art.

[1210] Compounds of formula (Ib) are compounds of the invention and are prepared as follows in Reaction Scheme 2 wherein A is ═CH— or ═N—, each R^1ais as defined in Reaction Scheme 1 above; R^2ais as defined in Reaction Scheme 1 above; R⁵is as defined in the Summary of the Invention for compounds of formula (I); R^5ais hydrogen; each R⁴and R¹³is as defined in the Summary of the Invention for compounds of formula (I), R¹⁴is as described above in the Summary of the Invention for compounds of formula (I); and X is chloro or bromo:

[1211] Compounds of formula (E) are prepared above in Reaction Scheme 1. Compounds of formula (J) are commercially available, e.g., from Lancaster, or may be prepared by methods known to those skilled in the art from compounds of formula (J) where X is —OCH₃(and where R¹³or R¹⁴do not contain a hydrolyzable group such as an ester), which is hydrolyzed to the acid and then converted to the acid chloride to form a compound of formula (J). In addition, compounds of formula (J) may be prepared according to methods disclosed herein.

[1212] In general, compounds of formula (Ib) are prepared by treating a compound of formula (E) with a compound of formula (J) in the presence of a base, preferably pyridine, at temperatures of between about −10° C. to about 10° C., preferably at 0° C. The reaction mixture is allowed to warm to ambient temperature and then stirred for about 8 to 20 hours, preferably for about 16 hours. The compound of formula (Ib) is then isolated from the reaction mixture by standard isolation techniques, such as filtration and recrystallization.

[1213] Compounds of formula (Ib) where R¹⁴is hydrogen, halo, formyl, acetyl, —N(R¹⁰)R¹¹, —N(R⁵)—R⁸—C(O)OR⁵, —C(O)OR⁵, —OR⁵, —S(O)_p—R⁵(where p is 0 to 2), —S(O)_p—N(R⁵)R⁶, or —C(O)N(R⁵)R⁶; and R^1a, R^2aor R¹³is alkyl, may be treated under standard halogenating conditions to form compounds where R^1a, R^2aor R¹³is haloalkyl. The resulting compounds may then be treated with HN(R¹⁰)R¹¹or HN(R⁵)R⁶to form compounds where R^1a, R^2aor R¹³is —C(R⁷)H—N(R¹⁰)R¹¹or —C(R⁷)H—N(R⁵)R⁶.

[1214] Compounds of formula (Ib) where R¹⁴is cyano may be treated with methanol or ethanol to form the corresponding imidate, which can then be treated with a compound of formula NH₂—R⁸—N(R⁵)R⁶where at least one R⁵or R⁶is hydrogen to form compounds of the invention where R¹⁴is heterocyclyl containing at least two nitrogen atoms. Alternatively, the imidate so formed can be treated with a compound of formula N(H)(R⁵)R⁶to form compounds of the invention where R¹⁴is —C(NH)—N(R⁵)R⁶which can be further treated under conditions similar to those described herein to form compounds of the invention where R¹⁴is —C(NR¹⁷)—N(R⁵)R⁶where R¹⁷is as described above in the Summary of the Invention for compounds of formula (I).

[1215] Compounds of formula (Ib) where one or more R^1a's is hydroxy and R²is hydrogen may be further treated with a compound of formula R⁵—C(O)—X where X is chloro or bromo to produce compounds of the invention where one or more R^1a's is —O—C(O)—R⁵.

[1216] Compounds of formula (Ib) where R¹⁴is —N(R¹⁰)R¹¹where at least one R¹⁰or R¹¹is hydrogen can be treated with the appropriate X—C(O)—R¹⁵where X is bromo or chloro and R¹⁵is as described above in the Summary of the Invention for compounds of formula (I) to form compounds of the invention where R¹⁴is —N(R¹⁰)(R¹¹) where R¹⁰is hydrogen, alkyl, aryl or aralkyl and R¹¹is —C(O)—R¹⁵. During this process, other substituents of compounds of formula (Ib) which contain a reactive hydroxy, amino or carboxy group may also be acylated.

[1217] Compounds of formula (Ic) are compounds of the invention. They are prepared from compounds of formula (Ib) where A is ═CH— or ═N—, R^14bis —CH₂—R⁷where R⁷is hydrogen or alkyl as illustrated below in Reaction Scheme 3 wherein each R^1a, R^2a, R⁴R⁵, R^5aand R^14aare as defined above in Reaction Scheme 1, and R¹³is as defined above in the Summary of the Invention for compounds of formula (I), and X is bromo and chloro:

[1218] Compounds of formula (Ib) are prepared herein. Compounds of formula (H) are commercially available or may be prepared according to methods known to those skilled in the art or by methods disclosed herein.

[1219] In general, compounds of formula (Ic) are prepared by first treating a compound of formula (Ib) in an organic solvent, such as benzene, with an halogenating agent under conditions to form the halide radical (such as irradiation). The compound of formula (K) is then isolated from the reaction mixture by standard techniques, such as concentration and trituration with solvent.

[1220] The compound of formula (K) in an aprotic solvent, such as methylene chloride, is treated with a compound of formula (H). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 18 hours. The compound of formula (Ic) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and purification by HPLC.

[1221] Compounds of the invention where R¹³is haloalkyl may be prepared by halogenating the corresponding alkyl substituent according to methods known to those skilled in the art. The compounds so formed can then be treated with the appropriate HN(R⁵)R⁶group under conditions similar to those described above for preparing compounds of formula (Ic) to produce compounds of the invention where R¹³is —C(R⁷)H—N(R⁵)R⁶.

[1222] For better yield in the above Reaction Scheme, it is recommended that R^1a, R^2a, R⁴, and R¹³do not contain an alkyl group, since this alkyl will also be halogenated and will subsequently react with compound of formula (H) during the reaction.

[1223] Compounds of formula (K) where X is bromo may be treated under standard substitution conditions to form compounds of formula (Ic) where R^14ais hydroxy. These compounds may be further oxidized under standard oxidizing conditions to form compounds of the invention where R¹⁴is formyl, which can further oxidized to form compounds of the invention where R¹⁴is —C(O)OR⁵.

[1224] Compounds of formula (Id) are compounds of the invention where R¹³is chloro. They are prepared from compounds of formula (M) which are compounds of either formula (G) or (K) as illustrated below in Reaction Scheme 4 where A is ═CH— or ═N-, each R^1a, R^2a, each R⁴, R⁵, R^5aand R⁷are as defined above in Reaction Scheme 1; R^14cis —OR⁵, —S—R¹⁵, —S—R⁸—C(O)OR⁵, —S—R⁸—N(R⁵)R⁶, —O—(R⁸—O)_t—R⁵(where t is 1 to 6), —S—R⁸—OR⁵, —CN or —N(R¹⁰)R¹¹(where R¹⁰and R¹¹together with the nitrogen to which they are attached form a a N-heterocyclic ring containing zero to three additional hetero atoms, where the N-heterocylic ring is optionally substituted by one or more substituents selected from the group consisting of alkyl, halo, haloalkyl, aryl, aralkyl, oxo, nitro, cyano, —R⁸—CN, ═N(R^17a), —OR^5b, —C(O)OR^5b, —R⁸—C(O)OR^5b, —N(R^5b)R^6b, —R⁸—N(R^5b)R^6b, —C(O)N(R⁵)R⁶, —R⁸—C(O)N(R^5b)R^6b, —N(R^5b)—N(R^5b)R^6b—C(O)R^5b, —C(O)—(R⁸—O)_tR^5b(where t is 1 to 6), —S(O)_p—R⁹(where p is 0 to 2), —R⁸—S(O)_p—R⁹(where p is 0 to 2), —(R^—O)_t—R^5b(where t is 1 to 6), and heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR^5b, —C(O)OR^5b, —N(R⁵)R^6b, and —C(O)N(R^5b)R^6b) where R^5band R^6bare alkyl, aryl or aralkyl and R^17ais as defined for R¹⁷in the Summary of the Invention for compounds of formula (I) except R^17acan not be hydrogen; and where each R⁸, R⁹and R¹⁵are as defined above in the Summary of the Invention for compounds of formula (I); and Y is a metal cation:

[1225] Compounds of formula (N) are commercially available or may be prepared according to methods known to those skilled in the art.

[1226] In general, the compounds of formula (Id) are prepared by reacting a compound of formula (M) in an aprotic solvent with a compound of formula (N). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration of product, and flash chromatography.

[1227] Alternatively, a compound of formula HR^14cin an aprotic solvent, such as DMF, is treated with a strong base, such as sodium hydride, at ambient temperature to form the corresponding salt. The compound of formula (M) in an aprotic solvent, such as DMF, is then added to the reaction mixture containing the salt. The reaction mixture is stirred at ambient temperature for about 10 to 20 hours, preferably for about 18 hours. The compound of formula (Id) is then isolated from the reaction mixture by standard isolation techniques, such as extraction, concentration and flash chromatography.

[1228] In general, this reaction scheme is used for those amines, alcohols and mercapto compounds of formula HR^14cwhich are not reactive enough to be used in Reaction Schemes 1 or 2 above. The salt can be formed in situ or can be isolated.

[1229] Compounds of formula (Ia) where R^14cis cyano may be further treated with hydroxylamine under basic conditions in a protic solvent to form compounds of the invention where R¹⁴is —C(R⁷)H—C(NR¹⁷)—R¹⁰where R¹⁷is —OH.

[1230] Compounds of formula (If) are compounds of the invention wherein a R¹⁴substituent is —C(R⁷)H—N(R¹⁰)R¹¹where R⁷is hydrogen or alkyl, R¹⁰is hydrogen, alkyl, aryl, aralkyl, —OR⁵(where R⁵is not hydrogen), —R⁸—OR⁵(where R⁵is not hydrogen), —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R⁵can not be hydrogen), and heterocyclylalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R⁵can not be hydrogen), and R¹¹is —S(O)₂—R^15awhere R^15ais alkyl, haloalkyl, aryl, aralkyl, —R⁸—O—C(O)—R⁵, —R—OR⁵, —R⁸—N(R⁵)R⁶, —R⁸—C(O)OR⁵, heterocyclyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, —OR^5b, —R⁸R^5b, —C(O)OR^5b, —N(R^5b)R^6Band —C(O)N(R^5b)R^6bwhere each R^5band R^6bis alkyl, aryl or aralkyl), or heterocyclylalkyl (optionally substituted by one or more substituents selected from the group consisting of alkyl, aryl, aralkyl, halo, haloalkyl, OR^5b, R⁸—OR^5b, —C(O)OR^5b, —N(R^5b)R^6bor —C(O)N(R^5b)R^6bwhere each R^5bor R^6bis alkyl, aryl or aralkyl). They are prepared from compounds of formula (M) as illustrated below in Reaction Scheme 5 where A is ═CH— or ═N—; R^1a, R^2a, R⁴, R⁵and R^5aare as described above in Reaction Scheme 1; R¹⁰and R^15aare as described above; and X is chloro or bromo:

[1231] Compounds of formula (O) are commercially available or may be prepared according to methods known to those of ordinary skill in the art. The compound of formula (Ie) is a compound of formula (Ia) where R^14ais —N(R¹⁰)R¹¹and is prepared herein.

[1232] In general, compounds of formula (If) are prepared by treating a compound of formula (Ie) in the presence of base, such as pyridine, at temperatures of between about −10° C. to about 10° C., preferably at 0° C., with a compound of formula (O). The reaction mixture is allowed to warm to ambient temperature and then stirred for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (If) is then isolated from the reaction mixture by standard isolation techniques, such as removal of solvents in vacuo and purification by flash chromatography.

[1233] This reaction scheme can also be used with compounds of the formula X—S(O)₂—N(R¹⁰)R¹¹to make compounds of the invention where R¹⁴is —C(R⁷)H—N(R₁₀)—S(O)₂—N(R¹⁰)R¹¹.

[1234] Compounds of formula (Ig) are compounds of the invention wherein a R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R⁷is hydrogen or alkyl, R¹⁰is hydrogen, alkyl, aryl, aralkyl, —OR⁵(where R⁵is not hydrogen), —R⁸—OR⁵, —R⁸—N(R⁵)R⁶, cycloalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R⁵can not be hydrogen), and heterocyclylalkyl (optionally substituted as described above in the Summary of the Invention for compounds of formula (I) except that R⁵can not be hydrogen); and R¹¹is either —C(O)—N(R⁵)R^15bor —C(S)—N(R⁵)R^15bwhere each R⁵is hydrogen and each R^5bis hydrogen, alkyl, aryl, aralkyl, —R⁸—R⁵, —R⁸—C(O)OR⁵or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶). They are prepared as described below in Reaction Scheme 6 wherein A is ═CH— or ═N—; R^1a, R^2a, R⁴, R⁵, and R^5aare as described above in Reaction Scheme 1; and R^15bis as described above; and Z is either oxygen or sulfur:

[1235] Compounds of formula (P) are commercially available, or may be prepared according to methods known to those skilled in the art. The compounds of formula (Ie) are compounds of formula (Ia) where R^14ais —N(R¹⁰)R¹¹and are prepared by methods disclosed herein.

[1236] In general, compounds of formula (Ig) are prepared by treating a compound of formula (Ie) in an aprotic solvent, such as dioxane, with a compound of formula (P). The reaction mixture is stirred at ambient temperature for about 8 to about 20 hours, preferably for about 16 hours. The compound of formula (Ig) is isolated from the reaction mixture by standard isolation techniques, such as concentration of product and purification by flash chromatography.

[1237] Alternatively, to produce compounds of formula (Ig) where R^15bis hydrogen, compounds of formula (Ie) may be reacted with potassium isocyanate (K—N═C═O). Alternatively, compounds of formula (Ie) may be reacted first with phosgene or equivalent, followed by reacting the resulting product with a disubstituted amine or a cyclic amine to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰is as described above for the compounds of formula (Ig) and R¹¹is —C(O)—N(R⁵)R¹⁵where R⁵and R¹⁵are independently alkyl, aryl or aralkyl, or R⁵and R¹⁵together with the nitrogen to which they are attached form a N-heterocyclic ring as defined in the Summary of the Invention for compounds of formula (I).

[1238] Compounds of formula (Ig) where R^15bis hydrogen can be further reacted with a halocetaldehyde dialkylacetal in the presence of a protic solvent, preferably an alkanol, to form compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R⁷is hydrogen or alkyl, and R¹⁰is as described above for the Reaction Scheme and R¹¹is an oxazol-2-yl substituent.

[1239] Compounds of formula (Ih) and (Ij) are compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R⁷is hydrogen or alkyl, R¹⁰is hydrogen, alkyl, aryl or aralkyl, and R¹¹is —C(O)—R¹⁵where R¹⁵is —R⁸—OR⁵, —R⁸—N(R⁵)R⁶or heterocyclylalkyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶(where R⁵and R⁶are as described above in the Summary of the Invention for compounds of formula (I))). These compounds are prepared as described below where A is ═CH— or ═N—; R^1a, R^2a, R⁴, R⁵, R^5aare as described above in Reaction Scheme 1; and R⁷and R⁸are as described in the Summary of the Invention for compounds of formula (I); and R^15cis —OR⁵, —N(R⁵)R⁶or heterocyclyl (optionally substituted by alkyl, aryl, aralkyl, halo, haloalkyl, —OR⁵, —C(O)OR⁵, —N(R⁵)R⁶or —C(O)N(R⁵)R⁶(where R⁵and R⁶are as described above in the Summary of the Invention for compounds of formula (I))), for example, 4-methylpiperidine; and each X is independently bromo or chloro:

[1240] Compounds of formula (Q) and formula (R) are commercially available or may be prepared by methods known to those skilled in the art.

[1241] In general, the compounds of formula (Ij) are prepared by first treating a compound of formula (Ie) in an aprotic solvent, such as methylene chloride, in the presence of a base, such as diisopropylethylamine, at temperatures of between about −10° C. and about 10° C., preferably at about 0° C., with a compound of formula (Q). The reaction mixture was allowed to warm to ambient temperature and stirred for about 4 to about 10 hours, preferably for about 7 hours. A compound of formula (R) is then added to the reaction mixture and the resulting reaction mixture is stirred about 10 to about 20 hours, preferably for about 16 hours. The compound of formula (Ij) is isolated from the reaction mixture by standard isolation techniques, such as concentration and purification by HPLC.

[1242] Alternatively, the compound of formula (Q) could be phosgene (Cl—C(O)—Cl). Under these circumstances, the final product would have the R^15csubstituent directly attached to the carbonyl in the compound of formula (Ij). Alternatively, the compound of formula (Q) could also be X—S(O)₂—R⁸—X to produce compounds of the invention where R¹⁴is —C(R⁷)H—N(R¹⁰)R¹¹where R¹⁰is as described above for compounds of formula (Ij) and R¹¹is —S(O)₂—R¹⁵where R¹⁵is as described above for R¹⁵.