Mitotic kinesin inhibitors and methods of use thereof

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to novel inhibitors of mitotic kinesins, in particular the mitotic kinesin KSP, and pharmaceutical compositions containing the inhibitors. The compounds of this invention are useful for the treatment of cellular proliferative diseases, for example cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, fungal infections and inflammation. This invention also provides methods for preparing these inhibitors.

2. Description of the State of the Art Among the therapeutic agents used to treat cancer are the taxanes and vinca alkaloids, which act on microtubules. Microtubules are the primary structural elements of the mitotic spindle, which is responsible for distribution of replicate copies of the genome to each of the two daughter cells that result from cell division. It is presumed that disruption of the mitotic spindle by these drugs results in inhibition of cancer cell division and induction of cancer cell death. However, microtubules form other types of cellular structures, including tracks for intracellular transport in nerve processes. Because drugs such as taxanes and vinca alkaloids do not specifically target mitotic spindles, they have side effects that limit their usefulness.

Improvements in the specificity of agents used to treat cancer is of considerable interest, in part because of the improved therapeutic benefits which would be realized if the side effects associated with administration of these agents could be reduced. Traditionally, dramatic improvements in the treatment of cancer have been associated with identification of therapeutic agents acting through novel mechanisms. Examples include not only the taxanes, but also the camptothecin class of topoisomerase I inhibitors. From both of these perspectives, mitotic kinesins are attractive targets for new anti-cancer agents.

Mitotic kinesins are enzymes essential for assembly and function of the mitotic spindle, but are not generally part of other microtubule structures such as nerve processes. Mitotic kinesins play essential roles during all phases of mitosis. These enzymes are “molecular motors” that transform energy released by hydrolysis of ATP into mechanical force which drives the directional movement of cellular cargoes along microtubules. The catalytic domain sufficient for this task is a compact structure of approximately 340 amino acids. During mitosis, kinesins organize microtubules into the bipolar structure that is the mitotic spindle. Kinesins mediate movement of chromosomes along spindle microtubules, as well as structural changes in the mitotic spindle associated with specific phases of mitosis. Experimental perturbation of mitotic kinesin function causes malformation or dysfunction of the mitotic spindle, frequently resulting in cell cycle arrest and cell death.

Among the identified mitotic kinesins is kinesin spindle protein (KSP). KSP belongs to an evolutionarily conserved kinesin subfamily of plus end-directed microtubule motors that assemble into bipolar homotetramers consisting of antiparallel homodimers. During mitosis, KSP associates with microtubules of the mitotic spindle. Microinjection of antibodies directed against KSP into human cells prevents spindle pole separation during prometaphase, giving rise to monopolar spindles and causing mitotic arrest and induction of programmed cell death. KSP and related kinesins in other non-human organisms bundle antiparallel microtubules and slide them relative to one another, thus forcing the spindle poles apart. KSP may also mediate in anaphase B spindle elongation and focusing of microtubules at the spindle pole.

Human KSP or HsEg5 has been described (Blangy, et al., Cell, 83:1159-69 (1995); Whitehead, et al., Arthritis Rheum., 39:1635-42 (1996); Galtio, et al., J. Cell Biol., 135:339-414 (1996); Blangy, et al., J. Bio. Chem., 272:19418-24 (1997); Blangy, et al., Cell Motil Cytoskeleton, 40:174-82 (1998); Whitehead and Rattner, J. Cell Sci., 111:2551-61 (1998); Kaiser, et al., JBC 274:18925-31 (1999); GenBank accession numbers: X85137, NM004523 and U37426), and a fragment of the KP gene (TRIPS) has been described (Lee, et al., Mol. Endocrinol., 9:243-54 (1995); GenBank accession number L40372). Xenopus KSP homologs (Eg5), as well as Drosophilia K-LP61 F/KRP 130 have been reported.

Small molecule inhibitors of KSP have recently been described in WO 03/079,973 and WO 2005/035512.

Mitotic kinesins are therefore attractive targets for the discovery and development of novel mitotic chemotherapeutics.

SUMMARY OF THE INVENTION

This invention provides novel compounds that inhibit mitotic kinesins, in particular the mitotic kinesin KSP. The compounds of this invention have utility as therapeutic agents for diseases that can be treated by the inhibition of the assembly and function of microtubule structures, including the mitotic spindle.

In general, the invention relates to kinesin inhibitors of the general Formula I:

and metabolites, solvates, tautomers, and pharmaceutically acceptable salts and prodrugs thereof, wherein W, Ar¹, Ar², R¹and R⁴are as defined below.

In a further aspect the present invention provides methods of modulating mitotic spindle formation, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides a method of treating abnormal cell growth conditions in a human or animal, which comprises administering to a warm-blooded animal an effective amount of a compound of Formula I, or a solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides a method of inhibiting abnormal cell growth, which comprises administering to said abnormal cells an effective amount of a compound of Formula I, or a solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides a method of providing a mitotic kinesin inhibitory effect in a human or animal, comprising administering to said human or animal an effective amount of a compound of Formula I, or a solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof.

In a further aspect the present invention provides methods of treating or preventing a microtubule-mediated condition in a human or animal, comprising administering to a human or animal in need thereof a compound of Formula I or a solvate, pharmaceutically acceptable salt or pharmaceutically acceptable prodrug thereof, in an amount effective to treat or prevent said microtubule-mediated condition. Microtubule-mediated conditions that can be treated or prevented according to the methods of this invention include, but are not limited to, cellular proliferative diseases, for example cancer, hyperplasias, restenosis, cardiac hypertrophy, immune disorders, infectious disease, fungal or other eukaryote infections, and inflammatory disease.

The compounds of the present invention may be used advantageously in combination with other known therapeutic agents.

The invention also relates to pharmaceutical compositions comprising a compound of Formula I or a solvate, pharmaceutically acceptable prodrug or pharmaceutically acceptable salt thereof, alone or in combination with a second therapeutic agent.

This invention also provides compounds of Formula I for use in therapy.

An additional aspect of the invention is the use of a compound of Formula I for the preparation of a medicament for use as a kinesin inhibitor.

This invention further provides kits comprising compounds of Formula I.

Additional advantages and novel features of this invention shall be set forth in part in the description that follows, and in part will become apparent to those skilled in the art upon examination of the following specification or may be learned by the practice of the invention. The advantages of the invention may be realized and attained by means of the instrumentalities, combinations, compositions, and methods particularly pointed out in the appended claims.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of Formula I are useful for inhibiting mitotic kinesins and microtubule-mediated events such as mitotic spindle production. Such compounds have utility for treating or inhibiting a microtubule-mediated condition in a human or animal.

In general, the invention relates to compounds of the general Formula I:

and metabolites, solvates, tautomers, salts and pharmaceutically acceptable salts and prodrugs thereof, wherein:

W is S(O)_m;

m is 0, 1 or 2;

R¹is H, alkyl, cycloalkyl, heteroalkyl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heteroalkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —C(═O)R¹⁰, —OC(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR¹⁰R¹¹, —NR¹⁰C(O)OR¹³, —NR¹⁰C(═O)(CH₂)_0-2R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(O)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, —OP(═O)(OR¹⁰)₂, an amino acid residue, a dipeptide, a tripeptide, or —NR¹⁰CR²²R²³NR¹¹R¹², with the proviso that said alkyl does not terminate with a —C(═O)OR¹⁰group,

or R¹is Z—NR¹⁷—C(═NR¹⁸)R¹⁹, Z—NR¹⁷—C(═NR¹⁸)NR²⁰R²¹, Z—C(═NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷C(═NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷—C(═NR¹⁸)R²⁰, Z—NR²²NR²³—C(═NR¹⁸)R¹⁹, or Z—NR²²—NR²³—C(═NR¹⁸)NR²⁰R²¹, wherein Z is alkylene optionally substituted with one or more halogen;

Ar¹and Ar²are independently phenyl or a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O and S, wherein said heteroaryl is a carbon radical and said phenyl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹—C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)R¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —NR¹⁰C(H)NR¹¹R¹², —NR¹⁰C(R¹³)NR¹¹R¹², —OP(═O)(OR¹⁰)₂, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R⁴is a partially unsaturated or fully unsaturated 5 membered heterocyclic ring comprising 1-4 heteroatoms independently selected from N, O or S,

or R⁴is a partially unsaturated or fully unsaturated 6 membered heterocyclic ring comprising 1-4 heteroatoms independently selected from N, O or S,

or R⁴is a partially unsaturated or fully unsaturated 7-12 membered bicyclic heterocyclic ring comprising two or more heteroatoms independently selected from N, O or S,

wherein R⁴is bonded to the ring nitrogen of Formula I through an unsaturated carbon bond and R⁴is optionally substituted with one or more groups independently selected from oxo (provided it is not on a nitrogen, oxygen or an unsaturated carbon), halogen, cyano, nitro, trifluoromethyl, difluoromethyl, fluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂NR¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹(OR¹²), —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —NR¹⁰C(H)NR¹¹R¹², —NR¹⁰C(R¹³)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, —OP(═O)(OR¹⁰⁾₂, an amino acid residue, a dipeptide and a tripeptide, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹⁰, R¹¹and R¹²independently are selected from hydrogen, alkyl, trifluoromethyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹³is alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl or arylalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionally substituted with one to three groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl,

or any two of R¹⁰, R¹¹, R¹²and R¹³together with the atoms to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted with one to three groups independently selected from oxo (with the proviso that it is not on said heteroaryl ring), halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R¹⁴and R¹⁵are independently selected from hydrogen, alkyl, alkenyl, lower alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl,

or R¹⁴and R¹⁵together with the atoms to which they are attached form a saturated, partially unsaturated or fully unsaturated 5-6 membered heterocyclyl;

R¹⁷, R²²and R²³are independently H or alkyl;

R¹⁸is H, OH, O-alkyl, CN, C(═O)NH₂, C(═O)NH(alkyl), C(═O)N(alkyl)₂, C(═O)alkyl, or alkyl optionally substituted with one or more groups independently selected from halogen, CN, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂and aryl;

R¹⁹is H or alkyl optionally substituted with one or more groups independently selected from halogen, NO₂, halogen, CN, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂and aryl; and

R²⁰and R²¹are independently H, C(═O)alkyl, or alkyl optionally substituted with one or more groups independently selected from halogen, CN, OH, O-alkyl, NH₂, NH-alkyl, N(alkyl)₂and aryl,

or R²⁰and R²¹together with the atoms to which they are attached form a 5-6 membered unsaturated or partially unsaturated heterocyclic ring;

or R¹⁸and R²⁰together with the atoms to which they are attached form a 5-6 membered partially unsaturated or fully unsaturated heterocyclic ring;

or R¹⁷and R²⁰together with the atoms to which they are attached form a 5-6 membered unsaturated or partially unsaturated heterocyclic ring.

In another embodiment there is provided a compound of Formula I

and metabolites, solvates, tautomers, and pharmaceutically acceptable salts and prodrugs thereof, wherein:

W is S(O)_m;

m is 0, 1 or 2;

R¹is H, alkyl, cycloalkyl, heteroalkyl, alkenyl or alkynyl, wherein said alkyl, cycloalkyl, heteroalkyl, alkenyl and alkynyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —C(O)R¹⁰, —OC(═O)R¹⁰, —C(═O)OR¹⁰, —C(═O)NR¹⁰R¹¹, —NR¹⁰C(O)OR¹³, —NR¹⁰C(O)R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, arylalkyl, heterocyclyl, heterocyclylalkyl, —OP(═O)(OR¹⁰)₂, an amino acid residue, a dipeptide and a tripeptide, with the proviso that said alkyl does not terminate with a —C(═O)OR¹⁰group;

Ar¹and Ar²are independently phenyl or a 5 or 6 membered heteroaryl ring having 1 to 3 heteroatoms independently selected from N, O or S, wherein said heteroaryl is a carbon radical and wherein said phenyl and heteroaryl are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R⁴is

wherein a dashed line represents an optional double bond;

D¹is N, NR⁶, CR⁵, CR⁵, CR⁵R^5a, or C(═O);

D²is CR⁵, CR⁵R^5a, N or NR⁶;

D³is S, O, N, NR⁶or CR⁵R^5a;

E is O, S or NR⁶;

A is a saturated, partially unsaturated, or fully unsaturated 5-8 carbocyclic ring or heterocyclic ring having 1 to 3 heteroatoms independently selected from N, O or S, wherein said carbocyclic and heterocyclic rings are optionally substituted with one or more groups independently selected from halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, oxo, —OR¹⁰, —N¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰—NR¹⁰C(═O)NR¹¹R¹², NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

each R⁵and R^5ais independently selected from H, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹¹, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R⁶is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R¹⁰, R¹¹and R¹²independently are selected from hydrogen, alkyl, trifluoromethyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl, wherein said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl portions), halogen, cyano, nitro, OR¹⁴, —NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R¹³is alkyl, alkenyl, cycloalkyl, aryl or arylalkyl, wherein said alkyl, alkenyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl are optionally substituted with one to three groups independently selected from oxo (with the proviso that it is not on said aryl portions), halogen, cyano, nitro, OR¹⁴, NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

or any two of R¹⁰, R¹¹, R¹²and R¹³together with the atoms to which they are attached form a 4 to 10 membered heteroaryl or heterocyclic ring, wherein said heteroaryl and heterocyclic rings are optionally substituted with one to three groups independently selected from oxo (with the proviso that it is not on said heteroaryl ring), halogen, cyano, nitro, OR¹⁴, NR¹⁴R¹⁵, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl; and

R¹⁴and R¹⁵are independently selected from hydrogen, alkyl, alkenyl, lower alkynyl, cycloalkyl, aryl, heteroaryl, heterocyclyl and arylalkyl.

In certain embodiments of Formula I, W is S.

According to another embodiment, R¹is alkyl or heteroalkyl, wherein said alkyl and heteroalkyl are optionally substituted with one or more groups independently selected from —OR¹⁰, —NR¹⁰R¹¹, OP(═O)(OR¹⁰⁾₂, an amino acid residue, a dipeptide and a tripeptide. In another embodiment, there is provided a compound of Formula I, wherein R¹is alkyl optionally substituted with NR¹⁰C(═O)(CH₂)_0-2R¹¹, NR¹⁰SO₂R¹³, heterocyclyl, or R¹is a heterocyclyl.

Exemplary embodiments include compounds of Formula I wherein R¹is (CH₂)₂—OH, (CH₂)₃—OH, (CH₂)—NH₂, (CH₂)₂—NH₂, (CH₂)₃—NH₂, (CH₂)₃—NHCH(CH₃)₂, (CH₂)₂—NHMe, (CH₂)₂—NMe₂, (CH₂)₃—NMe₂, (CH₂)₃—NHMe, (CH₂)₃NHC(═O)Me, (CH₂)₃NHC(═O)CH(CH₃)₂, (CH₂)₃NHC(═O)CH₂CH₂NMe₂, (CH₂)₃NHSO₂Me, (CH₂)₃-(pyrrolidin-1-yl), (CH₂)₃-(piperidin-1-yl), (CH₂)₃-(4-methylpiperidin-1-yl), (CH₂)₃-(morpholin-4-yl), (CH₂)₂-(pyrrolidin-2-yl), (CH₂)₃NH(C═O)CH(Me)NH(C═O)CH(Me)NH₂, (CH₂)₃OPO₃H₂, CH₂—O—CH₂OMe or piperidin-4-yl.

In particular embodiments, there is provided a compound of Formula I wherein R¹is —(CH₂)₃NH₂.

In certain embodiments, R¹is Z—NR¹⁷—C(═NR¹⁸)R¹⁹, Z—NR¹⁷—C(═NR¹⁸)NR²⁰R²¹, Z—C(═NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷C(NR¹⁸)NR²⁰R²¹, Z—O—NR¹⁷—C(═NR¹⁸)R²⁰, Z—NR²²—NR²³—C(NR¹⁸)R¹⁹, or Z—NR²²—NR²³—C(═NR¹⁸)NR²⁰R²¹.

In certain embodiments, there is provided a compound of Formula I wherein Ar¹is phenyl optionally substituted with one or more groups independently selected from halogen, alkyl, —OR¹⁰or —NR¹⁰R¹¹; or Ar¹is a heteroaryl selected from thiophenyl or pyridyl, wherein said pyridyl is optionally substituted independently with one or more halogens.

Exemplary embodiments of such Ar¹groups include phenyl, 2,4-difluorophenyl, 2-fluorophenyl, 3-fluorophenyl, 2-chlorophenyl, 3-chlorophenyl, 2,5-dichlorophenyl, 2,3-dichlorophenyl, 3,4-dichlorophenyl, 3,5-dichlorophenyl, 2-chloro-5-fluorophenyl, 2-fluoro-5-chlorophenyl, 2-chloro-5-methylphenyl, 2-trifluoromethyl-5-fluorophenyl, 2-fluoro-5-methoxyphenyl, thiophen-2-yl, thiophen-3-yl, 5-chlorothiophen-2-yl, 2-pyridyl, 3-pyridyl, 4-chloropyridin-3-yl, 3-chloropyridin-2-yl, 4-fluoropyridin-3-yl, or 3,6-difluoropyridin-2-yl.

In particular embodiments, Ar¹is 2,4-difluorophenyl.

According to yet another embodiment, Ar²is an optionally substituted phenyl group. In certain embodiments, Ar²is substituted with one or more halogen groups. In a particular embodiment, Ar²is 2,4-difluorophenyl, 2,5-difluorophenyl, or 3-fluorophenyl. In other embodiments, Ar²is phenyl, 2-chlorophenyl, 4-chlorophenyl, 4-fluorophenyl, 4-bromophenyl or 3,4-dichlorophenyl.

In other embodiments, there is provided a compound of Formula I wherein Ar²is phenyl optionally substituted with one or more groups independently selected from OR¹⁰, NR¹⁰R¹¹, CN, NO₂, —OP(═O)(OR¹⁰)₂, C(═O)OR¹⁰, or Ar²is a heteroaryl selected from pyridyl, thiophenyl optionally substituted with alkyl, imidazolyl, and pyrazolyl optionally substituted with NR¹⁰R¹¹. For example, in certain embodiments, Ar²is 2-methylphenyl, 3-methylphenyl, 4-methylphenyl, 3,4-dimethylphenyl, 3,5-dimethylphenyl, 2-ethylphenyl, 3-ethylphenyl, 4-t-butylphenyl, 3-nitrophenyl, 3-hydroxyphenyl, 3-(OPO₃H₂)-phenyl, 3-aminophenyl, 3-carboxyphenyl, 3-cyanophenyl, 2-pyridyl, 3-pyridyl, 5-methylthiophen-2-yl, 2-methylthiazol-4-yl, 2-(1H-imidazol-2-yl), 2-(1H-imidazol-4-yl) or 3-amino-1H-pyrazol-5-yl.

In particular embodiments, Ar²is phenyl.

In certain embodiments, there is provided a compound of Formula I, wherein R⁴is selected from:

wherein:

a dashed line represents an optional double bond;

D¹is N, NR⁶, O, CR⁵, CR⁵R^5a, or C(═O);

D²is CR⁵, CR⁵R^5a, N, NR⁶, O, S or C(═O), wherein only one of D¹and D²is C(═O);

D³is S, O, N, NR⁶, CR⁵or CR⁵R^5a;

D⁴and D⁵are independently N, NR⁶, S or O;

E is O, S or NR⁶;

Y¹and Y²are CH₂, C═O or SO₂;

Y³is CH₂or NR⁶;

X¹is O or S;

X²is C═O or SO₂;

X³and X⁴are independently CH₂or CMe₂when the bond represented by ---- is absent or X³and X⁴are independently CH or CMe when the bond represented by ---- is present;

X⁵is S, O, NR⁶, SO, SO₂, or CR⁵CR^5a

Z¹, Z², and Z³are independently N or CR⁵, wherein 1 or 2 of Z¹, Z²and Z³is N;

one of Z⁴and Z⁵is N and the other is CR⁵;

A is a saturated, partially unsaturated, or fully unsaturated 5-8 carbocyclic ring or heterocyclic ring having 1 to 3 ring heteroatoms independently selected from N, O, S, or SO₂, wherein said carbocyclic and heterocyclic rings are optionally substituted independently with one or more R⁷groups;

G is a saturated, or partially unsaturated, or fully unsaturated 5 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N S, O, SO and SO₂, wherein G is optionally substituted independently with one or more R⁷groups;

K is a benzene ring or a saturated or partially unsaturated 5-6 membered heterocyclic ring having 1-3 ring heteroatoms independently selected from N S, O, SO and SO₂, wherein K is optionally substituted with one or more R⁷groups;

each R⁵and R^5ais independently selected from H, halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹(OR¹²), —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², —OR¹⁰, alkyl, cycloalkyl, alkenyl, alkynyl, heteroalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(O)R¹, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R⁶is H, alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl or heterocyclyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl and heterocyclyl are optionally substituted with one or more groups independently selected from oxo, halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl, and heterocyclylalkyl;

R^6ais independently H or alkyl;

R⁷is halogen, cyano, nitro, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, oxo (provided it is not on a nitrogen, oxygen or unsaturated carbon), —OR¹⁰, —NR¹⁰R¹¹, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹³, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —C(═O)NR¹⁰OR¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰—NR¹⁰C(═O)NR¹¹R¹², C(═NH)NH(CN), —NR¹⁰C(NCN)NR¹¹R¹², alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl, wherein said alkyl, cycloalkyl, alkenyl, alkynyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl are optionally substituted with one or more groups independently selected from oxo (with the proviso that it is not on said aryl or heteroaryl portions), halogen, cyano, nitro, hydroxy, —OR¹⁰, NR¹⁰R¹¹, trifluoromethyl, difluoromethoxy, trifluoromethoxy, azido, —NR¹⁰SO₂R¹³, —SO₂NR¹⁰R¹¹, —C(═O)R¹⁰, —C(═O)OR¹⁰, —OC(═O)R¹⁰, —NR¹⁰C(═O)OR¹¹, —NR¹⁰C(═O)R¹¹, —C(═O)NR¹⁰R¹¹, —SR¹⁰, —S(O)R¹³, —SO₂R¹³, —SO₂NHC(═O)R¹⁰, —NR¹⁰C(═O)NR¹¹R¹², NR¹⁰C(═O)NR¹OR¹², —NR¹⁰C(NCN)NR¹¹R¹², OPO₃H, alkyl, cycloalkyl, aryl, heteroaryl, arylalkyl, heteroarylalkyl, heterocyclyl and heterocyclylalkyl;

R^cis H or Me; and

n is 0, 1 or 2.

Exemplary embodiments of R⁴include, but are not limited to, 2-thiazolyl, fused thiazolyl ring systems, 2-oxazolyl, fused oxazolyl ring systems, 2-imidazolyl, oxadiazolyl, thiadiazolyl, 4,5(H)-thiazolyl, 4-triazolyl, 4,5(H)-oxazolyl, fused 4,5(H)-thiazolyl ring systems, dihydropyrrol-2-on-yl, and substituted forms thereof, and shown as:

wherein the asterisk indicates the point of attachment, “A” is as defined above, and each R⁵and R^5ais independent of every other R⁵and R^5a.

More specific embodiments of R⁴include

Further exemplary embodiments include compounds of Formula I wherein R⁴is selected from

In certain embodiments, there is provided a compound of Formula I wherein R⁴is selected from the structures

wherein R⁵, R^5aand R⁶are as defined for Formula I. In certain embodiments, R⁵and R^5aare independently H, halogen, alkyl, aryl, or NR¹⁰R¹¹, wherein said alkyl and aryl are optionally substituted with one or more groups independently selected from halogen and —C(═O)OR¹⁰.

In certain embodiments, there is provided a compound of Formula I wherein R⁴is

and A is a saturated or partially unsaturated heterocyclic ring having a ring nitrogen, wherein 1-2 carbon atoms of said heterocyclic ring are optionally substituted with a group independently selected from halogen or alkyl optionally substituted with one or more halogen, and the nitrogen of said heterocyclic ring is optionally substituted with C(═O)NR¹⁰R¹¹, C(═O)N(R¹⁰)OR¹¹, C(═NH)CH—CN, or alkyl optionally substituted with one or more groups independently selected from OR¹⁰, OPO₃H₂, NR¹⁰R¹¹and heterocyclyl.