WO2008153701A1 - Compounds for inhibiting ksp kinesin activity - Google Patents

Compounds for inhibiting ksp kinesin activity Download PDF

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WO2008153701A1
WO2008153701A1 PCT/US2008/006472 US2008006472W WO2008153701A1 WO 2008153701 A1 WO2008153701 A1 WO 2008153701A1 US 2008006472 W US2008006472 W US 2008006472W WO 2008153701 A1 WO2008153701 A1 WO 2008153701A1
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alkyl
aryl
heteroaryl
heterocyclyl
group
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PCT/US2008/006472
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French (fr)
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Gerald W. Shipps, Jr.
Yao Ma
Brian Robert Lahue
Wolfgang Seghezzi
Ronald Herbst
Cheng-Chi Chuang
D. Allen Annis
Matthew Kirtley
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Schering Corporation
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Definitions

  • the present invention relates to compounds and compositions that are useful for treating cellular proliferative diseases or disorders associated with Kinesin Spindle Protein (“KSP”) kinesin activity and for inhibiting KSP kinesin activity.
  • KSP Kinesin Spindle Protein
  • Cancer is a leading cause of death in the United States and throughout the world. Cancer cells are often characterized by constitutive proliferative signals, defects in cell cycle checkpoints, as well as defects in apoptotic pathways. There is a great need for the development of new chemotherapeutic drugs that can block cell proliferation and enhance apoptosis of tumor cells.
  • Conventional therapeutic agents used to treat cancer include taxanes and vinca alkaloids, which target microtubules.
  • Microtubules are an integral structural element of the mitotic spindle, which is responsible for the distribution of the duplicated sister chromatids to each of the daughter cells that result from cell division. Disruption of microtubules or interference with microtubule dynamics can inhibit cell division and induce apoptosis.
  • microtubules are also important structural elements in nonproliferative cells. For example, they are required for organelle and vesicle transport within the cell or along axons. Since microtubule-targeted drugs do not discriminate between these different structures, they can have undesirable side effects that limit usefulness and dosage. There is a need for chemotherapeutic agents with improved specificity to avoid side effects and improve efficacy.
  • Microtubules rely on two classes of motor proteins, the kinesins and dyneins, for their function.
  • Kinesins are motor proteins that generate motion along microtubules. They are characterized by a conserved motor domain, which is approximately 320 amino acids in length. The motor domain binds and hydrolyses ATP as an energy source to drive directional movement of cellular cargo along microtubules and also contains the microtubule binding interface (Mandelkow and Mandelkow, Trends Cell Biol. 2002, 12:585-591 ).
  • Kinesins exhibit a high degree of functional diversity, and several kinesins are specifically required during mitosis and cell division. Different mitotic kinesins are involved in all aspects of mitosis, including the formation of a bipolar spindle, spindle dynamics, and chromosome movement. Thus, interference with the function of mitotic kinesins can disrupt normal mitosis and block cell division. Specifically, the mitotic kinesin KSP (also termed EG5), which is required for centrosome separation, was shown to have an essential function during mitosis.
  • EG5 also termed EG5
  • KSP has become a significant target for development of cancer therapeutica drugs
  • Kinesin inhibitors are known, and several molecules have recently been described in the literature. For example, adociasulfate-2 inhibits the microtubule-stimulated ATPase activity of several kinesins, including CENP- E (Sakowicz et al., Science 1998, 280:292-295). Rose Bengal lactone, another non-selective inhibitor, interferes with kinesin function by blocking the microtubule binding site (Hopkins et al., Biochemistry 2000, 39:2805- 2814). Monastrol, a compound that has been isolated using a phenotypic screen, is a selective inhibitor of the KSP motor domain (Mayer et al.,
  • KSP as well as other mitotic kinesins, are attractive targets for the discovery of novel chemotherapeutics with anti-proliferative activity.
  • chemotherapeutics with anti-proliferative activity.
  • the present invention provides a compound represented by the structural Formula I:
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent;
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, hetero
  • R 1 is -NH 2 , NH(alkyl), or NH(aryl), wherein the "alkyl” and “aryl” portion each of said R 1 is optionally independently substituted, then R 4 is other than unsubstituted alkyl or alkyl substituted with at least one moiety selected from the group consisting of alkoxy, -N(alkyl) 2) heterocyclyl, and heteroaryl;
  • R 4 is other than optionally substituted cycloalkyl, cycloalkenyl, heterocyclenyl, or heteroaryl;
  • R 1 is -NH(aryl)
  • R 4 is aryl substituted with at least one haloalkyl group, then said "aryl" of R 1 is substituted with group(s) other than halo or haloalkyl;
  • R 1 is other than optionally substituted heterocyclyl
  • R 1 is other than -NH 2 or -NH(heterocyclyl).
  • Pharmaceutical formulations or compositions for the treatment of cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject comprising administering a therapeutically effective amount of at least one of the inventive compounds and a pharmaceutically acceptable carrier to the subject also are provided.
  • Methods of treating cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject comprising administering to a subject in need of such treatment an effective amount of at least one of the inventive compounds also are provided.
  • all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about.”
  • A2780 cells were incubated for 48 hours with different concentrations of compound #33 as indicated on the x-axis. Cell proliferation was measured using the AlamarBlue dye method.
  • Figure 2 depicts the activity profile of reference compound 1 , alone, and incombination with fixed concentrations of compound #33.
  • A2780 cells were incubated for 48 hours with different concentrations of Reference compound 1 alone or in combination with two fixed concentrations of compound #33 of Table 1 , as indicated in the legend. Concentrations on the x-axis indicate the concentration of Reference compound 1 used. Cell proliferation was measured using the AlamarBlue dye method.
  • Figure 3 is a normalized response curve that shows that increasing concentrations of the titrant Reference Compound 1 cause an increase in the AS-MS response of ligands Compound #s 1 and 2.
  • the present invention discloses compounds represented by structural Formula I or a pharmaceutically acceptable salt or ester thereof, wherein the various moieties are as described above.
  • the present invention provides processes for producing such compounds, pharmaceutical formulations or compositions comprising one or more of such compounds, and methods of treating or preventing one or more conditions or diseases associated with KSP kinesin activity such as those discussed in detail below.
  • R is selected from the group consisting of H, alkyl, cyano, halo, and haloalkyl. wherein said alkyl is optionally substituted with one or two substituents selected from the group consisting of hydroxy, halo, alkoxy and haloalkoxy.
  • R is selected from the group consisting of -H, -CH 2 OH, -CN, -CF 3 , -F, and -Br.
  • R is selected from the group consisting of oxazolyl, phenyl, thiophenyl, benzofuranyl, pyrimidinyl, pyrazinyl, and pyrazolyl, each of which is optionally substituted.
  • R is selected from the group consisting of phenyl,
  • R 1 is selected from the group consisting of NH(aryl), N(alkyl)(aryl), and wherein said alkyl is CH 3 , and wherein each of said aryl, optionally with said five- to six- membered heterocyclyl, aryl, or heteroaryl is independently selected from
  • R 1 is selected
  • R 1 is selected from the group consisting of:
  • R 1 is selected from the group consisting of: -NH 2 , -NH-(4-sulfonamidophenyl), -NH-(4- methoxyphenyl), -NH-(4-fluorophenyl), -NH-(4-cyanophenyl), -NH-(4- acetylphenyl), -NH-(4-methylphenyl), -NH-(4-isopropylphenyl), -NH-(4- butylphenyl) -NH-(4-isopropyloxy-phenyl), -NH-(4-butyloxy-phenyl) -NH(4- dimethylaminophenyl), -NH-(4-carboxyphenyl) -NH-(4-carbomethoxyphenyl), -NH-(4-trifluoromethylphenyl), -NH-(4-trifluoromethoxyphenyl), -NH-(4-tri
  • R 2 and R 3 are both H.
  • R 2 is H
  • R 3 is alkyl
  • R 4 aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, naphthyl, benzothiophenyl, benzothiazolyl, pyridyl, thiophenyl, benzimidazolyl, isoxazolyl,
  • R 4 aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, ⁇ -naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2- thiophenyl,
  • R 4 is cycloalkyl, wherein when said cycloalkyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl or heteroaryl ring, wherein said cycloalkyl optionally with said five to six-membered aryl or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, and aryl.
  • said R 4 cycloalkyl optionally with said five to six-membered aryl or heteroaryl ring, is selected from the group consisting of cyclopropyl,
  • R 4 is alkyl
  • R 4 is alkyl, wherein said R 4 alkyl is optionally substituted with 1-2 substituents selected from the group consisting of hydroxyl, halo, alkoxy, haloalkyl, and haloalkoxy.
  • R 4 is -(CHb)- I ⁇ OH.
  • R 4 is selected from the group consisting of:
  • R 2 and R 3 are independently H and alkyl
  • R 1 is -NH(aryl) or -N(alkyl)(aryl), wherein the "aryl" portion of each of said R 1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R 1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloal
  • R 2 and R 3 are independently H and alkyl
  • the compound of formula I is selected from the group consisting of compound #s 1-106 in Table I, or or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • R 2 and R 3 are independently H and alkyl; or -CR 2 R 3 is absent
  • R 2 and R 3 are independently H and alkyl; or -CR 2 R 3 is absent
  • R 2 and R 3 are independently H and alkyl; Or-CR 2 R 3 is absent
  • R 4 is selected from the group consisting of cycloalkyl and heteroaryl, wherein said cycloalkyl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said cycloalkyl or heteroaryl, optionally with said five- to six-membered aryl or heteroaryl is selected from the group consisting of: cyclopropyl, 2-thiophenyl, 2-pyridyl,
  • the compound of formula I is selected from the group consisting of comound #s 107-153, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • R 2 and R 3 independently are H and alkyl
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 2 and R 3 independently are H and alkyl; and
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 1 is selected from the group consisting of of -NH(cycloalkyl), - NH(heterocyclyl), -NH(heteroaryl) wherein when each of the "cycloalkyl"
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • formula I in formula I:
  • R 1 is selected from the group consisting of: -NH-piperidinyl, -NH- cyclohexyl, -NH-benzimidazolyl, -NH-bezothiazolyl, and -NH-pyrazolyl, each of which is optionally substituted;
  • R 2 and R 3 independently are H and alkyl; and R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 1 is selected from the group consisting heterocyclyl and heteroaryl, wherein when each of said heterocyclyl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, or heteroaryl ring; wherein said R 1 heterocyclyl and heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, or heteroaryl ring, is optionally substituted with 1-3 substituents selected from the group consisting of -NH 2 , hydroxy, cyano, alkyl, -
  • R 2 and R 3 independently are H and alkyl
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 1 is selected from the group consisting of pyrrolidinyl, piperidinyl, and piperizinyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of -NH 2 , hydroxy, cyano, alkyl, -
  • R 2 and R 3 independently are H and alkyl; and R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 1 is selected from the group consisting of -NH 2 , -NH(alkyl), -
  • R 2 and R 3 are both H;
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 4 is aryl optionally substituted with at least one haloalkyl group.
  • the compound of formula I is selected from the group consistinf of compound #s 154-216 in Table I, or a pharmaceutically acceptable salt, solvate or ester thereof.
  • R 1 is alkyl optionally substituted with at least one aryl substituent, wherein when said aryl substituent has two moieties on adjacent carbon atoms, said moieties, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independently are H and alkyl
  • R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 2 and R 3 independently are H and alkyl; and R 4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
  • R 1 is alkyl optionally substituted with at least one aryl substituent, wherein when said aryl substituent has two moieties on adjacent carbon atoms, said moieties, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independently are H and alkyl
  • R 4 is aryl optionally substituted with at least one haloalkyl group.
  • the compound of formula I is selected from the group consisting of compound #s 217-222 in Table I, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent; and R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alk
  • R 1 is-NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said -NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent;
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent;
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent; and R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alk
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R 2 and R 3 are both H; and
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R 2 and R 3 are both alkyl; and
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; -C(R 2 XR 3 )- is absent; and
  • R 4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R 4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent; and R 4 is cycloalkyl, wherein when said cycloalkyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six- membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R 4 cycloalkyl, optionally with said five to six-membered aryl, is selected from the group consisting of cyclopropyl and
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 2 and R 3 independenly are H or alkyl, or -C(R 2 )(R 3 )- is absent; and R 4 is alkyl, optionally substituted with a hydroxyl.
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • R 1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
  • the compound of formula I is selected from the group consisting of compound #s 223-242 in Table I, or a pharmaceutically acceptable salt, solvate or ester thereof.
  • formula I in formula I:
  • R 2 and R 3 are both H;
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 2 and R 3 are both H; and R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 2 and R 3 are both H; and R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R is selected from the group consisting of halo, cyano, and haloalkyl;
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 2 and R 3 are both H;
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 2 and R 3 are both H;
  • R 4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is aryl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • R 4 is heteroaryl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
  • the compound of formula I is selected from the group consisting of compound #s 243-324 in Table I, or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • the present invention provides a composition comprising a combination of a compound of formula I, or pharmaceutically acceptable salt, solvate, or ester thereof, as set forth hereinabove, and a compound of formula Il
  • Ri is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
  • R 2 and Rz are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3-to 7-membered ring;
  • R 3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, R 15 0-and R 15 -NH-;
  • R 4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R 16 -alkylene-;
  • R 5 , Re. R7 and R$ are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
  • R- I5 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
  • R1 6 is chosen from alkoxy, amino, alkylamino, dialkylamino, N- heterocyclyl and substituted N-heterocyclyl;
  • R 2 and R 4 must be other than hydrogen.
  • R 1 is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted alkylaryl;
  • R 2 is chosen from hydrogen, alkyl and substituted alkyl;
  • R 2 is hydrogen;
  • R 3 is chosen from alkyl, aryl, alkylaryl, heteroaryl, substituted aryl, substituted alkyl, substituted heteroaryl, oxaalkylaryl, substituted oxaalkylaryl, R 15 0-and R 15 -NH-;
  • R 4 is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted 30 aryl, and R16-alkylene-;
  • R 5 is hydrogen
  • R 6 , R 7 and R 8 are independently chosen from hydrogen, halogen, methyl and trifluoromethyl;
  • R 15 is chosen from alkyl, aryl and substituted aryl
  • R 16 is chosen from alkoxy, amino, alkylamino, dialkylamino and N- heterocyclyl.
  • Ri is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl.
  • Ri is chosen from hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and
  • R 2 is chosen from hydrogen, lower alkyl and substituted lower alkyl, and R ⁇ is hydrogen.
  • R2 is chosen from hydrogen, methyl, ethyl, propyl, methylthioethyl, aminobutyl, (CBZ) aminobutyl, 20 cyclohexyl methyl, benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl, hydroxymethyl, benzyl and indolylmethyl.
  • R 3 is chosen from C 1 -C 13 alkyl; substituted lower alkyl; phenyl; naphthyl; phenyl substituted with one or more halo, lower alkyl, loweralkoxy, nitro, carboxy, methylenedioxy, or trifluoromethyl; biphenylyl; benzyl; phenoxymethyl; halophenoxymethyl; phenylvinyl; heteroaryl; heteroaryl substituted with lower alkyl; and benzyloxymethyl.
  • R 3 is chosen from ethyl, propyl, chloropropyl, butoxy, heptyl, butyl, octyl, tridecanyl, (ethoxycarbonyl)ethyl, dimethylaminoethyl, dimethylaminomethyl, phenyl, naphthyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl) phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, chloronaphthyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, phenoxymethyl, dim
  • R 3 is R-i 5 -NH-and Ri 5 is chosen from lower alkyl; cyclohexyl; phenyl; and phenyl substituted with halo, lower alkyl, loweralkoxy, or lower alkylthio.
  • R 15 is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.
  • R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R16-alkylene-, wherein R 16 is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
  • R 4 is chosen from methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylarninopropyl, aminopropyl, methylaminopropyl,, 2,2dimethyl-3-(dimethylamino)propyl, 1-cyclohexyl-4-(diethylamino)butyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, aminoethoxyethyl, isopropylaminopropyl, diisopropylaminoethyl, 1 -methyl-4-(diethylamino)butyl, (t-Boc)aminopropyl, 5
  • morpholinylpropyl piperidinyl, azetidinylmethyl, azetidinylpropyl pyrrol id inylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl, (methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl and indolylethyl.
  • Ri is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
  • R 2 is chosen from hydrogen, alkyl, substituted lower alkyl and benzyl;
  • Rz is hydrogen
  • R 3 is chosen from substituted phenyl and naphthyl
  • R 4 is chosen from substituted alkyl and R 16 -alkylene-;
  • R 5 is hydrogen or halo; Re is hydrogen, methyl or halo;
  • R 7 is hydrogen, halo, methyl or trifluoromethyl
  • R 16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino N- heterocyclyl and substituted N-heterocyclyl.
  • formula II in formula II:
  • Ri is benzyl or halobenzyl
  • R 2 is chosen from ethyl and propyl
  • Rz is hydrogen
  • R 3 is substituted phenyl
  • R 4 is (CH 2 ) m OH or (CH 2 ) p Ri 6 wherein m is or 3 and p is 1-3;
  • R 5 is hydrogen
  • R 7 is halo; Re is hydrogen;
  • Ri 6 is chosen from amino, propylamino, and azetidinyl.
  • the compound of formula Il is selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of :
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound of formula I is (compound #33 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • AS-MS Affinity selection mass spectrometry
  • the present invention also provides A composition comprising a combination of a compound of claim 1 , or pharmaceutically acceptable salt, solvate, or ester thereof, and a compound of formula III
  • n is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R 5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring; a is 0 or I; b is 0 or I; m is 0,1 , or 2; n is 0 to 4;
  • R 1 is selected from:
  • R2 and R3 are independently selected from: 1 ) H,
  • R5 is:
  • R7 and R8 are independently selected from: 1) H,
  • R 7 and R 8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O, and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
  • Ra is (C
  • the compounds of formula III are disclosed in International Publication WO03/039460 (assigned to Merck; published May 15, 2003). In another embodiment, the compounds of formula III are selected from the group consisting of:
  • the compound of formula I is selected from the group consisting of:
  • the compound of formula I is N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N-(2-aminoethyl)-2-aminoethyl-N
  • the compound of formula I is (compound #33 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof.
  • Subject includes both mammals and non-mammalian animals.
  • “Mammal” includes humans and other mammalian animals.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • alkyl means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain.
  • Lower alkyl means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched.
  • Non- limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl.
  • Alkyl includes "Alkylene” which refers to a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above.
  • alkylene include methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) and propylene (-C3H6-; which may be linear or branched).
  • Alkenyl means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain.
  • “Lower alkenyl” means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl.
  • Alkenyl includes “Alkenylene” which refers to a difunctional group obtained by removal of a hydrogen atom from an alkenyl group that is defined above.
  • Alkynyl means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain.
  • Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain.
  • Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain.
  • Lower alkynyl means about 2 to about 6 carbon atoms in the chain which may be straight or branched.
  • suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl.
  • Aryl means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms.
  • the aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined
  • Heteroaryl means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms.
  • the "heteroaryl” can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom.
  • a nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide.
  • suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl,
  • Aralkyl or “arylalkyl” means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
  • Alkylaryl means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl.
  • Cycloalkyl means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like.
  • Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
  • Cycloalkenyl means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms.
  • the cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above.
  • suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like.
  • Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
  • Cycloalkenylalkyl means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like, i
  • Halogen means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
  • Ring system substituent means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system.
  • Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, hydroxysulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthi
  • Ring system substituent may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system.
  • Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH 3 ) 2 - and the like which form moieties such as, for example:
  • Heteroarylalkyl means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
  • Heterocyclyl means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclyls contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention.
  • the heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein.
  • the nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like.
  • Heterocyclyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
  • Heterocyclylalkyl means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
  • Heterocyclenyl means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system.
  • Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms.
  • the prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom.
  • the heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above.
  • the nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide.
  • heterocyclenyl groups include 1 , 2,3,4- tetrahydropyridine, 1 ,2-dihydropyridyl, 1 ,4- dihydropyridyl, 1 ,2,3,6-tetrahydropyridine, 1 ,4,5,6-tetrahydropyrimidine, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like.
  • Heterocyclenyl may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogen
  • Heterocyclenylalkyl means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
  • hetero-atom containing ring systems of this invention there are no hydroxyl groups on carbon atoms adjacent to a N, O or S 1 as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • N, O or S 1 there are no hydroxyl groups on carbon atoms adjacent to a N, O or S 1 as well as there are no N or S groups on carbon adjacent to another heteroatom.
  • Alkynylalkyl means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl” means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
  • Hydroxyalkyl means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2- hydroxyethyl. "Acyl” means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl.
  • Aroyl means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl.
  • suitable groups include benzoyl and 1- naphthoyl.
  • Alkoxy means an alkyl-O- group in which the alkyl group is as previously described.
  • suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Aryloxy means an aryl-O- group in which the aryl group is as previously described.
  • suitable aryloxy groups include phenoxy and naphthoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkyloxy means an aralkyl-O- group in which the aralkyl group is as previously described.
  • suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy.
  • the bond to the parent moiety is through the ether oxygen.
  • Alkylthio means an alkyl-S- group in which the alkyl group is as previously described.
  • suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
  • Arylthio means an aryl-S- group in which the aryl group is as previously described.
  • suitable arylthio groups include phenylthio and naphthylthio.
  • the bond to the parent moiety is through the sulfur.
  • Alkylthio means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur.
  • Alkylsilyl means an alkyl-Si- group in which alkyl is as previously defined and the point of attachment to the parent moiety is on Si. Preferred alkylsilyls contain lower alkyl. An example of an alkylsilyl group is trimethylsilyl (-Si(CH 3 ) 3 ).
  • Alkoxycarbonyl means an alkyl-O-CO- group.
  • suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Aryloxycarbonyl means an aryl-O-C(O)- group.
  • suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl.
  • the bond to the parent moiety is through the carbonyl.
  • Aralkoxycarbonyl means an aralkyl-O-C(O)- group.
  • Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
  • Alkylsulfonyl means an alkyl-S(O 2 )- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
  • Arylsulfonyl means an aryl-S(O 2 )- group. The bond to the parent moiety is through the sulfonyl.
  • substituted means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds.
  • stable compound 1 or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
  • purified refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof.
  • purified refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
  • protecting groups When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
  • composition is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts.
  • pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • Prodrugs and solvates of the compounds of the invention are also contemplated herein.
  • a discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) t4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press.
  • the term "prodrug” means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood.
  • a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C 8 )alkyl, (C 2 -C 12 )alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1- methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbon
  • a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Cr
  • a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-Ci O )alkyl, (C 3 -C 7 ) cycloalkyl, benzyl, or R-carbonyl is a natural ⁇ -aminoacyl or natural ⁇ - aminoacyl, -C(OH)C(O)OY 1 wherein Y 1 is H, (C r C 6 )alkyl or benzyl, — C(OY 2 )Y 3 wherein Y 2 is (C 1 -C 4 ) alkyl and Y 3 is (C r C 6 )alkyl, carboxy (C 1 - C 6 )alkyl, amino(C 1 -C 4 )alkyl or mono-N —
  • R-carbonyl RO-carbonyl
  • One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms.
  • “Solvate” means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate” encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like.
  • “Hydrate” is a solvate wherein the solvent molecule is H 2 O.
  • One or more compounds of the invention may optionally be converted to a solvate.
  • Preparation of solvates is generally known.
  • M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem.
  • a typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods.
  • Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
  • Effective amount or “therapeutically effective amount” is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
  • the compounds of Formulae l-lll can form salts which are also within the scope of this invention.
  • Reference to a compound of Formulae l-lll herein is understood to include reference to salts thereof, unless otherwise indicated.
  • the term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases.
  • zwitterions may be formed and are included within the term "salt(s)" as used herein.
  • Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful.
  • Salts of the compounds of the Formulae l-lll may be formed, for example, by reacting a compound of Formulae l-lll with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
  • Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like.
  • Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like.
  • Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g.
  • dimethyl, diethyl, and dibutyl sulfates dimethyl, diethyl, and dibutyl sulfates
  • long chain halides e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides
  • aralkyl halides e.g. benzyl and phenethyl bromides
  • esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen, or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di-, di
  • the compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention.
  • the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
  • Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization.
  • Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers.
  • an appropriate optically active compound e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride
  • some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention.
  • Enantiomers can also be separated by use of chiral HPLC column
  • the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention.
  • all keto-enol and imine-enamine forms of the compounds are included in the invention.
  • All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl).
  • salt is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
  • the present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature.
  • isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2 H, 3 H, 13 C, 14 C, 15 N, 18 O, 17 0, 31 P, 32 P, 35 S, 18 F, and 36 CI, respectively.
  • Certain isotopically-labelled compounds of Formula (I) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3 H) and carbon-14 (i.e., 14 C) isotopes are particularly preferred for their ease of preparation and detectability.
  • lsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
  • the compounds of Formula I can be prepared by a variety of methods well known to those skilled in the art, for example, by the methods as outlined below and in the examples disclosed herein:
  • mitosis may be altered in a variety of ways; that is, one can affect mitosis either by increasing or decreasing the activity of a component in the mitotic pathway. Mitosis may be affected (e.g., disrupted) by disturbing equilibrium, either by inhibiting or activating certain components. Similar approaches may be used to alter meiosis.
  • the compounds of the invention can be used to inhibit mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis.
  • inhibit in this context is meant decreasing or interfering with mitotic spindle formation or causing mitotic spindle dysfunction.
  • mitotic spindle formation herein is meant organization of microtubules into bipolar structures by mitotic kinesins.
  • mitotic spindle dysfunction herein is meant mitotic arrest and monopolar spindle formation.
  • the compounds of the invention can be useful for binding to, and/or inhibiting the activity of, a mitotic kinesin, KSP.
  • the KSP is human KSP, although the compounds may be used to bind to or inhibit the activity of KSP kinesins from other organisms.
  • inhibit means either increasing or decreasing spindle pole separation, causing malformation, i.e., splaying, of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle.
  • variants and/or fragments of KSP see U.S. patent 6,437,115.
  • the present compounds are also useful for binding to or modulating other mitotic kinesins.
  • the compounds of the invention can be used to treat cellular proliferation diseases.
  • diseases which can be treated by the compounds, compositions and methods provided herein include, but are not limited to, cancer (further discussed below), hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, cellular proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like.
  • Treatment includes inhibiting cellular proliferation. It is appreciated that in some cases the cells may not be in a hyper- or hypoproliferation state (abnormal state) and still require treatment. For example, during wound healing, the cells may be proliferating "normally", but proliferation enhancement may be desired.
  • the invention herein includes application to cells or subjects afflicted or subject to impending affliction with any one of these disorders or states.
  • the compounds, compositions and methods provided herein are particularly useful for the treatment of cancer including solid tumors such as skin, breast, brain, colon, gall bladder, thyroid, cervical carcinomas, testicular carcinomas, etc.
  • cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
  • Lung bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
  • Gastrointestinal esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor
  • nephroblastoma lymphoma, leukemia
  • bladder and urethra squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
  • Liver hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
  • Bone osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
  • Nervous system skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
  • Gynecological uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma
  • cystadenocarcinoma mucinous cystadenocarcinoma, unclassified carcinoma
  • granulosa-thecal cell tumors Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma
  • vulva squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma
  • vagina vagina
  • squamous cell carcinoma intraepithelial carcinoma
  • adenocarcinoma fibrosarcoma
  • vagina vagina
  • clear cell carcinoma squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma)
  • Hematologic blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;
  • Skin malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;
  • Adrenal glands neuroblastoma
  • tumors including xenoderoma pigmentosum, keratoctanthoma and thyroid follicular cancer.
  • treatment of cancer includes treatment of cancerous cells, including cells afflicted by any one of the above-identified conditions.
  • the compounds of the present invention may also be useful in the chemoprevention of cancer.
  • Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse.
  • the compounds of the present invention may also be useful in inhibiting tumor angiogenesis and metastasis.
  • the compounds of the present invention may also be useful as antifungal agents, by modulating the activity of the fungal members of the bimC kinesin subgroup, as is described in U.S. Patent 6,284,480.
  • the present compounds are also useful in combination with one or more other known therapeutic agents and anti-cancer agents.
  • Combinations of the present compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by VT. Devita and S. Hellman (editors), 6 th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved.
  • anti- cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints.
  • the present compounds are also useful when co-administered with radiation therapy.
  • estrogen receptor modulators refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism.
  • examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381 , LY117081 , toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1 - piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2- dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl- ydrazone, aid SH646.
  • androgen receptor modulators refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism.
  • examples of androgen receptor modulators include finasteride and other 5 ⁇ -reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
  • retinoid receptor modulators refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism.
  • retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a difluoromethylomithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
  • cytotoxic/cytostatic agents refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mycosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, monoclonal antibody therapeutics, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
  • cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide (TEMODARTM from Schering-Plough Corporation, Kenilworth, New Jersey), cyclophosphamide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, doxorubicin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufos
  • hypoxia activatable compound is tirapazamine.
  • proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.
  • microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3 ⁇ 4'-didehydro-4'-deoxy-8'- norvincaleukoblastine, docetaxel, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881 , BMS184476, vinflunine, cryptophycin, 2,3 ) 4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N.N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, the epothilones (see for example U.S.
  • topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo- benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5- kl]acridine-2-(6H) propanamine, 1 -amino-9-ethyl-5-fluoro-2,3-dihydro-9- hydroxy-4-methyl-1 H,12H-benzo[de]pyrano[3',4':b,7]- indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N- isopropylamino) ethyl]-(20S)camptothecin, BNP1350
  • thymidilate synthase inhibitors such as 5- fluorouracil.
  • inhibitors of mitotic kinesins include, but are not limited to, inhibitors of KSP, inhibitors of MKLP1 , inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif 14, inhibitors of Mphosphi and inhibitors of Rab6-KIFL.
  • inhibitors of kinases involved in mitotic progression include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo- like kinases (PLK) (in particular inhibitors of PLK-1 ), inhibitors of bub-1 and inhibitors of bub-R1.
  • antiproliferative agents includes antisense RNA and
  • DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 , and INX3001 , and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'- deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4- dichlorophenyl)urea, N6-[4-deoxy-4
  • monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
  • monoclonal antibody therapeutics useful for treating cancer include Erbitux (Cetuximab).
  • HMG-CoA reductase inhibitors refers to inhibitors of 3- hydroxy-3-methylglutaryl-CoA reductase.
  • HMG-CoA reductase inhibitors include but are not limited to lovastatin
  • the structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patents 4,782,084 and 4,885,314.
  • HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open- acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open acid and lactone forms is included in the scope of this invention.
  • prenyl-protein transferase inhibitor refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl- protein transferase type I (GGPTase-l), and geranylgeranyl-protein transferase type-ll (GGPTase-l I, also called Rab GGPTase).
  • FPTase farnesyl-protein transferase
  • GGPTase-l geranylgeranyl- protein transferase type I
  • Rab GGPTase geranylgeranyl-protein transferase type-ll
  • prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701 , WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patents 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221 , European Patent Publ. 0 675 112, European Patent Publ. 0 604181 , European Patent Publ.
  • a prenyl-protein transferase inhibitor for an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European of Cancer, Vol. 35, No. 9, pp.1394-1401(1999).
  • farnesyl protein transferase inhibitors include
  • SARASARTM (4-[2-[4-[(11 R)-3,10-dibromo-8-chloro-6,11-dihydro-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -yl-]-1 -piperidinyl]-2-oxoehtyl]-1 - piperidinecarboxamide from Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra ® or R115777 from Janssen Pharmaceuticals), L778.123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey).
  • angiogenesis inhibitors refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism.
  • angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1 ) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon- ⁇ (for example lntron and Peg-lntron), interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol.
  • NSAIDs nonsteroidal anti-inflamm
  • steroidal antiinflammatories such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , angiotensin Il antagonists (see Fernandez et al., J. Lab. Clin. Med.
  • therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in CHn. Chem. La. Med. 38:679-692
  • TAFIa active thrombin activatable fibrinolysis inhibitor
  • agents that interfere with cell cycle checkpoints refers to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents.
  • agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
  • inhibitors of cell proliferation and survival signaling pathway refers to agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors.
  • agents include inhibitors of EGFR (for example gefitinib and erlotinib), antibodies to EGFR (for example C225), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO
  • Such agents include small molecule inhibitor compounds and antibody antagonists.
  • apoptosis inducing agents includes activators of TNF receptor family members (including the TRAIL receptors).
  • NSAID's which are selective COX-2 inhibitors are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays.
  • Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2- (5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5 pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
  • angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpimase, IM862, 5-methoxy-4-[2-methyl-3-(3- methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1 -[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl]methyl]-1 H-1 ,2,3-triazole-4-carboxamide, CM101 , squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N- methyl-4,2-pyrrole]-carbonylimino]-bis-(1 ,
  • integrin blockers refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ 3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the ⁇ v ⁇ s integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the ⁇ v ⁇ 3 integrin and the ⁇ v ⁇ s integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells.
  • the term also refers to antagonists of the ⁇ v ⁇ 6 , ⁇ v ⁇ 8 , ⁇ -i ⁇ -i, ⁇ -i, ⁇ s ⁇ -i, ⁇ i and ⁇ 4 integrins.
  • the term also refers to antagonists of any combination of ⁇ v ⁇ 3, ⁇ v ⁇ 5) ⁇ v ⁇ 6> ctv ⁇ s, ⁇ i ⁇ i, ⁇ 2 ⁇ i, ⁇ 5 ⁇ i, ⁇ ! and ⁇ 4 integrins.
  • tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4- dimethylpyrrol-5- yl)methylidenyl)indolin-2-one, 17-(allylamino)-17- demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3- (4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11 ,12-hexahydro- 10-(hydroxymethyl)-10-hydroxy-9-methyl-9, 12-epoxy-1 H-diindolo[1 ,2,3- fg:3',2',1 '- kl]pyrrolo[3,4-i
  • Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods.
  • combinations of the present compounds with PPAR- ⁇ (i.e., PPAR-gamma) agonists and PPAR- ⁇ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies.
  • PPAR- ⁇ and PPAR- ⁇ are the nuclear peroxisome proliferator-activated receptors ⁇ and ⁇ .
  • the expression of PPAR- ⁇ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J. Biol. Chem. 1999;274:9116-9121 ; Invest.
  • PPAR- ⁇ agonists and PPAR- ⁇ / ⁇ agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011 , troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501 , MCC- 555, GW2331 , GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1 ,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid, and 2(R)-7-(3-(2-chloro-4-(4- fluorophenoxy) phenoxy)propoxy)-2
  • useful anti-cancer (also known as anti-neoplastic) agents that can be used in combination with the present compounds include, but are not limited, to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATI NTM from Sanofi-Synthelabo Pharmaeuticals, France),
  • Pentostatine Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17 ⁇ - Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,
  • Megestrolacetate Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, doxorubicin (adriamycin), cyclophosphamide (Cytoxan), gemcitabine, interferons, pegylated interferons, Erbitux and mixtures thereof.
  • Another embodiment of the present invention is the use of the present compounds in combination with gene therapy for the treatment of cancer.
  • Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S.
  • Patent 6,069,134 for example, a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J Immunol 2000;164:217-222).
  • the present compounds can also be administered in combination with one or more inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins.
  • MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
  • the present compounds can also be employed in conjunction with one or more anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy.
  • a compound of the present invention may be used in conjunction with one or more other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor, antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or those as described in U.S.
  • neurokinin-1 receptor antagonists especially 5HT3 receptor, antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or those as described in U.S.
  • an antidopaminergic such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol.
  • an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the present compounds.
  • neurokinin-1 receptor antagonists that can be used in conjunction with the present compounds are described in U.S. Patents 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, and 5,719,147, content of which are incorporated herein by reference.
  • the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1 H,4H- 1 ,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent 5,719,147.
  • a compound of the present invention may also be administered with one or more immunologic-enhancing drug, such as for example, levamisole, isoprinosine and Zadaxin.
  • immunologic-enhancing drug such as for example, levamisole, isoprinosine and Zadaxin.
  • the present invention encompasses the use of the present compounds (for example, for treating or preventing cellular proliferative diseases) in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an immunologic- enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
  • a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferas
  • the present invention empassesses the composition and use of the present compounds in combination with a second compound selected from: a cytostatic agent, a cytotoxic agent, taxanes, a topoisomerase Il inhibitor, a topoisomerase I inhibitor, a tubulin interacting agent, hormonal agent, a thymidilate synthase inhibitors, antimetabolites, an alkylating agent, a farnesyl protein transferase inhibitor, a signal transduction inhibitor, an EGFR kinase inhibitor, an antibody to EGFR, a C-abl kinase inhibitor, hormonal therapy combinations, and aromatase combinations.
  • a second compound selected from: a cytostatic agent, a cytotoxic agent, taxanes, a topoisomerase Il inhibitor, a topoisomerase I inhibitor, a tubulin interacting agent, hormonal agent, a thymidilate synthase inhibitors, antimetabolites, an alkylating agent, a farnesyl protein transfer
  • treating cancer refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
  • the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MW (matrix metalloprotease) inhibitor, an integrin blocker, interferon- ⁇ , interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-(O-chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , or an antibody to VEGF.
  • a tyrosine kinase inhibitor an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MW (matrix metalloprotease) inhibitor, an integrin block
  • the estrogen receptor modulator is tamoxifen or raloxifene.
  • a method of treating cancer comprising administering a therapeutically effective amount of at least one compound of Formulae I in combination with radiation therapy and at least one compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG- CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR- ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an immunologic-enhancing drag, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
  • Yet another embodiment of the invention is a method of treating cancer comprising administering a therapeutically effective amount of at least one compound of Formula I in combination with paclitaxel or trastuzumab.
  • the present invention also includes a pharmaceutical composition useful for treating or preventing cellular proliferation diseases (such as cancer, hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, and cellular proliferation induced after medical procedures) that comprises a therapeutically effective amount of at least one compound of Formula I and at least one compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR ⁇ agonist, a PPAR- ⁇ agonist, an inhibitor of cell proliferation and survival signaling, an agent that interfers with
  • Another aspect of this invention relates to a method of selectively inhibiting KSP kinesin activity in a subject (such as a cell, animal or human) in need thereof, comprising contacting said subject with at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • KSP kinesin inhibitors are those which can specifically inhibit KSP kinesin activity at low concentrations, for example, those that cause a level of inhibition of 50% or greater at a concentration of 50 ⁇ M or less, more preferably 100 nM or less, most preferably 50 nM or less.
  • Another aspect of this invention relates to a method of treating or preventing a disease or condition associated with KSP in a subject (e.g., human) in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof to said subject.
  • a preferred dosage is about 0.001 to 500 mg/kg of body weight/day of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
  • phrases "effective amount” and “therapeutically effective amount” mean that amount of a compound of Formulae I, and other pharmacological or therapeutic agents described herein, that will elicit a biological or medical response of a tissue, a system, or a subject (e.g., animal or human) that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more cellular proliferation diseases.
  • the formulations or compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body of, for example, a mammal or human.
  • the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.
  • this invention includes combinations comprising an amount of at least one compound of Formulae I or a pharmaceutically acceptable salt or ester thereof, and an amount of one or more additional therapeutic agents listed above (administered together or sequentially) wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
  • the therapeutic agents in the combination may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like.
  • the amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts).
  • a compound of Formula I and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like).
  • a commercial example of such single dosage unit containing fixed amounts of two different active compounds is VYTORIN ® (available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey).
  • Such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range.
  • Compounds of Formula I may also be administered sequentially with known therapeutic agents when a combination formulation is inappropriate.
  • the invention is not limited in the sequence of administration; compounds of Formula I may be administered either prior to or after administration of the known therapeutic agent. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
  • the pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays.
  • the inhibitory activity of the present compounds towards KSP may be assayed by methods known in the art, for example, by using the methods as described in the examples.
  • compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers, adjuvants or vehicles thereof and optionally other therapeutic agents.
  • Each carrier, adjuvant or vehicle must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the mammal in need of treatment.
  • this invention also relates to pharmaceutical compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.
  • inert, pharmaceutically acceptable carriers can be either solid or liquid.
  • Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient.
  • Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
  • composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients.
  • the bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents".
  • the bulk composition is material that has not yet been formed into individual dosage units.
  • An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like.
  • the herein-described method of treating a subject by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
  • compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects.
  • Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
  • Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
  • Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
  • a pharmaceutically acceptable carrier such as an inert compressed gas, e.g. nitrogen.
  • solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration.
  • liquid forms include solutions, suspensions and emulsions.
  • the compounds of the invention may also be deliverable transdermally.
  • the transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
  • the compounds of this invention may also be delivered subcutaneously.
  • the compound is administered orally.
  • the pharmaceutical preparation is in a unit dosage form.
  • the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
  • the quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application.
  • the actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
  • a typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
  • kits comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.
  • kits comprising an amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
  • oxalyl chloride 4-Fluoro-4-nitrobenzoic acid (277 mg, 1.5mmol) was dissolved in DCM (5ml_) and oxalyl chloride was added (630 ⁇ L, 5 eq.) followed by 2 ⁇ l_ DMF. The solution was stirred for 1 h at rt. then concentrated to give 1.5 mmol of acid chloride which is stored under argon and must be used in the next step fresh.
  • Rink AM resin Novabiochem, 0.4 mmol was added a mixture of piperidine and DMF (6ml_, 50%) and the mixture was shaken for 45 min and filtered. The resin was thoroughly washed with DMF, i-PrOH, DCM (3x each), Et 2 O and dried. To the resin was added DCM (5ml_), DIEA (315 ⁇ L, 1.8mmol) and freshly prepared 4-fluoro-3-nitrobenzoyl chloride (1.5mmol) in 3mL DCM. The mixture was stirred overnight at rt. then filtered. The resin was washed with DCM, i-PrOH, DCM (3x each), Et 2 O and dried.
  • Rink AM resin Novabiochem, 0.4 mmol was added a mixture of piperidine and DMF (6ml_, 50%) and the mixture was shaken for 45 min and filtered. The resin was thoroughly washed with DMF, i-PrOH, DCM (3x each), Et 2 O and dried.
  • Serial dilutions of the compounds were prepared in a low binding, 96- well microtiter plate (Costar # 3600) using 40% DMSO (Fisher BP231 ). The diluted compounds were added to a 384-well microtiter plate (Fisher 12-565- 506).
  • ATP Sigma A-3377
  • final concentration of ATP 100 ⁇ M
  • the reaction was incubated for 1 hour at room temperature.
  • the reaction was stopped by the addition of 50 ⁇ l_ Biomol green reagent (Biomol AK111 ) per well, and was allowed to incubate for 20 minutes at room temperature.
  • the 384-well microtiter plate was then transferred to an absorbance reader (Molecular Devices SpectraMax plus) and a single measurement was taken at 620 nm.
  • 25A25 buffer consisted of the following: 25 mM ACES pH 6.9, 2 mM MgOAc (Sigma M-9147), 2 mM EGTA, 0.1 mM EDTA (Gibco 144475-038), 25 mM KCI, 1 mM 2-mercaptoethanol (Biorad 161-0710), 10 ⁇ M paclitaxel, and 0.5 mM DTT.
  • Solution 1 consisted of the following: 3.75 mM (final concentration) phosphoenol pyruvic acid (PEP, 2.5 X) (Sigma P-7127), 0.75 mM MgATP (2.5 X) (Sigma A-9187) in 1 X 25A25 buffer.
  • Solution 2 consisted of the following: 100-500 nM KSP motor domain (2 X), 6 U/mL pyruvate kinase/lactate dehydrogenase (2 X) (Sigma P-0294), 110 ⁇ g/tnL purified microtubules (2 X), 1.6 ⁇ M ⁇ -nicotinamide adenine di-nucleotide, reduced form (NADH, 2 X) (Sigma N-8129) in 1 X 25A25 buffer.
  • Compound dilutions (8) were added to a 96-well microtiter plate (Costar 9018), and 40 ⁇ l_ of solution 1 was added to each well. The reaction was started by adding 50 ⁇ L of solution 2 to each well.
  • the respective final assay concentrations were: 1.5 mM PEP, 0.3 mM MgATP, 50-250 nM KSP motor domain, 3 U/mL pyruvate kinase/lactate dehydrogenase, 55 ⁇ g/mL purified microtubules, 0.8 ⁇ M NADH (final concentrate).
  • the microtiter plate was then transferred to an absorbance reader and multiple readings were taken for each well in a kinetic mode at 340 nm (25 measurements for each well approximately every 12 seconds, spread approximately over about 5 minutes time span). For each reaction, a rate of change was determined.
  • Y is the % activity and X is the measured reading (OD620 or rate)
  • % activity was fit by the following equation using a nonlinear curve-fitting program for sigmoidal dose- responses (variable slopes) (GraphPad Prizm).
  • Y Bottom + (Top-Bottom)/(1 +10 ⁇ ((LogEC50-X) ⁇ illSlope))
  • X is the logarithm of concentration.
  • Y is the response.
  • A2780 human ovarian cancer cells are seeded at a density of 10,000 cells / well in a 96 well microtiter plate and incubated in 100 ul of complete DMEM (Dulbecco's modified Eagle's medium) plus 10% fetal bovine calf serum for 3-4 hours at 37oC. Test compounds are diluted to the appropriate concentration in DMEM medium and added as equal volume to the respective wells. Control wells receive an equivalent volume of DMEM and DMSO (solvent). Cells are returned to the 37oC / CO2 incubator for 42 hours after which 20 ul of AlamarBlue dye (Trek Diagnostic Systems Inc.) is added.
  • KSP inhibitory activities (IC 50 values based on end-point assay) for the compounds of the present invention shown in Table 1 below range from 20,000 ⁇ M or greater to about 500 ⁇ M.
  • M in “M+H” denotes the exact molecular weight.
  • compound #33 in Table I was identified as an inhibitor of the activity of the mitotic kinesin KSP with an IC50 of 0.52 uM (520 nM) in a KSP in vitro assay (AlamarBlue) measuring hydrolysis of ATP in the presence of microtubules.
  • Kinetic analysis employing model discrimination revealed an uncompetitive mode of inhibition (Dynafit kinetic analysis software package (Biokin Ltd.)).
  • A2780 cells were incubated for 48 hours either with concentration series of reference compound alone or in combination with fixed concentrations of compound #33 (3.75 uM, 7.5 uM: see Fig 2).
  • the IC50 for Reference compound 1 was found to be 1.8 nM in the absence of compound #33.
  • Addition of compound #33 at concentrations below its IC50 led to a notable increase in the potency of Reference compound 1 (see Fig 2) with the combination displaying a 2.5 (3.75 uM of compound #33) or 12 fold (7.5 uM of compound #33) improvement in the IC50 when compared to Reference compound 1 alone. This result implies a possible synergistic mechanism between the Reference compound 1 and compound #33.
  • SEC size exclusion chromatography
  • Ligands are dissociated from the complex and trapped at the head of the RPC column, where they are desalted and eluted into the mass spectrometer using a gradient of 0% to 95% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over five minutes using an Agilent capillary binary pump (G1376A) for eluant delivery at 20 ⁇ L/min.
  • G1376A Agilent capillary binary pump
  • MS analysis was performed using a Waters LCT "Classic" high resolution time-of-flight mass spectrometer (Manchester, U.K.) with positive-mode ionization occurring from a standard nebulized ESI source with the capillary at 3.5 kV, a desolvation temperature of 180° C, a source temperature of 100° C, and 30 V “cone” and 3 V extraction lens settings.
  • a mixture of test ligands at 40 ⁇ M per component is prepared by combining 2 ⁇ l_ aliquots of 400 ⁇ M stocks of each compound with 16 ⁇ L DMSO. 1 ⁇ l_ aliquots of this 40 ⁇ M per component mixture are combined with 1 ⁇ L DMSO aliquots of a serially diluted stock solution of titrant Reference Compound 1 (10, 5, 2.5, ..., 0.078 mM).
  • binding buffer PIPES- buffered saline: 50 mM, pH 7.0 PIPES buffer containing 350 mM NaCI, 1 mM MgCI 2 , 3.3 ⁇ M ADP, and 1 mM DTT.
  • the resulting solutions are mixed by repeated pipetting and clarified by centrifugation at 10,000 g for 10 minutes.
  • To 1.1 ⁇ L aliquots of the resulting supernatants is added 1.1 ⁇ L 10 ⁇ M KSP in binding buffer.
  • Each 2.2 ⁇ L experimental sample thus contains 11 pmol (0.4 ⁇ g) protein at 5.0 ⁇ M concentration in binding buffer plus 0.5 ⁇ M test ligands, 2.5 % DMSO, and varying concentrations (125, 62.5 0.98 ⁇ M) of the titrant.
  • Duplicate samples thus prepared for each concentration point are incubated at RT 60 minutes then chilled to 4 0 C prior to AS-MS analysis of 2.0 ⁇ l_ injections.
  • the titration data is then fit to a variable slope sigmoidal dose-response curve using GraphPad Prism (version 3.02 for Windows, GraphPad Software, San Diego, CA 1 www.graphpad.com) with a maximum normalized value of 1.0.
  • KSP assays endpoint and kinetics

Abstract

The present invention provides compounds of Formula (I); wherein R, R1, R2, R3, and R4 are as defined herein. The present invention also provides compositions comprising these compounds that are useful for treating cellular proliferative diseases or disorders associated with KSP kinesin activity and for inhibiting KSP kinesin activity.

Description

COMPOUNDS FOR INHIBITING KSP KINESIN ACTIVITY
FIELD OF THE INVENTION
The present invention relates to compounds and compositions that are useful for treating cellular proliferative diseases or disorders associated with Kinesin Spindle Protein ("KSP") kinesin activity and for inhibiting KSP kinesin activity.
BACKGROUND OF THE INVENTION Cancer is a leading cause of death in the United States and throughout the world. Cancer cells are often characterized by constitutive proliferative signals, defects in cell cycle checkpoints, as well as defects in apoptotic pathways. There is a great need for the development of new chemotherapeutic drugs that can block cell proliferation and enhance apoptosis of tumor cells. Conventional therapeutic agents used to treat cancer include taxanes and vinca alkaloids, which target microtubules. Microtubules are an integral structural element of the mitotic spindle, which is responsible for the distribution of the duplicated sister chromatids to each of the daughter cells that result from cell division. Disruption of microtubules or interference with microtubule dynamics can inhibit cell division and induce apoptosis.
However, microtubules are also important structural elements in nonproliferative cells. For example, they are required for organelle and vesicle transport within the cell or along axons. Since microtubule-targeted drugs do not discriminate between these different structures, they can have undesirable side effects that limit usefulness and dosage. There is a need for chemotherapeutic agents with improved specificity to avoid side effects and improve efficacy.
Microtubules rely on two classes of motor proteins, the kinesins and dyneins, for their function. Kinesins are motor proteins that generate motion along microtubules. They are characterized by a conserved motor domain, which is approximately 320 amino acids in length. The motor domain binds and hydrolyses ATP as an energy source to drive directional movement of cellular cargo along microtubules and also contains the microtubule binding interface (Mandelkow and Mandelkow, Trends Cell Biol. 2002, 12:585-591 ).
Kinesins exhibit a high degree of functional diversity, and several kinesins are specifically required during mitosis and cell division. Different mitotic kinesins are involved in all aspects of mitosis, including the formation of a bipolar spindle, spindle dynamics, and chromosome movement. Thus, interference with the function of mitotic kinesins can disrupt normal mitosis and block cell division. Specifically, the mitotic kinesin KSP (also termed EG5), which is required for centrosome separation, was shown to have an essential function during mitosis. Cells in which KSP function is inhibited arrest in mitosis with unseparated centrosomes (Blangy et al., Cell 1995, 83:1159-1169; Heald, R., Ce// 2000, 102, 399). This leads to the formation of a monoastral array of microtubules, at the end of which the duplicated chromatids are attached in a rosette-like configuration ((a) Mayer, T.U.; Kapoor, T.M.; Haggarty, S.J.; King, R.W.; Schreiber, S. L.; Mithison, TJ. Science, 1999, 286, 971. (b) Kapoor, T.M.; Mayer, T.U.; Coughlin, M. L.; Mitchison, TJ. J. Cell Biol. 2000, 150, 1975. (c) Sakowicz, R.; Finer, J.T.; Beraud, C; Crompton, A.; Lewis, E.; Fritsch, A.; Lee, Y.; Mak, J.; Moody, R.; Turincio, R.; Chabala, J.C.; Gonzales, Pm; Roth, S.; Weitman, S.; Wood, K.W. Cancer Res. 2004, 64, 3276).
Further, this mitotic arrest leads to growth inhibition of tumor cells (Kaiser et al., J. Biol. Chem. 1999, 274:18925-18931 ). As a result, KSP has become a significant target for development of cancer therapeutica drugs ((a) Wood, K.W.; Bergnes, G. Ann. Rep. Med. Chem. 2004, 39, 173. (b) Cox, CD.; Breslin, MJ.; Mariano, BJ.; Coleman, PJ.; Buser, C.A.; Walsh, E.S.; Hamilton, K.; Huber, H.E.; Kohl, N.E.; Torrent, M.; Yan, Y.; Kuo, L.C.; Hartman, G. D. Bioorg. Med. Chem. Lett. 2005, 15, 2041) with the potential to overcome the mechanism-based side effects of the microtubule-targeting taxanes and vinca alkaloids (Yan. Y.; Sardana, V.; Xu, B.; Homnick, C. ; Halczenko, W. ; Buser, C.A.; Schaber, M.; Hartman, G. D.; Huber, H. E.; Kuo, L.C. J. MoI. Biol. 2004, 335, 547). Inhibitors of KSP would be desirable for the treatment of proliferative diseases, such as cancer.
Kinesin inhibitors are known, and several molecules have recently been described in the literature. For example, adociasulfate-2 inhibits the microtubule-stimulated ATPase activity of several kinesins, including CENP- E (Sakowicz et al., Science 1998, 280:292-295). Rose Bengal lactone, another non-selective inhibitor, interferes with kinesin function by blocking the microtubule binding site (Hopkins et al., Biochemistry 2000, 39:2805- 2814). Monastrol, a compound that has been isolated using a phenotypic screen, is a selective inhibitor of the KSP motor domain (Mayer et al.,
Science 1999, 286:971-974). Treatment of cells with monastrol arrests cells in mitosis with monopolar spindles.
KSP, as well as other mitotic kinesins, are attractive targets for the discovery of novel chemotherapeutics with anti-proliferative activity. There is a need for compounds useful in the inhibition of KSP, and in the treatment of proliferative diseases, such as cancer.
SUMMARY OF THE INVENTION
In one embodiment, the present invention provides a compound represented by the structural Formula I:
Figure imgf000004_0001
Formula I or a pharmaceutically acceptable salt, solvate or ester thereof, wherein:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -S(=O)2NH2, - S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, - S(=O)2heterocyclyl, -S(=O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NHC(=O)alkyl, - C(=O)NH2) -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, - C(=O)OH, -C(=O)Oalkyl, -C(=O)heterocyclyl, -C(=O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the "heterocyclyl" and "aryl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six- membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl", and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, -C(O)OH, - C(=O)Oalkyl, and -C(O)NH2, ;
R1 is selected from the group consisting of alkyl, heterocyclyl, - C(=O)aryl, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)(cycloalkyl), - NH(heterocyclyl), -N(alkyl)(heterocyclyl), N(alkyl)2, -NH(aryl), -N(alkyl)(aryl), - N(aryl)2, -NH(heteroaryl), -N(alkyl)(heteroaryl), -NHC(=O)-alkyl, - N(alkyl)C(=O)-alkyl, -NHC(=O)Oalkyl, -N(alkyl)C(=O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the "alkyl", "cycloalkyl", "aryl", and "heteroaryl" portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S- alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -S(=O)2heterocyclyl, - S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), - N(alkyl)2, alkoxy, -NHC(=O)alkyl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, , - C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, -C(=O)N(alkyl)2 ; wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent;
R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2) -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2) -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl; with the proviso that:
(1 ) when R is -C(=O)Oalkyl, R1 is NH(aryl) wherein said aryl is optionally substituted, R2 and R3 are both H, and R4 is phenyl, then said R4 phenyl is substituted with at least one haloalkyl group;
(2) when R is -C(=O)Oalkyl, R1 is NH(aryl) or NH(alkyl), wherein the "alkyl" and "aryl" portions of said R1 are independently optionally substituted, R2 and R3 are both H, and R4 is optionally substituted heteroaryl, then said R4 heteroaryl is other than thiophenyl and furanyl; (3) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, and R1 is NH(aryl) wherein said aryl is unsubstituted or substituted with at least one substituent selected from the group consisting of halo, nitro, and alkyl, then R4 is other than unsubstituted cycloalkyl; (4) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is -NH2, and -CR2R3 is absent, then R4 is other than optionally substituted cycloalkyl; (5) when R is -C(=O)NH2, then R1 is -NH(alkyl) or -N(alkyl)(aryl), wherein each of said alkyl and aryl are independently optionally substituted;
(6) when R is -COOH or -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R1 is -NH(alkyl), or -N(alkyl)2 wherein the "alkyl" portion of each of said R1 is optionally substituted, and -CR2R3 is absent, then R4 is other than unsubstituted cycloalkyl;
(7) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is -NH2, NH(alkyl), or NH(aryl), wherein the "alkyl" and "aryl" portion each of said R1 is optionally independently substituted, then R4 is other than unsubstituted alkyl or alkyl substituted with at least one moiety selected from the group consisting of alkoxy, -N(alkyl)2) heterocyclyl, and heteroaryl;
(8) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted , R1 is -NH2, and -C(R2)(R3)- is absent, then R4 is other than optionally substituted cycloalkyl, cycloalkenyl, heterocyclenyl, or heteroaryl;
(9) when R is -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R1 is -NH(heterocyclyl) wherein said heterocyclyl is optionally substituted, R2 and R3 are both H, then R4 is other than optionally substituted heteroaryl; (10) when R is -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R2 and R3 are both H, and R4 is optionally substituted aryl or heteroaryl, then R1 is other than -NH2 or -NH(alkyl) wherein said alkyl is optionally substituted;
(11 ) when R is -C(=O)OH, -C(R2)(R3)- is absent, and R4 is optionally substituted cycloalkyl, then R1 is other than -NHC(=O)alkyl, -NH(aryl), or-
N(alkyl)(aryl) wherein the "alkyl" and "aryl" poritions of said R1 are optionally independently substituted;
(12) when R is -C(=O)OH, R1 is -NH2, and R2 and R3 are both H, then R4 is other than optionally substituted aryl; (13) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is optionally substituted heterocyclyl or heteroaryl, R2 and R3 are both H, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group;
(14) when R is -C(=O)OH, R1 is optionally substituted heterocyclyl, R2 and R3 are both H, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group; or
(15) when R is H or halo, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group,
(16) when R is H, R2 and R3 are both H, R1 is -NH(aryl), and R4 is aryl substituted with at least one haloalkyl group, then said "aryl" of R1 is substituted with group(s) other than halo or haloalkyl;
(17) when R is -C(=O)NH(aryl) or -C(=O)N(alkyl)(aryl), then R1 is other than optionally substituted heterocyclyl; or
(18) when R is H, R1 is other than -NH2 or -NH(heterocyclyl). Pharmaceutical formulations or compositions for the treatment of cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject comprising administering a therapeutically effective amount of at least one of the inventive compounds and a pharmaceutically acceptable carrier to the subject also are provided. Methods of treating cellular proliferative diseases, disorders associated with KSP kinesin activity and/or for inhibiting KSP kinesin activity in a subject comprising administering to a subject in need of such treatment an effective amount of at least one of the inventive compounds also are provided. Other than in the operating examples, or where otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, and so forth used in the specification and claims are to be understood as being modified in all instances by the term "about."
DESCRIPTION OF THE DRAWINGS Figure 1 depicts the activity profile of compound #33 in Table I.
A2780 cells were incubated for 48 hours with different concentrations of compound #33 as indicated on the x-axis. Cell proliferation was measured using the AlamarBlue dye method.
Figure 2 depicts the activity profile of reference compound 1 , alone, and incombination with fixed concentrations of compound #33. A2780 cells were incubated for 48 hours with different concentrations of Reference compound 1 alone or in combination with two fixed concentrations of compound #33 of Table 1 , as indicated in the legend. Concentrations on the x-axis indicate the concentration of Reference compound 1 used. Cell proliferation was measured using the AlamarBlue dye method. Figure 3 is a normalized response curve that shows that increasing concentrations of the titrant Reference Compound 1 cause an increase in the AS-MS response of ligands Compound #s 1 and 2.
DETAILED DESCRIPTION In one embodiment, the present invention discloses compounds represented by structural Formula I or a pharmaceutically acceptable salt or ester thereof, wherein the various moieties are as described above.
In other embodiments, the present invention provides processes for producing such compounds, pharmaceutical formulations or compositions comprising one or more of such compounds, and methods of treating or preventing one or more conditions or diseases associated with KSP kinesin activity such as those discussed in detail below.
In another embodiment, in the compound of formula I, R is selected from the group consisting of -C(=O)NH2, -C(=O)OH, and -C(=O)Oalkyl. In another embodiment, in the compound of formula I, R is selected from the group consisting of -C(=O)NH2, -C(=O)OH, and -C(=O)Oalkyl, wherein said -C(=O)Oalkyl is -C(=O)OCH3.
In another embodiment, in the compound of formula I, R is selected from the group consisting of -NHC(=O)alkyl, C(=O)NH(alkyl), - C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, -C(=O)heterocyclyl, and -
C(=O)NH(aryl), wherein when each of the "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, alkoxy, - C(O)OH, and -C(O)NH2. In another embodiment, in the compound of formula I, R is selected from the group consisting of -NHC(=O)CH3, -C(=O)NHCH2CN, - C(=O)N(CH3)2, -C(=O)NHCH3) -C(=O)NH(CH2)3CH3, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2N(CH3)2, -C(=O)NHCH(CH2OH)(CH(CH3)2), -C(=O)NH, -C(=O)N(CH3)CH2CH2OH, - C(=O)NH-cyclopentyl, C(=O)N(CH3)CH2CH3, -C(=O)NHCH2C(CH3)2CH2OH,
Figure imgf000010_0001
In another embodiment, in the compound of formula I, R is selected from the group consisting of -S(=O)2NH2, and -S(=O)2alkyl. In another embodiment, in the compound of formula I, R is selected from the group consisting of -S(=O)2NH2, -S(=O)2CH3, and - S(=O)2(CH2)2CH3.
In another embodiment, in the compound of formula I, R is selected from the group consisting of H, alkyl, cyano, halo, and haloalkyl. wherein said alkyl is optionally substituted with one or two substituents selected from the group consisting of hydroxy, halo, alkoxy and haloalkoxy. In another embodiment, in the compound of formula I, R is selected from the group consisting of -H, -CH2OH, -CN, -CF3, -F, and -Br.
In another embodiment, in the compound of formula I, R is selected from the group consisting of aryl and heteroaryl, wherein when each of said aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring; wherein each of the aforementioned R aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, C(O)OH, -C(=O)Oalkyl, and -C(=O)NH2.
In another embodiment, in the compound of formula I, R is selected from the group consisting of oxazolyl, phenyl, thiophenyl, benzofuranyl, pyrimidinyl, pyrazinyl, and pyrazolyl, each of which is optionally substituted. In another embodiment, in the compound of formula I, R is selected from the group consisting of phenyl,
Figure imgf000011_0001
Figure imgf000011_0002
Figure imgf000011_0003
In another embodiment, in the compound of formula I, R is selected from the group consisting of H, -CH2OH, -CN, -CF3, -F, -Br, -S(=O)2NH2, - S(=O)2CH3, -S(=O)2(CH2)2CH3 -C(=O)OCH3, -C(=O)OH, -C(=O)NH2, -C(=O)N(CH3)2, -NHC(=O)CH3, -C(=O)NHCH2CN, -C(=O)NHCH2COOH, -C(=O)NHCH3, - C(=O)NH(CH2)3CH3, -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2N(CH3)2, -C(=O)NHCH(CH2OH)(CH(CH3)2), -C(=O)NH, -C(=O)N(CH3)CH2CH2OH, - C(=O)NH-cyclopentyl, C(=O)NH-CH2-cyclopropyl, C(=O)N(CH3)CH2CH3, - C(=O)NHCH2C(CH3)2CH2OH, phenyl,
Figure imgf000012_0001
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -NH(alkyl), -N(alkyl)2, -NH(aryl), -N(alkyl)(aryl), - NH(aryl)2> -NH(heteroaryl), -NHC(=O)-alkyl, -N(alkyl)C(=O)-alkyl, - NHC(=O)Oalkyl, -N(alkyl)C(=O)O-alkyl, wherein when each of said "aryl" and "heteroaryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforesaid "alkyl", "aryl", and "heteroaryl" portions of said R1 groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -S(=O)2NH2, -S(=O)2NH(alkyl),
S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -S(=O)2heterocyclyl, S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), - N(alkyl)2) alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, , - C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, -C(=O)N(alkyl)2. In another embodiment, in the compound of formula I, R1 is selected from the group consisting of NH(aryl), N(alkyl)(aryl), and wherein said alkyl is CH3, and wherein each of said aryl, optionally with said five- to six- membered heterocyclyl, aryl, or heteroaryl is independently selected from
the group consisting of phenyl,
Figure imgf000013_0001
and
Figure imgf000014_0001
each of which is optionally substituted with 1-3 substituents selected from the group consisting of -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2OH, - S(=O)2heterocyclyl,
-S-alkyl, -S-haloalkyl, -S=(O)2N(alkyl)2, -S=(O)2NH(alkyl), S=(O)2NH(haloalkyl), -S=(O)2NH(cycloalkyl), alkoxy, aryloxy, halo, cyano, - C(=O)alkyl, alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)O-alkyl, haloalkyl, haloalkoxy, -Oalkylaryl, aryl, heteroaryl, -C(=O)NH2, and -C(=O)NH-alkyl. In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -NH(alkyl), -N(alkyl)2, -NH(aryl), -N(alkyl)(aryl), - NH(aryl)2, -NH(heteroaryl), -NHC(=O)-alkyl, -N(alkyl)C(=O)-alkyl, - NHC(=O)Oalkyl, -N(alkyl)C(=O)O-alkyl, wherein when each of said "aryl" and "heteroaryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforesaid "alkyl", "aryl", and "heteroaryl" portions of said R1 groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of -S(=O)2NH2, - S(=O)2CH3, -S(=O)2OH,
Figure imgf000015_0001
, -S-CH3, -S-
CF3, -S(=O)2N(CH3)2, -S=(O)2NH(CH3), -S=(O)2NH(CH2)3CI, S=(O)2NH(cyclopropyl), -OCH3, -O(CH2)3CH3, phenoxy, -OCH2-phenyl -F, - CN, -C(=O)CH3, -CH3, -CH(CH3)2, -(CH2)3CH3) -N(CHa)2, C(=O)OH, - C(=O)O-CH3, -CF3, -OCF3, -OCH2-phenyl, phenyl, triazolyl, oxazolyl, pyrazolyl, imidazolyl, and -C(=O)NHCH3.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -NH(heterocyclyl) and -NH(heteroaryl), wherein each of said heterocyclyl and heteroaryl, optionally with said five- to six- membered aryl, or heteroaryl is selected from the group consisting of piperidinyl, pyrazolyl, benzimidazolyl, and benzothiazolyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of alkyl, aryl, halo, haloalkyl, haloaryl, alkoxy, haloalkoxy, and - C(=O)Oalkyl.
In another embodiment, in the compound of formula I, R1 is selected
from the group consisting of
Figure imgf000015_0002
Figure imgf000015_0003
each of which is optionally substituted.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, - NHC(=O)-alkyl, -N(alkyl)C(=O)-alkyl, -NHC(=O)Oalkyl, -N(alkyl)C(=O)O- alkyl, wherein each of the aforesaid "alkyl" and "cycloalkyl" portion of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, -N(alkyl)2, alkynyl, aryl, aryloxy, heterocyclyl, heteroaryl, and -NHC(=O)alkyl, wherein each of said aryl, aryloxy, heterocyclyl and heteroaryl substituents is optionally substituted with 1-3 substituents selected from the group consisting of halo, alkyl, hydroxyl, alkoxy, -S(=O)2alkyl, and -S(=O)2NH2.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -NHCH2-(4-methylphenyl), -NHCH2-(4- methoxyphenyl), -NHCH2-phenyl-S(=O)2CH3, -NH(CH2)2-thiophenyl, - NHC(CH3)2-thiophenyl, -NH(CH2)2-pyrrolidinyl, -NH(CH2)2N(CH3)2, - NH(CH2)3N(CH3)2, -NH(CH2)2-piperizinyl, -NH(CH3)CH2N(CH3)2, -NH(CH2)2- piperidinyl-OH, -NH(CH2)2-morpholinyl, -NH(CH2)2-(2-chlorophenyl), - NH(CH2)2-phenyl-S(=O)2NH2, -NH(CH2)2-phenyl-(dimethylisoxazole), - NHCH2CH(OH)-(2-pyridyl), -NH(CH2)2-(dimethoxyphenyl), -NH(CH2)2-O- phenyl, -N(CH3)CH2CH2-(dimethoxyphenyl), -NH(CH2)2-NHC(=O)CH3, - N(CH3)CH2CH2-O-(4-chlrophenyl), -NH(CH2)2-O-(4-methoxyphenyl), NHC(=O)CH2-phenyl, -NHC(=O)OCH3, -NH-(4-hydroxycyclohexyl), and - NHC(=O)OCH2C≡CH.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of alkyl, cycloalkyl and heterocyclyl, wherein when each of said cycloalkyl and heterocyclyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl; wherein each of said R1 alkyl, cycloalkyl and heterocyclyl, optionally with said five- to six-membered aryl or heteroaryl, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, cyano, heterocyclyl, aryl, heteroaryl -NH2, -NH(alkyl), - N(alkyl)2, hydroxyl, -NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, -C(=O)H, - C(=O)alkyl, -C(=O)aryl, -C(=O)heteroaryl, -C(=O)NH2, wherein when each of said heterocyclyl, aryl and heteroaryl substituents has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six- membered aryl or heteroaryl ring.
In another embodiment, in the compound of formula I, R1 is alkyl optionally substituted with 1-2 aryl substitutents wherein said aryl is optionally substituted with 1-3 substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, cyano, -S(alkyl), alkoxy, - NHC(=O)alkyl, and -S(=O)2alkyl.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of -CH2-(4-trifluoromethylphenyl), -CH2-(4- isopropylphenyl), -CH2-(4-thiomethylphenyl), -CH2-(4-methoxyphenyl), -CH2- phenyl-S(=O)CH3, and -CH2-phenyl-NHC(=O)CH3.
In another embodiment, in the compound of formula I, R1 is heterocyclyl which is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, -NH2, hydroxyl, - N(alkyl)2, alkyl, aryl, heteroaryl, -NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, heterocyclyl, -C(=O)H, -C(=O)heteroaryl, C(=O)NH2, when each of the aforesaid aryl and heteroaryl substituents has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring.
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of:
Figure imgf000017_0001
Figure imgf000018_0001
In another embodiment, in the compound of formula I, R1 is selected from the group consisting of: -NH2, -NH-(4-sulfonamidophenyl), -NH-(4- methoxyphenyl), -NH-(4-fluorophenyl), -NH-(4-cyanophenyl), -NH-(4- acetylphenyl), -NH-(4-methylphenyl), -NH-(4-isopropylphenyl), -NH-(4- butylphenyl) -NH-(4-isopropyloxy-phenyl), -NH-(4-butyloxy-phenyl) -NH(4- dimethylaminophenyl), -NH-(4-carboxyphenyl) -NH-(4-carbomethoxyphenyl), -NH-(4-trifluoromethylphenyl), -NH-(4-trifluoromethoxyphenyl), -NH-(4- phenoxyphenyl), -NH-(4-benzyloxyphenyl), -NH-(4-methylsulfanyl-phenyl), - (4-trifluoromethyl-sulfanyl-phenyl) -NH-(3-fluoro-4-methoxyphenyl), NH-(2- fluoro-4-methoxyphenyl), -NH-(3-chloro-4-methoxyphenyl), phenyl,
Figure imgf000019_0001
Figure imgf000020_0001
Figure imgf000020_0002
Figure imgf000020_0003
Figure imgf000020_0004
-NHCH2-(4-methylphenyl), -NHCH2-(4-methoxyphenyl), -NHCH2-(4- methylsulfonylphenyl), -NH(CH2)2-(2-thiophenyl), -NHCH2C(CH3)2-(2-
thiophenyl),
Figure imgf000020_0005
-NH(CH2)2N(CH3)2, -NH(CH2)3N(CH3)2,
Figure imgf000020_0006
-N(CH3)(CH2)2N(CH3)2,
-NHCH(CH3)CH2N(CH3)2,
Figure imgf000020_0007
-NH(CH2)2-(2-chlorophenyl), -NH(CH2)2-(4-sulfonamido-phenyl),
Figure imgf000020_0008
-C(=O)-(4-methoxyphenyl), -NHCH2CH(OH)-(2-pyriclyl), -NH(CH2)2-(3,4-dimethoxyphenyl), -NH(CH2)2-(2,3-dimethoxyphenyl), NH(CH2)2-O-phenyl, -N(CH3)CH2CH2-(dimethoxyphenyl), -NH(CH2)2- NHC(=O)CH3> -N(CH3)CH2CH2-O-(4-chlrophenyl), -NH(CH2)2-O-(4- methoxyphenyl), -NHC(=O)OCH2-phenyl, -NHC(=O)OCH3, -NH-(4- hydroxycyclohexyl), and -NHC(=O)OCH2C≡CH, -CH(CH3)-(4- methoxyphenyl), -CH2-(4-trifluoromethylphenyl), -CH2-(4-isopropylphenyl), - CH2-(4-methylthiophenyl), -CH2-(4-methoxyphenyl), -CH2-(4- methylsulfonylphenyl), and -CH2-(4-acetamidophenyl),
Figure imgf000021_0001
N C(=O)OC(CH3)3
Figure imgf000021_0002
Figure imgf000021_0003
Figure imgf000021_0004
Figure imgf000022_0001
In another embodiment, in formula I, R2 and R3 are both H.
In another embodiment, in formula I, R2 is H, and R3 is alkyl.
In another embodiment, in formula I, -C(R2)(R3)- is absent.
In another embodiment, in formula I, R4 is selected from the group consisting of aryl and heteroaryl, wherein when said aryl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring, wherein said R4 aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring is optionally substituted with 1-3 substituents selected from the group consisting of halo, alkoxy, haloalkoxy, haloalkyl, alkyl, aryl, heterocyclyl, heteroaryl, -NH2, -NH(alkyl), -N(alkyl)2, -S(=O)2alkyl, -S(=O)2NH2> -S-alkyl, - S-haloalkyl, -C(=O)OH, and -C(=O)Oalkyl.
In another embodiment, in formula I, R4 aryl and heteroaryl, optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, naphthyl, benzothiophenyl, benzothiazolyl, pyridyl, thiophenyl, benzimidazolyl, isoxazolyl,
Figure imgf000022_0002
each of which is optionally substituted.
In another embodiment, in formula I, R4 aryl and heteroaryl, optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, α-naphthyl, 2-naphthyl, 2-pyridyl, 3-pyridyl, 2- thiophenyl,
Figure imgf000023_0001
■"cr , each of which is optionally substituted.
In another embodiment, in formula I, R4 is cycloalkyl, wherein when said cycloalkyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl or heteroaryl ring, wherein said cycloalkyl optionally with said five to six-membered aryl or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, and aryl.
In another embodiment, in formula I, said R4 cycloalkyl, optionally with said five to six-membered aryl or heteroaryl ring, is selected from the group consisting of cyclopropyl,
Figure imgf000023_0003
and
Figure imgf000023_0002
, each of which is optionally substituted.
In another embodiment, in formula I, R4 is alkyl.
In another embodiment, in formula I, R4 is alkyl, wherein said R4 alkyl is optionally substituted with 1-2 substituents selected from the group consisting of hydroxyl, halo, alkoxy, haloalkyl, and haloalkoxy. In another embodiment, in formula I, R4 is -(CHb)-I^OH. In another embodiment, in formula I, R4 is selected from the group consisting of:
Figure imgf000024_0001
Figure imgf000025_0001
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, - S(O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, - S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), -N(alkyl)2, alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, and -C(=O)N(alkyl)2;
R2 and R3 are independently H and alkyl;
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said aryl optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2; R1 is -NH(aryl) or -N(alkyl)(aryl), wherein the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, - S(O)2NH2, -S(O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(O)2N(alkyl)2, - S(O)2heterocyclyl, -S(0)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), -N(alkyl)2, alkoxy, -NC(O)alkyl, -C(O)H, -C(O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2) -C(O)NHalkyl, and -C(=O)N(alkyl)2; wherein the "aryl" portion of each of said R1 groups optionally with said five- to six-membered heterocyclyl, aryl, or heteroaryl is independently selected from the group consisting of phenyl,
Figure imgf000027_0001
with 1-3 substitutents selected from the group consisting of -S(=O)2NH2, alkoxy, halo, cyano, -C(=O)alkyl, alkyl, -C(=O)O-alkyl, -N(alkyl)2, haloalkyl, haloalkoxy, aryloxy, -S(=O)2alkyl, -S-alkyl, -S(=O)2OH, -S(=O)2heterocyclyl, -S=(O)2N(alkyl)2> -S=(O)2NH(cycloalkyl), -S=(O)2NH(alkyl), -S-haloalkyl, heteroaryl, -C(=O)NH-alkyl, -C(=O)OH, and -C(=O)NH2; R2 and R3 are independently H and alkyl;
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said aryl optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, - S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, - S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), -N(alkyl)2, alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, and -C(=O)N(alkyl)2;
R2 and R3 are independently H and alkyl;
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said aryl optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl; wherein said R4 aryl, optionally with said five- to six-membered heterocyclyl, aryl, or heteroaryl is independently selected from the group consisting of phenyl, 1- naphthyl, 2-naphthyl,
Figure imgf000029_0001
each of which is optionally substituted with 1-3 substituents selected from the group consisting of alkoxy, haloalkyl, alkyl, aryl, halo, heterocyclyl, haloalkoxy, -S(=O)2alkyl, -S(=O)2NH2, -S-alkyl, -C(=O)OH, heteroaryl, heterocyclyl, and -S-haloalkyl.
In another embodiment, the compound of formula I is selected from the group consisting of compound #s 1-106 in Table I, or or a pharmaceutically acceptable salt, solvate, or ester thereof. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -
S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -
S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2,
-NH(alkyl), -N(alkyl)2, alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, and
-C(=O)N(alkyl)2;
R2 and R3 are independently H and alkyl; or -CR2R3 is absent R4 is selected from the group consisting of cycloalkyl and heteroaryl, wherein said cycloalkyl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said cycloalkyl or heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -
S(=O)2N(alkyl)2) -S-alkyl, -S-haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), - N(alkyl)2) and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein the "aryl" portion of each of said R1 groups is phenyl which phenyl is optionally substituted with 1-3 substituents selected from the group consisting of -S-alkyl, -S(=O)2alkyl, - S(=O)2NH2, alkyl, and alkoxy;
R2 and R3 are independently H and alkyl; or -CR2R3 is absent
R4 is selected from the group consisting of cycloalkyl and heteroaryl, wherein said cycloalkyl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said cycloalkyl or heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)2alkyl, -S(=O)2NH2> -S(=O)2NH(alkyl), -
S(=O)2N(alkyl)2, -S-alkyl, -S-haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), - N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I: R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -
S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -
S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2,
-NH(alkyl), -N(alkyl)2, alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, and
-C(=O)N(alkyl)2;
R2 and R3 are independently H and alkyl; Or-CR2R3 is absent
R4 is selected from the group consisting of cycloalkyl and heteroaryl, wherein said cycloalkyl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said cycloalkyl or heteroaryl, optionally with said five- to six-membered aryl or heteroaryl is selected from the group consisting of: cyclopropyl, 2-thiophenyl, 2-pyridyl,
Figure imgf000031_0001
with 1-3 substituents selected from the group consisting of: hydroxy, halo, aryl, alkyl, -NH2, and haloalkyl.
In another embodiment, the compound of formula I is selected from the group consisting of comound #s 107-153, or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting of -NH2, -NH(alkyl), - NH(cycloalkyl), -NH(heterocyclyl), -NH(heteroaryl) -N(alkyl)2, heterocyclyl, heteroaryl, -NHC(=O)Oalkyl, and -NHC(=O)alkyl, wherein when each of said heterocyclyl, heteroaryl, and the "heterocyclyl" and "cycloalkyl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2; R1 is selected from the group consisting of -NH(alkyl) and -N(alkyl)2, wherein each alkyl independently is optionally substituted with 1-3 substituents selected from the group consisting of aryl, heteroaryl, heterocyclyl, hydroxy, aryloxy, -N(alkyl)2, wherein each of said aryl, heteroaryl, and heterocyclyl substituents is optionally substituted with 1-3 moieties selected from the group consisting of hydroxy, halo, alkyl, alkoxy, - S(=O)2alkyl, and -S(=O)2NH2; R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(O)NH2;
R1 is selected from the group consisting of of -NH(cycloalkyl), - NH(heterocyclyl), -NH(heteroaryl) wherein when each of the "cycloalkyl"
"heterocyclyl", and "heteroaryl" portions of said R1 groups is has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, or heteroaryl ring; wherein said "cycloalkyl", "heterocyclyl", and "heteroaryl" portions of said R1 groups, optionally with said five- to six-membered aryl, heterocyclyl, or heteroaryl ring is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, -C(=O)Oalkyl, alkyl, aryl, heteroaryl, alkoxy, halo, and haloalkoxy; R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=0)NH2;
R1 is selected from the group consisting of: -NH-piperidinyl, -NH- cyclohexyl, -NH-benzimidazolyl, -NH-bezothiazolyl, and -NH-pyrazolyl, each of which is optionally substituted;
R2 and R3 independently are H and alkyl; and R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting heterocyclyl and heteroaryl, wherein when each of said heterocyclyl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, or heteroaryl ring; wherein said R1 heterocyclyl and heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, or heteroaryl ring, is optionally substituted with 1-3 substituents selected from the group consisting of -NH2, hydroxy, cyano, alkyl, -
NH(alkyl), -N(alkyl)2, -NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, heterocyclyl, aryl, heteroaryl, and -C(=O)heteroaryl;
R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting of pyrrolidinyl, piperidinyl, and piperizinyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of -NH2, hydroxy, cyano, alkyl, -
NH(alkyl), -N(alkyl)2, -NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, heterocyclyl, aryl, heteroaryl, and -C(=O)heteroaryl;
R2 and R3 independently are H and alkyl; and R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring. In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting of -NH2, -NH(alkyl), -
NH(cycloalkyl), -NH(heterocyclyl), -NH(heteroaryl) -N(alkyl)2, heterocyclyl, heteroaryl, -NHC(=O)Oalkyl, and -NHC(=O)alkyl, wherein when each of said heterocyclyl, heteroaryl, and the "heterocyclyl" and "cycloalkyl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 are both H; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting of -NH2, -NH(alkyl), - NH(cycloalkyl), -NH(heterocyclyl), -NH(heteroaryl) -N(alkyl)2, heterocyclyl, heteroaryl, -NHC(=O)Oalkyl, and -NHC(=O)alkyl, wherein when each of said heterocyclyl, heteroaryl, and the "heterocyclyl" and "cycloalkyl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R2 and R3 independently are H and alkyl; and
R4 is aryl optionally substituted with at least one haloalkyl group.
In another embodiment, the compound of formula I is selected from the group consistinf of compound #s 154-216 in Table I, or a pharmaceutically acceptable salt, solvate or ester thereof.
In another embodiment, in formula I:
R is-C(=O)OH.
R1 is alkyl optionally substituted with at least one aryl substituent, wherein when said aryl substituent has two moieties on adjacent carbon atoms, said moieties, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I:
R is-C(=O)OH. R1 is alkyl substituted with an aryl substituent, wherein said aryl substituent is substituted with at least one group selected from the group consisting of: haloalkyl, alkyl, -S-alkyl, alkoxy, -S(=O)2alkyl, and -NH- C(=O)alkyl;
R2 and R3 independently are H and alkyl; and R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
In another embodiment, in formula I: R is-C(=O)OH. R1 is alkyl optionally substituted with at least one aryl substituent, wherein when said aryl substituent has two moieties on adjacent carbon atoms, said moieties, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independently are H and alkyl; and
R4 is aryl optionally substituted with at least one haloalkyl group.
In another embodiment, the compound of formula I is selected from the group consisting of compound #s 217-222 in Table I, or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl. In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is-NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said -NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is-NH(aryl), wherein when the "aryl" portion of said -NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein the "aryl" portion of said R1 optionally with said five to six-membered aryl or heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -S(=O)2NH2 and alkoxy; R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is -C(=O)Oalkyl; R1 is -NH(alkyl) wherein the "alkyl" portion of said R1 is optionally substituted with 1-2 substituents independently selected from the group consisting of -NHC(=O)alkyl and aryl;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I: R is -C(=O)Oalkyl;
R1 is heterocyclyl optionally substituted with 1-2 substituents selected from the group consisting of alkyl, -C(=O)H, -C(=O)alkyl, and -C(=O)NH2;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R2 and R3 are both H; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2) -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R2 and R3 are both alkyl; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
In another embodiment, in formula I:
R is -C(=O)Oalkyl; R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; -C(R2XR3)- is absent; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2) and -C(=O)Oalkyl. In another embodiment, in formula I: R is -C(=O)Oalkyl; R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is cycloalkyl, wherein when said cycloalkyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six- membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R4 cycloalkyl, optionally with said five to six-membered aryl, is selected from the group consisting of cyclopropyl and
Figure imgf000043_0001
each of which is optionally substituted. In another embodiment, in formula I: R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is alkyl, optionally substituted with a hydroxyl. In another embodiment, in formula I: R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is phenyl, optionally substituted with 1-2 substituents selected from the group consisting of: haloalkyl, -S(=O)2NH2, and halo, and -S(=O)2alkyl. In another embodiment, in formula I:
R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and R4 is heteroaryl, wherein when said heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R4 heteroaryl, optionally with said five to six-membered aryl is benzothiazolyl, optionally substituted with 1-2 substituents independently selected from the group consisting of halo, alkoxy, haloalkyl, haloalkoxy, haloalkyl, -S(=O)2NH2) and -S(=O)2alkyl.
In another embodiment, the compound of formula I is selected from the group consisting of compound #s 223-242 in Table I, or a pharmaceutically acceptable salt, solvate or ester thereof. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, - C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl;
R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
In another embodiment, in formula I:
R is selected from the group consisting of -C(=O)NH(alkyl), - C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, -C(=O)NH(aryl), -C(=O)heterocyclyl, when each of said "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl;
R2 and R3 are both H; and R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
In another embodiment, in formula I:
R is -NHC(=O)alkyl, wherein the "alkyl" portion of said R is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl;
R2 and R3 are both H; and R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
In another embodiment, in formula I: R is selected from the group consisting of -S(=O)2alkyl and -
S(=O)2NH2, wherein the "alkyl" portion of said R is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I: R is selected from the group consisting of aryl, and heteroaryl, when each of said aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R aryl, and heteroaryl, optionally with said five- to six- membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I: R is selected from the group consisting of halo, cyano, and haloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2> NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is -NH(aryl), wherein when the "aryl" portion of said R1 has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said "aryl" optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is -NH(phenyl), wherein the "phenyl" portion of said R1 is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I: R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is -NH(heteroaryl), wherein when the "heteroaryl" portion of said R1 has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said "heteroaryl" optionally with said five- to six- membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and - S(=O)2alkyl;
R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is pyridyl, optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, alkoxy, alkyl, - COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1 -3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2) C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2,
NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, and -C(=O)aryl, wherein when the "aryl" portion of said R1 has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 alkyl, and the "aryl" portion of said R1 group, optionally with said five- to six- membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, alkyl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, - S(=O)2NH2 and -S(=O)2alkyl;
R2 and R3 are both H; and
R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is selected from the group consisting of alkyl, -NH(aryl), -
NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is aryl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I: R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2> C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is phenyl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl. In another embodiment, in formula I:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2) C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and
R4 is heteroaryl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
In another embodiment, in formula I: R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl; R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and R4 is benzothiophenyl, optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
In another embodiment, the compound of formula I is selected from the group consisting of compound #s 243-324 in Table I, or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, the present invention provides a composition comprising a combination of a compound of formula I, or pharmaceutically acceptable salt, solvate, or ester thereof, as set forth hereinabove, and a compound of formula Il
Figure imgf000057_0001
Formula Il or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein in formula II:
Ri is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and Rz are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R2' taken together form a 3-to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, R150-and R15-NH-;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, Re. R7 and R$ are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R-I5 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and
R16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N- heterocyclyl and substituted N-heterocyclyl;
with the proviso that when R3 is Ri5-NH- attached to carbonyl, both of
R2 and R4 must be other than hydrogen.
Compounds of formula Il are disclosed in International Publication WO 01/30768.
In another embodiment, in formula II: R1 is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted alkylaryl;
R2 is chosen from hydrogen, alkyl and substituted alkyl; R2 is hydrogen; R3 is chosen from alkyl, aryl, alkylaryl, heteroaryl, substituted aryl, substituted alkyl, substituted heteroaryl, oxaalkylaryl, substituted oxaalkylaryl, R150-and R15-NH-; R4 is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted 30 aryl, and R16-alkylene-;
R5 is hydrogen;
R6, R7 and R8 are independently chosen from hydrogen, halogen, methyl and trifluoromethyl;
R15 is chosen from alkyl, aryl and substituted aryl; and
R16 is chosen from alkoxy, amino, alkylamino, dialkylamino and N- heterocyclyl.
In another embodiment, in formula II, Ri is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl.
In another embodiment, in formula II, Ri is chosen from hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and
(ethoxycarbonyl)ethyl.
In another embodiment, in formula II, R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl, and R^ is hydrogen. In another embodiment, in formula II, R2 is chosen from hydrogen, methyl, ethyl, propyl, methylthioethyl, aminobutyl, (CBZ) aminobutyl, 20 cyclohexyl methyl, benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl, hydroxymethyl, benzyl and indolylmethyl.
In another embodiment, in formula II, R3 is chosen from C1-C13 alkyl; substituted lower alkyl; phenyl; naphthyl; phenyl substituted with one or more halo, lower alkyl, loweralkoxy, nitro, carboxy, methylenedioxy, or trifluoromethyl; biphenylyl; benzyl; phenoxymethyl; halophenoxymethyl; phenylvinyl; heteroaryl; heteroaryl substituted with lower alkyl; and benzyloxymethyl. In another embodiment, in formula II, R3 is chosen from ethyl, propyl, chloropropyl, butoxy, heptyl, butyl, octyl, tridecanyl, (ethoxycarbonyl)ethyl, dimethylaminoethyl, dimethylaminomethyl, phenyl, naphthyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl) phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, chloronaphthyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, phenoxymethyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl, benzyloxymethyl, benzyl, furanyl, benzoftiranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.
In another embodiment, in formula II, R3 is R-i5-NH-and Ri5 is chosen from lower alkyl; cyclohexyl; phenyl; and phenyl substituted with halo, lower alkyl, loweralkoxy, or lower alkylthio.
In another embodiment, in formula II, R15 is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.
In another embodiment, in formula II, R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R16-alkylene-, wherein R16 is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
In another embodiment, in formula II, R4 is chosen from methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylarninopropyl, aminopropyl, methylaminopropyl,, 2,2dimethyl-3-(dimethylamino)propyl, 1-cyclohexyl-4-(diethylamino)butyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, aminoethoxyethyl, isopropylaminopropyl, diisopropylaminoethyl, 1 -methyl-4-(diethylamino)butyl, (t-Boc)aminopropyl, 5 hydroxyphenyl, benzyl, methoxyphenyl, methylmethoxyphenyl, dimethylphenyl, tolyl, ethylphenyl,
(oxopyrrolidinyl)propyl, (methoxycarbonyl)ethyl, benzylpiperidinyl, pyridinylethyl, pyridinyl methyl, morpholinylethyl. morpholinylpropyl, piperidinyl, azetidinylmethyl, azetidinylpropyl pyrrol id inylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl, (methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl and indolylethyl.
In another embodiment, in formula II:
Ri is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl; R2 is chosen from hydrogen, alkyl, substituted lower alkyl and benzyl;
Rz is hydrogen;
R3 is chosen from substituted phenyl and naphthyl;
R4 is chosen from substituted alkyl and R16-alkylene-;
R5 is hydrogen or halo; Re is hydrogen, methyl or halo;
R7 is hydrogen, halo, methyl or trifluoromethyl;
Rs is hydrogen or halo; and
R16 is chosen from di(lower alkylamino), (lower alkyl)amino, amino N- heterocyclyl and substituted N-heterocyclyl. In another embodiment, in formula II:
Ri is benzyl or halobenzyl;
R2 is chosen from ethyl and propyl;
Rz is hydrogen;
R3 is substituted phenyl; R4 is (CH2)mOH or (CH2)pRi6 wherein m is or 3 and p is 1-3;
R5 is hydrogen;
Re is hydrogen;
R7 is halo; Re is hydrogen; and
Ri6 is chosen from amino, propylamino, and azetidinyl. In another embodiment, wherein the compound of formula Il is selected from the group consisting of:
Figure imgf000062_0001
or a pharmaceutivally acceptable salt or solvate thereof.
In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula II, the compound of formula I is selected from the group consisting of :
Figure imgf000062_0002
Figure imgf000063_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula II, the compound of formula I is
Figure imgf000063_0002
(compound #1 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof. In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula II, the compound of formula I is
Figure imgf000064_0001
(compound #33 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof.
While not wishing to be bound by theory, from kinetic studies, the compounds of formula I of this invention are generally speaking un- competitive (non-competitive) inhibitors of KSP.
Temperature dependent circular dichroism studies have indicated that binding between KSP protein and the compounds of formula I occurs in the presence of Mg-ADP. These studies also indicate that the compounds of formula I are non-competititve with Mg-ADP and with the compounds of formula II. These studies also indicate that the likely simultaneous binding of KSP protein, the compounds of formula I, the compounds of formula II, and Mg-ADP.
Affinity selection mass spectrometry (AS-MS) studies are consistent with the conclusion that the compounds of formula Il enhance the binding of the compounds of formula I to the KSP protein. (For background on AS-MS, see "A General Technique to Rank Proten-Ligand Binding Affinities and Determine Allosteric versus Direct Binding Site Competitiion in Compound Mixtures" by Annis et al., J. Am. Chem. Soc. 2004, 126, 15495-15503) (See experimental section on "Affinity Selection-Mass Spectrometry methods to demonstrate positive-cooperative binding to KSP for Reference Compound 1 and a mixture of the test ligands Compound #s 1 and 2 (in Table I)) Available inhibition activity data are also consistent with the conclusion that that compounds of formula I enhance the potency of the compounds of formula Il on cells (see experimental section on " Inhibition Activity on combination of compound of formula I and M") The present invention also provides A composition comprising a combination of a compound of claim 1 , or pharmaceutically acceptable salt, solvate, or ester thereof, and a compound of formula III
Figure imgf000065_0001
Formula III or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein in Formula III:
Figure imgf000065_0002
is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring; a is 0 or I; b is 0 or I; m is 0,1 , or 2; n is 0 to 4;
R1 is selected from:
1) H, 2) Q-C10 alkyl,
3) aryl, 4) C2-C20 alkenyl,
5) C2-C10 alkynyl,
6) CrC6 perfluoroalkyl,
7) C3-C8 cycloalkyl, and 8) heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R2 and R3 are independently selected from: 1 ) H,
2)
Figure imgf000066_0001
alkyl,
3) (C=O)aObaryl,
4) (C=O)3ObC2-C10 alkenyl,
5) (C=O)3ObC2-C10 alkynyl, 6) CO2H,
7) C1-C6 perfluoroalkyl,
8) (C=O)3ObC3-C8 cycloalkyl,
9) (C=O)3Ob heterocyclyl, 1O) SO2NR7R8, and 11 ) SO2C|-C10 alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R4 is independently selected from: 1) (C=O)aObC|-C10 alkyl,
2) (C=O)aObaryl,
3) (C=O)3ObC2-C10 alkenyl,
4) (C=O)3ObC2-C10 alkynyl,
5) CO2H, 6) halo,
7) OH, 8) Ob CrC6 perfluoroalkyl,
9) (C=O)3NR7R8, 1O) CN,
11 ) (C=O)3ObC3-C8 cycloalkyl, 12) (C=O)aObheterocyclyl,
13) SO2NR7R8, and
14) SO2Ci-CiO alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R5 is:
1 ) (C=O)3ObC|-Cio alkyl,
2) (C=O)aObaryl,
3) C2-Ci0 alkenyl, 4) C2-Ci0 alkynyl,
5) (C=O)3Ob heterocyclyl
6) CO2H,
7) halo,
8) CN, 9) OH1
10) Ob CrC6 perfluoroalkyl, 11 ) Oa(C=O)bNR7Rs, 12) oxo,
13) CHO, 14) (N=O)R7R8, or
15) (C=O)3ObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6;
R6 is selected from: 1 ) (C=O)rOs(C|-Cio)alkyl, wherein r and s are independently 0 or
1 ,
2) Or(Ci-C3)perfluoroalkyl, wherein r is 0 or 1 ,
3) (C0-C6)alkylene-S(O)mRa, wherein m is 0, 1 , or 2, 4) oxo,
5) OH,
6) halo,
7) CN,
8) (C=O)rOs(C2-Cio)alkenyl, 9) (C=O)rOs(C2-C10)alkynyl,
10) (C=O)rOs(C3-C6)cycloalkyl,
11 ) (C=O)rOs(Co-C6)alkylene-aryl,
12) (C=O)rOs(Co-C6)alkylene-heterocyclyl,
13) (C=O)rOs(Co-C6)alkylene-N(Rb)2) 14) C(=O)Ra,
15) (C0-C6)alkylene-CO2Ra
16) C(O)H,
17) (C0-C6)alkylene-CO2H, and
18) C(O)N(Rb)2, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (CrC6)alkoxy, halogen, CO2H, CN, 0(C=O)C1-C6 alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from: 1) H,
2) (C=O)ObCrC10 alkyl,
3) (C=O)ObC3-C8 cycloalkyl,
4) (C=O)Obaryl,
5) (C=O)Obheterocyclyl, 6) C,-C10 alkyl,
7) aryl, 8) C2-Ci0 alkenyl,
9) C2-C10 alkynyl,
10) heterocyclyl,
11) C3-C8 cycloalkyl, 12) SO2R3, and
13) (C=O)NRb 2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted with one or more substituents selected from R6, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O, and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
Ra is (C|-C6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl; and
Rb is H. (Cι-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C=O)OC1-C6 alkyl, (C=O)C1-C6 alkyl or S(O)2R3.
The compounds of formula III are disclosed in International Publication WO03/039460 (assigned to Merck; published May 15, 2003). In another embodiment, the compounds of formula III are selected from the group consisting of:
Figure imgf000070_0001
Figure imgf000071_0001
Figure imgf000072_0002
or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula III, the compound of formula I is selected from the group consisting of:
Figure imgf000072_0001
Figure imgf000073_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula III, the compound of formula I is
Figure imgf000073_0002
(compound #1 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof. In another embodiment, in the composition comprising the combination of a compound of formula I and compound of formula III, the compound of formula I is
Figure imgf000074_0001
(compound #33 in Table I) or a pharmaceutically acceptable salt, solvate, or ester thereof.
As used above, and throughout the specification, the following terms, unless otherwise indicated, shall be understood to have the following meanings:
"Subject" includes both mammals and non-mammalian animals. "Mammal" includes humans and other mammalian animals. The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound" or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties. It should be noted that any atom with unsatisfied valences in the text, schemes, examples and tables herein is assumed to have the hydrogen atom(s) to satisfy the valences.
The following definitions apply regardless of whether a term is used by itself or in combination with other terms, unless otherwise indicated. Therefore, the definition of "alkyl" applies to "alkyl" as well as the "alkyl" portions of "hydroxyalkyl", "haloalkyl", "alkoxy", etc. "Alkyl" means an aliphatic hydrocarbon group which may be straight or branched and comprising about 1 to about 20 carbon atoms in the chain. Preferred alkyl groups contain about 1 to about 12 carbon atoms in the chain. More preferred alkyl groups contain about 1 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkyl chain. "Lower alkyl" means a group having about 1 to about 6 carbon atoms in the chain which may be straight or branched. "Alkyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, cyano, hydroxy, alkoxy, aryloxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), - N(alkyl)2, carboxy, -C(=O)O-alkyl, -NC(=O)alkyl, -C(=O)heterocyclyl. Non- limiting examples of suitable alkyl groups include methyl, ethyl, n-propyl, isopropyl and t-butyl. "Alkyl" includes "Alkylene" which refers to a difunctional group obtained by removal of a hydrogen atom from an alkyl group that is defined above. Non-limiting examples of alkylene include methylene (-CH2-) , ethylene (-CH2CH2-) and propylene (-C3H6-; which may be linear or branched).
"Alkenyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon double bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkenyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 6 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkenyl chain. "Lower alkenyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. "Alkenyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, cyano, hydroxy, alkoxy, aryloxy, alkylthio, amino, - NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, carboxy, -C(=O)O-alkyl, -NC(=O)alkyl, -C(=O)heterocyclyL Non-limiting examples of suitable alkenyl groups include ethenyl, propenyl, n-butenyl, 3-methylbut-2-enyl, n-pentenyl, octenyl and decenyl. "Alkenyl" includes "Alkenylene" which refers to a difunctional group obtained by removal of a hydrogen atom from an alkenyl group that is defined above. Non-limiting examples of alkenylene include vinylene (- CH=CH-) , and propenylene (-C3H4-; which may be linear or branched). "Alkynyl" means an aliphatic hydrocarbon group containing at least one carbon-carbon triple bond and which may be straight or branched and comprising about 2 to about 15 carbon atoms in the chain. Preferred alkynyl groups have about 2 to about 12 carbon atoms in the chain; and more preferably about 2 to about 4 carbon atoms in the chain. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl, are attached to a linear alkynyl chain. "Lower alkynyl" means about 2 to about 6 carbon atoms in the chain which may be straight or branched. Non-limiting examples of suitable alkynyl groups include ethynyl, propynyl, 2-butynyl and 3-methylbutynyl. "Alkynyl" may be unsubstituted or optionally substituted by one or more substituents which may be the same or different, each substituent being independently selected from the group consisting of halo, alkyl, alkenyl, alkynyl, aryl, cycloalkyl, heterocyclyl, heteroaryl, cyano, hydroxy, alkoxy, aryloxy, alkylthio, amino, -NH(alkyl), -NH(cycloalkyl), - N(alkyl)2, carboxy, -C(=O)O-alkyl, -NC(=O)alkyl, -C(=O)heterocyclyL "Aryl" means an aromatic monocyclic or multicyclic ring system comprising about 6 to about 14 carbon atoms, preferably about 6 to about 10 carbon atoms. The aryl group can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined herein. Non-limiting examples of suitable aryl groups include phenyl and naphthyl.
"Heteroaryl" means an aromatic monocyclic or multicyclic ring system comprising about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the ring atoms is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. Preferred heteroaryls contain about 5 to about 6 ring atoms. The "heteroaryl" can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The prefix aza, oxa or thia before the heteroaryl root name means that at least a nitrogen, oxygen or sulfur atom respectively, is present as a ring atom. A nitrogen atom of a heteroaryl can be optionally oxidized to the corresponding N-oxide. Non-limiting examples of suitable heteroaryls include pyridyl, pyrazinyl, furanyl, thienyl, pyrimidinyl, pyridone (including N-substituted pyridones), isoxazolyl, isothiazolyl, oxazolyl, thiazolyl, pyrazolyl, furazanyl, pyrrolyl, pyrazolyl, triazolyl, 1 ,2,4-thiadiazolyl, pyrazinyl, pyridazinyl, quinoxalinyl, phthalazinyl, oxindolyl, imidazo[1 ,2-a]pyridinyl, imidazo[2,1- b]thiazolyl, benzofurazanyl, indolyl, azaindolyl, benzimidazolyl, benzothienyl, quinolinyl, imidazolyl, thienopyridyl, quinazolinyl, thienopyrimidyl, pyrrolopyridyl, imidazopyridyl, isoquinolinyl, benzoazaindolyl, 1 ,2,4-triazinyl, benzothiazolyl and the like. The term "heteroaryl" also refers to partially saturated heteroaryl moieties such as, for example, tetrahydroisoquinolyl, tetrahydroquinolyl and the like.
"Aralkyl" or "arylalkyl" means an aryl-alkyl- group in which the aryl and alkyl are as previously described. Preferred aralkyls comprise a lower alkyl group. Non-limiting examples of suitable aralkyl groups include benzyl, 2- phenethyl and naphthalenylmethyl. The bond to the parent moiety is through the alkyl.
"Alkylaryl" means an alkyl-aryl- group in which the alkyl and aryl are as previously described. Preferred alkylaryls comprise a lower alkyl group. Non-limiting example of a suitable alkylaryl group is tolyl. The bond to the parent moiety is through the aryl. "Cycloalkyl" means a non-aromatic mono- or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms. Preferred cycloalkyl rings contain about 5 to about 7 ring atoms. The cycloalkyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkyls include cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl and the like. Non-limiting examples of suitable multicyclic cycloalkyls include 1-decalinyl, norbornyl, adamantyl and the like.
"Cycloalkenyl" means a non-aromatic mono or multicyclic ring system comprising about 3 to about 10 carbon atoms, preferably about 5 to about 10 carbon atoms which contains at least one carbon-carbon double bond. Preferred cycloalkenyl rings contain about 5 to about 7 ring atoms. The cycloalkenyl can be optionally substituted with one or more "ring system substituents" which may be the same or different, and are as defined above. Non-limiting examples of suitable monocyclic cycloalkenyls include cyclopentenyl, cyclohexenyl, cyclohepta-1 ,3-dienyl, and the like. Non-limiting example of a suitable multicyclic cycloalkenyl is norbornylenyl.
"Cycloalkenylalkyl" means a cycloalkenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable cycloalkenylalkyls include cyclopentenylmethyl, cyclohexenylmethyl and the like, i
"Halogen" means fluorine, chlorine, bromine, or iodine. Preferred are fluorine, chlorine and bromine.
"Ring system substituent" means a substituent attached to an aromatic or non-aromatic ring system which, for example, replaces an available hydrogen on the ring system. Ring system substituents may be the same or different, each being independently selected from the group consisting of alkyl, alkenyl, alkynyl, aryl, heteroaryl, aralkyl, alkylaryl, heteroaralkyl, heteroarylalkenyl, heteroarylalkynyl, alkylheteroaryl, hydroxy, hydroxyalkyl, alkoxy, aryloxy, aralkoxy, acyl, aroyl, halo, nitro, cyano, carboxy, alkoxycarbonyl, aryloxycarbonyl, aralkoxycarbonyl, alkylsulfonyl, arylsulfonyl, hydroxysulfonyl, heteroarylsulfonyl, alkylthio, arylthio, heteroarylthio, aralkylthio, heteroaralkylthio, cycloalkyl, heterocyclyl, -C(=N- CN)-NH2, -C(=NH)-NH2, -C(=NH)-NH(alkyl), YiY2N-, Y^N-alkyl-, Y1Y2NC(O)-, Y1Y2NSO2- and -SO2NY1Y2, wherein Y1 and Y2 can be the same or different and are independently selected from the group consisting of hydrogen, alkyl, aryl, cycloalkyl, and aralkyl, or wherein N, Y1, and Y2 together form a heterocyclyl. "Ring system substituent" may also mean a single moiety which simultaneously replaces two available hydrogens on two adjacent carbon atoms (one H on each carbon) on a ring system. Examples of such moiety are methylene dioxy, ethylenedioxy, -C(CH3)2- and the like which form moieties such as, for example:
Figure imgf000079_0001
"Heteroarylalkyl" means a heteroaryl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heteroaryls include 2-pyridinylmethyl, quinolinylmethyl and the like.
"Heterocyclyl" means a non-aromatic saturated monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur, alone or in combination. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclyls contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. Any -NH in a heterocyclyl ring may exist protected such as, for example, as an -N(Boc), -N(CBz), -N(Tos) group and the like; such protections are also considered part of this invention. The heterocyclyl can be optionally substituted by one or more "ring system substituents" which may be the same or different, and are as defined herein. The nitrogen or sulfur atom of the heterocyclyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable monocyclic heterocyclyl rings include piperidyl, pyrrolidinyl, piperazinyl, morpholinyl, thiomorpholinyl, thiazolidinyl, 1 ,4-dioxanyl, tetrahydrofuranyl, tetrahydrothiophenyl, lactam, lactone, and the like. "Heterocyclyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidone:
Figure imgf000080_0001
"Heterocyclylalkyl" means a heterocyclyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core. Non-limiting examples of suitable heterocyclylalkyls include piperidinylmethyl, piperazinylmethyl and the like.
"Heterocyclenyl" means a non-aromatic monocyclic or multicyclic ring system comprising about 3 to about 10 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is an element other than carbon, for example nitrogen, oxygen or sulfur atom, alone or in combination, and which contains at least one carbon-carbon double bond or carbon-nitrogen double bond. There are no adjacent oxygen and/or sulfur atoms present in the ring system. Preferred heterocyclenyl rings contain about 5 to about 6 ring atoms. The prefix aza, oxa or thia before the heterocyclenyl root name means that at least a nitrogen, oxygen or sulfur atom respectively is present as a ring atom. The heterocyclenyl can be optionally substituted by one or more ring system substituents, wherein "ring system substituent" is as defined above. The nitrogen or sulfur atom of the heterocyclenyl can be optionally oxidized to the corresponding N-oxide, S-oxide or S,S-dioxide. Non-limiting examples of suitable heterocyclenyl groups include 1 , 2,3,4- tetrahydropyridine, 1 ,2-dihydropyridyl, 1 ,4- dihydropyridyl, 1 ,2,3,6-tetrahydropyridine, 1 ,4,5,6-tetrahydropyrimidine, 2- pyrrolinyl, 3-pyrrolinyl, 2-imidazolinyl, 2-pyrazolinyl, dihydroimidazole, dihydrooxazole, dihydrooxadiazole, dihydrothiazole, 3,4-dihydro-2H-pyran, dihydrofuranyl, fluorodihydrofuranyl, 7-oxabicyclo[2.2.1]heptenyl, dihydrothiophenyl, dihydrothiopyranyl, and the like. "Heterocyclenyl" may also mean a single moiety (e.g., carbonyl) which simultaneously replaces two available hydrogens on the same carbon atom on a ring system. Example of such moiety is pyrrolidinone:
Figure imgf000081_0001
"Heterocyclenylalkyl" means a heterocyclenyl moiety as defined above linked via an alkyl moiety (defined above) to a parent core.
It should be noted that in hetero-atom containing ring systems of this invention, there are no hydroxyl groups on carbon atoms adjacent to a N, O or S1 as well as there are no N or S groups on carbon adjacent to another heteroatom. Thus, for example, in the ring:
Figure imgf000081_0002
there is no -OH attached directly to carbons marked 2 and 5. It should also be noted that tautomeric forms such as, for example, the moieties:
Figure imgf000081_0003
are considered equivalent in certain embodiments of this invention.
"Alkynylalkyl" means an alkynyl-alkyl- group in which the alkynyl and alkyl are as previously described. Preferred alkynylalkyls contain a lower alkynyl and a lower alkyl group. The bond to the parent moiety is through the alkyl. Non-limiting examples of suitable alkynylalkyl groups include propargylmethyl. "Heteroaralkyl" means a heteroaryl-alkyl- group in which the heteroaryl and alkyl are as previously described. Preferred heteroaralkyls contain a lower alkyl group. Non-limiting examples of suitable aralkyl groups include pyridylmethyl, and quinolin-3-ylmethyl. The bond to the parent moiety is through the alkyl.
"Hydroxyalkyl" means a HO-alkyl- group in which alkyl is as previously defined. Preferred hydroxyalkyls contain lower alkyl. Non-limiting examples of suitable hydroxyalkyl groups include hydroxymethyl and 2- hydroxyethyl. "Acyl" means an H-C(O)-, alkyl-C(O)- or cycloalkyl-C(O)-, group in which the various groups are as previously described. The bond to the parent moiety is through the carbonyl. Preferred acyls contain a lower alkyl. Non-limiting examples of suitable acyl groups include formyl, acetyl and propanoyl. "Aroyl" means an aryl-C(O)- group in which the aryl group is as previously described. The bond to the parent moiety is through the carbonyl. Non-limiting examples of suitable groups include benzoyl and 1- naphthoyl.
"Alkoxy" means an alkyl-O- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkoxy groups include methoxy, ethoxy, n-propoxy, isopropoxy and n-butoxy. The bond to the parent moiety is through the ether oxygen.
"Aryloxy" means an aryl-O- group in which the aryl group is as previously described. Non-limiting examples of suitable aryloxy groups include phenoxy and naphthoxy. The bond to the parent moiety is through the ether oxygen.
"Aralkyloxy" means an aralkyl-O- group in which the aralkyl group is as previously described. Non-limiting examples of suitable aralkyloxy groups include benzyloxy and 1- or 2-naphthalenemethoxy. The bond to the parent moiety is through the ether oxygen. "Alkylthio" means an alkyl-S- group in which the alkyl group is as previously described. Non-limiting examples of suitable alkylthio groups include methylthio and ethylthio. The bond to the parent moiety is through the sulfur.
"Arylthio" means an aryl-S- group in which the aryl group is as previously described. Non-limiting examples of suitable arylthio groups include phenylthio and naphthylthio. The bond to the parent moiety is through the sulfur.
"Aralkylthio" means an aralkyl-S- group in which the aralkyl group is as previously described. Non-limiting example of a suitable aralkylthio group is benzylthio. The bond to the parent moiety is through the sulfur. "Alkylsilyl" means an alkyl-Si- group in which alkyl is as previously defined and the point of attachment to the parent moiety is on Si. Preferred alkylsilyls contain lower alkyl. An example of an alkylsilyl group is trimethylsilyl (-Si(CH3)3).
"Alkoxycarbonyl" means an alkyl-O-CO- group. Non-limiting examples of suitable alkoxycarbonyl groups include methoxycarbonyl and ethoxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Aryloxycarbonyl" means an aryl-O-C(O)- group. Non-limiting examples of suitable aryloxycarbonyl groups include phenoxycarbonyl and naphthoxycarbonyl. The bond to the parent moiety is through the carbonyl. "Aralkoxycarbonyl" means an aralkyl-O-C(O)- group. Non-limiting example of a suitable aralkoxycarbonyl group is benzyloxycarbonyl. The bond to the parent moiety is through the carbonyl.
"Alkylsulfonyl" means an alkyl-S(O2)- group. Preferred groups are those in which the alkyl group is lower alkyl. The bond to the parent moiety is through the sulfonyl.
"Arylsulfonyl" means an aryl-S(O2)- group. The bond to the parent moiety is through the sulfonyl.
The term "substituted" means that one or more hydrogens on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency under the existing circumstances is not exceeded, and that the substitution results in a stable compound. Combinations of substituents and/or variables are permissible only if such combinations result in stable compounds. By "stable compound1 or "stable structure" is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.
The term "optionally substituted" means optional substitution with the specified groups, radicals or moieties.
The term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being isolated from a synthetic process or natural source or combination thereof. Thus, the term "purified", "in purified form" or "in isolated and purified form" for a compound refers to the physical state of said compound after being obtained from a purification process or processes described herein or well known to the skilled artisan, in sufficient purity to be characterizable by standard analytical techniques described herein or well known to the skilled artisan.
It should also be noted that any carbon as well as heteroatom with unsatisfied valences in the text, schemes, examples and Tables herein is assumed to have the sufficient number of hydrogen atom(s) to satisfy the valences.
When a functional group in a compound is termed "protected", this means that the group is in modified form to preclude undesired side reactions at the protected site when the compound is subjected to a reaction. Suitable protecting groups will be recognized by those with ordinary skill in the art as well as by reference to standard textbooks such as, for example, T. W. Greene et al, Protective Groups in organic Synthesis (1991 ), Wiley, New York.
When any variable (e.g., aryl, heterocycle, R2, etc.) occurs more than one time in any constituent or in any one of Formula Mil, its definition on each occurrence is independent of its definition at every other occurrence. As used herein, the term "composition" is intended to encompass a product comprising the specified ingredients in the specified amounts, as well as any product which results, directly or indirectly, from combination of the specified ingredients in the specified amounts. The term "pharmaceutical composition" is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a patient by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Prodrugs and solvates of the compounds of the invention are also contemplated herein. A discussion of prodrugs is provided in T. Higuchi and V. Stella, Pro-drugs as Novel Delivery Systems (1987) t4 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, (1987) Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press. The term "prodrug" means a compound (e.g, a drug precursor) that is transformed in vivo to yield a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound. The transformation may occur by various mechanisms (e.g., by metabolic or chemical processes), such as, for example, through hydrolysis in blood. A discussion of the use of prodrugs is provided by T. Higuchi and W. Stella, "Pro-drugs as Novel Delivery Systems," Vol. 14 of the A.C.S. Symposium Series, and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987.
For example, if a compound of Formula (I) or a pharmaceutically acceptable salt, hydrate or solvate of the compound contains a carboxylic acid functional group, a prodrug can comprise an ester formed by the replacement of the hydrogen atom of the acid group with a group such as, for example, (Ci-C8)alkyl, (C2-C12)alkanoyloxymethyl, 1-(alkanoyloxy)ethyl having from 4 to 9 carbon atoms, 1-methyl-1-(alkanoyloxy)-ethyl having from 5 to 10 carbon atoms, alkoxycarbonyloxymethyl having from 3 to 6 carbon atoms, 1-(alkoxycarbonyloxy)ethyl having from 4 to 7 carbon atoms, 1- methyl-1-(alkoxycarbonyloxy)ethyl having from 5 to 8 carbon atoms, N- (alkoxycarbonyl)aminomethyl having from 3 to 9 carbon atoms, 1-(N- (alkoxycarbonyl)amino)ethyl having from 4 to 10 carbon atoms, 3-phthalidyl, 4-crotonolactonyl, gamma-butyrolacton-4-yl, di-N,N-(CrC2)alkylamino(C2- C3)alkyl (such as β-dimethylaminoethyl), carbamoyl-(Ci-C2)alkyl, N,N-di (Cr C2)alkylcarbamoyl-(C1-C2)alkyl and piperidino-, pyrrolidino- or morpholino(C2-C3)alkyl, and the like.
Similarly, if a compound of Formula (I) contains an alcohol functional group, a prodrug can be formed by the replacement of the hydrogen atom of the alcohol group with a group such as, for example, (Cr
Cβjalkanoyloxymethyl, 1 -((C-ι-C6)alkanoyloxy)ethyl, 1 -methyl-1 -((Cr C6)alkanoyloxy)ethyl, (CrCβ)alkoxycarbonyloxymethyl, N-(Cr Cβjalkoxycarbonylaminomethyl, succinoyl, (CrC^alkanoyl, α-amino(Cr C4)alkanyl, arylacyl and α-aminoacyl, or α-aminoacyl-α-aminoacyl, where each α-aminoacyl group is independently selected from the naturally occurring L-amino acids, P(O)(OH)2, -P(O)(O(CrC6)alkyl)2 or glycosyl (the radical resulting from the removal of a hydroxyl group of the hemiacetal form of a carbohydrate), and the like.
If a compound of Formula (I) incorporates an amine functional group, a prodrug can be formed by the replacement of a hydrogen atom in the amine group with a group such as, for example, R-carbonyl, RO-carbonyl, NRR'-carbonyl where R and R' are each independently (Ci-CiO)alkyl, (C3-C7) cycloalkyl, benzyl, or R-carbonyl is a natural α-aminoacyl or natural α- aminoacyl, -C(OH)C(O)OY1 wherein Y1 is H, (CrC6)alkyl or benzyl, — C(OY2)Y3 wherein Y2 is (C1-C4) alkyl and Y3 is (CrC6)alkyl, carboxy (C1- C6)alkyl, amino(C1-C4)alkyl or mono-N — or di-N.N^CrCeJalkylaminoalkyl, — C(Y4)Y5 wherein Y4 is H or methyl and Y5 is mono-N— or di-N, N-(C1- C6)alkylamino morpholino, piperidin-1-yl or pyrrolidin-1-yl, and the like. ^
One or more compounds of the invention may exist in unsolvated as well as solvated forms with pharmaceutically acceptable solvents such as water, ethanol, and the like, and it is intended that the invention embrace both solvated and unsolvated forms. "Solvate" means a physical association of a compound of this invention with one or more solvent molecules. This physical association involves varying degrees of ionic and covalent bonding, including hydrogen bonding. In certain instances the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of the crystalline solid. "Solvate" encompasses both solution-phase and isolatable solvates. Non-limiting examples of suitable solvates include ethanolates, methanolates, and the like. "Hydrate" is a solvate wherein the solvent molecule is H2O. One or more compounds of the invention may optionally be converted to a solvate. Preparation of solvates is generally known. Thus, for example, M. Caira et al, J. Pharmaceutical Sci., 93(3). 601-611 (2004) describe the preparation of the solvates of the antifungal fluconazole in ethyl acetate as well as from water. Similar preparations of solvates, hemisolvate, hydrates and the like are described by E. C. van Tonder et al, AAPS PharmSciTech., 5(1 ), article 12 (2004); and A. L. Bingham et al, Chem. Commun., 603-604 (2001). A typical, non-limiting, process involves dissolving the inventive compound in desired amounts of the desired solvent (organic or water or mixtures thereof) at a higher than ambient temperature, and cooling the solution at a rate sufficient to form crystals which are then isolated by standard methods. Analytical techniques such as, for example I. R. spectroscopy, show the presence of the solvent (or water) in the crystals as a solvate (or hydrate).
"Effective amount" or "therapeutically effective amount" is meant to describe an amount of compound or a composition of the present invention effective in inhibiting the above-noted diseases and thus producing the desired therapeutic, ameliorative, inhibitory or preventative effect.
The compounds of Formulae l-lll can form salts which are also within the scope of this invention. Reference to a compound of Formulae l-lll herein is understood to include reference to salts thereof, unless otherwise indicated. The term "salt(s)", as employed herein, denotes acidic salts formed with inorganic and/or organic acids, as well as basic salts formed with inorganic and/or organic bases. In addition, when a compound of any one of Formulae l-lll contains both a basic moiety, such as, but not limited to a pyridine or imidazole, and an acidic moiety, such as, but not limited to a carboxylic acid, zwitterions ("inner salts") may be formed and are included within the term "salt(s)" as used herein. Pharmaceutically acceptable (i.e., non-toxic, physiologically acceptable) salts are preferred, although other salts are also useful. Salts of the compounds of the Formulae l-lll may be formed, for example, by reacting a compound of Formulae l-lll with an amount of acid or base, such as an equivalent amount, in a medium such as one in which the salt precipitates or in an aqueous medium followed by lyophilization.
Exemplary acid addition salts include acetates, ascorbates, benzoates, benzenesulfonates, bisulfates, borates, butyrates, citrates, camphorates, camphorsulfonates, fumarates, hydrochlorides, hydrobromides, hydroiodides, lactates, maleates, methanesulfonates, naphthalenesulfonates, nitrates, oxalates, phosphates, propionates, salicylates, succinates, sulfates, tartarates, thiocyanates, toluenesulfonates (also known as tosylates,) and the like. Additionally, acids which are generally considered suitable for the formation of pharmaceutically useful salts from basic pharmaceutical compounds are discussed, for example, by P. Stahl et al, Camille G. (eds.) Handbook of Pharmaceutical Salts. Properties, Selection and Use. (2002) Zurich: Wiley-VCH; S. Berge et al, Journal of Pharmaceutical Sciences (1977) 66(1 ) 1-19; P. Gould, International J. of Pharmaceutics (1986) 33 201-217; Anderson et al, The Practice of Medicinal Chemistry (1996), Academic Press, New York; and in The Orange Book (Food & Drug Administration, Washington, D.C. on their website). These disclosures are incorporated herein by reference thereto.
Exemplary basic salts include ammonium salts, alkali metal salts such as sodium, lithium, and potassium salts, alkaline earth metal salts such as calcium and magnesium salts, salts with organic bases (for example, organic amines) such as dicyclohexylamines, t-butyl amines, and salts with amino acids such as arginine, lysine and the like. Basic nitrogen-containing groups may be quartemized with agents such as lower alkyl halides (e.g. methyl, ethyl, and butyl chlorides, bromides and iodides), dialkyl sulfates (e.g. dimethyl, diethyl, and dibutyl sulfates), long chain halides (e.g. decyl, lauryl, and stearyl chlorides, bromides and iodides), aralkyl halides (e.g. benzyl and phenethyl bromides), and others.
All such acid salts and base salts are intended to be pharmaceutically acceptable salts within the scope of the invention and all acid and base salts are considered equivalent to the free forms of the corresponding compounds for purposes of the invention.
Pharmaceutically acceptable esters of the present compounds include the following groups: (1 ) carboxylic acid esters obtained by esterification of the hydroxy groups, in which the non-carbonyl moiety of the carboxylic acid portion of the ester grouping is selected from straight or branched chain alkyl (for example, acetyl, n-propyl, t-butyl, or n-butyl), alkoxyalkyl (for example, methoxymethyl), aralkyl (for example, benzyl), aryloxyalkyl (for example, phenoxymethyl), aryl (for example, phenyl optionally substituted with, for example, halogen,
Figure imgf000089_0001
or amino); (2) sulfonate esters, such as alkyl- or aralkylsulfonyl (for example, methanesulfonyl); (3) amino acid esters (for example, L-valyl or L-isoleucyl); (4) phosphonate esters and (5) mono-, di- or triphosphate esters. The phosphate esters may be further esterified by, for example, a C1^o alcohol or reactive derivative thereof, or by a 2,3-di (C6-24)acyl glycerol.
Compounds of Formulae l-lll, and salts, solvates, esters and prodrugs thereof, may exist in their tautomeric form (for example, as an amide or imino ether). All such tautomeric forms are contemplated herein as part of the present invention.
The compounds of Formula (I) may contain asymmetric or chiral centers, and, therefore, exist in different stereoisomeric forms. It is intended that all stereoisomeric forms of the compounds of Formula (I) as well as mixtures thereof, including racemic mixtures, form part of the present invention. In addition, the present invention embraces all geometric and positional isomers. For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention.
Diastereomeric mixtures can be separated into their individual diastereomers on the basis of their physical chemical differences by methods well known to those skilled in the art, such as, for example, by chromatography and/or fractional crystallization. Enantiomers can be separated by converting the enantiomeric mixture into a diastereomeric mixture by reaction with an appropriate optically active compound (e.g., chiral auxiliary such as a chiral alcohol or Mosher's acid chloride), separating the diastereomers and converting (e.g., hydrolyzing) the individual diastereomers to the corresponding pure enantiomers. Also, some of the compounds of Formula (I) may be atropisomers (e.g., substituted biaryls) and are considered as part of this invention. Enantiomers can also be separated by use of chiral HPLC column.
It is also possible that the compounds of Formula (I) may exist in different tautomeric forms, and all such forms are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention. All stereoisomers (for example, geometric isomers, optical isomers and the like) of the present compounds (including those of the salts, solvates, esters and prodrugs of the compounds as well as the salts, solvates and esters of the prodrugs), such as those which may exist due to asymmetric carbons on various substituents, including enantiomeric forms (which may exist even in the absence of asymmetric carbons), rotameric forms, atropisomers, and diastereomeric forms, are contemplated within the scope of this invention, as are positional isomers (such as, for example, 4- pyridyl and 3-pyridyl). (For example, if a compound of Formula (I) incorporates a double bond or a fused ring, both the cis- and trans-forms, as well as mixtures, are embraced within the scope of the invention. Also, for example, all keto-enol and imine-enamine forms of the compounds are included in the invention.) Individual stereoisomers of the compounds of the invention may, for example, be substantially free of other isomers, or may be admixed, for example, as racemates or with all other, or other selected, stereoisomers. The chiral centers of the present invention can have the S or R configuration as defined by the IUPAC 1974 Recommendations. The use of the terms "salt", "solvate", "ester", "prodrug" and the like, is intended to equally apply to the salt, solvate, ester and prodrug of enantiomers, stereoisomers, rotamers, tautomers, positional isomers, racemates or prodrugs of the inventive compounds.
The present invention also embraces isotopically-labelled compounds of the present invention which are identical to those recited herein, but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number usually found in nature. Examples of isotopes that can be incorporated into compounds of the invention include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine and chlorine, such as 2H, 3H, 13C, 14C, 15N, 18O, 170, 31P, 32P, 35S, 18F, and 36CI, respectively. Certain isotopically-labelled compounds of Formula (I) (e.g., those labeled with 3H and 14C) are useful in compound and/or substrate tissue distribution assays. Tritiated (i.e., 3H) and carbon-14 (i.e., 14C) isotopes are particularly preferred for their ease of preparation and detectability. Further, substitution with heavier isotopes such as deuterium (i.e., 2H) may afford certain therapeutic advantages resulting from greater metabolic stability (e.g., increased in vivo half-life or reduced dosage requirements) and hence may be preferred in some circumstances, lsotopically labelled compounds of Formula (I) can generally be prepared by following procedures analogous to those disclosed in the Schemes and/or in the Examples hereinbelow, by substituting an appropriate isotopically labelled reagent for a non-isotopically labelled reagent.
Polymorphic forms of the compounds of Formulae I, and of the salts, solvates, esters and prodrugs of the compounds of Formulae I, are intended to be included in the present invention.
Generally, the compounds of Formula I can be prepared by a variety of methods well known to those skilled in the art, for example, by the methods as outlined below and in the examples disclosed herein:
The compounds of the invention can be useful in a variety of applications involving alteration of mitosis. As will be appreciated by those skilled in the art, mitosis may be altered in a variety of ways; that is, one can affect mitosis either by increasing or decreasing the activity of a component in the mitotic pathway. Mitosis may be affected (e.g., disrupted) by disturbing equilibrium, either by inhibiting or activating certain components. Similar approaches may be used to alter meiosis.
In a particular embodiment, the compounds of the invention can be used to inhibit mitotic spindle formation, thus causing prolonged cell cycle arrest in mitosis. By "inhibit" in this context is meant decreasing or interfering with mitotic spindle formation or causing mitotic spindle dysfunction. By "mitotic spindle formation" herein is meant organization of microtubules into bipolar structures by mitotic kinesins. By "mitotic spindle dysfunction" herein is meant mitotic arrest and monopolar spindle formation. The compounds of the invention can be useful for binding to, and/or inhibiting the activity of, a mitotic kinesin, KSP. In one embodiment, the KSP is human KSP, although the compounds may be used to bind to or inhibit the activity of KSP kinesins from other organisms. In this context, "inhibit" means either increasing or decreasing spindle pole separation, causing malformation, i.e., splaying, of mitotic spindle poles, or otherwise causing morphological perturbation of the mitotic spindle. Also included within the definition of KSP for these purposes are variants and/or fragments of KSP (see U.S. patent 6,437,115). In addition, the present compounds are also useful for binding to or modulating other mitotic kinesins.
The compounds of the invention can be used to treat cellular proliferation diseases. Such disease states which can be treated by the compounds, compositions and methods provided herein include, but are not limited to, cancer (further discussed below), hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, cellular proliferation induced after medical procedures, including, but not limited to, surgery, angioplasty, and the like. Treatment includes inhibiting cellular proliferation. It is appreciated that in some cases the cells may not be in a hyper- or hypoproliferation state (abnormal state) and still require treatment. For example, during wound healing, the cells may be proliferating "normally", but proliferation enhancement may be desired. Thus, in one embodiment, the invention herein includes application to cells or subjects afflicted or subject to impending affliction with any one of these disorders or states. The compounds, compositions and methods provided herein are particularly useful for the treatment of cancer including solid tumors such as skin, breast, brain, colon, gall bladder, thyroid, cervical carcinomas, testicular carcinomas, etc. More particularly, cancers that may be treated by the compounds, compositions and methods of the invention include, but are not limited to: Cardiac: sarcoma (angiosarcoma, fibrosarcoma, rhabdomyosarcoma, liposarcoma), myxoma, rhabdomyoma, fibroma, lipoma and teratoma;
Lung: bronchogenic carcinoma (squamous cell, undifferentiated small cell, undifferentiated large cell, adenocarcinoma), alveolar (bronchiolar) carcinoma, bronchial adenoma, sarcoma, lymphoma, chondromatous hamartoma, mesothelioma;
Gastrointestinal: esophagus (squamous cell carcinoma, adenocarcinoma, leiomyosarcoma, lymphoma), stomach (carcinoma, lymphoma, leiomyosarcoma), pancreas (ductal adenocarcinoma, insulinoma, glucagonoma, gastrinoma, carcinoid tumors, vipoma), small bowel (adenocarcinoma, lymphoma, carcinoid tumors, Karposi's sarcoma, leiomyoma, hemangioma, lipoma, neurofibroma, fibroma), large bowel (adenocarcinoma, tubular adenoma, villous adenoma, hamartoma, leiomyoma); Genitourinary tract: kidney (adenocarcinoma, Wilm's tumor
(nephroblastoma), lymphoma, leukemia), bladder and urethra (squamous cell carcinoma, transitional cell carcinoma, adenocarcinoma), prostate (adenocarcinoma, sarcoma), testis (seminoma, teratoma, embryonal carcinoma, teratocarcinoma, choriocarcinoma, sarcoma, interstitial cell carcinoma, fibroma, fibroadenoma, adenomatoid tumors, lipoma);
Liver: hepatoma (hepatocellular carcinoma), cholangiocarcinoma, hepatoblastoma, angiosarcoma, hepatocellular adenoma, hemangioma;
Bone: osteogenic sarcoma (osteosarcoma), fibrosarcoma, malignant fibrous histiocytoma, chondrosarcoma, Ewing's sarcoma, malignant lymphoma (reticulum cell sarcoma), multiple myeloma, malignant giant cell tumor chordoma, osteochronfroma (osteocartilaginous exostoses), benign chondroma, chondroblastoma, chondromyxofibroma, osteoid osteoma and giant cell tumors;
Nervous system: skull (osteoma, hemangioma, granuloma, xanthoma, osteitis deformans), meninges (meningioma, meningiosarcoma, gliomatosis), brain (astrocytoma, medulloblastoma, glioma, ependymoma, germinoma (pinealoma), glioblastoma multiform, oligodendroglioma, schwannoma, retinoblastoma, congenital tumors), spinal cord neurofibroma, meningioma, glioma, sarcoma);
Gynecological: uterus (endometrial carcinoma), cervix (cervical carcinoma, pre-tumor cervical dysplasia), ovaries (ovarian carcinoma
(serous cystadenocarcinoma, mucinous cystadenocarcinoma, unclassified carcinoma), granulosa-thecal cell tumors, Sertoli-Leydig cell tumors, dysgerminoma, malignant teratoma), vulva (squamous cell carcinoma, intraepithelial carcinoma, adenocarcinoma, fibrosarcoma, melanoma), vagina (clear cell carcinoma, squamous cell carcinoma, botryoid sarcoma (embryonal rhabdomyosarcoma), fallopian tubes (carcinoma);
Hematologic: blood (myeloid leukemia (acute and chronic), acute lymphoblastic leukemia, acute and chronic lymphocytic leukemia, myeloproliferative diseases, multiple myeloma, myelodysplastic syndrome), Hodgkin's disease, non-Hodgkin's lymphoma (malignant lymphoma), B-cell lymphoma, T-cell lymphoma, hairy cell lymphoma, Burkett's lymphoma, promyelocytic leukemia;
Skin: malignant melanoma, basal cell carcinoma, squamous cell carcinoma, Karposi's sarcoma, moles dysplastic nevi, lipoma, angioma, dermatofibroma, keloids, psoriasis;
Adrenal glands: neuroblastoma; and
Other tumors: including xenoderoma pigmentosum, keratoctanthoma and thyroid follicular cancer.
As used herein, treatment of cancer includes treatment of cancerous cells, including cells afflicted by any one of the above-identified conditions.
The compounds of the present invention may also be useful in the chemoprevention of cancer. Chemoprevention is defined as inhibiting the development of invasive cancer by either blocking the initiating mutagenic event or by blocking the progression of pre-malignant cells that have already suffered an insult or inhibiting tumor relapse. The compounds of the present invention may also be useful in inhibiting tumor angiogenesis and metastasis.
The compounds of the present invention may also be useful as antifungal agents, by modulating the activity of the fungal members of the bimC kinesin subgroup, as is described in U.S. Patent 6,284,480.
The present compounds are also useful in combination with one or more other known therapeutic agents and anti-cancer agents. Combinations of the present compounds with other anti-cancer or chemotherapeutic agents are within the scope of the invention. Examples of such agents can be found in Cancer Principles and Practice of Oncology by VT. Devita and S. Hellman (editors), 6th edition (February 15, 2001 ), Lippincott Williams & Wilkins Publishers. A person of ordinary skill in the art would be able to discern which combinations of agents would be useful based on the particular characteristics of the drugs and the cancer involved. Such anti- cancer agents include, but are not limited to, the following: estrogen receptor modulators, androgen receptor modulators, retinoid receptor modulators, cytotoxic/cytostatic agents, antiproliferative agents, prenyl-protein transferase inhibitors, HMG-CoA reductase inhibitors and other angiogenesis inhibitors, inhibitors of cell proliferation and survival signaling, apoptosis inducing agents and agents that interfere with cell cycle checkpoints. The present compounds are also useful when co-administered with radiation therapy.
The phrase "estrogen receptor modulators" refers to compounds that interfere with or inhibit the binding of estrogen to the receptor, regardless of mechanism. Examples of estrogen receptor modulators include, but are not limited to, tamoxifen, raloxifene, idoxifene, LY353381 , LY117081 , toremifene, fulvestrant, 4-[7-(2,2-dimethyl-l-oxopropoxy-4-methyl-2-[4-[2-(1 - piperidinyl)ethoxy]phenyl]-2H-1-benzopyran-3-yl]-phenyl-2,2- dimethylpropanoate, 4,4'-dihydroxybenzophenone-2,4-dinitrophenyl- ydrazone, aid SH646. The phrase "androgen receptor modulators" refers to compounds which interfere or inhibit the binding of androgens to the receptor, regardless of mechanism. Examples of androgen receptor modulators include finasteride and other 5α-reductase inhibitors, nilutamide, flutamide, bicalutamide, liarozole, and abiraterone acetate.
The phrase "retinoid receptor modulators" refers to compounds which interfere or inhibit the binding of retinoids to the receptor, regardless of mechanism. Examples of such retinoid receptor modulators include bexarotene, tretinoin, 13-cis-retinoic acid, 9-cis-retinoic acid, a difluoromethylomithine, ILX23-7553, trans-N-(4'-hydroxyphenyl) retinamide, and N-4-carboxyphenyl retinamide.
The phrase "cytotoxic/cytostatic agents" refer to compounds which cause cell death or inhibit cell proliferation primarily by interfering directly with the cell's functioning or inhibit or interfere with cell mycosis, including alkylating agents, tumor necrosis factors, intercalators, hypoxia activatable compounds, microtubule inhibitors/microtubule-stabilizing agents, inhibitors of mitotic kinesins, inhibitors of kinases involved in mitotic progression, antimetabolites; biological response modifiers; hormonal/anti-hormonal therapeutic agents, haematopoietic growth factors, monoclonal antibody targeted therapeutic agents, monoclonal antibody therapeutics, topoisomerase inhibitors, proteasome inhibitors and ubiquitin ligase inhibitors.
Examples of cytotoxic agents include, but are not limited to, sertenef, cachectin, ifosfamide, tasonermin, lonidamine, carboplatin, altretamine, prednimustine, dibromodulcitol, ranimustine, fotemustine, nedaplatin, oxaliplatin, temozolomide (TEMODAR™ from Schering-Plough Corporation, Kenilworth, New Jersey), cyclophosphamide, heptaplatin, estramustine, improsulfan tosilate, trofosfamide, nimustine, dibrospidium chloride, pumitepa, lobaplatin, satraplatin, profiromycin, cisplatin, doxorubicin, irofulven, dexifosfamide, cis-aminedichloro(2-methyl-pyridine)platinum, benzylguanine, glufosfamide, GPX100, (trans, trans, trans)-bis-mu-(hexane- 1 ,6-diamine)-mu-[diamine-platinum(ll)]bis[diamine(chloro)platinum(ll)] tetrachloride, diarizidinylspermine, arsenic trioxide, 1-(11-dodecylamino-10- hydroxyundecyl)-3,7-dimethylxanthine, zorubicin, idarubicin, daunorubicin, bisantrene, mitoxantrone, pirarubicin, pinafide, valrubicin, amrubicin, antineoplaston, 3'-deansino-3'-morpholino-13-deoxo-10- hydroxycarminomycin, annamycin, galarubicin, elinafide, MEN10755, 4- demethoxy-3-deamino-3-aziridinyl-4-methylsulphonyl-daunombicin (see WO 00/50032), methotrexate, gemcitabine, and mixture thereof .
An example of a hypoxia activatable compound is tirapazamine. Examples of proteasome inhibitors include, but are not limited to, lactacystin and bortezomib.
Examples of microtubule inhibitors/microtubule-stabilising agents include paclitaxel, vindesine sulfate, 3\4'-didehydro-4'-deoxy-8'- norvincaleukoblastine, docetaxel, rhizoxin, dolastatin, mivobulin isethionate, auristatin, cemadotin, RPR109881 , BMS184476, vinflunine, cryptophycin, 2,3)4,5,6-pentafluoro-N-(3-fluoro-4-methoxyphenyl) benzene sulfonamide, anhydrovinblastine, N.N-dimethyl-L-valyl-L-valyl-N-methyl-L-valyl-L-prolyl-L- proline-t-butylamide, TDX258, the epothilones (see for example U.S. Patents 6,284,781 and 6,288,237) and BMS188797. Some examples of topoisomerase inhibitors are topotecan, hycaptamine, irinotecan, rubitecan, 6-ethoxypropionyl-3',4'-O-exo- benzylidene-chartreusin, 9-methoxy-N,N-dimethyl-5-nitropyrazolo[3,4,5- kl]acridine-2-(6H) propanamine, 1 -amino-9-ethyl-5-fluoro-2,3-dihydro-9- hydroxy-4-methyl-1 H,12H-benzo[de]pyrano[3',4':b,7]- indolizino[1,2b]quinoline-10,13(9H,15H)dione, lurtotecan, 7-[2-(N- isopropylamino) ethyl]-(20S)camptothecin, BNP1350, BNPM 100, BN80915, BN80942, etoposide phosphate, teniposide, sobuzoxane, 2'-dimethylamino- 2'-deoxy-etoposide, GL331 , N-[2-(dimethylamino)ethyl]-9-hydroxy-5,6- dimethyl-6H-pyrido[4,3-b]carbazole-1-carboxamide, asulacrine, (5a, 5aB, 8aa,9b)-9-[2-[N-[2-(dimethylamino)ethyl]-N-methylamino]ethyl]-5-[4-hydroxy- 3,5-dimethoxyphenyl]-515a,6,8,8a,9-hexohydrofuro(3',4':6,7)naphtho(2,3-d)- 1 ,3-dioxol-6-one, 2,3-(methylenedioxy)-5- methyl-7-hydroxy-8- methoxybenzo[c]-phenanthridinium, 6,9-bis[(2-aminoethyl)amino] benzo[g]isoguinoline-5,10-dione, 5-(3-aminopropylamino)-7,10-dihydroxy-2- (2-hydroxyethylaminomethyl)-6H-pyrazolo[4,5,1-de]acridin-6-one, N-[1- [2- (diethylamino)ethylamino]-7-methoxy-9-oxo-9H-thioxanthen-4- ylmethyl]formamide, N-(2-(dimethylamino)ethyl)acridine-4-carboxamide> 6- [[2-(dimethylamino)ethyl]amino]-3-hydroxy-7H-indeno[2,1-c]quinolin-7-one, dimesna, and camptostar.
Other useful anti-cancer agents that can be used in combination with the present compounds include thymidilate synthase inhibitors, such as 5- fluorouracil.
In one embodiment, inhibitors of mitotic kinesins include, but are not limited to, inhibitors of KSP, inhibitors of MKLP1 , inhibitors of CENP-E, inhibitors of MCAK, inhibitors of Kif 14, inhibitors of Mphosphi and inhibitors of Rab6-KIFL.
The phrase "inhibitors of kinases involved in mitotic progression" include, but are not limited to, inhibitors of aurora kinase, inhibitors of Polo- like kinases (PLK) (in particular inhibitors of PLK-1 ), inhibitors of bub-1 and inhibitors of bub-R1. The phrase "antiproliferative agents" includes antisense RNA and
DNA oligonucleotides such as G3139, ODN698, RVASKRAS, GEM231 , and INX3001 , and antimetabolites such as enocitabine, carmofur, tegafur, pentostatin, doxifluridine, trimetrexate, fludarabine, capecitabine, galocitabine, cytarabine ocfosfate, fosteabine sodium hydrate, raltitrexed, paltitrexid, emitefur, tiazofurin, decitabine, nolatrexed, pemetrexed, nelzarabine, 2'-deoxy-2'-methylidenecytidine, 2'-fluoromethylene-2'- deoxycytidine, N-[5-(2,3-dihydro-benzofuryl)sulfonyl]-N'-(3,4- dichlorophenyl)urea, N6-[4-deoxy-4-[N2-[2(E),4(E)- tetradecadienoyltølycylaminoJ-L-glycero-B-L-manno- heptopyranosyl]adenine, aplidine, ecteinascidin, troxacitabine, 4-[2-amino-4- oxo- 4,6,7,8-tetrahydro-3H-pyrimidino[5,4-b][1 ,4]thiazin-6-yl-(S)-ethyl]-2,5- thienoyl-L-glutamic acid, aminopterin, 5-flurouracil, alanosine, 11-acetyl-8- (carbamoyloxymethyl)-4-formyl-6-methoxy-14-oxa-1 ,11- diazatetracyclo(7.4.1.0.0)-tetradeca-2,4,6-trien-9-yl acetic acid ester, swainsonine, lometrexol, dexrazoxane, methioninase, 2'-cyano-2'-deoxy-N4- palmitoyl-1-B-D-arabino furanosyl cytosine and 3-aminopyridine-2- carboxaldehyde thiosemicarbazone.
Examples of monoclonal antibody targeted therapeutic agents include those therapeutic agents which have cytotoxic agents or radioisotopes attached to a cancer cell specific or target cell specific monoclonal antibody. Examples include Bexxar.
Examples of monoclonal antibody therapeutics useful for treating cancer include Erbitux (Cetuximab).
The phrase "HMG-CoA reductase inhibitors" refers to inhibitors of 3- hydroxy-3-methylglutaryl-CoA reductase. Examples of HMG-CoA reductase inhibitors that may be used include but are not limited to lovastatin
(MEVACOR®; see U.S. Patents 4,231 ,938, 4,294,926 and 4,319,039), simvastatin(ZOCOR®; see U.S. Patents 4,444,784, 4,820,850 and 4,916,239), pravastatin (PRAVACHOL®; see U.S. Patents 4,346,227, 4,537,859, 4,410,629, 5,030,447 and 5,180,589), fluvastatin (LESCOL®; see U.S. Patents 5,354,772, 4,911 ,165, 4,929,437, 5,189,164, 5,118,853, 5,290,946 and 5,356,896) and atorvastatin (LIPITOR®; see U.S. Patents 5,273,995, 4,681 ,893, 5,489,691 and 5,342,952). The structural formulas of these and additional HMG-CoA reductase inhibitors that may be used in the instant methods are described at page 87 of M. Yalpani, "Cholesterol Lowering Drugs", Chemistry & Industry, pp. 85-89 (5 February 1996) and US Patents 4,782,084 and 4,885,314. The term HMG-CoA reductase inhibitor as used herein includes all pharmaceutically acceptable lactone and open- acid forms (i.e., where the lactone ring is opened to form the free acid) as well as salt and ester forms of compounds which have HMG-CoA reductase inhibitory activity, and therefore the use of such salts, esters, open acid and lactone forms is included in the scope of this invention. The phrase "prenyl-protein transferase inhibitor" refers to a compound which inhibits any one or any combination of the prenyl-protein transferase enzymes, including farnesyl-protein transferase (FPTase), geranylgeranyl- protein transferase type I (GGPTase-l), and geranylgeranyl-protein transferase type-ll (GGPTase-l I, also called Rab GGPTase).
Examples of prenyl-protein transferase inhibitors can be found in the following publications and patents: WO 96/30343, WO 97/18813, WO 97/21701 , WO 97/23478, WO 97/38665, WO 98/28980, WO 98/29119, WO 95/32987, U.S. Patents 5,420,245, 5,523,430, 5,532,359, 5,510,510, 5,589,485, 5,602,098, European Patent Publ. 0 618 221 , European Patent Publ. 0 675 112, European Patent Publ. 0 604181 , European Patent Publ. 0 696 593, WO 94/19357, WO 95/08542, WO 95/11917, WO 95/12612, WO 95/12572, WO 95/10514, U.S. Pat. No. 5,661 ,152, WO 95/10515, WO 95/10516, WO 95/24612, WO 95/34535, WO 95/25086, WO 96/05529, WO 96/06138, WO 96/06193, WO 96/16443, WO 96/21701 , WO 96/21456, WO 96/22278, WO 96/24611 , WO 96/24612, WO 96/05168, WO 96/05169, WO 96/00736, U.S. Patent 5,571 ,792, WO 96/17861 , WO 96/33159, WO 96/34850, WO 96/34851 , WO 96/30017, WO 96/30018, WO 96/30362, WO 96/30363, WO 96/31111 , WO 96/31477, WO 96/31478, WO 96/31501 , WO 97/00252, WO 97/03047, WO 97/03050, WO 97/04785, WO 97/02920, WO 97/17070, WO 97/23478, WO 97/26246, WO, 97/30053, WO 97/44350, WO 98/02436, and U.S. Patent 5,532,359. For an example of the role of a prenyl-protein transferase inhibitor on angiogenesis see European of Cancer, Vol. 35, No. 9, pp.1394-1401(1999). Examples of farnesyl protein transferase inhibitors include
SARASAR™(4-[2-[4-[(11 R)-3,10-dibromo-8-chloro-6,11-dihydro-5H- benzo[5,6]cyclohepta[1 ,2-b]pyridin-11 -yl-]-1 -piperidinyl]-2-oxoehtyl]-1 - piperidinecarboxamide from Schering-Plough Corporation, Kenilworth, New Jersey), tipifarnib (Zarnestra® or R115777 from Janssen Pharmaceuticals), L778.123 (a farnesyl protein transferase inhibitor from Merck & Company, Whitehouse Station, New Jersey), BMS 214662 (a farnesyl protein transferase inhibitor from Bristol-Myers Squibb Pharmaceuticals, Princeton, New Jersey).
The phrase "angiogenesis inhibitors" refers to compounds that inhibit the formation of new blood vessels, regardless of mechanism. Examples of angiogenesis inhibitors include, but are not limited to, tyrosine kinase inhibitors, such as inhibitors of the tyrosine kinase receptors Flt-1 (VEGFR1 ) and Flk-1/KDR (VEGFR2), inhibitors of epidermal-derived, fibroblast-derived, or platelet derived growth factors, MMP (matrix metalloprotease) inhibitors, integrin blockers, interferon-α (for example lntron and Peg-lntron), interleukin-12, pentosan polysulfate, cyclooxygenase inhibitors, including nonsteroidal anti-inflammatories (NSAIDs) like aspirin and ibuprofen as well as selective cyclooxygenase-2 inhibitors like celecoxib and rofecoxib (PNAS, Vol. 89, p. 7384 (1992); JNCI, Vol. 69, p. 475 (1982); Arch. Opthalmol., Vol. 108, p.573 (1990); Anat. Rec, Vol. 238, p. 68 (1994); FEBS Letters, Vol. 372, p. 83 (1995); Clin. Orthop. Vol. 313, p. 76 (1995); J. MoI. Endocrinol., Vol. 16, p.107 (1996); Jpn. J. Pharmacol., Vol. 75, p.105 (1997); Cancer Res., Vol. 57, p.1625 (1997); Cell, Vol. 93, p. 705 (1998); Intl. J. MoI. Med., Vol. 2, p. 715 (1998); J. Biol. Chem., Vol. 274, p. 9116 (1999)), steroidal antiinflammatories (such as corticosteroids, mineralocorticoids, dexamethasone, prednisone, prednisolone, methylpred, betamethasone), carboxyamidotriazole, combretastatin A-4, squalamine, 6-O-chloroacetyl- carbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , angiotensin Il antagonists (see Fernandez et al., J. Lab. Clin. Med. 105:141-145 (1985)), and antibodies to VEGF (see, Nature Biotechnology, Vol. 17, pp. 963-968 (October 1999); Kim et al., Nature, 362, 841-844 (1993); WO 00/44777; and WO 00/61186).
Other therapeutic agents that modulate or inhibit angiogenesis and may also be used in combination with the compounds of the instant invention include agents that modulate or inhibit the coagulation and fibrinolysis systems (see review in CHn. Chem. La. Med. 38:679-692
(2000)). Examples of such agents that modulate or inhibit the coagulation and fibrinolysis pathways include, but are not limited to, heparin (see Thromb. Haemost. 80:10-23 (1998)), low molecular weight heparins and carboxypeptidase U inhibitors (also known as inhibitors of active thrombin activatable fibrinolysis inhibitor [TAFIa]) (see Thrombosis Res. 101 :329-354 (2001 )). Examples of TAFIa inhibitors have been described in PCT Publication WO 03/013,526.
The phrase "agents that interfere with cell cycle checkpoints" refers to compounds that inhibit protein kinases that transduce cell cycle checkpoint signals, thereby sensitizing the cancer cell to DNA damaging agents. Such agents include inhibitors of ATR, ATM, the Chk1 and Chk2 kinases and cdk and cdc kinase inhibitors and are specifically exemplified by 7- hydroxystaurosporin, flavopiridol, CYC202 (Cyclacel) and BMS-387032.
The phrase "inhibitors of cell proliferation and survival signaling pathway" refers to agents that inhibit cell surface receptors and signal transduction cascades downstream of those surface receptors. Such agents include inhibitors of EGFR (for example gefitinib and erlotinib), antibodies to EGFR (for example C225), inhibitors of ERB-2 (for example trastuzumab), inhibitors of IGFR, inhibitors of cytokine receptors, inhibitors of MET, inhibitors of PI3K (for example LY294002), serine/threonine kinases (including but not limited to inhibitors of Akt such as described in WO
02/083064, WO 02/083139, WO 02/083140 and WO 02/083138), inhibitors of Raf kinase (for example BAY-43-9006), inhibitors of MEEK (for example CI-1040 and PD-098059), inhibitors of mTOR (for example Wyeth CCI-779), and inhibitors of C-abl kinase (for example GLEEVEC™, Novartis Pharmaceuticals). Such agents include small molecule inhibitor compounds and antibody antagonists.
The phrase "apoptosis inducing agents" includes activators of TNF receptor family members (including the TRAIL receptors).
The invention also encompasses combinations with NSAID's which are selective COX-2 inhibitors. For purposes of this specification NSAID's which are selective inhibitors of COX-2 are defined as those which possess a specificity for inhibiting COX-2 over COX-1 of at least 100 fold as measured by the ratio of IC50 for COX-2 over IC50 for COX-1 evaluated by cell or microsomal assays. Inhibitors of COX-2 that are particularly useful in the instant method of treatment are: 3-phenyl-4-(4-(methylsulfonyl)phenyl)-2- (5H)-furanone; and 5-chloro-3-(4-methylsulfonyl)phenyl-2-(2-methyl-5 pyridinyl)pyridine; or a pharmaceutically acceptable salt thereof.
Compounds that have been described as specific inhibitors of COX-2 and are therefore useful in the present invention include, but are not limited to, parecoxib, CELIEBREX®and BEXTRA® or a pharmaceutically acceptable salt thereof.
Other examples of angiogenesis inhibitors include, but are not limited to, endostatin, ukrain, ranpimase, IM862, 5-methoxy-4-[2-methyl-3-(3- methyl-2-butenyl)oxiranyl]-1-oxaspiro[2,5]oct-6-yl(chloroacetyl)carbamate, acetyldinanaline, 5-amino-1 -[[3,5-dichloro-4-(4- chlorobenzoyl)phenyl]methyl]-1 H-1 ,2,3-triazole-4-carboxamide, CM101 , squalamine, combretastatin, RPI4610, NX31838, sulfated mannopentaose phosphate, 7,7-(carbonyl-bis[imino-N-methyl-4,2-pyrrolocarbonylimino[N- methyl-4,2-pyrrole]-carbonylimino]-bis-(1 ,3-naphthalene disulfonate), and 3- [(2,4-dimethylpyrrol-5-yl)methylene]-2-indolinone (SU5416). As used above, "integrin blockers" refers to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβ3 integrin, to compounds which selectively antagonize, inhibit or counteract binding of a physiological ligand to the αvβs integrin, to compounds which antagonize, inhibit or counteract binding of a physiological ligand to both the αvβ3 integrin and the αvβs integrin, and to compounds which antagonize, inhibit or counteract the activity of the particular integrin(s) expressed on capillary endothelial cells. The term also refers to antagonists of the αvβ6, αvβ8, α-iβ-i, α^β-i, αsβ-i, αββi and αββ4 integrins. The term also refers to antagonists of any combination of αvβ3, αvβ5) αvβ6> ctvβs, αiβi, α2βi, α5βi, αββ! and αββ4 integrins. Some examples of tyrosine kinase inhibitors include N- (trifluoromethylphenyl)-5-methylisoxazol-4-carboxamide, 3-[(2,4- dimethylpyrrol-5- yl)methylidenyl)indolin-2-one, 17-(allylamino)-17- demethoxygeldanamycin, 4-(3-chloro-4-fluorophenylamino)-7-methoxy-6-[3- (4-morpholinyl)propoxyl]quinazoline, N-(3-ethynylphenyl)-6,7-bis(2- methoxyethoxy)-4-quinazolinamine, BIBX1382, 2,3,9,10,11 ,12-hexahydro- 10-(hydroxymethyl)-10-hydroxy-9-methyl-9, 12-epoxy-1 H-diindolo[1 ,2,3- fg:3',2',1 '- kl]pyrrolo[3,4-i][1 ,6]benzodiazocin-1-one, SH268, genistein, STI571 , CEP2563, 4-(3- chlorophenylamino)-5,6-dimethyl-7H-pyrrolo[2,3- d]pyrimidinemethane sulfonate, 4-(3-bromo-4-hydroxyphenyl)amino-6,7- dimethoxyquinazoline, 4-(4'-hydroxyphenyl)amino-6,7-dimethoxyquinazoline, SU6668, STI571A, N-4-chlorophenyl-4-(4-pyridylmethyl)-1- phthalazinamine, and EMD121974.
Combinations with compounds other than anti-cancer compounds are also encompassed in the instant methods. For example, combinations of the present compounds with PPAR-γ (i.e., PPAR-gamma) agonists and PPAR-δ (i.e., PPAR-delta) agonists are useful in the treatment of certain malingnancies. PPAR-γ and PPAR-δ are the nuclear peroxisome proliferator-activated receptors γ and δ. The expression of PPAR-γ on endothelial cells and its involvement in angiogenesis has been reported in the literature (see J. Cardiovasc. Pharmacol. 1998; 31 :909-913; J. Biol. Chem. 1999;274:9116-9121 ; Invest. Ophthalmol Vis. Sci. 2000; 41 :2309- 2317). More recently, PPAR-γ agonists have been shown to inhibit the angiogenic response to VEGF in vitro; both troglitazone and rosiglitazone maleate inhibit the development of retinal neovascularization in mice (Arch. Ophthamol. 2001 ; 119:709-717). Examples of PPAR-γ agonists and PPAR- γ/α agonists include, but are not limited to, thiazolidinediones (such as DRF2725, CS-011 , troglitazone, rosiglitazone, and pioglitazone), fenofibrate, gemfibrozil, clofibrate, GW2570, SB219994, AR-H039242, JTT-501 , MCC- 555, GW2331 , GW409544, NN2344, KRP297, NP0110, DRF4158, NN622, GI262570, PNU182716, DRF552926, 2-[(5,7-dipropyl-3-trifluoromethyl-1 ,2- benzisoxazol-6-yl)oxy]-2-methylpropionic acid, and 2(R)-7-(3-(2-chloro-4-(4- fluorophenoxy) phenoxy)propoxy)-2-ethylchromane-2-carboxylic acid.
In one embodiment, useful anti-cancer (also known as anti-neoplastic) agents that can be used in combination with the present compounds include, but are not limited, to Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin (ELOXATI N™ from Sanofi-Synthelabo Pharmaeuticals, France),
Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α- Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,
Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, doxorubicin (adriamycin), cyclophosphamide (Cytoxan), gemcitabine, interferons, pegylated interferons, Erbitux and mixtures thereof.
Another embodiment of the present invention is the use of the present compounds in combination with gene therapy for the treatment of cancer. For an overview of genetic strategies to treating cancer, see Hall et al (Am J Hum Genet 61 :785-789,1997) and Kufe et al (Cancer Medicine, 5th Ed, pp 876-889, BC Decker, Hamilton 2000). Gene therapy can be used to deliver any tumor suppressing gene. Examples of such genes include, but are not limited to, p53, which can be delivered via recombinant virus-mediated gene transfer (see U.S. Patent 6,069,134, for example), a uPA/uPAR antagonist ("Adenovirus-Mediated Delivery of a uPA/uPAR Antagonist Suppresses Angiogenesis-Dependent Tumor Growth and Dissemination in Mice," Gene Therapy, August 1998;5(8):1105-13), and interferon gamma (J Immunol 2000;164:217-222). The present compounds can also be administered in combination with one or more inhibitor of inherent multidrug resistance (MDR), in particular MDR associated with high levels of expression of transporter proteins. Such MDR inhibitors include inhibitors of p-glycoprotein (P-gp), such as LY335979, XR9576, OC144-093, R101922, VX853 and PSC833 (valspodar).
The present compounds can also be employed in conjunction with one or more anti-emetic agents to treat nausea or emesis, including acute, delayed, late-phase, and anticipatory emesis, which may result from the use of a compound of the present invention, alone or with radiation therapy. For the prevention or treatment of emesis, a compound of the present invention may be used in conjunction with one or more other anti-emetic agents, especially neurokinin-1 receptor antagonists, 5HT3 receptor, antagonists, such as ondansetron, granisetron, tropisetron, and zatisetron, GABAB receptor agonists, such as baclofen, a corticosteroid such as Decadron (dexamethasone), Kenalog, Aristocort, Nasalide, Preferid, Benecorten or those as described in U.S. Patents 2,789,118, 2,990,401 , 3,048,581 , 3,126,375, 3,929,768, 3,996,359, 3,928,326 and 3,749,712, an antidopaminergic, such as the phenothiazines (for example prochlorperazine, fluphenazine, thioridazine and mesoridazine), metoclopramide or dronabinol. In one embodiment, an anti-emesis agent selected from a neurokinin-1 receptor antagonist, a 5HT3 receptor antagonist and a corticosteroid is administered as an adjuvant for the treatment or prevention of emesis that may result upon administration of the present compounds. Examples of neurokinin-1 receptor antagonists that can be used in conjunction with the present compounds are described in U.S. Patents 5,162,339, 5,232,929, 5,242,930, 5,373,003, 5,387,595, 5,459,270, 5,494,926, 5,496,833, 5,637,699, and 5,719,147, content of which are incorporated herein by reference. In an embodiment, the neurokinin-1 receptor antagonist for use in conjunction with the compounds of the present invention is selected from: 2-(R)-(1-(R)-(3,5- bis(trifluoromethyl)phenyl)ethoxy)-3-(S)-(4-fluorophenyl)-4-(3-(5-oxo-1 H,4H- 1 ,2,4-triazolo)methyl)morpholine, or a pharmaceutically acceptable salt thereof, which is described in U.S. Patent 5,719,147.
A compound of the present invention may also be administered with one or more immunologic-enhancing drug, such as for example, levamisole, isoprinosine and Zadaxin.
Thus, the present invention encompasses the use of the present compounds (for example, for treating or preventing cellular proliferative diseases) in combination with a second compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an immunologic- enhancing drug, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
In one embodiment, the present invention empassesses the composition and use of the present compounds in combination with a second compound selected from: a cytostatic agent, a cytotoxic agent, taxanes, a topoisomerase Il inhibitor, a topoisomerase I inhibitor, a tubulin interacting agent, hormonal agent, a thymidilate synthase inhibitors, antimetabolites, an alkylating agent, a farnesyl protein transferase inhibitor, a signal transduction inhibitor, an EGFR kinase inhibitor, an antibody to EGFR, a C-abl kinase inhibitor, hormonal therapy combinations, and aromatase combinations. The term "treating cancer" or "treatment of cancer" refers to administration to a mammal afflicted with a cancerous condition and refers to an effect that alleviates the cancerous condition by killing the cancerous cells, but also to an effect that results in the inhibition of growth and/or metastasis of the cancer.
In one embodiment, the angiogenesis inhibitor to be used as the second compound is selected from a tyrosine kinase inhibitor, an inhibitor of epidermal-derived growth factor, an inhibitor of fibroblast-derived growth factor, an inhibitor of platelet derived growth factor, an MW (matrix metalloprotease) inhibitor, an integrin blocker, interferon-α, interleukin-12, pentosan polysulfate, a cyclooxygenase inhibitor, carboxyamidotriazole, combretastatin A-4, squalamine, 6-(O-chloroacetylcarbonyl)-fumagillol, thalidomide, angiostatin, troponin-1 , or an antibody to VEGF. In an embodiment, the estrogen receptor modulator is tamoxifen or raloxifene. Also included in the present invention is a method of treating cancer comprising administering a therapeutically effective amount of at least one compound of Formulae I in combination with radiation therapy and at least one compound selected from: an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG- CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, an immunologic-enhancing drag, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
Yet another embodiment of the invention is a method of treating cancer comprising administering a therapeutically effective amount of at least one compound of Formula I in combination with paclitaxel or trastuzumab. The present invention also includes a pharmaceutical composition useful for treating or preventing cellular proliferation diseases (such as cancer, hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, and cellular proliferation induced after medical procedures) that comprises a therapeutically effective amount of at least one compound of Formula I and at least one compound selected from: an estrogen receptor modulator, an androgen receptor modulator, a retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, a PPAR^γ agonist, a PPAR-δ agonist, an inhibitor of cell proliferation and survival signaling, an agent that interfers with a cell cycle checkpoint, and an apoptosis inducing agent.
Another aspect of this invention relates to a method of selectively inhibiting KSP kinesin activity in a subject (such as a cell, animal or human) in need thereof, comprising contacting said subject with at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
Preferred KSP kinesin inhibitors are those which can specifically inhibit KSP kinesin activity at low concentrations, for example, those that cause a level of inhibition of 50% or greater at a concentration of 50μM or less, more preferably 100 nM or less, most preferably 50 nM or less.
Another aspect of this invention relates to a method of treating or preventing a disease or condition associated with KSP in a subject (e.g., human) in need thereof comprising administering a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof to said subject.
A preferred dosage is about 0.001 to 500 mg/kg of body weight/day of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof. An especially preferred dosage is about 0.01 to 25 mg/kg of body weight/day of a compound of Formula I or a pharmaceutically acceptable salt or ester thereof.
The phrases "effective amount" and "therapeutically effective amount" mean that amount of a compound of Formulae I, and other pharmacological or therapeutic agents described herein, that will elicit a biological or medical response of a tissue, a system, or a subject (e.g., animal or human) that is being sought by the administrator (such as a researcher, doctor or veterinarian) which includes alleviation of the symptoms of the condition or disease being treated and the prevention, slowing or halting of progression of one or more cellular proliferation diseases. The formulations or compositions, combinations and treatments of the present invention can be administered by any suitable means which produce contact of these compounds with the site of action in the body of, for example, a mammal or human.
For administration of pharmaceutically acceptable salts of the above compounds, the weights indicated above refer to the weight of the acid equivalent or the base equivalent of the therapeutic compound derived from the salt.
As described above, this invention includes combinations comprising an amount of at least one compound of Formulae I or a pharmaceutically acceptable salt or ester thereof, and an amount of one or more additional therapeutic agents listed above (administered together or sequentially) wherein the amounts of the compounds/ treatments result in desired therapeutic effect.
When administering a combination therapy to a patient in need of such administration, the therapeutic agents in the combination, or a pharmaceutical composition or compositions comprising the therapeutic agents, may be administered in any order such as, for example, sequentially, concurrently, together, simultaneously and the like. The amounts of the various actives in such combination therapy may be different amounts (different dosage amounts) or same amounts (same dosage amounts). Thus, for illustration purposes, a compound of Formula I and an additional therapeutic agent may be present in fixed amounts (dosage amounts) in a single dosage unit (e.g., a capsule, a tablet and the like). A commercial example of such single dosage unit containing fixed amounts of two different active compounds is VYTORIN® (available from Merck Schering-Plough Pharmaceuticals, Kenilworth, New Jersey).
If formulated as a fixed dose, such combination products employ the compounds of this invention within the dosage range described herein and the other pharmaceutically active agent or treatment within its dosage range. Compounds of Formula I may also be administered sequentially with known therapeutic agents when a combination formulation is inappropriate. The invention is not limited in the sequence of administration; compounds of Formula I may be administered either prior to or after administration of the known therapeutic agent. Such techniques are within the skills of persons skilled in the art as well as attending physicians.
The pharmacological properties of the compounds of this invention may be confirmed by a number of pharmacological assays. The inhibitory activity of the present compounds towards KSP may be assayed by methods known in the art, for example, by using the methods as described in the examples.
While it is possible for the active ingredient to be administered alone, it is preferable to present it as a pharmaceutical composition. The compositions of the present invention comprise at least one active ingredient, as defined above, together with one or more acceptable carriers, adjuvants or vehicles thereof and optionally other therapeutic agents. Each carrier, adjuvant or vehicle must be acceptable in the sense of being compatible with the other ingredients of the composition and not injurious to the mammal in need of treatment.
Accordingly, this invention also relates to pharmaceutical compositions comprising at least one compound of Formula I, or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle. For preparing pharmaceutical compositions from the compounds described by this invention, inert, pharmaceutically acceptable carriers can be either solid or liquid. Solid form preparations include powders, tablets, dispersible granules, capsules, cachets and suppositories. The powders and tablets may be comprised of from about 5 to about 95 percent active ingredient. Suitable solid carriers are known in the art, e.g., magnesium carbonate, magnesium stearate, talc, sugar or lactose. Tablets, powders, cachets and capsules can be used as solid dosage forms suitable for oral administration. Examples of pharmaceutically acceptable carriers and methods of manufacture for various compositions may be found in A.
Gennaro (ed.), Remington's Pharmaceutical Sciences, 18th Edition, (1990), Mack Publishing Co., Easton, Pennsylvania.
The term pharmaceutical composition is also intended to encompass both the bulk composition and individual dosage units comprised of more than one (e.g., two) pharmaceutically active agents such as, for example, a compound of the present invention and an additional agent selected from the lists of the additional agents described herein, along with any pharmaceutically inactive excipients. The bulk composition and each individual dosage unit can contain fixed amounts of the afore-said "more than one pharmaceutically active agents". The bulk composition is material that has not yet been formed into individual dosage units. An illustrative dosage unit is an oral dosage unit such as tablets, pills and the like. Similarly, the herein-described method of treating a subject by administering a pharmaceutical composition of the present invention is also intended to encompass the administration of the afore-said bulk composition and individual dosage units.
Additionally, the compositions of the present invention may be formulated in sustained release form to provide the rate controlled release of any one or more of the components or active ingredients to optimize the therapeutic effects. Suitable dosage forms for sustained release include layered tablets containing layers of varying disintegration rates or controlled release polymeric matrices impregnated with the active components and shaped in tablet form or capsules containing such impregnated or encapsulated porous polymeric matrices.
Liquid form preparations include solutions, suspensions and emulsions. As an example may be mentioned water or water-propylene glycol solutions for parenteral injection or addition of sweeteners and opacifiers for oral solutions, suspensions and emulsions. Liquid form preparations may also include solutions for intranasal administration.
Aerosol preparations suitable for inhalation may include solutions and solids in powder form, which may be in combination with a pharmaceutically acceptable carrier, such as an inert compressed gas, e.g. nitrogen.
Also included are solid form preparations that are intended to be converted, shortly before use, to liquid form preparations for either oral or parenteral administration. Such liquid forms include solutions, suspensions and emulsions.
The compounds of the invention may also be deliverable transdermally. The transdermal compositions can take the form of creams, lotions, aerosols and/or emulsions and can be included in a transdermal patch of the matrix or reservoir type as are conventional in the art for this purpose.
The compounds of this invention may also be delivered subcutaneously.
Preferably the compound is administered orally.
Preferably, the pharmaceutical preparation is in a unit dosage form. In such form, the preparation is subdivided into suitably sized unit doses containing appropriate quantities of the active component, e.g., an effective amount to achieve the desired purpose.
The quantity of active compound in a unit dose of preparation may be varied or adjusted from about 1 mg to about 100 mg, preferably from about 1 mg to about 50 mg, more preferably from about 1 mg to about 25 mg, according to the particular application. The actual dosage employed may be varied depending upon the requirements of the patient and the severity of the condition being treated. Determination of the proper dosage regimen for a particular situation is within the skill of the art. For convenience, the total daily dosage may be divided and administered in portions during the day as required.
The amount and frequency of administration of the compounds of the invention and/or the pharmaceutically acceptable salts or esters thereof will be regulated according to the judgment of the attending clinician considering such factors as age, condition and size of the patient as well as severity of the symptoms being treated. A typical recommended daily dosage regimen for oral administration can range from about 1 mg/day to about 500 mg/day, preferably 1 mg/day to 200 mg/day, in two to four divided doses.
Another aspect of this invention is a kit comprising a therapeutically effective amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof and at least one pharmaceutically acceptable carrier, adjuvant or vehicle.
Yet another aspect of this invention is a kit comprising an amount of at least one compound of Formula I or a pharmaceutically acceptable salt or ester thereof and an amount of at least one additional therapeutic agent listed above, wherein the amounts of the two or more ingredients result in desired therapeutic effect.
The invention disclosed herein is exemplified by the following preparations and examples which should not be construed to limit the scope of the disclosure. Alternative mechanistic pathways and analogous structures will be apparent to those skilled in the art.
The following solvents and reagents may be referred to by their abbreviations in parenthesis: Thin layer chromatography: TLC dichloromethane: CH2CI2 ethyl acetate: AcOEt or EtOAc methanol: MeOH trifluoroacetate: TFA triethylamine: Et3N or TEA butoxycarbonyl: n-Boc or Boc nuclear magnetic resonance spectroscopy: NMR liquid chromatography mass spectrometry: LCMS high resolution mass spectrometry: HRMS milliliters: ml_ millimoles: mmol microliters: μl grams: g milligrams: mg room temperature or rt (ambient): about 25°C. dimethoxyethane: DME
EXAMPLES
Illustrating the invention are the following examples which, however, are not to be considered as limiting the invention to their details. Unless otherwise indicated, all parts and percentages in the following examples, as well as throughout the specification, are by weight. Method A
Standard operating procedure (SOP) For Solid Phase Synthesis of
Benzimidazoles
4-Fluoro-3-nitrobenzoyl chloride
oxalyl chloride ►
Figure imgf000116_0001
Figure imgf000116_0002
4-Fluoro-4-nitrobenzoic acid (277 mg, 1.5mmol) was dissolved in DCM (5ml_) and oxalyl chloride was added (630μL, 5 eq.) followed by 2 μl_ DMF. The solution was stirred for 1 h at rt. then concentrated to give 1.5 mmol of acid chloride which is stored under argon and must be used in the next step fresh.
RESIN 1
Figure imgf000117_0001
To Wang resin (3.0mmol) was added DMF (3OmL) and 4-fluoro-3- nitrobenzoic acid (1.66g, 9.0mmol), DIC (1.4ml_, Θ.Ommol) and DMAP (80mg). The mixture was stirred overnight at rt. and filtered. The resin was washed with DMF (4x), i-PrOH, DCM (3x each, Et2O and dried in vacuo.
RESIN 2
Figure imgf000117_0002
To Rink AM resin (Novabiochem, 0.4 mmol) was added a mixture of piperidine and DMF (6ml_, 50%) and the mixture was shaken for 45 min and filtered. The resin was thoroughly washed with DMF, i-PrOH, DCM (3x each), Et2O and dried. To the resin was added DCM (5ml_), DIEA (315μL, 1.8mmol) and freshly prepared 4-fluoro-3-nitrobenzoyl chloride (1.5mmol) in 3mL DCM. The mixture was stirred overnight at rt. then filtered. The resin was washed with DCM, i-PrOH, DCM (3x each), Et2O and dried.
RESIN 3
,NFmoc
Figure imgf000118_0001
To Rink AM resin (Novabiochem, 0.4 mmol) was added a mixture of piperidine and DMF (6ml_, 50%) and the mixture was shaken for 45 min and filtered. The resin was thoroughly washed with DMF, i-PrOH, DCM (3x each), Et2O and dried.
To the resin was added THF (8mL), a mixture of aldehydes (0.4 mmol total) followed by a mixture of acetic acid and deionized water (50%, 800 μl_). The mixture was shaken for 5 min and then NaCNBH3 in THF was added (1 M, 400 μl_). The mixture was shaken for 3 hours at rt. and filtered (handle waste separately due to cyanoborohydride). The resin was washed with THF, H2O, MeOH, THF, DCM (3x each), Et2O and dried.
To the resin was added DCM (5ml_), DIEA (315μL, 1.8mmol) and freshly prepared 4-fluoro-3-nitrobenzoyl chloride (1.5mmol) in 3mL DCM. The mixture was stirred overnight at rt. then filtered. The resin was washed with DCM, i-PrOH, DCM (3x each), Et2O and dried. 4-(R)Amino-3-nitrobenzoic acid analogs
Figure imgf000119_0001
To resin (O.i mmol) was added 5% DIEA in DMF (1 mL) and the amine (2.3 eq.) and the mixture was shaken overnight at rt. To vessels that contain hindered or slow reacting building blocks, a fast reacting building block from the same building block set was added (5 eq) and the mixture was shaken for 3h at rt (capping). The resin was filtered off, washed with DMF, i-PrOH, DCM (3x each), Et2O and dried.
4-(R)Amino-3-aminobenzoic acid analogs
Figure imgf000119_0002
(Fresh anhydrous tin(ll)-chloride and DMF are used for this step)
To resin (O.i mmol) was added a 2M solution of tin(ll)-chloride (fresh, anhydrous) in DMF (anhydrous, 1 ml_) and the mixture was shaken overnight at rt. The resin was filtered off, washed with DMF, i-PrOH, DCM (3x each), Et2O and dried.
Benzimidazole analogs
Figure imgf000120_0001
To resin (O.i mmol) was added DMF (O.δmL) and isothiocyanate (O.δmmol) and the mixture was shaken for 1 day at rt. DIC (79μL, O.δmmol) was injected and the mixture was shaken overnight at rt. The resin was filtered off, washed with DMF, i-PrOH, DCM (3x each), Et2O and dried.
Cleavage
Figure imgf000120_0002
To the resin (0.1-0.2 mmol) was added TFA/H2O (95:5, 1mL) and the mixture was stirred for 1 h at rt. The resin was filtered and washed with acetonitrile (2x2mL). The filtrate was concentrated in vacuo to yield the product.
Method B Similar reaction sequence and conditions to above protocol, however reaction was carried out in solution.
Method C
Compounds were further modified after the cleavage step in Method A
KSP assays: Endpoint assay:
Serial dilutions of the compounds were prepared in a low binding, 96- well microtiter plate (Costar # 3600) using 40% DMSO (Fisher BP231 ). The diluted compounds were added to a 384-well microtiter plate (Fisher 12-565- 506). The following was then added to each well of the 384 microtiter plate: 55 μg/mL purified microtubules (Cytoskeleton TL238), 2.5-10 nM KSP motor domain (made according to Hopkins et al, Biochemistry, (2000) 39, 2805- 2814), 20 mM ACES pH 7.0 (Sigma A-7949), 1 mM EGTA (Sigma E-3889), 1 mM MgCI2 (Sigma M-2670), 25 mM KCI (Sigma P-9333), 10 μM paclitaxel (Cytoskeleton TXD01 ), and 1 mM DTT (Sigma D5545) (final concentration). Following a 10 minute incubation, ATP (Sigma A-3377) (final concentration of ATP: 100μM) was added to start the reaction. The final reaction volume was 25 μl_. Final test compound concentration ranged from 50 μM to 5 nM and in another embodiment from 0.128 nM to 10 μM from. The reaction was incubated for 1 hour at room temperature. The reaction was stopped by the addition of 50 μl_ Biomol green reagent (Biomol AK111 ) per well, and was allowed to incubate for 20 minutes at room temperature. The 384-well microtiter plate was then transferred to an absorbance reader (Molecular Devices SpectraMax plus) and a single measurement was taken at 620 nm. Kinetic assay:
Compound dilutions were prepared as described previously. 25A25 buffer consisted of the following: 25 mM ACES pH 6.9, 2 mM MgOAc (Sigma M-9147), 2 mM EGTA, 0.1 mM EDTA (Gibco 144475-038), 25 mM KCI, 1 mM 2-mercaptoethanol (Biorad 161-0710), 10 μM paclitaxel, and 0.5 mM DTT. Solution 1 consisted of the following: 3.75 mM (final concentration) phosphoenol pyruvic acid (PEP, 2.5 X) (Sigma P-7127), 0.75 mM MgATP (2.5 X) (Sigma A-9187) in 1 X 25A25 buffer. Solution 2 consisted of the following: 100-500 nM KSP motor domain (2 X), 6 U/mL pyruvate kinase/lactate dehydrogenase (2 X) (Sigma P-0294), 110 μg/tnL purified microtubules (2 X), 1.6 μM β-nicotinamide adenine di-nucleotide, reduced form (NADH, 2 X) (Sigma N-8129) in 1 X 25A25 buffer. Compound dilutions (8) were added to a 96-well microtiter plate (Costar 9018), and 40 μl_ of solution 1 was added to each well. The reaction was started by adding 50 μL of solution 2 to each well. The respective final assay concentrations were: 1.5 mM PEP, 0.3 mM MgATP, 50-250 nM KSP motor domain, 3 U/mL pyruvate kinase/lactate dehydrogenase, 55 μg/mL purified microtubules, 0.8 μM NADH (final concentrate). The microtiter plate was then transferred to an absorbance reader and multiple readings were taken for each well in a kinetic mode at 340 nm (25 measurements for each well approximately every 12 seconds, spread approximately over about 5 minutes time span). For each reaction, a rate of change was determined.
Calculations: For both endpoint and kinetic assays, the percent activity for each concentration is calculated using the following equation:
Y = ((X- background)/(positive control - background))*100
Y is the % activity and X is the measured reading (OD620 or rate) For an IC50 determination, the % activity was fit by the following equation using a nonlinear curve-fitting program for sigmoidal dose- responses (variable slopes) (GraphPad Prizm).
Y=Bottom + (Top-Bottom)/(1 +10Λ((LogEC50-X)ΗillSlope)) X is the logarithm of concentration. Y is the response.
Y starts at Bottom and goes to Top with a sigmoid shape. Cell proliferation / viability assay using AlamarBlue dye
A2780 human ovarian cancer cells are seeded at a density of 10,000 cells / well in a 96 well microtiter plate and incubated in 100 ul of complete DMEM (Dulbecco's modified Eagle's medium) plus 10% fetal bovine calf serum for 3-4 hours at 37oC. Test compounds are diluted to the appropriate concentration in DMEM medium and added as equal volume to the respective wells. Control wells receive an equivalent volume of DMEM and DMSO (solvent). Cells are returned to the 37oC / CO2 incubator for 42 hours after which 20 ul of AlamarBlue dye (Trek Diagnostic Systems Inc.) is added. After 6 hours of incubation at 37oC plates are read in a microplate reader for absorbance at two wavelengths, 570 and 600 nm, respectively. Background absorbance at 600 nm is subtracted from the OD reading at 570 nm and the % activity of proliferation is determined by the ratio of the OD differential (570-600) between compound treated and untreated cells.
The KSP inhibitory activities (IC50 values based on end-point assay) for the compounds of the present invention shown in Table 1 below range from 20,000 μM or greater to about 500 μM. In Table I, "M" in "M+H" denotes the exact molecular weight.
Table 1
Figure imgf000124_0001
Figure imgf000125_0001
Figure imgf000126_0001
Figure imgf000127_0001
Figure imgf000128_0001
Figure imgf000129_0001
Figure imgf000130_0001
Figure imgf000131_0001
Figure imgf000132_0001
Figure imgf000133_0001
Figure imgf000134_0001
Figure imgf000135_0001
Figure imgf000136_0001
Figure imgf000137_0001
Figure imgf000138_0001
Figure imgf000139_0001
Figure imgf000140_0001
Figure imgf000141_0001
Figure imgf000142_0001
Figure imgf000143_0001
Figure imgf000144_0001
Figure imgf000145_0001
Figure imgf000146_0001
Figure imgf000147_0001
Figure imgf000148_0001
Figure imgf000149_0001
Figure imgf000150_0001
Figure imgf000151_0001
Figure imgf000152_0001
Figure imgf000153_0001
Figure imgf000154_0001
Figure imgf000155_0001
Figure imgf000156_0001
Figure imgf000157_0001
Figure imgf000158_0001
Figure imgf000159_0001
Figure imgf000160_0001
Figure imgf000161_0001
Figure imgf000162_0001
Figure imgf000163_0001
Figure imgf000164_0001
Figure imgf000165_0001
Figure imgf000166_0001
Figure imgf000167_0001
Figure imgf000168_0001
Figure imgf000169_0001
Figure imgf000170_0001
Figure imgf000171_0001
Figure imgf000172_0001
Figure imgf000173_0001
Figure imgf000174_0001
Figure imgf000175_0001
Figure imgf000176_0001
Figure imgf000177_0001
Figure imgf000178_0001
Figure imgf000179_0001
Figure imgf000180_0001
Figure imgf000181_0001
Figure imgf000182_0001
Figure imgf000183_0001
Figure imgf000184_0001
Figure imgf000185_0001
Figure imgf000186_0001
Figure imgf000187_0001
Figure imgf000188_0001
Inhibition Activity on combination of compound of formula I and II:
As an example, compound #33 in Table I was identified as an inhibitor of the activity of the mitotic kinesin KSP with an IC50 of 0.52 uM (520 nM) in a KSP in vitro assay (AlamarBlue) measuring hydrolysis of ATP in the presence of microtubules. Kinetic analysis employing model discrimination revealed an uncompetitive mode of inhibition (Dynafit kinetic analysis software package (Biokin Ltd.)).
Cell-based activity of compound #33 was assessed in a cellular proliferation assay using cells of the A2780 cancer line: cells were incubated for 48 hours with compound at various concentrations and cellular growth and viability was assessed using an AlamarBlue detection system. Compound #33 when administered on its own was found to inhibit cell proliferation with an IC50 of 15 uM as shown in Figure 1. In an effort to analyze possible synergism between compound #33 and a reference KSP inhibitor, a compound of formula Il having the specific formula
Figure imgf000189_0001
compound 1 ),
A2780 cells were incubated for 48 hours either with concentration series of reference compound alone or in combination with fixed concentrations of compound #33 (3.75 uM, 7.5 uM: see Fig 2). In this study the IC50 for Reference compound 1 was found to be 1.8 nM in the absence of compound #33. Addition of compound #33 at concentrations below its IC50 led to a notable increase in the potency of Reference compound 1 (see Fig 2) with the combination displaying a 2.5 (3.75 uM of compound #33) or 12 fold (7.5 uM of compound #33) improvement in the IC50 when compared to Reference compound 1 alone. This result implies a possible synergistic mechanism between the Reference compound 1 and compound #33.
Affinity Selection-Mass Spectrometry methods to demonstrate positive-cooperative binding to KSP for Reference Compound 1 and a mixture of the test ligands Compound #s 1 and 2 (in Table I):
Hardware and Data Acquisition The size exclusion chromatography (SEC)-based AS-MS hardware configuration used in this study has been described previously.1 Briefly, this system uses continuous SEC to isolate protein-ligand complexes from unbound library members. Samples containing a target protein, protein- ligand complexes, and unbound compounds are injected onto an SEC column, where the complexes are separated from non-binding component by a rapid SEC step. SEC is performed at 4° C using 50 mM pH 7.5 HEPES buffer containing 350 mM NaCI. SEC columns are available from Regis Technologies, Inc. (Morton Grove, IL).2 An Agilent (Palo Alto, CA) isocratic pump (G1310A) fitted with an Agilent online degasser (G1322A) is used for eluant delivery at 300 μL/min. The eluant from the SEC column is passed through a UV detector (Agilent G1314A using a G1313 micro flow cell) where the band containing the protein-ligand complex is identified by its native UV absorbance at 230 nm. After a pause to allow the band to leave the first detector and enter a valving arrangement, the protein-ligand complex peak is automatically transferred to a reverse-phase chromatography column (Higgins Targa-C18, Higgins Analytical Inc.,
1 (a) Annis, D. A.; Athanasopoulos, J.; Curran, P. J.; Felsch, J. S.; Kalghatgi, K.; Lee, W. H.; Nash, H. M.; Oπninati, J. P. A.; Rosner, K. E.; Shipps, G. W., Jr.; Thaddupathy, G. R. A.; Tyler, A. N.; Vilenchik, L.; Wagner, C. R.; Wintner, E. A. Int. J. Mass Spectrom., 2004, 238, 77-83. (b) Nash, H. N.; Birnbaum, S.; Wintner, E. A.; Kalghatgi, K.; Shipps, G. W., Jr.; Jindal, S. U.S. Patent 6,207,861, 2001.
2 Hagestam, I. H.; Pinkerton, T. C. Anal. Chem. 1985, 57, 1757-1763. Mountain View, CA). Ligands are dissociated from the complex and trapped at the head of the RPC column, where they are desalted and eluted into the mass spectrometer using a gradient of 0% to 95% acetonitrile (0.1% formic acid) in water (0.1% formic acid) over five minutes using an Agilent capillary binary pump (G1376A) for eluant delivery at 20 μL/min. To promote dissociation of ligands from the complex the RPC column is maintained at 60° C using an Agilent G1316A column compartment. MS analysis was performed using a Waters LCT "Classic" high resolution time-of-flight mass spectrometer (Manchester, U.K.) with positive-mode ionization occurring from a standard nebulized ESI source with the capillary at 3.5 kV, a desolvation temperature of 180° C, a source temperature of 100° C, and 30 V "cone" and 3 V extraction lens settings.
Sample Preparation The following procedure for an Affinity Competition Experiment (ACE50) between titrant Reference Compound 1 and a mixture of the test ligands Compound #s 1 and 2 (in Table I) is representative: A mixture of test ligands at 40 μM per component is prepared by combining 2 μl_ aliquots of 400 μM stocks of each compound with 16 μL DMSO. 1 μl_ aliquots of this 40 μM per component mixture are combined with 1 μL DMSO aliquots of a serially diluted stock solution of titrant Reference Compound 1 (10, 5, 2.5, ..., 0.078 mM). These 2 μL samples are dissolved in 38 μL of binding buffer (PIPES- buffered saline: 50 mM, pH 7.0 PIPES buffer containing 350 mM NaCI, 1 mM MgCI2, 3.3 μM ADP, and 1 mM DTT). The resulting solutions are mixed by repeated pipetting and clarified by centrifugation at 10,000 g for 10 minutes. To 1.1 μL aliquots of the resulting supernatants is added 1.1 μL 10 μM KSP in binding buffer. Each 2.2 μL experimental sample thus contains 11 pmol (0.4 μg) protein at 5.0 μM concentration in binding buffer plus 0.5 μM test ligands, 2.5 % DMSO, and varying concentrations (125, 62.5 0.98 μM) of the titrant. Duplicate samples thus prepared for each concentration point are incubated at RT 60 minutes then chilled to 4 0C prior to AS-MS analysis of 2.0 μl_ injections.
Data Analysis The data analysis method for ACE50 experiments has been described previously.3 Briefly, for each AS-MS experiment representing a single data point in an ACE50 titration, the areas underlying the extracted ion chromatograms (XICs) for each compound's singly protonated, doubly protonated, and monosodiated ([M + H]+, [M + 2H]2+, [M + Na]+) species are summed. The resulting raw response for each data point is then normalized for the entire titration curve by dividing each ligand's raw response by its highest response in the titration experiment (typically a data point where the titrant concentration is lowest). The titration data is then fit to a variable slope sigmoidal dose-response curve using GraphPad Prism (version 3.02 for Windows, GraphPad Software, San Diego, CA1 www.graphpad.com) with a maximum normalized value of 1.0. The titrant concentration where the fit curve passes through 0.5, as reported by GraphPad, represents the ACE50 value.
In the representative experiment described here, increasing concentrations of the titrant Reference Compound 1 cause an increase in the AS-MS response of ligands Compound #s 1 and 2 (in Table I). This is shown in Figure 3. This result is consistent with positive-cooperative binding.
References -
KSP / kinesin as target
1 ) Blangy, A et al. (1995) Cell 83, 1159-1169 (cloning of human KSP, function in mitosis).
3 Annis, D. A.; Nazef, N.; Chuang, C-C; Scott, M. P.; Nash, H. M. J. Am. Chem. Soc. 2004, 126, 15495-15503 2) Sawin, K. and Mitchison, TJ. (1995) Proc. Natl. Acad. Sci. 92, 4289-4293 (Xenopus Egd5, conserved motor domain, function).
3) Huang, T.-G. and Hackney, D.D. (1994) J. Biol. Chem. 269, 16493-16501 (Drosphila kinesin minimal motor domain definition, expression and purification from E. coli).
4) Kaiser A. et al. (1999) J. Biol. Chem. 274, 18925-18931 (overexpression of KSP motor domain, function in mitosis, inhibition of growth by targeting KSP).
5) Kapoor T.M and Mitchison, T.J. (1999) Proc. Natl. Acad. Sci. 96, 9106- 9111 (use of KSP motor domain, inhibitors thereof).
6) Mayer, T.U. (1999) Science 286, 971-974 (KSP inhibitors as anticancer drugs).
KSP assays (endpoint and kinetics) 7) Wohlke, G. et al. (1997) Cell 90, 207-216 (expression and purification of kinesin motor domain, kinetics assay, endpoint assay).
8) Geladeopoulos, T.P. et al. (1991 ) Anal. Biochem. 192, 112-116 (basis for endpoint assay).
9) Sakowicz, R. et al. (1998) Science 280, 292-295 (kinetics assay). 10) Hopkins, S.C. et al. (2000) Biochemistry 39, 2805-2814 (endpoint and kinetics assay).
11 ) Maliga, Z. et al. (2002) Chem. & Biol. 9, 989-996 (kinetics assay).
Each and every reference (e.g., patent publications, issued patents, or scientific journal publications) mentioned in this patent application is incorporated herein by reference in its entirety for all purposes.
It will be appreciated by those skilled in the art that changes could be made to the embodiments described above without departing from the broad inventive concept thereof. It is understood, therefore, that this invention is not limited to the particular embodiments disclosed, but it is intended to cover modifications that are within the spirit and scope of the invention, as defined by the appended claims.

Claims

CLAIMSWhat is claimed is:
1. A compound of Formula I
Figure imgf000194_0001
Formula I or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -S(=O)2NH2, - S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, - S(=O)2heterocyclyl,
-S(=O)2heteroaryl, cycloalkyl, aryl, heterocyclyl, heteroaryl, -NHC(=O)alkyl, - C(=O)NH2, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, - C(=O)OH, -C(=O)Oalkyl, -C(=O)heterocyclyl, -C(=O)NH(aryl), wherein when each of said cycloalkyl, aryl, heterocyclyl, heteroaryl, and the
"heterocyclyl" and "aryl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six- membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, cycloalkyl, heterocyclyl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl", and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, alkenyl, alkynyl, hydroxyl, cyano, halo, haloalkyl, haloalkoxy, -C(O)OH, - C(=O)Oalkyl, and -C(O)NH2, ; R1 is selected from the group consisting of alkyl, heterocyclyl, - C(=O)aryl, -NH2, -NH(alkyl), -NH(cycloalkyl), -N(alkyl)(cycloalkyl), - NH(heterocyclyl), -N(alkyl)(heterocyclyl), N(alkyl)2, -NH(aryl), -N(alkyl)(aryl), - N(aryl)2, -NH(heteroaryl), -N(alkyl)(heteroaryl), -NHC(=O)-alkyl, - N(alkyl)C(=O)-alkyl, -NHC(=O)Oalkyl, -N(alkyl)C(=O)O-alkyl, wherein each of the aforesaid alkyl, heterocyclyl, and the "alkyl", "cycloalkyl", "aryl", and "heteroaryl" portions of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S- alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -S(=O)2heterocyclyl, - S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), - N(alkyl)2> alkoxy, -NHC(=O)alkyl, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, , - C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, -C(=O)N(alkyl)2 ; wherein when each of said heterocyclyl, aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; R4 is selected from the group consisting of alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, wherein when each of said cycloalkyl, heterocyclyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, heterocyclyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2) -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2) and -C(=O)Oalkyl; with the proviso that:
(1 ) when R is -C(=O)Oalkyl, R1 is NH(aryl) wherein said aryl is optionally substituted, R2 and R3 are both H, and R4 is phenyl, then said R4 phenyl is substituted with at least one haloalkyl group;
(2) when R is -C(=O)Oalkyl, R1 is NH(aryl) or NH(alkyl), wherein the "alkyl" and "aryl" portions of said R1 are independently optionally substituted, R2 and R3 are both H, and R4 is optionally substituted heteroaryl, then said R4 heteroaryl is other than thiophenyl and furanyl;
(3) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, and R1 is NH(aryl) wherein said aryl is unsubstituted or substituted with at least one substituent selected from the group consisting of halo, nitro, and alkyl, then R4 is other than unsubstituted cycloalkyl; (4) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is -NH2, and -CR2R3 is absent, then R4 is other than optionally substituted cycloalkyl;
(5) when R is -C(=O)NH2, then R1 is -NH(alkyl) or -N(alkyl)(aryl), wherein each of said alkyl and aryl are independently optionally substituted; (6) when R is -COOH or -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R1 is -NH(alkyl), or -N(alkyl)2 wherein the "alkyl" portion of each of said R1 is optionally substituted, and -CR2R3 is absent, then R4 is other than unsubstituted cycloalkyl;
(7) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is -NH2, NH(alkyl), or NH(aryl), wherein the "alkyl" and "aryl" portion each of said R1 is optionally independently substituted, then R4 is other than unsubstituted alkyl or alkyl substituted with at least one moiety selected from the group consisting of alkoxy, -N(alkyl)2, heterocyclyl, and heteroaryl; (8) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted , R1 is -NH2, and -C(R2)(R3)- is absent, then R4 is other than optionally substituted cycloalkyl, cycloalkenyl, heterocyclenyl, or heteroaryl;
(9) when R is -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R1 is -NH(heterocyclyl) wherein said heterocyclyl is optionally substituted, R2 and R3 are both H, then R4 is other than optionally substituted heteroaryl;
(10) when R is -C(=O)Oalkyl, wherein said alkyl is optionally substituted, R2 and R3 are both H, and R4 is optionally substituted aryl or heteroaryl, then R1 is other than -NH2 or -NH(alkyl) wherein said alkyl is optionally substituted;
(11 ) when R is -C(=O)OH, -C(R2)(R3)- is absent, and R4 is optionally substituted cycloalkyl, then R1 is other than -NHC(=O)alkyl, -NH(aryl), or - N(alkyl)(aryl) wherein the "alkyl" and "aryl" poritions of said R1 are optionally independently substituted;
(12) when R is -C(=O)OH, R1 is -NH2, and R2 and R3 are both H, then R4 is other than optionally substituted aryl;
(13) when R is -C(=O)Oalkyl wherein said alkyl is optionally substituted, R1 is optionally substituted heterocyclyl or heteroaryl, R2 and R3 are both H, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group;
(14) when R is -C(=O)OH, R1 is optionally substituted heterocyclyl, R2 and R3 are both H, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group; or (15) when R is H or halo, and R4 is aryl, then said R4 aryl is substituted with at least one haloalkyl group,
(16) when R is H, R2 and R3 are both H, R1 is -NH(aryl), and R4 is aryl substituted with at least one haloalkyl group, then said "aryl" of R1 is substituted with group(s) other than halo or haloalkyl; (17) when R is -C(=O)NH(aryl) or -C(=O)N(alkyl)(aryl), then R1 is other than optionally substituted heterocyclyl; or (18) when R is H, R1 is other than -NH2 or-NH(heterocyclyl).
2. The compound of claim 1 , wherein R is selected from the group consisting of -C(=O)NH2, -C(=O)OH, and -C(=O)Oalkyl.
3. The compound of claim 2, wherein said -C(=O)Oalkyl is - C(=O)OCH3.
4. The compound of claim 1 , wherein R is selected from the group consisting of -NHC(=O)alkyl, C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), - C(=O)N(alkyl)2, -C(=O)heterocyclyl, and -C(=O)NH(aryl), wherein when each of the "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, hydroxyl, hydroxyalkyl, alkoxy, -C(O)OH, and -C(O)NH2.
5. The compound of claim 4, wherein R is selected from the group consisting of -NHC(=O)CH3, -C(=O)NHCH2CN, -C(=O)N(CH3)2, - C(=O)NHCH3) -C(=O)NH(CH2)3CH3, -C(=O)NH(CH2)2OH, - C(=O)NH(CH2)2N(CH3)2,
-C(=O)NHCH(CH2OH)(CH(CH3)2), -C(=O)NH, -C(=O)N(CH3)CH2CH2OH, - C(=O)NH-cyclopentyl, C(=O)N(CH3)CH2CH3, -C(=O)NHCH2C(CH3)2CH2OH,
Figure imgf000198_0001
6. The compound of claim 1 , wherein R is selected from the group consisting of -S(O)2NH2, and -S(=O)2alkyl.
7. The compound of claim 6, wherein R is selected from the group consisting of -S(=O)2NH2, -S(=O)2CH3, and -S(=O)2(CH2)2CH3.
8. The compound of claim 1 , wherein R is selected from the group consisting of H, alkyl, cyano, halo, and haloalkyl. wherein said alkyl is optionally substituted with one or two substituents selected from the group consisting of hydroxy, halo, alkoxy and haloalkoxy.
9. The compound of claim 8, wherein R is selected from the group consisting of -H, -CH2OH, -CN, -CF3, -F, and -Br.
10. The compound of claim 1 , wherein R is selected from the group consisting of aryl and heteroaryl, wherein when each of said aryl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring; wherein each of the aforementioned R aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of alkyl, C(O)OH, -C(=O)Oalkyl, and -C(=O)NH2.
11. The compound of claim 10, wherein R is selected from the group consisting of oxazolyl, phenyl, thiophenyl, benzofuranyl, pyrimidinyl, pyrazinyl, and pyrazolyl, each of which is optionally substituted.
12. The compound of claim 11 , wherein R is selected from the group consisting of phenyl,
Figure imgf000200_0001
13. The compound of claim 1 , wherein R is selected from the group consisting of H, -CH2OH, -CN, -CF3, -F, -Br, -S(=O)2NH2, -S(=O)2CH3, -S(=O)2(CH2)2CH3 -C(=O)OCH3l -C(=O)OH, -C(=O)NH2j -C(=O)N(CH3)2l -NHC(=O)CH3l -C(=O)NHCH2CN, -C(=O)NHCH2COOH, -C(=O)NHCH3, - C(=O)NH(CH2)3CH3) -C(=O)NH(CH2)2OH, -C(=O)NH(CH2)2N(CH3)2, -C(=O)NHCH(CH2OH)(CH(CH3)2), -C(=O)NH, -C(=O)N(CH3)CH2CH2OH, - C(=O)NH-cyclopentyl, C(=O)NH-CH2-cyclopropyl, C(=O)N(CH3)CH2CH3, - C(=O)NHCH2C(CH3)2CH2OH, phenyl,
Figure imgf000200_0002
Figure imgf000201_0001
14. The compound of claim 1 , wherein R1 is selected from the group consisting of -NH(alkyl), -N(alkyl)2, -NH(aryl), -N(alkyl)(aryl), -NH(aryl)2, - NH(heteroaryl), -NHC(=O)-alkyl, -N(alkyl)C(=O)-alkyl, -NHC(=O)Oalkyl, - N(alkyl)C(=O)O-alkyl, wherein when each of said "aryl" and "heteroaryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforesaid "alkyl", "aryl", and "heteroaryl" portions of said R1 groups, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, - S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, - S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2, -NH(alkyl), -N(alkyl)2) alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, - C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, - C(=O)N(alkyl)2.
15. The compound of claim 13, wherein R1 is selected from the group consisting of NH(aryl), N(alkyl)(aryl), and wherein said alkyl is CH3, and wherein each of said aryl, optionally with said five- to six-membered heterocyclyl, aryl, or heteroaryl is independently selected from the group
Figure imgf000202_0001
each of which is optionally substituted with 1-3 substituents selected from the group consisting of -S(=O)2NH2, -S(=O)2alkyl, -S(=O)2OH, -
S(=O)2heterocyclyl,
-S-alkyl, -S-haloalkyl, -S=(O)2N(alkyl)2, -S=(O)2NH(alkyl),
S=(O)2NH(haloalkyl), -S=(O)2NH(cycloalkyl), alkoxy, aryloxy, halo, cyano, -
C(=O)alkyl, alkyl, -N(alkyl)2, -C(=O)OH, -C(=O)O-alkyl, haloalkyl, haloalkoxy,
-Oalkylaryl, aryl, heteroaryl, -C(=O)NH2, and -C(=O)NH-alkyl.
16. The compound of claim 14, wherein said 1-3 substituents are independently selected from the group consisting of -S(=O)2NH2, -
S(=O)2CH3, -S(=O)2OH,
Figure imgf000202_0002
-S-CH3, -S- CF3, -S(=O)2N(CH3)2, -S=(O)2NH(CH3), -S=(O)2NH(CH2)3CI, S=(O)2NH(cyclopropyl), -OCH3, -O(CH2)3CH3, phenoxy, -OCH2-phenyl -F, - CN, -C(=O)CH3) -CH3, -CH(CH3)2, -(CH2)3CH3, -N(CH3J2, C(=O)OH, - C(=O)O-CH3, -CF3, -OCF3, -OCH2-phenyl, phenyl, triazolyl, oxazolyl, pyrazolyl, imidazolyl, and -C(=O)NHCH3.
17. The compound of claim 13, wherein R1 is selected from the group consisting of -NH(heterocyclyl) and -NH(heteroaryl), wherein each of said heterocyclyl and heteroaryl, optionally with said five- to six-membered aryl, or heteroaryl is selected from the group consisting of piperidinyl, pyrazolyl, benzimidazolyl, and benzothiazolyl, each of which is optionally substituted with 1-3 substituents selected from the group consisting of alkyl, aryl, halo, haloalkyl, haloaryl, alkoxy, haloalkoxy, and -C(=O)Oalkyl.
18. The compound of claim 17, wherein R1 is selected from the group consisting of:
Figure imgf000203_0001
is optionally substituted.
19. The compound of claim 13, wherein R1 is selected from the group consisting of -NH(alkyl), -NH(cycloalkyl), -N(alkyl)2, -NHC(=O)-alkyl, - N(alkyl)C(=O)-alkyl, -NHC(=O)Oalkyl, -N(alkyl)C(=O)O-alkyl, wherein each of the aforesaid "alkyl" and "cycloalkyl" portion of said R1 groups is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxyl, -N(alkyl)2, alkynyl, aryl, aryloxy, heterocyclyl, heteroaryl, and -NHC(=O)alkyl, wherein each of said aryl, aryloxy, heterocyclyl and heteroaryl substituents is optionally substituted with 1-3 substituents selected from the group consisting of halo, alkyl, hydroxyl, alkoxy, -S(=O)2alkyl, and -S(=O)2NH2.
20. The compound of claim 18, wherein R1 is selected from the group consisting of -NHCH2-(4-methylphenyl), -NHCH2-(4-methoxyphenyl), - NHCH2-phenyl-S(=O)2CH3, -NH(CH2)2-thiophenyl, -NHC-CChbk-thiophenyl, - NH(CH2)2-pyrrolidinyl, -NH(CH2)2N(CH3)2, -NH(CH2)3N(CH3)2, -NH(CH2)2- piperizinyl, -NH(CH3)CH2N(CH3)2, -NH(CH2)2-piperidinyl-OH, -NH(CH2)2- morpholinyl, -NH(CH2)2-(2-chlorophenyl), -NH(CH2)2-phenyl-S(=O)2NH2, - NH(CH2)2-phenyl-(dimethylisoxazole), -NHCH2CH(OH)-(2-pyridyl), NH(CH2)2-(dimethoxyphenyl), -NH(CH2)2-O-phenyl, -N(CH3)CH2CH2-
(dimethoxyphenyl), -NH(CH2)2-NHC(=O)CH3> -N(CH3)CH2CH2-O-(4- chlrophenyl), -NH(CH2)2-O-(4-methoxyphenyl), -NHC(=O)CH2-phenyl, - NHC(=O)OCH3) -NH-(4-hydroxycyclohexyl), and -NHC(=O)OCH2C≡CH.
21. The compound of claim 1 , wherein R1 is selected from the group consisting of alkyl, cycloalkyl and heterocyclyl, wherein when each of said cycloalkyl and heterocyclyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl; wherein each of said R1 alkyl, cycloalkyl and heterocyclyl, optionally with said five- to six-membered aryl or heteroaryl, is optionally substituted with 1- 3 substituents independently selected from the group consisting of alkyl, cyano, heterocyclyl, aryl, heteroaryl -NH2, -NH(alkyl), -N(alkyl)2, hydroxyl, - NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, -C(=O)H, -C(=O)alkyl, -C(=O)aryl, - C(=O)heteroaryl, -C(=O)NH2, wherein when each of said heterocyclyl, aryl and heteroaryl substituents has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring.
22. The compound of claim 20, wherein R1 is alkyl optionally substituted with 1-2 aryl substitutents wherein said aryl is optionally substituted with 1-3 substituents selected from the group consisting of alkyl, halo, haloalkyl, haloalkoxy, cyano, -S(alkyl), alkoxy, -NHC(=O)alkyl, and - S(=O)2alkyl.
23. The compound of claim 21 , wherein R1 is selected from the group consisting of -CH2-(4-trifluoromethylphenyl), -CH2-(4-isopropylphenyl), -CH2- (4-thiomethylphenyl), -CH2-(4-methoxyphenyl), -CH2-phenyl-S(=O)CH3, and -CH2-phenyl-NHC(=O)CH3.
24. The compound of claim 20, wherein R1 is heterocyclyl which is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, -NH2, hydroxyl, -N(alkyl)2, alkyl, aryl, heteroaryl, - NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, heterocyclyl, -C(=O)H, - C(=O)heteroaryl, C(=O)NH2, when each of the aforesaid aryl and heteroaryl substituents has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring.
25. The compound of claim 23, wherein R1 is selected from the group consisting of:
Figure imgf000205_0001
Figure imgf000206_0001
26. The compound of claim 1 , wherein R1 is selected from the group consisting of: -Nh^, -NH-(4-sulfonamidophenyl), -NH-(4-methoxyphenyl), - NH-(4-fluorophenyl), -NH-(4-cyanophenyl), -NH-(4-acetylphenyl), -NH-(4- methylphenyl), -NH-(4-isopropylphenyl), -NH-(4-butylphenyl) -NH-(4- isopropyloxy-phenyl), -NH-(4-butyloxy-phenyl) -NH(4-dimethylaminophenyl), -NH-(4-carboxyphenyl) -NH-(4-carbomethoxyphenyl), -NH-(4- trifluoromethylphenyl), -NH-(4-trifluoromethoxyphenyl), -NH-(4- phenoxyphenyl), -NH-(4-benzyloxyphenyl), -NH-(4-methylsulfanyl-phenyl), - (4-trifluoromethyl-sulfanyl-phenyl) -NH-(3-fluoro-4-methoxyphenyl), NH-(2- fluoro-4-methoxyphenyl), -NH-(3-chloro-4-methoxyphenyl), phenyl,
Figure imgf000206_0002
Figure imgf000207_0001
Figure imgf000208_0001
-NHCH2-(4-methylphenyl), -NHCH2-(4-methoxyphenyl), -NHCH2-(4- methylsulfonylphenyl), -NH(CH2)2-(2-thiophenyl), -NHCH2C(CH3)2-(2-
thiophenyl),
Figure imgf000208_0002
-NH(CH2)2N(CH3)2, -NH(CH2)3N(CH3)2,
N-(H2C)2 H N I 1 -(H2C)2 ,—- N— I
, -N(CH3)(CH2)2N(CH3)2,
-NHCH(CH3)CH2N(CH3)2,
Figure imgf000208_0003
-NH(CH2)2-(2-chlorophenyl), -NH(CH2)2-(4-sulfonamido-phenyl),
Figure imgf000208_0004
-C(=O)-(4-methoxyphenyl), -NHCH2CH(OH)-(2-pyridyl),
-NH(CH2)2-(3,4-dimethoxyphenyl), -NH(CH2)2-(2,3-dimethoxyphenyl), NH(CH2)2-O-phenyl, -N(CH3)CH2CH2-(dimethoxyphenyl), -NH(CH2)2- NHC(=O)CH3, -N(CH3)CH2CH2-O-(4-chlrophenyl), -NH(CH2)2-O-(4- methoxyphenyl), -NHC(=O)OCH2-phenyl, -NHC(=O)OCH3, -NH-(4- hydroxycyclohexyl), and -NHC(=O)OCH2C≡CH, -CH(CH3)-(4- methoxyphenyl), -CH2-(4-trifluoromethylphenyl), -CH2-(4-isopropylphenyl), - CH2-(4-methylthiophenyl), -CH2-(4-methoxyphenyl), -CH2-(4- methylsulfonylphenyl), and -CH2-(4-acetamidophenyl),
Figure imgf000209_0001
Figure imgf000209_0002
and
Figure imgf000209_0003
27. The compound of claim 1 , wherein R2 and R3 independently are H or alkyl.
28. The compound of claim 27, wherein R2 and R3 are both H.
29. The compound of claim 27, wherein R2 is H, and R3 is alkyl.
30. The compound of claim 27, wherein -C(R2)(R3)- is absent.
31. The compound of claim 1 , wherein R4 is selected from the group consisting of aryl and heteroaryl, wherein when said aryl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl or heteroaryl ring, wherein said R4 aryl and heteroaryl optionally with said five- to six-membered aryl or heteroaryl ring is optionally substituted with 1-3 substituents selected from the group consisting of halo, alkoxy, haloalkoxy, haloalkyl, alkyl, aryl, heterocyclyl, heteroaryl, -NH2, -NH(alkyl), -N(alkyl)2) -S(=O)2alkyl, -S(=O)2NH2, -S-alkyl, - S-haloalkyl, -C(=O)OH, and -C(=O)Oalkyl.
32. The compound of claim 31 , wherein R4 aryl and heteroaryl, optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, naphthyl, benzothiophenyl, benzothiazolyl, pyridyl, thiophenyl, benzimidazolyl, isoxazolyl,
Figure imgf000210_0001
Figure imgf000210_0002
and each of which is optionally substituted.
33. The compound of claim 30, wherein R4 aryl and heteroaryl, optionally with said five- to six-membered aryl or heteroaryl ring are selected from the group consisting of: phenyl, α-naphthyl, 2-naphthyl, 2-pyridyl, 3- pyridyl, 2-thiophenyl,
Figure imgf000211_0001
Figure imgf000211_0002
each of which is optionally substituted.
34. The compound of claim 1 , wherein R4 is cycloalkyl, wherein when said cycloalkyl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl or heteroaryl ring, wherein said cycloalkyl optionally with said five to six-membered aryl or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, alkyl, haloalkyl, haloalkoxy, hydroxy, alkoxy, and aryl.
35. The compound of claim 32, wherein said R4 cycloalkyl, optionally with said five to six-membered aryl or heteroaryl ring, is selected from the group consisting of cyclopropyl,
Figure imgf000211_0004
and
Figure imgf000211_0003
, each of which is optionally substituted.
36. The compound of claim 1 , wherein R4 is alkyl.
37. The compound of claim 36, wherein said R4 alkyl is optionally substituted with 1-2 substituents selected from the group consisting of hydroxyl, halo, alkoxy, haloalkyl, and haloalkoxy.
38. The compound of claim 37, wherein said R4 is -(CH2)i-2θH.
39. The compound of claim 1 , wherein R4 is selected from the group consisting of:
Figure imgf000212_0001
Figure imgf000213_0001
40. The compound of claim 1 , wherein:
R is selected from the group consisting of -C(=O)OH and - C(O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, -
S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2) -
S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2,
-NH(alkyl), -N(alkyl)2> alkoxy, -NC(=O)alkyl, -C(O)H, -C(O)alkyl, - C(O)aryl, , -C(0)heteroaryl, -C(O)0alkyl, -C(O)NH2, -C(O)NHalkyl, and
-C(O)N(alkyl)2; R2 and R3 are independently H and alkyl;
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said aryl optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
41. The compound of claim 40, wherein the "aryl" portion of each of said R1 groups optionally with said five- to six-membered heterocyclyl, aryl, or heteroaryl is independently selected from the group consisting of phenyl, ,
Figure imgf000214_0001
with 1-3 substitutents selected from the group consisting of -S(=O)2NH2, alkoxy, halo, cyano, -C(=O)alkyl, alkyl, -C(=O)O-alkyl, -N(alkyl)2, haloalkyl, haloalkoxy, aryloxy, -S(=O)2alkyl, -S-alkyl, -S(=O)2OH, -S(=O)2heterocyclyl, -S=(O)2N(alkyl)2> -S=(O)2NH(cycloalkyl), -S=(O)2NH(alkyl), -S-haloalkyl, heteroaryl, -C(=O)NH-alkyl, -C(=O)OH, and -C(=O)NH2.
42. The compound of claim 40, wherein said R4 aryl, optionally with said five- to six-membered heterocyclyl, aryl, or heteroaryl is independently selected from the group consisting of phenyl, 1-naphthyl, 2-naphthyl,
Figure imgf000215_0001
each of which is optionally substituted with 1-3 substituents selected from the group consisting of alkoxy, haloalkyl, alkyl, aryl, halo, heterocyclyl, haloalkoxy,
-S(=O)2alkyl, -S(=O)2NH2) -S-alkyl, -C(=O)OH, heteroaryl, heterocyclyl, and
-S-haloalkyl.
43. The compound of claim 40, selected from the group consisting of:
Figure imgf000215_0002
Figure imgf000216_0001
Figure imgf000217_0001
Figure imgf000218_0001
Figure imgf000219_0001
Figure imgf000220_0001
Figure imgf000221_0001
Figure imgf000222_0001
Figure imgf000223_0001
Figure imgf000224_0001
Figure imgf000225_0001
Figure imgf000226_0001
Figure imgf000227_0001
Figure imgf000228_0001
Figure imgf000229_0001
Figure imgf000230_0001
Figure imgf000231_0001
Figure imgf000232_0001
Figure imgf000233_0001
Figure imgf000234_0001
Figure imgf000235_0001
Figure imgf000236_0001
Figure imgf000237_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
44. The compound of claim 1 , wherein:
R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is -NH(aryl) or -N(alkyl)(aryl), wherein when the "aryl" portion of each of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said R1 optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of halo, heterocyclyl, aryl, heteroaryl, haloalkyl, haloalkoxy, aryloxy, cyano, -SH, -S-alkyl, -S-haloalkyl, -S(=O)2alkyl, -S(=O)2OH, - S(=O)2NH2, -S(=O)2NH(alkyl), S(=O)2NH(cycloalkyl), -S(=O)2N(alkyl)2, -
S(=O)2heterocyclyl, -S(=O)2heteroaryl, hydroxy, alkyl, alkenyl, alkynyl, -NH2,
-NH(alkyl), -N(alkyl)2l alkoxy, -NC(=O)alkyl, -C(=O)H, -C(=O)alkyl, -
C(=O)aryl, , -C(=O)heteroaryl, -C(=O)Oalkyl, -C(=O)NH2, -C(O)NHalkyl, and
-C(=O)N(alkyl)2; R2 and R3 are independently H and alkyl; or -CR2R3 is absent
R4 is selected from the group consisting of cycloalkyl and heteroaryl, wherein said cycloalkyl or heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein said cycloalkyl or heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, -S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), - S(=O)2N(alkyl)2, -S-alkyl, -S-haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), - N(alkyl)2, and -C(=O)Oalkyl.
45. The compound of claim 44, wherein the "aryl" portion of each of said R1 groups is phenyl which phenyl is optionally substituted with 1-3 substituents selected from the group consisting of -S-alkyl, -S(=O)2alkyl, - S(=O)2NH2, alkyl, and alkoxy.
46. The compound of claim 44, wherein said R4 cycloalkyl and heteroaryl, optionally with said five- to six-member aryl or heteroaryl is selected from the group consisting of: cyclopropyl, 2-thiophenyl, 2-pyridyl,
Figure imgf000238_0001
Figure imgf000238_0002
which is optionally substituted with 1-3 substituents selected from the group consisting of: hydroxy, halo, aryl, alkyl, -NH2, and haloalkyl.
47. The compound of claim 44, selected from the group consisting of:
Figure imgf000238_0003
Figure imgf000239_0001
Figure imgf000240_0001
Figure imgf000241_0001
Figure imgf000242_0001
Figure imgf000243_0001
Figure imgf000244_0001
Figure imgf000245_0001
Figure imgf000246_0001
Figure imgf000247_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
48. The compound of claim 1 , wherein: R is selected from the group consisting of -C(=O)OH and - C(=O)NH2;
R1 is selected from the group consisting of -NH2, -NH(alkyl), -
NH(cycloalkyl), -NH(heterocyclyl), -NH(heteroaryl) -N(alkyl)2, heterocyclyl, heteroaryl, -NHC(=O)Oalkyl, and -NHC(=O)alkyl, wherein when each of said heterocyclyl, heteroaryl, and the "heterocyclyl" and "cycloalkyl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
49. The compound of claim 48, wherein R1 is selected from the group consisting of -NH(alkyl) and -N(alkyl)2, wherein each alkyl independently is optionally substituted with 1-3 substituents selected from the group consisting of aryl, heteroaryl, heterocyclyl, hydroxy, aryloxy, -N(alkyl)2> wherein each of said aryl, heteroaryl, and heterocyclyl substituents is optionally substituted with 1-3 moieties selected from the group consisting of hydroxy, halo, alkyl, alkoxy, -S(=O)2alkyl, and -S(=O)2NH2.
50. The compound of claim 48, wherein R1 is selected from the group consisting of -NH(cycloalkyl), -NH(heterocyclyl), and -NH(heteroaryl) wherein when each of the "cycloalkyl" "heterocyclyl", and "heteroaryl" portions of said R1 groups is has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, or heteroaryl ring; wherein said "cycloalkyl", "heterocyclyl", and "heteroaryl" portions of said R1 groups, optionally with said five- to six-membered aryl, heterocyclyl, or heteroaryl ring is optionally substituted with 1-3 substituents selected from the group consisting of hydroxy, -C(=O)Oalkyl, alkyl, aryl, heteroaryl, alkoxy, halo, and haloalkoxy.
51. the compound of claim 50, wherein said R1 is selected from the group consisting of: -NH-piperidinyl, -NH-cyclohexyl, -NH-benzimidazolyl, - NH-bezothiazolyl, and -NH-pyrazolyl, each of which is optionally substituted.
52. The compound of claim 48, wherein R1 is selected from the group consisting of heterocyclyl and heteroaryl, wherein when each of said heterocyclyl and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, or heteroaryl ring; wherein said R1 heterocyclyl and heteroaryl, optionally with said five- to six-membered aryl, heterocyclyl, or heteroaryl ring, is optionally substituted with 1-3 substituents selected from the group consisting of - NH2, hydroxy, cyano, alkyl,
-NH(alkyl), -N(alkyl)2, -NHC(=O)alkyl, -C(=O)Oalkyl, alkoxy, heterocyclyl, aryl, heteroaryl, and -C(=O)heteroaryl.
53. The compound of claim 52, wherein said R1 is selected from the group consisting of pyrrolidinyl, piperidinyl, and piperizinyl, each of which is optionally substituted.
54. The compound of claim 48, wherein R2 and R3 are both H.
55. The compound of claim 48, wherein R4 is aryl optionally substituted with at least one haloalkyl group.
56. The compound of claim 48, selected from the group consisting of:
Figure imgf000249_0001
Figure imgf000250_0001
Figure imgf000251_0001
Figure imgf000252_0001
Figure imgf000253_0001
Figure imgf000254_0001
Figure imgf000255_0001
Figure imgf000256_0001
Figure imgf000257_0001
Figure imgf000258_0001
Figure imgf000259_0001
Figure imgf000260_0001
or a pharmaceutically acceptable salt, solvate or ester thereof.
57. The compound of claim 1 , wherein:
R is-C(=O)OH.
R1 is alkyl optionally substituted with at least one aryl substituent, wherein when said aryl substituent has two moieties on adjacent carbon atoms, said moieties, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independently are H and alkyl; and
R4 is aryl, wherein when said aryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring.
58. The compound of claim 57, wherein R1 is alkyl substituted with an aryl substituent, wherein said aryl substituent is substituted with at least one group selected from the group consisting of: haloalkyl, alkyl, -S-alkyl, alkoxy, -S(=O)2alkyl, and -NH-C(=O)alkyl.
59. The compound of claim 57, wherein R2 and R3 are both H.
60. The compound of claim 57, wherein R4 is aryl optionally substituted with at least one haloalkyl group.
61. The compound of claim 57, selected from the group consisting of:
Figure imgf000261_0001
Figure imgf000262_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
62. The compound of claim 1 , wherein:
R is -C(=O)Oalkyl;
R1 is selected from the group consisting of -NH(alkyl), -NH(aryl), and heterocyclyl, wherein when said heterocyclyl and the "aryl" portion of said - NH(aryl) has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring;
R2 and R3 independenly are H or alkyl, or -C(R2)(R3)- is absent; and
R4 is selected from the group consisting of alkyl, cycloalkyl, aryl, and heteroaryl, wherein when each of said cycloalkyl, aryl, and heteroaryl has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R4 alkyl, cycloalkyl, aryl and heteroaryl, optionally with said five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring is optionally substituted with 1-3 substituents independently selected from the group consisting of cyano, halo, haloalkyl, alkyl, alkoxy, hydroxyl, haloalkoxy, cycloalkyl, heterocyclyl, aryl, heteroaryl, - S(=O)2alkyl, -S(=O)2NH2, -S(=O)2NH(alkyl), -S(=O)2N(alkyl)2, -S-alkyl, -S- haloalkyl, -C(=O)OH, -NH2, -NH(alkyl), -N(alkyl)2, and -C(=O)Oalkyl.
63. The compound of claim 62, wherein R1 is -NH(aryl), wherein said the "aryl" portion of said R1, optionally with said five to six-membered aryl or heteroaryl is optionally substituted with 1-2 substituents independently selected from the group consisting of -S(=O)2NH2 and alkoxy.
64. The compound of claim 62, wherein said R1 is -NH(alkyl) wherein the "alkyl" portion of said R1 is optionally substituted with 1-2 substituents independently selected from the group consisting of - NHC(=O)alkyl and aryl.
65. The compound of claim 62, wherein R1 is heterocyclyl optionally substituted with 1-2 substituents selected from the group consisting of alkyl, -C(O)H, -C(=O)alkyl, and -C(=O)NH2,
66. The compound of claim 62, wherein R2 and R3 are both H.
67. The compound of claim 62, wherein R2 and R3 are both alkyl.
68. The compound of claim 62, wherein -CR2R3- is absent.
69. The compound of claim 62, wherein said R4 is cycloalkyl, wherein said cycloalkyl optionally with said five- to six-membered aryl is optionally substituted with 1-2 substituents independently selected from the group consisting of: aryl, hydroxy,
70. The compound of claim 69, wherein said R4 cycloalkyl, optionally with said five- to six-membered aryl is selected from the group consisting of cyclopropyl and
Figure imgf000264_0001
each of which is optionally substituted.
71. The compound of claim 62, wherein R4 is alkyl, optionally substituted with a hydroxy.
72. The compound of claim 62, wherein said R4 aryl is phenyl, optionally substituted with 1-2 substituents selected from the group consisting of: haloalkyl, -S(=O)2NH2, and halo, and -S(=O)2alkyl.
73. The compound of claim 62, wherein said R4 heteroaryl, optionally with said five- to six-membered aryl is benzothiazolyl, optionally substituted with 1-2 substituents independently selected from the group consisting of halo, alkoxy, haloalkyl, haloalkoxy, haloalkyl, -S(=O)2NH2, and -S(=O)2alkyl.
74. The compound of claim 62 selected from the group consisting of:
Figure imgf000264_0002
Figure imgf000265_0001
Figure imgf000266_0001
Figure imgf000267_0001
Figure imgf000268_0001
or a pharmaceutically acceptable salt, solvate or ester thereof.
75. The compound of claim 1 , wherein:
R is selected from the group consisting of H, alkyl, cyano, haloalkyl, halo, -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2> - C(=O)NH(aryl), -C(=O)heterocyclyl, -S(=O)2alkyl, -S(=O)2NH2, NHC(=O)alkyl, aryl, and heteroaryl, when each of said aryl, heteroaryl, and the "cycloalkyl", "aryl", and "heterocyclyl" portions of said R groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five- to six-membered cycloalkyl, aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of the aforementioned R alkyl, aryl, and heteroaryl, and the "alkyl", "cycloalkyl", "heterocyclyl" and "aryl" portions of said R groups, optionally with said five- to six-membered aryl, heterocycylyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of hydroxy, alkoxy, alkyl, -C(=O)Oalkyl, -COOH, cyano, -NH2, and cycloalkyl;
R1 is selected from the group consisting of alkyl, -NH(aryl), - NH(heteroaryl), -C(=O)aryl, wherein when each of the "aryl", "heteroaryl", and "aryl" portions of said R1 groups has two substituents on adjacent carbon atoms, said substituents, may optionally be taken together with the carbon atoms to which they are attached to form a five to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring; wherein each of said R1 alkyl, and the "aryl", "heteroaryl", and "aryl" portions of said R1 groups optionally with said five- to six-membered aryl, heterocyclyl, heterocyclenyl, or heteroaryl ring, is optionally substituted with 1-3 substituents independently selected from the group consisting of: halo, hydroxy, aryl, alkoxy, alkyl, -COOH, -NH2, -S-alkyl, -S(=O)2NH2 and -S(=O)2alkyl; R2 and R3 are both H; and R4 is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted with 1-3 substituents independently selected from the group consisting halo and haloalkyl.
76. The compound of claim 75, wherein R is selected from the group consisting of -C(=O)NH(alkyl), -C(=O)NH(cycloalkyl), -C(=O)N(alkyl)2, - C(=O)NH(aryl), and -C(=O)heterocyclyl,.
77. The compound of claim 75, wherein R is -NHC(=O)alkyl.
78. The compound of claim 75, wherein R is selected from the group consisting of -S(=O)2alkyl and -S(O)2NH2
79. The compound of claim 75, wherein R is selected from the group consisting of aryl and heteroaryl, each of which is optionally substituted
80. The compound of claim 75, wherein R is selected from the group consisting of halo, cyano, and haloalkyl.
81. The compound of claim 75, wherein R1 is -NH(aryl).
82. The compound of claim 81 , wherein R1 is -NH(phenyl).
83. The compound of claim 75, wherein R1 is -NH(heteroaryl).
84. The compound of claim 83, wherein said heteroaryl is pyridyl.
85. The compound of claim 75, wherein R1 is selected from the group consisting of alkyl and -C(=O)aryl.
86. The compound of claim 75, wherein R4 is aryl.
87. The compound claim 81, wherein R4 is phenyl.
88. The compound of claim 75, wherein R4 is heteroaryl.
89. The compound of claim 83, wherein R4 is benzothiophenyl.
90. The compound of claim 75, selected from the group consisting of:
Figure imgf000270_0001
Figure imgf000271_0001
Figure imgf000272_0001
Figure imgf000273_0001
Figure imgf000274_0001
Figure imgf000275_0001
Figure imgf000276_0001
Figure imgf000277_0001
Figure imgf000278_0001
Figure imgf000279_0001
Figure imgf000280_0001
Figure imgf000281_0001
Figure imgf000282_0001
Figure imgf000283_0001
Figure imgf000284_0001
Figure imgf000285_0001
Figure imgf000286_0001
Figure imgf000287_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
91. An isolated or purified form of a compound of any one of claims 1 , 40, 43, 44, 47, 48, 56, 57, 61 , 62, 74, 75, or 90.
92. A pharmaceutical composition comprising an effective amount of a compound of any one of claims 1 , 40, 43, 44, 47, 48, 56, 57, 61 , 62, 74, 75, 90, or 91 , or a pharmaceutically acceptable salt, solvate, or ester thereof, and a pharmaceutically acceptable carrier.
93. The pharmaceutical composition of claim 92, further comprising one or more compounds selected from the group consisting of an anti-cancer agent, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, and an immunologic- enhancing drug.
94. The pharmaceutical composition of claim 93, wherein the anticancer agent is selected from the group consisting of an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, an inhibitor of cell proliferation and survival signaling, an agent that interferes with a cell cycle checkpoint, and an apoptosis inducing agent.
95. The pharmaceutical composition of claim 94, further comprising one or more anti-cancer agents selected from the group consisting of cytostatic agent, cytotoxic agent, taxane, topoisomerase Il inhibitor, topoisomerase I inhibitor, tubulin interacting agent, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent, farnesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor, antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination, and aromatase combination.
96. The pharmaceutical composition of claim 95, further comprising one or more agents selected from the group consisting of Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone, Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, doxorubicin, cyclophosphamide, gemcitabine, interferons, pegylated interferons, Erbitux and mixtures thereof.
97. A composition comprising a combination of a compound of claim 1 , or pharmaceutically acceptable salt, solvate, or ester thereof, and a compound of formula M
Figure imgf000289_0001
Formula Il or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein in formula II:
R1 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl;
R2 and R? are independently chosen from hydrogen, alkyl, oxaalkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; or R2 and R21 taken together form a 3-to 7-membered ring;
R3 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, oxaalkyl, oxaalkylaryl, substituted oxaalkylaryl, R150-and R15-NH-;
R4 is chosen from hydrogen, alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, substituted alkylheteroaryl, and R16-alkylene-;
R5, Re, R7 and R8 are independently chosen from hydrogen, alkyl, alkoxy, halogen, fluoroalkyl, nitro, dialkylamino, alkylsulfonyl, alkylsulfonamido, sulfonamidoalkyl, sulfonamidoaryl, alkylthio, carboxyalkyl, carboxamido, aminocarbonyl, aryl and heteroaryl;
R15 is chosen from alkyl, aryl, alkylaryl, heteroaryl, alkylheteroaryl, substituted alkyl, substituted aryl, substituted alkylaryl, substituted heteroaryl, and substituted alkylheteroaryl; and
R-16 is chosen from alkoxy, amino, alkylamino, dialkylamino, N- heterocyclyl and substituted N-heterocyclyl;
with the proviso that when R3 is Ri5-NH- attached to carbonyl, both of R2 and R4 must be other than hydrogen.
98. The composition of claim 92, wherein in formula II:
R1 is chosen from hydrogen, alkyl, aryl, substituted alkyl, substituted aryl, heteroaryl, substituted heteroaryl, alkylaryl, alkylheteroaryl and substituted alkylaryl; R2 is chosen from hydrogen, alkyl and substituted alkyl;
R2 is hydrogen; R3 is chosen from alkyl, aryl, alkylaryl, heteroaryl, substituted aryl, substituted alkyl, substituted heteroaryl, oxaalkylaryl, substituted oxaalkylaryl, R150-and R15-NH-;
R4 is chosen from alkyl, aryl, alkylaryl, alkylheteroaryl, substituted alkyl, substituted 30 aryl, and R16-alkylene-;
R5 is hydrogen;
R6, R7 and R8 are independently chosen from hydrogen, halogen, methyl and trifluoromethyl;
R15 is chosen from alkyl, aryl and substituted aryl; and R16 is chosen from alkoxy, amino, alkylamino, dialkylamino and N- heterocyclyl.
99. The compsition of claim 93, wherein in formula II, Ri is chosen from hydrogen, lower alkyl, substituted lower alkyl, benzyl, substituted benzyl, phenyl, naphthyl and substituted phenyl.
100. The composition of claim 94, wherein in formula II, Ri is chosen from hydrogen, ethyl, propyl, methoxyethyl, naphthyl, phenyl, bromophenyl, chlorophenyl, methoxyphenyl, ethoxyphenyl, tolyl, dimethylphenyl, chorofluorophenyl, methylchlorophenyl, ethylphenyl, phenethyl, benzyl, chlorobenzyl, methylbenzyl, methoxybenzyl, tetrahydrofuranylmethyl and (ethoxycarbonyl)ethyl.
101. The composition of claim 92, wherein in formula II, R2 is chosen from hydrogen, lower alkyl and substituted lower alkyl, and Rz is hydrogen.
102. The composition of claim 96, wherein in formula II, R2 is chosen from hydrogen, methyl, ethyl, propyl, methylthioethyl, aminobutyl, (CBZ) aminobutyl, 20 cyclohexylmethyl, benzyloxymethyl, methylsulfinylethyl, methylsulfinylmethyl, hydroxymethyl, benzyl and indolylmethyl.
103. The composition of claim 92, wherein in formula II, R3 is chosen from C1-C13 alkyl; substituted lower alkyl; phenyl; naphthyl; phenyl substituted with one or more halo, lower alkyl, loweralkoxy, nitro, carboxy, methylenedioxy, or trifluoromethyl; biphenylyl; benzyl; phenoxymethyl; halophenoxymethyl; phenylvinyl; heteroaryl; heteroaryl substituted with lower alkyl; and benzyloxymethyl.
104. The composition of claim 98, wherein in formula II, R3 is chosen from ethyl, propyl, chloropropyl, butoxy, heptyl, butyl, octyl, tridecanyl, (ethoxycarbonyl)ethyl, dimethylaminoethyl, dimethylaminomethyl, phenyl, naphthyl, halophenyl, dihalophenyl, cyanophenyl, halo(trifluoromethyl) phenyl, chlorophenoxymethyl, methoxyphenyl, carboxyphenyl, ethylphenyl, tolyl, biphenylyl, methylenedioxyphenyl, methylsulfonylphenyl, methoxychlorophenyl, chloronaphthyl, methylhalophenyl, trifluoromethylphenyl, butylphenyl, pentylphenyl, methylnitrophenyl, phenoxymethyl, dimethoxyphenyl, phenylvinyl, nitrochlorophenyl, nitrophenyl, dinitrophenyl, bis(trifluoromethyl)phenyl, benzyloxyrnethyl, benzyl, furanyl, benzoftiranyl, pyridinyl, indolyl, methylpyridinyl, quinolinyl, picolinyl, pyrazolyl, and imidazolyl.
105. The composition of claim 92, wherein in formula II, R3 is R15-
NH-and R15 is chosen from lower alkyl; cyclohexyl; phenyl; and phenyl substituted with halo, lower alkyl, loweralkoxy, or lower alkylthio.
106. The composition of claim 100, wherein in formula II, R15 is chosen from isopropyl, butyl, cyclohexyl, phenyl, bromophenyl, dichlorophenyl, methoxyphenyl, ethylphenyl, tolyl, trifluoromethylphenyl and methylthiophenyl.
107. The composition of claim 92, wherein in formula II, R4 is chosen from lower alkyl, substituted lower alkyl, cyclohexyl; phenyl substituted with hydroxy, lower alkoxy or lower alkyl; benzyl; heteroarylmethyl; heteroarylethyl; heteroarylpropyl and R16-alkylene-, wherein Ri6 is amino, lower alkylamino, di(lower alkyl)amino, lower alkoxy, or N-heterocyclyl.
108. The composition of claim 102, wherein in formula II, R4 is chosen from methyl, ethyl, propyl, butyl, cyclohexyl, carboxyethyl, carboxymethyl, methoxyethyl, hydroxyethyl, hydroxypropyl, dimethylaminoethyl, dimethylaminopropyl, diethylaminoethyl, diethylarninopropyl, aminopropyl, methylarninopropyl,, 2,2dimethyl-3- (dimethylamino)propyl, 1-cyclohexyl-4-(diethylamino)butyl, aminoethyl, aminobutyl, aminopentyl, aminohexyl, aminoethoxyethyl, isopropylaminopropyl, diisopropylaminoethyl, 1 -methyl-4-(diethylamino)butyl, (t-Boc)aminopropyl, 5 hydroxyphenyl, benzyl, methoxyphenyl, methylmethoxyphenyl, dimethylphenyl, tolyl, ethylphenyl,
(oxopyrrolidinyl)propyl, (methoxycarbonyl)ethyl, benzylpiperidinyl, pyridinylethyl, pyridinylmethyl, morpholinylethyl. morpholinylpropyl, piperidinyl, azetidinylmethyl, azetidinylpropyl pyrrolidinylethyl, pyrrolidinylpropyl, piperidinylmethyl, piperidinylethyl, imidazolylpropyl, imidazolylethyl, (ethylpyrrolidinyl)methyl, (methylpyrrolidinyl)ethyl,
(methylpiperidinyl)propyl, (methylpiperazinyl)propyl, furanylmethyl and indolylethyl.
109. The composition of claim 92, wherein in formula II:
Ri is chosen from lower alkyl, benzyl, substituted benzyl and substituted phenyl;
R2 is chosen from hydrogen, alkyl, substituted lower alkyl and benzyl;
R2- is hydrogen;
R3 is chosen from substituted phenyl and naphthyl;
R4 is chosen from substituted alkyl and R-iβ-alkylene-; R5 is hydrogen or halo;
R6 is hydrogen, methyl or halo;
R7 is hydrogen, halo, methyl or trifluoromethyl;
R8 is hydrogen or halo; and
Ri6 is chosen from di(lower alkylamino), (lower alkyl)amino, amino N- heterocyclyl and substituted N-heterocyclyl.
110. The composition of claim 92, wherein in formula II: Ri is benzyl or halobenzyl;
R2 is chosen from ethyl and propyl; R2- is hydrogen; R3 is substituted phenyl;
R4 is (CH2)mOH or (CH2)pRi6 wherein m is or 3 and p is 1-3; Rs is hydrogen; Re is hydrogen;
R7 is halo; R8 is hydrogen; and R-I6 is chosen from amino, propylamino, and azetidinyl.
111. The composition of claim 92, wherein the compound of formula lected from the group consisting of:
Figure imgf000294_0001
armaceutivally acceptable salt or solvate thereof.
112. The composition of claim 92, wherein the compound of formula ted from the group consisting of:
Figure imgf000294_0002
Figure imgf000295_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
113. The composition of claim 112, wherein the compound of formula Ms
Figure imgf000295_0002
or a pharmaceutically acceptable salt, solvate, or ester thereof.
114. The composition of claim 112, wherein the compound of formula Ms
Figure imgf000296_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
115. A composition comprising a combination of a compound of claim 1 , or pharmaceutically acceptable salt, solvate, or ester thereof, and a compound of formula III
Figure imgf000296_0002
Formula III or a pharmaceutically acceptable salt, solvate, or ester thereof, wherein in Formula III:
Figure imgf000296_0003
is a 5-12 membered nitrogen-containing heterocycle, which is optionally substituted with from one to six R5 groups and which optionally incorporates from one to two additional heteroatoms, selected from N, O and S in the heterocycle ring; a is 0 or I; b is 0 or I; m is 0,1 , or 2; n is 0 to 4;
R1 is selected from:
1 ) H, 2) Ci-C10 alkyl,
3) aryl,
4) C2-C20 alkenyl,
5) C2-C10 alkynyl,
6) C1-C6 perfluoroalkyl, 7) C3-C8 cycloalkyl, and
8) heterocyclyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R2 and R3 are independently selected from: 1 ) H,
2) (C=O)3ObCrC10 alkyl,
3) (C=O)aObaryl,
4) (C=O)3ObC2-C10 alkenyl, 5) (C=O)3ObC2-C10 alkynyl,
6) CO2H1
7) C1-C6 perfluoroalkyl,
8) (C=O)3ObC3-C8 cycloalkyl,
9) (C=O)3Ob heterocyclyl, 1O) SO2NR7R8, and
11) SO2CrC10 alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R4 is independently selected from: I ) (C=O)3ObQ-C10 alkyl, 2) (C=O)aObaryl,
3) (C=O)aObC2-Cio alkenyl,
4) (C=O)3ObC2-C10 alkynyl,
5) CO2H, 6) halo,
7) OH,
8) Ob CrC6 perfluoroalkyl,
9) (C=O)3NR7R8, 1O) CN, 11 ) (C=O)3ObC3-C8 cycloalkyl,
12) (C=O)aObheterocyclyl,
13) SO2NR7R8, and
14) SO2Ci-CiO alkyl, said alkyl, aryl, alkenyl, alkynyl, cycloalkyl, and heterocyclyl is optionally substituted with one or more substituents selected from R5;
R5 is:
I ) (C=O)3ObCrC10 alkyl, 2) (C=O)aObaryl, 3) C2-C10 alkenyl,
4) C2-C10 alkynyl,
5) (C=O)3Ob heterocyclyl
6) CO2H,
7) halo, 8) CN,
9) OH,
10) Ob C1-C6 perfluoroalkyl, 1 I ) O3(C=OJbNR7R8, 12) oxo, 13) CHO,
U) (N=O)R7R8, or 15) (C=O)3ObC3-C8 cycloalkyl, said alkyl, aryl, alkenyl, alkynyl, heterocyclyl, and cycloalkyl optionally substituted with one or more substituents selected from R6;
R6 is selected from:
1 ) (C=O)rOs(C|-Cio)alkyl, wherein r and s are independently O or
1 ,
2) Or(Ci-C3)perfluoroalkyl, wherein r is 0 or 1 ,
3) (C0-C6)alkylene-S(O)mRa, wherein m is 0, 1 , or 2, 4) oxo,
5) OH,
6) halo,
7) CN,
8) (C=O)rOs(C2-C1o)alkenyl> 9) (C=O)rOs(C2-Cio)alkynyl,
10) (C=O)rOs(C3-C6)cycloalkyl,
11 ) (C=O)rOs(Co-C6)alkylene-aryl,
12) (C=O)rOs(Co-C6)alkylene-heterocyclyl,
13) (C=O)rOs(Co-C6)alkylene-N(Rb)2, 14) C(=O)Ra,
15) (C0-C6)alkylene-CO2Ra
16) C(O)H,
17) (C0-C6)alkylene-CO2H, and
18) C(O)N(Rb)2, said alkyl, alkenyl, alkynyl, cycloalkyl, aryl, and heterocyclyl is optionally substituted with up to three substituents selected from Rb, OH, (C|-C6)alkoxy, halogen, CO2H, CN, 0(C=O)C1-C6 alkyl, oxo, and N(Rb)2;
R7 and R8 are independently selected from: 1) H,
2) (C=O)ObCrC10 alkyl, 3) (C=O)ObC3-C8 cycloalkyl,
4) (C=O)Obaryl,
5) (C=O)Obheterocyclyl,
6) Ci-C10 alkyl,
7) aryl,
8) C2-CiO alkenyl,
9) C2-C-I0 alkynyl,
10) heterocyclyl,
11 ) C3-C8 cycloalkyl,
12) SO2R3, and
13) (C=O)NRb 2, said alkyl, cycloalkyl, aryl, heterocylyl, alkenyl, and alkynyl is optionally substituted < with one or more substituents selected from R6, or
R7 and R8 can be taken together with the nitrogen to which they are attached to form a monocyclic or bicyclic heterocycle with 5-7 members in each ring and optionally containing, in addition to the nitrogen, one or two additional heteroatoms selected from N, O, and S, said monocyclic or bicyclic heterocycle optionally substituted with one or more substituents selected from R6;
Ra is (CrC6)alkyl, (C3-C6)cycloalkyl, aryl, or heterocyclyl; and
Rb is H. (Cι-C6)alkyl, aryl, heterocyclyl, (C3-C6)cycloalkyl, (C=O)OC1-C6 alkyl, (C=O)C1-C6 alkyl or S(O)2R3.
116. The composition of claim 115, wherein the compound of formula III is selected from the group consisting of:
Figure imgf000301_0001
Figure imgf000302_0001
Figure imgf000303_0002
or a pharmaceutically acceptable salt, solvate, or ester thereof.
117. The composition of claim 115, wherein the compound of formula I is selected from the group consisting of:
Figure imgf000303_0001
Figure imgf000304_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
118. The composition of claim 117, wherein the compound of formula Ms
Figure imgf000304_0002
or a pharmaceutically acceptable salt, solvate, or ester thereof.
119. The composition of claim 117, wherein the compound of formula Ms
Figure imgf000305_0001
or a pharmaceutically acceptable salt, solvate, or ester thereof.
120. A method of inhibiting KSP activity in a subject in need thereof comprising administering to said subject an effective amount of at least one compound of any one of claims 1 , 40, 43, 44, 47, 48, 56, 57, 61 , 62, 74, 75, 90, or 91 , or a pharmaceutically acceptable salt, solvate, or ester thereof.
121. A method of treating a cellular proliferative disease in a subject comprising administering to said subject in need of such treatment an effective amount of at least one compound of any one of claims 1 , 40, 43, 44, 47, 48, 56, 57, 61 , 62, 74, 75, 90, or 91 , or a pharmaceutically acceptable salt, solvate or ester thereof.
122. The method of claim 116, wherein the cellular proliferative disease is cancer, hyperplasia, cardiac hypertrophy, autoimmune diseases, fungal disorders, arthritis, graft rejection, inflammatory bowel disease, immune disorders, inflammation, cellular proliferation induced after medical procedures.
123. The method of claim 117, wherein the cancer is selected from cancers of the brain, genitourinary tract, cardiac, gastrointestine, liver, bone, nervous system, and lung.
124. The method of claim 117, wherein the cancer is selected from lung adenocarcinama, small cell lung cancer, pancreatic cancer, and breast carcinoma.
125. The method of claim 116, further comprising radiation therapy.
126. The method of claim 116, further comprising administering to the subject at least one compound selected from the group consisting of an anti-cancer agent, a PPAR-γ agonist, a PPAR-δ agonist, an inhibitor of inherent multidrug resistance, an anti-emetic agent, and an immunologic- enhancing drug.
127. The method of claim 117, wherein the disease is cancer.
128. The method of claim 122, further comprising radiation therapy.
129. The method of any one of claims 121 -122, wherein the anticancer agent is selected from the group consisting of an estrogen receptor modulator, an androgen receptor modulator, retinoid receptor modulator, a cytotoxic/cytostatic agent, an antiproliferative agent, a prenyl-protein transferase inhibitor, an HMG-CoA reductase inhibitor, an angiogenesis inhibitor, an inhibitor of cell proliferation and survival signaling, an agent that interferes with a cell cycle checkpoint, and an apoptosis inducing agent.
130. The method of any one of claims 121 -123, further comprising one or more anti-cancer agent selected from the group consisting of cytostatic agent, cytotoxic agent, taxane, topoisomerase Il inhibitor, topoisomerase I inhibitor, tubulin interacting agent, hormonal agent, thymidilate synthase inhibitor, anti-metabolite, alkylating agent, famesyl protein transferase inhibitor, signal transduction inhibitor, EGFR kinase inhibitor, antibody to EGFR, C-abl kinase inhibitor, hormonal therapy combination, and aromatase combination.
131. The method of any one of claims 121 -123, further comprising one or more agents selected from the group consisting of Uracil mustard, Chlormethine, Ifosfamide, Melphalan, Chlorambucil, Pipobroman, Triethylenemelamine, Triethylenethiophosphoramine, Busulfan, Carmustine, Lomustine, Streptozocin, Dacarbazine, Floxuridine, Cytarabine, 6-Mercaptopurine, 6-Thioguanine, Fludarabine phosphate, oxaliplatin, leucovirin, oxaliplatin, Pentostatine, Vinblastine, Vincristine, Vindesine, Bleomycin, Dactinomycin, Daunorubicin, Doxorubicin, Epirubicin, Idarubicin, Mithramycin, Deoxycoformycin, Mitomycin-C, L-Asparaginase, Teniposide 17α-Ethinylestradiol, Diethylstilbestrol, Testosterone, Prednisone, Fluoxymesterone, Dromostanolone propionate, Testolactone,
Megestrolacetate, Methylprednisolone, Methyltestosterone, Prednisolone, Triamcinolone, Chlorotrianisene, Hydroxyprogesterone, Aminoglutethimide, Estramustine, Medroxyprogesteroneacetate, Leuprolide, Flutamide, Toremifene, goserelin, Cisplatin, Carboplatin, Hydroxyurea, Amsacrine, Procarbazine, Mitotane, Mitoxantrone, Levamisole, Navelbene, Anastrazole, Letrazole, Capecitabine, Reloxafine, Droloxafine, Hexamethylmelamine, doxorubicin, cyclophosphamide, gemcitabine, interferons, pegylated interferons, Erbitux and mixtures thereof.
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