WO2009151914A1

WO2009151914A1 - Methods for treating neoplasms with a combination of a plk inhibitor and retinoid

Info

Publication number: WO2009151914A1
Application number: PCT/US2009/044849
Authority: WO
Inventors: Robert Scott Powers
Original assignee: Smithkline Beecham Corporation
Priority date: 2008-05-27
Filing date: 2009-05-21
Publication date: 2009-12-17

Abstract

The present invention provides methods for the treatment of neoplasms with a benzimidazole thiophene compound and a retinoid. A kit and pharmaceutical compositions containing the same, and their use as pharmaceutical agents is also provided

Description

METHODS FOR TREATING NEOPLASMS WITH A COMBINATION OF A PLK INHIBITOR AND A RETINOID

GOVERNMENT LICENSE RIGHTS

The U.S. Government has a paid-up license in this invention and the right in limited circumstances to require the patent owner to license others on reasonable terms provided for by the term of Government Contract or Grant No. 5RO 1 CA124648-02 awarded by the National Cancer Institute (NCI).

FIELD OF THE INVENTION

The present invention relates to novel methods for treating susceptible neoplasms with a combination of agents. Pharmaceutical formulations, a kit and uses of these combinations in therapy are also disclosed.

BACKGROUND OF THE INVENTION

Polo-like kinases ("PLK") are evolutionarily conserved serine/threonine kinases that play critical roles in regulating processes in the cell cycle. PLK plays a role in the entry into and the exit from mitosis in diverse organisms from yeast to mammalian cells. PLK includes PLK1 , PLK2, PLK3 and PLK4.

Overexpression of PLK1 appears to be strongly associated with neoplastic cells (including cancers). A published study has shown high levels of PLK1 RNA expression in >80% of lung and breast tumors, with little to no expression in adjacent normal tissue. Several studies have shown correlations between PLK expression, histological grade, and prognosis in several types of cancer. Significant correlations were found between percentages of PLK- positive cells and histological grade of ovarian and endometrial cancer (P<0.001 ). These studies noted that PLK is strongly expressed in invading endometrial carcinoma cells and that this could reflect the degree of malignancy and proliferation in endometrial carcinoma. Using RT-PCR analysis, PLK overexpression was detected in 97% of esophageal carcinomas and 73% of gastric carcinomas as compared to the corresponding normal tissues. Further, patients with high levels of PLK overexpression in esophageal carcinoma represented a significantly poorer prognosis group than those with low levels of PLK overexpression. In head and neck cancers, elevated mRNA expression of PLK1 was observed in most tumors; a Kaplan-Meier analysis showed that those patients with moderate levels of PLK1 expression survived longer than those with high levels of PLK1 expression.

Analysis of patients with non-small cell lung carcinoma showed similar outcomes related to PLK1 expression.

Retinoids are naturally-occurring or synthetic analogs of vitamin A and play important roles in cell proliferation, differentiation, and apoptosis in several normal or transformed cell types. Retinoids exert the effect in these cellular processes via two classes of ligand-dependent, nuclear hormone receptors of the retinoic acid receptors (RARs) and retinoic X receptors (RXRs). Both classes comprise three subtypes of alpha, beta, and gamma. Chambon, P. (1996) A decade of molecular biology of retinoic acid receptors, FASEB J. 10: 940-954.

Since the achievement of complete remission by ATRA therapy in acute promylelocytic leukemia (APL) patients (See, Huang, ME et. al. (1988) Use of a\\-trans retinoic acid in the treatment of acute promyelocytic leukemia, Blood 72:567-572) retinoids are among the most intensely-researched agents in cancer chemoprevention and chemotherapeutics. To date, ATRA and 9-cis-Retinoic acid (9-cis-RA) are FDA-approved oncology drugs (See, G. M. Wilkes and T.B.Ades (2004) American Cancer Society Consumer Guide to Cancer Drugs, The American Cancer Society and Jones and Bartlett Publishers. ISBN: 0-76372254-5). Am80 has been approved by The Pharmaceutical and Medical Devices Agency in Japan for the treatment of APL. The Pharmaceutical and Medical Devices Agency in Japan, 2005.

PCT Publication Nos. WO2004/014899, WO2007/030359, WO2007/030361 , WO2007/143456, and WO20007/143506 all to SmithKline Beecham Corp. disclose novel benzimidazole thiophene PLK inhibitors. Also disclosed are pharmaceutical compositions containing these compounds, processes for their preparation, methods for treatment of neoplasms using these compounds, and combinations with other chemotherapeutic agents.

5-{6-[(4-Methylpiperazin-1 -yl)methyl]-1 H-benzimidazol-1 -yl}-3-{( 1 R)- 1 -[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

is disclosed in PCT Publication No. WO2007/030361 to SmithKline Beecham Corp. 3-[((1 R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1 H- pyrazol-4-yl)-1 H-benzimidazol-1 -yl]-2-thiophenecarboxamide;

is disclosed in PCT Publication No. WO2007/143456 to SmithKline Beecham Corp.

BRIEF SUMMARY OF THE INVENTION

According to a first aspect of the invention there is provided a method for treating a susceptible neoplasm in a mammal (e.g., a human) in need thereof. The method comprises administering to the mammal a compound of formula (I):

wherein:

^* indicates a chiral carbon R¹ is H, halo, or Het¹, Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =O or OH;

R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl;

R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, SO₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid. In one embodiment, the compound of formula (I) is

or a pharmaceutically acceptable salt thereof.

In one particular embodiment, the compound of formula (I) is

3-[((1 R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1 H- pyrazol-4-yl)-1 H-benzimidazol-1 -yl]-2-thiophenecarboxamide

or a pharmaceutically acceptable salt thereof.

In one embodiment, the retinoid is seleceted from retinoic acid, all-frans-retinoic acid, tamibarotene, 9-c/s-retinoic acid, isotretinoin, Am580, TTNPB, and BMS753.

As another aspect, the present invention provides a method for treating breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, or a haematologic malignancy in a mammal (e.g., human) in need thereof. The method comprises administering to the mammal a compound of formula (I) and a retinoid.

As another aspect, the present invention provides a kit comprising a compound of formula (I) and a retinoid. As another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a retinoid. The pharmaceutical composition may further comprise at least one pharmaceutically acceptable carrier, diluent or excipient.

As another aspect, the present invention provides the use of a compound of formula (I) and a retinoid for the preparation of a medicament for the treatment of a susceptible neoplasm in a mammal.

As another aspect, the present invention provides a pharmaceutical composition comprising a compound of formula (I) and a retinoid for use in the treatment of a susceptible neoplasm in a mammal.

These and other aspects and embodiments of the invention are further described in the detailed description of the invention and the examples which follow.

DETAILED DESCRIPTION OF THE INVENTION

As used herein, "compound(s) of formula (I)" means any compound having the structural formula (I) as defined by the variable definitions provided, possible solvates, including hydrates thereof, and amorphous and crystal forms, including polymorphic forms thereof. In the case of compounds of formula (I) which possess one or more chiral centres, the compounds may be in the form of a racemic mixture, or compositions of one or more isomerically enriched or pure stereoisomers, including enantiomers and disastereomers thereof. Stereoisomerism of the compounds is discussed in further detail below. "Compound(s) of formula (I)" includes the racemic form as well as the enriched or pure enantiomers and diastereomers. It should also be understood that compounds of formula (I) may exist in tautomeric forms other than that shown in the formula and alternative tautomeric forms are also included within "compound(s) of formula (I)."

As used herein, the term "PLK inhibitor" means a compound which exhibits plC₅₀ greater than 6 in a PLK Enzyme Inhibition assay or an IC₅₀ of less than 10 μM in the Cell-Titer GIo or Methlene Blue Cell Growth Inhibition assays, described in the patent literature, including WO2004/014899, WO2007/030361 , WO2007/030359 and WO2007/143456, all to SmithKline Beecham Corp. More particularly a PLK inhibitor is a compound which exhibits a plC₅₀ greater than 7 in the PLK Inhibition assay or an IC₅₀ less than 1 μM in the Cell-Titer GIo or Methylene Blue Cell Growth Inhibition assay using the methods previously described. As used herein, the term "retinoid(s)" means a compound that binds to and activates at least one retinoic acid receptor selected from RARα, RARβ, and RARY and/or a compound that binds to and activates at least one of RARα, RARβ, and RARY and also at least one retinoic X receptor (RXR), including RXRα, RXRβ, and RXRy. Among naturally occurring retinoids (herein natural retinoids, including all-frans-retinoic acid (ATRA), 9-cis-RA, and 13-cis-RA), ATRA binds molecularly with RAR only, 9-cis-RA binds to both RAR and RXR, and 13-cis- RA binds to neither RARs or RXRs directly but is isomerized in cells to become ATRA and hence activates the receptor pathway (Lippman & Lotan, (2000) Advances in the Development of Retinoids as Chemopreventive Agents. Symposium: Diet, Natural Products and Cancer Prevention: Progress and Promise.). However, all three natural retinoids can activate RAR-RXR heterodimers formed following retinoid stimulation (Lippman & Lotan, (2000)). The natural retinoids' binding capacity to RARs is documented (Idres, et al., (2002) Activation of retinoic acid receptor-dependent transcription by all-trans-retinoic acid metabolites and isomers. J. Biol. Chem. 277:31491-31498.) in a competition assay using unlabeled RA isomers and metabolites to compete with the binding of tritiated ATRA to the RARα, RARβ, and RARY isotypes in COS-7 cells expressing ectopic RARα, RARβ, and RARy. The concentration of unlabeled ligand required to inhibit 50% of tritiated ATRA binding to the RA receptors differed among the natural retinoids (Idres et al 2002, page 31493).

In a particular embodiment, "retinoid(s)" as used herein refers to a compound that binds to and activiates RARα, RARβ, or RARy. By "binding to and activating RAR" is meant a retinoid that exhibits an IC₅₀ of less than about 150 μM on at least one isotope RARα, RARβ, or RARy.

As used herein, the term "alkyl" refers to straight or branched hydrocarbon chains containing from 1 to 8 carbon atoms, unless a different number of atoms is specified (e.g., "Ci_₃alkyl"). Examples of "alkyl" as used herein include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, tert-butyl and n-pentyl. As used herein, the term "Ci- ₃alkyl" is intended to describe each individual alkyl group having 1 , 2 or 3 carbons; i.e., methyl, ethyl, n-propyl, and isopropyl. Similarly, the term "alkylene" refers to linear or branched divalent hydrocarbon chains containing from 1 to 8 carbon atoms, unless a different number of atoms is specificed (e.g., "Ci_₃alkylene"). Examples of "alkylene" as used herein include, but are not limited to, methylene, ethylene, propylene, isopropylene, butylene, and isobutylene. "Ci_₃alkylene" is intended to describe each of methylene, ethylene, propylene and isopropylene individually.

The terms "halo" and "halogen" are synonymous and refer to fluoro, chloro, bromo and iodo.

The term "haloalkyl" refers to alkyl, as defined above, substituted by one or more halogen atoms, fluoro, chloro, bromo or iodo. Where the haloalkyl group is defined as having less than 8 carbon atoms, the number of carbon atoms in the group is indicated as, for example, "haloCi.₃alkyl", which indicates that the haloalkykl group has 1 , 2 or 3 carbon atoms. Examples of haloalkyls include but are not limited to perhaloalkyls such as trifluoromethyl, as well as fluoromethyl, difluoromethyl, fluoroethyl, trifluoroethyl, and the like.

As used herein, the term "N-heterocycle" refers to monocyclic saturated or unsaturated non- aromatic groups having 5 or 6 members, including at least one N and optionally 1 additional heteroatom selected from N, O and S, unless a different number of additional heteroatoms is specified. By "additional heteroatom" is meant a heteroatom in addition to the N already specified in the N-heterocycle ring. In all embodiments wherein the heterocycle includes an additional heteroatom, the heteroatoms may be the same or different and are independently selected from N, O and S. N-heterocycles include both groups bound through the N of the N-heterocycle and groups bound through a C of the N-heterocycle. In all embodiments wherein the compound of formula (I) includes two or more N-heterocyclic groups, the N- heterocyclic groups may be the same or different and are independently selected. Examples of N-heterocycles include piperidine, piperazine, pyrrolidine, imidazolidine, morpholine, thiomorpholine and the like.

As used herein, the term "N-heteroaryl" refers to aromatic, monocyclic groups having 5 or 6 members (unless a different number of members is specified) including at least one N and optionally 1 additional heteroatom selected from N, O and S, unless a different number of heteroatoms is specified. By "additional heteroatom" is meant a heteroatom in addition to the N already specified in the N-heteroaryl ring. In all embodiments wherein the heteroaryl includes an additional heteroatom, the heteroatoms may be the same or different and are independently selected from N, O and S. N-heteroaryls include both groups bound through the N of the N-heteroaryl and groups bound through a C of the N-heteroaryl. Examples of N- heteroaryls include pyrrole, imidazole, pyrazole, thiazole, isothiazole, oxazole, isoxazole, pyridine, pyridazine, pyrazine, and pyrimidine.

As used herein, the term "members" (and variants thereof e.g., "membered") in the context of N-heterocyclic and N-heteroaryl groups refers to the total number of ring atoms, including carbon and heteroatoms N, O and/or S. Thus, an example of a 6-membered N-heterocyclic ring is piperidine and an example of a 6-membered N-heteroaryl ring is pyridine.

As used herein, the term "optionally substituted" means unsubstituted groups or rings (e.g., N-heterocycle, and N-heteroaryl rings) and groups or rings substituted with one or more of the same or different specified substituents.

The present invention provides a combination of a PLK inhibitor, particularly a compound of formula (I), and a retinoid for use in therapy. The combination of a compound of formula (I) and a retinoid may be used in the treatment of a condition mediated by PLK, particularly

PLK1. In one embodiment, the combination of a compound of formula (I) and a retinoid may be used in the treatment of a condition attenuated by inhibition of PLK, particularly PLK1. The combination of a compound of formula (I) and a retinoid may be used in the treatment of a susceptible neoplasm.

As used herein, the term "treatment" refers to alleviating the specified condition, eliminating or reducing the symptoms of the condition, slowing or eliminating the progression of the condition and/or preventing or delaying the reoccurrance of the condition in a previously afflicted subject.

A method is provided, for treating a susceptible neoplasm in a mammal (e.g., human) in need thereof. The method comprises administering a compound of formula (I) and a retinoid each in an amount that when used in combination is therapeutically effective.

"Susceptible neoplasm" as used herein refers to neoplasms which are susceptible to treatment with a PLK (particularly PLK1 ) inhibitor and/or which expresses retinoic acid receptor such as RARα. Neoplasms which have been associated with PLK and are therefore susceptible to treatment with a PLK inhibitor are known in the art, and include both primary and metastatic tumors and cancers. See e.g., M. Whitfield et al., (2006) Nature Reviews / Cancer 6:99. Neoplasms which have a translocation of the retinoic acid receptor α gene (RARA) are also known in the art. See e.g., Chen Z, Chen SJ. (1992) RARA and PML genes in acute promyelocytic leukemia. Leuk Lymphoma 8:253-260.

For example, susceptible neoplasms within the scope of the present invention include but are not limited to breast cancer, colon cancer (aka "colo-rectal cancer"), lung cancer

(including small cell lung cancer, non-small cell lung cancer and squamous cell carcinoma), prostate cancer, endometrial cancer, gastric cancers (including Gl stromal tumor, signet ring cell carcinoma and carcinomas of the omentum), ovarian cancers, pancreatic cancers (including pancreatic islet cell carcinoma), liver/hepatocellular carcinoma, renal cell cancer (including Wilms' tumor), sarcoma (including cancers of connective tissue), and haematologic malignancies including but not limited to acute leukemias and aggressive lymphomas and non-Hodgkins lymphomas.

"Acute leukemias" includes acute myeloid leukemias (AML), multiple myeloma, acute promelocytic leukemia (APL) and acute lymphoid leukemias. See, N. Harris, et al., J Clin. One. (1999) 17(12):3835-3849. "Aggressive lymphomas" including highly aggressive lymphomas, is a term of art, which includes Diffuse Large B Cell lymphoma, lymphoblastic lymphoma and Burkitt's lymphoma. See, J. Chan, Hematological One. (2001 ) 19:129-150.

The uses and methods of the present invention utilize a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹, Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =O or OH;

R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof.

In one embodiment, the compounds of the invention are defined wherein only one of R¹ and R² is H. In one embodiment, R¹ is H and R² is halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het².

Het² is a 5 or 6 membered N-heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl, or any subset thereof. The substituents may be the same or different. Examples of groups defining Het² include but are not limited to pyrrolinyl, pyrrolidinyl, imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl and piperazinyl.

The optionally substituent(s) on Het² may be bound to any available carbon or nitrogen of the ring. In one embodiment, Het² is selected from pyrrolidinyl, imidazolidinyl, piperidinyl, morpholinyl, thiomorpholinyl, and piperazinyl, or any subset thereof. In one embodiment, R¹ is H and R² is halo, particularly F, Cl or Br, more particularly Cl or Br.

In another embodiment R¹ is H and R² is CH₂-Het², wherein Het² is as described above. In one embodiment, Het² in the definition of R² is a 6 membered N-heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, S0₂alkyl or alkylene-SO₂alkyl, or any subset thereof. In a particular embodiment, the optional substituents are selected from alkyl and haloalkyl, particularly Ci_₃alkyl and haloCi_₃alkyl, or any subset thereof. In one particular embodiment, Het² in the definition of R² is piperadinyl, piperazinyl or morpholinyl, or any subset thereof and is optionally substituted 1 or 2 times with alkyl, particularly Ci_₃alkyl, or any subset thereof. In one particular embodiment, Het² in the definition of R² is piperadinyl or piperazinyl and is optionally substituted 1 time with alkyl, particularly Ci_₃alkyl, or any subset thereof.

In another embodiment, R¹ is H and R² is CH₂SO₂-alkyl. In one particular embodiment, R¹ is H and R² is CH₂SO₂-Ci-₃alkyl, particularly CH₂SO₂CH₃. In another embodiment, R¹ is H and R² is O-Het², wherein Het² is as described above. In one embodiment R² is O-Het² wherein Het² is a 6 membered N-heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, S0₂alkyl or alkylene-SO₂alkyl, or any subset thereof. In a particular embodiment, the optional substituents are selected from alkyl and haloalkyl, particularly Ci_₃alkyl and haloCi_₃alkyl, or any subset thereof. In one particular embodiment, R² is O-Het² wherein Het² is piperadinyl, piperazinyl or morpholinyl, or any subset thereof and is optionally substituted 1 or 2 times with alkyl, particularly Ci_₃alkyl, or any subset thereof.

In another embodiment, R² is H and R¹ is halo, particularly F, Cl or Br, more particularly Cl or Br.

In another embodiment, R¹ is Het¹ and R² is H. Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =0 (i.e., oxo) or OH. Examples of groups defining Het¹ include but are not limited to pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, and pyrazinyl. The optionally substituent(s) on Het¹ may be bound to any available carbon, sulfur, or nitrogen of the ring. In one embodiment, Het¹ is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyrazinyl and pyridazinyl, or any subset thereof. In one embodiment, Het¹ is selected from pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, and pyrimidinyl, or any subset thereof.

In one particular embodiment, Het¹ is selected from pyrrolyl, pyrazolyl, and imidazolyl, or any subset thereof, more particularly pyrazolyl.

In one embodiment R³ is halo, Ci_₃alkyl, or haloCi_₃alkyl, or any subset thereof. In one particular embodiment, R³ is F, Cl, Br, fluoroCi_₃alkyl, or chloroCi_₃alkyl, or any subset thereof. In one embodiment, R³ is F, Cl, or fluoroCi_₃alkyl, or any subset thereof. In one particular embodiment, R³ is F, Cl, CF₃, CHF₂, CH₂F, CH₂CHF₂, CH₂CH₂F, or CH₂CF₃, or any subset thereof; more particularly R³ is F, Cl or CF₃, or any subset thereof.

In one embodiment, R⁴ is CH₂-Het² or O-Het², or any subset thereof. In one particular embodiment, R⁴ is O-Het². In one embodiment, Het² in the definition of R⁴ is a 6 membered N-heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, SO₂alkyl or alkylene-SO₂alkyl, or any subset thereof. In a particular embodiment, the optional substituents are selected from alkyl and haloalkyl, particularly Ci_₃alkyl and haloCi-₃alkyl, or any subset thereof. In one particular embodiment, Het² in the definition of R⁴ is piperadinyl, piperazinyl or morpholinyl, or any subset thereof and is optionally substituted 1 or 2 times with alkyl, particularly Ci_₃alkyl, or any subset thereof. In one particular embodiment, Het² in the definition of R⁴ is piperadinyl or piperazinyl and is optionally substituted 1 time with alkyl, particularly Ci_₃alkyl, or any subset thereof.

In one embodiment, R³ is F, Cl, or fluoroCi_₃alkyl, and R⁴ is O-Het². In one embodiment, R³ is F, Cl, or fluoroCi-₃alkyl, and R⁴ is O-piperadinyl, O-piperazinyl or O-morpohlinyl, wherein each of the piperadinyl, piperazinyl and morpholinyl is optionally substituted 1 time with alkyl, particularly Ci.₃alkyl, or any subset thereof.

Compounds of the invention exist in stereoisomeric forms (e.g. they contain one or more chiral or asymmetric carbon atoms). The term "chiral" refers to a molecule that is not superimposable on its mirror image. The term "achiral" refers to a molecule that is superimposable on its mirror image.

The term "stereoisomers" refers to compounds which are have a common chemical constitution but differ in the arrangment of the atoms or groups in space. Stereoisomers may be optical isomers or geometric isomers. Optical isomers include both enantiomers and diastereomers. An "enantiomer" is one of a pair of optical isomers containing a chiral carbon atom whose molecular configuration have left- and right-hand (chiral) forms. That is, "enantiomer" refers to each of a pair of optical isomers of a compound which are non- superimposable mirror images of one another. A "diastereomer" is one of a pair of optical isomers of a compound with two or more centers of dissymmetry and whose molecules are not mirror images of one another. The nomenclature of a chiral center is governed by the (R)-(S) system. Whether a particular compound is designated as the "R" or "S" enantiomer according to the system depends upon the nature of the atoms or groups which are bound to the chiral carbon.

Enantiomers differ in their behavior toward plane-polarized light, that is, their optical activity. An enantiomer that rotates plane-polarized light in a clockwise direction is said to be dextrorotatory and is designated by the symbol "d" or "(+)" for positive rotation. An enantiomer that rotates plane-polarized light in the counterclockwise direction is said to be levorotatory and is designated by the symbol "I" or "(-)" for negative rotation. There is no correlation between the configuration of enantiomers and the direction in which they rotate plane-polarized light. There is also no necessary correlation between the (R) and (S) designation and the direction of rotation of the plane-polarized light. The optical activity, or direction of rotation of plane-polarized light, of an enantiomer of a compound of formula (I) may be determined using conventional techniques.

The terms "racemate" and "racemic mixture" as used herein refer to a mixture of the (R)- and the (S)- optical isomers (e.g., enantiomers) of a compound in equal, i.e. 50:50 proportion.

The term "enantiomerically enriched" as used herein refers to preparations comprising a mixture of optical isomers in which the quantity of one enantiomer is higher than the quantity of the other. Thus, "enantiomerically enriched" refers to mixtures of optical isomers wherein the ratio of enantiomer is greater than 50:50. An enantiomerically enriched composition comprises greater than 50% by weight of one enantiomer relative to the other. For example enantiomerically enriched 5-{6-[(Methylsulfonyl)methyl]-1 /-/-benzimidazol-1-yl}-3-({(1 R)-1-[2- (trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxamide refers to a composition comprising greater than 50% by weight of the (R)-enantiomer relative to the (S)-enantiomer of the compound. In one embodiment, an enantiomerically enriched composition comprises at least 75% by weight of one enantiomer relative to the other. In another embodiment, an enantiomerically enriched composition comprises at least 80% by weight of one enantiomer relative to the other. In one particular embodiment, an enantiomerically enriched composition comprises at least 85% by weight of one enantiomer relative to the other.

The term "enantiomerically pure" as used herein refers to enantiomerically enriched compositions comprising at least 90% by weight of one enantiomer relative to the other. In one embodiment, an enantiomerically pure composition comprises at least 95% by weight of one enantiomer relative to the other. In one particular embodiment, an enantiomerically pure composition comprises at least 99% by weight of one enantiomer relative to the other.

In one preferred embodiment, the compounds of formula (I) and pharmaceutically acceptable salts thereof are defined wherein the stereochemistry of the chiral carbon (^*) is R. That is, in on embodiment, the compound of formula (I) is the R-enantiomer of the compound of formula (I) (i.e., a compound of formula (I^R)) or a pharmaceutically acceptable salt thereof:

wherein all variables are as defined herein. Reference to "compounds of formula (I)" in the following description is specifically intended to refer also to compounds of formula (I^R). Specific examples of compounds of formula (I) that may be used in the present invention include those described in the Examples which follow, including racemic mixtures of those compounds, enantiomerically enriched and/or pure compositions of the same and pharmaceutically acceptable salts or free-base versions of the same.

In one preferred embodiment, the compound of formula (I) is 5-{6-[(4-Methylpiperazin-1- yl)methyl]-1 H-benzimidazol-1-yl}-3-{(±)-1-[2-(trifluoromethyl)phenyl]ethoxy}-thiophene-2- carboxamide

or a pharmaceutically acceptable salt thereof.

In one particular preferred embodiment, the compound is 5-{6-[(4-Methylpiperazin-1- yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-thiophene-2- carboxamide

or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, the compound is the free base, 5-{6-[(4-Methylpiperazin-1- yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-(trifluoromethyl)phenyl]ethoxy}-thiophene-2- carboxamide. In another preferred embodiment, the compound of formula (I) is 3-[((±)-1-{2-Chloro-3-[(1- methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol- 1 -yl]-2-thiophenecarboxamide

or a pharmaceutically acceptable salt thereof.

In a particular preferred embodiment, the compound is 3-[((1 R)-1-{2-Chloro-3-[(1-methyl-4- piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol-1-yl]-2- thiophenecarboxamide

or a pharmaceutically acceptable salt thereof.

In one preferred embodiment, the compound is the free base, 3-[((1 R)-1-{2-Chloro-3-[(1- methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl-1 H-pyrazol-4-yl)-1 H-benzimidazol- 1 -yl]-2-thiophenecarboxamide.

It will be appreciated by those skilled in the art that the compounds of formula (I) may be utilized in the form of a pharmaceutically acceptable salt thereof. The pharmaceutically acceptable salts of the compounds of the present invention (or the enantiomerically enriched or pure forms thereof) include conventional salts formed from pharmaceutically acceptable inorganic or organic acids or bases as well as quaternary ammonium salts. More specific examples of suitable acid salts include hydrochloric, hydrobromic, sulfuric, phosphoric, nitric, perchloric, fumaric, acetic, propionic, succinic, glycolic, formic, lactic, maleic, tartaric, citric, palmoic, malonic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, fumaric, toluenesulfonic, methanesulfonic (mesylate), naphthalene-2-sulfonic, benzenesulfonic hydroxynaphthoic, hydroiodic, malic, steroic, tannic and the like. Other acids such as trifluoroacetic and oxalic, while not in themselves pharmaceutically acceptable, may be useful in the preparation of salts useful as intermediates in obtaining the compounds of the invention and their pharmaceutically acceptable salts. Specific examples of suitable basic salts include sodium, lithium, potassium, magnesium, aluminium, calcium, zinc, N, N'- dibenzylethylenediamine, chloroprocaine, choline, diethanolamine, ethylenediamine, N- methylglucamine and procaine salts.

The compounds of formula (I) or pharmaceutically acceptable salts thereof are used in the methods of the invention in combination with a retinoid. Retinoids for use in the present invention typically have affinity for RAR, and particularly for RARα and/or RARβ. However, certain synthetic retinoids, such as 9-cis-retinoic acid also have affinity for RXR. In one embodiment, the retinoid has affinity for RARα (an "RARα agonist").

Examples of specific retinoids that may be used in the present invention include: retinoic acid; all-trans-retinoic acid ("ATRA" also known as "tretinoin"); tamibarotene ("Am80"); 9-cis-retinoic acid ((2E,4E,6Z,8E)-3,7-Dimethyl-9-(2,6,6-trimethylcyclohex-1- enyl)nona-2,4,6,8-tetraenoic Acid) (also known as "9-cis-Tretinoin") (available from Sigma); Isotretinoin ((2Z,4E,6E,8E)-3,7-dimethyl-9-(2,6,6-trimethyl-1-cyclohexenyl)nona-

2,4,6,8-tetraenoic acid) (also known as "13-cis-retinoic acid") (ACCUTANE®); Am580 (4-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphtamido) benzoic acid), See,

M. Gianni, Blood 1996 87(4): 1520- 1531. TTNPB (4-[E-2-(5,6,7,8-Tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1- propenyl]benzoic acid) (also known as "Ro 13-7410") See, M. F. Boehm et al. J. Med. Chem. 1994 37:2930 and RP. Bissonnette et al., MoI. Cell. Biol. 1995 15:5576; and

BMS753 (4-[[(2,3-dihydro-1 , 1 ,3,3-tetramethyl-2-oxo-1 H-inden-5- yl)carbonyl]amino]benzoic acid) See, USPN 6184256. Other RARα agonists known the art may also be used in the present invention.

In one particular embodiment, the present invention provides a method of treating breast cancer in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating ovarian cancer in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating non- small cell lung cancer in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating prostate cancer in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating a haematologic malignancy including lymphoma and leukemia in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating acute leukemia, including acute myeloid leukemia, acute promelocytic leukemia, and acute lymphoid leukemia, in a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

In another particular embodiment, the present invention provides a method of treating an aggressive lymphoma or Non-Hodgkins lymphoma in an animal, such as a mammal (e.g., a human) in need thereof by administering a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid each in an amount that when used in combination is therapeutically effective.

The amount of each of the compound of formula (I) or a pharmaceutically acceptable salt thereof, and the retinoid which are used in the methods of the present invention will depend upon a number of factors. There are variables inherent to the compounds of formula (I), and pharmaceutically acceptable salts thereof, and retinoids including, but not limited to, the following: molecular weight, PLK inhibitory activity at the target kinase, affinity for the retinoic acid receptor, absorption, bioavailability, distribution in the body, tissue penetration, half-life, metabolism, protein binding, and excretion. These variables determine what dose of the compound needs to be administered in order to inhibit the target kinase, or bind to the retinoic acid receptor, by a sufficient percentage and for a sufficient amount of time to have the desired effect on the neoplasm. In general, the goal will be to inhibit the target kinase by 50% or more for as long as possible. The duration of drug exposure will be limited only by the half-life of each of the compounds, and side effects from treatment requiring cessation of dosing. The amount of each compound in the combination will also depend on factors related to patients and disease including, but not limited to, the following: the age, weight, concomitant medications and medical condition of the subject being treated, the precise condition requiring treatment and its severity, the nature of the formulation, and the route of administration.

The amount of each component, the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid, that when used in combination is therapeutically effective is referred to herein as the "therapeutically effective combination." More specifically, as used herein, the term "therapeutically effective combination" means an amount of each of the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid that, when used in combination, is sufficient in the subject to which it is administered, to elicit the biological or medical response of a cell culture, tissue, system, mammal (including human) that is being sought, for instance, by a researcher or clinician. A therapeutically effective combination may require less of the compound of formula (I), or pharmaceutically acceptable salt thereof, and/or the retinoid than would be required to elicit the same biological or medical response when either is used alone. For example, a therapeutically effective combination for the treatment of a susceptible neoplasm is an amount of the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid that, when used in combination, is sufficient to treat the susceptible neoplasm in the subject. In one embodiment of the present invention, the therapeutically effective combination is an amount of each component that is sufficient when used in combination to treat non-small cell lung cancer in a human in need thereof. In another embodiment of the present invention, the therapeutically effective combination is an amount of each component that is sufficient when used in combination to treat a haematologic malignancy in a human in need thereof.

When used together, typically the compound of formula (I) or pharmaceutically acceptable salt thereof, will be given for treatment in the range of 0.1 to 200 mg/kg body weight of recipient (mammal) per day or per dose or per cycle of treatment and the retinoid will be given for treatment in the range of 0.07-1 1 mg/kg body weight / 3 to 140 mg/m² body surface area of recipient (mammal) per day or per dose or per cycle of treatment. In one embodiment, the compound of formula (I) or pharmaceutically acceptable salt thereof will be given for treatment in the range of 1 to 100 mg/kg body weight per day or per dose or per cycle of treatment and the retinoid will be given for treatment in the range of 0.07-1 1 mg/kg body weight / 3 to 140 mg/m² body surface area per day or per dose or per cycle of treatment. Thus, for a 70kg, 5'8" tall adult human being treated for a neoplasm, the actual amount per day would usually be from 1 to 2000 mg of the compound of formula (I) and preferably from about 0.1 to about 500 mg per day, dose, or cycle of treatment; and about 5- 260 mg of the retinoid and preferably from about 45-80 mg of the retinoid per day, dose or cycle of treatment.

The compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid may be given concurrently or sequentially in any order, in separate or a combined (single) pharmaceutical composition, and in a single or multiple doses per day or cycle of treatment. Dosing regimens may vary significantly and will be determined and altered based on clinical experience with the compounds. The full spectrum of dosing regimens may be employed ranging from continuous dosing (with daily doses) to intermittent dosing. The appropriate dose of the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid, and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.

The method of administration will be determined by the formulation, bioavailability of different formulations, the condition being treated, the subject to which the compounds are being administered, and will generally be within the discretion of the skilled clinician or veterinarian. Typically, cancer chemotherapy treatments are administered by intravenous injection and/or orally. In one embodiment, the compound of formula (I) or pharmaceutically acceptable salt thereof is administered by intravenous injection. In one embodiment, the retinoid is administered by intravenous injection or orally.

The compounds of the invention can be used alone in the treatment of such susceptible neoplasms or can be used to provide additive or synergistic effects with one or more other compounds of the invention, or in combination with certain other existing chemotherapies and/or other anti-neoplastic therapies. As used herein, "antineoplastic therapies" includes but is not limited to cytotoxic chemotherapy, hormonal therapy, targeted kinase inhibitors, therapeutic monoclonal antibodies, surgery and radiation therapy. In particular, in methods of treating susceptible neoplasms combination with other chemotherapeutic agents is envisaged as well as combination with surgical therapy and radiation therapy. The term "chemotherapeutic" as used herein refers to any chemical agent having a therapeutic effect on the subject to which it is administered.

"Chemotherapeutic" agents include but are not limited to anti-neoplastic agents, analgesics and anti-emetics. As used herein, "anti-neoplastic agents" include both cytostatic and cytotoxic agents such as but not limited to cytotoxic chemotherapy, hormonal therapy, targeted kinase inhibitors and therapeutic monoclonal antibodies. Further combination therapies according to the present invention thus comprise the administration of a compound of formula (I) or a pharmaceutically acceptable salt thereof, a retinoid and at least one compound of formula (I) or a pharmaceutically acceptable salt thereof, and the use of at least one other cancer treatment method. In one embodiment, combination therapies according to the present invention comprise the administration of at least one compound of formula (I) or pharmaceutically acceptable salt thereof, at least one retinoid and at least one other chemotherapeutic agent. In one particular embodiment, the present invention comprises the administration of at least one compound of formula (I) or pharmaceutically acceptable salt thereof, at least one retinoid and at least one anti-neoplastic agent. In one particular embodiment, the present invention comprises the administration of at least one compound of formula (I) or pharmaceutically acceptable salt thereof, at least one retinoid and at least one anti-emetic. In another embodiment, the present invention provides a pharmaceutical composition as described below further comprising at least one other chemotherapeutic agent, more particularly, the chemotherapeutic agent is an anti-neoplastic agent.

Typically, any chemotherapeutic agent that has activity against a susceptible neoplasm being treated may be utilized in combination with the compounds of formula (I) or pharmaceutically acceptable salts thereof and the retinoid, provided that the particular agent is clinically compatible with therapy employing these components. Typical anti-neoplastic agents useful in the present invention include, but are not limited to, anti-microtubule agents such as diterpenoids and vinca alkaloids; platinum coordination complexes; alkylating agents such as nitrogen mustards, oxazaphosphor-ines, alkylsulfonates, nitrosoureas, and triazenes; antibiotic agents such as anthracyclins, actinomycins and bleomycins; topoisomerase Il inhibitors such as epipodophyllotoxins; antimetabolites such as purine and pyrimidine analogues and anti-folate compounds; topoisomerase I inhibitors such as camptothecins; hormones and hormonal analogues; signal transduction pathway inhibitors; non-receptor tyrosine kinase angiogenesis inhibitors; immunotherapeutic agents; proapoptotic agents; and cell cycle signaling inhibitors. Examples of such agents are well known in the art and may be found in the literature, including in for example PCT Publication Nos. WO2004/014899, WO2007030361 , WO2007/030359, and WO2007143456 all to SmithKline Beecham Corp.

The methods and uses employing these combinations may comprise the administration of the compound of formula (I) or pharmaceutically acceptable salt thereof, the retinoid, and the other chemotherapeutic/anti-neoplastic agent either sequentially in any order or concurrently in separate or combined pharmaceutical compositions and in single or multiple doses per day or cycle of treatment. When combined in the same formulation it will be appreciated that the components of the combination must be stable and compatible with each other. When formulated separately they may be provided in any convenient formulation, in such a manner as are known for such compounds in the art.

When a compound of formula (I) or pharmaceutically acceptable salt thereof, a retinoid and another anti-neoplastic agent are used in combination, the dose of each compound may differ from that when each the compound is used alone. Appropriate doses may be determined by those skilled in the art based on the factors described above. The appropriate dose of the compound of formula (I) or pharmaceutically acceptable salt thereof, the retinoid and the other therapeutically active agent(s) and the relative timings of administration will be selected in order to achieve the desired combined therapeutic effect, and are within the expertise and discretion of the attendant clinician.

The present invention also provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoind for use in therapy, in particular for use in the treatment of a susceptible neoplasm in a mammal (e.g., a human).

In one embodiment, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoind for use in the treatment of breast cancer, ovarian cancer, non-small cell lung cancer, prostate cancer or a haematologic malignancy (including leukemia and lymphoma) in a mammal (e.g., a human).

In one embodiment, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoind for use in the treatment of acute leukemia, including acute myeloid leukemia, acute promelocytic leukemia, and acute lymphoid leukemia in a mammal (e.g., a human).

In one embodiment, the present invention provides a combination comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoind for use in the treatment of an aggressive lymphoma or Non-Hodgkins lymphoma in a mammal (e.g., a human).

In one embodiment, the combination comprises:

or a pharmaceutically acceptable salt thereof and a retinoid, paricularly retinoic acid, all- frans-retinoic acid (ATRA), tamibarotene (Am80), 9-c/s-retinoic acid, Am580, TTNPB, or BMS753; more particularly all-frans-retinoic acid, tamibarotene (Am80), or 9-c/s-retinoic acid.

In one embodiment, the combination comprises 5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H- benzimidazol-1-yl}-3-{(1 R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

or a pharmaceutically acceptable salt thereof, and a retinoid, particularly retinoic acid, all- frans-retinoic acid (ATRA), tamibarotene (Am80), 9-c/s-retinoic acid, Am580, TTNPB, or BMS753; more particularly all-frans-retinoic acid, tamibarotene (Am80) or 9-c/s-retinoic acid. The present invention also provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid for the preparation of a medicament for the treatment of a susceptible neoplasm in a mammal (e.g., a human).

In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid for the preparation of a medicament for the treatment of breast cancer, ovarian cancer, non-small cell lung cancer, prostate cancer or a haematologic malignancy (including leukemia and lymphoma) in a mammal (e.g., a human).

In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid for the preparation of a medicament for the treatment of acute leukemia, including acute myeloid leukemia, acute promelocytic leukemia, and acute lymphoid leukemia in a mammal (e.g., a human).

In one embodiment, the present invention provides the use of a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid for the preparation of a medicament for the treatment of an aggressive lymphoma or Non-Hodgkins lymphoma in a mammal (e.g., a human).

While it is possible that, for use in therapy, a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoind may be administered as raw chemicals, it is typically that such compounds would be presented as the active ingredient of a pharmaceutical composition or formulation. While the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid may be used in the present invention in the form of separate pharmaceutical compositions, as one embodiment, the present invention provides a pharmaceutical composition comprising both a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid. The pharmaceutical composition may further comprise one or more pharmaceutically acceptable carriers, diluents, and/or excipients. The carrier(s), diluent(s) and/or excipient(s) must be acceptable in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. In accordance with another aspect of the invention there is also provided a process for the preparation of a pharmaceutical formulation including admixing a compound of formula (I) or a pharmaceutically acceptable salt thereof, and the retinoid with one or more pharmaceutically acceptable carriers, diluents and/or excipients. Pharmaceutical formulations may be presented in unit dose form containing a predetermined amount of each active ingredient per unit dose. Such a unit may contain a therapeutically effective combination or a fraction of a therapeutically effective combination such that multiple unit dosage forms might be administered at a given time to achieve the desired therapeutically effective dosage. Preferred unit dosage formulations are those containing a daily dose or sub-dose, as herein above recited, or an appropriate fraction thereof, of the active ingredients. Furthermore, such pharmaceutical formulations may be prepared by any of the methods well known in the pharmacy art.

Pharmaceutical formulations may be adapted for administration by any appropriate route, for example by the oral (including buccal or sublingual), rectal, or parenteral (including subcutaneous, intramuscular, intravenous or intradermal) route. Such formulations may be prepared by any method known in the art of pharmacy, for example by bringing into association the active ingredient(s) (i.e., the compound of formula (I) or pharmaceutically acceptable salt thereof and the retinoid) with the carrier(s) or excipient(s).

Pharmaceutical formulations adapted for oral administration may be presented as discrete units such as capsules or tablets; powders or granules; solutions or suspensions in aqueous or non-aqueous liquids; edible foams or whips; or oil-in-water liquid emulsions or water-in-oil liquid emulsions. For instance, for oral administration in the form of a tablet or capsule, the active ingredients can be combined with an oral, non-toxic pharmaceutically acceptable inert carrier such as ethanol, glycerol, water and the like. Powders are prepared by comminuting the active ingredients to a suitable fine size and mixing with a similarly comminuted pharmaceutical carrier such as an edible carbohydrate, as, for example, starch or mannitol. Flavoring, preservative, dispersing and coloring agent can also be present.

Capsules are made by preparing a powder mixture as described above, and filling formed gelatin sheaths. Glidants and lubricants such as colloidal silica, talc, magnesium stearate, calcium stearate or solid polyethylene glycol can be added to the powder mixture before the filling operation. A disintegrating or solubilizing agent such as agar-agar, calcium carbonate or sodium carbonate can also be added to improve the availability of the medicament when the capsule is ingested.

Moreover, when desired or necessary, suitable binders, lubricants, disintegrating agents and coloring agents can also be incorporated into the mixture. Suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes and the like. Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride and the like. Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum and the like. Tablets are formulated, for example, by preparing a powder mixture, granulating or slugging, adding a lubricant and disintegrant and pressing into tablets. A powder mixture is prepared by mixing the active ingredients, suitably comminuted, with a diluent or base as described above, and optionally, with a binder such as carboxymethylcellulose, an aliginate, gelatin, or polyvinyl pyrrolidone, a solution retardant such as paraffin, a resorption accelerator such as a quartemary salt and/or an absorption agent such as bentonite, kaolin or dicalcium phosphate. The powder mixture can be granulated by wetting with a binder such as syrup, starch paste, acadia mucilage or solutions of cellulosic or polymeric materials and forcing through a screen. As an alternative to granulating, the powder mixture can be run through the tablet machine and the result is imperfectly formed slugs broken into granules. The granules can be lubricated to prevent sticking to the tablet forming dies by means of the addition of stearic acid, a stearate salt, talc or mineral oil. The lubricated mixture is then compressed into tablets. The active ingredients can also be combined with a free flowing inert carrier and compressed into tablets directly without going through the granulating or slugging steps. A clear or opaque protective coating consisting of a sealing coat of shellac, a coating of sugar or polymeric material and a polish coating of wax can be provided. Dyestuffs can be added to these coatings to distinguish different unit dosages.

Oral fluids such as solution, syrups and elixirs can be prepared in dosage unit form so that a given quantity contains a predetermined amount of active ingredient. Syrups can be prepared by dissolving the active ingredients in a suitably flavored aqueous solution, while elixirs are prepared through the use of a non-toxic alcoholic vehicle. Suspensions can be formulated by dispersing the active ingredients in a non-toxic vehicle. Solubilizers and emulsifiers such as ethoxylated isostearyl alcohols and polyoxy ethylene sorbitol ethers, preservatives, flavor additive such as peppermint oil or natural sweeteners or saccharin or other artificial sweeteners, and the like can also be added.

Where appropriate, dosage unit formulations for oral administration can be microencapsulated. The formulation can also be prepared to prolong or sustain the release as for example by coating or embedding particulate material in polymers, wax or the like. The compounds of formula (I) or pharmaceutically acceptable salts thereof and the retinoid can also be administered in the form of liposome delivery systems, such as small unilamellar vesicles, large unilamellar vesicles and multilamellar vesicles. Liposomes can be formed from a variety of phospholipids, such as cholesterol, stearylamine or phosphatidylcholines.

The compounds of formula (I) or pharmaceutically acceptable salts thereof and the retinoid may also be delivered by the use of monoclonal antibodies as individual carriers to which the compound molecules are coupled. The active ingredients may also be coupled with soluble polymers as targetable drug carriers. Such polymers can include peptides, polyvinylpyrrolidone, pyran copolymer, polyhydroxypropylmethacrylamide -phenol, polyhydroxyethylaspartamidephenol, or polyethyleneoxidepolylysine substituted with palmitoyl residues. Furthermore, the active ingredients may be coupled to a class of biodegradable polymers useful in achieving controlled release of a drug, for example, polylactic acid, polepsilon caprolactone, polyhydroxy butyric acid, polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates and cross-linked or amphipathic block copolymers of hydrogels.

Pharmaceutical formulations adapted for parenteral administration include aqueous and non-aqueous sterile injection solutions which may contain anti-oxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi- dose containers, for example sealed ampoules and vials, and may be stored in a freeze- dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets.

It should be understood that in addition to the ingredients particularly mentioned above, the formulations may include other agents conventional in the art having regard to the type of formulation in question, for example those suitable for oral administration may include flavouring agents.

In one embodiment, the pharmaceutical formulation comprises:

In one embodiment, the pharmaceutical composition comprises 5-{6-[(4-Methylpiperazin-1- yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2- carboxamide

or a pharmaceutically acceptable salt thereof, and a retinoid, particularly retinoic acid, all- frans-retinoic acid (ATRA), tamibarotene (Am80), 9-c/s-retinoic acid, Am580, TTNPB, or BMS753; more particularly all-frans-retinoic acid, tamibarotene (Am80) or 9-c/s-retinoic acid.

In one particular embodiment, the pharmaceutical composition further comprises a chemotherapeutic agent (as described above).

In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof, and a retinoid for use in the treatment of a susceptible neoplasm. The present invention also provides a kit comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof and a retinoid. The kit may further include instructions for the concurrent or sequential administration of the components of the kit for use in therapy. In particular, the kit may include instructions for the administration of the components of the kit for the treatment of a susceptible neoplasm in a mammal (e.g., human).

The following examples are intended for illustration only and are not intended to limit the scope of the invention in any way. The invention is defined by the claims which follow.

EXAMPLES

The following abbreviations as employed in the examples, have the recited meanings. NSCLC: non-small cell lung cancer; μM: micromolar; nM : nanomolar; μL: microliter; nm: nanometers; RPMI-1640: Roswell Park Memorial Institute media 1640, ATCC, Cat. No 30-2001 - containing varying amounts of inorganic salts, amino acids, vitamins, and other nutrients;

FBS: fetal bovine serum; and

MTT: Cell Proliferation Kit I (Roche, Cat No. 1 1 465 007 001 ) (3-[4,5-dimethylthiazol- 2-yl]-2,5-diphenyltetrazolium bromide.

Reagents are commercially available or are prepared according to procedures in the literature.

Example Compounds of Formula (I).

Table 2 includes specific examples of compounds of formula (I). The compounds may be employed in the present invention either as racemic mixtures, enantiomerically enriched or pure forms and as a pharmaceutically acceptable salt or free base form thereof.

Processes for preparing Examples 603-A - 603-H, enantiomers and pharmaceutically acceptable salts thereof are described in PCT Publication No. 2007/030361 to SmithKline Beecham Corp. PLK enzyme inhibition and or cell proliferation data for these compounds is also provided therein. Processes for preparing Examples 602-5, -6, -22, -41 , -43, -63, -64, -95, -96, -97, -99, -100, - 102, -103, -105, -108, -1 12, -133, and -135, enantiomers and pharmaceutically acceptable salts thereof are described in PCT Publication No. 2007/030366 to SmithKline Beecham Corp.

Processes for preparing Examples 604-5 and 604-9, enantiomers and pharmaceutically acceptable salts thereof are described in PCT Publication No. 2007/030359 to SmithKline Beecham Corp. PLK enzyme inhibition and or cell proliferation data for these compounds is also provided therein.

Processes for preparing Examples 992-3, -6 through -14, -19, -21 , -23, -24, -29 through -31 , -37, -47 through -55, -75, and -76, enantiomers and pharmaceutically acceptable salts thereof are described in PCT Publication No. 2007/143456 to SmithKline Beecham Corp. PLK enzyme inhibition and or cell proliferation data for these compounds is also provided therein.

Table 2

-yl}-

- -yl]-3-

-yl}- R)-1-[2- R)- 1 -(2-

-[2- /-/- -yl]-2-

-

R)-

-yl]-3-

R)-

-yl]-2-

-yl]- -

-yl}-2- salt H- -yl]-3-

-yl]-

R)- 1 -{2- R)-1-{2- R)-1-[2-

R)- 1 -[2-

R)-1 -{2-

R)-1 -(2-

- -yl]-

-methyl- -yl]-2-

R)-1-{2-

R)-1 -[2- R)-1 -{2-

-yl}-

Biological Examples -Washout Proliferation Assay

A panel of NSCLC cells (NCI-H460, A549, NCI-H322, NCI-H1299, and NCI-H157) were seeded in 96-well flat bottom microplates. 16-18 hours post cell seeding, the cells were pre- treated with different retinoic acid ligands (ATRA, 9-cis RA, and Am80) at 1 μM (a concentration that mimics the plasma level in patients), for either 1 day or 4 days followed by addition of Example 603-C (at 2OnM, 3OnM, 10OnM, and 30OnM) in the presence of ATRA (1 μM) for 3 days. The cells were then washed three times with wash medium (RPMI-1640 supplemented with 20% FBS, 1 % P/S) and allowed to proliferate for 4 days in the presence of ATRA at 1 μM, daily dosing. 10μL of MTT (thiazole blue, Roche) was added to each well in complete medium (RPMI-1640 supplemented with 10% FBS, 1 % P/S) at 37⁰C for 4 hours followed by addition of 100μl_ of solubilization buffer (Roche) at 37⁰C for 16-18 hours. The absorbance at 595nm was determined (the absorbance at 655nm was used as reference) using a microplate reader (BioRad or a Wallac 1420 VICTOR², PerkinElmer). The percentage of viable cells was determined relative to control cells. Each treated was performed in 8 replicates.

A. Combination treatment of PLKi with Different RA Ligands in NCI-H460 Table 3A: Example No. 603-C + ATRA

The data suggest that combination treatment of ATRA with high concentration levels of 603- C (10OnM and 30OnM) leads to a more than 50% reduction in viable cells compared to treatment with 603-C alone in NCI-H460 cells. The same dosage regimen at low concentration levels of 603-C (2OnM and 3OnM) results in a less than 50% reduction in viable cells compared to 603-C alone. ATRA treatment alone showed no effect on cell viability.

Table 3B: Example No. 603-C + 9-cis RA

The data suggest that combination treatment of 9-cis RA with high concentration levels of 603-C (10OnM and 30OnM) leads to a more than 50% reduction in viable cells compared to 603-C treatment alone in NCI-H460 cells. The same dosage regimen at low concentration levels of 603-C (2OnM and 3OnM) results in a less than 50% reduction in viable cells compared to 603-C alone. 9-cis RA treatment alone had no effect on cell viability.

Table 3C: Example No. 603-C + Am80

The data suggest that combination treatment of Am80 with all concentration levels of 603-C (2OnM, 3OnM, 10OnM and 30OnM) leads to a more than 50% reduction in viable cells compared to 603-C treatment alone in NCI-H460 cells. Am80 treatment alone had no effect on cell viability. From this data, Am80, a RARalpha specific ligand appeard to have a greater effect in combination with 603-C on NSCLC cells in comparison to ATRA or 9-cis

RA.

B. Combination treatment of 603-C with ATRA in Different NSCLC Cell Lines

Table 4A: 603-C+ ATRA

The data suggest that combination treatment of ATRA with high concentration levels of 603-C

(10OnM and 30OnM) in the above-described NSCLC cell lines leads to a more than 50% reduction in viable cells at the highest 603-C concentration compared to 603-C treatment alone. ATRA treatment alone has no effect on cell viability in these other NSCLC cell lines.

C. Xenograft Study

2.3 X 10⁶ cells of NCI-H322 were injected subcutaneously to female nu/nu mice, one flank per animal. Combination therapy of ATRA + 603-C via intraperitoneal (i.p.) injection was administered two weeks post H322 cell implantation. Sixteen mice with varying tumor volume were assigned to four different treatment groups using a random-block method. The four groups include (1 ) Vehicle, (2) ATRA, (3) 603-C, and (4) ATRA+603-C. The table below summarizes dosing regimen. Changes in tumor volume were measured every 3-4 days during the entire drug administration using the equation: (I) (W²) / 2 (I = length; W = width). The findings suggest that NCI-H322 tumor is sensitive to treatment with 603-C and ATRA individually. The combination of ATRA + 603-C accelerated the rate to reach close-to- complete-remission of tumor volume by one week post treatment, compared to mice administered with mono therapy with either ATRA or 603-C alone.

Dosing Schedule

The following data were collected.

Table 5: Efficacy in NCI-H322 Xenograft Model

Claims

THAT WHICH IS CLAIMED IS:

1. A method for treating a susceptible neoplasm in a mammal in need thereof, said method comprising administering to the mammal a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =0 or OH; R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl; R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid each in an amount that when used in combination is therapeutically effective.

2. The method according to claim 1 , wherein the stereochemistry of the chiral carbon is R.

3. The method according to claim 1 or 2, wherein said compound is

4. The method according to claim 1 , wherein said compound is

5. The method according to claim 1 , wherein said compound is

5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-

(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

3-[((1 R)-1-{2-Chloro-3-[(1-methyl-4-piperidinyl)oxy]phenyl}ethyl)oxy]-5-[5-(1-methyl- 1 H-pyrazol-4-yl)-1 H-benzimidazol-1 -yl]-2-thiophenecarboxamide

6. The method according to claim 1 , wherein said compound is 5-{6-[(4- Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl}-3-{(1 R)-1 -[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

7. The method according to any of claims 1-6, wherein said retinoid is seleceted from retinoic acid, all-frans-retinoic acid, tamibarotene, 9-c/s-retinoic acid, isotretinoin, Am580, TTNPB, and BMS753.

8. The method according to any of claims 1-7, wherein said retinoid is selected from all-frans-retinoic acid, tamibarotene, and 9-c/s-retinoic acid.

9. The method according to any of claims 1-6, wherein said retinoid is a\\-trans- retinoic acid.

10. The method according to any of claims 1-9, wherein said mammal is a human.

11. The method according to any of claims 1-10, wherein said susceptible neoplasm is selected from breast cancer, colon cancer, small cell lung cancer, non- small cell lung cancer, prostate cancer, endometrial cancer, gastric cancer, ovarian cancer, pancreatic cancer, esophageal carcinoma, hepatocellular carcinoma, renal cell cancer, sarcoma, and haematologic malignancies.

12. The method according to any of claims 1-10, wherein said susceptible neoplasm is selected from breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, and haematologic malignancies.

13. The method according to any of claims 1-10, wherein said susceptible neoplasm is selected from breast cancer, non-small cell lung cancer and haematologic malignancies.

14. The method according to any of claims 1-10, wherein said susceptible neoplasm is non-small cell lung cancer.

15. The method according to any of claims 1-14, wherein said compound and said retinoid are administered sequentially.

16. The method according to any of claims 1-14, wherein said compound and said retinoid are administering concomitantly.

17. The method according to any of claims 1-16, wherein said compound is administered by intravenous injection.

18. The method according to any of claims 1-17, wherein said retinoid is administered by intravenous injection or orally.

19. A kit comprising a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =0 or OH; R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl; R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N,

O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0,

OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid.

20. A pharmaceutical composition comprising a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0,

21. The pharmaceutical composition according to claim 20, further comprising a pharmaceutically acceptable carrier, diluent or excipient.

22. The pharmaceutical composition according to claim 20 or 21 wherein said compound is

23. The pharmaceutical composition according to any of claims 20-22, wherein said compound is

24. The pharmaceutical composition according to any of claims 20-23, wherein said compound is

5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

25. The pharmaceutical composition according to any of claims 20-24, wherein said compound is 5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl}-3- {(1 R)-1-[2-(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

26. The pharmaceutical composition according to any of claims 20-25, wherein said retinoid is seleceted from retinoic acid, all-frans-retinoic acid, tamibarotene, 9- c/s-retinoic acid, isotretinoin, Am580, TTNPB, and BMS753.

27. The pharmaceutical composition according to any of claims 20-25, wherein said retinoid is selected from all-frans-retinoic acid, tamibarotene, and 9-c/s-retinoic acid.

28. The pharmaceutical composition according to any of claims 20-25, wherein said retinoid is all-frans-retinoic acid.

29. The pharmaceutical composition according to any of claims 20-28, further comprising a chemotherapeutic agent.

30. A combination comprising a compound of formula (I)

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or

2 times with alkyl, =0 or OH; R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl;

R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid, for use in therapy.

31. The combination according to claim 30 wherein said compound is

32. The combination according to any of claims 30-31 , wherein said compound is

33. The combination according to any of claims 30-32, wherein said compound is

5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-

(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

34. The combination according to any of claims 30-33, wherein said compound is

5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1-yl}-3-{(1 R)-1-[2-

(trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

35. The combination according to any of claims 30-34, wherein said retinoid is seleceted from retinoic acid, all-frans-retinoic acid, tamibarotene, 9-c/s-retinoic acid, isotretinoin, Am580, TTNPB, and BMS753.

36. The combination according to any of claims 30-35, wherein said retinoid is selected from all-frans-retinoic acid, tamibarotene, and 9-c/s-retinoic acid.

37. The combination according to any of claims 30-35, wherein said retinoid is all- frans-retinoic acid.

38. The combination according to any of claims 30-37, for use in the treatment of a susceptible neoplasm (e.g., breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, endometrial cancer, gastric cancer, ovarian cancer, pancreatic cancer, esophageal carcinoma, hepatocellular carcinoma, renal cell cancer, sarcoma, or a haematologic malignancy) in a mammal (e.g., human).

39. The combination according to according to any of claims 30-37, for use in the treatment of breast cancer, ovarian cancer, prostate cancer, non-small cell lung cancer, or a haematologic malignancy, in a mammal (e.g., human).

40. Use of a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =0 or OH; R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl; R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid for the preparation of a medicament for the treatment of a susceptible neoplasm (e.g., breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, endometrial cancer, gastric cancer, ovarian cancer, pancreatic cancer, esophageal carcinoma, hepatocellular carcinoma, renal cell cancer, sarcoma, or a haematologic malignancy) in a mammal (e.g., human).

41. The use according to claim 40 wherein said compound is

42. The use according to any of claims 40-41 , wherein said compound is

43. The use according to any of claims 40-42, wherein said compound is 5-{6-[(4-Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl}-3-{(1 R)-1 -[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

44. The use according to any of claims 40-43, wherein said compound is 5-{6-[(4- Methylpiperazin-1-yl)methyl]-1 H-benzimidazol-1 -yl}-3-{(1 R)-1 -[2- (trifluoromethyl)phenyl]ethoxy}thiophene-2-carboxamide

45. The use according to any of claims 40-44, wherein said retinoid is seleceted from retinoic acid, all-frans-retinoic acid, tamibarotene, 9-c/s-retinoic acid, isotretinoin, Am580, TTNPB, and BMS753.

46. The use according to any of claims 40-44, wherein said retinoid is selected from all-frans-retinoic acid, tamibarotene, and 9-c/s-retinoic acid.

47. The use according to any of claims 40-44, wherein said retinoid is a\\-trans- retinoic acid.

48. A pharmaceutical composition comprising a compound of formula (I):

wherein:

^* indicates a chiral carbon

R¹ is H, halo, or Het¹ ,

Het¹ is a 5 or 6 membered N-heteroaryl optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, =0 or OH; R² is H, halo, CH₂SO₂-alkyl, CH₂-Het², or O-Het², wherein at least one of R¹ and R² is H; R³ is halo, alkyl, or haloalkyl; R⁴ is H, CH₂-Het², O-Het², or N(H)Het², each Het² is the same or different and is independently a 5 or 6 membered N- heterocycle optionally containing 1 additional heteroatom selected from N, O and S, and optionally substituted 1 or 2 times with alkyl, haloalkyl, =0, OH, S0₂alkyl, or alkylene-SO₂alkyl; or a pharmaceutically acceptable salt thereof; and a retinoid for use in the treatment of a susceptible neoplasm (e.g., breast cancer, colon cancer, small cell lung cancer, non-small cell lung cancer, prostate cancer, endometrial cancer, gastric cancer, ovarian cancer, pancreatic cancer, esophageal carcinoma, hepatocellular carcinoma, renal cell cancer, sarcoma, or a haematologic malignancy) in a mammal (e.g., human).