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WO2013185202A1 - Apoptosis inducers - Google Patents

Apoptosis inducers Download PDF

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Publication number
WO2013185202A1
WO2013185202A1 PCT/CA2012/000591 CA2012000591W WO2013185202A1 WO 2013185202 A1 WO2013185202 A1 WO 2013185202A1 CA 2012000591 W CA2012000591 W CA 2012000591W WO 2013185202 A1 WO2013185202 A1 WO 2013185202A1
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substituted
unsubstituted
branched
linear
group
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PCT/CA2012/000591
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French (fr)
Inventor
Zhaoyin Wang
Lianhai Li
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Beta Pharma Canada Inc
Astar Biotech LLC
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Beta Pharma Canada Inc
Astar Biotech LLC
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Priority to PCT/CA2012/000591 priority Critical patent/WO2013185202A1/en
Publication of WO2013185202A1 publication Critical patent/WO2013185202A1/en
Anticipated expiration legal-status Critical
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
    • A61K31/496—Non-condensed piperazines containing further heterocyclic rings, e.g. rifampin, thiothixene or sparfloxacin
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/535—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with at least one nitrogen and one oxygen as the ring hetero atoms, e.g. 1,2-oxazines
    • A61K31/5375—1,4-Oxazines, e.g. morpholine
    • A61K31/5377—1,4-Oxazines, e.g. morpholine not condensed and containing further heterocyclic rings, e.g. timolol
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/695—Silicon compounds
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
    • C07F7/00—Compounds containing elements of Groups 4 or 14 of the Periodic Table
    • C07F7/02—Silicon compounds
    • C07F7/08—Compounds having one or more C—Si linkages
    • C07F7/0803—Compounds with Si-C or Si-Si linkages
    • C07F7/081—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te
    • C07F7/0812—Compounds with Si-C or Si-Si linkages comprising at least one atom selected from the elements N, O, halogen, S, Se or Te comprising a heterocyclic ring

Definitions

  • the subject matter disclosed generally relates to novel compounds for promoting apoptosis involved in some diseases. More specifically, the subject matter relates to novel compounds which inhibit the activity of anti-apoptotic Bcl-2 family protein members, compositions containing the compounds and methods of treating diseases involving a defect in apoptosis, such as, for the treatment of cancer.
  • Bcl-2 family of proteins which include, for example, Bcl-2, Bcl-xl and Bel- w.
  • Bcl-2 inhibitors Vogler et al, Cell Death and Differentiation (2009) 16, 360-367.
  • Recently inhibitors of Bcl-2 family members have been reported in the literature, see, for example, WO 2005/049594, US 6,720,338, US 7,030,115., US7,709,467 and US2008/0188460.
  • This invention is directed to a series of novel compounds that promote apoptosis with demonstrated cellular activity.
  • the present invention provides compounds with improved selectivity for Bcl-2 over Bcl-xl, with the potential for better safety profile in clinics.
  • Bcl-2 and Bcl-xL are highly homologous in their ligand binding groove, and previous inhibitors such as ABT-737 or ABT-263 were designed to inhibit both proteins. Clinical experience, however, suggests that Bcl-xL inhibition is responsible for the thrombocytopenia observed in ABT-263 clinical trials, which raises interest in Bcl-2 inhibitors with improved selectivity over Bcl-xl.
  • the present invention is directed to a series of novel spiro-compounds which were unexpectedly found to preferentially inhibit the activity of anti-apoptotic Bcl-2 over Bcl-xl, and are therefore useful for the treatment of diseases involving a defect in apoptosis, such as, for example, in the treatment of cancer with a better safety profile.
  • Pharmaceutical compositions and methods of use are also included.
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF 5 and halogen atoms;
  • W is -CH 2 -, -C(CH 3 ) 2 -, -C(CH 2 -CH 2 )- or -CH 2 CH 2 -;
  • Het represents a carbocycle, or a hetereocycle, each of which contains 1-3 heteroatoms chosen from O, S, N, or Si, and each of which is saturated or contains one or more unsaturated bonds; or
  • Het is unsubstituted or substituted with halo, alkyl, oxo, amido, amino, alkylamino, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, aryl, heteroaryl;
  • R 1 is selected from H, halo, or -O-aryl which is substituted or unsubstituted;
  • R 2 represents
  • R 10 is H, R 12 , OR 12 , SR 12 , S(0)R 12 , S0 2 R 12 , C(0)R 12 , NHC(0)R 12 , NC
  • R 12 is a linear or branched (Ci-Ce)alkyl group unsubstituted or substituted with one or more halogen atoms;
  • R 11 represents a hydrogen atom or a -NR 12 R 13 or -CH 2 -NR 12 R 13 group wherein each of R 12 and R 13 , are identical or different, and independently represents a hydrogen atom or a linear or branched (C-i ⁇ alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyi or -NR 14 R 15 groups wherein:
  • R 14 and R 15 are identical or different, and are selected from hydrogen, linear or branched (Ci -6 )alkyl, linear or branched (C -6 )alkoxy, aryl and heteroaryl, or [0023] R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ; or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10
  • R 1 is selected from H, or halo; [0028] R 2 represents
  • Z is -C(O-) or -CH 2 -
  • A is N or C(R 10 );
  • R 9 is H or halo
  • R 10 is H, R 12 , OR 12 , SR 12 , S(0)R 12 , S0 2 R 12 , C(0)R 12 , NHC(0)R 12 , NC 6 alkylC(0)R 12 , NHC(0)OR 12 , NCi- 6 alkylC(O)OR 12 , NHC(O)NHR 12 , NHC(0)N(R 12 ) 2 , NCi- ealkylNHR 12 , SO 2 NH 2 , S0 2 NHR 12 , S0 2 N(R 12 ) 2 , NHS0 2 R 12 , Nd-ealkylSOzR 12 , NHS0 2 NHR 12 , NHS0 2 N(R 12 ) 2 , Nd-ealkylSOsNHR 12 , NCi- 6 alkylSO 2 N(R 12 )2, C(0)NHNOH, C(0)NHNOR 12 , C(O)NHSO 2 R 12 , C(NH)NH 2) halogen, CN, N0 2 ,
  • R 12 is a linear or branched (CrC 6 )alkyl group is unsubstituted or substituted by one or more halogen atoms;
  • R 11 represents a hydrogen atom or a -NR 12 R 13 or -CH 2 -NR 12 R 13 group wherein each of R 2 and R 3 , are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci -6 )alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR 14 R 15 groups wherein:
  • R 14 and R 15 are identical or different, and are selected from hydrogen, linear or branched (C ⁇ alkyl, linear or branched (C 1-6 )alkoxy, aryl and heteroaryl, or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R 10 ; or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ;
  • R 3 , R 4 , R 5 and R 6 are independently selected from H, F, Ci -3 alkyl unsubstituted or substituted by halogen atom or Ci -3 alkoxyl;
  • n and m are 0, 1 , 2 or 3, where 0 ⁇ n+m ⁇ 6;
  • Y is O, S, NR 12 or -C(R 3 )(R 4 );
  • W is -CH 2 -, -C(CH 3 ) 2 - or -CH 2 CH 2 -;
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C Ceialkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC 6 )alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF 5 and halogen atoms.
  • R 1 is selected from H, or halo
  • R 2 represents a group of the following:
  • Z is -C(O-) or -CH 2 -;
  • R 9 is H or halo
  • R 10 is -CN, -N0 2 or -S0 2 -R 12 ;
  • R 12 is an amino or a linear or branched (Ci-C 6 )alkyl group unsubstituted or substituted by one or more halogen atoms;
  • R 11 represents a hydrogen atom or a -NR 12 R 13 or -CH 2 -NR 12 R 13 group wherein each of R 12 and R 3 , are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci -6 )alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR 14 R 15 groups wherein: [0054] R 14 and R 15 , are identical or different, and are selected from hydrogen, linear or branched (Ci -6 )alkyl, linear or branched (Ci ⁇ alkoxy, aryl and heteroaryl, or
  • R 14 and R 15 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R 10 ; or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ;
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC 6 )alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C 6 )alkyl, alkoxycarbonyl, SF 5 and halogen atoms; and
  • R 1 is selected from H, halo;
  • R 2 represents
  • Z is -C(O-) or -CH 2 -;
  • R 9 is H or halo
  • R 0 is-CN, -N0 2 or -S0 2 -R 12 ;
  • R 2 is an amino or a linear or branched (CrC 6 )alkyl group unsubstituted or substituted by one or more halogen atoms;
  • R 11 represents a hydrogen atom or a -NR 12 R 13 or -CH 2 -NR 12 R 13 group wherein each of R 12 and R 13 , are identical or different, and independently represents a hydrogen atom or a linear or branched group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR 14 R 15 groups wherein:
  • R 14 and R 15 are identical or different, and are selected from hydrogen, linear or branched (Ci -6 )alkyl, linear or branched (Ci -6 )alkoxy, aryl and heteroaryl, or
  • R 14 and R 15 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ; or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (d-C 6 )alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (Ci-C 6 )alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C 6 )alkyl, alkoxycarbonyl, SF 5 and halogen atoms; and
  • R 7 and R 8 are independently selected from Ci -6 alkyl, C 1 -6 cyclolkyl, C ⁇ . efluorocycloalkyl, Ci -6 fluoroalkyl, or R 7 , R 8 , together with the silicon atom to which they are both attached to, complete a four- to six-membered carbocyclic ring which is unsubstituted or substituted with one or more R°wherein R c is Ci -3 alkyl unsubstituted or substituted by halogen atom or Ci-3 alkoxyl.
  • Y is -C(O)-.
  • R 10 is -NO2 or -S(0) 2 CF3.
  • composition comprising a combination of a compound of the present invention and an anti-cancer agent selected from, a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and kinase inhibitors, in association with a pharmaceutically acceptable carrier.
  • an anti-cancer agent selected from, a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and kinase inhibitors, in association with a pharmaceutically acceptable carrier.
  • a method of treating a cancer comprising the step of administering to the patient in need thereof a therapeutically effective amount of a compound of the present invention, or the composition of the present invention in combination with radiotherapy.
  • the invention encompasses a genus of compounds of Formula I as apoptosis inducers
  • R is selected from H, halo, or O-aryl which is substituted or unsubstituted; [0085] R 2 represents:
  • A is N or C(R 10 ); [0089] R 9 is H or halo;
  • R 10 is H, R 12 , OR 12 , SR 12 , S(0)R 12 , S0 2 R 12 , C(0)R 12 , NHC(0)R 12 , NC
  • R 12 is linear or branched (C ⁇ -C 6 )alkyl group unsubstituted or substituted with one or more halogen atoms;
  • R 11 represents a hydrogen atom or a -NR 12 R 13 or -CH 2 -NR 12 R 13 group wherein each of R 12 and R 13 , are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci.6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyi or -NR 14 R 15 groups wherein:
  • R 14 and R 15 are identical or different, and are selected from hydrogen, linear or branched (Ci -6 )alkyl, linear or branched (Ci -6 )alkoxy, aryl and heteroaryl, or
  • R 14 and R 5 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group oris unsubstituted or substituted with one or more R 10 ; or [0095] R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ;
  • R a is
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (Ci-C6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-iC-i-CeJalkyl, alkoxycarbonyl, SF 5 and halogen atoms;
  • W is -CH 2 -, -C(CH 3 ) 2 -, -C(CH 2 -CH 2 )- or -CH 2 CH 2 -;
  • Het represents a carbocycle, or a hetereocycle, each of which contains 1-3 heteroatoms, chosen from O, S, N, or Si and each of which is saturated or contains one or more unsaturated bonds; or
  • Het is unsubstituted or substituted with halo, alkyl, oxo, amido, amino, alkylamino, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, aryl, heteroaryl.
  • Another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R a is
  • R 3 , R 4 , R 5 and R 6 are independently selected from H, F, C 1-3 alkyl unsubstituted or substituted by halogen atom or Ci-3 alkoxyl;
  • n and m are 0, 1 , 2 or 3, where 0 ⁇ n+m ⁇ 6;
  • Y is O, S, NR 12 or -C(R 3 )(R 4 );
  • W is -CH 2 -, -C(CH 3 ) 2 - or -CH 2 CH 2 -;
  • Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C -i -C 6 )alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (C i -C 6 )alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(C i -C 6 )alkyl, alkoxycarbonyl, SF 5 and halogen atoms.
  • Another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R a is
  • R 3 , R 4 , R 5 and R 6 are independently selected from H, F and Ci unsubstituted or substituted by halogen atom or Ci-3 alkoxyl;
  • n and m are independently 0, 1 , 2 or 3, where 2 ⁇ n+m ⁇ 6;
  • Y is O, S, NR 12 or -C(R 3 )(R 4 ); [00111] Ar is defined as above.
  • Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R 3 is
  • Ar is defined as above.
  • Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R a is
  • Ar and R 12 are defined as above.
  • Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R a is
  • V and V" are independently selected from O, S;
  • q is 2, 3, 4 or 5;
  • R 3 , R 4 and Ar are defined as above;
  • Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R a is
  • R 7 and R 8 are independently selected from Ci- 6 alkyl, Ci -6 cyclolkyl, d. 6 fluorocycloalkyl, Ci- 6 fluoroalkyl, or R 7 , R 8 , together with the silicon atom to which they are both attached to, complete a four- to six-membered carbocyclic ring which is unsubstitted or substituted with one or more R 3
  • Ar is defined as above.
  • Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R 2 is
  • R 10 is defined as above; [00125] R b is a -NR 14 R 15 groups wherein:
  • R 14 and R 15 are identical or different, and are selected from hydrogen, linear or branched (C 1-6 )alkyl, linear or branched (Ci -6 )alkoxy, aryl and heteroaryl, or [00127] R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 ; or
  • R 14 and R 15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10 .
  • alkyl by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons).
  • saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like.
  • An unsaturated alkyl group is one having one or more double bonds or triple bonds.
  • unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4-pentadienyl), ethynyl, 1-and 3- propynyl, 3-butynyl, and the higher homologs and isomers.
  • Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl".
  • “Fluoroalkyl” means alkyl as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
  • an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention.
  • a “lower alkyl” or “lower alkylene” is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
  • Alkynyl means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
  • Cycloalkyl means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms.
  • a "fused analog" of cycloalkyl means a monocyclic rings fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
  • Alkoxy means alkoxy groups of a straight or branched having the indicated number of carbon atoms.
  • C ⁇ alkoxy for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
  • Heteroalkyl by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized.
  • the heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule.
  • heteroalkylene by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, - CH 2 -CH 2 -S -CH 2 -CH 2 - and -CH 2 -S-CH 2 -CH 2 -NH-CH 2 -.
  • heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0)OR'- represents both-C(0)OR'- and -R'OC(O)-.
  • heteroalkyl groups include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R ⁇ -C(0)NR', -NR'R", -OR', -SR', and/or - S0 2 R'.
  • heteroalkyl is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R” or the like, it will be understood that the terms heteroalkyl and- NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term “heteroalkyl” should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R” or the like.
  • Cycloalkoxy means cycloalkyi as defined above bonded to an oxygen atom, such as cyclopropyloxy.
  • Fluoroalkoxy means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
  • Aryl means mono- or bicyclic aromatic rings containing only carbon atoms.
  • a "fused analog" of aryl means an aryl group fused to a monocyclic cycloalkyi or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1 ,4- benzodioxanyl, and the like.
  • Heteroaryl means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms.
  • a "fused analog" of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyi or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion.
  • heteroaryl examples include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
  • the said substituents a are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from I to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an aikylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl
  • Heterocyclyl means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen.
  • a "fused analog" of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion.
  • heterocyclyl and fused analogs thereof include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like.
  • the term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1 H,3H)-pyrimidine-2,4-diones (N-substituted uracils).
  • halo or "halogen,” by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as “haloalkyl,” are meant to include monohaloalkyl and polyhaloalkyl. For example, the term “halo(Ci-C 4 )alkyl” is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
  • a “prodrug” refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug.
  • An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial.
  • a further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
  • Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
  • tautomers Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
  • Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof.
  • the pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
  • any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
  • salts refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids.
  • Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts.
  • Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, ⁇ , ⁇ '-dibenzylethylenediamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
  • basic ion exchange resins
  • salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids.
  • acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like.
  • Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
  • Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
  • an inert solid diluent for example, calcium carbonate, calcium phosphate or kaolin
  • an oil medium for example peanut oil, liquid paraffin, or olive oil.
  • Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions.
  • excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene
  • the aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
  • preservatives for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • coloring agents for example ethyl, or n-propyl, p-hydroxybenzoate
  • flavoring agents such as sucrose, saccharin or aspartame.
  • sweetening agents such as sucrose, saccharin or aspartame.
  • Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin.
  • the oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
  • Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives.
  • a dispersing or wetting agent e.g., sodium EDTA
  • suspending agent e.g., sodium EDTA
  • preservatives e.g., sodium EDTA, sodium bicarbonate, sodium bicarbonate
  • the pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions.
  • the oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these.
  • Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate.
  • the emulsions may also contain sweetening and flavouring agents.
  • Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents.
  • the pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above.
  • the sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol.
  • Suitable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution.
  • sterile, fixed oils are conventionally employed as a solvent or suspending medium.
  • any bland fixed oil may be employed including synthetic mono- or diglycerides.
  • fatty acids such as oleic acid find use in the preparation of injectables.
  • the compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane.
  • the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
  • the pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • a surfactant such as sorbitan trioleate, oleic acid, or an oligolactic acid.
  • This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
  • Capsules made, for example, from gelatin or HPMC
  • blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate.
  • the lactose may be anhydrous or in the form of the monohydrate, preferably the latter.
  • Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
  • a suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from log to 20mg of the compound of the invention per actuation and the actuation volume may vary from 11 to 1001.
  • a typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride.
  • Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
  • Suitable flavours such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
  • Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA).
  • Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
  • the dosage unit is determined by means of a valve which delivers a metered amount.
  • Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1 fig to 10 mg of the compound of formula I.
  • the overall daily dose will typically be in the range 1 lag to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
  • Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug.
  • These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug.
  • Such materials are cocoa butter and polyethylene glycols.
  • creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed.
  • topical application shall include mouth washes and gargles.
  • Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day.
  • inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
  • the amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration.
  • a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition.
  • Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
  • the compounds of the present invention are useful for treating diseases during which are expressed antiapoptotic Bcl-2 protein, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula I.
  • the present invention also comprises methods of treating diseases in a patient during which are expressed antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula I.
  • the compounds according to the invention will be useful in the treatment treating diseases of abnormal cell growth and/or dysregulated apoptosis,.
  • diseases of abnormal cell growth and/or dysregulated apoptosis such as cancer, mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, ovarian cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the
  • Still another embodiment comprises methods of treating mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, ovarian cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular cancer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain
  • the present invention relates also to pharmaceutical compositions comprising at least one compound of Formula I on its own or in combination with one or more pharmaceutically acceptable excipients.
  • compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, sachets, packets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules.
  • the dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.
  • the present invention relates also to the combination of a compound of formula I with one or more anticancer agents selected from cytotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors, and to the use of that type of combination in the manufacture of medicaments for use in the treatment of cancer.
  • one or more anticancer agents selected from cytotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors
  • the compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
  • Compounds having Formula I are also expected to be useful as chemotherapeutic agents in combination with therapeutic agents that include, but are not limited to, angiogenesis inhibitors, antiproliferative agents, kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal antiinflammatory drugs (NSAIDS), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum containing agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids/deltoids plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors
  • Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TTE2 inhibitors, IGFIR inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, thrombospondin analogs such as thrombospondin- 1 and N-Ac-Sar-Gly-Val-D-allolle- Thr-Nva-He-Arg-Pro- NHCH 2 CH 3 or a salt thereof and analogues of N-Ac-Sar-Gly-Val- D-allolle-Thr-Nva-lle-Arg- PrO-NHCH 2 CH 3 such as N-Ac-GlyVal-D-alle-Ser-Gln-lle-Arg- ProNHCH 2 CH 3 or a salt thereof.
  • Examples of EGFR inhibitors include, but are not limited to, Iressa (gefitinib), Tarceva (erlotinib or OSI-774), lcotinib, Erbitux (cetuximab), EMD-7200, ABX- EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusion protein, EGF- vaccine, anti-EGFr immunoliposomes and Tykerb (lapatinib).
  • PDGFR inhibitors include, but are not limited to, CP-673,451 and CP- 868596.
  • VEGFR inhibitors include, but are not limited to, Avastin (bevacizumab), Sutent (sunitinib, SUI 1248), Nexavar (sorafenib, BAY43-9006), CP- 547,632, axitinib (AG13736), Apatinib, cabozantinib, Zactima (vandetanib, ZD-6474), AEE788, AZD-2171 , VEGF trap, Vatalanib (PTK-787, ZK-222584), Macugen, M862, Pazopanib (GW786034), ABT-869 and angiozyme.
  • thrombospondin analogs include, but are not limited to, TSP-I and ABT- 510.
  • aurora kinase inhibitors include, but are not limited to, VX-680, AZD- 1152 and MLN-8054.
  • Example of polo-like kinase inhibitors include, but are not limited to, BI-2536.
  • Examples of bcr-abl kinase inhibitors include, but are not limited to, Gleevec (imatinib) and Dasatinib (BMS354825).
  • platinum containing agents includes, but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin) or satraplatin.
  • Examples of mTOR inhibitors includes, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001 , INK-128 and ridaforolimus.
  • HSP-90 inhibitors includes, but are not limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF- 01 , CNF-1010, 17-AAG- nab, NCS-683664, Mycograb, CNF-2024, PU3, PU24FC1 , VER49009, IPI-504, SNX- 21 12 and STA-9090.
  • HDAC histone deacetylase inhibitors
  • SAHA Suberoylanilide hydroxamic acid
  • MS-275 valproic acid
  • TSA valproic acid
  • LAQ- 824 Trapoxin, tubacin, tubastatin, ACY-1215 and Depsipeptide.
  • Examples of MEK inhibitors include, but are not limited to, PD325901 , ARRY-142886, ARRY-438162 and PD98059.
  • CDK inhibitors include, but are not limited to, flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, R-roscovitine), ZK-304709, PHA-690509, BMI- 1040, GPC-286199, BMS-387,032, PD0332991 and AZD-5438.
  • COX-2 inhibitors include, but are not limited to, CELEBREXTM (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 Lumiracoxib), BMS347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD- 8381 , 4-Methyl-2-(3,4-dimethylphenyl)-l-(4-sulfamoyl-phenyl-IH-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).
  • NSAIDs non-steroidal anti-inflammatory drugs
  • examples of non-steroidal anti-inflammatory drugs include, but are not limited to, Salsalate (Amigesic), Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol) and Oxaprozin (Daypro).
  • Exambles of ErbB2 receptor inhibitors include, but are not limited to, CP- 724-714, CI-1033, (canertinib), Herceptin (trastuzumab), Omitarg (2C4, petuzumab), TAK-165, GW- 572016 (lonafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti-HER/2neu bispecific antibody, B7.her2lgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209 and mAB 2B-1.
  • alkylating agents include, but are not limited to, nitrogen mustard N- oxide, cyclophosphamide, ifosfamide, trofosfamide, Chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2 70, mafosfamide, and mitolactol, carmustine (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decarbazine and Temozolomide.
  • antimetabolites include but are not limited to, methotrexate, 6- mercaptopurine riboside, mercaptopurine, uracil analogues such as 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine), fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethnylcytidine, cytosine arabinoside, hydroxyurea, TS-I, melphalan, nelarabine, nolatrexed, ocfosate, dis
  • antibiotics include intercalating antibiotics but are not limited to, aclarubicin, actinomycins such as actinomycin D, amrubicin, annamycin, adriamycin, bleomycin a, bleomycin b, daunorubicin, doxorubicin, elsamitrucin, epirbucin, glarbuicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
  • actinomycins such as actinomycin D, amrubicin, annamycin, adriamycin, bleomycin a, bleomycin b, daunorubicin, doxorubicin, elsamitrucin, epirbucin, glarbuicin,
  • topoisomerase inhibiting agents include, but are not limited to, one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCL (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, orathecin (Supergen), BN-80915, mitoxantrone, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.
  • antibodies include, but are not limited to, Rituximab, Cetuximab, Bevacizumab, Trastuzimab, specific CD40 antibodies and specific IGFIR antibodies,
  • hormonal therapies include, but are not limited to, exemestane (Aromasin), leuprolide acetate, anastrozole (Arimidex), fosrelin (Zoladex), goserelin, doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen), Casodex, Abarelix, Trelstar, finasteride, fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole, flutamide, bicalutamide, megesterol, mifepristone, nilutamide, dexamethasone, predisone and other glucocorticoids.
  • retinoids/deltoids include, but are not limited to, seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, Aliretinoin, Bexarotene and LGD-1550.
  • plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine.
  • proteasome inhibitors include, but are not limited to, bortezomib (Velcade), MGI 32, NPI-0052 and PR-171.
  • immunologicals include, but are not limited to, interferons and numerous other immune enhancing agents.
  • Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- 1a, interferon gamma- 1 b (Actimmune), or interferon gamma-nl and combinations thereof.
  • agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, decarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAC- CL, sargaramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFGI), Provenge (Dendreon), CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and agents capable of blocking CTLA4 such as MDX-0
  • Examples of biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity.
  • Such agents include krestin, lentinan, sizofrran, picibanil and ubenimex.
  • pyrimidine analogs include, but are not limited to, 5- Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, cytarabine (ara C), Cytosine arabinoside, Fludarabine, and Gemcitabine.
  • Examples of purine analogs include but are not limited to, Mercaptopurine and thioguanine.
  • antimitotic agents include, but are not limited to, ABT-751 , paclitaxel, docetaxel, epothilone D (KOS-862) and ZK-EPO.
  • Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy.
  • radiotherapy include but are not limited to, external beam radiotherapy (XBRT), or teletherapy, brachtherapy or sealed source radiotherapy, unsealed source radiotherapy.
  • DBU means 1,8- diazabicyclo[5.4.0]undec- 7-ene
  • DIBAL means diisobutylaluminum hydride
  • DIEA means diisopropylethylamine
  • DMAP means ⁇ , ⁇ -dimethylaminopyridine
  • DME means 1 ,2-dimethoxyethane
  • DMF means ⁇ , ⁇ -dimethylformamide
  • dmpe means l,2- bis(dimethylphosphino)ethane
  • DMSO means dimethylsulfoxide
  • dppb means l,4- bis(diphenylphosphino)butane
  • dppe means 1 ,2- bis(diphenylphosphino)ethane
  • dppf means l,r-bis(diphenylphosphino)ferrocene
  • dppm means bis(diphenylphosphino)methane
  • EDCI means l-(
  • Stepl 9-methylene-1 ,5-dioxaspiro[5.5]undecane
  • Step 2 7, 1 1-dioxadispiro[2.2.5.2]tridecane
  • Step 3 spiro[2.5]octan-6-one
  • Step 5 6-(4-chlorophenyl)spiro[2.5]oct-5-ene-5-carbaldehyde
  • Step 6 ethyl 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)benzoate
  • Step 7 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1 -yl)benzoic acid
  • the resulting suspension was stirred for 0.5 h and the solid was collected by filtration, washed with 3 x 5 mL of water, 5 mL of hexanes, and air-dried to give 5.5 g of the title product as a white solid.
  • Step 8 (R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
  • Step 1 1 ,1-difluoro-7,11-dioxadispiro[2.2.5.2]tridecane
  • Step 2 1 ,1-difluorospiro[2.5]octan-6-one
  • Step 4 6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-ene-5- carbaldehyde
  • Step 5 ethyl 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en- 5-yl)methyl)piperazin-1-yl)benzoate
  • Step 6 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1 -yl)benzoic acid
  • Step 7 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
  • Step 1 diethyl cyclopentane-1 , 1 -dicarboxylate
  • Step 2 cyclopentane-1 , 1-diyldimethanol
  • LiAIH4 (10.82 g) was suspended in 100 mL of THF anhydrous at r.t. under N 2 .
  • the reaction mixture was then stirred overnight at r.t. and cooled in a ice bath.
  • 100ml_ of EtOAc was added , followed by addition of 22 mL of saturated solution of NH 4 CI dropwise carefully through dropping funnel.
  • Step 3 cyclopentane-1 ,1-diylbis(methylene) dimethanesulfonate
  • Step 4 2,2'-(cyclopentane-1 ,1-diyl)diacetonitrile
  • Step 6 2,2'-(cyclopentane-1 ,1-diyl)diethanol
  • LiAIH 4 (3.2 g) was suspended in 100 mL of THF anhydrous at r.t. under
  • Step 7 2,2'-(cyclopentane-1 ,1-diyl)bis(ethane-2,1-diyl)
  • Step 8 3,3'-(cyclopentane-1 ,1-diyl)dipropanenitrile
  • Step 9 3,3'-(cyclopentane-1 ,1-diyl)dipropanoic acid
  • Step 10 dimethyl 3, 3'-(cyclopentane-1 ,1-diyl)dipropanoate
  • Step 1 1 methyl 8-hydroxyspiro[4.5]dec-7-ene-7-carboxylate
  • Step 12 methyl 8-(((trifluoromethyl)sulfonyl)oxy)spiro[4.5]dec-7-ene-7- carboxylate
  • Step 13 methyl 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carboxylate
  • Step 14 (8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methanol
  • Step 15 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carbaldehyde
  • Step 16 ethyl 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1-yl)benzoate
  • Step 17 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1 -yl)benzoic acid
  • Step 18 (R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
  • Step 1 bis(3-bromo ropoxy)dimethylsilane
  • Step 2 3,3'-(dimethylsilanediyl)dipropan-1-ol
  • Step 3 dimethyl 3,3'-(dimethylsilanediyl)dipropanoate
  • Step 4 methyl 1 ,1 -dimethyl-4-oxosilinane-3-carboxylate
  • the reaction mixture was cooled to 0 °C and quenched with 10 mL of a saturated solution of NH4CI and followed by 50 ml_ 20% EtOAc/hexanes. The two layers were separated, and the aqueous was extracted with 50ml_ of 20% of EtOAc/hexanes once. The combined organic layers were washed with brine (50ml_), dried over Na 2 SO 4 and filter through a pad of silica gel and celite. The filtrate was concentrated to dryness, and the residue was then purified by silica gel chromatography eluted with 3%-10% EtOAc/hexane to give 0.3 g pale yellow oil as product.
  • Step 5 methyl 1 , 1-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-1 , 2,5,6- tet ra hyd ros i I i ne-3-ca rboxy I ate
  • Step 6 methyl 4-(4-chlorophenyl)-1 ,1-dimethyl-1 , 2,5,6- tetra hyd rosi I i ne-3-carboxy late
  • Step 7 (4-(4-chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosilin-3- yl)methanol
  • the reaction mixture was cooled in an ice bath and quenched with 20% aqueous solution of potassium sodium tratrate (50 mL) and 50 mL of EtOAc was added. The reaction mixture was stirred for 1 h and two layers were separated. The aqueous was further extracted with 2 x 30 mL of EtOAc. The combined organic layers was washed, in turn, with a saturated solution of NH 4 CI (30mL), brine (50mL) dried over Na 2 SO 4 and filtered through a pad of silica gel and celite. The filtrate was concentrated to dryness and the residue was purified by CombiFlash eluted with 1 %-50% EtOAc/Hexanes to give 0.090g pale yellow oil as the product.
  • Step 8 4-(4-chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosiline-3- carbaldehyde
  • Step 9 Methyl 4-(4-((4-(4-chlorophenyl)-1 ,1 -dimethyl-1 ,2,5,6- tetrahydrosilin-3-yl)methyl)piperazin-1 -yl)benzoate
  • reaction mixture was quenched with a saturated solution of NH4CI (20 mL) and extracted with a solution of 1 :1 EtOAc/hexanes (3x50mL). The combined organic layers was washed with brine (50 mL), dried over Na2S0 4 , and filtered. The filtrate was concentrated and the residue was purified by CombiFlash eluted with 1 %-25% EtOAc/hexanes to give 55 mg pale yellow solid as the product.
  • Step 10 4-(4-((4-(4-chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin- 3-yl)methyl)piperazin-1 -yl)benzoic acid
  • Step 1 1 (R)-4-(4-((4-(4-chlorophenyl)-1 , -dimethyl-1 , 2,5,6- tetrahydrosilin-3-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2- yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
  • apoptosis regulator protein Bcl2 and Bcl-xL The inhibitory activities of apoptosis regulator protein Bcl2 and Bcl-xL by the compounds in the invention were assay at Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern PA 19355. Compounds were tested in a 10-dose IC50 with 3-fold serial dilution starting at 1uM. Control compound, ABT-737, was tested in a 10-dose IC50 with 3-fold serial dilution starting at 10 uM.
  • Assay Format The assay is based on the competition of fluorescently labeled BakBH3 peptide (5FAM-GQVGRQLAIIGDDINR) for binding to Bcls. 5FAM- BakBH3 binds to surface pocket of Bel family, which is essential for its death antagonist function. [00356] Assay conditions: 5 nM 5FAM-BakBH3, 30 nM Bcl2 or Bcl-xL, in 20 mM Hepes, pH 7.5, 50 mM NaCI, 1 mM EDTA, 0.05% PF-127
  • Cell death detection by trypan blue staining After drug treatment, as the portion of dead cells detached from the culture substratum into the medium, these cells were collected by centrigufation of the medium at 1500 rpm for 3 min, and the adhesion cells were harvested by trypsinization with trypsin/EDTA for 10 min at 37°C. Then, the pooled cell pellets were resuspended and mixed with trypan blue dye for 5 min. After Trypan blue staining was done, cells were counted by using a light microscope and a hemocytometer. Blue dye-incorporating cells were scored as being dead.

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Description

Title: APOPTOSIS INDUCERS
CROSS-REFERENCE TO RELATED APPLICATIONS
[0001] This application claims priority under of US provisional patent application 61/457,828 filed on June 14, 2011.
BACKGROUND
(a) Field
[0002] The subject matter disclosed generally relates to novel compounds for promoting apoptosis involved in some diseases. More specifically, the subject matter relates to novel compounds which inhibit the activity of anti-apoptotic Bcl-2 family protein members, compositions containing the compounds and methods of treating diseases involving a defect in apoptosis, such as, for the treatment of cancer.
(b) Related Prior Art
[0003] Anti-apoptotic family protein members are associated with a number of diseases and thus are under investigation as potential therapeutic drug targets. Important targets for interventional therapy are the Bcl-2 family of proteins which include, for example, Bcl-2, Bcl-xl and Bel- w. A recent review described the therapeutic potential of small molecule Bcl-2 inhibitors (Vogler et al, Cell Death and Differentiation (2009) 16, 360-367). Recently inhibitors of Bcl-2 family members have been reported in the literature, see, for example, WO 2005/049594, US 6,720,338, US 7,030,115., US7,709,467 and US2008/0188460. This invention is directed to a series of novel compounds that promote apoptosis with demonstrated cellular activity. In addition, the present invention provides compounds with improved selectivity for Bcl-2 over Bcl-xl, with the potential for better safety profile in clinics.
[0004] Bcl-2 and Bcl-xL are highly homologous in their ligand binding groove, and previous inhibitors such as ABT-737 or ABT-263 were designed to inhibit both proteins. Clinical experience, however, suggests that Bcl-xL inhibition is responsible for the thrombocytopenia observed in ABT-263 clinical trials, which raises interest in Bcl-2 inhibitors with improved selectivity over Bcl-xl. The present invention is directed to a series of novel spiro-compounds which were unexpectedly found to preferentially inhibit the activity of anti-apoptotic Bcl-2 over Bcl-xl, and are therefore useful for the treatment of diseases involving a defect in apoptosis, such as, for example, in the treatment of cancer with a better safety profile. Pharmaceutical compositions and methods of use are also included.
SUMMARY
[0006] According to an embodiment, there is provided a compound of Formula I
Figure imgf000003_0001
a pharmaceutically acceptable salt thereof, wherein
Figure imgf000003_0002
[0008] wherein
[0009] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms;
[0010] W is -CH2-, -C(CH3)2-, -C(CH2-CH2)- or -CH2CH2-;
[0011] Het represents a carbocycle, or a hetereocycle, each of which contains 1-3 heteroatoms chosen from O, S, N, or Si, and each of which is saturated or contains one or more unsaturated bonds; or
[0012] Het is unsubstituted or substituted with halo, alkyl, oxo, amido, amino, alkylamino, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, aryl, heteroaryl; [0013] R1 is selected from H, halo, or -O-aryl which is substituted or unsubstituted;
[0014] R2 represents
Figure imgf000004_0001
[0015] wherein [0016] Z is -C(O-) or -CH2-; [0017] A is N or C(R10); [0018] R9 is H or halo;
[0019] R10 is H, R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, NHC(0)R12, NC
6alkylC(0)R12, NHC(0)OR12, NC 6alkylC(0)OR12, NHC(0)NHR12, NHC(O)N(R12)2, NC 6alkylNHR12, S02NH2, SO2NHR12, S02N(R12)2, NHS02R12, NC 6alkylS02R12, NHS02NHR12, NHSO2N(R12)2, NC 6alkylS02NHR12, NCi-6alkylS02N(R12)2, C(0)NHNOH, C(0)NHNOR12, C(0)NHS02R12, C(NH)NH2, halogen, CN, N02, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, or C(O)OR12;
[0020] R12 is a linear or branched (Ci-Ce)alkyl group unsubstituted or substituted with one or more halogen atoms; and
[0021] R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR12R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (C-i^alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyi or -NR14R15 groups wherein:
[0022] R14 and R15 are identical or different, and are selected from hydrogen, linear or branched (Ci-6 )alkyl, linear or branched (C -6)alkoxy, aryl and heteroaryl, or [0023] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10; or
[0024] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 10
[0025] According to another embodiment, there is provided a compound of
Formula la
Figure imgf000005_0001
[0026] or a pharmaceutically acceptable salt thereof, wherein:
[0027] R1 is selected from H, or halo; [0028] R2 represents
Figure imgf000005_0002
[0029] wherein
[0030] Z is -C(O-) or -CH2- [0031] A is N or C(R10);
[0032] R9 is H or halo;
[0033] R10 is H, R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, NHC(0)R12, NC 6alkylC(0)R12, NHC(0)OR12, NCi-6alkylC(O)OR12, NHC(O)NHR12, NHC(0)N(R12)2, NCi- ealkylNHR12, SO2NH2, S02NHR12, S02N(R12)2, NHS02R12, Nd-ealkylSOzR12, NHS02NHR12, NHS02N(R12)2, Nd-ealkylSOsNHR12, NCi-6alkylSO2N(R12)2, C(0)NHNOH, C(0)NHNOR12, C(O)NHSO2R12, C(NH)NH2) halogen, CN, N02, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, or C(O)OR12;
[0034] R12 is a linear or branched (CrC6)alkyl group is unsubstituted or substituted by one or more halogen atoms;
[0035] R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR12R13 group wherein each of R 2 and R 3, are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci-6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR14R15 groups wherein:
[0036] R14 and R15 are identical or different, and are selected from hydrogen, linear or branched (C^alkyl, linear or branched (C1-6)alkoxy, aryl and heteroaryl, or
[0037] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R10; or
[0038] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10 ;
[0039] R3, R4, R5 and R6 are independently selected from H, F, Ci-3 alkyl unsubstituted or substituted by halogen atom or Ci-3 alkoxyl;
[0040] n and m are 0, 1 , 2 or 3, where 0<n+m<6;
[0041] Y is O, S, NR12 or -C(R3)(R4);
[0042] W is -CH2-, -C(CH3)2- or -CH2CH2-; and
[0043] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C Ceialkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms.
[0044] According to another embodiment, there is provided a compound of Formula lb
Figure imgf000007_0001
[0045] or a pharmaceutically acceptable salt thereof, wherein:
[0046] R1 is selected from H, or halo;
[0047] R2 represents a group of the following:
Figure imgf000007_0002
[0048] wherein
[0049] Z is -C(O-) or -CH2-;
[0050] R9 is H or halo;
[0051] R10 is -CN, -N02 or -S02-R12;
[0052] R12 is an amino or a linear or branched (Ci-C6)alkyl group unsubstituted or substituted by one or more halogen atoms;
[0053] R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR12R13 group wherein each of R12 and R 3, are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci-6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR14R15 groups wherein: [0054] R14 and R15 , are identical or different, and are selected from hydrogen, linear or branched (Ci-6)alkyl, linear or branched (Ci^alkoxy, aryl and heteroaryl, or
[0055] R14 and R15 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R10; or
[0056] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10 ;
[0057] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CrC6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms; and
[0058] -A-B-C- is selected from (1 ) -N=C(R12)-0-; (2) -C(R12)=N-0-; (3) -N(R12)-
C(0)-0-; (4) -0-C(R12)=N-; (5) -0-N=C(R12)-; (6) -0-C(0)-NR12-.
[0059] According to another embodiment, there is provided a compound of Formula lb
Figure imgf000008_0001
[0060] or a pharmaceutically acceptable salt thereof, wherein: [0061] R1 is selected from H, halo; [0062] R2 represents
Figure imgf000008_0002
[0063] wherein
[0064] Z is -C(O-) or -CH2-;
[0065] R9 is H or halo;
[0066] R 0 is-CN, -N02 or -S02-R12;
[0067] R 2 is an amino or a linear or branched (CrC6)alkyl group unsubstituted or substituted by one or more halogen atoms;
[0068] R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR12R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched
Figure imgf000009_0001
group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR14R15 groups wherein:
[0069] R14 and R15 are identical or different, and are selected from hydrogen, linear or branched (Ci-6)alkyl, linear or branched (Ci-6)alkoxy, aryl and heteroaryl, or
[0070] R14 and R15 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10; or
[0071] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10
[0072] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (d-C6)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (Ci-C6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(Ci-C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms; and
[0073] R7 and R8 are independently selected from Ci-6alkyl, C1 -6cyclolkyl, C^. efluorocycloalkyl, Ci-6fluoroalkyl, or R7, R8, together with the silicon atom to which they are both attached to, complete a four- to six-membered carbocyclic ring which is unsubstituted or substituted with one or more R°wherein Rc is Ci-3 alkyl unsubstituted or substituted by halogen atom or Ci-3 alkoxyl.
[0074] In the compound of Formula la, Y is -C(O)-.
[0075] In the compounds of the present invention, R10 is -NO2 or -S(0)2CF3.
[0076] According to another embodiment, there is provided a compounds of the present invention which may be selected from:
(R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)-1 , 1 -difluorospiro[2.5]oct-5-en-5-yl)methyl)piperazin-1 -yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-
1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-
1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((7-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-N-(4-(4- morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((3-(4-chlorophenyl)spiro[5.5]undec-2-en-2-yl)methyl)piperazin-1-yl)-N-(4-(4- morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((8-(4-chlorophenyl)-1-oxa-2-azaspiro[4.5]deca-2,7-dien-7-yl)methyl)piperazin-1-yl)-N-(4-
((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((8-(4-chlorophenyl)-3-methyl-1-oxa-2-azaspiro[4.5]deca-2,7-dien-7-yl)methyl)piperazin-1- yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4-(4-chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosilin-3-yl)methyl)piperazin-1-yl)-N-
(4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide. [0077] According to another embodiment, there is provided a method of using compounds of the present invention to treat patients with cancer of bladder, brain, breast and uterus, chronic lymphoid leukemia, colon, esophagus, liver, lymphoblastic leukemia, follicular lymphomas, melanomas, malignant homeopathies, myelomas, ovarian cancers, non-small-cell lung cancers, prostate cancers, small-cell lung cancers, lymphoid malignancy of B-cell origin.
[0078] According to another embodiment, there is provided a composition comprising a combination of a compound of the present invention and an anti-cancer agent selected from, a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and kinase inhibitors, in association with a pharmaceutically acceptable carrier.
[0079] According to another embodiment, there is provided a method of treating a cancer comprising the step of administering to the patient in need thereof a therapeutically effective amount of a compound of the present invention, or the composition of the present invention in combination with radiotherapy.
[0080] According to another embodiment, there is provided a use of a compound of the present invention for the preparation of a medicament for the treatment of a cancer.
[0081] According to another embodiment, there is provided a use of a compound of the present invention for the treatment of a cancer.
DETAILED DESCRIPTION OF THE INVENTION
[0082] The invention encompasses a genus of compounds of Formula I as apoptosis inducers
Figure imgf000011_0001
[0083] or a pharmaceutically acceptable salt thereof, wherein:
[0084] R is selected from H, halo, or O-aryl which is substituted or unsubstituted; [0085] R2 represents:
Figure imgf000012_0001
[0086] wherein [0087] Z is -C(O-) or -CH2-;
[0088] A is N or C(R10); [0089] R9 is H or halo;
[0090] R10 is H, R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, NHC(0)R12, NC
6alkylC(0)R12, NHC(0)OR12, NCr6alkylC(0)OR12, NHC(0)NHR12, NHC(0)N(R12)2, NC 6alkylNHR12, S02NH2) S02NHR12, S02N(R1 )2, NHS02R12, Nd-ealkylSOsR12, NHS02NHR12, NHS02N(R12)2, Nd-ealkylSOzNHR12, NCi-6alkylS02N(R12)2, C(0)NHNOH, C(0)NHNOR12, C(0)NHS02R12, C(NH)NH2, halogen, CN, NO2, N3, OH, C(O)H, CHNOH, CH(NOCH3), CF3, C(O)OH, or C(O)OR12;
[0091] R12 is linear or branched (C ^ -C 6 )alkyl group unsubstituted or substituted with one or more halogen atoms;
[0092] R11 represents a hydrogen atom or a -NR 12 R13 or -CH 2 -NR 12 R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (Ci.6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyi or -NR14R15 groups wherein:
[0093] R 14 and R15 , are identical or different, and are selected from hydrogen, linear or branched (Ci-6)alkyl, linear or branched (Ci-6)alkoxy, aryl and heteroaryl, or
[0094] R 14 and R 5 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group oris unsubstituted or substituted with one or more R10; or [0095] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10 ;
[0096] Ra is
Figure imgf000013_0001
[0097] wherein
[0098] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (Ci-Ce)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (Ci-C6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-iC-i-CeJalkyl, alkoxycarbonyl, SF5 and halogen atoms;
[0099] W is -CH2-, -C(CH3)2-, -C(CH2-CH2)- or -CH2CH2-;
[00100] Het represents a carbocycle, or a hetereocycle, each of which contains 1-3 heteroatoms, chosen from O, S, N, or Si and each of which is saturated or contains one or more unsaturated bonds; or
Het is unsubstituted or substituted with halo, alkyl, oxo, amido, amino, alkylamino, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, aryl, heteroaryl.
[00101] Another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where Ra is
Figure imgf000014_0001
[00102] R3, R4, R5 and R6 are independently selected from H, F, C1-3 alkyl unsubstituted or substituted by halogen atom or Ci-3 alkoxyl;
[00103] n and m are 0, 1 , 2 or 3, where 0<n+m<6;
[00104] Y is O, S, NR12 or -C(R3)(R4);
[00105] W is -CH2-, -C(CH3)2- or -CH2CH2-; and
[00106] Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C -i -C 6 )alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (C i -C 6 )alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(C i -C 6 )alkyl, alkoxycarbonyl, SF5 and halogen atoms.
[00107] Another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where Ra is
Figure imgf000014_0002
[00108] R3, R4, R5 and R6 are independently selected from H, F and Ci unsubstituted or substituted by halogen atom or Ci-3 alkoxyl;
[00109] n and m are independently 0, 1 , 2 or 3, where 2<n+m<6;
[00110] Y is O, S, NR12 or -C(R3)(R4); [00111] Ar is defined as above.
[00112] Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R3 is
Figure imgf000015_0001
[00113] Ar is defined as above.
[00114] Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where Ra is
Figure imgf000015_0002
[00115] Ar and R12 are defined as above.
[00116] Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where Ra is
Figure imgf000015_0003
[00117] V and V" are independently selected from O, S;
[00118] q is 2, 3, 4 or 5;
[00119] R3, R4 and Ar are defined as above;
[00120] Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where Ra is
Figure imgf000016_0001
[00121] R7 and R8 are independently selected from Ci-6alkyl, Ci-6cyclolkyl, d. 6fluorocycloalkyl, Ci-6fluoroalkyl, or R7, R8, together with the silicon atom to which they are both attached to, complete a four- to six-membered carbocyclic ring which is unsubstitted or substituted with one or more R3
[00122] Ar is defined as above.
[00123] Still another embodiment comprises compounds having formula I, and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof, where R2 is
Figure imgf000016_0002
[00124] R10 is defined as above; [00125] Rb is a -NR14R15 groups wherein:
[00126] R14 and R15 , are identical or different, and are selected from hydrogen, linear or branched (C1-6)alkyl, linear or branched (Ci-6)alkoxy, aryl and heteroaryl, or [00127] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10; or
[00128] R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10.
[00129] More specifically, the invention relates to compounds of formula I which are:
[00130] (R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00131] 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00132] (R)-4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00133] (R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1 -yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00134] (R)-4-(4-((7-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-6- yl)methyl)piperazin-1-yl)-N-(4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00135] (R)-4-(4-((3-(4-chlorophenyl)spiro[5.5]undec-2-en-2-yl)methyl)piperazin-1- yl)-N-(4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide, [00136] 4-(4-((8-(4-chlorophenyl)-1-oxa-2-azaspiro[4.5]deca-2,7-dien-7- yl)methyl)piperazin-1-yl)-N-(4-((R)-4-m
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00137] 4-(4-((8-(4-chlorophenyl)-3-methyl-1-oxa-2-azaspiro[4.5]deca-2,7-dien-7- yl)methyl)piperazin-1-yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylami
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
[00138] (R)-4-(4-((4-(4-chlorophenyl)-1 ,1-dimethyl-l ,2,5,6-tetrahydrosilin-3- yl)methyl)piperazin-1-yl)-N-(4-(4-morpholino-1-(phenylthio)butan-2-ylamin
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide.
[00139] and therapeutically acceptable salts, prodrugs, salts of prodrugs and metabolites thereof.
DEFINITIONS
[00140] Abbreviations used herein have their conventional meaning within the chemical and biological arts.
[00141] "alkyl," by itself or as part of another substituent, means, unless otherwise stated, a straight (i.e. unbranched) or branched chain, or cyclic hydrocarbon radical, or combination thereof, which may be fully saturated, mono-or polyunsaturated and can include di-and multivalent radicals, having the number of carbon atoms designated (i.e. C1-C10 means one to ten carbons). Examples of saturated hydrocarbon radicals include, but are not limited to, groups such as methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, cyclohexyl, (cyclohexyl)methyl, cyclopropylmethyl, homologs and isomers of, for example, n-pentyl, n-hexyl, n-heptyl, n-octyl, and the like. An unsaturated alkyl group is one having one or more double bonds or triple bonds. Examples of unsaturated alkyl groups include, but are not limited to, vinyl, 2-propenyl, crotyl, 2- isopentenyl, 2-(butadienyl), 2,4-pentadienyl, 3-(1 ,4-pentadienyl), ethynyl, 1-and 3- propynyl, 3-butynyl, and the higher homologs and isomers. Alkyl groups which are limited to hydrocarbon groups are termed "homoalkyl".
[00142] "Fluoroalkyl" means alkyl as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms. [00143] "Alkylene" by itself or as part of another substituent means a divalent radical derived from an alkyl, as exemplified, but not limited, by -CH2CH2CH2CH2-, - CH2CH=CHCH2-, -CH2 C≡CCH2-, -CH2CH2CH(CH2CH2CH3)CH2-. Typically, an alkyl (or alkylene) group will have from 1 to 24 carbon atoms, with those groups having 10 or fewer carbon atoms being preferred in the present invention. A "lower alkyl" or "lower alkylene" is a shorter chain alkyl or alkylene group, generally having eight or fewer carbon atoms.
[00144] "Alkynyl" means carbon chains which contain at least one carbon-carbon triple bond, and which may be linear or branched or combinations thereof. Examples of alkynyl include ethynyl, propargyl, 3-methyl-1-pentynyl, 2-heptynyl and the like.
[00145] "Cycloalkyl" means mono- or bicyclic saturated carbocyclic rings, each of which having from 3 to 10 carbon atoms. A "fused analog" of cycloalkyl means a monocyclic rings fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of cycloalkyl and fused analogs thereof include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, tetrahydronaphthyl, decahydronaphthyl, indanyl, and the like.
[00146] "Alkoxy" means alkoxy groups of a straight or branched having the indicated number of carbon atoms. C^alkoxy, for example, includes methoxy, ethoxy, propoxy, isopropoxy, and the like.
[00147] "Heteroalkyl," by itself or in combination with another term, means, unless otherwise stated, a stable straight or branched chain, or cyclic hydrocarbon radical, or combinations thereof, consisting of at least one carbon atoms and at least one heteroatom selected from the group consisting of O, N, P, Si and S, and wherein the nitrogen, phosphorus, and sulfur atoms may optionally be oxidized and the nitrogen heteroatom may optionally be quaternized. The heteroatom(s) O, N, P and S and Si may be placed at any interior position of the heteroalkyl group or at the position at which alkyl group is attached to the remainder of the molecule. Examples include, but are not limited to,-CH2-CH2-0-CH3, -CH2-CH2-NH-CH3, -CH2-CH2-N(CH3)-CH3, -CH2-S-CH2- CH3, -CH2-CH2, -S(0)-CH3, -CH2-CH2-S(O) 2-CH3, -CH=CH-0-CH3, -Si(CH3)3, -CH2- CH=N-OCH3, -CH=CH-N(CH3)-CH3, -O-CH3,-0-CH2-CH 3, and -CN. Up to two or three heteroatoms may be consecutive, such as, for example, -CH2-NH-OCH3 and -CH2-0- Si(CH3)3. Similarly, the term "heteroalkylene" by itself or as part of another substituent means a divalent radical derived from heteroalkyl, as exemplified, but not limited by, - CH2 -CH2-S -CH2-CH2- and -CH2-S-CH2-CH2-NH-CH2-. For heteroalkylene groups, heteroatoms can also occupy either or both of the chain termini (e.g., alkyleneoxo, alkylenedioxo, alkyleneamino, alkylenediamino, and the like). Still further, for alkylene and heteroalkylene linking groups, no orientation of the linking group is implied by the direction in which the formula of the linking group is written. For example, the formula - C(0)OR'- represents both-C(0)OR'- and -R'OC(O)-. As described above, heteroalkyl groups, as used herein, include those groups that are attached to the remainder of the molecule through a heteroatom, such as -C(0)R\ -C(0)NR', -NR'R", -OR', -SR', and/or - S02R'. Where "heteroalkyl" is recited, followed by recitations of specific heteroalkyl groups, such as -NR'R" or the like, it will be understood that the terms heteroalkyl and- NR'R" are not redundant or mutually exclusive. Rather, the specific heteroalkyl groups are recited to add clarity. Thus, the term "heteroalkyl" should not be interpreted herein as excluding specific heteroalkyl groups, such as -NR'R" or the like.
[00148] "Cycloalkoxy" means cycloalkyi as defined above bonded to an oxygen atom, such as cyclopropyloxy.
[00149] "Fluoroalkoxy" means alkoxy as defined above wherein one or more hydrogen atoms have been replaced by fluoro atoms.
[00150] "Aryl" means mono- or bicyclic aromatic rings containing only carbon atoms. A "fused analog" of aryl means an aryl group fused to a monocyclic cycloalkyi or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of aryl and fused analogs thereof include phenyl, naphthyl, indanyl, indenyl, tetrahydronaphthyl, 2,3-dihydrobenzofuranyl, dihydrobenzopyranyl, 1 ,4- benzodioxanyl, and the like.
[00151] "Heteroaryl" means a mono- or bicyclic aromatic ring containing at least one heteroatom selected from N, O and S, with each ring containing 5 to 6 atoms. A "fused analog" of heteroaryl means a heteroaryl group fused to a monocyclic cycloalkyi or monocyclic heterocyclyl group in which the point of attachment is on the aromatic portion. Examples of heteroaryl include pyrrolyl, isoxazolyl, isothiazolyl, pyrazolyl, pyridyl, oxazolyl, oxadiazolyl, thiadiazolyl, thiazolyl, imidazolyl, triazolyl, tetrazolyl, furanyl, triazinyl, thienyl, pyrimidyl, pyridazinyl, pyrazinyl, benzoxazolyl, benzothiazolyl, benzimidazolyl, benzofuranyl, benzothiophenyl, furo(2,3-b)pyridyl, quinolyl, indolyl, isoquinolyl, and the like.
[00152] The said aryl groups and said heteroaryl groups referred to in the definitions are unsubstituted or are substituted by at least one substituent selected from the group consisting of substituents a;
[00153] The said substituents a are selected from the group consisting of halogen atoms, alkyl groups having from 1 to 4 carbon atoms, alkoxy groups having from 1 to 4 carbon atoms, haloalkyl groups having from 1 to 4 carbon atoms, haloalkoxy groups having from I to 4 carbon atoms, cyano groups, alkynyl groups having from 2 to 6 carbon atoms, alkanoyl groups having from 1 to 5 carbon atoms, cycloalkyl groups having from 3 to 7 ring atoms, heteroaryl groups, aryl groups, aralkoxy groups having from 7 to 10 carbon atoms, arylcarbonyl groups, two adjacent-x groups are optionally joined together to form an aikylene or an alkenylene chain having 3 or 4 carbon atoms, aminocarbonyl groups, alkenyl groups having from 2 to 5 carbon atoms, alkylthio groups having from 1 to 4 carbon atoms, aminosulfinyl groups, aminosulfonyl groups, hydroxy groups, hydroxyalkyl groups having from 1 to 4 carbon atoms, nitro groups, amino groups, carboxy groups, alkoxycarbonyl groups having from 2 to 5 carbon atoms, alkoxyalkyl groups having from 1 to 4 carbon atoms, alkylsulfonyl groups having from I to 4 carbon atoms, alkanoylamino groups having from 1 to 4 carbon atoms, alkanoyl(alkyl)amino groups having from 1 to 6 carbon atoms, alkanoylaminoalkyi groups having from 1 to 6 carbon atoms in both the alkanoyl and alkyl part, alkanoyl(alkyl)aminoalkyl groups having from 1 to 6 carbon atoms in both the alkanoyl and each alkyl part, alkylsulfonylamino groups having from 1 to 4 carbon atoms, mono-or di- alkylaminocarbonyl groups having from 1 to 6 carbon atoms, mono-or di- alkylaminosulfinyl groups having from 1 to 6 carbon atoms, mono-or di alkylaminosulfonyl groups having from 1 to 6 carbon atoms, aminoalkyl groups having from 1 to 4 carbon atoms, mono-or di-alkylamino groups having from 1 to 6 carbon atoms, mono-or di-alkylaminoalkyl groups having from 1 to 6 carbon atoms in each alkyl part, aralkyl groups having from 7 to 10 carbon atoms, heteroarylalkyl groups having from 1 to 4 carbon atoms in the alkyl part, heteroarylalkoxy groups having from 1 to 4 carbon atoms in the alkoxy part and alkylsulfonylamino groups having from I to 4 carbon atoms;
[00154] "Heterocyclyl" means mono- or bicyclic saturated rings containing at least one heteroatom selected from N, S and O, each of said ring having from 3 to 10 atoms in which the point of attachment may be carbon or nitrogen. A "fused analog" of heterocyclyl means a monocyclic heterocycle fused to an aryl or heteroaryl group in which the point of attachment is on the non-aromatic portion. Examples of "heterocyclyl" and fused analogs thereof include pyrrolidinyl, piperidinyl, piperazinyl, imidazolidinyl, 2,3-dihydrofuro(2,3-b)pyridyl, benzoxazinyl, tetrahydrohydroquinolinyl, tetrahydroisoquinolinyl, dihydroindolyl, and the like. The term also includes partially unsaturated monocyclic rings that are not aromatic, such as 2- or 4-pyridones attached through the nitrogen or N-substituted-(1 H,3H)-pyrimidine-2,4-diones (N-substituted uracils).
[00155] "halo" or "halogen," by themselves or as part of another substituent, mean, unless otherwise stated, a fluorine, chlorine, bromine, or iodine atom. Additionally, terms such as "haloalkyl," are meant to include monohaloalkyl and polyhaloalkyl. For example, the term "halo(Ci-C4)alkyl" is mean to include, but not be limited to, trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl, 3-bromopropyl, and the like.
[00156] A "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound of any of Formula I, which is administered as an ester (the "prodrug") to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) bonded to an acid group where the peptide is metabolized to reveal the active moiety.
[00157] Optical Isomers - Diastereomers - Geometric Isomers - Tautomers
[00158] Compounds of Formula I contain one or more asymmetric centers and can thus occur as racemates and racemic mixtures, single enantiomers, diastereomeric mixtures and individual diastereomers. The present invention is meant to comprehend all such isomeric forms of the compounds of Formula I.
[00159] Some of the compounds described herein contain olefinic double bonds, and unless specified otherwise, are meant to include both E and Z geometric isomers.
[00 60] Some of the compounds described herein may exist with different points of attachment of hydrogen, referred to as tautomers. Such an example may be a ketone and its enol form known as keto-enol tautomers. The individual tautomers as well as mixture thereof are encompassed with compounds of Formula I.
[00161] Compounds of the Formula I may be separated into diastereoisomeric pairs of enantiomers by, for example, fractional crystallization from a suitable solvent, for example MeOH or EtOAc or a mixture thereof. The pair of enantiomers thus obtained may be separated into individual stereoisomers by conventional means, for example by the use of an optically active amine as a resolving agent or on a chiral HPLC column.
[00162] Alternatively, any enantiomer of a compound of the general Formula I may be obtained by stereospecific synthesis using optically pure starting materials or reagents of known configuration.
Salts
[00163] The term "pharmaceutically acceptable salts" refers to salts prepared from pharmaceutically acceptable non-toxic bases or acids including inorganic or organic bases and inorganic or organic acids. Salts derived from inorganic bases include aluminum, ammonium, calcium, copper, ferric, ferrous, lithium, magnesium, manganic salts, manganous, potassium, sodium, zinc, and the like. Particularly preferred are the ammonium, calcium, magnesium, potassium, and sodium salts. Salts derived from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins, such as arginine, betaine, caffeine, choline, Ν,Ν'-dibenzylethylenediamine, diethylamine, 2-diethyl- aminoethanol, 2-dimethylaminoethanol, ethanolamine, ethylenediamine, N-ethyl- morpholine, N-ethylpiperidine, glucamine, glucosamine, histidine, hydrabamine, isopropylamine, lysine, methylglucamine, morpholine, piperazine, piperidine, polyamine resins, procaine, purines, theobromine, triethylamine, trimethylamine, tripropylamine, tromethamine, and the like.
[00164] When the compound of the present invention is basic, salts may be prepared from pharmaceutically acceptable non-toxic acids, including inorganic and organic acids. Such acids include acetic, benzenesulfonic, benzoic, camphorsulfonic, citric, ethanesulfonic, fumaric, gluconic, glutamic, hydrobromic, hydrochloric, isethionic, lactic, maleic, malic, mandelic, methanesulfonic, mucic, nitric, pamoic, pantothenic, phosphoric, succinic, sulfuric, tartaric, p-toluenesulfonic acid, and the like. Particularly preferred are citric, hydrobromic, hydrochloric, maleic, phosphoric, sulfuric, and tartaric acids.
[00165] It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
[00166] It will be understood that, as used herein, references to the compounds of Formula I are meant to also include the pharmaceutically acceptable salts.
[00167] Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredients is mixed with water or an oil medium, for example peanut oil, liquid paraffin, or olive oil.
[00168] Aqueous suspensions contain the active material in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethyl-cellulose, methylcellulose, hydroxypropylmethy-cellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethylene-oxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl, p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose, saccharin or aspartame.
[00169] Oily suspensions may be formulated by suspending the active ingredient in a vegetable oil, for example arachis oil, olive oil, sesame oil or coconut oil, or in mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide a palatable oral preparation. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
[00170] Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
[00171] The pharmaceutical compositions of the invention may also be in the form of an oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachis oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavouring agents.
[00172] Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleagenous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example as a solution in 1 ,3-butane diol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
[00173] The compounds of the invention can also be administered intranasally or by inhalation, typically in the form of a dry powder (either alone, as a mixture, for example, in a dry blend with lactose, or as a mixed component particle, for example, mixed with phospholipids, such as phosphatidylcholine) from a dry powder inhaler or as an aerosol spray from a pressurised container, pump, spray, atomiser (preferably an I atomiser using electrohydrodynamics to produce a fine mist), or nebuliser, with or without the use of a suitable propellant, such as 1 , 1 ,1 ,2-tetrafluoroethane or 1 ,1 ,1 ,2,3,3,3-heptafluoropropane. For intranasal use, the powder may comprise a bioadhesive agent, for example, chitosan or cyclodextrin.
[00174] The pressurised container, pump, spray, atomizer, or nebuliser contains a solution or suspension of the compound(s) of the invention comprising, for example, ethanol, aqueous ethanol, or a suitable alternative agent for dispersing, solubilising, or extending release of the active, a propellant(s) as solvent and an optional surfactant, such as sorbitan trioleate, oleic acid, or an oligolactic acid. [00175] Prior to use in a dry powder or suspension formulation, the drug product is micronised to a size suitable for delivery by inhalation (typically less than 5 microns).
[00176] This may be achieved by any appropriate comminuting method, such as spiral jet milling, fluid bed jet milling, supercritical fluid processing to form nanoparticles, high pressure homogenization, or spray drying.
[00177] Capsules (made, for example, from gelatin or HPMC), blisters and cartridges for use in an inhaler or insufflator may be formulated to contain a powder mix of the compound of the invention, a suitable powder base such as lactose or starch and a performance modifier such as l-leucine, mannitol, or magnesium stearate. The lactose may be anhydrous or in the form of the monohydrate, preferably the latter. Other suitable excipients include dextran, glucose, maltose, sorbitol, xylitol, fructose, sucrose and trehalose.
[00178] A suitable solution formulation for use in an atomiser using electrohydrodynamics to produce a fine mist may contain from log to 20mg of the compound of the invention per actuation and the actuation volume may vary from 11 to 1001. A typical formulation may comprise a compound of formula I, propylene glycol, sterile water, ethanol and sodium chloride. Alternative solvents which may be used instead of propylene glycol include glycerol and polyethylene glycol.
[00179] Suitable flavours, such as menthol and levomenthol, or sweeteners, such as saccharin or saccharin sodium, may be added to those formulations of the invention intended for inhaled/intranasal administration.
[00180] Formulations for inhaled/intranasal administration may be formulated to be immediate and/or modified release using, for example, poly(DL-lactic-coglycolic acid (PGLA). Modified release formulations include delayed-, sustained-, pulsed-, controlled-, targeted and programmed release.
[00181] In the case of dry powder inhalers and aerosols, the dosage unit is determined by means of a valve which delivers a metered amount. Units in accordance with the invention are typically arranged to administer a metered dose or "puff' containing from 1 fig to 10 mg of the compound of formula I. The overall daily dose will typically be in the range 1 lag to 10 mg which may be administered in a single dose or, more usually, as divided doses throughout the day.
[00182] Compounds of Formula I may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
[00183] For topical use, creams, ointments, jellies, solutions or suspensions, etc., containing the compound of Formula I are employed. (For purposes of this application, topical application shall include mouth washes and gargles.)
[00184] Dosage levels of the order of from about 0.01 mg to about 140 mg/kg of body weight per day are useful in the treatment of the above-indicated conditions, or alternatively about 0.5 mg to about 7 g per patient per day. For example, inflammation may be effectively treated by the administration of from about 0.01 to 50 mg of the compound per kilogram of body weight per day, or alternatively about 0.5 mg to about 3.5 g per patient per day, preferably 2.5 mg to 1 g per patient per day.
[00185] The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. For example, a formulation intended for the oral administration of humans may contain from 0.5 mg to 5 g of active agent compounded with an appropriate and convenient amount of carrier material which may vary from about 5 to about 95 percent of the total composition. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient, typically 25 mg, 50 mg, 100 mg, 200 mg, 300 mg, 400 mg, 500 mg, 600 mg, 800 mg, or 1000 mg.
[00186] It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the age, body weight, general health, sex, diet, time of administration, route of administration, rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
UTILITIES [00187] The compounds of the present invention are useful for treating diseases during which are expressed antiapoptotic Bcl-2 protein, said compositions comprising an excipient and a therapeutically effective amount of the compound having Formula I.
[00188] The present invention also comprises methods of treating diseases in a patient during which are expressed antiapoptotic Bcl-2 protein or antiapoptotic Bcl-w protein, said methods comprising administering to the patient a therapeutically effective amount of a compound having Formula I.
[00189] More especially, the compounds according to the invention will be useful in the treatment treating diseases of abnormal cell growth and/or dysregulated apoptosis,. such as cancer, mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, ovarian cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular cancer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblastoma, or a combination thereof. Still another embodiment comprises methods of treating mesothioloma, bladder cancer, pancreatic cancer, skin cancer, cancer of the head or neck, cutaneous or intraocular melanoma, ovarian cancer, breast cancer, uterine cancer, carcinoma of the fallopian tubes, carcinoma of the endometrium, carcinoma of the cervix, carcinoma of the vagina, carcinoma of the vulva, bone cancer, ovarian cancer, cervical cancer, colon cancer, rectal cancer, cancer of the anal region, stomach cancer, gastrointestinal (gastric, colorectal, and duodenal), chronic lymphocytic leukemia , esophageal cancer, cancer of the small intestine, cancer of the endocrine system, cancer of the thyroid gland, cancer of the parathyroid gland, cancer of the adrenal gland, sarcoma of soft tissue, cancer of the urethra, cancer of the penis, testicular cancer, hepatocellular cancer (hepatic and billiary duct), primary or secondary central nervous system tumor, primary or secondary brain tumor, Hodgkin's disease, chronic or acute leukemia, chronic myeloid leukemia, lymphocytic lymphomas, lymphoblastic leukemia, follicular lymphoma, lymphoid malignancies of T-cell or B-cell origin, melanoma, multiple myeloma, oral cancer, ovarian cancer, non-small cell lung cancer, prostate cancer, small cell lung cancer, cancer of the kidney and ureter, renal cell carcinoma, carcinoma of the renal pelvis, neoplasms of the central nervous system, primary central nervous system lymphoma, non Hodgkin's lymphoma, spinal axis tumors, brains stem glioma, pituitary adenoma, adrenocortical cancer, gall bladder cancer, cancer of the spleen, cholangiocarcinoma, fibrosarcoma, neuroblastoma, retinoblasitoma, or a combination of one or more of the above cancers in a patient, said methods comprising administering thereto a therapeutically effective amount of a compound having Formula I.
[00190] The present invention relates also to pharmaceutical compositions comprising at least one compound of Formula I on its own or in combination with one or more pharmaceutically acceptable excipients.
[00191] Among the pharmaceutical compositions according to the invention there may be mentioned more especially those that are suitable for oral, parenteral, nasal, per- or transcutaneous, rectal, perlingual, ocular or respiratory administration, especially tablets or dragees, sublingual tablets, sachets, packets, gelatin capsules, glossettes, lozenges, suppositories, creams, ointments, dermal gels, and drinkable or injectable ampoules. [00192] The dosage varies according to the sex, age and weight of the patient, the route of administration, the nature of the therapeutic indication, or any associated treatments, and ranges from 0.01 mg to 1 g per 24 hours in one or more administrations.
[00193] Moreover, the present invention relates also to the combination of a compound of formula I with one or more anticancer agents selected from cytotoxic agents, mitotic poisons, anti-metabolites, proteasome inhibitors and kinase inhibitors, and to the use of that type of combination in the manufacture of medicaments for use in the treatment of cancer.
[00194] The compounds of the invention may also be used in combination with radiotherapy in the treatment of cancer.
[00195] Compounds having Formula I are also expected to be useful as chemotherapeutic agents in combination with therapeutic agents that include, but are not limited to, angiogenesis inhibitors, antiproliferative agents, kinase inhibitors, receptor tyrosine kinase inhibitors, aurora kinase inhibitors, polo-like kinase inhibitors, bcr-abl kinase inhibitors, growth factor inhibitors, COX-2 inhibitors, non-steroidal antiinflammatory drugs (NSAIDS), antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, platinum containing agents, growth factor inhibitors, ionizing radiation, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biologic response modifiers, immunologicals, antibodies, hormonal therapies, retinoids/deltoids plant alkaloids, proteasome inhibitors, HSP-90 inhibitors, histone deacetylase inhibitors (HDAC) inhibitors, purine analogs, pyrimidine analogs, MEK inhibitors, CDK inhibitors, ErbB2 receptor inhibitors, mTOR inhibitors and combinations thereof as well as other antitumor agents.
[00196] Angiogenesis inhibitors include, but are not limited to, EGFR inhibitors, PDGFR inhibitors, VEGFR inhibitors, TTE2 inhibitors, IGFIR inhibitors, matrix metalloproteinase 2 (MMP-2) inhibitors, matrix metalloproteinase 9 (MMP-9) inhibitors, thrombospondin analogs such as thrombospondin- 1 and N-Ac-Sar-Gly-Val-D-allolle- Thr-Nva-He-Arg-Pro- NHCH2CH3 or a salt thereof and analogues of N-Ac-Sar-Gly-Val- D-allolle-Thr-Nva-lle-Arg- PrO-NHCH2CH3 such as N-Ac-GlyVal-D-alle-Ser-Gln-lle-Arg- ProNHCH2CH3 or a salt thereof. [00197] Examples of EGFR inhibitors include, but are not limited to, Iressa (gefitinib), Tarceva (erlotinib or OSI-774), lcotinib, Erbitux (cetuximab), EMD-7200, ABX- EGF, HR3, IgA antibodies, TP-38 (IVAX), EGFR fusion protein, EGF- vaccine, anti-EGFr immunoliposomes and Tykerb (lapatinib).
[00198] Examples of PDGFR inhibitors include, but are not limited to, CP-673,451 and CP- 868596.
[00199] Examples of VEGFR inhibitors include, but are not limited to, Avastin (bevacizumab), Sutent (sunitinib, SUI 1248), Nexavar (sorafenib, BAY43-9006), CP- 547,632, axitinib (AG13736), Apatinib, cabozantinib, Zactima (vandetanib, ZD-6474), AEE788, AZD-2171 , VEGF trap, Vatalanib (PTK-787, ZK-222584), Macugen, M862, Pazopanib (GW786034), ABT-869 and angiozyme.
[00200] Examples of thrombospondin analogs include, but are not limited to, TSP-I and ABT- 510.
[00201] Examples of aurora kinase inhibitors include, but are not limited to, VX-680, AZD- 1152 and MLN-8054. Example of polo-like kinase inhibitors include, but are not limited to, BI-2536.
[00202] Examples of bcr-abl kinase inhibitors include, but are not limited to, Gleevec (imatinib) and Dasatinib (BMS354825).
[00203] Examples of platinum containing agents includes, but are not limited to, cisplatin, Paraplatin (carboplatin), eptaplatin, lobaplatin, nedaplatin, Eloxatin (oxaliplatin) or satraplatin.
[00204] Examples of mTOR inhibitors includes, but are not limited to, CCI-779, rapamycin, temsirolimus, everolimus, RAD001 , INK-128 and ridaforolimus.
[00205] Examples of HSP-90 inhibitors includes, but are not limited to, geldanamycin, radicicol, 17-AAG, KOS-953, 17-DMAG, CNF- 01 , CNF-1010, 17-AAG- nab, NCS-683664, Mycograb, CNF-2024, PU3, PU24FC1 , VER49009, IPI-504, SNX- 21 12 and STA-9090. [00206] Examples of histone deacetylase inhibitors (HDAC) includes, but are not limited to, Suberoylanilide hydroxamic acid (SAHA), MS-275, valproic acid, TSA, LAQ- 824, Trapoxin, tubacin, tubastatin, ACY-1215 and Depsipeptide.
[00207] Examples of MEK inhibitors include, but are not limited to, PD325901 , ARRY-142886, ARRY-438162 and PD98059.
[00208] Examples of CDK inhibitors include, but are not limited to, flavopyridol, MCS-5A, CVT-2584, seliciclib (CYC-202, R-roscovitine), ZK-304709, PHA-690509, BMI- 1040, GPC-286199, BMS-387,032, PD0332991 and AZD-5438.
[00209] Examples of COX-2 inhibitors include, but are not limited to, CELEBREX™ (celecoxib), parecoxib, deracoxib, ABT-963, MK-663 (etoricoxib), COX-189 Lumiracoxib), BMS347070, RS 57067, NS-398, Bextra (valdecoxib), paracoxib, Vioxx (rofecoxib), SD- 8381 , 4-Methyl-2-(3,4-dimethylphenyl)-l-(4-sulfamoyl-phenyl-IH-pyrrole, T-614, JTE-522, S-2474, SVT-2016, CT-3, SC-58125 and Arcoxia (etoricoxib).
[00210] Examples of non-steroidal anti-inflammatory drugs (NSAIDs) include, but are not limited to, Salsalate (Amigesic), Diflunisal (Dolobid), Ibuprofen (Motrin), Ketoprofen (Orudis), Nabumetone (Relafen), Piroxicam (Feldene), Naproxen (Aleve, Naprosyn), Diclofenac (Voltaren), Indomethacin (Indocin), Sulindac (Clinoril), Tolmetin (Tolectin), Etodolac (Lodine), Ketorolac (Toradol) and Oxaprozin (Daypro).
[00211] Exambles of ErbB2 receptor inhibitors include, but are not limited to, CP- 724-714, CI-1033, (canertinib), Herceptin (trastuzumab), Omitarg (2C4, petuzumab), TAK-165, GW- 572016 (lonafarnib), GW-282974, EKB-569, PI-166, dHER2 (HER2 Vaccine), APC8024 (HER2 Vaccine), anti-HER/2neu bispecific antibody, B7.her2lgG3, AS HER2 trifunctional bispecfic antibodies, mAB AR-209 and mAB 2B-1.
[00212] Examples of alkylating agents include, but are not limited to, nitrogen mustard N- oxide, cyclophosphamide, ifosfamide, trofosfamide, Chlorambucil, melphalan, busulfan, mitobronitol, carboquone, thiotepa, ranimustine, nimustine, temozolomide, AMD-473, altretamine, AP-5280, apaziquone, brostallicin, bendamustine, carmustine, estramustine, fotemustine, glufosfamide, KW-2 70, mafosfamide, and mitolactol, carmustine (BCNU), lomustine (CCNU), Busulfan, Treosulfan, Decarbazine and Temozolomide.
[00213] Examples of antimetabolites include but are not limited to, methotrexate, 6- mercaptopurine riboside, mercaptopurine, uracil analogues such as 5-fluorouracil (5-FU) alone or in combination with leucovorin, tegafur, UFT, doxifluridine, carmofur, cytarabine, cytarabine ocfosfate, enocitabine, S-l, Alimta (premetrexed disodium, LY231514, MTA), Gemzar (gemcitabine), fludarabine, 5-azacitidine, capecitabine, cladribine, clofarabine, decitabine, eflornithine, ethnylcytidine, cytosine arabinoside, hydroxyurea, TS-I, melphalan, nelarabine, nolatrexed, ocfosate, disodium premetrexed, pentostatin, pelitrexol, raltitrexed, triapine, trimetrexate, vidarabine, vincristine, vinorelbine, mycophenolic acid, tiazofurin, Ribavirin, EICAR, hydroxyurea and deferoxamine.
[00214] Examples of antibiotics include intercalating antibiotics but are not limited to, aclarubicin, actinomycins such as actinomycin D, amrubicin, annamycin, adriamycin, bleomycin a, bleomycin b, daunorubicin, doxorubicin, elsamitrucin, epirbucin, glarbuicin, idarubicin, mitomycin C, nemorubicin, neocarzinostatin, peplomycin, pirarubicin, rebeccamycin, stimalamer, streptozocin, valrubicin, zinostatin and combinations thereof.
[00215] Examples of topoisomerase inhibiting agents include, but are not limited to, one or more agents selected from the group consisting of aclarubicin, amonafide, belotecan, camptothecin, 10-hydroxycamptothecin, 9-aminocamptothecin, diflomotecan, irinotecan HCL (Camptosar), edotecarin, epirubicin (Ellence), etoposide, exatecan, gimatecan, lurtotecan, orathecin (Supergen), BN-80915, mitoxantrone, pirarbucin, pixantrone, rubitecan, sobuzoxane, SN-38, tafluposide and topotecan.
[00216] Examples of antibodies include, but are not limited to, Rituximab, Cetuximab, Bevacizumab, Trastuzimab, specific CD40 antibodies and specific IGFIR antibodies,
[00217] Examples of hormonal therapies include, but are not limited to, exemestane (Aromasin), leuprolide acetate, anastrozole (Arimidex), fosrelin (Zoladex), goserelin, doxercalciferol, fadrozole, formestane, tamoxifen citrate (tamoxifen), Casodex, Abarelix, Trelstar, finasteride, fulvestrant, toremifene, raloxifene, lasofoxifene, letrozole, flutamide, bicalutamide, megesterol, mifepristone, nilutamide, dexamethasone, predisone and other glucocorticoids.
[00218] Examples of retinoids/deltoids include, but are not limited to, seocalcitol (EB 1089, CB 1093), lexacalcitrol (KH 1060), fenretinide, Aliretinoin, Bexarotene and LGD-1550.
[00219] Examples of plant alkaloids include, but are not limited to, vincristine, vinblastine, vindesine and vinorelbine.
[00220] Examples of proteasome inhibitors include, but are not limited to, bortezomib (Velcade), MGI 32, NPI-0052 and PR-171.
[00221] Examples of immunologicals include, but are not limited to, interferons and numerous other immune enhancing agents. Interferons include interferon alpha, interferon alpha-2a, interferon, alpha-2b, interferon beta, interferon gamma- 1a, interferon gamma- 1 b (Actimmune), or interferon gamma-nl and combinations thereof. Other agents include filgrastim, lentinan, sizofilan, TheraCys, ubenimex, WF-10, aldesleukin, alemtuzumab, BAM-002, decarbazine, daclizumab, denileukin, gemtuzumab ozogamicin, ibritumomab, imiquimod, lenograstim, lentinan, melanoma vaccine (Corixa), molgramostim, OncoVAC- CL, sargaramostim, tasonermin, tecleukin, thymalasin, tositumomab, Virulizin, Z-100, epratuzumab, mitumomab, oregovomab, pemtumomab (Y-muHMFGI), Provenge (Dendreon), CTLA4 (cytotoxic lymphocyte antigen 4) antibodies and agents capable of blocking CTLA4 such as MDX-0 0.
[00222] Examples of biological response modifiers are agents that modify defense mechanisms of living organisms or biological responses, such as survival, growth, or differentiation of tissue cells to direct them to have anti-tumor activity. Such agents include krestin, lentinan, sizofrran, picibanil and ubenimex.
[00223] Examples of pyrimidine analogs include, but are not limited to, 5- Fluorouracil, Floxuridine, Doxifluridine, Ratitrexed, cytarabine (ara C), Cytosine arabinoside, Fludarabine, and Gemcitabine.
[00224] Examples of purine analogs include but are not limited to, Mercaptopurine and thioguanine. [00225] Examples of antimitotic agents include, but are not limited to, ABT-751 , paclitaxel, docetaxel, epothilone D (KOS-862) and ZK-EPO.
[00226] Compounds of the present invention are also intended to be used as a radiosensitizer that enhances the efficacy of radiotherapy. Examples of radiotherapy include but are not limited to, external beam radiotherapy (XBRT), or teletherapy, brachtherapy or sealed source radiotherapy, unsealed source radiotherapy.
SYNTHESIS
[00227] Compounds of the present invention may be made by synthetic chemical processes, examples of which are shown herein below. It is meant to be understood that the order of the steps in the processes may be varied, that reagents, solvents and reaction conditions may be substituted for those specifically mentioned, and that vulnerable moieties may be protected and deprotected, as necessary.
[00228] The following abbreviations have the meanings indicated. DBU means 1,8- diazabicyclo[5.4.0]undec- 7-ene; DIBAL means diisobutylaluminum hydride; DIEA means diisopropylethylamine; DMAP means Ν,Ν-dimethylaminopyridine; DME means 1 ,2-dimethoxyethane; DMF means Ν,Ν-dimethylformamide; dmpe means l,2- bis(dimethylphosphino)ethane; DMSO means dimethylsulfoxide; dppb means l,4- bis(diphenylphosphino)butane; dppe means 1 ,2- bis(diphenylphosphino)ethane; dppf means l,r-bis(diphenylphosphino)ferrocene; dppm means bis(diphenylphosphino)methane; EDCI means l-(3-dimethylaminopropyl)-3- ethylcarbodiimide; HATU means 0-(7- azabenzotriazol-l-y -N.NTSr'N'- tetramethyluronium hexafluorophosphate; HMPA means hexamethylphosphorarnide; IPA means isopropyl alcohol; LDA means lithium diisopropylamide; LHMDS means lithium bis(hexamethyldisilylamide); LAH means lithium aluminum hydride; NCS means N-chlorosuccinimide; PyBOP means benzotriazol-1- yloxytripyrrolidinophosphonium hexafluorophosphate; TDA-I means tris(2-(2- methoxyethoxy)ethyl)amine; TEA means triethylamine; TFA means trifluoroacetic acid; THF means tetrahydrofuran; NCS means N-chlorosuccinimide; NMM means N-methylmorpholine; NMP means N- methylpyrrolidine; PPh3 means triphenylphosphine. [00229] The following preparations and Examples illustrate the invention but do not limit it in any way.
EXAMPLE 1
[00230] (R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000037_0001
[00231] Stepl : 9-methylene-1 ,5-dioxaspiro[5.5]undecane
Figure imgf000037_0002
[00232] The title was prepared according to the procedure described in PCT Int. Appl., WO2006010094.
[00233] 1H NMR (500 MHz, acetone-d6): δ 4.63 (s, 2H), 3.92 (s, 4H), 2.25 (t, 4H), 1.63 (t, 4H).
[00234] Step 2: 7, 1 1-dioxadispiro[2.2.5.2]tridecane
Figure imgf000037_0003
[00235] To a solution of Et2Zn (7.6 mL) in 22 mL of CH2CI2 at 0 oC was CH2I2(5.4 mL) dropwise . The resulted slush was stirred for 10 minutes at 0 °C and a solution of - methylene-1 ,5-dioxaspiro[5.5]undecane (3.46 g in 10 mL of CH2CI2) was added dropwise. The clear reaction mixture was stirred under a dry air atmosphere overnight and quenched with saturated aqueous solution of NH4CI (~30 mL). The mixture was extracted with 2 x 50 mL of CH2CI2, and the combined extract was washed with brine, dried over Na2S04 and filtrated. The filtrate was concentrated to give the title compound as oil.
[00236] 1H NMR (500 MHz, acetone-d6): δ 3.90 (s, 4H), 1.61 (t, 4H), 1.40 (m, 4H), 0.26 (s, 4H).
[00237] Step 3: spiro[2.5]octan-6-one
Figure imgf000038_0001
[00238] To a solution of 7,1 1-dioxadispiro[2.2.5.2]tridecane (5.0 g) in 10 mL of acetone was added 55.7 mL of 3 N HCI. After stirring for 3 h at room temperature, the mixture was extracted with 3 x 150 mL of CH2CI2. The combined extract was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 0 % EtOAc/hexanes to give 2.43 g of the title product as oil.
[00239] 1H NMR (500 MHz, acetone-d6): δ 2.35 (t, 4H), 1.66 (t, 4H), 0.50 (s, 4H). [00240] Step 4: 6-chlorospiro[2.5]oct-5-ene-5-carbaldehyde
Figure imgf000038_0002
[00241] To a solution of N,N-dimethylformide (2.04 g) in 3.1 mL of CH2CI2 cooled at 0 °C was added POCI3 (2.28 mL) dropwise over 10 minutes. After warming up to room temperature and stirring for 20 minutes, a solution of spiro[2.5]octan-6-one (2.34 g) in 12.5 ml_ of CH2CI2 was added dropwise over 10 minutes. The reaction mixture was then heated at 45 °C for 4 h, cooled to room temperature and poured into 100 mL of ice- cooled saturated aqueous solution of NaHC03. The resulting mixture was adjusted to pH ~7 with solid NaHC03 and extracted with 3 x 50 mL of CH2CI2. The combined extract was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 10 % EtOAc/hexanes to give 4.5 g of the title product as yellow oil.
[00242] 1 H NMR (500 MHz, acetone-d6): δ 10.16 (s, 1 H), 2.72 (m, 2H), 2.05 (m, 2H), 1.60 (t, 2H), 0.40 (m, 4H).
[00243] Step 5: 6-(4-chlorophenyl)spiro[2.5]oct-5-ene-5-carbaldehyde
Figure imgf000039_0001
[00244] A mixture of 6-chlorospiro[2.5]oct-5-ene-5-carbaldehyde (4.0 g), 4- chlorophenylboronic acid (4.4 g), Bu4NBr (7.56 g), Pd(OAc)2 (0.21 g) and K2C03 (8.1 g) in 81 mL of water was vented with N2 and heated at 45 °C under N2 atmosphere for 10 h. Water (50 mL) was added and the mixture was extracted with 4 x 50 mL of 1 :1 EtOAc/hexanes. The combined extract was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 10 % EtOAc/hexanes to give 3.91 g of the title product as a pale yellow solid.
[00245] 1H NMR (500 MHz, acetone-d6): δ 9.48 (s, 1 H), 7.50 (d, 2H), 7.40 (d, 2H), 2.67 (m, 2H), 2.16 (m, 2H), 1.60 (t, 2H), 0.41 (s, 4H).
[00246] Step 6: ethyl 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)benzoate
Figure imgf000040_0001
[00247] To a solution of 6-(4-chlorophenyl)spiro[2.5]oct-5-ene-5-carbaldehyde (3.64 g) and ethyl 4-(piperazin-1-yl)benzoate (3.3 g) in 73 mL of THF was added 5.97 g of NaBH(OAc)3. After stirring at room temperature for 16 h, additional 0.33 g of ethyl 4- (piperazin-l-yl)benzoate and 0.5 g of NaBH(OAc)3 were added. The reaction mixture was continued being stirred for 5 h, and treated with 100 mL of t-butyl methyl ether and 50 mL of sat, NH4CI. The mixture was extracted with 3 x 75 mL of 1 :1 EtOAc/hexanes. The combined extract was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 20 % EtOAc/hexanes to give 3.53 g of the title product as a white solid.
[00248] 1H NMR (500 MHz, acetone-d6): δ 7.84 (d, 2H), 7.37 (d, 2H), 7.18 (d, 2H), 6.93 (d, 2H), 4.25 (q, 2H), 3.27 (m, 4H), 2.83 (s, 2H), 2.35-2.42 (m, 6H), 2.16 (s, 2H), 1.55 (t, 2H), 1.32 (t, 3H), 0.48 (s, 4H).
[00249] Step 7: 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1 -yl)benzoic acid
Figure imgf000040_0002
[00250] To a solution of ethyl 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)benzoate (6.2 g) in 49 mL of THF, 12 mL of water and 25 mL of EtOH was added 1.17 g of NaOH. After stirring at 65 °C for 16 h, the reaction mixture was concentrated to dryness. The residue was suspended in 5 mL of MeOH, and the solid was collected by filtration. The solid was then treated with 10 mL of water followed by 29.3 mL of 1 N HCI. The resulting suspension was stirred for 0.5 h and the solid was collected by filtration, washed with 3 x 5 mL of water, 5 mL of hexanes, and air-dried to give 5.5 g of the title product as a white solid.
[00251] 1H NMR (500 MHz, acetone-d6): δ 7.87 (d, 2H), 7.38 (d, 2H), 7.20 (d, 2H), 6.95 (d, 2H), 3.30 (m, 4H), 2.85 (s, 2H), 2.35-2.42 (m, 6H), 2.15 (s, 2H), 1.53 (t, 2H), 0.38 (s, 4H).
[00252] Step 8: (R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000041_0001
[00253] A mixture of 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)benzoic acid (1.25 g), (R)-4-(4-morpholino-1-(phenylthio)butan- 2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (1.58 g), ECDI (0.8 g) and DMAP (0.87 g) in 28.6 mL of CH2CI2 was stirred under N2 atmosphere at 25 °C for 16 h. Additional 0.05 g of 4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1- yl)benzoic acid, 0.08 g of EDCI and 0.10 g of DMAP were added. After stirring overnight, the reaction mixture was concentrated to dryness and the residue was dissolved in 200 mL of EtOAc. The EtOAc solution was washed with 3 x 50 mL of 10% aqueous solution containing 0.75% NaCI, followed by 100 mL of 20% K2HP04 and 100 mL of half-saturated brine. The EtOAc layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient up to 4% MeOH/CH2CI2 to give 2.5 g of the title compound as a white solid. [00254] 1H NMR (500 MHz, acetone-d6): δ 8.34 (s, 1 H), 8.07 (d, 1 H), 7.82 (d, 2H), 7.40 (d, 2H), 7.35 (d, 2H), 7.28 (t, 2H), 7.22 (t, 1 H), 7.17 (d, 2H), 7.10 (d, 1 H), 7.06 (d, 1 H), 6.92 (d, 2H), 4.20-4.30 (m, 1 H), 3.48-3.60 (m, 4H), 3.40 (dd, 1 H), 3.32 (dd, 1 H), 2.28 (m, 4H), 2.60-3.00 (bs, 1 H), 2.30-2.50 (m, 10H), 2.18-2.28 (m, 2H), 2.10-2.18 (m, 3H), 1.95 (s, 2H), 1.76-1.90 (m, 1 H), 1.53 (t, 2H), 0.37 (d, 4H).
EXAMPLE 2
[00255] 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000042_0001
[00256] Step 1 : 1 ,1-difluoro-7,11-dioxadispiro[2.2.5.2]tridecane
Figure imgf000042_0002
[00257] To a solution of 9-methylene-1 ,5-dioxaspiro[5.5]undecane (2.0 g) in 20 mL of diglyme heated at 160 °C was added a solution of CIF2C02Na in 100 mL of diglyme dropwise over a period of 1 h. The reaction mixture was then heated at 180 °C for 0.5 h, cooled to room temperature and poured into 100 mL of water. The resulting mixture was extracted with 6 x 50 mL of hexanes and the extract was dried over Na2S04. After filtration, the filtrate was concentrated and the residue was purified by silica gel chromatography eluted with a gradient up to 2% EtOAc/hexanes to give 1.0 g of the title compound as a white solid. [00258] 1H NMR (300 MHz, CDCI3): δ 3.95 (s, 4H), 1.70 (s, 8H), 1.05 (t, 2H).
[00259] Step 2: 1 ,1-difluorospiro[2.5]octan-6-one
Figure imgf000043_0001
[00260] To a solution of 1 ,1-difluoro-7,11-dioxadispiro[2.2.5.2]tridecane (2.83 g) in 14 ml_ of acetone was added 36 ml_ of 3 N HCI. After stirring overnight at room temperature, the mixture was extracted with 3 x 150 mL of CH2CI2. The combined extract was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated to give 1.3 g of the title product as oil.
[00261] 1H NMR (300 MHz, CDCI3): δ 2.45 (t, 4H), 1.94 (t, 4H), 1.24 (t, 2H). [00262] Step 3: 6-chloro-1 ,1-difluorospiro[2.5]oct-5-ene-5-carbaldehyde
Figure imgf000043_0002
[00263] To a solution of Ν,Ν-dimethylformide (0.66mL) in 1 mL of CH2CI2 cooled at 0 °C was added POC (0.73 mL) dropwise over 10 minutes. After warming up to room temperature and stirring for 20 minutes, a solution of 1 ,1-difluorospiro[2.5]octan-6-one (0.97 g) in 4 mL of CH2CI2 was added dropwise over 10 minutes. The reaction mixture was then heated at 45 °C for 4 h, cooled to room temperature and poured into a mixture of 100 mL of ice-cooled saturated aqueous solution of NaHC03 and 100 mL of EtOAc. The aqueous layer was further extracted with 3 x 50 mL of EtOAc. The combined extract was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 5 % EtOAc/hexanes to give 0.56 g of the title product as yellow oil. [00264] 1H NMR (300 MHz, CDCI3): δ 10.20 (s, 1 H), 2.60-2.80 (m, 2H),
1 H), 2.16 (d, 1 H), 1.80-1.90 (m, 2H), 1.10-1.25 (m, 2H).
[00265] Step 4: 6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-ene-5- carbaldehyde
Figure imgf000044_0001
[00266] A mixture of 6-chloro-1 ,1-difluorospiro[2.5]oct-5-ene-5-carbaldehyde (0.5 g), 4-chlorophenylboronic acid (0.45 g), Bu4NBr (0.78 g), Pd(OAc)2 (0.022 g) and K2C03 (0.84 g) in 8 mL of water was vented with N2 and heated at 45 °C under N2 atmosphere for 9 h. Water (10 mL) was added and the mixture was extracted with 3 x 15 mL of 1 :1 EtOAc/hexanes. The combined extract was washed with brine, dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with 10 % EtOAc/hexanes to give 0.22 g of the title product as a pale yellow solid.
[00267] 1H NMR (300 MHz, CDCI3): δ 9.46 (s, 1 H), 7.35 (d, 2H), 7.18 (d, 2H), 2.60- 2.70 (m, 2H), 2.55 (d, 1 H), 2.35 (d, 1 H), 1.84 (m, 2H), 1.12-1.23 (m, 2H).
[00268] Step 5: ethyl 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en- 5-yl)methyl)piperazin-1-yl)benzoate
Figure imgf000045_0001
[00269] To a solution of 6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-ene-5- carbaldehyde (0.21 g) and ethyl 4-(piperazin-1-yl)benzoate (0.22 g) in 3.6 mL of THF was added 0.46 g of NaBH(OAc)3. After stirring at room temperature for 16 h, the reaction mixture was treated 10 mL of sat, NhUCI, and extracted with 3 x 15 mL of 1 :1 EtOAc/hexanes. The combined extract was washed with brine, dried over Na2S04 and filtered. The filtrate was concentrated and the residue was purified by silica gel chromatograph y eluted with a gradient from hexanes to EtOAc to give 0.13 g of the title product as a white solid.
[00270] 1H NMR (300 MHz, CDCI3): δ 7.91 (d, 2H), 7.30 (d, 2H), 7.03 (d, 2H), 6.81 (d, 2H), 4.32 (q, 2H), 3.25 (t, 4H), 2.85 (s, 2H), 2.24-2.45 (m, 8H), 1.74-1.90 (m, 2H), 1.35 (t, 3H), 1.12-1.22 (m, 2H).
[00271] MS (ES-API): m/e 501.1 (M+1 )+.
[00272] Step 6: 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1 -yl)benzoic acid
Figure imgf000045_0002
[00273] To a solution of ethyl 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5- en-5-yl)methyl)piperazin-1-yl)benzoate (0.13 g) in 0.96 ml_ of THF, 0.24 ml_ of water and 0.48 ml_ of EtOH was added 0.023 g of NaOH. After stirring at 65 °C for 16 h, the reaction mixture was adjusted to pH 4 with 1 N HCI (~2 ml_) and concentrated to dryness. The resulting solid was washed with minimum amount of water and air-dried to give 0.1 1 g of the title compound as a white solid.
[00274] MS (ES-API): m/e 473.2 (M+1)+.
[00275] Step 7: 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)-N-((4-(((R)-4-morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000046_0001
[00276] A mixture of 4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5- yl)methyl)piperazin-1-yl)benzoic acid (0.10 g), (R)-4-(4-morpholino-1-(phenylthio)butan- 2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (0.12 g), EDCI (0.060 g) and DMAP (0.66 g) in 2.2 mL of CH2CI2 was stirred under N2 atmosphere at 25 °C for 16 h. Additional 0.066 g of EDCI and 0.10 g of DMAP were added. After stirring overnight, the reaction mixture was diluted with 100 mL of CH2CI2 and washed with 3 x 15 mL of 10% aqueous solution containing 0.75% NaCI, followed by 10 mL of half-saturated brine. The CH2CI2 layer was dried over Na2S04, filtered, and concentrated. The residue was purified by silica gel chromatography eluted with a gradient up to 4% MeOH/CH2CI2 to give 0.026 g of the title compound as a white solid.
[00277] 1H NMR (300 MHz, CDCI3): δ 8.85-9.00 (bs, 1 H), 8.24 (d, 1 H), 8.08 (dd, 1 H), 7.68 (d, 2H), 7.32-7.38 (m, 2H), 7.22-32 (m, 6H), 6.98-7.04 (m, 3H), 6.75 (d, 2H), 6.58 (d, 1 H), 3.88 (m, 1 H), 3.70 (m, 4H), 3.26 (m, 4H), 2.83-3.13 (m, 4H), 2.20-2.58 (m, 10 H), 2.05 (s, 2H), 1.65-1.90 (m, 4H), 1.24 (m, 2H), 1.13 (m, 2H).
[00278] MS (ES+): m/e 1008.41 (M+1).
EXAMPLE 3
[00279] (R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000047_0001
[00280] Step 1 : diethyl cyclopentane-1 , 1 -dicarboxylate
Figure imgf000047_0002
[00281] To a solution of 1 ,4-dibromobutane, diethylmalonate in DMF at r.t. under N2 were added K2CO3 and TBAF. The reaction mixture was then stirred at r.t. overnight. The reaction mixture was then quenched with cold water ((200. mL) and extracted with 10% EtOAc/hexanes (3 x 150mL). The combined organic layers were washed with half- saturated brine (150 mL x 2) then brine (150 mL), dried over Na2S04 and filtered. The filtrate was concentrated to dryness and the residue was purified by flash silica gel column eluted with 2% EtOAc/hexanes to give 36.7g (84% yield) colorless oil.
[00282] Step 2: cyclopentane-1 , 1-diyldimethanol
Figure imgf000047_0003
[00283] LiAIH4 (10.82 g)was suspended in 100 mL of THF anhydrous at r.t. under N2. A solution of diethyl cyclopentane-1 ,1-dicarboxylate (20.36 g) in 90 mL of THF was then added dropwise through dropping funnel over 30 min. The reaction mixture was then stirred overnight at r.t. and cooled in a ice bath. 100ml_ of EtOAc was added , followed by addition of 22 mL of saturated solution of NH4CI dropwise carefully through dropping funnel. The suspension was filtered and the filter cake was washed with EtOAc (6 x 50 mL). The filtrate was concentrated and the residue was purified by flash column with 30% -50% EtOAc/hexanes to give 6.33g of the title compound as a colorless oil.
[00284] Step 3: cyclopentane-1 ,1-diylbis(methylene) dimethanesulfonate
Figure imgf000048_0001
[00285] Diol (6.0 g) was dissolved in CH2CI2 ( 84 mL) at r.t. under N2 and then Et3N (19.9 mL) was added. The reaction solution was cooled over brine-ice bath for 30 min., and MsCI (10.72 mL) was added dropwise by controlling internal temperature below -3°C over 30 minutes. The reaction mixture stirred over brine-ice bath and then warmed up to r.t. over overnight. MeOH (3 mL) was added followed by addition of 50 mL of half-saturated brine. The organic layer was separated, washed with brine (50 mL), dried over Na2S04 and filtered. The filtrate was concentrated to dryness and the residue was triturated with 20 mL of 10% EtOAc/hexanes to give 1 1.5 of the title compound as a pale yellow solid.
[00286] Step 4: 2,2'-(cyclopentane-1 ,1-diyl)diacetonitrile
Figure imgf000048_0002
[00287] To a solution of cyclopentane-1 ,1-diylbis(methylene) dimethanesulfonate ( 1 g) in 77 mL of DMF at r.t. under N2l was added NaCN (7.9 g) and the reaction mixture was heated at 100 °C overnight. DMF was removed with evaporation under vaccum and the residue was purified by silica gel flash chromatography eluted with 10% - 30% EtOAc to give 3.92 g of the title compound as pale yellow oil. [00288] Step 5: 2,2'-(cyclopentane-1 ,1-diyl)diacetic acid
Figure imgf000049_0001
[00289] 2,2'-(Cyclopentane-1 ,1-diyl)diacetonitrile (3.92 g) was dissolved in EtOH ( 53 ml_) at r.t. under N2 atmosphere. A solution of NaOH (8.5 g) in water (26 ml_) was then added dropwise. The reaction mixture was heated to reflux overnight. Additional NaOH (7.1 g) and 30 ml_ of EtOH and 15 mL of water were added and the mixture was continued to reflux for another overnight. The reaction mixture was cooled to r.t. and then diluted with 100 mL of water to give clear solution. The solution was cooled over ice bath and 29 mL of 85% phosphoric acid was added dropwise. The mixture was extracted with EtOAc 3 x 150mL. The combined organic layers were washed with brine (100mL), dried over Na2SO4 and filtered through a pad of silica gel and celite. The filtrate was concentrated to give the title compound (4.5 g) as a pale yellow solid.
[00290] Step 6: 2,2'-(cyclopentane-1 ,1-diyl)diethanol
Figure imgf000049_0002
[00291] LiAIH4 (3.2 g) was suspended in 100 mL of THF anhydrous at r.t. under
N2. A solution of 2,2'-(cyclopentane-1 ,1-diyl)diacetic acid (3.5 g) in 80 mL of THF was then added dropwise through dropping funnel over 30 min. The reaction mixture was stirred at r.t. overnight and then heated to reflux for 2 h. The reaction mixture was cooled in an ice bath for 30 minutes. A 20% solution of potassium sodium tartrate (50 mL) was added slowly to the reaction mixture followed by 100mL EtOAc. The reaction mixture was stirred at r.t. for 1 h and the two phases were separated. The aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and filtered out through a pad of silica gel and celite. The filtrate was concentrated to give the title compound (2.8 g) as a pale yellow oil.
[00292] Step 7: 2,2'-(cyclopentane-1 ,1-diyl)bis(ethane-2,1-diyl)
dimethanesulfonate
Figure imgf000050_0001
[00293] 2,2'-(Cyclopentane-1 ,1-diyl)diethanol (2.8.0 g) was dissolved in CH2CI2 (72 mL) at r.t. under N2 and then ΕίβΝ (7.8 mL) was added. The reaction solution was cooled over brine-ice bath for 30 minutes., and MsCI (4.2 mL) was added dropwise by controlling internal temperature below -3°C over 30min. The reaction mixture stirred over brine-ice bath for 2 h and then at r.t. for 2 h. Water (10 mL) was added followed by addition of 50 mL of brine. The organic layer was separated, washed with brine (50 mL), dried over Na2SO4 and filtered. The filtrate was concentrated to dryness and the residue was triturated with 20 mL of 10% EtOAc/hexanes to give 4.25 g of the title compound as a pale yellow solid.
[00294] Step 8: 3,3'-(cyclopentane-1 ,1-diyl)dipropanenitrile
Figure imgf000050_0002
[00295] solution of 2,2'-(cyclopentane-1 ,1-diyl)bts(ethane-2,1-diyl) dimethanesulfonate (3.8 g) in 77 mL of DMF at r.t. under N2, was added NaCN (3.0 g) and the reaction mixture was heated at 100 °C overnight. DMF was removed with evaporation under vaccum and the residue was treated with 200 mL of 20% EtOAc/hexanes. The mixture was filtered out to remove solid and the filtrate was washed with a saturated solution of NaHCO3 (50mL), then brine 50ml. The organic layer was dried over Na2SO4 and filtered through a pad of silica gel and celite. The filtrate was concentrated to dryness to give 2.65 of the title compound as colorless oil.
[00296] Step 9: 3,3'-(cyclopentane-1 ,1-diyl)dipropanoic acid
Figure imgf000050_0003
[00297] 3,3'-(cyclopentane-1 ,1-diyl)dipropanenitrile (2.14 g) was dissolved in EtOH ( 35 mL) at r.t. under N2 atmosphere. A solution of NaOH (9.7 g) in water (17 mL) was then added dropwise. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to r.t. and then diluted with 100 mL of water to give clear solution. The solution was cooled over ice bath and 18.3 mL of 85% phosphoric acid was added dropwise. The mixture was extracted with EtOAc 3 x 150mL. The combined organic layers were washed with brine (100ml_), dried over Na2S04 and filtered through a pad of silica gel and celite. The filtrate was concentrated to give the title compound (2.42 g) as a pale yellow solid.
[00298] Step 10: dimethyl 3, 3'-(cyclopentane-1 ,1-diyl)dipropanoate
Figure imgf000051_0001
[00299] 3,3'-(Cyclopentane-1 ,1-diyl)dipropanoic acid (1.12g, 5.2mmol) was dissolved in anhydrous MeOH (17mL) at r.t. under N2 atmopsphere. SOCI2 (0.92mL, 12.5mmol) was added dropwise over 10 min. and the reaction mixture was then heated to reflux overnight. The reaction mixture was cooled to r.t. and then concentrated. The residue was participated between 100 mL of 20% EtOAc/hexanes and 50 mL of a saturated solution of NH4CI. Two layers were separated and the aqueous layer was extracted with 100 mL of EtOAc. The combined organic layers were washed with 50 mL of saturated solution of NaHC03, 50 mL of brine, dried over Na2S04 and filtered through a pad of silica gel and celite. The filtrate was concentrated to give the title compound (2.5 g) as pale yellow oil.
[00300] Step 1 1 : methyl 8-hydroxyspiro[4.5]dec-7-ene-7-carboxylate
Figure imgf000051_0002
[00301] To a solution of dimethyl 3,3'-(cyclopentane-1 ,1-diyl)dipropanoate (0.514 g) in anhydrous toluene at r.t. under N2 atmosphere cooled in an ice bath was added NaH (0.093 g). After stirring for10 min, MeOH (0.009 mL) was added and the mixture was maintained in an ice bath for 10 min. The reaction mixture was warmed up to r.t. and then heated to reflux overnight. The reaction mixture was cooled in an ice bath and quenched with 10 mL of saturated solution of NH4CI and 50 mL 20% EtOAc/hexanes. The two layers were separated and the aqueous layer was extracted with 20% of EtOAc/hexanes (50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2S04 and filtered through a pad of silica gel and celite. The filtrate was concentrated to dryness to give 0.4 g of the title compound as pale yellow oil.
[00302] Step 12: methyl 8-(((trifluoromethyl)sulfonyl)oxy)spiro[4.5]dec-7-ene-7- carboxylate
Figure imgf000052_0001
[00303] To a solution of Methyl 8-oxospiro[4.5]decane-7-carboxylate (0.39 g) and diisopropylethylamine (0.78 mL) in 3.84 mL of CH2CI2 cooled at -78 °C under N2 atmosphere was added trifluoromethansulfinyl anhydride. The reaction mixture was then warmed to r.t. and stirred overnight. The reaction mixture was quenched with 10 mL H20 and diluted with 10 mL CH2CI2. The organic layer was separated and the aqueous layer was further extracted with 10 mL CH2CI2 . The combined organic layers were washed with 10 ml saturated solution of NaHC03, 10 mL solution of 5% KH2P04) 10 ml brine in turn, dried over Na2S04 and then filter through a pad of silica gel and celite. The filtrate was then concentrated to give 0.63 g brown oil as the product.
[00304] Step 13: methyl 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carboxylate
Figure imgf000052_0002
[00305] Methyl 8-(((trifluoromethyl)sulfonyl)oxy)spiro[4.5]dec-7-ene-7-carboxylate (0.30 g), p-chlorobenzeneboronic acid (0.72 g), K3P04 (0.45 g) and Pd(PPh3)4 (0.15 g) were placed in a 50 ml round-bottom flask and purged with N2 three times. 1 ,4-Dioxane (5 mL) was then added and the resulting mixture was heated at 100 °C for two overnights. The reaction mixture was cooled to r.t. and filter through a pad of celite. The filter cake was washed with 3x10 mL EtOAc. The filtrate was concentrated and the residue was purified by CombiFlash (1 % -15% EtOAc/hexanes) to give 0.19 g of the product as a pale yellow solid.
[00306] Step 14: (8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methanol
Figure imgf000053_0001
[00307] To a solution of methyl 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7- carboxylate (0.19 g, 0.62 mmol) in THF cooled at -78 °C was added a solution DIBAL (1.56 mL, 1.56 mmol, 1.0 M in THF) dropwise through syringe. After stirring for 5 min at - 78 °C, the reaction mixture was warmed to r.t. and stirred for additional 4 h. After cooling at -78 °C, the reaction mixture treated with a more solution of DIBAL (1.56 mL, 1.56 mmol, 1.0 M in THF) and stirred for additional 30 min at r.t.. The reaction mixture was then cooled at -78 °C and quenched with 20% solution of potassium sodium tratrate (50 mL) and 50 mL of EtOAc. The reaction mixture was stirred for 1h and the organic layer was separated. The aqueous was extracted with EtOAc (2x30 mL). The combined organic layers were washed, in turn, with a saturated solution of NH4CI (30mL) and brine (50 mL), dried over Na2SO4 and filtered through a pad of silical gel and celite. The filtrate was concentrated to dryness to give 0.081 g the product as pale yellow oil.
[00308] Step 15: 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carbaldehyde
Figure imgf000053_0002
[00309] To a solution of (8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methanol ( 0.081g, 0.29 mmol) in 3 mL of CH2CI2 at rt under N2 atmosphere was added MnO2 [(activated, 85%) 0.449g, 4.39 mmol) and the resulting reaction mixture was heated to reflux for 5h. More MnO2 (0.130g, 1.46 mmol) was added and refluxing was continued for another 1h. The reaction mixture was cooled to r.t. and filtered through a pad of celite. The filtrate was concentrated to give 0.080g the product as pale yellow oil.
[00310] Step 16: ethyl 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1-yl)benzoate
Figure imgf000054_0001
[00311] To a solution of 8-(4-chlorophenyl)spiro[4.5]dec-7-ene-7-carbaldehyde (0.073g, 0.26 mmol) and ethyl 4-(piperazin-1-yl)benzoate (0.079g, 0.34 mmol) in 1.3 mL of THF was added of NaBH(OAc)3 (0.162g, 0.77 mmol). After stirring at room temperature for 16 h, the reaction mixture was treated a saturated solution of NH4CI (20 mL) and extracted with 3 x 50 mL of 1 :1 EtOAc/hexanes. The combined organic layers was washed with brine (50 mL), dried over Na2S04, and filtered. The filtrate was concentrated and the residue was purified by silca gel chromatography eluted with a mobile phase of 10%-20% EtOAc/hexanes to give 65 mg the product as a pale yellow solid.
[00312] Step 17: 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1 -yl)benzoic acid
Figure imgf000054_0002
[00313] To a solution of ethyl 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1-yl)benzoate (0.065g, 0.13mmol) in THF(0.49 mL) and EtOH (0.24 mL) at rt under N2 atmosphere were added 0.12 mL H2O and NaOH (0.012g, 0.29 mmol). The resulting reaction mixture was heated at 65 °C overnight. The reaction mixture was concentrated and the residue was triturated with 1 :1 TBME/hexanes (1 mL) and filtered. The filter cake re-dissolved in H2O (2 mL) and added with 5% solution of KH2PO4 (0.5 mL) to ~pH 4. The resulting suspension was filtered and the filter cake was washed with H20 (2x0.2 mL) and hexanes (0.5 mL). The solid was dried over high vacuum pump to give 35 mg the product as a white solid.
[00314] Step 18: (R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000055_0001
[00315] A solution of 4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7- yl)methyl)piperazin-1 -yl)benzoic acid (30mg, 0.065 mmol), (R)-4-(4-morpholino-1- (phenylthio)butan-2-ylamino)-3-(trifluoromethylsulfonyl)benzenesulfonamide (38 mg, 0.068 mmol), EDCI (20 mg, 0.103 mmol), DMAP (20 mg, 0.168 mmol) in CH2CI2 (0.6 mL) was stirred at r.t. under N2 atmosphere overnight. The reaction mixture was then concentrated and the residue was dissolved in EtOAc (100 mL) and the resulting solution was washed, in turn, with a solution of 10% AcOH in 0.75% brine (2 x 20 mL), a solution of 20% K2HP04 (20 mL) and a solution of saturated brine (30 mL). The organic layer was dried over Na2S04 and then concentrated. The residue was purified by silica gel chromatography eluted with 1 %-3% MeOH/CH2CI2 as mobile phase to give 28.5 mg the product as a off-white solid.
[00316] MS (ES+): m/e 1000.565 (M+1).
EXAMPLE 4
[00317] (R)-4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-
N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000056_0001
[00318] The title compound was prepared from 1 ,3-dibromopropane and diethylmalonate by following the exact reaction sequence as described for Example 3.
[00319] MS (ES+): m/e 986.336 (M+1).
EXAMPLE 5
[00320] (R)-4-(4-((4-(4-chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin-3- yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000056_0002
[00321] Step 1 : bis(3-bromo ropoxy)dimethylsilane
Figure imgf000056_0003
[00322] To a solution imidazole (14.3 g) in 200 mL of THF cooled at 0 °C was treated with 12.13 mL of dichlorodimenthyisilane. After stirring for 1 h at r.t., the mixture was cooled at 0 °C, and treated with 18.99 mL of 3-bromo-1-propanol. The cloudy suspension was stirred overnight at r.t. and then diluted with 500 mL of hexanes, washed with 100 mL of saturated solution of NH4CI, 200 mL of water and 200 mL of brine. After drying over MgS04, the solvent was evaporated to afford 33.88 g of the title compound as oil.
[00323] 1H NMR (300 MHz, CDCI3): δ 3.50 (4H, t), 3.08 (4H, t), 1.68 (4H, m), 0.00 (6H, s).
[00324] Step 2: 3,3'-(dimethylsilanediyl)dipropan-1-ol
Figure imgf000057_0001
[00325] A solution bis(3-bromopropoxy)dimethylsilane (31.4 g) in 400 mL of THF was added dropwise to a suspension of Mg powder (4.7 g) in THF which was activated by 1 ,2-dibromoethane at a speed to keep the internal temperature at 55 °C. The mixture was then worked up by addition of 100 mL of saturated solution of NH4CI, followed by 200 mL of EtOAc. The organic layer was washed with 200 mL of water and 200 mL of brine. After drying over MgSO4, and evaporating the solvent, the residue was purified by ISCO Combiflash eluted with 0 to 100% EtOAc/hexanes to afford 5.8 g of the title compound as oil.
[00326] 1H NMR (300 MHz, DMSO-d6): 5 4.75 (2H, t), 3.35 (4H, t), 1.40 (4H, m), 0.45 (4H, m), -0.10 (6H, s).
[00327] Step 3: dimethyl 3,3'-(dimethylsilanediyl)dipropanoate
Figure imgf000057_0002
[00328] To a solution of 9.2 g of Cr03 in 30 mL of water cooled at 0 °C was added 1 1.5 mL of concentrated sulfuric acid, followed by addition of 50 mL of cold water. The solution thus obtained was transferred to a dropping funnel and added dropwise to a solution of 2 g of 3,3'-(dimethylsilanediyl)dipropan-1-ol in 20 mL of acetone cooled at 0 °C. After addition, the mixture was stirred at r.t. for 3 h and then cooled back to 0 °C. 2- Propanol was added dropwise until the color turned to green, and then 2 g of Na2S03 was added. The mixture was extracted with ether, and washed with brine. The crude diacid was dissolved in 20 mL of anhydrous methanol and treated with 0.5 mL of SOCI2 at 0 °C. The mixture was stirred at r.t. for 3h and then evaporated. The residue was purified by ISCO Combiflash eluted with 0 to 40% EtOAc/hexanes to afford 1.95 g of the title compound as oil.
[00329] 1H NMR (300 MHz, CDCI3): δ , 3.35 (6H, s), 2.05 (4H, m), 0.80 (4H, m), - 0.24 (6H, s).
[00330] Step 4: methyl 1 ,1 -dimethyl-4-oxosilinane-3-carboxylate
Figure imgf000058_0001
[00331] Dimethyl 3,3'-(dimethylsilanediyl)dipropanoate (1.560 g, 6.7 mmol) was disolved in anhydrous toluene (34 ml_) at r.t. under N2 atmosphere and cooled at -78 °C for 30 min. NaH (0.0295 g, 7.4 mmol) was added and stirred for another 10 min. 0.027 ml_ of MeOH was added and stirred in a ice bath for 10 min. The reaction mixture was warmed up to r.t. and then heated to reflux overnight. The reaction mixture was cooled to 0 °C and quenched with 10 mL of a saturated solution of NH4CI and followed by 50 ml_ 20% EtOAc/hexanes. The two layers were separated, and the aqueous was extracted with 50ml_ of 20% of EtOAc/hexanes once. The combined organic layers were washed with brine (50ml_), dried over Na2SO4 and filter through a pad of silica gel and celite. The filtrate was concentrated to dryness, and the residue was then purified by silica gel chromatography eluted with 3%-10% EtOAc/hexane to give 0.3 g pale yellow oil as product.
[00332] 1H NMR (300 MHz, CDCI3): δ, 3.72 (3H, s), 2.47 (2H, t), 1.40 (2H, s), 0.75 (2H, t), 0.06 (6H, s).
[00333] Step 5: methyl 1 , 1-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-1 , 2,5,6- tet ra hyd ros i I i ne-3-ca rboxy I ate
Figure imgf000058_0002
[00334] To a solution of methyl 1 ,1-dimethyl-4-oxosilinane-3-carboxylate (0.174 g, 0.87 mmol) in CH2CI2 (9 mL) at r.t. under N2 atmosphere was added DIPEA (0.484). The resulting reaction mixture was cooled over dry ice/acetone bath for 0.5 h and then trifluoromethanesulfonic anhydride (0.22 mL) was added dropwise over 3 min. The reaction mixture was stirred at -78 °C for 5 min. and then warmed up to r.t. overnight. The reaction mixture was then quenched with 10 mL H20 and diluted with 10 mL CH2CI2. Two layers were separated and the aqueous layer was extracted with additional 10 mL of CH2CI2. The combined organic layers were washed with 10 ml saturated solution of NaHC03, 10 mL solution of 5% KH2P04, 10 ml brine in turn, dried over Na2S04 and then filtered through a pad of silica gel and celite. The filtrate was then concentrated and the residue was purified by silica gel chromatography eluted with 1 %- 10% EtOAc to give 0.077g the product.
[00335] H NMR (300 MHz, CDCI3): 6, 3.85 (3H, s), 2.62 (2H, t), 1.70 (2H, s), 0.92 (2H, t), 0.18 (6H, s).
[00336] Step 6: methyl 4-(4-chlorophenyl)-1 ,1-dimethyl-1 , 2,5,6- tetra hyd rosi I i ne-3-carboxy late
Figure imgf000059_0001
[00337] A mixture of methyl 1 ,1-dimethyl-4-(((trifluoromethyl)sulfonyl)oxy)-1 , 2,5,6- tetrahydrosiline-3-carboxylate (0.077g), 4-chlorophenylboronic acid (0.054 g), K3PO4 (0.086 g), Pd(PPh3)4 (0.21 g) and K2C03 (8.1 g) was vented with N2 and the treated heated with 2.32 mL of 1 ,4-dioxane. The mixture was stirred at 100 °C under N2 atmosphere for 4 h. The reaction mixture was cooled to r.t. and filtered through a pad of celite to remove the catalyst. The filter cake was washed with 3x10 mL EtOAc. The filtrate was concentrated and the residue was purified by CombiFlash (eluted with 1 % - 15% EtOAc/hexanes) to give 0.10 g pale yellow solid as the product [00338] 1H NMR (300 MHz, CDCI3): δ 7.25 (d, 2H), 7.08 (d, 2H), 3.45 (s, 3H), 2.55 (t, 2H), 1.70 (s, 2H), 0.80 (t, 2H), 0.08 (s, 6H).
[00339] Step 7: (4-(4-chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosilin-3- yl)methanol
[00340] (4-(4-Chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosilin-3- yl)methanolmethyl ester (0.10 g, 0.34 mmol) was dissolved in THF and cooled to -78 °C under N2 atmosphere for 20 min. A solution DIBAL (2.205 mL, 2.2 mmol, 1.0 M solution in THF) was then added dropwise through a syringe and stirred at -78 °C for 5 min. Dry- ice acetone bath was removed and the reaction mixture was warmed up to r.t for 1.5 h. The reaction mixture was cooled in an ice bath and quenched with 20% aqueous solution of potassium sodium tratrate (50 mL) and 50 mL of EtOAc was added. The reaction mixture was stirred for 1 h and two layers were separated. The aqueous was further extracted with 2 x 30 mL of EtOAc. The combined organic layers was washed, in turn, with a saturated solution of NH4CI (30mL), brine (50mL) dried over Na2SO4 and filtered through a pad of silica gel and celite. The filtrate was concentrated to dryness and the residue was purified by CombiFlash eluted with 1 %-50% EtOAc/Hexanes to give 0.090g pale yellow oil as the product.
[00341] 1H NMR (300 MHz, CDCI3): δ 7.26 (d, 2H), 7.07 (d, 2H), 3.95 (s, 2H), 1.72 (t, 2H), 1.53 (s, 2H), 0.75 (t, 2H), 0.10 (s, 6H).
[00342] Step 8: 4-(4-chlorophenyl)-1 ,1-dimethyl-1 ,2,5,6-tetrahydrosiline-3- carbaldehyde
Figure imgf000061_0001
[00343] (4-(4-Chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin-3-yl)methanol ( 0.090g, 0.034 mmol) was dissolved in 2 mL CH2CI2 at r.t. under N2 atmosphere. Mn02 [(activated, 85%) 0.345g, 3.37 mmol) was added and the resulting reaction mixture was stirred at r.t. overnight. More Mn02 (0.200g, 2.02 mmol) was added and stirred for another overnight. The reaction mixture was filtered out through a pad of celite to give 0.0651g colorless oil as the product.
[00344] 1H NMR (300 MHz, CDCI3): δ 9.48 (s, 1 H), 7.35 (d, 2H), 7.14 (d, 2H), 2.66 (t, 2H), 1.70 (s, 2H), 0.88 (t, 2H), 0.10 (s, 6H).
[00345] Step 9: Methyl 4-(4-((4-(4-chlorophenyl)-1 ,1 -dimethyl-1 ,2,5,6- tetrahydrosilin-3-yl)methyl)piperazin-1 -yl)benzoate
Figure imgf000061_0002
[00346] 4-(4-Chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosiline-3-carbaldehyde (0.0651 g, 0.25 mmol) and methyl 4-(piperazin-1-yl)benzoate (0.0749g, 0.32 mmol) were dissolved in THF(1.2ml_) at r.t . under N2 atmosphere and stirred for 10 min. NaBH(OAc)3 (0.1563g, 0.74 mmol) was then added and the resulting reaction mixture was stirred at r.t. overnight. The reaction mixture was quenched with a saturated solution of NH4CI (20 mL) and extracted with a solution of 1 :1 EtOAc/hexanes (3x50mL). The combined organic layers was washed with brine (50 mL), dried over Na2S04, and filtered. The filtrate was concentrated and the residue was purified by CombiFlash eluted with 1 %-25% EtOAc/hexanes to give 55 mg pale yellow solid as the product.
[00347] 1H NMR (300 MHz, CDCI3): δ 7.90 (d, 2H), 7.25 (d, 2H), 6.98 (d, 2H), 6.80 (d, 2H), 3.85 (3, 3H), 3.25 (m, 4H), 2.85 (s, 2H), 2.36-2.42 (m, 6H), 1.58 (s, 2H), 0.73 (t, 2H), 0.10 (s, 6H).
[00348] Step 10: 4-(4-((4-(4-chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin- 3-yl)methyl)piperazin-1 -yl)benzoic acid
Figure imgf000062_0001
[00349] Methyl 4-(4-((4-(4-chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin-3- yl)methyl)piperazin-1-yl)benzoate (0.0157g, 0.033mmol) was dissolved in THF(0.6 mL) and MeOH (0.6 mL) at r.t. under N2 atmosphere. 0.14 mL 2M solution of LiOH (6.694 mmol) was added. The resulting reaction mixture was stirred at r.t. overnight, and then concentrated. The residue was then partitioned between 10 mL H20 and 50mL EtOAc. The mixture was cooled over ice bath and a solution of H3P04 (2.2 mL, 2.23 mmol) was added to adjust pH ~4. The resulting two layers were separated and the aqueous layer was extracted with EtOAc (2x20mL). The combine organic layers were washed with brine (40 mL), dried over Na2SO4, filtered and the filtrate was concentrated. The residue was purified by silica gel chromatography eluted with 2%-6% MeOH/CH2CI2 to give 2.7 mg white solid as the product.
[00350] MS ES+ : m/z 455.1 16 (M+1)+.
[00351] Step 1 1 : (R)-4-(4-((4-(4-chlorophenyl)-1 , -dimethyl-1 , 2,5,6- tetrahydrosilin-3-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-1-(phenylthio)butan-2- yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide
Figure imgf000063_0001
[00352] In 50 ml_ RBF were added in turn with the product of Step 10 (2.7mg, 0.0059 mmol), (R)-4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
(trifluoromethylsulfonyl)benzenesulfonamide (3.0 mg, 0.053mmol), EDCI (18 mg, 0.0095 mmol), DMAP (19 mg, 0.0154 mmol) and CH2CI2 (0.6 ml_) at r.t. under N2 atmosphere. The reaction mixture was stirred at r.t. overnight and then concentrated. The residue was dissolved in EtOAc (50 ml_) and the resulting solution was washed, in turn, with a saturated solution of NH4CI (10mL), a solution of 10% AcOH in 0.75% brine (2 x 10 ml_), a solution of 20% K2HP04 (10 ml_) and a solution of brine (30 mL). The resulting organic layer was dried over Na2S04 and then concentrated under reduced pressure. The residue was purified by silica gel chromatography eluted with 1 %-3% MeOH in CH2CI2 to give 2.4 mg off white solid as the final product after high vacuum drying overnight.
[00353] MS (Turbo Spray): m/z 990 (M+1)+.
EXAMPLE 6
BIOCHEMICAL EVALUATION
[00354] The inhibitory activities of apoptosis regulator protein Bcl2 and Bcl-xL by the compounds in the invention were assay at Reaction Biology Corporation, 1 Great Valley Parkway, Suite 2, Malvern PA 19355. Compounds were tested in a 10-dose IC50 with 3-fold serial dilution starting at 1uM. Control compound, ABT-737, was tested in a 10-dose IC50 with 3-fold serial dilution starting at 10 uM.
[00355] Assay Format: The assay is based on the competition of fluorescently labeled BakBH3 peptide (5FAM-GQVGRQLAIIGDDINR) for binding to Bcls. 5FAM- BakBH3 binds to surface pocket of Bel family, which is essential for its death antagonist function. [00356] Assay conditions: 5 nM 5FAM-BakBH3, 30 nM Bcl2 or Bcl-xL, in 20 mM Hepes, pH 7.5, 50 mM NaCI, 1 mM EDTA, 0.05% PF-127
[00357] Assay Procedure: Compounds in DMSO were added into Bcl/5FAM- BakBH3 mixture by using Acoustic Technology Measure FP after 30 min incubation and calculate mP. Table 1. Inhibitory Activities (IC50 ) of Examples
Figure imgf000064_0001
[00358] Cell death detection by trypan blue staining: After drug treatment, as the portion of dead cells detached from the culture substratum into the medium, these cells were collected by centrigufation of the medium at 1500 rpm for 3 min, and the adhesion cells were harvested by trypsinization with trypsin/EDTA for 10 min at 37°C. Then, the pooled cell pellets were resuspended and mixed with trypan blue dye for 5 min. After Trypan blue staining was done, cells were counted by using a light microscope and a hemocytometer. Blue dye-incorporating cells were scored as being dead. Five hundred cells from randomly chosen fields were counted, and the number of dead cells was counted and expressed as a percentage of the total number of cells counted. ABT-263 was used as a standard compound. The following tables show the cytotoxicities of the examples of the invention.
Table 2. Cytotoxicity of tested compounds
Figure imgf000064_0002
Figure imgf000065_0001
Table 3. Cytotoxicity of tested compounds
Cell Death (%) after 3-day treatment
Compound Cell Line
H-28 Su86.86 HTC116 HT29
EXAMPLE 1 99 26.8 24.5 42.4
EXAMPLE 2 99 24.2 25.1 44.9
ABT-263 99 27.3 22.7 41.2
Table 4. Cytotoxicity of tested compounds
Figure imgf000065_0002
Table 5. Cytotoxicity of tested compounds
Figure imgf000065_0003
Table 6. Cytotoxicity of tested compounds
Figure imgf000065_0004

Claims

WHAT IS CLAIMED IS:
1. A compound of Formula I
Figure imgf000066_0001
wherein
Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (CrC6)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (CVCeJalkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(CrC6)alkyl, alkoxycarbonyl, SF5 and halogen atoms;
W is -CHr, -C(CH3)2-, -C(CH2-CH2)- or -CH2CH2-;
Het represents a carbocycle, or a hetereocycle, each of which contains 1-3 heteroatoms chosen from O, S, N, or Si, and each of which is saturated or contains one or more unsaturated bonds; or
Het is unsubstituted or substituted with halo, alkyl, oxo, amido, amino, alkylamino, alkoxy, alkylthio, alkylsulfonyl, arylsulfonyl, aryl, heteroaryl;
R1 is selected from H, halo, or -O-aryl which is substituted or unsubstituted;
R2 represents
Figure imgf000066_0002
wherein Z is -C(O-) or -CH2-;
A is N or C(R10);
R9 is H or halo;
R10 is H, R12, OR12, SR12, S(0)R12, S02R12, C(0)R12, NHC(0)R12, NC 6alkylC(0)R12, NHC(0)OR12, NCrealkylCCO R12, NHC(0)NHR12, NHC(0)N(R 2)2, Nd-ealkylNHR12, S02NH2, S02NHR12, S02N(R12)2, NHS02R12, NC 6alkylS02R12, NHS02NHR12, NHS02N(R1 )2, NC 6alkylS02NHR12, Nd-ealkylSC^NKR12^, C(0)NHNOH, C(0)NHNOR12, C(0)NHS02R12, C(NH)NH2, halogen, CN, N02, N3, OH, C(0)H, CHNOH, CH(NOCH3), CF3, C(0)OH, or C(0)OR12;
R12 is a linear or branched (C C6)alkyl group unsubstituted or substituted with one or more halogen atoms; and
R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR12R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (C -6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR14R15 groups wherein:
R14 and R15 are identical or different, and are selected from hydrogen, linear or branched (C -6 )alkyl, linear or branched (Ci.6)alkoxy, aryl and heteroaryl, or
R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10; or
R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10.
2. A compound of Formula la
Figure imgf000067_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from H, or halo; R2 represents
Figure imgf000068_0001
wherein
Z is -C(O-) or -CH2-;
A is N or C(R10);
R9 is H or halo;
R 0 is H, R 2, OR12, SR12, S(0)R12, S02R12, C(0)R12, NHC(0)R12, Nd-ealkylC^R12, NHC(0)OR12, Nd-ealkylCCO R12, NHC(0)NHR12, NHC(0)N(R1 )2, NC 6alkylNHR12, S02NH2, S02NHR12, S02N(R12)2, NHS02R12, NCr6alkylS02R12, NHS02NHR12, NHS02N(R12)2, NC 6alkylS02NHR12, Nd-ealkylSOzNiR12^, C(0)NHNOH, C(0)NHNOR12, C(0)NHS02R12, C(NH)NH2, halogen, CN, N02, N3, OH, C(0)H, CHNOH, CH(NOCH3), CF3, C(0)OH, or C(0)OR12;
R 2 is a linear or branched (C C6)alkyl group is unsubstituted or substituted by one or more halogen atoms;
R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR 2R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (C1-6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR1 R15 groups wherein:
R14 and R 5 are identical or different, and are selected from hydrogen, linear or branched (d-e)alkyl, linear or branched (Ci-6)alkoxy, aryl and heteroaryl, or
R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R 0; or
R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R 0 ;
R3, R4, R5 and R6 are independently selected from H, F, Ci-3 alkyl unsubstituted or substituted by halogen atom or C1.3 alkoxyl;
n and m are 0, 1 , 2 or 3, where 0<n+m<6;
Y is O, S, NR12 or -C(R3)(R4); W is -CH , -C(CH3)2- or -CH2CH2-; and
Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (d-Ceialkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (d-CeJalkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(d-C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms.
3. A compound of Formula
Figure imgf000069_0001
or a pharmaceutically acceptable salt thereof, wherein:
R1 is selected from H, or halo;
R2 represents a group of the followi
Figure imgf000069_0002
wherein
Z is -C(O-) or -CH2-;
R9 is H or halo;
R 0 is -CN, -N02 or -SC-2-R12;
R12 is an amino or a linear or branched (C C6)alkyl group unsubstituted or substituted by one or more halogen atoms;
R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR1 R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (C1-6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR14R15 groups wherein:
R14 and R15 , are identical or different, and are selected from hydrogen, linear or branched (d- 6)alkyl, linear or branched (C1-6)alkoxy, aryl and heteroaryl, or
R14 and R 5 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted withan oxo group or is unsubstituted or substituted with one or more R 0; or R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10 ;
Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C C6)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (C C6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(CrC6)alkyl, alkoxycarbonyl, SF5 and halogen atoms; and
-A-B-C- is selected from (1) -N=C(R12)-0-; (2) -C(R12)=N-0-; (3) -N(R 2)-C(0)-0-;
(4) -O- C(R12)=N-; (5) -0-N=C(R12)-; (6) -0-C(0)-NR12-.
Figure imgf000070_0001
or a pharmaceutically acceptable salt thereof, wherein:
R is selected from H, halo;
R2 represents
Figure imgf000070_0002
wherein
Z is -C(O-) or -CH2-;
R9 is H or halo;
R10 is-CN, -N02 or -S02-R12;
R 2 is an amino or a linear or branched (CrC6)alkyl group unsubstituted or substituted by one or more halogen atoms;
R11 represents a hydrogen atom or a -NR12R13 or -CH2-NR 2R13 group wherein each of R12 and R13, are identical or different, and independently represents a hydrogen atom or a linear or branched (C -6)alkyl group substituted by one or more aryl, heteroaryl, aryloxy, heteroaryloxy, arylthio, heteroarylthio, heterocycloalkyl or -NR 4R15 groups wherein: R14 and R15 are identical or different, and are selected from hydrogen, linear or branched (C^alkyl, linear or branched (C1-6)alkoxy, aryl and heteroaryl, or
R14 and R15 are a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10; or
R14 and R15 form a saturated or unsaturated cyclic or bicyclic group in which one or more of the ring members is replaced by a hetero atom selected from oxygen, nitrogen and sulphur, and one or more of the ring members is unsubstituted or substituted with an oxo group or is unsubstituted or substituted with one or more R10
Ar represents an aryl or heteraryl group, which is unsubstituted or substituted by 1 to 3 groups selected from linear or branched (C1-C6)alkyl unsubstituted or substituted by a hydroxy or amino group, linear or branched (C C6)alkoxy, hydroxy, carboxy, nitro, cyano, amino, linear or branched polyhalo-(C C6)alkyl, alkoxycarbonyl, SF5 and halogen atoms; and
R7 and R8 are independently selected from C^alkyl, C^cyclolkyl, C efluorocycloalkyl, 6fluoroalkyl, or R7, R8, together with the silicon atom to which they are both attached to, complete a four- to six-membered carbocyclic ring which is unsubstituted or substituted with one or more R' herein Rc is C1-3 alkyl unsubstituted or substituted by halogen atom or C1-3 alkoxyl.
5. The compound according to Claim2, wherein Y is -C(O)-.
6. The compound according to any one of claims 1-4, wherein R10 is -N02 or -S(0)2CF3.
7. The compound according to any one of claims 1-4 which is selected from:
(R)-4-(4-((6-(4-chlorophenyl)spiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino- 1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((6-(4-chlorophenyl)-1 ,1-difluorospiro[2.5]oct-5-en-5-yl)methyl)piperazin-1-yl)-N-((4-(((R)-4- morpholino-1-(phenylthio)butan-2-yl)amino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((7-(4-chlorophenyl)spiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-
1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((8-(4-chlorophenyl)spiro[4.5]dec-7-en-7-yl)methyl)piperazin-1-yl)-N-((4-((4-morpholino-
1-(phenylthio)butan-2-yl)amino)-3-((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((7-(4-chlorophenyl)-2-oxaspiro[3.5]non-6-en-6-yl)methyl)piperazin-1-yl)-N-(4-(4- morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide, (R)-4-(4-((3-(4-chlorophenyl)spiro[5.5]undec-2-en-2-yl)me^
morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4-(4-((8-(4-chlorophenyl)-1-oxa-2-azaspiro[4.5]deca-2,7-dien-7-yl)methyl)piperazin^
((R)-4-morpholino-1 -(phenylthio)butan-2-ylamino)-3- ((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
4_(4.((8-(4-chlorophenyl)-3-methyl-1-oxa-2-azaspiro[4.5]deca-2J-dien-7-yl)methyl)pi^
yl)-N-(4-((R)-4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide,
(R)-4-(4-((4-(4-chlorophenyl)-1 , 1 -dimethyl-1 ,2,5,6-tetrahydrosilin-3-yl)methyl)piperazin-1 -yl)-N-
(4-(4-morpholino-1-(phenylthio)butan-2-ylamino)-3-
((trifluoromethyl)sulfonyl)phenyl)sulfonyl)benzamide.
8. A method of using compounds in Claim 1-7 to treat patients with cancer of bladder, brain, breast and uterus, chronic lymphoid leukemia, colon, esophagus, liver, lymphoblastic leukemia, follicular lymphomas, melanomas, malignant homeopathies, myelomas, ovarian cancers, non- small-cell lung cancers, prostate cancers, small-cell lung cancers, lymphoid malignancy of B-cell origin.
9. A composition comprising a combination of a compound of any one of claims 1-7 and an anti-cancer agent selected from a cytotoxic agent, a antimitotic agent, an anti-metabolite, a proteasome inhibitor, a HDAC inhibitor and kinase inhibitors, in association with a pharmaceutically acceptable carrier.
10. A method of treating a cancer comprising the step of administering to the patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-7, or the composition of claim 9 in combination with radiotherapy.
11. Use of a compound of any one of claims 1-7 for the preparation of a medicament for the treatment of a cancer.
12. Use of a compound of any one of claims 1-7 for the treatment of a cancer.
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