WO2013185202A1 - Inducteurs d'apoptose - Google Patents

Inducteurs d'apoptose 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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English (en)
Inventor
Zhaoyin Wang
Lianhai Li
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Beta Pharma Canada Inc
Astar Biotech Llc
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Priority to PCT/CA2012/000591 priority Critical patent/WO2013185202A1/fr
Publication of WO2013185202A1 publication Critical patent/WO2013185202A1/fr

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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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Abstract

L'invention concerne de nouveaux composés qui inhibent l'activité de membres de la famille de protéines anti-apoptotiques Bcl-2, des compositions contenant lesdits composés et des méthodes de traitement de maladies impliquant un défaut d'apoptose, tel que par exemple dans le traitement du cancer.
PCT/CA2012/000591 2012-06-14 2012-06-14 Inducteurs d'apoptose WO2013185202A1 (fr)

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CN105061352A (zh) * 2015-07-29 2015-11-18 广州市广金投资管理有限公司 芳基哌嗪衍生物ⅲ及其盐、制备方法和用途
US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
WO2019210828A1 (fr) 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
WO2023030453A1 (fr) 2021-09-01 2023-03-09 四川海思科制药有限公司 Composé pour dégrader des protéines de la famille bcl-2 et utilisation médicale associée

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US9782408B2 (en) 2014-10-06 2017-10-10 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10258624B2 (en) 2014-10-06 2019-04-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11426407B2 (en) 2014-10-06 2022-08-30 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US10758534B2 (en) 2014-10-06 2020-09-01 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
CN105061352A (zh) * 2015-07-29 2015-11-18 广州市广金投资管理有限公司 芳基哌嗪衍生物ⅲ及其盐、制备方法和用途
US10738030B2 (en) 2016-03-31 2020-08-11 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator
US11186566B2 (en) 2016-09-30 2021-11-30 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10570115B2 (en) 2016-09-30 2020-02-25 Vertex Pharmaceuticals Incorporated Modulator of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11453655B2 (en) 2016-12-09 2022-09-27 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US10793547B2 (en) 2016-12-09 2020-10-06 Vertex Pharmaceuticals Incorporated Modulator of the cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
US11253509B2 (en) 2017-06-08 2022-02-22 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11517564B2 (en) 2017-07-17 2022-12-06 Vertex Pharmaceuticals Incorporated Methods of treatment for cystic fibrosis
US11434201B2 (en) 2017-08-02 2022-09-06 Vertex Pharmaceuticals Incorporated Processes for preparing pyrrolidine compounds
US10654829B2 (en) 2017-10-19 2020-05-19 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11155533B2 (en) 2017-10-19 2021-10-26 Vertex Pharmaceuticals Incorporated Crystalline forms and compositions of CFTR modulators
US11465985B2 (en) 2017-12-08 2022-10-11 Vertex Pharmaceuticals Incorporated Processes for making modulators of cystic fibrosis transmembrane conductance regulator
US11318134B2 (en) 2018-01-10 2022-05-03 Recurium Ip Holdings, Llc Benzamide compounds
US11344546B2 (en) 2018-01-10 2022-05-31 Recurium IP Holding, LLC Benzamide compounds
US11590126B2 (en) 2018-01-10 2023-02-28 Recurium Ip Holdings, Llc Benzamide compounds
US11813260B1 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds
US11813259B2 (en) 2018-01-10 2023-11-14 Recurium Ip Holdings, Llc Benzamide compounds
US11179367B2 (en) 2018-02-05 2021-11-23 Vertex Pharmaceuticals Incorporated Pharmaceutical compositions for treating cystic fibrosis
US11414439B2 (en) 2018-04-13 2022-08-16 Vertex Pharmaceuticals Incorporated Modulators of cystic fibrosis transmembrane conductance regulator, pharmaceutical compositions, methods of treatment, and process for making the modulator
WO2019210828A1 (fr) 2018-04-29 2019-11-07 Beigene, Ltd. Inhibiteurs de bcl-2
WO2023030453A1 (fr) 2021-09-01 2023-03-09 四川海思科制药有限公司 Composé pour dégrader des protéines de la famille bcl-2 et utilisation médicale associée

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