WO2021127042A1 - Combinaisons - Google Patents

Combinaisons Download PDF

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WO2021127042A1
WO2021127042A1 PCT/US2020/065407 US2020065407W WO2021127042A1 WO 2021127042 A1 WO2021127042 A1 WO 2021127042A1 US 2020065407 W US2020065407 W US 2020065407W WO 2021127042 A1 WO2021127042 A1 WO 2021127042A1
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optionally substituted
cancer
compound
alkyl
pharmaceutically acceptable
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PCT/US2020/065407
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English (en)
Inventor
Ahmed Abdi SAMATAR
Jianhui Ma
Jiali Li
Hooman IZADI
Peter Qinhua HUANG
Sayee Gajanan HEGDE
Joseph Robert PINCHMAN
Kevin Duane BUNKER
Fernando Donate
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Recurium Ip Holdings, Llc
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Publication of WO2021127042A1 publication Critical patent/WO2021127042A1/fr

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • 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
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/4353—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems
    • A61K31/437—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom ortho- or peri-condensed with heterocyclic ring systems the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
    • 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
    • A61K31/5355—Non-condensed oxazines and containing further heterocyclic rings
    • 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
    • A61K31/63—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide
    • A61K31/635—Compounds containing para-N-benzenesulfonyl-N-groups, e.g. sulfanilamide, p-nitrobenzenesulfonyl hydrazide having a heterocyclic ring, e.g. sulfadiazine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K2300/00—Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine. More particularly, disclosed herein are combination therapies, and methods of treating diseases and/or conditions with a combination therapies descried herein.
  • Cancers are a family of diseases that involve abnormal cell growth with the potential to invade or spread to other parts of the body. Cancer treatments today include surgery, hormone therapy, radiation, chemotherapy, immunotherapy, targeted therapy and combinations thereof. Survival rates vary by cancer type and by the stage at which the cancer is diagnosed. In 2019, roughly 1.8 million people will be diagnosed with cancer, and an estimated 606,880 people will die of cancer in the United States. Thus, there still exists a need for effective cancer treatments.
  • Some embodiments described herein relate to a combination of compounds that can include an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.
  • Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination includes an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.
  • Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, wherein the combination includes an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.
  • Some embodiments described herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination includes an effective amount of Compound (C), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.
  • Other embodiments described herein relate to the use of a combination of compounds in the manufacture of a medicament for treating a disease or condition, wherein the combination includes an effective amount of Compound (C), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof.
  • the disease or condition can be a cancer described herein.
  • Figure 1 provides examples of Bcl-2 inhibitors.
  • Figure 2 shows the results of a combination study of Compound (A) with Compound 3 in a MCF-7 xenograft tumor model.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) individually and independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), cycloalkyl(alkyl), heteroaryl(alkyl), heterocyclyl(alkyl), hydroxy, alkoxy, acyl, cyano, halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S- sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, nitro, sulfenyl, sulfinyl
  • C a to Ct > in which “a” and “b” are integers refer to the number of carbon atoms in a group.
  • the indicated group can contain from “a” to “b”, inclusive, carbon atoms.
  • a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CIUCtbCHlCtU)- and (CH 3 ) 3 C-. If no “a” and “b” are designated, the broadest range described in these definitions is to be assumed.
  • R groups are described as being “taken together” the R groups and the atoms they are attached to can form a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocycle.
  • R a and R b of an NR a R b group are indicated to be “taken together,” it means that they are covalently bonded to one another to form a ring:
  • alkyl refers to a fully saturated aliphatic hydrocarbon group. The alkyl moiety may be branched or straight chain.
  • Examples of branched alkyl groups include, but are not limited to, iso-propyl, sec -butyl, t-butyl and the like.
  • Examples of straight chain alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, n-butyl, n- pentyl, n-hexyl, n-heptyl and the like.
  • the alkyl group may have 1 to 30 carbon atoms (whenever it appears herein, a numerical range such as “1 to 30” refers to each integer in the given range; e.g., “1 to 30 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 30 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 12 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • An alkyl group may be substituted or unsubstituted.
  • alkenyl refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon double bond(s) including, but not limited to, 1-propenyl, 2-propenyl, 2-methyl- 1-propenyl, 1-butenyl, 2-butenyl and the like.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to a monovalent straight or branched chain radical of from two to twenty carbon atoms containing a carbon triple bond(s) including, but not limited to, 1-propynyl, 1-butynyl, 2-butynyl and the like.
  • An alkynyl group may be unsubstituted or substituted.
  • cycloalkyl refers to a completely saturated (no double or triple bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • fused refers to two rings which have two atoms and one bond in common.
  • bridged cycloalkyl refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • spiro refers to two rings which have one atom in common and the two rings are not linked by a bridge.
  • Cycloalkyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • a cycloalkyl group may be unsubstituted or substituted.
  • Typical mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl.
  • fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-lH-phenalenyl and tetradecahydroanthracenyl; examples of bridged cycloalkyl groups are bicyclo[l.l.l]pentyl, adamantanyl, and norbornanyl; and examples of spiro cycloalkyl groups include spiro[3.3]heptane and spiro[4.5]decane.
  • cycloalkenyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more double bonds in at least one ring; although, if there is more than one, the double bonds cannot form a fully delocalized pi-electron system throughout all the rings (otherwise the group would be “aryl,” as defined herein). Cycloalkenyl groups can contain 3 to 10 atoms in the ring(s) or 3 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be connected together in a fused, bridged or spiro fashion. A cycloalkenyl group may be unsubstituted or substituted.
  • cycloalkynyl refers to a mono- or multi- cyclic hydrocarbon ring system that contains one or more triple bonds in at least one ring. If there is more than one triple bond, the triple bonds cannot form a fully delocalized pi-electron system throughout all the rings. Cycloalkynyl groups can contain 6 to 10 atoms in the ring(s) or 6 to 8 atoms in the ring(s). When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion. A cycloalkynyl group may be unsubstituted or substituted.
  • aryl refers to a carbocyclic (all carbon) monocyclic or multicyclic aromatic ring system (including fused ring systems where two carbocyclic rings share a chemical bond) that has a fully delocalized pi-electron system throughout all the rings.
  • the number of carbon atoms in an aryl group can vary.
  • the aryl group can be a Ce- Ci4 aryl group, a C6-C10 aryl group, or a Ce aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system) that contain(s) one or more heteroatoms (for example, 1, 2 or 3 heteroatoms), that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur.
  • the number of atoms in the ring(s) of a heteroaryl group can vary.
  • the heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine
  • heterocyclyl or “heteroalicyclyl” refers to three-, four-, five- , six-, seven-, eight-, nine-, ten-, up to 18-membered monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the heteroatom(s) is an element other than carbon including, but not limited to, oxygen, sulfur and nitrogen.
  • a heterocycle may further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates.
  • the rings When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro fashion.
  • the term “fused” refers to two rings which have two atoms and one bond in common.
  • bridged heterocyclyl or “bridged heteroalicyclyl” refers to compounds wherein the heterocyclyl or heteroalicyclyl contains a linkage of one or more atoms connecting non-adjacent atoms.
  • spiro refers to two rings which have one atom in common and the two rings are not linked by a bridge.
  • Heterocyclyl and heteroalicyclyl groups can contain 3 to 30 atoms in the ring(s), 3 to 20 atoms in the ring(s), 3 to 10 atoms in the ring(s), 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s).
  • heterocyclyl or heteroalicyclic groups may be unsubstituted or substituted.
  • heterocyclyl or heteroalicyclyl groups include but are not limited to, 1,3- dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-l,4-thiazine, 2H-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil
  • spiro heterocyclyl groups examples include 2-azaspiro[3.3]heptane, 2-oxaspiro[3.3]heptane, 2-oxa-6-azaspiro[3.3]heptane, 2,6- diazaspiro[3.3]heptane, 2-oxaspiro[3.4]octane and 2-azaspiro[3.4]octane.
  • aralkyl and “aryl(alkyl)” refer to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, 2-phenylalkyl, 3-phenylalkyl and naphthylalkyl.
  • heteroarylkyl and “heteroaryl(alkyl)” refer to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2-thienylalkyl, 3-thienylalkyl, furylalkyl, thienylalkyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl and imidazolylalkyl and their benzo-fused analogs.
  • heteroalicyclyl(alkyl) and “heterocyclyl(alkyl)” refer to a heterocyclic or a heteroalicyclylic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a (heteroalicyclyl)alkyl may be substituted or unsubstituted. Examples include but are not limited tetrahydro-2H-pyran-4-yl(methyl), piperidin-4-yl(ethyl), piperidin-4-yl(propyl), tetrahydro-2H-thiopyran-4-yl(methyl) and l,3-thiazinan-4-yl(methyl).
  • lower alkylene groups are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (- CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group and/or by substituting both hydrogens on the same carbon with a cycloalkyl group (e.g., -C- ).
  • hydroxy refers to a -OH group.
  • alkoxy refers to the Formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • alkoxy s are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
  • An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen, alkyl, alkenyl, alkynyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) and heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
  • a “cyano” group refers to a “-CN” group.
  • halogen atom or “halogen” as used herein, means any one of the radio-stable atoms of column 7 of the Periodic Table of the Elements, such as, fluorine, chlorine, bromine and iodine.
  • a thiocarbonyl may be substituted or unsubstituted.
  • An O-carbamyl may be substituted or unsubstituted.
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • a C-amido may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-amido may be substituted or unsubstituted.
  • S-sulfonamido refers to a “-S0 2 N(RAR B )” group in which RA and R B can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a “RS0 2 N(RA)-” group in which R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-sulfonamido may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a “nitro” group refers to an “ -NO2” group.
  • a “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl).
  • a halogen e.g., mono-haloalkyl, di-haloalkyl and tri- haloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to an alkoxy group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a halogen e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy.
  • groups include but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, l-chloro-2-fluoromethoxy and 2-fluoroisobutoxy.
  • a haloalkoxy may be substituted or unsubstituted.
  • amino refers to a -Nth group.
  • a “mono-substituted amino” group refers to a “-NHR” group in which R can be an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • a mono-substituted amino may be substituted or unsubstituted. Examples of mono-substituted amino groups include, but are not limited to, -NH(methyl), -NH(phenyl) and the like.
  • a “di-substituted amino” group refers to a “-NR A R B ” group in which R A and R B can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, cycloalkyl(alkyl), aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • a di-substituted amino may be substituted or unsubstituted. Examples of di-substituted amino groups include, but are not limited to, -N(methyl)2, -N(phenyl) (methyl), -N(ethyl) (methyl) and the like.
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • a radical indicates species with a single, unpaired electron such that the species containing the radical can be covalently bonded to another species.
  • a radical is not necessarily a free radical. Rather, a radical indicates a specific portion of a larger molecule.
  • the term “radical” can be used interchangeably with the term “group.”
  • linking groups are chemical groups that are indicated as having multiple open valencies for connecting to two or more other groups.
  • lower alkylene groups of the general formula -(CH2) n - where n is in the range of 1 to 10 are examples of linking groups that are described elsewhere herein as connecting molecular fragments via their terminal carbon atoms.
  • Other examples of linking groups include -(CFh) n O-, -(CH2) n NH-, - (CFh) n N(Ci-C 6 alkyl)-, and -(CH2) n S-, wherein each n is 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10.
  • n can be zero for some linking groups such as -(CH2) n O-, in which case the linking group is simply -0-.
  • reference herein to an asymmetrical linking group will be understood as a reference to all orientations of that group (unless stated otherwise).
  • reference herein to -(CH2) n O- will be understood as a reference to both -(CH2) n O- and -0-(CH 2 ) n - ⁇
  • salts refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), a sulfuric acid, a nitric acid and a phosphoric acid (such as 2,3-dihydroxypropyl dihydrogen phosphate).
  • Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, trifluoroacetic, benzoic, salicylic, 2-oxopentanedioic, or naphthalenesulfonic acid.
  • an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium, a potassium or a lithium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of a carbonate, a salt of a bicarbonate, a salt of organic bases such
  • a salt is formed by protonation of a nitrogen-based group (for example, NEb)
  • the nitrogen-based group can be associated with a positive charge (for example, NFh can become NFh + ) and the positive charge can be balanced by a negatively charged counterion (such as Cl ).
  • each center may independently be of R-configuration or S -configuration or a mixture thereof.
  • the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture.
  • each double bond may independently be E or Z a mixture thereof.
  • all tautomeric forms are also intended to be included.
  • valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • each chemical element as represented in a compound structure may include any isotope of said element.
  • a hydrogen atom may be explicitly disclosed or understood to be present in the compound.
  • the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium).
  • reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
  • the methods and combinations described herein include crystalline forms (also known as polymorphs, which include the different crystal packing arrangements of the same elemental composition of a compound), amorphous phases, salts, solvates, and hydrates.
  • the compounds described herein exist in solvated forms with pharmaceutically acceptable solvents such as water, ethanol, or the like.
  • the compounds described herein exist in unsolvated form.
  • Solvates contain either stoichiometric or non- stoichiometric amounts of a solvent, and may be formed during the process of crystallization with pharmaceutically acceptable solvents such as water, ethanol, or the like. Hydrates are formed when the solvent is water, or alcoholates are formed when the solvent is alcohol.
  • the compounds provided herein can exist in unsolvated as well as solvated forms. In general, the solvated forms are considered equivalent to the unsolvated forms for the purposes of the compounds and methods provided herein.
  • the term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least”.
  • the term “comprising” means that the process includes at least the recited steps, but may include additional steps.
  • the term “comprising” means that the compound, composition or device includes at least the recited features or components, but may also include additional features or components.
  • Some embodiments disclosed herein relate to the use of a combination of compounds for treating a disease or condition, wherein the combination can include an effective amount of Compound (A), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein: the Compound (A) has the structure: the one or more of Compound (B) can be a Bcl-2 inhibitor, or a pharmaceutically acceptable salt thereof.
  • Compound (A) can be a salt.
  • Compound (A) can be a hydrogen sulfate salt.
  • the hydrosulfate salt of Compound (A) has a single molecule of Compound (A) for a single molecule of hydrogen sulfate.
  • Compound (A) can be a sulfate salt.
  • the sulfate salt of Compound (A) has two molecules of Compound (A) for a single molecule of sulfate.
  • hydrogen sulfate and sulfate salts of Compound (A) are where the nitrogen of Compound (A) can be protonated.
  • Compound (A) can be a pharmaceutically acceptable salt form of Compound (A) that can include the hydrosulfate salt of Compound A and the sulfate salt of Compound (A).
  • a pharmaceutically acceptable salt form of Compound (A) can be a pharmaceutically acceptable salt form of Compound (A) that consists essentially of the hydrosulfate salt of Compound (A) and the sulfate salt of Compound (A).
  • Exemplary salt forms of Compound (A) include Form A and Form C.
  • Compound (A), or a pharmaceutically acceptable salt thereof can be Form A.
  • Compound (A), or a pharmaceutically acceptable salt thereof can be Form C.
  • Compound (A), or a pharmaceutically acceptable salt thereof can include Form A and Form C. Additional details regarding Form A and Form C of Compound (A) are provided in International Application No. PCT/US2020/058526, filed November 2, 2020, which is hereby incorporated by reference in its entirety.
  • a combination of compounds for treating a disease or condition wherein the combination can include an effective amount of Compound (C), or a pharmaceutically acceptable salt thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein: the Compound (C) has the structure: wherein: X 1 , Y 1 and Z 1 can be each independently C or N; with the first proviso that at least one of X 1 , Y 1 and Z 1 is N; with the second proviso that each of X 1 , Y 1 and Z 1 is uncharged; with third proviso that two of the dotted lines indicate double bonds; with the fourth proviso that the valencies of X 1 , Y 1 and Z 1 can be each independently satisfied by attachment to a substituent selected from H and R 12 ; X 2 can be O; A 1 can be selected from an optionally substituted cycloalkyl, an optionally substituted aryl, an optional
  • R 10 when R 10 is hydrogen, X 1 is NH, Y 1 and Z 1 are each C, A 1 is an optionally substituted phenyl, one of R 2 and R 3 is hydrogen or an optionally substituted Ci- 6 alkyl and the other of R 2 and R 3 is an optionally substituted Ci- 6 alkyl, then R 1 cannot be a substituted Ci- 6 alkyl substituted with one or more substituents selected from the group consisting of halogen and hydroxy.
  • a 1 can be an optionally substituted aryl.
  • a 1 can be an optionally substituted phenyl.
  • a 1 can be a substituted phenyl or an unsubstituted phenyl.
  • a 1 can be an optionally substituted cycloalkyl, such as an optionally substituted bicyclopentyl.
  • R 1 can be selected from an optionally substituted Ci- 6 alkyl, an optionally substituted cycloalkyl, an optionally substituted cycloalkyl(Ci- 6 alkyl), an optionally substituted heterocyclyl and an optionally substituted heterocyclyl(Ci- 6 alkyl).
  • R 1 can be a substituted cycloalkyl.
  • R 1 is substituted cycloalkyl that can be substituted with one or more substituents selected from halogen, hydroxy, haloalkyl, an optionally substituted alkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.
  • R 1 can be an optionally substituted cycloalkyl selected from unsubstituted cyclobutyl, unsubstituted difluorocyclobutyl, unsubstituted cyclopentyl and unsubstituted bicyclopentyl.
  • R 1 can be an optionally substituted cycloalkyl(Ci- 6 alkyl) selected from unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl and unsubstituted trifluoromethylcyclopropylmethyl.
  • cycloalkyl(Ci- 6 alkyl) selected from unsubstituted cyclopropylmethyl, unsubstituted bicyclopentylmethyl, unsubstituted fluorocyclopropylmethyl, unsubstituted fluorocyclobutylmethyl, unsubstituted methoxycyclopropylmethyl and unsubstituted trifluoromethylcyclopropylmethyl.
  • R 1 can be an optionally substituted heterocyclyl selected from unsubstituted tetrahydropyranyl, unsubstituted tetrahydrofuranyl, and unsubstituted oxetanyl.
  • R 1 is an optionally substituted heterocyclyl(Ci- 6 alkyl) can be selected from unsubstituted oxetanylmethyl and unsubstituted fluorooxetanylmethyl
  • R 1 can be a substituted alkyl.
  • R 1 can be a substituted alkyl that is substituted with one or more substituents selected from halogen, hydroxy, haloalkyl, an optionally substituted cycloalkyl, a substituted alkoxy, a substituted mono-substituted amine and a substituted di-substituted amine.
  • R 1 can be a substituted alkyl that is a haloalkyl.
  • R 1 can be an optionally substituted Ci- 6 alkyl selected from C4 alkyl, fluoro(C4 alkyl), and trifluoro(C2 alkyl).
  • R 2 and R 3 can be each independently selected from hydrogen, halogen, an optionally substituted Ci- 6 alkyl and an optionally substituted Ci- 6 haloalkyl.
  • R 2 and R 3 together with the carbon to which R 2 and R 3 are attached can form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
  • R 2 can be selected from hydrogen, methyl, fluoromethyl and difluoromethyl.
  • R 4 and R 5 can be each independently selected from hydrogen, halogen, an optionally substituted Ci- 6 alkyl and an optionally substituted Ci- 6 haloalkyl.
  • R 4 and R 5 together with the carbon to which R 4 and R 5 are attached can form an optionally substituted cycloalkyl, an optionally substituted cycloalkenyl or an optionally substituted heterocyclyl.
  • R 7 can be selected from halogen, hydroxy and unsubstituted alkoxy.
  • R 7 can be selected from fluoro and methoxy.
  • R 12 can be hydrogen. In other embodiments, R 12 can be not hydrogen.
  • Compound (A), or a pharmaceutically acceptable salt thereof can be used in combination with one or more Bcl-2 inhibitors, or a pharmaceutically acceptable salt thereof.
  • Compound (C), or a pharmaceutically acceptable salt thereof can be used in combination with one or more Bcl-2 inhibitors, or a pharmaceutically acceptable salt thereof.
  • Bcl-2 inhibitors are described herein, and include those provided in Figure 1. Further information regarding Bcl-2 inhibitors shown in Figure 1 are provided in the following publications: WO 2020/089286, WO 2015/011400, U.S. 2014/0199234, WO 2018/027097, WO 2019/210828, WO 2018/192462, WO 2018/127130 and WO 2018/154004, each of which is hereby incorporated by reference for the limited purpose of describing each of the compounds shown in Figure 1. [0080] Examples of Compound (C) include the following:
  • Compound (A) along with pharmaceutically acceptable salts thereof, can be prepared as described herein and in WO 2017/172957, which is hereby incorporated by reference in its entirety. As described in WO 2017/172957, Compound (A) is an estrogen receptor alpha (ERoc) inhibitor.
  • ERoc estrogen receptor alpha
  • Embodiments of combinations of Compound (A), including pharmaceutically acceptable salts and salt forms thereof (such as Form A and/or Form C), and Compound (B), including pharmaceutically acceptable salts thereof, are provided in Table 1.
  • Table 1 “A” represents Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and the numbers represent a compound as provided in Figure 1, including pharmaceutically acceptable salts thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof can be administered prior to all of Compound (B), or a pharmaceutically acceptable salt thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof can be administered prior to at least one Compound (B), or a pharmaceutically acceptable salt thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof can be administered concomitantly with Compound (B), or a pharmaceutically acceptable salt thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof can be administered subsequent to the administration of at least one Compound (B), or a pharmaceutically acceptable salt thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof can be administered subsequent to the administration of all Compound (B), or a pharmaceutically acceptable salt thereof.
  • a combination as described herein of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can decrease the number and/or severity of side effects that can be attributed to a compound described herein, such as Compound (B), or a pharmaceutically acceptable salt thereof.
  • a combination as described herein of Compound (C), including pharmaceutically acceptable salts thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can decrease the number and/or severity of side effects that can be attributed to Compound (B), or a pharmaceutically acceptable salt thereof.
  • Using a combination of compounds described herein can results in additive, synergistic or strongly synergistic effect.
  • a combination of compounds described herein can result in an effect that is not antagonistic.
  • a combination as described herein of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in an additive effect.
  • a combination as described herein of Compound (C), including pharmaceutically acceptable salts thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in an additive effect.
  • a combination as described herein of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in a synergistic effect.
  • a combination as described herein of Compound (C), including pharmaceutically acceptable salts thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in a synergistic effect.
  • a combination as described herein of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in a strongly synergistic effect.
  • a combination as described herein of Compound (C), including pharmaceutically acceptable salts thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof can result in a strongly synergistic effect.
  • a combination as described herein of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof is not antagonistic.
  • a combination as described herein of Compound (C), including pharmaceutically acceptable salts thereof, and one or more of Compound (B), or pharmaceutically acceptable salts thereof is not antagonistic.
  • the term “antagonistic” means that the activity of the combination of compounds is less compared to the sum of the activities of the compounds in combination when the activity of each compound is determined individually (i.e., as a single compound).
  • the term “synergistic effect” means that the activity of the combination of compounds is greater than the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • the term “additive effect” means that the activity of the combination of compounds is about equal to the sum of the individual activities of the compounds in the combination when the activity of each compound is determined individually.
  • a potential advantage of utilizing a combination as described herein may be a reduction in the required amount(s) of the compound(s) that is effective in treating a disease condition disclosed herein compared to when each compound is administered as a monotherapy.
  • the amount of Compound (B), or a pharmaceutically acceptable salt thereof, used in a combination described herein can be less compared to the amount of Compound (B), or a pharmaceutically acceptable salt thereof, needed to achieve the same reduction in a disease marker (for example, tumor size) when administered as a monotherapy.
  • Another potential advantage of utilizing a combination as described herein is that the use of two or more compounds having different mechanisms of action can create a higher barrier to the development of resistance compared to when a compound is administered as monotherapy.
  • Additional advantages of utilizing a combination as described herein may include little to no cross resistance between the compounds of a combination described herein; different routes for elimination of the compounds of a combination described herein; and/or little to no overlapping toxicities between the compounds of a combination described herein.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof, can be provided in a pharmaceutical composition.
  • Compound (B), including pharmaceutically acceptable salts thereof, can be provided in a pharmaceutical composition.
  • Compound (C), including pharmaceutically acceptable salts thereof, can be provided in a pharmaceutical composition.
  • composition refers to a mixture of one or more compounds and/or salts disclosed herein with other chemical components, such as diluents, carriers and/or excipients.
  • the pharmaceutical composition facilitates administration of the compound to an organism.
  • Pharmaceutical compositions can also be obtained by reacting compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks appreciable pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the pH and isotonicity of human blood.
  • an “excipient” refers to an essentially inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • stabilizers such as anti-oxidants and metal-chelating agents are excipients.
  • the pharmaceutical composition comprises an anti-oxidant and/or a metal-chelating agent.
  • a “diluent” is a type of excipient.
  • Compounds (B), along with pharmaceutically acceptable salts thereof can be provided in a pharmaceutical composition that includes Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and/or Compound (C), including pharmaceutically acceptable salts thereof.
  • Compound (B), along with pharmaceutically acceptable salts thereof can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition that includes Compound (A), including pharmaceutically acceptable salts and salt forms thereof.
  • Compounds (B), along with pharmaceutically acceptable salts thereof can be administered in a pharmaceutical composition that is separate from a pharmaceutical composition that includes Compound (C), including pharmaceutically acceptable salts thereof.
  • compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.
  • compositions include, but not limited to, oral, rectal, pulmonary, topical, aerosol, injection, infusion and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
  • Compound (A) including pharmaceutically acceptable salts and salt forms thereof, can be administered orally.
  • Compound (C) including pharmaceutically acceptable salts thereof, can be administered orally.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof can be provided to a subject by the same route of administration as Compound (B), along with pharmaceutically acceptable salts thereof.
  • Compound (A), including pharmaceutically acceptable salts and salt forms thereof can be provided to a subject by a different route of administration as Compound (B), along with pharmaceutically acceptable salts thereof.
  • Compound (C), including pharmaceutically acceptable salts thereof can be provided to a subject by the same route of administration as Compound (B), along with pharmaceutically acceptable salts thereof.
  • Compound (C), including pharmaceutically acceptable salts thereof can be provided to a subject by a different route of administration as Compound (B), along with pharmaceutically acceptable salts thereof.
  • the liposomes will be targeted to and taken up selectively by the organ. For example, intranasal or pulmonary delivery to target a respiratory disease or condition may be desirable.
  • compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient.
  • the pack may for example comprise metal or plastic foil, such as a blister pack.
  • the pack or dispenser device may be accompanied by instructions for administration.
  • the pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert.
  • Compositions that can include a compound and/or salt described herein formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition. Uses and Methods of Treatment
  • a combination of compounds that includes an effective amount of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition.
  • a combination of compounds that includes an effective amount of Compound (C), including pharmaceutically acceptable salts thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof can be used to treat a disease or condition.
  • the disease or condition can be selected from a breast cancer, a cervical cancer, an ovarian cancer, an uterine cancer, a vaginal cancer, a vulvar cancer, a bladder cancer, a brain cancer, a bone marrow cancer, a colorectal cancer, an esophageal cancer, a hepatocellular cancer, a lymphoblastic leukemia, a follicular lymphoma, a lymphoid malignancy of T-cell or B-cell origin, a melanoma, a myelogenous leukemia, a Hodgkin’s lymphoma, a Non-Hodgkin’s lymphoma, a head and neck cancer (including oral cancer), a non small cell lung cancer, a chronic lymphocytic leukemia, a myeloma, a prostate cancer, a small cell lung cancer, a spleen cancer, a polycythemia vera,
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject can be human.
  • the subject can be a child and/or an infant, for example, a child or infant with a fever.
  • the subject can be an adult.
  • treat do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of the disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • an effective amount of compound, salt or composition can be the amount needed to prevent, alleviate or ameliorate symptoms of the disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease or condition being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • an effective amount of a compound, or radiation is the amount that results in: (a) the reduction, alleviation or disappearance of one or more symptoms caused by the cancer, (b) the reduction of tumor size, (c) the elimination of the tumor, and/or (d) long-term disease stabilization (growth arrest) of the tumor.
  • the breast cancer can be ER positive breast cancer.
  • the breast cancer can be ER positive, HER2-negative breast cancer.
  • the breast cancer can be local breast cancer (as used herein, “local” breast cancer means the cancer has not spread to other areas of the body).
  • the breast cancer can be metastatic breast cancer.
  • a subject can have a breast cancer that has not been previously treated.
  • a subject can relapse or have reoccurrence of breast cancer.
  • the terms “relapse” and “reoccurrence” are used in their normal sense as understood by those skilled in the art.
  • the breast cancer can be recurrent breast cancer.
  • the subject has relapsed after a previous treatment for breast cancer.
  • the subject has relapsed after receiving one or more treatments with a SERM, a SERD and/or aromatase inhibitor, such as those described herein.
  • ESR1 Within ESR1, several amino acid mutations have been identified. Mutations in ESR1 have been proposed as playing a role in resistance. There are several therapies for inhibiting estrogen receptors, including selective ER modulators (SERM), selective ER degraders (SERD) and aromatase inhibitors.
  • SERM selective ER modulators
  • SESD selective ER degraders
  • aromatase inhibitors One issue that can arise from the aforementioned cancer therapies is the development of resistance to the cancer therapy. Acquired resistance to cancer therapy, such as endocrine therapy, has been noted in nearly one-third of women treated with tamoxifen and other endocrine therapies. See Alluri et al., “Estrogen receptor mutations and their role in breast cancer progression” Breast Cancer Research (2014) 16:494. researchers have suspected mutations in the estrogen receptor as one of the reasons for acquired resistance to cancer therapy, such as endocrine therapy. Thus, there is a need for compounds that can treat breast cancer wherein the cancer has one or more mutations within ESR1.
  • Some embodiments disclosed herein are relate to the use of a combination of compounds that includes an effective amount of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, in the manufacture for a medicament for treating breast cancer in a subject in need thereof, wherein the breast cancer has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc).
  • ESR1 Estrogen Receptor 1
  • kits for treating breast cancer in a subject in need thereof wherein the breast cancer has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc).
  • ESR1 Estrogen Receptor 1
  • Still other embodiments disclosed herein are relate to a method of treating breast cancer in a subject in need thereof with a combination of compounds that includes an effective amount of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein the breast cancer has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc).
  • ESR1 Estrogen Receptor 1
  • ERoc Estrogen receptor alpha
  • the mutation can be in the ligand binding domain (LBD) of ESR1.
  • one or more mutations can be at an amino acid selected from: A593, S576, G557, R555, L549, A546, E542, L540, D538, Y537, L536, P535, V534, V533, N532, K531, C530, H524, E523, M522, R503, L497, K481, V478, R477, E471, S463, F461, S432, G420, V418, D411, L466, S463, L453, G442, M437, M421, M396, V392, M388, E380, G344, S338, L370, S329, K303, A283, S282, E279, G274, K252, R233, P222, G160, N156, P147, G145, F97, N69, A65, A58 and S47.
  • one or more mutations can be at an amino acid selected from: D538, Y537, L536, P535, V534, S463, V392 and E380. In some embodiments, one or more mutations can be at an amino acid selected from: D538 and Y537.
  • one or more mutations can be selected from: K303R, D538G, Y537S, E380Q, Y537C, Y537N, A283V, A546D, A546T, A58T, A593D, A65V, C530L, D411H, E279V, E471D, E471V, E523Q, E542G, F461V, F97L, G145D, G160D, G274R, G344D, G420D, G442R, G557R, H524L, K252N, K481N, K531E, L370F, L453F, L466Q, L497R, L536H, L536P, L536Q, L536R, L540Q, L549P, M388L, M396V, M421V, M437I, M522I, N156T, N532K,
  • Some embodiments disclosed herein are relate to the use of a combination of compounds that includes an effective amount of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, in the manufacture for a medicament for treating breast cancer in a subject in need thereof, wherein the breast cancer does not include at least one point mutation (for example, a point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc)).
  • ESR1 Estrogen Receptor 1
  • ERoc Estrogen receptor alpha
  • kits for treating breast cancer in a subject in need thereof wherein the breast cancer does not include has at least one point mutation, such as a point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc).
  • ESR1 Estrogen Receptor 1
  • Still other embodiments disclosed herein are relate to a method of treating breast cancer in a subject in need thereof with a combination of compounds that includes an effective amount of Compound (A), including pharmaceutically acceptable salts and salt forms thereof, and an effective amount of one or more of Compound (B), or a pharmaceutically acceptable salt thereof, wherein the breast cancer does not include has at least one point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc) (for example, a point mutation within the Estrogen Receptor 1 (ESR1) that encodes Estrogen receptor alpha (ERoc)).
  • ESR1 Estrogen Receptor 1
  • ERoc Estrogen receptor alpha
  • ER-positive breast cancer As provided herein, several studies have shown that a potential cause of resistance in ER-positive breast cancer is due to acquired mutations in ESR1 due to endocrine therapy.
  • the subject had been previously treated with one or more selective ER modulators.
  • subject had been treated previously with one or more selected ER modulators selected from tamoxifen, raloxifene, ospemifene, apeledoxifene, toremifene and lasofoxifene, or a pharmaceutically acceptable salt of any of the foregoing.
  • the subject had been treated previously with one or more selective ER degraders, such as fulvestrant, (E)-3-[3,5-Difluoro-4-[(lR,3R)-2-(2-fluoro-2-methylpropyl)-3- methyl-l,3,4,9-tetrahydropyrido[3,4-b]indol-l-yl]phenyl]prop-2-enoic acid (AZD9496), (R)-6- (2-(ethyl(4-(2-(ethylamino)ethyl)benzyl)amino)-4-methoxyphenyl)-5, 6,7,8- tetrahydronaphthalen-2-ol (elacestrant, RAD1901), (E)-3-(4-((E)-2-(2-chloro-4-fluorophenyl)-l- (lH-indazol-5-yl)but-l-en-l-yl)pheny
  • the subject had been treated previously with one or more aromatase inhibitors.
  • the aromatase inhibitors can be a steroidal aromatase inhibitor or a non-steroidal aromatase inhibitor.
  • the one or more aromatase inhibitors can be selected from (exemestane (steroidal aromatase inhibitor), testolactone (steroidal aromatase inhibitor); anastazole (non-steroidal aromatase inhibitor) and letrazole (non-steroidal aromatase inhibitor), including pharmaceutically acceptable salts of any of the foregoing.
  • the breast cancer can be present in subject, wherein the subject can be a woman. As women approach middle-age, a woman can be in a stage of menopause.
  • the subject can be a premenopausal woman.
  • the subject can be a perimenopausal woman.
  • the subject can be a menopausal woman.
  • the subject can be a postmenopausal woman.
  • the breast cancer can be present in a subject, wherein the subject can be a man.
  • the serum estradiol level of the subject can vary.
  • the serum estradiol level (E2) of the subject can be in the range of >15 pg/mL to 350 pg/mL. In other embodiments, the serum estradiol level (E2) of the subject can be ⁇ 15 pg/mL. In other embodiments, the serum estradiol level (E2) of the subject can be ⁇ 10 pg/mL.
  • the amount of compound, salt and/or composition required for use in treatment will vary not only with the particular compound or salt selected but also with the route of administration, the nature and/or symptoms of the disease or condition being treated and the age and condition of the patient and will be ultimately at the discretion of the attendant physician or clinician.
  • dosages may be calculated as the free base.
  • the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight, the severity of the affliction, the mammalian species treated, the particular compounds employed and the specific use for which these compounds are employed.
  • the determination of effective dosage levels can be accomplished by one skilled in the art using routine methods, for example, human clinical trials, in vivo studies and in vitro studies.
  • useful dosages of compounds (A), (B) and/or (C), or pharmaceutically acceptable salts of any of the foregoing can be determined by comparing their in vitro activity, and in vivo activity in animal models. Such comparison can be done by comparison against an established drug, such as cisplatin and/or gemcitabine)
  • Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC).
  • MEC minimal effective concentration
  • the MEC will vary for each compound but can be estimated from in vivo and/or in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations. Dosage intervals can also be determined using MEC value.
  • Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%. In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.
  • the attending physician would know how to and when to terminate, interrupt or adjust administration due to toxicity or organ dysfunctions. Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity).
  • the magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the disease or condition to be treated and to the route of administration. The severity of the disease or condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.
  • Compounds, salts and compositions disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans.
  • the toxicity of particular compounds in an animal model such as mice, rats, rabbits, dogs or monkeys, may be determined using known methods.
  • the efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, route of administration and/or regime.
  • MCF-7 cells were grown in DMEM Medium supplemented with 15% heat inactivated fetal bovine serum at 37 °C in an atmosphere of 5% CO2 in air.
  • B ALB/c nude mice were implanted subcutaneously on the 2 nd right mammary fat pad with a single cell suspension of 95% viable tumor cells (1.5 x 10 7 ) in 200 pL DMEM Matrigel mixture (1:1 ratio) without serum.
  • mice were randomly distributed into treatment groups of 10 animals each and dosed orally, once a day for 28 days as follows: vehicle at same volume as the single agent treatment; freebase Compound (A) at 10 mg/kg; Compound 3 at 50 mg/kg; and combination treatment of freebase Compound (A) (10 mg/kg) and Compound 3 (50 mg/kg).
  • estradiol benzoate injections were given subcutaneously (subcutaneously (40 pg / 20 pL, twice weekly) to all animals. Tumor volumes were evaluated twice per week to calculate tumor volume over time, and mice were weighed twice per week as a surrogate for signs of toxicity.
  • TGI Tumor growth inhibition
  • the top line (indicated with “x”) represents the data for Compound 3 (50 mg/kg), and the second line from the bottom (indicated with “x”) represents data for Compound (A) (10 mg/kg).
  • x represents data for Compound (A) (10 mg/kg).
  • a combination of Compound (A) and Compound 3 was more effective in reducing tumor size than each compound alone.
  • a combination of Compound (A) with Compound 3 produced significant antitumor activity with TGI values of 133.8%.
  • Compound 3 showed a minor antitumor activity with TGI of 6.3%.
  • the data provided herein demonstrates that a combination of a SERD inhibitor and a Bcl-2 inhibitor described herein can be used to treat a disease or condition described herein.

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  • Health & Medical Sciences (AREA)
  • Animal Behavior & Ethology (AREA)
  • Public Health (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Veterinary Medicine (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Epidemiology (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne des combinaisons de composés destinées au traitement d'une maladie ou d'un état, tel que le cancer. Une combinaison de composés pour le traitement d'une maladie ou d'un état peut comprendre un inhibiteur de SERD et un inhibiteur de Bcl-2, ainsi que des sels pharmaceutiquement acceptables de l'un quelconque de ceux-ci.
PCT/US2020/065407 2019-12-20 2020-12-16 Combinaisons WO2021127042A1 (fr)

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US201962952010P 2019-12-20 2019-12-20
US62/952,010 2019-12-20
US202063009770P 2020-04-14 2020-04-14
US63/009,770 2020-04-14

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Citations (2)

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