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WO2025185702A1 - Composés spirocycliques utilisés en tant qu'inhibiteurs de tead - Google Patents

Composés spirocycliques utilisés en tant qu'inhibiteurs de tead

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Publication number
WO2025185702A1
WO2025185702A1 PCT/CN2025/081036 CN2025081036W WO2025185702A1 WO 2025185702 A1 WO2025185702 A1 WO 2025185702A1 CN 2025081036 W CN2025081036 W CN 2025081036W WO 2025185702 A1 WO2025185702 A1 WO 2025185702A1
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WO
WIPO (PCT)
Prior art keywords
unsubstituted
substituted
alkyl
compound
heterocyclyl
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
PCT/CN2025/081036
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English (en)
Other versions
WO2025185702A8 (fr
Inventor
He Xu
Jian Wang
Jun Lu
Yugui Gu
Peter Qinhua HUANG
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Zai Lab Shanghai Co Ltd
Zai Lab US LLC
Original Assignee
Zai Lab Shanghai Co Ltd
Zai Lab US LLC
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Filing date
Publication date
Application filed by Zai Lab Shanghai Co Ltd, Zai Lab US LLC filed Critical Zai Lab Shanghai Co Ltd
Publication of WO2025185702A1 publication Critical patent/WO2025185702A1/fr
Publication of WO2025185702A8 publication Critical patent/WO2025185702A8/fr
Pending legal-status Critical Current
Anticipated expiration legal-status Critical

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Classifications

    • 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
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains three hetero rings
    • C07D471/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/12—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains three hetero rings
    • C07D487/20—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D519/00—Heterocyclic compounds containing more than one system of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring system not provided for in groups C07D453/00 or C07D455/00
    • 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
    • C07F9/00—Compounds containing elements of Groups 5 or 15 of the Periodic Table
    • C07F9/02—Phosphorus compounds
    • C07F9/547—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom
    • C07F9/6561—Heterocyclic compounds, e.g. containing phosphorus as a ring hetero atom containing systems of two or more relevant hetero rings condensed among themselves or condensed with a common carbocyclic ring or ring system, with or without other non-condensed hetero rings

Definitions

  • the present application relates to compounds that inhibit certain transcription factors in the TEAD family, pharmaceutical compositions thereof and uses of the same to treat diseases mediated by such transcription factors, including cancer.
  • Cancer is among the leading causes of death worldwide.
  • One challenge in effectively treating cancer patients is due to the development of drug resistance by cancer cells to the drug used for treatment which oftentimes results in recurrence or relapse of the cancer.
  • therapeutics to treat cancer.
  • R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heterocyclyl and an unsubstituted or a substituted aryl (C 1-4 alkyl) , wherein when the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and the aryl (C 1-4 alkyl) are substituted, the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and the aryl (C 1-4 alkyl) are substituted, the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl
  • Embodiment 1 is identical to the embodiment of Formula (I) provided above.
  • compositions that can include one or more of compounds of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, and at least one pharmaceutically acceptable excipient.
  • Some embodiments disclosed herein relate to a method for treating a cancer in a subject that can include administering to the subject in need thereof a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof.
  • Other embodiments disclosed herein relate to use of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for use in treating a cancer.
  • Still other embodiments disclosed herein relate to a compound of any one of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, for use in treating a cancer.
  • Yet still other embodiments disclosed herein related to a method for treating a cancer in a subject that can include contacting a cancer cell in the subject with a therapeutically effective amount of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof.
  • Some embodiments disclosed herein relate to a method for inhibiting the growth of a cancer cell that can include contacting the cancer cell with a therapeutically effective amount of a compound of any one of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof.
  • Other embodiments disclosed herein relate to use of a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, in the preparation of a medicament for use in inhibiting the growth of a cancer cell.
  • Yet still other embodiments disclosed herein relate to a compound of any one of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, for use in inhibiting growth of a cancer cell.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group (s) (such as 1, 2 or 3) individually and independently selected from deuterium, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl (alkyl) , heteroaryl (alkyl) , heterocyclyl (alkyl) , hydroxy, alkoxy, acyl, cyano, -SF 5 , halogen, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, C-amido (alkyl) , isocyan
  • a -CH 2 - is substituted with a cycloalkyl or a heterocyclyl
  • one or two hydrogens on the same carbon can be replaced with the cycloalkyl or the heterocyclyl (for example, one hydrogen: or two hydrogens: ) .
  • Some non-limiting examples of when two hydrogens on a substituted carbon (e.g., -CH 2 -R) are replaced with a cycloalkyl or a heterocyclyl include: where the cycloalkyl or the heterocyclyl is connected in a “spiro” fashion.
  • C a to C b refers to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, cycloalkenyl, aryl, heteroaryl or heterocyclyl group.
  • the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the cycloalkenyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b” , inclusive, carbon atoms.
  • a “C 1 to C 4 alkyl” or “C 1-4 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 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH (CH 3 ) -and (CH 3 ) 3 C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 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 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as “C 1 -C 4 alkyl” or similar designations.
  • “C 1 -C 4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and t-butyl.
  • Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl and hexyl.
  • the alkyl group may be substituted or unsubstituted.
  • alkenyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds.
  • the length of an alkenyl can vary.
  • the alkenyl can be a C 2-4 alkenyl, C 2-6 alkenyl or C 2-8 alkenyl.
  • alkenyl groups include allenyl, vinylmethyl and ethenyl.
  • An alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • the length of an alkynyl can vary.
  • the alkynyl can be a C 2-4 alkynyl, C 2-6 alkynyl or C 2-8 alkynyl.
  • Examples of alkynyls include ethynyl and propynyl.
  • 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. As used herein, the term “fused” refers to two rings which have two atoms and one bond in common. As used herein, the term “bridged cycloalkyl” refers to compounds wherein the cycloalkyl contains a linkage of one or more atoms connecting non-adjacent atoms. As used herein, the term “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. Examples of mono-cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • fused cycloalkyl groups are decahydronaphthalenyl, dodecahydro-1H-phenalenyl and tetradecahydroanthracenyl;
  • bridged cycloalkyl groups are bicyclo [1.1.1] pentyl, adamantanyl and norbornanyl;
  • spiro cycloalkyl groups include spiro [3.3] heptane, spiro spiro [3.4] octane, spiro [3.5] nonane, spiro [4.4] nonane, spiro [4.3] octane, spiro [4.5] decane and spiro [5.5] undecane.
  • 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) . When composed of two or more rings, the rings may be connected together in a fused-, bridged-or spiro-fashion.
  • a cycloalkenyl can contain 3 to 10 atoms in the ring (s) or 3 to 8 atoms in the ring (s) .
  • a cycloalkenyl 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 C 6 -C 14 aryl group, a C 6 -C 10 aryl group, or a C 6 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 monocyclic, bicyclic and tricyclic aromatic ring systems (ring systems with a fully delocalized pi-electron system throughout all the ring (s) ) that contain (s) one or more heteroatoms (for example, 1 to 5 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, 1, 3, 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
  • heterocyclyl refers to monocyclic, bicyclic and tricyclic ring systems wherein the 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 number of atoms in the ring (s) of a heterocyclyl group can vary.
  • the heterocyclyl 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) .
  • 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, thiocarbonyl or sulfonyl functionalities, so as to make the definition include oxo-systems, thio-systems and SO 2 -systems, such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates and cyclic sulfones. When composed of two or more rings, the rings may be joined together in a fused-, bridged-or spiro-fashion. Additionally, any nitrogens in a heterocyclyl may be quaternized.
  • Heterocyclyl groups may be unsubstituted or substituted.
  • heterocyclyl 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-1, 4-thiazine, 2H-1, 2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline
  • cycloalkyl (alkyl) refers to a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and cycloalkyl group of a cycloalkyl (alkyl) may be substituted or unsubstituted.
  • a cycloalkyl (alkyl) group may be unsubstituted or substituted.
  • aryl (alkyl) refers to an aryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of an aryl (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, 2-phenyl (alkyl) , 3-phenyl (alkyl) and naphthyl (alkyl) .
  • heteroaryl (alkyl) refers to a heteroaryl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heteroaryl group of heteroaryl (alkyl) may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienyl (alkyl) , 3-thienyl (alkyl) , furyl (alkyl) , thienyl (alkyl) , pyrrolyl (alkyl) , pyridyl (alkyl) , isoxazolyl (alkyl) , imidazolyl (alkyl) , and their benzo-fused analogs.
  • heterocyclyl (alkyl) refers to a heterocyclic group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and heterocyclyl of a heterocyclyl (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 1, 3-thiazinan-4-yl (methyl) .
  • “Lower alkylene groups” are straight-chained -CH 2 -tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include, but are not limited to, methylene (-CH 2 -) , ethylene (-CH 2 CH 2 -) , propylene (-CH 2 CH 2 CH 2 -) and butylene (-CH 2 CH 2 CH 2 CH 2 -) .
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group with a substituent (s) listed under the definition of “substituted. ” Further, when a lower alkylene group is substituted, the lower alkylene can be substituted by replacing both hydrogens on the same carbon with a cycloalkyl group (e.g., ) .
  • alkoxy refers to the formula –OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, a cycloalkyl (alkyl) , an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) is defined herein.
  • alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy) , n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzyloxy.
  • an alkoxy can be –OR, wherein R is an unsubstituted C 1-4 alkyl.
  • An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl 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, 1-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to a O-alkyl group and O-monocyclic cycloalkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di-haloalkoxy and tri-haloalkoxy) .
  • Such groups include, but are not limited to, chloromethoxy, fluoromethoxy, difluoromethoxy, trifluoromethoxy, 1-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chloro-substituted cyclobutyl and fluoro-substituted cyclobutyl.
  • a haloalkoxy can be –OR, wherein R is a C 1-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted.
  • a “sulfenyl” group refers to an “–SR” group in which R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • R can be hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • a sulfenyl may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • a sulfonyl may be substituted or unsubstituted.
  • An O-carboxy may be substituted or unsubstituted.
  • An ester and C-carboxy may be substituted or unsubstituted.
  • a thiocarbonyl may be substituted or unsubstituted.
  • a phosphine oxide may be substituted or unsubstituted.
  • a phosphonate may be substituted or unsubstituted.
  • amino refers to a “–NH 2 ” group.
  • hydroxy refers to a “–OH” group.
  • a “cyano” group refers to a “–CN” group.
  • An “isocyanato” group refers to a “–NCO” group.
  • a “thiocyanato” group refers to a “–SCN” group.
  • An “isothiocyanato” group refers to an “–NCS” group.
  • a “mercapto” group refers to an “–SH” group.
  • An S-sulfonamido may be substituted or unsubstituted.
  • R and R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • An N-sulfonamido may be substituted or unsubstit
  • 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 R A can be independently hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • An N-amido may be substituted or unsubstituted.
  • a “mono-substituted amine” refers to a “–NHR A ” in which R A can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be –NHR A , wherein R A can be an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
  • a “di-substituted amine” refers to a “–NR A R B ” in which R A and R B can be independently can be independently an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, an aryl, a heteroaryl, a heterocyclyl, an aryl (alkyl) , a heteroaryl (alkyl) or a heterocyclyl (alkyl) .
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be –NR A R B , wherein R A and R B can be independently an unsubstituted C 1-6 alkyl or an unsubstituted or a substituted benzyl.
  • 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.
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • pharmaceutically acceptable salt 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 term “comprising” is to be interpreted synonymously with the phrases “having at least” or “including at least” .
  • the term “comprising” means that the compound or composition includes at least the recited features or components but may also include additional features or components.
  • 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 or 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.
  • each of the embodiments described herein envisions within its scope pharmaceutically acceptable salts of the compounds, stereoisomers of the compounds, and pharmaceutically acceptable salts of the stereoisomers described herein. Any of the compounds described in the Examples, or pharmaceutically acceptable salts thereof, may be claimed individually or grouped together with one or more other compounds of the Examples, or a pharmaceutically acceptable salt thereof.
  • Embodiment 2 The compound of embodiment 1, wherein R 1 can be an unsubstituted or a substituted aryl.
  • Embodiment 3 The compound of embodiment 2, wherein the unsubstituted or a substituted aryl can be an unsubstituted or a substituted phenyl.
  • R 1 can be an unsubstituted phenyl. In other embodiments, R 1 can be a substituted phenyl.
  • R 1 can be a substituted phenyl, wherein the phenyl is substituted with one or more moieties (such as 1, 2, 3, 4 or 5 moieties) independently selected from halogen, -SF 5 , -OH, -CN, -NH 2 , an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted C 1-6 alkoxy, an unsubstituted C 1-6 haloalkoxy, -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 and -S (an unsubstituted C 1-6 haloalkyl) .
  • moieties such as 1, 2, 3, 4 or 5 moieties
  • the phenyl can be a para-substituted phenyl, a meta-substituted phenyl or an ortho-substituted phenyl.
  • R 1 can be a mono-substituted phenyl where the moiety is on the para-position. In other embodiments, R 1 can be a di-or tri-substituted phenyl.
  • Embodiment 4 The compound of embodiment 1, wherein R 1 can be an unsubstituted or a substituted heteroaryl.
  • R 1 can be an unsubstituted or a substituted heteroaryl that includes 1, 2 or 3 heteroatoms selected from oxygen, sulfur and NH.
  • R 1 is substituted, one or more hydrogens of the substituted heteroaryl, including the hydrogen of NH, can be replaced with a moiety described herein.
  • Embodiment 5 The compound of embodiment 4, wherein the unsubstituted or a substituted heteroaryl can be an unsubstituted or a substituted monocyclic heteroaryl.
  • Embodiment 6 The compound of embodiment 5, wherein the unsubstituted or the substituted monocyclic heteroaryl can be an unsubstituted or a substituted monocyclic 5-or 6-membered heteroaryl.
  • R 1 can be an unsubstituted or a substituted monocyclic, nitrogen-containing, 5-or 6-membered heteroaryl.
  • suitable heteroaryls for R 1 include pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, pyrrolyl, furanyl, thiophene and thiazolyl.
  • Embodiment 7 The compound of embodiment 1, wherein R 1 can be an unsubstituted or a substituted heterocyclyl.
  • R 1 can be an unsubstituted or a substituted heterocyclyl that includes 1, 2 or 3 heteroatoms selected from oxygen, sulfur, NH and NH 2 .
  • R 1 is a substituted heterocyclyl, one or more hydrogens (including the hydrogen (s) of NH and NH 2 ) can be replaced with a moiety described herein.
  • a heterocyclyl can be monocyclic or multicyclic. Some examples of multicyclic heterocyclyls include spiro-bicyclic heterocyclyls and fused-bicyclic heterocyclyls.
  • each ring of a spiro-bicyclic heterocyclyl and a fused-bicyclic heterocyclyl can vary.
  • each ring can be 4-, 5-or 6-membered ring wherein each ring can include 0, 1 or 2 heteroatoms selected from N (nitrogen) , O (oxygen) and S (sulfur) , provided that at least one heteroatom is present.
  • Embodiment 8 The compound of embodiment 7, wherein the unsubstituted or a substituted heterocyclyl can be an unsubstituted or a substituted monocyclic heterocyclyl.
  • Embodiment 9 The compound of embodiment 8, wherein the unsubstituted or a substituted monocyclic heterocyclyl can be an unsubstituted or a substituted monocyclic 4-, 5-or 6-membered heterocyclyl.
  • Embodiment 10 The compound of embodiment 1, wherein R 1 can be an unsubstituted or a substituted aryl (C 1-4 alkyl) .
  • Embodiment 11 The compound of embodiment 10, wherein the unsubstituted or a substituted aryl (C 1-4 alkyl) can be an unsubstituted or a substituted benzyl.
  • Embodiment 12 The compound of embodiment 1, wherein R 1 can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 1 can be a 4-, 5-, or 6-membered cycloalkyl.
  • a C 3-8 cycloalkyl can be monocyclic or multicyclic (such as bicyclic) .
  • Embodiment 13 The compound of embodiment 12, wherein the unsubstituted or a substituted C 3-8 cycloalkyl can be an unsubstituted or a substituted monocyclic C 3-8 cycloalkyl.
  • Embodiment 14 The compound of embodiment 12, wherein the unsubstituted or a substituted C 3-8 cycloalkyl can be an unsubstituted or a substituted bicyclic C 3- 8 cycloalkyl.
  • the unsubstituted or a substituted bicyclic C 3-8 cycloalkyl can be an unsubstituted or a substituted spiro-bicyclic C 3-8 cycloalkyl or an unsubstituted or a substituted fused-bicyclic C 3-8 cycloalkyl.
  • a non-limiting list of spiro-bicyclic C 3-8 cycloalkyl are a spiro [3.3] heptane and spiro [3.4] octane.
  • a non-limiting example of a fused bicyclic C 3-8 cycloalkyl is bicyclo [1.1.1] pentyl.
  • Embodiment 15 The compound of any one of embodiments 2-14, wherein R 1 can be unsubstituted.
  • Embodiment 16 The compound of any one of embodiments 2-14, wherein R 1 can be substituted.
  • R 1 can be substituted with one or more moieties (such as 1, 2 or 3 moieties) independently selected from halogen, -SF 5 , -OH, -CN, -NH 2 , an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted C 1-6 alkoxy, an unsubstituted C 1-6 haloalkoxy, -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 and -S (an unsubstituted C 1-6 haloalkyl) .
  • moieties such as 1, 2 or 3 moieties
  • unsubstituted C 1-6 alkyls examples include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) .
  • a non-limiting list of unsubstituted C 1-6 haloalkyls include -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Exemplary unsubstituted C 1-6 alkoxys include methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (branched and straight-chained) and hexoxy (branched and straight-chained) .
  • Examples of an unsubstituted C 1-6 haloalkoxys include, but are not limited to, -OCH 2 F, -OCHF 2 , -OCF 3 , -OCF 2 CF 3 and -OCH 2 CF 3 .
  • the phenyl can be substituted with F or Cl.
  • unsubstituted C 1-6 alkyls can be present for -NH (an unsubstituted C 1-6 alkyl) and/or -N (an unsubstituted C 1-6 alkyl) 2 .
  • -NH an unsubstituted C 1-6 alkyl
  • examples of -NH include, but are not limited to, -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 and -NHC (CH 2 CH 2 CH 3 ) 2 .
  • Examples of -N (an unsubstituted C 1-6 alkyl) 2 include, but are not limited to, -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 2 CH 3 ) 2 and -N (CH (CH 3 ) 2 ) 2 .
  • Exemplary unsubstituted C 1-6 haloalkyls that can be part of a -S (an unsubstituted C 1-6 haloalkyl) include those described herein.
  • R 1 can be substituted with -S (CF 3 ) .
  • R 1 can vary. In some embodiments, R 1 can be mono-substituted. In other embodiments, R 1 can be di-substituted. In still other embodiments, R 1 can be substituted with 3, 4 or 5 moieties described herein.
  • R 1 examples include, but are not limited to, Further examples of R 1 groups include Additional examples of R 1 groups include the following: Further examples of R 1 groups include In some embodiments, R 1 can be selected from
  • Embodiment 18 The compound of embodiment 17, wherein R 7a can be halogen.
  • R 7a can be fluoro.
  • Embodiment 19 The compound of embodiment 17, wherein R 7a can be an unsubstituted C 1-6 alkyl.
  • unsubstituted C 1-6 alkyls are described herein and include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) .
  • R 7a can be -CH 3 .
  • Embodiment 20 The compound of embodiment 17, wherein R 7a can be a substituted C 1-6 alkyl.
  • the C 1-6 alkyl of R 7a can be substituted with one or more (such as 1, 2 or 3) -OH.
  • the C 1-6 alkyl of R 7a can be substituted with one or more (such as 1, 2 or 3) unsubstituted C 1-6 alkoxy (such as -OCH 3 ) .
  • Embodiment 21 The compound of embodiment 17, wherein R 7a can be an unsubstituted C 1-6 haloalkyl.
  • R 7a can be -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 or -CH 2 CF 3.
  • Embodiment 22 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted C 2-6 alkenyl. In some embodiments, R 7a can be an unsubstituted C 2- 6 alkenyl. In other embodiments, R 7a can be a substituted C 2-6 alkenyl. In some embodiments of this paragraph, R 7a can be a C 2-4 alkenyl.
  • Embodiment 23 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted C 2-6 alkynyl. In some embodiments, R 7a can be an unsubstituted C 2- 6 alkynyl. In other embodiments, R 7a can be a substituted C 2-6 alkynyl. In some embodiments of this paragraph, R 7a can be a C 2-4 alkynyl.
  • Embodiment 24 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted C 3-8 cycloalkyl. In some embodiments, R 7a can be an unsubstituted C 3-8 cycloalkyl. In other embodiments, R 7a can be a substituted C 3-8 cycloalkyl. In some embodiments, R 7a can be an unsubstituted monocyclic C 3-6 cycloalkyl. In other embodiments, R 7a can be a substituted monocyclic C 3-6 cycloalkyl.
  • R 7a can be an unsubstituted bicyclic C 3-8 cycloalkyl. In other embodiments, R 7a can be a substituted bicyclic C 3-8 cycloalkyl. Examples of bicyclic C 3-8 cycloalkyls are described herein. In some embodiments, R 7a can be bicyclo [1.1.1] pentyl.
  • Embodiment 25 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted aryl. In some embodiments, R 7a can be an unsubstituted aryl. In other embodiments, R 7a can be a substituted aryl. As an example, R 7a can be an unsubstituted or a substituted phenyl.
  • Embodiment 26 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted heteroaryl.
  • R 7a can be an unsubstituted heteroaryl.
  • R 7a can be a substituted heteroaryl.
  • the heteroaryl can be monocyclic or multi-cyclic.
  • the heteroaryl can be a 5-, 6-, 7-, 8-, 9-or 10-membered heteroaryl.
  • the heterocyclyl can include 1, 2 or 3 heteroatoms selected from oxygen, sulfur, NH and NH 2 .
  • R 7a can be an unsubstituted or a substituted monocyclic heteroaryl.
  • R 7a can be an unsubstituted or a substituted multicyclic heteroaryl (such as a bicyclic heteroaryl) .
  • Embodiment 27 The compound of embodiment 17, wherein R 7a can be an unsubstituted or a substituted heterocyclyl.
  • R 7a can be an unsubstituted heterocyclyl.
  • R 7a can be a substituted heterocyclyl.
  • R 7a can be an unsubstituted monocyclic heterocyclyl.
  • R 7a can be a substituted monocyclic heterocyclyl.
  • R 7a can be an unsubstituted bicyclic heterocyclyl.
  • R 7a can be a substituted bicyclic heterocyclyl.
  • Embodiment 28 The compound of any one of embodiments 22-27, wherein R 7a can be unsubstituted.
  • Embodiment 29 The compound of any one of embodiments 22-27, wherein R 7a can be substituted.
  • Embodiment 31 The compound of embodiment 30, wherein R 7b can be halogen. In some embodiments, R 7b can be fluoro.
  • Embodiment 32 The compound of embodiment 30, wherein R 7b can be an unsubstituted C 1-6 alkyl.
  • R 7b can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained) .
  • R 7b can be -CH 3 .
  • Embodiment 33 The compound of embodiment 30, wherein R 7b can be a substituted C 1-6 alkyl.
  • the C 1-6 alkyl of R 7b can be substituted with one or more (such as 1, 2 or 3) -OH.
  • the C 1-6 alkyl of R 7b can be substituted with one or more (such as 1, 2 or 3) unsubstituted C 1-6 alkoxy (such as -OCH 3 ) .
  • Embodiment 34 The compound of embodiment 30, wherein R 7b can be an unsubstituted C 1-6 haloalkyl, such as -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Embodiment 35 The compound of embodiment 30, wherein R 7b can be an unsubstituted or a substituted C 2-6 alkenyl. In some embodiments, R 7b can be an unsubstituted C 2- 6 alkenyl. In other embodiments, R 7b can be a substituted C 2-6 alkenyl. In some embodiments, R 7b can be an unsubstituted C 2-4 alkenyl. In other embodiments, R 7b can be an unsubstituted C 2-4 alkenyl.
  • Embodiment 36 The compound of embodiment 30, wherein R 7b can be an unsubstituted or a substituted C 2-6 alkynyl. In some embodiments, R 7b can be an unsubstituted C 2- 6 alkynyl. In other embodiments, R 7b can be a substituted C 2-6 alkynyl. In some embodiments of this paragraph, R 7b can be a C 2-4 alkynyl.
  • Embodiment 37 The compound of embodiment 30, wherein R 7b is an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 7b can be an unsubstituted C 3-8 cycloalkyl.
  • R 7b can be a substituted C 3-8 cycloalkyl.
  • R 7b can be an unsubstituted monocyclic C 3-6 cycloalkyl.
  • R 7b can be a substituted monocyclic C 3-6 cycloalkyl.
  • R 7b can be an unsubstituted bicyclic C 3-8 cycloalkyl. In other embodiments, R 7b can be a substituted bicyclic C 3-8 cycloalkyl. Examples of bicyclic C 3-8 cycloalkyls are described herein. In some embodiments, R 7b can be bicyclo [1.1.1] pentyl.
  • Embodiment 38 The compound of embodiment 30, wherein R 7b can be an unsubstituted or a substituted aryl. In some embodiments, R 7b can be an unsubstituted aryl. In other embodiments, R 7b can be a substituted aryl. In some embodiments, R 7b can be an unsubstituted phenyl. In other embodiments, R 7b can be a substituted phenyl.
  • Embodiment 39 The compound of embodiment 30, wherein R 7b can be an unsubstituted or a substituted heteroaryl. In some embodiments, R 7b can be an unsubstituted heteroaryl. In other embodiments, R 7b can be a substituted heteroaryl. In some embodiments, R 7b can be an unsubstituted monocyclic heteroaryl. In other embodiments, R 7b can be a substituted monocyclic heteroaryl. Examples of monocyclic heteroaryls for R 7b include 5-or 6-membered monocyclic heteroaryls. In still other embodiments, R 7b can be an unsubstituted bicyclic heteroaryl. In yet still other embodiments, R 7b can be a substituted bicyclic heteroaryl. Examples of bicyclic heteroaryls for R 7b include 9-or 10-membered bicyclic heteroaryls.
  • Embodiment 40 The compound of embodiment 30, wherein R 7b can be an unsubstituted or a substituted heterocyclyl. In some embodiments, R 7b can be an unsubstituted heterocyclyl. In other embodiments, R 7b can be a substituted heterocyclyl. In some embodiments, R 7b can be an unsubstituted monocyclic heterocyclyl. In other embodiments, R 7b can be a substituted monocyclic heterocyclyl. In still other embodiments, R 7b can be an unsubstituted bicyclic heterocyclyl. In yet still other embodiments, R 7b can be a substituted bicyclic heterocyclyl.
  • Embodiment 41 The compound of any one of embodiments 35-40, wherein R 7b can be unsubstituted.
  • Embodiment 42 The compound of any one of embodiments 35-40, wherein R 7b can be substituted.
  • R 7a and R 7b can be substituted.
  • the C 1-6 alkyl of R 7a and/or R 7b can be substituted with one or more moieties (such as 1 or 2 moieties) independently selected from -OH and an unsubstituted C 1-6 alkoxy.
  • R 7a and/or R 7b can be selected from -CH 2 OH, -CH 2 CH 2 OH, -CH (OH) CH 3 , -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 3 and -CH 2 CH 2 OCH 3 .
  • the C 2-6 alkenyl and the C 2-6 alkynyl of R 7a and/or R 7b can be substituted with one or more moieties (such as 1 or 2 moieties) independently selected from halogen, -CN, -NH 2 , -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 haloalkyl, an unsubstituted heterocyclyl and an unsubstituted C 1-6 alkoxy.
  • moieties such as 1 or 2 moieties
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl of R 7a and/or R 7b are substituted with one or more moieties (such as 1, 2 or 3 moieties) independently selected from halogen, -OH, -CN, -NH 2 , -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl and an unsubstituted C 1-6 alkoxy.
  • moieties such as 1, 2 or 3 moieties
  • halogens are described herein.
  • the halogen substituted on R 7a and/or R 7b can be fluoro.
  • Exemplary C 1-6 alkoxys are described herein and include, but are not limited to, methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (branched and straight-chained) and hexoxy (branched and straight-chained) .
  • Examples of unsubstituted C 1-6 haloalkyls are described herein, such as -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Examples of -NH (an unsubstituted C 1-6 alkyl) and -N (an unsubstituted C 1-6 alkyl) 2 are described herein.
  • a non-limiting list of examples of -NH (an unsubstituted C 1-6 alkyl) and -N (an unsubstituted C 1-6 alkyl) 2 include -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 2 CH 3 ) 2 , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 and -N (CH (CH 3 )
  • unsubstituted heterocyclyls for R 7a and/or R 7b include those described for “heterocyclyl. ”
  • the heterocyclyl for R 7a and/or R 7b can be a monocyclic heterocyclyl.
  • heteroatoms can be present as ring atoms of the heteroaryl and/or heterocyclyl of R 7a and R 7b and the number of heteroatoms can also vary for the heteroaryl and/or heterocyclyl R 7a and R 7b .
  • suitable heteroatoms include N (nitrogen) , NH, O (oxygen) and S (sulfur) .
  • the heteroaryl and/or heterocyclyl can include 1, 2, 3 or 4 heteroatoms, such as those described herein.
  • the number of ring atoms for a heterocyclyl for R 7a and/or R 7b can also vary.
  • R 7a and/or R 7b can be a 3-9 membered monocyclic heterocyclyl.
  • R 7a and/or R 7b can be a 4-, 5-or 6-membered monocyclic heterocyclyl.
  • Embodiment 45 The compound of embodiment 43, wherein R 8a can be an unsubstituted C 1-6 alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained) .
  • R 8a can be -CH 3 .
  • Embodiment 46 The compound of embodiment 43, wherein R 8a can be a substituted C 1-6 alkyl.
  • Embodiment 47 The compound of embodiment 43, wherein R 8a can be an unsubstituted C 1-6 haloalkyl.
  • R 8a can be -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 or -CH 2 CF 3 .
  • Embodiment 48 The compound of embodiment 43, wherein R 8a can be selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • R 8a can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 8a can be an unsubstituted or a substituted aryl.
  • R 8a can be an unsubstituted or a substituted heteroaryl.
  • R 8a can be an unsubstituted or a substituted heterocyclyl.
  • Embodiment 49 The compound of any one of embodiments 43-48, wherein R 9a can be hydrogen.
  • Embodiment 50 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted C 1-6 alkyl.
  • R 9a can be selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained) .
  • R 9a can be -CH 3 .
  • Embodiment 51 The compound of any one of embodiments 43-48, wherein R 9a can be a substituted C 1-6 alkyl.
  • Embodiment 52 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted C 1-6 haloalkyl, such as those described herein.
  • R 9a can be selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Embodiment 53 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted or a substituted C 3-8 cycloalkyl. In some embodiments, R 9a can be an unsubstituted C 3-8 cycloalkyl. In some embodiments, R 9a can be a substituted C 3-8 cycloalkyl.
  • Embodiment 54 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted or a substituted aryl. In some embodiments, R 9a can be an unsubstituted aryl. In some embodiments, R 9a can be a substituted aryl.
  • Embodiment 55 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted or a substituted heteroaryl. In some embodiments, R 9a can be an unsubstituted heteroaryl. In some embodiments, R 9a can be a substituted heteroaryl.
  • Embodiment 56 The compound of any one of embodiments 43-48, wherein R 9a can be an unsubstituted or a substituted heterocyclyl. In some embodiments, R 9a can be an unsubstituted heterocyclyl. In some embodiments, R 9a can be a substituted heterocyclyl.
  • Embodiment 57 The compound of any one of Claims 53-56, wherein R 9a is unsubstituted.
  • Embodiment 58 The compound of any one of Claims 53-56, wherein R 9a is substituted.
  • Embodiment 61 The compound of embodiment 59, wherein R 8b can be an unsubstituted C 1-6 alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained) .
  • R 8b can be -CH 3 .
  • Embodiment 62 The compound of embodiment 59, wherein R 8b can be a substituted C 1-6 alkyl.
  • Embodiment 63 The compound of embodiment 59, wherein R 8b can be an unsubstituted C 1-6 haloalkyl.
  • R 8b can be -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 or -CH 2 CF 3 .
  • Embodiment 64 The compound of embodiment 59, wherein R 8b can be selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • R 8b can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 8b can be an unsubstituted or a substituted aryl.
  • R 8b can be an unsubstituted or a substituted heteroaryl.
  • R 8b can be an unsubstituted or a substituted heterocyclyl.
  • Embodiment 65 The compound of any one of embodiments 59-64, wherein R 9b can be hydrogen.
  • Embodiment 66 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted C 1-6 alkyl.
  • R 9b can be selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) .
  • R 9b can be -CH 3 .
  • Embodiment 67 The compound of any one of embodiments 59-64, wherein R 9b can be a substituted C 1-6 alkyl.
  • Embodiment 68 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted C 1-6 haloalkyl, such as those described herein.
  • R 9b can be selected from -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Embodiment 69 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted or a substituted C 3-8 cycloalkyl. In some embodiments, R 9b can be an unsubstituted C 3-8 cycloalkyl. In some embodiments, R 9b can be a substituted C 3-8 cycloalkyl.
  • Embodiment 70 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted or a substituted aryl. In some embodiments, R 9b can be an unsubstituted aryl. In some embodiments, R 9b can be a substituted aryl.
  • Embodiment 71 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted or a substituted heteroaryl. In some embodiments, R 9b can be an unsubstituted heteroaryl. In some embodiments, R 9b can be a substituted heteroaryl.
  • Embodiment 72 The compound of any one of embodiments 59-64, wherein R 9b can be an unsubstituted or a substituted heterocyclyl. In some embodiments, R 9b can be an unsubstituted heterocyclyl. In some embodiments, R 9b can be a substituted heterocyclyl.
  • Embodiment 73 The compound of any one of embodiments 69-72, wherein R 9b can be unsubstituted.
  • Embodiment 74 The compound of any one of embodiments 69-72, wherein R 9b can be substituted.
  • Embodiment 77 The compound of embodiment 75, wherein R 8c can be an unsubstituted C 1-6 alkyl.
  • exemplary unsubstituted C 1-6 alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) .
  • R 8c can be -CH 3 .
  • Embodiment 78 The compound of embodiment 75, wherein R 8c can be a substituted C 1-6 alkyl.
  • Embodiment 79 The compound of embodiment 75, wherein R 8c can be an unsubstituted C 1-6 haloalkyl.
  • R 8c can be -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 or -CH 2 CF 3 .
  • Embodiment 80 The compound of embodiment 75, wherein R 8c can be selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • R 8c can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 8c can be an unsubstituted or a substituted aryl.
  • R 8c can be an unsubstituted or a substituted heteroaryl.
  • R 8c can be an unsubstituted or a substituted heterocyclyl.
  • Embodiment 81 The compound of any one of embodiments 75-80, wherein R 9c can be hydrogen.
  • Embodiment 81 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted C 1-6 alkyl.
  • R 9c can be methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) or hexyl (branched and straight-chained) .
  • Embodiment 83 The compound of any one of embodiments 75-80, wherein R 9c can be a substituted C 1-6 alkyl.
  • Embodiment 84 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted C 1-6 haloalkyl.
  • R 9c can be an unsubstituted C 1-6 haloalkyl.
  • unsubstituted C 1-6 haloalkyls include -CH 2 F, -CHF 2 , -CF 3 , -CF 2 CF 3 and -CH 2 CF 3 .
  • Embodiment 85 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted or a substituted C 3-8 cycloalkyl. In some embodiments, R 9c can be an unsubstituted C 3-8 cycloalkyl. In some embodiments, R 9c can be a substituted C 3-8 cycloalkyl.
  • Embodiment 86 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted or a substituted aryl. In some embodiments, R 9c can be an unsubstituted aryl. In some embodiments, R 9c can be a substituted aryl.
  • Embodiment 87 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted or a substituted heteroaryl. In some embodiments, R 9c can be an unsubstituted heteroaryl. In some embodiments, R 9c can be a substituted heteroaryl.
  • Embodiment 88 The compound of any one of embodiments 75-80, wherein R 9c can be an unsubstituted or a substituted heterocyclyl. In some embodiments, R 9c can be an unsubstituted heterocyclyl. In some embodiments, R 9c can be a substituted heterocyclyl.
  • R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c can be a monocyclic version of C 3-8 cycloalkyl (for example, C 3-6 cycloalkyl) , aryl (i.e., phenyl) , heteroaryl (such as a 5-or 6-membered heteroaryl) or heterocyclyl (for example, a 4-, 5-, 6-, 7-or 8-membered heterocyclyl) .
  • aryl i.e., phenyl
  • heteroaryl such as a 5-or 6-membered heteroaryl
  • heterocyclyl for example, a 4-, 5-, 6-, 7-or 8-membered heterocyclyl
  • heteroaryls and/or the heterocyclyls for R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c are described herein in the definitions of “heteroaryl” and “heterocyclyl, ” respectively.
  • the heteroaryl and/or heterocyclyl can include 1, 2 or 3 heteroatoms selected from N (nitrogen) , O (oxygen) and S (sulfur) .
  • Embodiment 89 The compound of any one of embodiments 85-88, wherein R 9c can be unsubstituted.
  • Embodiment 90 The compound of any one of embodiments 85-88, wherein R 9c can be substituted.
  • the C 1-6 alkyl for R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c are substituted, the C 1-6 alkyl are substituted with one or more moieties (such as 1, 2, 3, 4, 5 or 6 moieties) independently selected from -OH and an unsubstituted C 1-6 alkoxy.
  • moieties such as 1, 2, 3, 4, 5 or 6 moieties
  • R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c can be selected from -CH 2 OH, -CH 2 CH 2 OH, -CH (OH) CH 3 , -CH 2 OCH 3 , -CH 2 OCH 2 CH 3 , -CH 2 CH 2 OCH 2 CH 3 and -CH 2 CH 2 OCH 3 .
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl for R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c are substituted
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl are substituted with one or more moieties (such as 1, 2, 3, 4, 5 or 6 moieties) independently selected from halogen, -CN, -NH 2 , an unsubstituted C 1-6 alkoxy, -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 alkyl and an unsubstituted C 1-6 haloalkyl.
  • moieties such as 1, 2, 3, 4, 5 or 6 moieties
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl for R 8a , R 9a , R 8b , R 9b , R 8c and/or R 9c can be substituted with one or more (for example, 1, 2, 3, 4, 5 or 6) moieties selected from F, Cl, -CN, -NH 2 , methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (branched and straight-chained) , hexoxy (branched and straight-chained) , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 2 CH 3 ) 2 ,
  • Embodiment 92 The compound of embodiment 91, wherein R 10 can be halogen.
  • R 10 can be F or Cl.
  • Embodiment 93 The compound of embodiment 91, wherein R 10 can be an unsubstituted C 1-6 alkyl.
  • unsubstituted C 1-6 alkyls are described herein and include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) .
  • R 10 can be an unsubstituted C 1-4 alkyl.
  • Embodiment 94 The compound of embodiment 91, wherein R 10 can be a substituted C 1-6 alkyl.
  • Embodiment 95 The compound of embodiment 91, wherein R 10 can be an unsubstituted C 1-6 haloalkyl.
  • Various unsubstituted C 1-6 haloalkyl can be present for R 10 .
  • Exemplary unsubstituted C 1-6 haloalkyl include, but are not limited to, -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 and -CH (CF 3 ) 2 .
  • Embodiment 96 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted C 2-6 alkenyl. In some embodiments, R 10 can be an unsubstituted C 2- 6 alkenyl. In other embodiments, R 10 can be a substituted C 2-6 alkenyl. In still other embodiments, R 10 can be an unsubstituted C 2-4 alkenyl. In yet still other embodiments, R 10 can be a substituted C 2-4 alkenyl. In some embodiments, R 10 can be a C 2-4 alkenyl substituted with a halogen (e.g., Cl, Br or F) .
  • a halogen e.g., Cl, Br or F
  • Embodiment 97 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted C 2-6 alkynyl. In some embodiments, R 10 can be an unsubstituted C 2- 6 alkynyl. In other embodiments, R 10 can be a substituted C 2-6 alkynyl. In still other embodiments, R 10 can be an unsubstituted C 2-4 alkynyl. In yet still other embodiments, R 10 can be a substituted C 2-4 alkynyl.
  • Embodiment 98 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 10 can be an unsubstituted monocyclic C 3-8 cycloalkyl.
  • R 10 can be a substituted monocyclic C 3-8 cycloalkyl.
  • R 10 can be an unsubstituted bicyclic C 3-8 cycloalkyl.
  • R 10 can be a substituted bicyclic C 3-8 cycloalkyl.
  • R 10 can be selected from cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, bicyclo [1.1.1] pentyl, wherein each can be unsubstituted or substituted.
  • Embodiment 99 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted aryl. In some embodiments, R 10 can be an unsubstituted aryl. In other embodiments, R 10 can be a substituted aryl. In some embodiments, R 10 can be an unsubstituted phenyl. In other embodiments, R 10 can be a substituted phenyl. For example, R 10 can be a mono-substituted, di-substituted or tri-substituted phenyl.
  • Embodiment 100 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted heteroaryl.
  • R 10 can be an unsubstituted monocyclic heteroaryl.
  • R 10 can be a substituted monocyclic heteroaryl.
  • R 10 can be an unsubstituted bicyclic heteroaryl.
  • R 10 can be a substituted bicyclic heteroaryl.
  • Embodiment 101 The compound of embodiment 91, wherein R 10 can be an unsubstituted or a substituted heterocyclyl.
  • R 10 can be an unsubstituted monocyclic heterocyclyl.
  • R 10 can be a substituted monocyclic heterocyclyl.
  • R 10 can be an unsubstituted bicyclic heterocyclyl.
  • R 10 can be a substituted bicyclic heterocyclyl.
  • R 10 A variety of heteroaryls and heterocyclyls can be present for R 10 .
  • the heteroaryls and heterocyclyls for R 10 can include 1, 2, 3 or 4 heteroatoms, such as N (nitrogen) , O (oxygen) and S (sulfur) .
  • R 10 can be a nitrogen-containing heteroaryl or a nitrogen-containing heterocyclyl.
  • Embodiment 102 The compound of any one of embodiments 96-101, wherein R 10 can be unsubstituted.
  • Embodiment 103 The compound of any one of embodiments 96-101, wherein R 10 can be substituted.
  • the C 1-6 alkyl for R 10 can be substituted with one or more (such as 1, 2 or 3) -OH.
  • R 10 can be selected from -CH 2 OH, -CH 2 CH 2 OH or -CH (OH) CH 3 .
  • the C 1-6 alkyl for R 10 can be substituted with one or more (such as 1, 2 or 3) unsubstituted C 1-6 alkoxy (such as -OCH 3 ) .
  • the C 2-6 alkenyl and the C 2-6 alkynyl for R 10 can be substituted with one or more moieties (such as 1, 2, 3 or 4) independently selected from halogen (e.g., Br, F or Cl) , -CN, -NH 2 , -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 haloalkyl, an unsubstituted heterocyclyl and an unsubstituted C 1-6 alkoxy.
  • halogen e.g., Br, F or Cl
  • the C 2-6 alkenyl and the C 2-6 alkynyl for R 10 can be substituted with one or more moieties (for example, 1, 2, 3 or 4) independently selected from F, Cl, Br, -CN, -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 2 CH 3 ) 2 , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH (CH 3 ) 2 )
  • R 10 is a substituted C 3-8 cycloalkyl, a substituted aryl, a substituted heteroaryl or a substituted heterocyclyl
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl are substituted with one or more moieties (for example, 1, 2, 3, 4, 5 or 6 moieties) independently selected from halogen, -OH, -CN, -NH 2 , -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl and an unsubstituted C 1-6 alkoxy.
  • moieties for example, 1, 2, 3, 4, 5 or 6 moieties
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and the heterocyclyl are substituted with one or more moieties (for example, 1, 2, 3, 4, 5 or 6 moieties) independently selected from F, Cl, Br, -OH, -CN, -NH 2 , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 2 CH 3 ) 2 , -N (CH 3 ) 2 , -N (CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 , -N (CH 2 CH 2 CH 3 ) 2 ,
  • Embodiment 106 The compound of embodiment 104, wherein R 11 can be an unsubstituted C 1-6 alkyl.
  • exemplary unsubstituted C 1-6 alkyls include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) .
  • Embodiment 107 The compound of embodiment 104, wherein R 11 can be a substituted C 1-6 alkyl.
  • Embodiment 108 The compound of embodiment 104, wherein R 11 can be an unsubstituted C 1-6 haloalkyl.
  • R 11 can be selected from -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 and -CH (CF 3 ) 2 .
  • Embodiment 109 The compound of embodiment 104, wherein R 11 can be an unsubstituted or a substituted C 3-8 cycloalkyl.
  • R 11 can be an unsubstituted monocyclic C 3-8 cycloalkyl.
  • R 11 can be a substituted monocyclic C 3-8 cycloalkyl.
  • R 11 can be an unsubstituted bicyclic C 3-8 cycloalkyl.
  • R 11 can be a substituted bicyclic C 3-8 cycloalkyl.
  • Embodiment 110 The compound of embodiment 104, wherein R 11 can be an unsubstituted or a substituted aryl. In some embodiments, R 11 can be an unsubstituted aryl. In other embodiments, R 11 can be a substituted aryl. In some embodiments, R 11 can be an unsubstituted phenyl. In other embodiments, R 11 can be a substituted phenyl. For example, R 11 can be a mono-substituted, di-substituted or tri-substituted phenyl.
  • R 11 can be an unsubstituted monocyclic heteroaryl.
  • R 11 can be a substituted monocyclic heteroaryl.
  • R 11 can be an unsubstituted bicyclic heteroaryl.
  • R 11 can be a substituted bicyclic heteroaryl.
  • Embodiment 112 The compound of embodiment 104, wherein R 11 can be an unsubstituted or a substituted heterocyclyl.
  • R 11 can be an unsubstituted monocyclic heterocyclyl.
  • R 11 can be a substituted monocyclic heterocyclyl.
  • R 11 can be an unsubstituted bicyclic heterocyclyl.
  • R 11 can be a substituted bicyclic heterocyclyl.
  • R 11 various heteroaryls and heterocyclyls can be present for R 11 .
  • the heteroaryls and heterocyclyls for R 11 can include 1, 2, 3 or 4 heteroatoms, such as N (nitrogen) , O (oxygen) and S (sulfur) .
  • R 11 can be a nitrogen-containing heteroaryl or a nitrogen-containing heterocyclyl.
  • Embodiment 113 The compound of any one of embodiments 109-112, wherein R 11 can be unsubstituted.
  • Embodiment 114 The compound of any one of embodiments 109-112, wherein R 11 can be substituted.
  • the C 1-6 alkyl for R 11 when the C 1-6 alkyl for R 11 are substituted, the C 1-6 alkyl can be substituted with one or more moieties (for example, 1, 2, 3, 4, 5 or 6 moieties) independently selected from -OH and an unsubstituted C 1-6 alkoxy.
  • moieties for example, 1, 2, 3, 4, 5 or 6 moieties
  • each can be substituted with one or more moieties (for example, 1, 2, 3, 4, 5 or 6 moieties) independently selected from halogen, -CN, -NH 2 , an unsubstituted C 1-6 alkoxy, -NH (an unsubstituted C 1-6 alkyl) , -N (an unsubstituted C 1-6 alkyl) 2 , an unsubstituted C 1-6 alkyl and an unsubstituted C 1-6 haloalkyl.
  • moieties for example, 1, 2, 3, 4, 5 or 6 moieties
  • the C 3-8 cycloalkyl, the aryl, the heteroaryl and/or the heterocyclyl for R 11 can be substituted with one or more moieties (such as 1, 2, 3, 4, 5 or 6) independently selected from F, Cl, Br, -CN, -NH 2 , methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (branched and straight-chained) , hexoxy (branched and straight-chained) , -NHCH 3 , -NHCH 2 CH 3 , -NHCH 2 CH 2 CH 3 , -NHCH 2 CH 2 CH 2 CH 3 , -NHC (CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 3 ) 2 , -NHC (CH 2 CH 2 CH 3 ) 2 , -N (CH 3 ) 2
  • Embodiment 115 The compound of any one of embodiments 1-16, wherein R 5 can be hydrogen.
  • R 8c can be hydrogen; and
  • R 9c can be an unsubstituted or a substituted C 1-6 alkyl.
  • R 5 groups include the following: wherein each can be unsubstituted or substituted as described herein. Additional examples of R 5 groups include the following: wherein each can be unsubstituted or substituted as described herein.
  • the R 5 group can include one or more (such as 1, 2, or 3) halogen atoms (for example ) .
  • the R 5 group can include one or more (such as 1, 2, or 3) -OH (for example ) .
  • Other exemplary substituted R 5 groups include In some embodiments, R 5 can be selected from In some further embodiments, R 5 can be In other embodiments, R 5 can be selected from
  • Embodiment 116 The compound of any one of embodiments 1-115, wherein n and m can be each 1.
  • Embodiment 117 The compound of any one of embodiments 1-115, wherein n can be 1; and m can be 2.
  • Embodiment 118 The compound of any one of embodiments 1-115, wherein n can be 2; and m can be 1.
  • Embodiment 119 The compound of any one of embodiments 1-118, wherein q can be 0. Those skilled in the art understand that when q is 0, the 4-or 5-membered ring shown in Formula (I) is unsubstituted.
  • Embodiment 120 The compound of any one of embodiments 1-118, wherein q can be 1.
  • Embodiment 121 The compound of any one of embodiments 1-118, wherein q can be 2.
  • Embodiment 122 The compound of any one of embodiments 1-118, wherein q can be 3 or 4.
  • Embodiment 123 The compound of any one of embodiments 1-115 or 117-118, wherein q can be 5 or 6.
  • each R 4 can be independently selected from halogen, -CN, an unsubstituted C 1-6 alkyl and an unsubstituted C 1-6 haloalkyl. In some embodiments, each R 4 can be independently selected from halogen, -CN and an unsubstituted C 1-6 haloalkyl. In other embodiments, each R 4 can be independently selected from halogen and an unsubstituted C 1-6 haloalkyl.
  • Embodiment 124 The compound of any one of embodiments 1-123, wherein X 1 can be N (nitrogen) .
  • Embodiment 125 The compound of any one of embodiments 1-123, wherein X 1 can be CR 6a .
  • Embodiment 126 The compound of embodiment 125, wherein R 6a can be hydrogen.
  • Embodiment 127 The compound of embodiment 125, wherein R 6a can be halogen (such as F, Cl or Br) .
  • Embodiment 128 The compound of embodiment 125, wherein R 6a can be an unsubstituted C 1-6 alkyl or an unsubstituted C 1-6 haloalkyl.
  • Non-limiting examples of an unsubstituted C 1-6 alkyl include –CH 3 , –CH 2 CH 3 and –CH (CH 3 ) 2 .
  • Non-limiting examples of an unsubstituted C 1-6 haloalkyl include –CH 2 F, –CHF 2 , –CF 3 and –CF 2 CH 3 .
  • Embodiment 129 The compound of embodiment 125, wherein R 6a can be a substituted C 1-6 alkyl.
  • R 6a can be a substituted C 1-3 alkyl.
  • Embodiment 130 The compound of embodiment 125, wherein R 6a can be an unsubstituted or a substituted C 2-6 alkenyl or an unsubstituted or a substituted C 2-6 alkynyl.
  • R 6a is a substituted C 2-6 alkenyl or a substituted C 2-6 alkynyl
  • the C 2-6 alkenyl and/or the C 2-6 alkynyl can be substituted with one or more (such as 1 or 2) moieties described herein (e.g., a C 2-6 alkenyl and/or a C 2-6 alkynyl can be substituted with one or more (such as 1 or 2) hydroxy moieties) .
  • R 6a can be an unsubstituted or a substituted C 2-3 alkenyl.
  • R 6a can be an unsubstituted or a substituted C 2-3 alkynyl.
  • R 6a can be -S (C 1-6 alkyl substituted by hydroxy) .
  • Embodiment 132 The compound of embodiment 125, wherein R 6a can be -OH.
  • Embodiment 133 The compound of embodiment 125, wherein R 6a can be an unsubstituted C 1-6 alkoxy or an unsubstituted C 1-6 haloalkoxy.
  • Embodiment 134 The compound of embodiment 125, wherein R 6a can be a substituted C 1-6 alkoxy.
  • Embodiment 135 The compound of embodiment 125, wherein R 6a can be -CN.
  • Embodiment 138 The compound of embodiment 125, wherein R 6a can be -NH 2 , an unsubstituted or a substituted -NH (C 1-6 alkyl) or an unsubstituted or a substituted -N (C 1-6 alkyl) 2 .
  • R 6a is a substituted -NH (C 1-6 alkyl) or a substituted -N (C 1-6 alkyl) 2
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from halogen, -OH, -CN and -NH 2 .
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • Embodiment 140 The compound of embodiment 125, wherein R 6a can be an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl.
  • R 6a can be an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl.
  • R 6a can be an unsubstituted or a substituted phenyl.
  • R 6a can be an unsubstituted or a substituted monocyclic 5-or 6-membered heteroaryl.
  • R 6a can be an unsubstituted or a substituted monocyclic 4-to 6-membered heterocyclyl.
  • R 6a can be selected from an unsubstituted or a substituted C 1-6 alkyl, an unsubstituted or a substituted C 2-6 alkynyl, an unsubstituted or a substituted -NH (C 1-6 alkyl) , an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • R 6a can be selected from –CH 2 OH, -NH 2 ,
  • Embodiment 143 The compound of any one of embodiments 1-142, wherein X 2 can be N (nitrogen) .
  • Embodiment 144 The compound of any one of embodiments 1-142, wherein X 2 can be CR 6b .
  • Embodiment 145 The compound of embodiment 144, wherein R 6b can be hydrogen.
  • Embodiment 146 The compound of embodiment 144, wherein R 6b can be halogen (such as F, Cl or Br) .
  • Embodiment 147 The compound of embodiment 144, wherein R 6b can be an unsubstituted C 1-6 alkyl or an unsubstituted C 1-6 haloalkyl.
  • Non-limiting examples of an unsubstituted C 1-6 alkyl include –CH 3 , –CH 2 CH 3 and –CH (CH 3 ) 2 .
  • Non-limiting examples of an unsubstituted C 1-6 haloalkyl include –CH 2 F, –CHF 2 , –CF 3 and –CF 2 CH 3 .
  • Embodiment 148 The compound of embodiment 144, wherein R 6b can be a substituted C 1-6 alkyl.
  • R 6b can be a substituted C 1-3 alkyl.
  • Embodiment 149 The compound of embodiment 144, wherein R 6b can be an unsubstituted or a substituted C 2-6 alkenyl or an unsubstituted or a substituted C 2-6 alkynyl.
  • R 6b is a substituted C 2-6 alkenyl or a substituted C 2-6 alkynyl
  • the C 2-6 alkenyl and/or the C 2-6 alkynyl can be substituted with one or more (such as 1 or 2) moieties described herein.
  • R 6b can be an unsubstituted or a substituted C 2-3 alkenyl.
  • R 6b can be an unsubstituted or a substituted C 2-3 alkynyl.
  • Embodiment 150 The compound of embodiment 144, wherein R 6b can be -S (an unsubstituted or a substituted C 1-6 alkyl) or -S (an unsubstituted C 1-6 haloalkyl) .
  • Embodiment 151 The compound of embodiment 144, wherein R 6b can be -OH.
  • Embodiment 152 The compound of embodiment 144, wherein R 6b can be an unsubstituted C 1-6 alkoxy or an unsubstituted C 1-6 haloalkoxy.
  • Embodiment 153 The compound of embodiment 144, wherein R 6b can be a substituted C 1-6 alkoxy.
  • Embodiment 154 The compound of embodiment 144, wherein R 6b can be -CN.
  • Embodiment 157 The compound of embodiment 144, wherein R 6b can be -NH 2 , an unsubstituted or a substituted -NH (C 1-6 alkyl) or an unsubstituted or a substituted -N (C 1-6 alkyl) 2 .
  • R 6b can be -NH 2 .
  • R 6b is a substituted -NH (C 1-6 alkyl) or a substituted -N (C 1-6 alkyl) 2
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from halogen, -OH, -CN and -NH 2 .
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • Embodiment 159 The compound of embodiment 144, wherein R 6b can be an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl.
  • R 6b can be an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl.
  • R 6b can be an unsubstituted or a substituted phenyl.
  • R 6b can be an unsubstituted or a substituted monocyclic 5-or 6-membered heteroaryl.
  • R 6b can be an unsubstituted or a substituted monocyclic 4-to 6-membered heterocyclyl.
  • Embodiment 162 The compound of any one of embodiments 1-161, wherein X 3 can be N (nitrogen) .
  • Embodiment 163 The compound of any one of embodiments 1-161, wherein X 3 can be CR 6c .
  • Embodiment 164 The compound of embodiment 163, wherein R 6c can be hydrogen.
  • Embodiment 165 The compound of embodiment 163, wherein R 6c can be halogen.
  • Embodiment 166 The compound of embodiment 163, wherein R 6c can be an unsubstituted C 1-6 alkyl or an unsubstituted C 1-6 haloalkyl.
  • Non-limiting examples of an unsubstituted C 1-6 alkyl include –CH 3 , –CH 2 CH 3 and –CH (CH 3 ) 2 .
  • Non-limiting examples of an unsubstituted C 1-6 haloalkyl include –CH 2 F, –CHF 2 , –CF 3 and –CF 2 CH 3 .
  • Embodiment 167 The compound of embodiment 163, wherein R 6c can be a substituted C 1-6 alkyl.
  • R 6c can be a substituted C 1-3 alkyl.
  • Embodiment 168 The compound of embodiment 163, wherein R 6c can be an unsubstituted or a substituted C 2-6 alkenyl or an unsubstituted or a substituted C 2-6 alkynyl.
  • R 6c is a substituted C 2-6 alkenyl or a substituted C 2-6 alkynyl
  • the C 2-6 alkenyl and/or the C 2-6 alkynyl can be substituted with one or more (such as 1 or 2) moieties described herein.
  • R 6c can be an unsubstituted or a substituted C 2-3 alkenyl.
  • R 6c can be an unsubstituted or a substituted C 2-3 alkynyl.
  • Embodiment 169 The compound of embodiment 163, wherein R 6c can be -S (an unsubstituted or a substituted C 1-6 alkyl) or -S (an unsubstituted C 1-6 haloalkyl) .
  • Embodiment 170 The compound of embodiment 163, wherein R 6c can be -OH.
  • Embodiment 171 The compound of embodiment 163, wherein R 6c can be an unsubstituted C 1-6 alkoxy or –an unsubstituted C 1-6 haloalkoxy.
  • Embodiment 172 The compound of embodiment 163, wherein R 6c can be a substituted C 1-6 alkoxy.
  • Embodiment 173 The compound of embodiment 163, wherein R 6c can be -CN.
  • Embodiment 176 The compound of embodiment 163, wherein R 6c can be -NH 2 , an unsubstituted or a substituted -NH (C 1-6 alkyl) or an unsubstituted or a substituted -N (C 1-6 alkyl) 2 .
  • R 6c is a substituted -NH (C 1-6 alkyl) or a substituted -N (C 1-6 alkyl) 2
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from halogen, -OH, -CN and -NH 2 .
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • Embodiment 178 The compound of embodiment 163, wherein R 6c can be an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl.
  • R 6c can be an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl.
  • R 6c can be an unsubstituted or a substituted phenyl.
  • R 6c can be an unsubstituted or a substituted monocyclic 5-or 6-membered heteroaryl.
  • R 6c can be an unsubstituted or a substituted monocyclic 4-to 6-membered heterocyclyl.
  • Embodiment 181 The compound of any one of embodiments 1-180, wherein X 4 can be N (nitrogen) .
  • Embodiment 182 The compound of any one of embodiments 1-180, wherein X 4 can be CR 6d .
  • Embodiment 183 The compound of embodiment 182, wherein R 6d can be hydrogen.
  • Embodiment 184 The compound of embodiment 182, wherein R 6d can be halogen.
  • Embodiment 185 The compound of embodiment 182, wherein R 6d can be an unsubstituted C 1-6 alkyl or an unsubstituted C 1-6 haloalkyl.
  • R 6d can be an unsubstituted C 1-6 alkyl or an unsubstituted C 1-6 haloalkyl.
  • Non-limiting examples of an unsubstituted C 1-6 alkyl include –CH 3 , –CH 2 CH 3 and –CH (CH 3 ) 2 .
  • Non-limiting examples of an unsubstituted C 1-6 haloalkyl include –CH 2 F, –CHF 2 , –CF 3 and –CF 2 CH 3 .
  • Embodiment 186 The compound of embodiment 182, wherein R 6d can be a substituted C 1-6 alkyl.
  • R 6d can be a substituted C 1-3 alkyl.
  • Embodiment 187 The compound of embodiment 182, wherein R 6d can be an unsubstituted or a substituted C 2-6 alkenyl or an unsubstituted or a substituted C 2-6 alkynyl.
  • R 6d is a substituted C 2-6 alkenyl or a substituted C 2-6 alkynyl
  • the C 2-6 alkenyl and/or the C 2-6 alkynyl can be substituted with one or more (such as 1 or 2) moieties described herein.
  • R 6d can be an unsubstituted or a substituted C 2-3 alkenyl.
  • R 6d can be an unsubstituted or a substituted C 2-3 alkynyl.
  • Embodiment 188 The compound of embodiment 182, wherein R 6d can be -S (an unsubstituted or a substituted C 1-6 alkyl) or -S (an unsubstituted C 1-6 haloalkyl) .
  • Embodiment 189 The compound of embodiment 182, wherein R 6d can be -OH.
  • Embodiment 190 The compound of embodiment 182, wherein R 6d can be an unsubstituted C 1-6 alkoxy or an unsubstituted C 1-6 haloalkoxy.
  • Embodiment 191 The compound of embodiment 182, wherein R 6d can be a substituted C 1-6 alkoxy.
  • Embodiment 192 The compound of embodiment 182, wherein R 6d can be -CN.
  • Embodiment 195 The compound of embodiment 182, wherein R 6d can be -NH 2 , an unsubstituted or a substituted -NH (C 1-6 alkyl) or an unsubstituted or a substituted -N (C 1-6 alkyl) 2 .
  • R 6d is a substituted -NH (C 1-6 alkyl) or a substituted -N (C 1-6 alkyl) 2
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from halogen, -OH, -CN and -NH 2 .
  • the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 can be substituted with one or more (such as 1 or 2) moieties independently selected from an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted heteroaryl and an unsubstituted or a substituted heterocyclyl.
  • Embodiment 197 The compound of embodiment 182, wherein R 6d can be an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl or an unsubstituted or a substituted heterocyclyl.
  • R 6d can be an unsubstituted or a substituted monocyclic C 3-6 cycloalkyl.
  • R 6d can be an unsubstituted or a substituted phenyl.
  • R 6d can be an unsubstituted or a substituted monocyclic 5-or 6-membered heteroaryl.
  • R 6d can be an unsubstituted or a substituted monocyclic 4-to 6-membered heterocyclyl.
  • the bottom ring of Formula (I) that includes X 1 , X 2 , X 3 and X 4 can be a phenyl ring, when X 1 is CR 6a , X 2 is CR 6b , X 3 is CR 6c and X 4 is CR 6d .
  • the bottom ring of Formula (I) can be pyridinyl.
  • the bottom ring of Formula (I) can be a pyridazine, a pyrimidine or a pyrazine.
  • the bottom ring of Formula (I) can be unsubstituted where each of R 6a , R 6b , R 6c and R 6d , if present, are hydrogen. When at least one of R 6a , R 6b , R 6c and R 6d , if present, is a non-hydrogen moiety, then the bottom ring of Formula (I) is substituted.
  • R 6a , R 6b , R 6c and R 6d can be a non-hydrogen moiety independently selected from halogen (for example, F, Br and Cl) , an unsubstituted or a substituted C 1-6 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) ) , an unsubstituted or a substituted C 2-6 alkenyl (for example, ethenyl, propenyl, butenyl, pentenyl and hexenyl) , an unsubstituted or a substituted C 2-6 alkynyl (for example, ethynyl, propynyl, butynyl, pen
  • Non-limiting exemplary unsubstituted or substituted sulfenyls include -S-CH 3 , -S-CH 2 F, -S-CH 2 Cl, -S-CH 2 Br and -S-CH 2 OH.
  • the C 1-6 alkyl can be substituted with one or more (such as 1, 2 or 3) –OH groups (for example, -CH 2 OH and -CH 2 CH 2 OH) .
  • heteroaryls and heterocyclyls that can be present for R 6a , R 6b , R 6c and/or R 6d include a 5-membered monocyclic heteroaryl, a 6-membered monocyclic heteroaryl, a 9-membered bicyclic heteroaryl, a 10-membered bicyclic heteroaryl, a 4-membered monocyclic heterocyclyl, a 5-membered monocyclic heterocyclyl, a 6-membered monocyclic heterocyclyl, a 7-membered monocyclic heterocyclyl, an 8-membered monocyclic heterocyclyl, a 9-membered bicyclic heterocyclyl or a 10-membered bicyclic heterocyclyl.
  • the number and type of heteroatom can vary for each of these heteroaryls and heterocyclyls.
  • the number of heteroatoms can be 1, 2, 3 or 4 and the heteroatom (s) can be independently selected from N (nitrogen) , NH, S (sulfur) and O (oxygen) .
  • heteroaryls and heterocyclyls include 1H-pyrazolyl, 1H-imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, azetidinyl, azetidin-2-one, pyrrolidinyl, pyrrolidin-2-one, piperidinyl, morpholinyl, oxetanyl, tetrahydrofuranyl, 2, 3-dihydrofuranyl, tetrahydro-2H-pyran, 3, 6-dihydro-2H-pyran, thiomorpholine, thietane, tetrahydrothiophene, 2, 3-dihydrothiophene, tetrahydro-2H-thiopyranyl, 3, 6-dihydro-2H-thiopyrany
  • R 6a , R 6b , R 6c and/or R 6d can be a substituted C 3-8 cycloalkyl, where the substituted C 3-8 cycloalkyl can be substituted with one or more moieties (such as 1, 2, 3, 4, or 5) independently selected from halogen (such as F, Cl or Br) , -OH, -CN, -NH 2 , an unsubstituted C 1-6 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) ) , an unsubstituted C 1-6 haloalkyl (such as -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH 3 ) F,
  • halogen
  • halogens unsubstituted C 1-6 alkyls, unsubstituted C 1-6 haloalkyls, unsubstituted C 1-6 alkoxys and unsubstituted C 1-6 haloalkoxys are described herein and include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) , -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -
  • the C 1-6 alkyl can be substituted with one or more (such as 1, 2 or 3) –OH (for example, -CH 2 OH and -CH 2 CH 2 OH) .
  • halogens unsubstituted C 1-6 alkyls, unsubstituted C 1-6 haloalkyls, unsubstituted C 1-6 alkoxys and unsubstituted C 1-6 haloalkoxys are described herein and include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) , -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -
  • any hydrogen attached to a nitrogen or a carbon can be replaced with a moiety described herein.
  • the C 1-6 alkyl can be substituted with one or more (such as 1, 2 or 3) –OH (for example, -CH 2 OH and -CH 2 CH 2 OH) .
  • halogens unsubstituted C 1-6 alkyls, unsubstituted C 1-6 haloalkyls, unsubstituted C 1-6 alkoxys and unsubstituted C 1-6 haloalkoxys are described herein and include, but are not limited to, fluoro, chloro, bromo, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) , hexyl (branched and straight-chained) , -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -
  • any hydrogen attached to a nitrogen or a carbon can be replaced with a moiety described herein.
  • R 6a , R 6b , R 6c and/or R 6d can be selected from
  • the C 1-6 alkyl can be substituted with one or more (such as 1, 2 or 3) –OH (for example, -CH 2 OH and -CH 2 CH 2 OH) .
  • the heterocyclyl of R 6a , R 6b , R 6c and/or R 6d can be substituted with one or more (such as 1, 2 or 3) heteroaryl, wherein the heteroaryl is substituted with one or more C 1-6 alkyl (such as methyl or ethyl) .
  • a non-limiting list of heterocyclyls and heteroaryls that can be present for R 6a , R 6b , R 6c and/or R 6d include: Some examples of substituted heteroaryls and heterocyclyls that can be present for R 6a , R 6b , R 6c and/or R 6d include, but are not limited to, the following:
  • R 6a , R 6b , R 6c and/or R 6d include, but are not limited to, the following:
  • substituted C 1-6 alkyls that can be present for R 6a , R 6b , R 6c and/or R 6d include, but are not limited to, substituted methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, pentyl (branched and straight-chained) and hexyl (branched and straight-chained) .
  • a substituted ethyl can be, but is not limited to, -CH 2 CH 2 OH, -CH (OH) CH 3 and -CH (OH) CH 2 OH.
  • substituted alkyls that can be present for R 6a , R 6b , R 6c and/or R 6d include, but are not limited to, the
  • the C 1-6 alkoxy when the C 1-6 alkoxy is substituted, the C 1-6 alkoxy can be substituted with one or more (such as 1, 2 or 3) -OH groups. In some embodiments, when the heterocyclyl and/or the heteroaryl are substituted, the heterocyclyl and/or the heteroaryl can be substituted with one or more (such as 1, 2 or 3) C 1-6 alkyl groups (such as methyl and ethyl) .
  • a non-limiting list of halogens and unsubstituted C 1-6 haloalkyls that can be present on a C 2-6 alkenyl and/or a C 2-6 alkynyl include fluoro, chloro, bromo, -CH 2 F, -CH 2 Cl, -CH 2 Cl, -CH (CH 3 ) F, -CH (CH 3 ) Cl, -CH (CH 3 ) Br, -CHF 2 , -CHCl 2 , -CHBr 2 , -CHFCl, -CF 3 , -CH 2 CF 3 , -CF 2 CF 3 and -CH (CF 3 ) 2 .
  • Some examples of substituted alkynyls that can be present for R 6a , R 6b , R 6c and/or R 6d include, but are not limited to, the following:
  • R 6a , R 6b , R 6c and/or R 6d can be an unsubstituted or a substituted –S (C 1-6 alkyl) or –S (an unsubstituted C 1-6 haloalkyl) .
  • the –S (C 1-6 alkyl) is substituted with one or more (such as 1, 2 or 3) -OH.
  • Some non-limiting examples of an unsubstituted or a substituted –S (C 1-6 alkyl) include –S-CH 3 , S-CH 2 CH 3 , –S-CH 2 OH and –S-CH 2 CH 2 OH.
  • R 6a , R 6b , R 6c and/or R 6d can be an unsubstituted alkoxy, such as –O (an unsubstituted C 1-6 alkyl) , -O (an unsubstituted monocyclic C 3-6 cycloalkyl) , -O (an unsubstituted bicyclic C 8-10 cycloalkyl) , –O (an unsubstituted 4-6-membered monocyclic heterocyclyl) , –O (an unsubstituted 8-10-membered bicyclic heterocyclyl) , –O (an unsubstituted 5-6-membered monocyclic heteroaryl) and –O (an unsubstituted 8-10-membered bicyclic heteroaryl) .
  • –O an unsubstituted C 1-6 alkyl
  • -O an unsubstituted monocyclic C 3-6 cycloalkyl
  • a non-limiting list of –O includes methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, pentoxy (branched and straight-chained) and hexoxy (branched and straight-chained) .
  • Some non-limiting examples of –O (an unsubstituted 4-6-membered monocyclic heterocyclyl) and –O (an unsubstituted 5-6-membered monocyclic heteroaryl) include
  • the alkoxy of R 6a , R 6b , R 6c and/or R 6d can be substituted with one or more (such as 1, 2, or 3) -OH (for example, ) .
  • the alkoxy of R 6a , R 6b , R 6c and/or R 6d (the first alkoxy) can be substituted with one or more (such as 1, 2, or 3) second C 1-6 alkoxy, which can be further optionally substituted with one or more (such as 1, 2, or 3) -OH.
  • a substituted -C ( O) -NH (C
  • the alkoxy of R 6a , R 6b , R 6c and/or R 6d can be substituted with one or more (such as 1, 2, or 3) moieties selected from an unsubstituted C 3-8 cycloalkyl (such as a monocyclic C 3-6 cycloalkyl or a bicyclic C 5-8 cycloalkyl) , an unsubstituted heteroaryl (such as a monocyclic 3-6 membered heteroaryl with 1-3 heteroatoms or a bicyclic 9-10-membered heteroaryl with 1-3 heteroatoms) and an unsubstituted heterocyclyl (such as a monocyclic 4-8-membered heterocyclyl with 1-3 heteroatoms or a bicyclic 9-10-membered heterocyclyl with 1-3 heteroatoms) .
  • an unsubstituted C 3-8 cycloalkyl such as a monocyclic C 3-6 cycloalkyl or a bicyclic C 5-8
  • the alkoxy of R 6a , R 6b , R 6c and/or R 6d can be substituted with one or more (such as 1, 2 or 3) moieties selected from a C 3-8 cycloalkyl, a heteroaryl and a heterocyclyl, wherein the C 3-8 cycloalkyl, the heteroaryl and/or the heterocyclyl can be optionally substituted with one or more (such as 1, 2 or 3) moieties independently selected from –OH and an unsubstituted C 1-6 alkyl (for example, –CH 3 ) .
  • one or more (such as 1, 2 or 3) moieties selected from a C 3-8 cycloalkyl, a heteroaryl and a heterocyclyl wherein the C 3-8 cycloalkyl, the heteroaryl and/or the heterocyclyl can be optionally substituted with one or more (such as 1, 2 or 3) moieties independently selected from –OH and an unsubstituted C 1-6 al
  • the alkoxy of R 6a , R 6b , R 6c and/or R 6d can be substituted with a monocyclic 5-or 6-membered heteroaryl, where the heteroaryl is further substituted with one or more (such as 1, 2 or 3) unsubstituted C 1-6 alkyl (for example, –CH 3 ) .
  • R 6a , R 6b , R 6c and/or R 6d can be an unsubstituted haloalkoxy.
  • a haloalkoxy that can be present for R 6a , R 6b , R 6c and/or R 6d include –OCH 2 F, -OCH 2 Cl, -OCH 2 Br, –OCHF 2 , -OCHCl 2 , -OCHBr 2 , –OCF 3 , –OCCl 3 , –OCBr 3 , -OCHFCl, –OCF 2 CH 3 , -OCF 2 CF 3 , -OCH (CH 3 ) F, -OCH (CH 3 ) Cl, -OCH (CH 3 ) Br and -OCH (CF 3 ) 2 .
  • the C 3-8 cycloalkyl, the heteroaryl and/or the heterocyclyl attached to the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 of R 6a , R 6b , R 6c and/or R 6d can be attached in a “spiro” fashion (for example, ) .
  • the C 3-8 cycloalkyl, the heteroaryl and/or the heterocyclyl attached to the -NH (C 1-6 alkyl) or the -N (C 1-6 alkyl) 2 of R 6a , R 6b , R 6c and/or R 6d are substituted
  • the C 3-8 cycloalkyl, the heteroaryl and/or the heterocyclyl can be substituted with one or more moieties independently selected from -OH and an unsubstituted C 1-6 alkyl (for example, –CH 3 ) .
  • Some non-limiting examples of a substituted -NH (C 1-6 alkyl) that can be present for R 6a , R 6b , R 6c and/or R 6d include An example of a substituted -N (C 1-6 alkyl) 2 that can be present for R 6a , R 6b , R 6c and/or R 6d is
  • R 6a , R 6b , R 6c and/or R 6d can be a substituted -NH (C 3-8 cycloalkyl) (for example, -NH (monocyclic C 3-8 cycloalkyl) and -NH (bicyclic C 3-8 cycloalkyl) ) substituted with one or more (such as 1, 2, 3, 4, or 5) -OH.
  • R 6a , R 6b , R 6c and/or R 6d can be a substituted -NH (C 3-8 cycloalkyl) (for example, -NH (monocyclic C 3-8 cycloalkyl) and -NH (bicyclic C 3-8 cycloalkyl) ) substituted with one or more (such as 1, 2, 3, 4, or 5) -OH.
  • R 6a , R 6b , R 6c and/or R 6d can be
  • R 6a , R 6b , R 6c and/or R 6d can be a substituted -NH (heterocyclyl) substituted with one or more (such as 1, 2, 3, 4 or 5) moieties independently selected from -OH, an unsubstituted C 1-6 alkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted C 1-6 alkoxy and an unsubstituted C 1-6 haloalkoxy.
  • heterocyclyl of the substituted -NH can be a monocyclic heterocyclyl, such as a 4-8 membered monocyclic heterocyclyl, or a 7-10 membered bicyclic heterocyclyl.
  • R 6a , R 6b , R 6c and/or R 6d can be a substituted -NH (heteroaryl) substituted with one or more (such as 1, 2, 3, 4 or 5) moieties independently selected from the -OH, an unsubstituted C 1-6 alkyl (such as methyl) , an unsubstituted C 1-6 haloalkyl, an unsubstituted C 1-6 alkoxy and an unsubstituted C 1-6 haloalkoxy.
  • the heteroaryl of the substituted -NH (heteroaryl) can be a monocyclic heteroaryl, such as a 5-6 membered monocyclic heteroaryl.
  • R 6a , R 6b , R 6c and/or R 6d can be
  • Embodiment 200 The compound of any one of embodiments 1-199, wherein R 2 and R 3 can be independently selected from hydrogen, halogen, an unsubstituted C 1-6 haloalkyl and an unsubstituted C 1-6 alkyl.
  • Embodiment 202 The compound of embodiment 1, wherein the compound can have a structure selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • the compound can have a structure selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • the compound can have a structure selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • the compound can be or a pharmaceutically acceptable salt or solvate thereof.
  • Embodiment 203 The compound of embodiment 202, wherein R 6a , R 6b , R 6c and R 6d , if present, can be each hydrogen.
  • Embodiment 204 The compound of embodiment 202, wherein R 6a is present and is not hydrogen, and wherein R 6b , R 6c and R 6d , if present, can each be hydrogen.
  • Embodiment 205 The compound of embodiment 202, wherein R 6b is present and is not hydrogen, and wherein R 6a , R 6c and R 6d , if present, can each be hydrogen.
  • Embodiment 210 The compound of embodiment 1, wherein the compound can be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • Embodiment 211 The compound of embodiment 210, wherein the compound can be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • Embodiment 212 The compound of embodiment 1, wherein the compound can be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • Embodiment 214 The compound of embodiment 1, wherein the compound can be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • Embodiment 215 The compound of embodiment 214, wherein the compound can be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • Embodiment 216 –A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heterocyclyl and an unsubstituted or a substituted aryl (C 1-4 alkyl) , wherein when the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and aryl (C 1-4 alkyl) are substituted, the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and the aryl (C 1-4 alkyl) are substituted,
  • Embodiment 217 –A compound of Formula (I) or a pharmaceutically acceptable salt thereof, wherein: R 1 is selected from the group consisting of hydrogen, an unsubstituted C 1-6 alkyl, an unsubstituted or a substituted C 3-8 cycloalkyl, an unsubstituted C 1-6 haloalkyl, an unsubstituted or a substituted aryl, an unsubstituted or a substituted heteroaryl, an unsubstituted or a substituted heterocyclyl and an unsubstituted or a substituted aryl (C 1-4 alkyl) , wherein when the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and the aryl (C 1-4 alkyl) are substituted, the C 3-8 cycloalkyl, the aryl, the heteroaryl, the heterocyclyl and the aryl (C 1-4 alkyl) are substituted
  • Embodiment 218 The compound of any one of embodiments 1 and 115-217, wherein R 1 and R 5 are not both hydrogen.
  • a compound of formula (I) can be a compound provided in Table 2 that has an IC 50 activity level indicated as A.
  • R 1 cannot be hydrogen. In other embodiments, R 1 cannot be an unsubstituted or a substituted aryl, such as an unsubstituted or substituted phenyl. For example, in some embodiments, R 1 cannot be In still other embodiments, R 1 cannot be an unsubstituted or a substituted heteroaryl. For example, in some embodiments, R 1 cannot be an unsubstituted or a substituted monocyclic heteroaryl, such as a 5-or 6-membered monocyclic heteroaryl.
  • R 1 cannot be In some embodiments, R 1 cannot be an unsubstituted or a substituted heterocyclyl, such as a bicyclic 9-membered heterocyclyl (for example, ) . In some embodiments, R 1 cannot be a substituted bicyclic 9-membered heterocyclyl (such as ) . In yet still other embodiments, R 1 cannot be an unsubstituted or a substituted aryl (C 1-4 alkyl) .
  • R 1 and R 5 cannot be each hydrogen.
  • R 2 and R 3 cannot be each hydrogen.
  • X 1 , X 2 , X 3 and X 4 cannot be each CH.
  • one of X 1 , X 2 , X 3 and X 4 cannot be N (nitrogen) .
  • X 1 cannot be N or X 4 cannot be N.
  • R 6a , R 6b , R 6d and/or R 6d cannot be halogen, for example, chloro.
  • R 6a , R 6b , R 6d and/or R 6d cannot be an unsubstituted C 1-6 alkyl, such as those described herein.
  • R 6a , R 6b , R 6d and/or R 6d cannot be methyl.
  • R 6a , R 6b , R 6d and/or R 6d cannot be an unsubstituted C 1-6 alkoxy, for example, those described herein. In some embodiments, R 6a , R 6b , R 6d and/or R 6d cannot be methoxy. In some embodiments, R 6a , R 6b , R 6d and/or R 6d cannot be halogen. For example, in some embodiments, R 6a , R 6b , R 6d and/or R 6d cannot be Cl. In some embodiments, R 6a , R 6b , R 6d and/or R 6d cannot be an unsubstituted or a substituted monocyclic heterocyclyl.
  • R 6a , R 6b , R 6d and/or R 6d cannot be In some embodiments, m and n cannot be each 1. In other embodiments, m cannot be 2. In still other embodiments, n cannot be 2.
  • a compound of Formula (I) cannot be a compound provided in WO 2008/144507, WO 2009/089454, WO 2021/008173, WO 2020/092621, WO 2022/109363, WO 2022/116995, WO 2023/082428, WO 2023/091561, WO 2023/109926, CN 113024438, CN118047800, EP4257584, Chen et al., European Journal of Medicinal Chemistry (2020) , 206: 112793, Nakazaki et al., Chemistry -An Asian Journal (2016) , 11 (22) , 3267-3274 and/or Wang et al., Yingyong Huagong (2014) , 43 (1) , 108-110.
  • a compound of Formula (I) or a pharmaceutically acceptable salt or solvate thereof cannot be selected from: or a pharmaceutically acceptable salt or solvate of any of the foregoing.
  • a metal e.g., Pd with appropriate ligands
  • the PMB group can then be removed, and v can be reacted with an aryl/alkyl halide (R 1 -Z) with a Cu or Pd catalyst to provide vi.
  • the Boc group of vi can be removed (e.g., TFA or HCl) , and the resulting amine can be subjected to alkylation, acylation or sulfonylation to obtain a compound of Formula (I) of Formula vii.
  • the keto-group in vi can be removed by a reducing agent (such as borane-DMS) to provide viii. Removal of Boc protecting group in viii followed by an alkylation, acylation or sulfonylation can provide a compound of Formula (I) of Formula ix.
  • Oxidation of cyano group in xi with hydrogen peroxide can provide the amide xii, which can undergo metal-catalyzed intramolecular cyclization to provide v.
  • Scheme 3 :
  • a compound of Formula (I) can be provided in a pharmaceutical composition.
  • composition refers to a composition with a compound of Formula (I) , or a pharmaceutically acceptable salt or solvate thereof, as described herein, and at least one pharmaceutically acceptable excipient.
  • an “excipient” refers to a substance that is added to a pharmaceutical composition to provide a dosage form suitable for providing/administering to a subject including, but not limited to, substances that facilitates the incorporation of the compound and/or provides desirable properties for manufacture and/or stability of such dosage form.
  • Techniques for formulation of a pharmaceutical composition and administration thereof are known to those skilled in the art. Uses and Methods of Treatment
  • TEAD family of transcription factors comprise four highly homologous genes (TEAD1, TEAD2, TEAD3, and TEAD4) that function to regulate expression of genes that influence a variety of cellular processes.
  • TEAD-dependent gene transcription can control cell proliferation, cell survival, stem cell maintenance, wound healing, developmental processes and organ size.
  • TEAD proteins consist of an N-terminal DNA binding domain that recognizes a specific DNA sequence (5’-CAATTCCA/T-3’) and a C-terminal protein-protein interaction domain that functions to bind regulatory proteins, including transcriptional coactivator proteins yes-associated protein (YAP) or its paralog transcriptional coactivator protein PDZ-binding motif (TAZ) .
  • YAP transcriptional coactivator proteins yes-associated protein
  • TAZ paralog transcriptional coactivator protein
  • TEAD activation promotes cellular proliferation and cell survival in cancer
  • inhibition of TEAD function is a viable therapeutic strategy to treat cancers dependent on TEAD activity.
  • Small molecule inhibitors of TEAD that occupy its site of palmitoylation, the “lipid pocket, ” can disrupt TEAD auto-palmitoylation.
  • Some embodiments described herein relate to a method for treating cancer in a subject that can include administering to the subject in need thereof a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Other embodiments described herein relate to use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein in the manufacture of a medicament for treating a cancer.
  • Still other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein for use in treating a cancer.
  • Some embodiments disclosed herein relate to a method for treating a cancer that can include contacting a cell infected with the cancer with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Some embodiments disclosed herein relate to a method for inhibiting replication of a cancer that can include contacting a cell infected with the cancer with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein in the manufacture of a medicament for inhibiting replication of a cancer.
  • Still other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein for use in inhibiting replication of a cancer.
  • Some embodiments disclosed herein relate to a method for inhibiting growth of a cancer cell that can include contacting the cancer cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein in the manufacture of a medicament for inhibiting growth of a cancer cell.
  • Still other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein for use in inhibiting growth of a cancer cell.
  • Some embodiments disclosed herein relate to a method for treating a disease that is mediated by TEAD that can include administering to a subject in need thereof and/or contacting a cell infected with the disease with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein in the manufacture of a medicament for a disease that is mediated by TEAD.
  • Still other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein for use in mediating TEAD, and thereby treating a disease mediated by TEAD.
  • An example of a disease that is mediated by TEAD is cancer, such as those described herein.
  • Some embodiments disclosed herein relate to a method for inhibiting one or more TEAD transcription factors that can include administering to a subject in need thereof and/or contacting a cell with a therapeutically effective amount of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein.
  • Other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein in the manufacture of a medicament for inhibiting one or more TEAD transcription factors.
  • Still other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt or solvate thereof, as described herein for use in inhibiting one or more TEAD transcription factors.
  • a disease can be treated, such as a cancer (including those described herein) .
  • a compound (along with pharmaceutically acceptable salts and solvates thereof) described herein can selectively inhibit 1, 2 or 3 of the TEAD transcription factors relative one or more of the other TEAD transcription factors.
  • a compound, or a pharmaceutically acceptable salt or solvate thereof, described herein can selectively inhibit TEAD1 and/or TEAD4 compared to TEAD3 and/or TEAD2.
  • a compound, or a pharmaceutically acceptable salt or solvate thereof, described herein can selectively inhibit TEAD1, TEAD3 and/or TEAD4 compared to TEAD2.
  • a compound, or a pharmaceutically acceptable salt or solvate thereof, described herein can selectively inhibit TEAD1, TEAD3 and TEAD4 compared to TEAD2. In some embodiments, a compound, or a pharmaceutically acceptable salt or solvate thereof, described herein can selectively inhibit TEAD1 and TEAD4 compared to TEAD3 and TEAD 2.
  • the cancer can be a breast cancer, an ovarian cancer, a cervical cancer, an uterine cancer, a lung cancer, an esophageal cancer, a stomach cancer, a gastric cancer, a colorectal cancer, a pancreatic cancer, a bladder cancer, a thyroid cancer, a brain cancer, a hepatocellular cancer, a prostate cancer, a head and neck cancer, a renal cell carcinoma, a mesothelioma, a medulloblastoma, a leukemia, a melanoma and/or a multiple myeloma.
  • the cancer cell can be selected from a breast cancer cell, an ovarian cancer cell, a cervical cancer cell, an uterine cancer cell, a lung cancer cell, an esophageal cancer cell, a stomach cancer cell, a gastric cancer cell, a colorectal cancer cell, a pancreatic cancer cell, a bladder cancer cell, a thyroid cancer cell, a brain cancer cell, a hepatocellular cancer cell, a prostate cancer cell, a head and neck cancer cell, a renal cell carcinoma cell, a mesothelioma cell, a medulloblastoma cell, a leukemia cell, a melanoma cell and a multiple myeloma cell.
  • a “subject” refers to any animal, including mammals, preferably a human, that is the object of treatment.
  • treat means alleviation or amelioration of one or more signs or symptoms of a disease or condition.
  • treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • a therapeutically effective amount is used to indicate an amount of a compound that is suitable for treatment of a subject.
  • a therapeutically effective amount of compound can be the amount needed to elicit the biological or medicinal response indicated, alleviate or ameliorate symptoms of a disease or condition, or prolong the survival of the subject being treated. This response may occur in a tissue, system or subject.
  • a therapeutically effective amount of a compound 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.
  • All starting materials, building blocks, reagents, acids, bases, dehydrating agents, solvents, and catalysts utilized to synthesize the compounds of the present invention are either commercially available or can be produced by organic synthesis methods known to one of ordinary skill in the art. Further, the compounds of the present invention can be produced by organic synthesis methods known to one of ordinary skill in the art as shown in the following examples.
  • Mass spectra were acquired on LC-MS systems using electrospray, chemical and electron impact ionization methods with a range of instruments of the following configurations: Waters Acquity UPLC with Waters SQ detector, Agilent 1260 &6125B, Shimadzu LC-20AD XR&MS 2020, Agilent 1200 &6120B.
  • [M+H] + refers to the protonated molecular ion of the chemical species.
  • NMR spectra were run with Bruker Ultrashield TM 400 (400 MH Z ) , Bruker Ultrashield TM 400 Plus (400 MH Z ) , all with and without tetramethylsilane as an internal standard. Chemical shifts are reported in ppm downfield from tetramethylsilane, spectra splitting patterns are designated as singlet (s) , doublet (d) , triplet (t) , multiplet (m) , unresolved or more overlapping signals (m) , broad signal (br) . Solvents are given in parentheses.
  • reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (3 x 20 mL) .
  • EtOAc 3 x 20 mL
  • the combined organic layers were washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD C18 150*40mm*10 ⁇ m; mobile phase: [H 2 O (10mM NH 4 HCO 3 ) -ACN] ; gradient: 40%-80%B over 8.0 min) .
  • reaction mixture was quenched by addition H 2 O (50 mL) and extracted with EtOAc (3 x 30 mL) .
  • EtOAc 3 x 30 mL
  • the combined organic layers were washed with brine (50 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition H 2 O (15 mL) and extracted with EtOAc (3 x 20 mL) .
  • EtOAc 3 x 20 mL
  • the combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition H 2 O (15 mL) and extracted with EtOAc (3 x 20 mL) .
  • EtOAc 3 x 20 mL
  • the combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched with aqueous sat. Na 2 SO 3 (50 mL) .
  • the reaction mixture was diluted with H 2 O (30 mL) and extracted with EtOAc (3 x 30 mL) .
  • the combined organic layers were washed with brine (3 x 30 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure.
  • the residue was purified by flash silica gel chromatography ( 12 g Silica Flash Column, eluent of 0 ⁇ 20%ethyl acetate/petroleum ether gradient @100 mL/min) to give the title compound (150 mg, 62.87%yield, 97%purity) as a white solid.
  • Step 3 Tert-butyl5'-methoxy-2'-oxo-1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-indoline] - 1-carboxylate
  • Step 2 Tert-butyl5'-chloro-2'-oxo-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -1- carboxylate
  • reaction mixture was quenched by addition H 2 O (15 mL) and extracted with EtOAc (3 x 20 mL) .
  • EtOAc 3 x 20 mL
  • the combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • reaction mixture was quenched by addition of H 2 O (15 mL) and extracted with EtOAc (3 x 20 mL) . The combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 7 1- (2-fluoroprop-2-enoyl) -4'-methyl-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'- indoline] -2'-one
  • Step 2 4'- (3, 6-dihydro-2H-pyran-4-yl) -1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-indolin] -2'-one
  • Step 3 Tert-butyl 1'- (4-methoxybenzyl) -2'-oxo-1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 6 Tert-butyl 2'-oxo-1'- (4- (trifluoromethyl) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'- pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 8 1- (2-fluoroacryloyl) -1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-pyrrolo [2, 3- b] pyridin] -2' (1'H) -one
  • Step 3 Tert-butyl1'- (4-methoxybenzyl) -2'-oxo-1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [3, 2-b] pyridine] -1-carboxylate
  • reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (3 x 5 mL) .
  • the organic phases were concentrated under reduced pressure.
  • the residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 ⁇ m; mobile phase: [H 2 O (0.2%FA) -ACN] ; gradient: 35%-65%B over 8.0 min) to give compound 15 (17.1 mg, 99.75%purity) as a white solid.
  • reaction mixture was diluted with H 2 O (5 mL) and extracted with EtOAc (3 x 5 mL) .
  • the combined organic phases were concentrated under reduced pressure.
  • the residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 ⁇ m; mobile phase: [H 2 O (0.2%FA) -ACN] ; gradient: 35%-65%B over 8.0 min) to give compound 17 (25.8 mg, 99.90%purity) as a white solid.
  • Step 3 Tert-butyl 1'- [ (4-methoxyphenyl) methyl] -2'-oxo-spiro [pyrrolidine -3, 3'-pyrrolo [3, 2-b] pyridine] -1-carboxylate
  • reaction mixture was diluted with H 2 O (50 mL) and extracted with EtOAc (3 x 50 mL) .
  • EtOAc 3 x 50 mL
  • the combined organic layers were washed with brine (30 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • the residue was purified by flash silica gel chromatography ( 120 g Silica Flash Column, eluent of 0 ⁇ 50%ethyl acetate/petroleum ether gradient @100 mL/min) to give the title compound (3.1 g, 90%purity) as a yellow solid.
  • Step 8 1- (2-fluoroprop-2-enoyl) -1'- [4- (trifluoromethyl) phenyl] spiro [pyrrolidine-3, 3'-pyrrolo [3, 2-b] pyridine] -2'-one
  • Peak 1 (compound 19) was obtained as a white solid (21.3 mg, 97.99%purity) .
  • Peak 2 (compound 20) was obtained as a white solid (22.1 mg, 97.90%purity) .
  • Peak 1 (compound 22) was obtained as a white solid (3.4 mg, 22.67%yield, 100%purity) .
  • the racemate compound 24 (50 mg) was purified by chiral SFC (column: REGIS WHELK-O1 (250mm*30mm, 5 ⁇ m) ; mobile phase: [CO 2 -EtOH] ; B%: 30%, isocratic elution) to give compound 25 and compound 26.
  • the stereochemistry configuration of compound 25 and compound 26 was arbitrarily assigned.
  • Peak 1 (compound 25) was obtained as a white solid (11.8 mg, 96.93%purity) .
  • LCMS: m/z 422.0 [M+H] + ;
  • Peak 2 (compound 26) was obtained as a white solid (11.4 mg, 96.99%purity) .
  • LCMS: m/z 422.0 [M+H] + ; 1 H NMR (400 MHz, DMSO-d6) ⁇ 8.26 (m, 1H) , 7.72 -7.64 (m, 2H) , 7.63 -7.56 (m, 2H) , 7.35 -7.18 (m, 2H) , 5.61 -5.26 (m, 2H) , 4.19 -3.97 (m, 2H) , 3.96 -3.80 (m, 2H) , 2.46 -2.27 (m, 2H) .
  • the racemate compound 27 (60 mg) was purified by chiral SFC (column: REGIS WHELK-O1 (250mm*30mm, 5 ⁇ m) ; mobile phase: [CO 2 -EtOH] ; B%: 35%, isocratic elution) to give compound 28 and compound 29.
  • the stereochemistry configuration compound 28 and compound 29 was arbitrarily assigned.
  • Peak 1 (compound 28) was obtained as a white solid (13.5 mg, 99.21%purity) .
  • LCMS: m/z 4 04.0 [M+H] + ;
  • reaction mixture was quenched by addition H 2 O (15 mL) and extracted with EtOAc (20 mL *3) .
  • the combined organic layers were washed with brine (20 mL) , dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue.
  • Step 3 Tert-butyl 5'-methyl-2'-oxo-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -1 -carboxylate
  • the racemate compound 39 (50 mg) was purified by chiral SFC (column: DAICEL CHIRALPAK IC (250mm*30mm, 10 ⁇ m) ; mobile phase: [CO 2 -EtOH (0.1%NH 3 H 2 O) ] ; B%: 35%, isocratic elution) to give compound 40 and compound 41.
  • the stereochemistry configuration compound 40 and compound 41 was arbitrarily assigned.
  • Peak 1 (compound 40) was obtained as a white solid (19.6 mg, 98.50%purity) .
  • Peak 2 (compound 41) was obtained as a white solid (19.8 mg, 95.67%purity) .
  • Step 2 4'- (2, 3-dihydrofuran-4-yl) -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] - 2'-one
  • Step 3 1- (2-fluoroprop-2-enoyl) -4'-tetrahydrofuran-3-yl-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine -3, 3'-indoline] -2'-one
  • Table E-2 Synthesis of 1- (2-fluoroprop-2-enoyl) -4'- (1-hydroxyethyl) -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -2'-one (Compound 62) Step 1: tert-butyl 4'- (1-butoxyvinyl) -2'-oxo-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'- indoline] -1-carboxylate
  • Step 5 1- (2-fluoroprop-2-enoyl) -2'-oxo-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'- indoline] -4'-carboxamide
  • Step 3 4'- (1, 2-dihydroxyethyl) -1- (2-fluoroacryloyl) -1'- (4- (trifluoromethyl) phenyl) spiro [azetidine -3, 3'-indolin] -2'-one
  • Step 2 tert-butyl 4'- [2- [tert-butyl (dimethyl) silyl] oxyethyl-methyl-amino] -2'-oxo-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -1-carboxylate
  • Step 3 4'- [2- [tert-butyl (dimethyl) silyl] oxyethyl-methyl-amino] -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -2'-one
  • Step 4 4'- [2- [tert-butyl (dimethyl) silyl] oxyethyl-methyl-amino] -1- (2-fluoroprop-2-enoyl) -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -2'-one
  • Step 2 tert-butyl 5'-hydroxy-2'-oxo-1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-indoline] - 1-carboxylate (Int-16)
  • Step 3 tert-butyl 2'-oxo-5'- ( (tetrahydrofuran-3-yl) oxy) -1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-indoline] -1-carboxylate
  • Step 5 1- (2-fluoroacryloyl) -5'- ( (tetrahydrofuran-3-yl) oxy) -1'- (4- (trifluoromethyl) phenyl) spiro [azetidine-3, 3'-indolin] -2'-one
  • Step 3 1- (2-fluoroprop-2-enoyl) -5'- (oxetan-3-yl) -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine- 3, 3'-indoline] -2'-one
  • Step 2 5'- (oxetan-3-yl) -1-prop-2-enoyl-1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'- indoline] -2'-one
  • Step 3 1- (2-fluoroprop-2-enoyl) -5'- (trifluoromethyl) -1'- [4- (trifluoromethyl) phenyl] spiro [azetidine-3, 3'-indoline] -2'-one
  • Step 4 tert-butyl 4'-methyl-2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine- 3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 4 tert-butyl 2'-oxo-1'- [4- (trifluoromethoxy) phenyl] -4'- (trifluoromethyl) spiro [azetidine-3, 3'- pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 5 1'- [4- (trifluoromethoxy) phenyl] -4'- (trifluoromethyl) spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -2'-one
  • Step 6 1- (2-fluoroprop-2-enoyl) -1'- [4- (trifluoromethoxy) phenyl] -4'- (trifluoromethyl) spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -2'-one
  • Step 2 tert-butyl 4'-methoxy-2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • the residue was purified by flash silica gel chromatography to give a crude product.
  • the crude product was further purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 ⁇ m; mobile phase: [H 2 O (0.2%FA) -ACN] ; gradient: 40%-70%B over 8.0 min) to give compound 95 (30.5 mg, 99.77%purity) as a white solid.
  • Step 2 tert-butyl 4'-formyl-2'-oxo-1'- [4- (trifluoromethoxy) phenyl] spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 3 tert-butyl 4'- (difluoromethyl) -2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 4 tert-butyl 6'-methyl-2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine- 3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Table E-12 Synthesis of 6'- (1, 1-difluoroethyl) -1- (2-fluoroacryloyl) -1'- (4- (trifluoromethoxy) phenyl) spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridin] -2' (1'H) -one (Compound 109) and 6'-acetyl-1- (2-fluoroacryloyl) -1'- (4- (trifluoromethoxy) phenyl) spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridin] -2' (1'H) -one (Compound 110) Step 1: tert-butyl-6'-chloro-2'-
  • Step 2 tert-butyl 6'- (1-butoxyvinyl) -2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 4 tert-butyl 6'-acetyl-2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine- 3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • Step 5 tert-butyl 6'- (1, 1-difluoroethyl) -2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate
  • reaction mixture was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*5 ⁇ m; mobile phase: [H 2 O (0.2%FA) -ACN] ; gradient: 45%-75%B over 8.0 min) to give compound 109 (21.4 mg, 43.55%yield, 99.03%purity) as a light yellow solid.
  • Step 8 6'-acetyl-1- (2-fluoroacryloyl) -1'- (4- (trifluoromethoxy) phenyl) spiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridin] -2' (1'H) -one
  • Step 2 tert-butyl 5'-bromo-2'-oxo-1'- (4- (trifluoromethoxy) phenyl) -1', 2'-dihydrospiro [azetidine-3, 3'-pyrrolo [2, 3-b] pyridine] -1-carboxylate (Int-22)
  • Step 3-7 1- (2-fluoroacryloyl) -5'-methoxy-1'- (4- (trifluoromethoxy) phenyl) spiro [azetidine-3, 3'- pyrrolo [2, 3-b] pyridin] -2' (1'H) -one (Compound 111)

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Abstract

L'invention concerne des composés de formule (I) (ainsi que des sels et solvates pharmaceutiquement acceptables de ceux-ci), des compositions pharmaceutiques qui comprennent un composé décrit dans la description, ou un sel ou solvate pharmaceutiquement acceptable de celui-ci, et des méthodes de traitement de maladies et/ou d'états, tels que le cancer, avec un composé de formule (I), ou un sel ou solvate pharmaceutiquement acceptable de celui-ci.
PCT/CN2025/081036 2024-03-06 2025-03-06 Composés spirocycliques utilisés en tant qu'inhibiteurs de tead Pending WO2025185702A1 (fr)

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