WO2023133413A1 - Multicyclic compounds - Google Patents

Multicyclic compounds Download PDF

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Publication number
WO2023133413A1
WO2023133413A1 PCT/US2023/060104 US2023060104W WO2023133413A1 WO 2023133413 A1 WO2023133413 A1 WO 2023133413A1 US 2023060104 W US2023060104 W US 2023060104W WO 2023133413 A1 WO2023133413 A1 WO 2023133413A1
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Prior art keywords
cancer
unsubstituted
compound
alkyl
pharmaceutically acceptable
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PCT/US2023/060104
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French (fr)
Inventor
Sunil Paliwal
Ahmed Abdi Samatar
Lawrence Saunders CRIPE
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Slap Pharmaceuticals Llc
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Publication of WO2023133413A1 publication Critical patent/WO2023133413A1/en

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    • 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
    • C07D471/02—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 two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links

Definitions

  • the present application relates to the fields of chemistry, biochemistry and medicine.
  • compounds of Formula (I), or pharmaceutically acceptable salt thereof pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same.
  • methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof are also disclosed herein.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • Some embodiments described herein relate to a method of treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting the activity of PARP1 in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARPl.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of PARP1.
  • PARP1/2 Poly (ADP-ribose) polymerases
  • PARP inhibitors are a class of small molecules that inhibit both PARP1 and PARP2 and have been approved as cancer drugs for tumors with BRCA1/2 mutations.
  • PARP1 is considered the major target of PARP inhibitors
  • the currently approved PARP inhibitors also inhibit PARP2 and PARP3.
  • PARP1 has additional biological roles which include the regulation of transcription of several genes implicated in several cancers. Inhibition of PARP1 with a PARP1 selective small molecule could potentially overcome some of the major toxicities observed with the current PARP1/2 inhibitors and bring meaningful benefit to cancer patients.
  • PARP 1/2 Poly (ADP-ribose) polymerases
  • 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, 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), isocyanato, thiocyanato, nitro, azi
  • C a to Cb in which “a” and “b” are integers refer 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. That is, 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 “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH 3 ) 2 CH-, CH3CH2CH2CH2-, 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 “C1-C4 alkyl” or similar designations.
  • C1-C4 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 C2-4 alkenyl, C2-6 alkenyl or C2-8 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 C2-4 alkynyl, C2-6 alkynyl or C2-8 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- or spiro-fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted.
  • Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
  • 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- 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 C6-C14 aryl group, a Ce-Cio aryl group, or a Cf> aryl group.
  • Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene.
  • An aryl group may be substituted or unsubstituted.
  • heteroaryl refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) 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, 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, pyrim
  • heterocyclyl refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system.
  • a heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings.
  • the 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 or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quatemized. 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-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazoline,
  • cycloalkyl(alkyl) refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group.
  • the lower alkylene and aryl group of a cycloalkyl(alkyl) may be substituted or unsubstituted.
  • Examples include but are not limited to cyclopropyl-Ctk-, cyclobutyl-CH2-, cyclopentyl-Ctk-, cyclohexyl-Ctk-, cyclopropyl-CtECth-, cyclobutyl- CH2CH2-, cyclopentyl-CtkCth-, cyclohexyl-CtECtk-, cyclopropyl-CtECthCth-, cyclobutyl-CH 2 CH 2 CH 2 -C,H c2y-clopentyl-CH2CH2CH2-C,H cy-clohexyl-CH 2 CH 2 CH 2 CH c 222 y---clopropyl-CH 2 CH 2 CH 2 CH 2 --, cyclobutyl-CH 2 CH 2 CH 2 CH 2 -, cyclopentylCH 2 CH 2 CH 2 -- and cyclohexyl-CH 2 CH 2 CH 2 CH 2 -.
  • 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) refer 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) refer 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 l,3-thiazinan-4-yl(methyl).
  • “Lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-).
  • a lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group 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, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein.
  • a non-limiting list of 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 Ci-4 alkyl. An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
  • hydroxyalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group.
  • exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3 -hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl.
  • a hydroxyalkyl may be substituted or unsubstituted.
  • haloalkyl refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl).
  • a halogen e.g., mono-haloalkyl, di-haloalkyl and tri-haloalkyl.
  • groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl.
  • a haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to 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, l-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chlorosubstituted cyclobutyl and fluoro-substituted cyclobutyl.
  • a haloalkoxy can be -OR, wherein R is a Ci-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, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a sulfenyl may be substituted or unsubstituted.
  • a sulfinyl may be substituted or unsubstituted.
  • a “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl.
  • a sulfonyl may be substituted or unsubstituted.
  • R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein.
  • 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 “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(RA)-” group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • amino refers to a -NH2 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” group refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An S-sulfonamido may be substituted or unsubstituted.
  • N-sulfonamido refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl
  • RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An O-carbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-carbamyl may be substituted or unsubstituted.
  • An O-thiocarbamyl may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-thiocarbamyl may be substituted or unsubstituted.
  • RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a C-amido may be substituted or unsubstituted.
  • R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • An N-amido may be substituted or unsubstituted.
  • a “mono-substituted amine” refers to a “-NHRA” in which RA can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be -NHRA, wherein RA can be an unsubstituted Ci-6 alkyl or an unsubstituted or a substituted benzyl.
  • a “di-substituted amine” refers to a “-NRARB” in which RA and RB can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • a mono-substituted amine may be substituted or unsubstituted.
  • a mono-substituted amine can be -NRARB, wherein RA and RB can be independently an unsubstituted Ci-6 alkyl or an unsubstituted or a substituted benzyl.
  • a ketoamide may be substituted or unsubstituted.
  • 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.
  • C1-C3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • 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 salt is an acid addition salt of the compound.
  • Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid.
  • compositions can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid.
  • organic acid such as aliphatic or aromatic carboxylic or sulfonic acids
  • Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine
  • 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 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.
  • Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof: wherein: X 1 can be -CH2-, -CHR 1A -, -CR 1B R lc -, N (nitrogen) or O (oxygen); Y 1 can be -CH2- , -CHR 2A - -CR 2B R 2C -, N (nitrogen) or O (oxygen) ; Z 1 can be -CH 2 - -CHR 3A - -CR 3B R 3C - N (nitrogen) or O (oxygen); provided that when X 1 is N or O, then Y 1 can be -CH2-, -CHR 2A - or -CR 2B R 2C -; and Z 1 can be -CH2-, -CHR 3A -, -CR 3B R 3C -; provided that when Y 1 is N or O; then X 1 can be -CH 2 - -CHR
  • Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted , wherein when the aryl, the heteroaryl and the substituted, the aryl, the heteroaryl can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted Ci-4 alkyl, an unsubstituted C3-6 cycloalkyl, a deuterium-substituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; Ring DI and Ring D2 can be independently a phenyl, a 5-membered heteroaryl,
  • X 1 can be -CH2-, -CHR 1A -, -CR 1B R lc -, N (nitrogen) or O (oxygen); Y 1 can be -CH2-, -CHR 2A -, -CR 2B R 2C -, N (nitrogen) or O (oxygen); and Z 1 can be -CH2-, -CHR 3A -, -CR 3B R 3C -, N (nitrogen) or O (oxygen).
  • Table 1 Table 1
  • R 1A , R 2A and/or R 3A can be halogen.
  • R 1A , R 2A and/or R 3A can be an unsubstituted Ci-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • R 1A , R 2A and/or R 3A can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl.
  • R 1A , R 2A and/or R 3A can be an unsubstituted C1-4 haloalkyl.
  • R 1A , R 2A and/or R 3A can be -CF 3 , -CHF 2 , -C(CH 3 )F 2 , -CHC1 2 , -CH 2 F, -CH(CH 3 )F, -CH 2 CF 3 , -CH 2 C1, -CH 2 CH 2 F, -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 F and -CH 2 CH 2 CH 2 C1.
  • Possible cycloalkyls that can be present for a monocyclic C 3 -6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Possible substituents that can be present on a substituted monocyclic C 3 -6 cycloalkyl include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl and an unsubstituted CM haloalkyl. Suitable halogens, C alkyls and C haloalkyls are described herein.
  • R 1B and/or R 1C can be halogen. In other embodiments, including those in Table 1, R 1B and/or R 1C can be an unsubstituted C alkyl. In still other embodiments, including those in Table 1, R 1B and/or R 1C can be an unsubstituted or a substituted monocyclic C 3 -6 cycloalkyl. In yet still other embodiments, R 1B and/or R 1C can be an unsubstituted CM haloalkyl. In some embodiments, including those in Table 1, R 2B and/or R 2C can be halogen.
  • R 2B and/or R 2C can be an unsubstituted C alkyl. In still other embodiments, including those in Table 1, R 2B and/or R 2C can be an unsubstituted or a substituted monocyclic C 3 -6 cycloalkyl. In yet still other embodiments, R 2B and/or R 2C can be an unsubstituted C haloalkyl. In some embodiments, including those in Table 1, R 3B and/or R 3C can be halogen. In other embodiments, including those in Table 1, R 3B and/or R 3C can be an unsubstituted C alkyl.
  • R 3B and/or R 3C can be an unsubstituted or a substituted monocyclic C 3 -6 cycloalkyl. In yet still other embodiments R 3B and/or R 3C can be an unsubstituted C haloalkyl.
  • Examples of unsubstituted C alkyls for R 1B , R 1C , R 2B , R 2C , R 3B and/or R 3C include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • R 1B , R 1C , R 2B , R 2C , R 3B and R 3C is an unsubstituted CM haloalkyl
  • R 1B , R 1C , R 2B , R 2C , R 3B and/or R 3C can be -CF 3 , -CHF 2 , -C(CH 3 )F 2 , -CHC1 2 , -CH 2 F, -CH(CH 3 )F, -CH 2 CF 3 , -CH 2 C1, -CH 2 CH 2 F, -CH 2 CH 2 C1, -CH 2 CH 2 CH 2 F and -CH 2 CH 2 CH 2 C1.
  • This list of possible unsubstituted C haloalkyls for R 1B , R 1C , R 2B , R 2C , R 3B and R 3C is not inclusive.
  • Possible cycloalkyls that can be present for a monocyclic C 3 -6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Exemplary substituents that can be present on a substituted monocyclic C 3 -6 cycloalkyl include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl and an unsubstituted CM haloalkyl.
  • Ring A can be a pyrrole. In other embodiments, Ring A can be a thiophene. In still other embodiments, Ring A can be a pyridine. In yet still other embodiments, Ring A can be a phenyl.
  • Each of the pyrrole, the thiophene, the pyridine and the phenyl can substituted with 1 or more times with a moiety (such as 1, 2 or 3 moieties) independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), a deuterium-substituted C1-4 alkyl (for example, -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and
  • -CD2CD3 and an unsubstituted C1-4 haloalkyl (including -CF3, -CCI3, -CHF2, -C(CH3)F2, -CHC12, -CH 2 F, -CH(CH 3 )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and
  • Ring A examples include the following: an , wherein the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I).
  • Ring A a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure:
  • a variety or heterocyclic ring(s) can be present for Ring B.
  • the heterocyclyl for Ring B can be a monocyclic or a bicyclic ring.
  • Ring B can be connected in a fused-fashion.
  • Ring B when Ring B is a bicyclic ring, the rings can be connected in a spiro-fashion.
  • Ring B can include a ring nitrogen. Additional ring heteroatoms, such as an additional nitrogen, oxygen and/or sulfur, can be present in Ring B.
  • Ring B can be an unsubstituted 6-membered monocyclic nitrogen-containing heterocyclyl.
  • Ring B can be a substituted 6-membered monocyclic nitrogen-containing heterocyclyl. In still other embodiments, Ring B can be an unsubstituted 7-membered bicyclic nitrogen-containing heterocyclyl. In yet still other embodiments, Ring B can be a substituted 7-membered bicyclic nitrogen-containing heterocyclyl. In some embodiments, Ring B can be an unsubstituted 8-membered bicyclic nitrogen-containing heterocyclyl. In other embodiments, Ring B can be a substituted 8-membered bicyclic nitrogencontaining heterocyclyl.
  • Ring B can be unsubstituted when m is 0. In other embodiments, Ring B can be substituted with R 3a when m is 1. When Ring B is substituted, a variety of substituents can be present. In some embodiments, Ring B can be substituted with a substituent selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl.
  • Suitable halogens, unsubstituted C1-4 alkyls, unsubstituted C1-4 haloalkyls and an unsubstituted monocyclic C3-6 cycloalkyls are described herein, and include chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CF3, -CHF 2 , -C(CH 3 )F 2 , -CHCI2, -CH 2 F, -CH(CH 3 )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CI, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexy
  • Exemplary Ring B groups include, but are not limited to, the following:
  • Ring B can be substituted one or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl) and an unsubstituted Ci-4 haloalkyl (including -CF3, -CHF2, -C(CH3)F2, -CHCI2, -CH2F, -CH(CH 3 )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI).
  • halogen for example, F, Cl or Br
  • Ci-4 alkyl such as methyl, ethyl, n-propyl, iso
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can have the structure: be substituted 1 or more times (such as 1, 2, 3 or 4 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl), a deuter
  • Suitable halogens, C1-4 alkyls, C3-6 cycloalkyls, a deuterium-substituted C1-4 alkyl and CM haloalkyls are described herein. For example, can be substituted 1 or more times
  • Ring DI can be a phenyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl.
  • Ring DI can be a phenyl.
  • Ring DI can be a 5-membered heteroaryl.
  • Ring DI can be a 6-membered heteroaryl.
  • Ring DI can be a 5-membered heterocyclyl.
  • Ring DI can be a 6-membered heterocyclyl.
  • the heteroaryl and heterocyclyl for Ring DI can include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur).
  • a non-limiting list of heteroaryls for Ring DI include pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, furan and pyrrole.
  • Exemplary heterocyclyls for Ring DI include pyrrolidin-2-one, pyrazolidin-3-one, 4,5-dihydro-lH-pyrazole, 4,5-dihydro-lH-imidazole, oxazolidin-2-one and
  • Ring D2 can be a phenyl.
  • Ring D2 can be a 5-membered heteroaryl.
  • Ring D2 can be a 6-membered heteroaryl.
  • Ring D2 can be a 5-membered heterocyclyl.
  • Ring D2 can be a 6-membered heterocyclyl.
  • the heteroaryl and/or heterocyclyl for Ring D2 can include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur).
  • Ring D2 Exemplary rings for Ring D2 are pyrrolidin-2-one, pyrazolidin-3-one, 4,5-dihydro-lH-pyrazole, 4,5-dihydro-lH-imidazole, oxazolidin-2-one and 2,3-dihydro-lH-pyrrole.
  • Ring D2 examples include, but are not limited , wherein the asterisks indicate the points of attachment to Ring DI.
  • Ring D2 can be In other embodiments, Ring D2 can be still other embodiments, Ring D2 can yet still other embodiments, Ring D2 can some embodiments, Ring D2 can be In other embodiments, Ring D2 can be In still other embodiments, Ring D2 can be In yet still other embodiments, Ring D2 can be For each of the Ring D2 moieties shown, the asterisks
  • n can be 0; and Ring C can be an unsubstituted aryl.
  • n can be 0; and Ring C can be a substituted aryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted CM alkyl, an unsubstituted C3-6 cycloalkyl, a deuterium-substituted C alkyl and an unsubstituted C haloalkyl.
  • n can be 0; and Ring C can be an unsubstituted monocyclic heteroaryl.
  • n can be 0; and Ring C can be a substituted monocyclic heteroaryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl), a deuterium-substituted CM alkyl and an unsubstituted CM haloalkyl.
  • An example of a suitable aryl can be an unsubstituted or a substituted phenyl.
  • Exemplary monocyclic heteroaryls for Ring C can be a 5- or 6-membered monocyclic heteroaryl that includes 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur).
  • suitable moieties include deuterium, F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -CHF 2 , -C(CH 3 )F 2 , -CHC12, -CH 2 F, -CH(CH 3 )F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2F, -CH2CH2F, -
  • Ring C can be pyrrole. In other embodiments, Ring C can be thiophene. In still other embodiments, Ring C can be thiazole. In yet still other embodiments, Ring C can be pyridine. In some embodiments, Ring C can be pyridazine. In other embodiments, Ring C can be pyrimidine. In still other embodiments, Ring C can be pyrazine. In yet still other embodiments, Ring C can be phenyl. Exemplary rings for Ring C are as follows:
  • moieties can be present on Ring C.
  • Suitable moieties that can be present on Ring C include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C alkyl), a deuterium-substituted C alkyl and an unsubstituted C haloalkyl.
  • Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C i - alkyl, an unsubstituted C2- 4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C alkyl), a deuteriumsubstituted C alkyl and an unsubstituted C i - haloalkyl.
  • a moiety independently selected from deuterium, halogen, an unsubstituted C i - alkyl, an unsubstituted C2- 4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C alkyl), a deuteriumsubstituted C alkyl and an unsubstituted C i - haloalkyl.
  • Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, ethenyl, propenyl, butenyl, cyclopropyl-CFh-, cyclobutyl-CFh-, cyclopentyl-CFh-, cyclohexyl-CFh-, cyclopropyl-CFhCFh-, cyclobutyl-CFECFh-, cyclopentyl-CFECFh-, cyclohexyl-CFECFh-, cyclopropyl-CH2CH2-, cyclobutyl-CH2CH2CH2-, cyclopentyl-CH2CH2CH2-, cyclohexyl-CFECFh-,
  • R 4 can be a C-amido.
  • R 5 can be an unsubstituted CM alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl or tertbutyl.
  • R 6 can be hydrogen.
  • R 6 can be an unsubstituted CM alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl).
  • CM alkyl for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl.
  • one or more hydrogens such as 1, 2, 3, 4, 5 or 6 hydrogens
  • R 6 can be a deuterium-substituted CM alkyl.
  • R 6 can be an unsubstituted monocyclic C 3 -6 cycloalkyl.
  • R 6 can be an unsubstituted bicyclic C5-8 cycloalkyl. In still other embodiments, R 6 can be an unsubstituted monocyclic C 3 - 6 cycloalkyl(an unsubstituted C 1-4 alkyl). In yet still other embodiments, R 6 can be an unsubstituted bicyclic C 5-8 cycloalkyl(an unsubstituted CM alkyl).
  • R 6 is a monocyclic C 3 - 6 cycloalkyl or a monocyclic C 3 - 6 cycloalkyl(an unsubstituted CM alkyl)
  • the C 3-6 cycloalkyl can be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • Exemplary bicyclic C 5-8 cycloalkyls for a bicyclic C 5-8 cycloalkyl and a bicyclic C5-8 cycloalkyl (an unsubstituted CM alkyl) include, but are not limited to, bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane and bicyclo[2.2.2]octane.
  • Exemplary moieties for each R 3b can be deuterium, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CF 3 , -CHF2, -C(CH 3 )F 2 , -CHC12, -CH 2 F, -CH(CH 3 )F, -CH 2 CF 3 , -CH 2 CI, -CH 2 CH 2 F, -CH 2 CH 2 CI, -CH 2 CH 2 CH 2 F, -CH 2 CH 2 CH 2 C1, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
  • R 2 and R 3 can be each hydrogen. In other embodiments, R 2 and R 3 can be each deuterium. In other embodiments, R 2 and R 3 can be each an unsubstituted C1-4 alkyl.
  • R 2 and R 3 can be independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl.
  • one of R 2 and R 3 can be deuterium; and the other of R 2 and R 3 can be hydrogen or an unsubstituted C1-4 alkyl.
  • R 2 and R 3 can be taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted monocyclic C 3 -6 cycloalkyl.
  • R 2 and R 3 can be taken together along with the carbon to which R 2 and R 3 are attached to form an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl, an unsubstituted or a substituted cyclopentyl or an unsubstituted or a substituted cyclohexyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: X 1 can be -CH 2 -, -CHR 1A -, -CR 1B R lc -, N or O; Y 1 can be -CH 2 -, -CHR 2A -, -CR 2B R 2C -, N or O; Z 1 can be -CH 2 -, -CHR 3A -, -CR 3B R 3C -, N or O; provided that when X 1 is N or O, then Y 1 can be -CH 2 -, -CHR 2A - or -CR 2B R 2C -; and Z 1 can be -CH 2 -, -CHR 3A -, -CR 3B R 3C -; provided that when Y 1 is N or O; then X 1 can be -CH 2 -, -CHR 1A - or -CR 1B R 1C
  • Ring DI and Ring D2 can be independently a phenyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted,
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be where: X 1 can be -CH2-, -CHR 1A -, -CR 1B R lc -, N or O; Y 1 can be -CH2-, -CHR 2A -, -CR 2B R 2C -, N or O; Z 1 can be -CH2-, -CHR 3A -, -CR 3B R 3C -, N or O; provided that when X 1 is N or O, then Y 1 can be -CH2-, -CHR 2A - or -CR 2B R 2C -; and Z 1 can be -CH2-, -CHR 3A -, -CR 3B R 3C -; provided that when Y 1 is N or O; then X 1 can be -CH2-, -CHR 1A - or -CR 1B R 1C -; and Z 1 can be -CH2-CH2-, -CHR 1A
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can , wherein: Ring A can be , where the asterisks indicate the points of attachment to the pyrimidine-
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-d
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can be J , wherein: Ring A can be N , where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
  • R 2 and R 3 can be each hydrogen; Ring B can be ; ml can be 1; R 3a can be halogen (such as fluoro) or an unsubstituted C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl); Ring C can be ; m2 can be 1 ; R 3b can be halogen
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof can the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula
  • Ring A can be , where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)- dione ring of Formula (I);
  • R 2 and R 3 can be each hydrogen;
  • Ring B can be ml can be 1;
  • R 3a can be halogen (such as fluoro) or an unsubstituted Ci- alkyl (such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl);
  • Ring C can be ;
  • m2 can be 1;
  • R 3b can be halogen (such as fluoro);
  • n can be 1;
  • Ring A can be , where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
  • R 2 and R 3 can be each hydrogen;
  • Ring B can be ;
  • ml can be 1 ;
  • R can be halogen (such as fluoro) or an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl);
  • Ring C can be ;
  • m2 can be 1;
  • R 3b can be an unsubstituted C i - alkyl (for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl);
  • n
  • R 6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl).
  • Ci-4 alkyl such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof cannot be selected from including pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be selected from and , including pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in U.S. 2022/0348574 and/or WO 2022/225934. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in CN 115232129.
  • Examples of compounds of Formula (I), include the following:
  • Scheme 1 provides an exemplary method for preparing a compound of Formula (I), including pharmaceutically acceptable salts thereof.
  • compositions described herein relate to a pharmaceutical composition, which can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof.
  • a pharmaceutical composition described herein is suitable for human and/or veterinary applications.
  • a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues.
  • DMSO dimethyl sulfoxide
  • DMSO dimethyl sulfoxide
  • a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable.
  • a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation.
  • a common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • a “diluent” is a type of excipient.
  • Proper formulation is dependent upon the route of administration chosen.
  • Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • the liposomes may be targeted to and taken up selectively by the organ.
  • compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes.
  • compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof)
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
  • Some embodiments described herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARP1.
  • Some embodiments described herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein.
  • a method for inhibiting the activity of PARP1 that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of PARP1.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof).
  • inventions described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1.
  • Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of PARP1.
  • Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of PARP1.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of PARP1.
  • Some embodiments disclosed herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein.
  • a compound described herein for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof
  • inventions disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1.
  • Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARP1.
  • suitable cancers include, but are not limited to: a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma,
  • treat do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
  • a “subject” refers to an animal that is the object of treatment, observation or experiment.
  • Animal includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals.
  • “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans.
  • the subject can be human, for example a human subject that is 18 years old or older.
  • an effective amount of compound is used to indicate an amount of an active compound, or pharmaceutical agent, which elicits the biological or medicinal response indicated.
  • an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein.
  • the effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
  • the filtrate was concentrated under reduced pressure, and the residue was diluted with chloroform and methanol (50 mL, 10:1). The pH was adjusted to 8 with saturated aqueous NaHCCh, and the two layers were separated. The aqueous layer was extracted with chloroform and methanol (3 x 30 mL, 10:1). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with a mixture of solvents of PE and EA (30 mL, 1:1). The solid was collected by filtration, and the cake was dried in high vacuum to give 6 (1.2 g, 60.50% yield) as a brown solid.
  • Prep-HPLC method column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-CH3CN] ; B%: 30%-50%,8 min.
  • LC/MS The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in O.Olmin, Flow rate was 1.0 mL/min.
  • Mobile phase A was 0.04% trifluoroacetic acid in water
  • Mobile phase B was 0.02% trifluoroacetic acid in acetonitrile.
  • the column used for chromatography was a Kinetex C18 2.1 x 50 mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.
  • LC/MS The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in O.Olmin, the flow rate was 1.0 ml/min.
  • Mobile phase A was 0.04% Trifluoroacetic Acid in water
  • mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile.
  • the column used for chromatography was a Kinetex C18 2.1 x 50 mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.
  • Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.
  • the PARP1 and PARP 2 protein and the PARPi-FL were purchased from BPS Bioscience.
  • the assay buffer was 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCh, 150 mM NaCl.
  • the compounds were diluted into top point concentration in 384PP-plate and transferred serially into an Optiplate-384F plate.
  • Compound (20 nF) or DMSO was added to assay plate and then 10 uL of 40 nM PARP1 or PARP2 (diluted using assay buffer) was added.
  • the assay plate was centrifuged at 1000 rpm for 1 min and then incubated for 30 min at rt.
  • DLD-1 -wt and DLD-1 mutant cells are cultured in RPMI 1640+10%FBS+l%PS. The cells are harvested into culture media for 2-3 days. The cells are diluted into culture media (density 2-3 x 10 6 ) and 40 uL of cell suspension (50 cells/well for DLD- 1 wt and 50 cells/well for DLD-1 BRCA (-/-). The plates are covered and spun at rt at 1000 rpm, for 1 minute and then transferred. The plates are placed into 37 °C 5% CO2 incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution and then 40 uL of stock solution is transferred to a 384 PP-plate.
  • a 10-point dilution is carried out by transferring 10 uL compound into 30 pL DMSO by using TECAN (EV0200) liquid handler. The plates are spun at rt at 1000 rpm for 1 minute and then shaken on a plate shaker for 2 minutes. Forty nL of diluted compound is transferred into the cell plate by using a liquid handler. After 7 days of incubation, a CTG detection assay is performed. The CTG detection assay is carried out by removing the plates from the incubators and then equilibrated at rt for 15 minutes. The cellTiter Gio reagents are thawed and equilibrated at rt.
  • % Inhibition 100 x (LumHC - LumSample) / (LumHC -LumLC).

Abstract

Provided herein are compounds of Formula (I), or pharmaceutically acceptable salts thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also provided herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

Description

MULTICYCLIC COMPOUNDS
INCORPORATION BY REFERENCE TO ANY PRIORITY APPLICATIONS
[0001] Any and all applications for which a foreign or domestic priority claim is identified, for example, in the Application Data Sheet or Request as filed with the present application, are hereby incorporated by reference under 37 CFR 1.57, and Rules 4.18 and 20.6, including U.S. Provisional Application Nos. 63/266,536, filed January 7, 2022 and 63/363,152, filed April 18, 2022, each of which is incorporated by reference in their entireties.
BACKGROUND
Field
[0002] The present application relates to the fields of chemistry, biochemistry and medicine. Disclosed herein are compounds of Formula (I), or pharmaceutically acceptable salt thereof, pharmaceutical compositions that include a compound described herein (including pharmaceutically acceptable salts of a compound described herein) and methods of synthesizing the same. Also disclosed herein are methods of treating diseases and/or conditions with a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
Description
[0003] According to the National Cancer Institute, an estimated 1,806,590 new cases of cancer will be diagnosed in the United States and 606,520 people will die from the disease in 2020. The most common cancers are breast cancer, lung and bronchus cancer, prostate cancer, colon and rectum cancer, melanoma of the skin, bladder cancer, non-Hodgkin lymphoma, kidney and renal pelvis cancer, endometrial cancer, leukemia, pancreatic cancer, thyroid cancer, and liver cancer.
SUMMARY
[0004] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof. [0005] Some embodiments disclosed herein relate to a pharmaceutical composition that can contain an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
[0006] Some embodiments described herein relate to a method of treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
[0007] Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
[0008] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
[0009] Some embodiments described herein relate to a method for inhibiting the activity of PARP1 in a cell that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARPl.
[0010] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of PARP1.
[0011] These are other embodiments are described in greater detail below.
DETAILED DESCRIPTION
[0012] Accumulation of DNA damage without repair over a period can lead to the development of cancer. Poly (ADP-ribose) polymerases (PARP1/2) are enzymes that sense DNA damage and add branched PAR chains to facilitate DNA repair. PARP inhibitors are a class of small molecules that inhibit both PARP1 and PARP2 and have been approved as cancer drugs for tumors with BRCA1/2 mutations.
[0013] Although PARP1 is considered the major target of PARP inhibitors, the currently approved PARP inhibitors also inhibit PARP2 and PARP3. Beyond its DNA repair role, PARP1 has additional biological roles which include the regulation of transcription of several genes implicated in several cancers. Inhibition of PARP1 with a PARP1 selective small molecule could potentially overcome some of the major toxicities observed with the current PARP1/2 inhibitors and bring meaningful benefit to cancer patients.
[0014] Poly (ADP-ribose) polymerases (PARP) 1/2 Poly inhibitors selectively kill cancer cells that defect in the homologous recombination repair pathway and have been approved for use in ovarian cancer, metastatic breast cancer and prostate cancer. Although clinical studies have shown that the PARP1/2 inhibitors have antitumor activity in tumors with BRCA1/2 mutations, cancer patients with alterations in DNA damage repair pathway may be able to benefit from PARP inhibitors. Mutations in DNA damage repair pathway is observed in a broad range of tumor types suggesting that the PARP 1/2 inhibitors could potentially have antitumor activity in several cancer types.
[0015] Although PARP inhibitors have demonstrated antitumor activity, the adverse events seen in patients treated with the PARP1/2 inhibitors have necessitated dose reductions and discontinuation of the PARP 1/2 inhibitors. The adverse events of the PARP 1/2 inhibitors are thought to arise from inhibition of PARP2, hence small molecules that are potent and selective for PARP1 could retain the antitumor activity and potentially minimize the adverse events observed with the current PARP 1/2 inhibitors.
Definitions
[0016] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. All patents, applications, published applications and other publications referenced herein are incorporated by reference in their entirety unless stated otherwise. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.
[0017] Whenever a group is described as being “optionally substituted” that group may be unsubstituted or substituted with one or more of the indicated substituents. Likewise, when a group is described as being “unsubstituted or substituted” if substituted, the substituent(s) may be selected from one or more of the indicated substituents. If no substituents are indicated, it is meant that 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, 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), isocyanato, thiocyanato, nitro, azido, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, an amino, a mono-substituted amine and a di-substituted amine.
[0018] As used herein, “Ca to Cb” in which “a” and “b” are integers refer 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. That is, 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. Thus, for example, a “Ci to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CH3)3C-. 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.
[0019] As used herein, “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 “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 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.
[0020] As used herein, “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. For example, the alkenyl can be a C2-4 alkenyl, C2-6 alkenyl or C2-8 alkenyl. Examples of alkenyl groups include allenyl, vinylmethyl and ethenyl. An alkenyl group may be unsubstituted or substituted.
[0021] As used herein, “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. For example, the alkynyl can be a C2-4 alkynyl, C2-6 alkynyl or C2-8 alkynyl. Examples of alkynyls include ethynyl and propynyl. An alkynyl group may be unsubstituted or substituted.
[0022] As used herein, “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- or spiro-fashion. Cycloalkyl groups can contain 3 to 10 atoms in the ring(s). 3 to 8 atoms in the ring(s) or 3 to 6 atoms in the ring(s). A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.
[0023] As used herein, “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- 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.
[0024] As used herein, “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. For example, the aryl group can be a C6-C14 aryl group, a Ce-Cio aryl group, or a Cf> aryl group. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted.
[0025] As used herein, “heteroaryl” refers to a monocyclic, bicyclic and tricyclic aromatic ring system (a ring system with fully delocalized pi-electron system) 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. For example, 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). Furthermore, the term “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. Examples of heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4-oxadiazole, thiazole, 1,2,3- thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine. A heteroaryl group may be substituted or unsubstituted.
[0026] As used herein, “heterocyclyl” refers to a monocyclic, bicyclic and tricyclic ring system wherein carbon atoms together with from 1 to 5 heteroatoms constitute said ring system. A heterocycle may optionally contain one or more unsaturated bonds situated in such a way, however, that a fully delocalized pi-electron system does not occur throughout all the rings. The number of atoms in the ring(s) of a heterocyclyl group can vary. For example, 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 or thiocarbonyl functionalities, so as to make the definition include oxo-systems and thio-systems such as lactams, lactones, cyclic imides, cyclic thioimides and cyclic carbamates. When composed of two or more rings, the rings may be joined together in a fused fashion. Additionally, any nitrogens in a heterocyclyl may be quatemized. Heterocyclyl groups may be unsubstituted or substituted. Examples of such “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-l,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1, 3, 5-triazine, imidazoline, imidazolidine, isoxazoline, isoxazolidine, oxazoline, oxazolidine, oxazolidinone, thiazoline, thiazolidine, morpholine, oxirane, piperidine A-Oxide, piperidine, piperazine, pyrrolidine, pyrrolidone, pyrrolidione, 4- piperidone, pyrazoline, pyrazolidine, 2-oxopyrrolidine, tetrahydropyran, 4H-pyran, tetrahydrothiopyran, thiamorpholine, thiamorpholine sulfoxide, thiamorpholine sulfone and their benzo-fused analogs (e.g., benzimidazolidinone, tetrahydroquinoline and 3,4- methy lenedioxypheny 1) .
[0027] As used herein, “cycloalkyl(alkyl)” refer to a cycloalkyl group connected, as a substituent, via a lower alkylene group. The lower alkylene and aryl group of a cycloalkyl(alkyl) may be substituted or unsubstituted. Examples include but are not limited to cyclopropyl-Ctk-, cyclobutyl-CH2-, cyclopentyl-Ctk-, cyclohexyl-Ctk-, cyclopropyl-CtECth-, cyclobutyl- CH2CH2-, cyclopentyl-CtkCth-, cyclohexyl-CtECtk-, cyclopropyl-CtECthCth-, cyclobutyl-CH2CH2CH2-C,H c2y-clopentyl-CH2CH2CH2-C,H cy-clohexyl-CH2CH2CH2CH c222y---clopropyl-CH2CH2CH2CH2--, cyclobutyl-CH2CH2CH2CH2-, cyclopentylCH2CH2CH2CH2-- and cyclohexyl-CH2CH2CH2CH2-.
[0028] As used herein, “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).
[0029] As used herein, “heteroaryl(alkyl)” refer 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.
[0030] A “heterocyclyl(alkyl)” refer 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 l,3-thiazinan-4-yl(methyl).
[0031] “Lower alkylene groups” are straight-chained -CH2- tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms. Examples include but are not limited to methylene (-CH2-), ethylene (-CH2CH2-), propylene (-CH2CH2CH2-) and butylene (-CH2CH2CH2CH2-). A lower alkylene group can be substituted by replacing one or more hydrogen of the lower alkylene group 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.,
Figure imgf000011_0001
)•
[0032] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) is defined herein. A non-limiting list of alkoxys are methoxy, ethoxy, n-propoxy, 1 -methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec -butoxy, tert-butoxy, phenoxy and benzyloxy. In some instances, an alkoxy can be -OR, wherein R is an unsubstituted Ci-4 alkyl. An alkoxy may be substituted or unsubstituted.
[0033] As used herein, “acyl” refers to a hydrogen, an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl) connected, as substituents, via a carbonyl group. Examples include formyl, acetyl, propanoyl, benzoyl and acryl. An acyl may be substituted or unsubstituted.
[0034] As used herein, “hydroxyalkyl” refers to an alkyl group in which one or more of the hydrogen atoms are replaced by a hydroxy group. Exemplary hydroxyalkyl groups include but are not limited to, 2-hydroxyethyl, 3 -hydroxypropyl, 2-hydroxypropyl and 2,2-dihydroxyethyl. A hydroxyalkyl may be substituted or unsubstituted.
[0035] As used herein, “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). Such groups include but are not limited to, chloromethyl, fluoromethyl, difluoromethyl, trifluoromethyl, l-chloro-2-fluoromethyl and 2-fluoroisobutyl. A haloalkyl may be substituted or unsubstituted.
[0036] As used herein, “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, l-chloro-2-fluoromethoxy, 2-fluoroisobutoxy, chloro-substituted cyclopropyl, fluoro-substituted cyclopropyl, chlorosubstituted cyclobutyl and fluoro-substituted cyclobutyl. In some instances, a haloalkoxy can be -OR, wherein R is a Ci-4 alkyl substituted by 1, 2 or 3 halogens. A haloalkoxy may be substituted or unsubstituted. [0037] A “sulfenyl” group refers to an “-SR” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A sulfenyl may be substituted or unsubstituted.
[0038] A “sulfinyl” group refers to an “-S(=O)-R” group in which R can be the same as defined with respect to sulfenyl. A sulfinyl may be substituted or unsubstituted.
[0039] A “sulfonyl” group refers to an “SO2R” group in which R can be the same as defined with respect to sulfenyl. A sulfonyl may be substituted or unsubstituted.
[0040] An “O-carboxy” group refers to a “RC(=O)O-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl), as defined herein. An O-carboxy may be substituted or unsubstituted.
[0041] The terms “ester” and “C-carboxy” refer to a “-C(=O)OR” group in which R can be the same as defined with respect to O-carboxy. An ester and C-carboxy may be substituted or unsubstituted.
[0042] A “thiocarbonyl” group refers to a “-C(=S)R” group in which R can be the same as defined with respect to O-carboxy. A thiocarbonyl may be substituted or unsubstituted.
[0043] A “trihalomethanesulfonyl” group refers to an “X3CSO2-” group wherein each X is a halogen.
[0044] A “trihalomethanesulfonamido” group refers to an “X3CS(O)2N(RA)-” group wherein each X is a halogen, and RA is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
[0045] The term “amino” as used herein refers to a -NH2 group.
[0046] As used herein, the term “hydroxy” refers to a -OH group.
[0047] A “cyano” group refers to a “-CN” group.
[0048] The term “azido” as used herein refers to a -N3 group.
[0049] An “isocyanato” group refers to a “-NCO” group.
[0050] A “thiocyanato” group refers to a “-SCN” group.
[0051] An “isothiocyanato” group refers to an “-NCS” group.
[0052] A “mercapto” group refers to an “-SH” group.
[0053] A “carbonyl” group refers to a “C(=O)” group. [0054] An “S-sulfonamido” group refers to a “-SO2N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An S-sulfonamido may be substituted or unsubstituted.
[0055] An “N-sulfonamido” group refers to a “RSO2N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-sulfonamido may be substituted or unsubstituted.
[0056] An “O-carbamyl” group refers to a “-OC(=O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-carbamyl may be substituted or unsubstituted.
[0057] An “N-carbamyl” group refers to an “ROC(=O)N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-carbamyl may be substituted or unsubstituted.
[0058] An “O-thiocarbamyl” group refers to a “-OC(=S)-N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An O-thiocarbamyl may be substituted or unsubstituted.
[0059] An “N-thiocarbamyl” group refers to an “ROC(=S)N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-thiocarbamyl may be substituted or unsubstituted.
[0060] A “C-amido” group refers to a “-C(=O)N(RARB)” group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A C-amido may be substituted or unsubstituted.
[0061] An “N-amido” group refers to a “RC(=O)N(RA)-” group in which R and RA can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). An N-amido may be substituted or unsubstituted.
[0062] A “mono-substituted amine” refers to a “-NHRA” in which RA can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be -NHRA, wherein RA can be an unsubstituted Ci-6 alkyl or an unsubstituted or a substituted benzyl.
[0063] A “di-substituted amine” refers to a “-NRARB” in which RA and RB can be independently alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A mono-substituted amine may be substituted or unsubstituted. In some instances, a mono-substituted amine can be -NRARB, wherein RA and RB can be independently an unsubstituted Ci-6 alkyl or an unsubstituted or a substituted benzyl.
[0064] A “ketoamide” group refers to a -C(=O)-C(=O)N(RARB) group in which RA and RB can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl). A ketoamide may be substituted or unsubstituted.
[0065] The term “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.
[0066] Where the number of substituents is not specified (e.g., haloalkyl), there may be one or more substituents present. For example, “haloalkyl” may include one or more of the same or different halogens. As another example, “C1-C3 alkoxyphenyl” may include one or more of the same or different alkoxy groups containing one, two or three atoms.
[0067] As used herein, the abbreviations for any protective groups, amino acids and other compounds, are, unless indicated otherwise, in accord with their common usage, recognized abbreviations, or the IUPAC-IUB Commission on Biochemical Nomenclature (See, Biochem. 11:942-944 (1972)).
[0068] The term “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. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid and phosphoric acid. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example formic, acetic, succinic, lactic, malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluenesulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
[0069] Terms and phrases used in this application, and variations thereof, especially in the appended claims, unless otherwise expressly stated, should be construed as open ended as opposed to limiting. As examples of the foregoing, the term ‘including’ should be read to mean ‘including, without limitation,’ ‘including but not limited to,’ or the like; the term ‘comprising’ as used herein is synonymous with ‘including,’ ‘containing,’ or ‘characterized by,’ and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps; the term ‘having’ should be interpreted as ‘having at least;’ the term ‘includes’ should be interpreted as ‘includes but is not limited to;’ the term ‘example’ is used to provide exemplary instances of the item in discussion, not an exhaustive or limiting list thereof. In addition, the term “comprising” is to be interpreted synonymously with the phrases "having at least" or "including at least". When used in the context of a compound or composition, 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.
[0070] With respect to the use of substantially any plural and/or singular terms herein, those having skill in the art can translate from the plural to the singular and/or from the singular to the plural as is appropriate to the context and/or application. The various singular/plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality.
[0071] It is understood that, in any compound described herein having one or more chiral centers, if an absolute stereochemistry is not expressly indicated, then each center may independently be of (R)-configuration or (S)-configuration or a mixture thereof. Thus, the compounds provided herein may be enantiomerically pure, enantiomerically enriched, racemic mixture, diastereomerically pure, diastereomerically enriched, or a stereoisomeric mixture. In addition, it is understood that, in any compound described herein having one or more double bond(s) generating geometrical isomers that can be defined as E or Z, each double bond may independently be E or Z a mixture thereof. Likewise, it is understood that, in any compound described, all tautomeric forms are also intended to be included.
[0072] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens or isotopes thereof, e.g., hydrogen- 1 (protium) and hydrogen-2 (deuterium).
[0073] It is understood that the compounds described herein can be labeled isotopically. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo halflife or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium) and hydrogen-2 (deuterium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.
[0074] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.
Compounds
[0075] Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof:
Figure imgf000017_0001
wherein: X1 can be -CH2-, -CHR1A-, -CR1BRlc-, N (nitrogen) or O (oxygen); Y1 can be -CH2- , -CHR2A- -CR2BR2C-, N (nitrogen) or O (oxygen) ; Z1 can be -CH2- -CHR3A- -CR3BR3C- N (nitrogen) or O (oxygen); provided that when X1 is N or O, then Y1 can be -CH2-, -CHR2A- or -CR2BR2C-; and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-; provided that when Y1 is N or O; then X1 can be -CH2- -CHR1A- or -CR1BRlc-; and Z1 can be -CH2- -CHR3A- -CR3BR3C-; and provided that when Z1 is N or O; then X1 can be -CH2-, -CHR1A- or -CR1BRlc-; and Y1 can be -CH2-, -CHR2A-, -CR2BR2C-; Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl, a deuteriumsubstituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7-membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8-membered bicyclic nitrogen-containing heterocyclyl; R1A, R1B, R1C, R2A, R2B, R2C, R3A, R3B and R3C can be independently selected from halogen, an unsubstituted
C1-4 alkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 haloalkyl; n can be 0 or 1 ; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted
Figure imgf000017_0002
, wherein when the aryl, the heteroaryl and the
Figure imgf000017_0003
substituted, the aryl, the heteroaryl
Figure imgf000018_0001
can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted Ci-4 alkyl, an unsubstituted C3-6 cycloalkyl, a deuterium-substituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; Ring DI and Ring D2 can be independently a phenyl, a 5-membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted Ci- alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl), a deuterium-substituted C1-4 alkyl and an unsubstituted Ci- 4 haloalkyl; R2 and R3 can be independently hydrogen, deuterium or an unsubstituted C1-4 alkyl; or R2 and R3 can be taken together along with the carbon to which are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; ml can be 0 or 1; m2 can be 0, 1 or 2; R3a can be deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R3b can be deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R4 can be -C(=O)NR5R6; R5 can be hydrogen or an unsubstituted C1-4 alkyl; and R6 can be hydrogen, an unsubstituted C1-4 alkyl, a substituted C1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C1-4 alkyl), wherein the substituted C1-4 alkyl can be substituted by 1 or more deuteriums.
[0076] As provided herein, X1 can be -CH2-, -CHR1A-, -CR1BRlc-, N (nitrogen) or O (oxygen); Y1 can be -CH2-, -CHR2A-, -CR2BR2C-, N (nitrogen) or O (oxygen); and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-, N (nitrogen) or O (oxygen). Various embodiments for the ring that includes X1, Y1 and Z1 are provided below in Table 1. Table 1
Figure imgf000019_0001
[0077] In some embodiments, including those in Table 1, R1A, R2A and/or R3A can be halogen. In other embodiments, including those in Table 1, R1A, R2A and/or R3A can be an unsubstituted Ci-4 alkyl, such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In still other embodiments, including those in Table 1, R1A, R2A and/or R3A can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. In yet still other embodiments, R1A, R2A and/or R3A can be an unsubstituted C1-4 haloalkyl. For example, when R1A is an unsubstituted C haloalkyl, R1A, R2A and/or R3A can be -CF3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F and -CH2CH2CH2C1. Possible cycloalkyls that can be present for a monocyclic C3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Possible substituents that can be present on a substituted monocyclic C3-6 cycloalkyl include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl and an unsubstituted CM haloalkyl. Suitable halogens, C alkyls and C haloalkyls are described herein.
[0078] In some embodiments, including those in Table 1, R1B and/or R1C can be halogen. In other embodiments, including those in Table 1, R1B and/or R1C can be an unsubstituted C alkyl. In still other embodiments, including those in Table 1, R1B and/or R1C can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. In yet still other embodiments, R1B and/or R1C can be an unsubstituted CM haloalkyl. In some embodiments, including those in Table 1, R2B and/or R2C can be halogen. In other embodiments, including those in Table 1, R2B and/or R2C can be an unsubstituted C alkyl. In still other embodiments, including those in Table 1, R2B and/or R2C can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. In yet still other embodiments, R2B and/or R2C can be an unsubstituted C haloalkyl. In some embodiments, including those in Table 1, R3B and/or R3C can be halogen. In other embodiments, including those in Table 1, R3B and/or R3C can be an unsubstituted C alkyl. In still other embodiments, including those in Table 1, R3B and/or R3C can be an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. In yet still other embodiments R3B and/or R3C can be an unsubstituted C haloalkyl.
[0079] Examples of unsubstituted C alkyls for R1B, R1C, R2B, R2C, R3B and/or R3C include methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. When R1B, R1C, R2B, R2C, R3B and R3C is an unsubstituted CM haloalkyl, R1B, R1C, R2B, R2C, R3B and/or R3C can be -CF3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F and -CH2CH2CH2C1. This list of possible unsubstituted C haloalkyls for R1B, R1C, R2B, R2C, R3B and R3C is not inclusive. Possible cycloalkyls that can be present for a monocyclic C3-6 cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary substituents that can be present on a substituted monocyclic C3-6 cycloalkyl include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl and an unsubstituted CM haloalkyl. Suitable halogens, C alkyls and CM haloalkyls are described herein. [0080] In some embodiments, Ring A can be a pyrrole. In other embodiments, Ring A can be a thiophene. In still other embodiments, Ring A can be a pyridine. In yet still other embodiments, Ring A can be a phenyl. Each of the pyrrole, the thiophene, the pyridine and the phenyl can substituted with 1 or more times with a moiety (such as 1, 2 or 3 moieties) independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), a deuterium-substituted C1-4 alkyl (for example, -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and
-CD2CD3) and an unsubstituted C1-4 haloalkyl (including -CF3, -CCI3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and
-CH2CH2CH2CI). Examples of rings for Ring A include the following:
Figure imgf000021_0001
Figure imgf000021_0002
an , wherein the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I). For example, when Ring A is
Figure imgf000021_0003
, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure:
Figure imgf000021_0004
[0081] A variety or heterocyclic ring(s) can be present for Ring B. The heterocyclyl for Ring B can be a monocyclic or a bicyclic ring. When Ring B is a bicyclic ring, the rings can be connected in a fused-fashion. In other instances, when Ring B is a bicyclic ring, the rings can be connected in a spiro-fashion. As provided herein, Ring B can include a ring nitrogen. Additional ring heteroatoms, such as an additional nitrogen, oxygen and/or sulfur, can be present in Ring B. In some embodiments, Ring B can be an unsubstituted 6-membered monocyclic nitrogen-containing heterocyclyl. In other embodiments, Ring B can be a substituted 6-membered monocyclic nitrogen-containing heterocyclyl. In still other embodiments, Ring B can be an unsubstituted 7-membered bicyclic nitrogen-containing heterocyclyl. In yet still other embodiments, Ring B can be a substituted 7-membered bicyclic nitrogen-containing heterocyclyl. In some embodiments, Ring B can be an unsubstituted 8-membered bicyclic nitrogen-containing heterocyclyl. In other embodiments, Ring B can be a substituted 8-membered bicyclic nitrogencontaining heterocyclyl.
[0082] In some embodiments, Ring B can be unsubstituted when m is 0. In other embodiments, Ring B can be substituted with R3a when m is 1. When Ring B is substituted, a variety of substituents can be present. In some embodiments, Ring B can be substituted with a substituent selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C1-4 haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl. Suitable halogens, unsubstituted C1-4 alkyls, unsubstituted C1-4 haloalkyls and an unsubstituted monocyclic C3-6 cycloalkyls are described herein, and include chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CF3, -CHF2, -C(CH3)F2, -CHCI2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0083] Exemplary Ring B groups include, but are not limited to, the following:
Figure imgf000022_0001
[0084] A variety of substituents can be present when Ring B is substituted. For example, Ring B can be substituted one or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl) and an unsubstituted Ci-4 haloalkyl (including -CF3, -CHF2, -C(CH3)F2, -CHCI2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F and -CH2CH2CH2CI). [0085] In some embodiments, n can be 0; and Ring C can
Figure imgf000023_0001
, such that a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can have the structure:
Figure imgf000023_0002
be substituted 1 or more times (such as 1, 2, 3 or 4 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl), a deuterium-substituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl. Suitable halogens, C1-4 alkyls, C3-6 cycloalkyls, a deuterium-substituted C1-4 alkyl and CM haloalkyls are described herein. For example,
Figure imgf000023_0003
can be substituted 1 or more times
(for example, 1, 2, 3 or 4 times) with a moiety independently selected from F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -CHF2, -C(CH3)F2, -CHCI2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CD3, -CD2H, -CDH2, -CHDCH3,
-CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3,
-CD2CH3 and -CD2CD3.
[0086] As provided herein, Ring DI can be a phenyl, a 5-membered heteroaryl, a 6- membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl. In some embodiments, Ring DI can be a phenyl. In other embodiments, Ring DI can be a 5-membered heteroaryl. In still other embodiments, Ring DI can be a 6-membered heteroaryl. In yet still other embodiments, Ring DI can be a 5-membered heterocyclyl. In some embodiments, Ring DI can be a 6-membered heterocyclyl. The heteroaryl and heterocyclyl for Ring DI can include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). A non-limiting list of heteroaryls for Ring DI include pyridine, pyridazine, pyrimidine, pyrazine, thiophene, thiazole, furan and pyrrole. Exemplary heterocyclyls for Ring DI include pyrrolidin-2-one, pyrazolidin-3-one, 4,5-dihydro-lH-pyrazole, 4,5-dihydro-lH-imidazole, oxazolidin-2-one and
Figure imgf000024_0001
[0087] Various cyclyls can be present for Ring D2. In some embodiments, Ring D2 can be a phenyl. In other embodiments, Ring D2 can be a 5-membered heteroaryl. In still other embodiments, Ring D2 can be a 6-membered heteroaryl. In yet still other embodiments, Ring D2 can be a 5-membered heterocyclyl. In some embodiments, Ring D2 can be a 6-membered heterocyclyl. The heteroaryl and/or heterocyclyl for Ring D2 can include 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). Exemplary rings for Ring D2 are pyrrolidin-2-one, pyrazolidin-3-one, 4,5-dihydro-lH-pyrazole, 4,5-dihydro-lH-imidazole, oxazolidin-2-one and 2,3-dihydro-lH-pyrrole.
[0088] Examples of cyclyls that can be present for Ring D2 include, but are not limited
Figure imgf000024_0002
Figure imgf000024_0003
, wherein the asterisks indicate the points of attachment to Ring DI. In some embodiments, Ring D2 can be
Figure imgf000025_0001
In other embodiments, Ring D2 can be
Figure imgf000025_0002
still other embodiments, Ring D2 can
Figure imgf000025_0003
yet still other embodiments, Ring D2 can
Figure imgf000025_0004
some embodiments, Ring D2 can be
Figure imgf000025_0005
In other embodiments, Ring D2 can be
Figure imgf000025_0006
In still other embodiments, Ring D2 can be
Figure imgf000025_0007
In yet still other embodiments, Ring D2 can be
Figure imgf000025_0008
For each of the Ring D2 moieties shown, the asterisks
Figure imgf000025_0009
Figure imgf000026_0001
can be optionally substituted 1 or more times (for example, 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen (for example, F, Cl or Br), an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl), an unsubstituted C3-6 cycloalkyl (for example, an unsubstituted monocyclic C3-6 cycloalkyl that includes cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl), a deuterium-substituted C1-4 alkyl (-CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and -CD2CD3) and an unsubstituted CM haloalkyl (including -CF3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2C1, -CH2CH2F, -CH2CH2C1, -CH2CH2CH2F and -CH2CH2CH2C1).
[0089] In some embodiments, n can be 0; and Ring C can be an unsubstituted aryl. In other embodiments, n can be 0; and Ring C can be a substituted aryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted CM alkyl, an unsubstituted C3-6 cycloalkyl, a deuterium-substituted C alkyl and an unsubstituted C haloalkyl. In still other embodiments, n can be 0; and Ring C can be an unsubstituted monocyclic heteroaryl. In yet still other embodiments, n can be 0; and Ring C can be a substituted monocyclic heteroaryl substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C alkyl, an unsubstituted C3-6 cycloalkyl (such as a monocyclic C3-6 cycloalkyl), a deuterium-substituted CM alkyl and an unsubstituted CM haloalkyl. An example of a suitable aryl can be an unsubstituted or a substituted phenyl. Exemplary monocyclic heteroaryls for Ring C can be a 5- or 6-membered monocyclic heteroaryl that includes 1, 2 or 3 heteroatoms independently selected from N (nitrogen), O (oxygen) and S (sulfur). When the aryl and/or the heteroaryl is substituted, suitable moieties include deuterium, F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl, tert-butyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, -CF3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D,
-CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and -CD2CD3.
[0090] In some embodiments, Ring C can be pyrrole. In other embodiments, Ring C can be thiophene. In still other embodiments, Ring C can be thiazole. In yet still other embodiments, Ring C can be pyridine. In some embodiments, Ring C can be pyridazine. In other embodiments, Ring C can be pyrimidine. In still other embodiments, Ring C can be pyrazine. In yet still other embodiments, Ring C can be phenyl. Exemplary rings for Ring C are as follows:
Figure imgf000027_0001
[0091] Additionally moieties can be present on Ring C. Suitable moieties that can be present on Ring C include, but are not limited to, deuterium, halogen, an unsubstituted C alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C alkyl), a deuterium-substituted C alkyl and an unsubstituted C haloalkyl. In some embodiments, Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from deuterium, halogen, an unsubstituted C i - alkyl, an unsubstituted C2- 4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C alkyl), a deuteriumsubstituted C alkyl and an unsubstituted C i - haloalkyl. In some embodiments, Ring C can be substituted 1 or more times (such as 1, 2 or 3 times) with a moiety independently selected from F, Cl, Br, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl, tert-butyl, ethenyl, propenyl, butenyl, cyclopropyl-CFh-, cyclobutyl-CFh-, cyclopentyl-CFh-, cyclohexyl-CFh-, cyclopropyl-CFhCFh-, cyclobutyl-CFECFh-, cyclopentyl-CFECFh-, cyclohexyl-CFECFh-, cyclopropyl-CH2CH2CH2-, cyclobutyl-CH2CH2CH2-, cyclopentyl-CH2CH2CH2-, cyclohexyl- CH2CH2CH2-, cyclopropyl-CFhCFhCFhCFh-, cyclobutyl-CfhCffeCffeCffe- cyclopentyl- CH2CH2CH2CH2-, cyclohexyl-CH2CH2CH2CH2- -CF3, -CHF2, -C(CH3)F2, -CHCI2, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2CI, -CD3, -CD2H, -CDH2, -CHDCH3, -CH2CHD2, -CH2CH2D, -CHDCHD2, -CHDCH2D, -CD2CHD2, -CD2CH2D, -CH2CD3, -CD2CH3 and -CD2CD3.
[0092] As provided herein, R4 can be a C-amido. In some embodiments, R5 can be hydrogen, such that R4 can be -C(=O)NHR6. In other embodiments, R5 can be an unsubstituted CM alkyl, for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl or tertbutyl. In some embodiments, R4 can be-C(=O)N(CH3)R6. In some embodiments, R6 can be hydrogen. In other embodiments, R6 can be an unsubstituted CM alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl or tert-butyl). When R6 is a deuterium substituted CM alkyl, one or more hydrogens (such as 1, 2, 3, 4, 5 or 6 hydrogens) can be replaced with deuteriums. In still other embodiments, R6 can be a deuterium-substituted CM alkyl. In some embodiments, R6 can be an unsubstituted monocyclic C3-6 cycloalkyl. In other embodiments, R6 can be an unsubstituted bicyclic C5-8 cycloalkyl. In still other embodiments, R6 can be an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl). In yet still other embodiments, R6 can be an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted CM alkyl). When R6 is a monocyclic C3-6 cycloalkyl or a monocyclic C3-6 cycloalkyl(an unsubstituted CM alkyl), the C3-6 cycloalkyl can be selected from cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl. Exemplary bicyclic C5-8 cycloalkyls for a bicyclic C5-8 cycloalkyl and a bicyclic C5-8 cycloalkyl (an unsubstituted CM alkyl) include, but are not limited to, bicyclo[l.l.l]pentyl, bicyclo[2.2.1]heptane, bicyclo[3.1.1]heptane, bicyclo[3.2.1]octane and bicyclo[2.2.2]octane.
[0093] In some embodiments, when n is 1 and m2 is 0, Ring C can be unsubstituted except for -C(=O)NR5R6. In other embodiments, when n is 1 and m2 is 1, Ring C can be substituted with one R3b group. In still other embodiments, when m2 is 2, Ring C can be substituted with two R3b groups. As provided herein, each R3b can be independently selected from deuterium, halogen, an unsubstituted CM alkyl, an unsubstituted CM haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl. Exemplary moieties for each R3b can be deuterium, chloro, fluoro, methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl, tert-butyl, -CF3, -CHF2, -C(CH3)F2, -CHC12, -CH2F, -CH(CH3)F, -CH2CF3, -CH2CI, -CH2CH2F, -CH2CH2CI, -CH2CH2CH2F, -CH2CH2CH2C1, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl.
[0094] In some embodiments, R2 and R3 can be each hydrogen. In other embodiments, R2 and R3 can be each deuterium. In other embodiments, R2 and R3 can be each an unsubstituted C1-4 alkyl. For example, R2 and R3 can be independently selected from methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl. In still other embodiments, one of R2 and R3 can be deuterium; and the other of R2 and R3 can be hydrogen or an unsubstituted C1-4 alkyl. In some embodiments, R2 and R3 can be taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl. For example, R2 and R3 can be taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted cyclopropyl, an unsubstituted or a substituted cyclobutyl, an unsubstituted or a substituted cyclopentyl or an unsubstituted or a substituted cyclohexyl.
[0095] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: X1 can be -CH2-, -CHR1A-, -CR1BRlc-, N or O; Y1 can be -CH2-, -CHR2A-, -CR2BR2C-, N or O; Z1 can be -CH2-, -CHR3A-, -CR3BR3C-, N or O; provided that when X1 is N or O, then Y1 can be -CH2-, -CHR2A- or -CR2BR2C-; and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-; provided that when Y1 is N or O; then X1 can be -CH2-, -CHR1A- or -CR1BR1C-; and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-; and provided that when Z1 is N or O; then X1 can be -CH2-, -CHR1A- or -CR1BRlc-; and Y1 can be -CH2-, -CHR2A-, -CR2BR2C-; Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7-membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8-membered bicyclic nitrogen-containing heterocyclyl; R1A, R1B, R1C, R2A, R2B, R2C, R3A, R3B and R3C can be independently selected from halogen, an unsubstituted C1-4 alkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 haloalkyl; n can be 0 or 1 ; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted
Figure imgf000030_0001
selected from deuterium, halogen, an unsubstituted C i - alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C1-4 haloalkyl; Ring DI and Ring D2 can be independently a phenyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl) and an unsubstituted C1-4 haloalkyl; R2 and R3 can be independently hydrogen, deuterium or an unsubstituted C1-4 alkyl; or R2 and R3 can be taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; R4 can be -C(=O)NR5R6; R5 can be hydrogen or an unsubstituted C i - alkyl; and R6 can be hydrogen, an unsubstituted Ci- alkyl, a substituted C1-4 alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C1-4 alkyl), wherein the substituted C1-4 alkyl can be substituted by 1 or more deuteriums.
[0096] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be where: X1 can be -CH2-, -CHR1A-, -CR1BRlc-, N or O; Y1 can be -CH2-, -CHR2A-, -CR2BR2C-, N or O; Z1 can be -CH2-, -CHR3A-, -CR3BR3C-, N or O; provided that when X1 is N or O, then Y1 can be -CH2-, -CHR2A- or -CR2BR2C-; and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-; provided that when Y1 is N or O; then X1 can be -CH2-, -CHR1A- or -CR1BR1C-; and Z1 can be -CH2-, -CHR3A-, -CR3BR3C-; and provided that when Z1 is N or O; then X1 can be -CH2-, -CHR1A- or -CR1BRlc-; and Y1 can be -CH2-, -CHR2A-, -CR2BR2C-; Ring A can be selected from a pyrrole, a thiophene, a pyridine and a phenyl, wherein the pyrrole, the thiophene, the pyridine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected deuterium, halogen, an unsubstituted C1-4 alkyl and an unsubstituted C1-4 haloalkyl; Ring B can be selected from an unsubstituted or a substituted 6-membered monocyclic nitrogen-containing heterocyclyl, an unsubstituted or a substituted 7-membered bicyclic nitrogen-containing heterocyclyl and an unsubstituted or a substituted 8-membered bicyclic nitrogen-containing heterocyclyl; R1A, R1B, R1C, R2A, R2B, R2C, R3A, R3B and R3C can be independently selected from halogen, an unsubstituted Ci-4 alkyl, an unsubstituted or a substituted monocyclic C3-6 cycloalkyl and an unsubstituted C1-4 haloalkyl; n can be 0 or 1 ; wherein when n is 0, then Ring C can be an unsubstituted or a substituted aryl, an unsubstituted or a substituted monocyclic heteroaryl or an unsubstituted or a substituted
Figure imgf000031_0001
selected from deuterium, halogen, an unsubstituted C i - alkyl, an unsubstituted C3-6 cycloalkyl and an unsubstituted C1-4 haloalkyl; Ring DI and Ring D2 can be independently a phenyl, a 5- membered heteroaryl, a 6-membered heteroaryl, a 5-membered heterocyclyl or a 6-membered heterocyclyl; wherein when n is 1, then Ring C can be selected from a pyrrole, a thiophene, a thiazole, a pyridine, a pyridazine, a pyrimidine, a pyrazine and a phenyl, wherein the pyrrole, the thiophene, the thiazole, the pyridine, the pyridazine, the pyrimidine, the pyrazine and the phenyl can be optionally substituted, and when substituted, each can be substituted 1 or more times with a moiety independently selected from deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C2-4 alkenyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C1-4 alkyl) and an unsubstituted C1-4 haloalkyl; R2 and R3 can be independently hydrogen, deuterium or an unsubstituted C1-4 alkyl; or R2 and R3 can be taken together along with the carbon to which R2 and R3 are attached to form an unsubstituted or a substituted monocyclic C3-6 cycloalkyl; ml can be 0 or 1; m2 can be 0, 1 or 2; R3a can be deuterium, halogen, an unsubstituted C1-4 alkyl, an unsubstituted C haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R3b can be deuterium, halogen, an unsubstituted C alkyl, an unsubstituted CM haloalkyl or an unsubstituted monocyclic C3-6 cycloalkyl; R4 can be -C(=O)NR5R6; R5 can be hydrogen or an unsubstituted Ci- 4 alkyl; and R6 can be hydrogen, an unsubstituted C alkyl, a substituted C alkyl, an unsubstituted monocyclic C3-6 cycloalkyl, an unsubstituted bicyclic C5-8 cycloalkyl, an unsubstituted monocyclic C3-6 cycloalkyl(an unsubstituted C i - alkyl) or an unsubstituted bicyclic C5-8 cycloalkyl(an unsubstituted C alkyl), wherein the substituted C alkyl can be substituted by 1 or more deuteriums.
[0097] In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can
Figure imgf000032_0001
, wherein: Ring A can be
Figure imgf000032_0002
, where the asterisks indicate the points of attachment to the pyrimidine-
2,4(lH,3H)-dione ring of Formula (I); R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000032_0003
m2 can be 1 ; R3b can be halogen (such as fluoro); n can be 1; and R4 can be -C(=O)NHR6, wherein R6 can be an unsubstituted C alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl). In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be
Figure imgf000032_0004
the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000032_0005
ml can be 0; Ring C can be
Figure imgf000032_0006
; m2 can be 1; R3b can be an unsubstituted CM alkyl (for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl); n can be 1; and R4 can be - C(=O)NHR6, wherein R6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec -butyl and tert-butyl). In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be
Figure imgf000033_0001
the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000033_0002
ml can be 0; Ring C can be
Figure imgf000033_0003
; m2 can be 1; R3b can be halogen (such as fluoro); n can be 1; and R4 can be - C(=O)NHR6, wherein R6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be
Figure imgf000033_0004
asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000033_0005
; ml can be 0; Ring C can be
Figure imgf000033_0006
; m2 can be 1; R3b can be an unsubstituted CM alkyl (for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl); n can be 1; and R4 can be - C(=O)NHR6, wherein R6 can be an unsubstituted C alkyl (such as methyl, ethyl, n-propyl, isopropyl, n-butyl, iso-butyl, sec-butyl and tert-butyl). In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can be J
Figure imgf000034_0001
, wherein: Ring A can be N , where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I);
R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000034_0002
; ml can be 1; R3a can be halogen (such as fluoro) or an unsubstituted C1-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl); Ring C can be
Figure imgf000034_0003
; m2 can be 1 ; R3b can be halogen
(such as fluoro); n can be 1; and R4 can be -C(=O)NHR6, wherein R6 can be an unsubstituted Ci- 4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl). In other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can
Figure imgf000034_0004
the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula
(I); R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000034_0005
; ml can be 1 ; R3a can be halogen (such as fluoro) or an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl); Ring C can be
Figure imgf000034_0006
m2 can be 1; R3b can be an unsubstituted Ci-4 alkyl (for example, methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, secbutyl and tert-butyl); n can be 1; and R4 can be -C(=O)NHR6, wherein R6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl). In still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt
Figure imgf000035_0001
wherein: Ring A can be
Figure imgf000035_0002
, where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)- dione ring of Formula (I); R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000035_0003
ml can be 1; R3a can be halogen (such as fluoro) or an unsubstituted Ci- alkyl (such as methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl); Ring C can be
Figure imgf000035_0004
; m2 can be 1; R3b can be halogen (such as fluoro); n can be 1; and R4 can be -C(=O)NHR6, wherein R6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl). In yet still other embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, can
Figure imgf000035_0005
, wherein: Ring A can be
Figure imgf000035_0006
, where the asterisks indicate the points of attachment to the pyrimidine-2,4(lH,3H)-dione ring of Formula (I); R2 and R3 can be each hydrogen; Ring B can be
Figure imgf000035_0007
; ml can be 1 ; R can be halogen (such as fluoro) or an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl); Ring C can be
Figure imgf000035_0008
; m2 can be 1; R3b can be an unsubstituted C i - alkyl (for example, methyl, ethyl, n- propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl and tert-butyl); n can be 1; and R4 can be -
C(=O)NHR6, wherein R6 can be an unsubstituted Ci-4 alkyl (such as methyl, ethyl, n-propyl, iso- propyl, n-butyl, iso-butyl, sec -butyl and tert-butyl). In some embodiments of this paragraph, Ring
C can
Figure imgf000036_0001
[0098] In some embodiments, a compound of Formula (I), or a pharmaceutically
Figure imgf000036_0002
acceptable salt thereof, cannot be selected from
Figure imgf000036_0003
including pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be selected from
Figure imgf000036_0004
and
Figure imgf000037_0001
, including pharmaceutically acceptable salts of any of the foregoing. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in U.S. 2022/0348574 and/or WO 2022/225934. In some embodiments, a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be a compound provided in CN 115232129.
[0099] Examples of compounds of Formula (I), include the following:
Figure imgf000037_0002
Figure imgf000038_0001
Figure imgf000039_0001
Figure imgf000040_0001
pharmaceutically acceptable salt of any of the foregoing. [0100] In some embodiments, a compound of Formula (I), or a pharmaceutically
Figure imgf000041_0001
Figure imgf000041_0002
, or a pharmaceutically acceptable salt of any of the foregoing.
Synthesis
[0101] Compounds of Formula (I) along with those described herein may be prepared in various ways. General synthetic routes for preparing compounds of Formula (I) are shown and described herein along with some examples of starting materials used to synthesize compounds described herein. Additionally, for the purpose of the general synthetic routes, the structures depicted are appropriately protected, as known by one skilled in the art and the generic structures are meant to include these protecting groups. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on the disclosures herein; all such modifications and alternate routes are within the scope of the claims. Scheme 1
Figure imgf000042_0001
[0102] Scheme 1 provides an exemplary method for preparing a compound of Formula (I), including pharmaceutically acceptable salts thereof.
Pharmaceutical Compositions
[0103] Some embodiments described herein relate to a pharmaceutical composition, which can include an effective amount of a compound described herein (e.g., a compound, or a pharmaceutically acceptable salt thereof, as described herein) and a pharmaceutically acceptable carrier, excipient or combination thereof. A pharmaceutical composition described herein is suitable for human and/or veterinary applications.
[0104] As used herein, a “carrier” refers to a compound that facilitates the incorporation of a compound into cells or tissues. For example, without limitation, dimethyl sulfoxide (DMSO) is a commonly utilized carrier that facilitates the uptake of many organic compounds into cells or tissues of a subject.
[0105] As used herein, a “diluent” refers to an ingredient in a pharmaceutical composition that lacks pharmacological activity but may be pharmaceutically necessary or desirable. For example, a diluent may be used to increase the bulk of a potent drug whose mass is too small for manufacture and/or administration. It may also be a liquid for the dissolution of a drug to be administered by injection, ingestion or inhalation. A common form of diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
[0106] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.
[0107] Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art. Multiple techniques of administering a compound exist in the art including, but not limited to, oral, rectal, topical, aerosol, injection, inhalation and parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal and intraocular injections. Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
[0108] One may also administer the compound in a local rather than systemic manner, for example, via injection of the compound directly into the infected area, often in a depot or sustained release formulation. Furthermore, one may administer the compound in a targeted drug delivery system, for example, in a liposome coated with a tissue- specific antibody. The liposomes may be targeted to and taken up selectively by the organ.
[0109] The pharmaceutical compositions disclosed herein may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. As described herein, compounds used in a pharmaceutical composition may be provided as salts with pharmaceutically compatible counterions.
Methods of Use
[0110] Some embodiments described herein relate to a method for treating a cancer described herein that can include administering an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein.
[0111] Some embodiments described herein relate to a method for inhibiting growth of a malignant growth or a tumor that can include contacting the growth or the tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the malignant growth or tumor is due to a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting growth of a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
[0112] Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a malignant growth or a tumor with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer that can include contacting a malignant growth or a tumor, wherein the malignant growth or tumor is due to a cancer described herein.
[0113] Some embodiments described herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARP1. Some embodiments described herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a cancer cell from a cancer described herein. Other embodiments described herein relate to a method for inhibiting the activity of PARP1 that can include contacting a cancer cell from a cancer described herein with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), and thereby inhibiting the activity of PARP1.
[0114] Some embodiments described herein relate to a method for treating a cancer described herein that can include inhibiting the activity of PARP1 using an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof). Other embodiments described herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for treating a cancer described herein by inhibiting the activity of PARP1. Still other embodiments described herein relate to an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for treating a cancer described herein by inhibiting the activity of PARP1. Some embodiments described herein relate to a method for treating a cancer described herein that can include contacting a cancer cell with an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof), wherein the compound inhibits the activity of PARP1.
[0115] Some embodiments disclosed herein relate to a method for inhibiting the activity of PARP1 that can include providing an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) to a subject having a cancer described herein or a cancer cell from a cancer described herein. Other embodiments disclosed herein relate to the use of an effective amount of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for inhibiting the activity of PARP1. Still other embodiments disclosed herein relate to a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) or a pharmaceutical composition that includes of a compound described herein (for example, a compound of Formula (I), or a pharmaceutically acceptable salt thereof) for inhibiting the activity of PARP1.
[0116] Examples of suitable cancers include, but are not limited to: a lung cancer, a pancreatic cancer, a colon cancer (e.g., colorectal cancer), a myeloid leukemia (e.g., AML, CML, and CMML), a thyroid cancer, a myelodysplastic syndrome (MDS), a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers (e.g., squamous cell cancer of the head and neck), an ovarian cancer, a brain cancer (e.g., gliomas, such as glioma blastoma multiforme), a cancer of mesenchymal origin (e.g., fibrosarcomas and rhabdomyosarcomas), a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma or an anaplastic thyroid carcinoma.
[0117] As used herein, the terms “treat,” “treating,” “treatment,” “therapeutic,” and “therapy” do not necessarily mean total cure or abolition of the disease or condition. Any alleviation of any undesired signs or symptoms of a disease or condition, to any extent can be considered treatment and/or therapy. Furthermore, treatment may include acts that may worsen the subject’s overall feeling of well-being or appearance.
[0118] As used herein, a “subject” refers to an animal that is the object of treatment, observation or experiment. “Animal” includes cold- and warm-blooded vertebrates and invertebrates such as fish, shellfish, reptiles and, in particular, mammals. “Mammal” includes, without limitation, mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, camels, non-human primates, such as monkeys, chimpanzees, and apes, and, in particular, humans. In some embodiments, the subject can be human, for example a human subject that is 18 years old or older.
[0119] The term “effective amount” is used to indicate an amount of an active compound, or pharmaceutical agent, which elicits the biological or medicinal response indicated. For example, an effective amount of compound can be the amount needed to alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. This response may occur in a tissue, system, animal or human and includes alleviation of the signs or symptoms of the disease being treated. Determination of an effective amount is well within the capability of those skilled in the art, in view of the disclosure provided herein. The effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize.
EXAMPLES
[0120] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.
Figure imgf000048_0001
Example 1 Compound Al
Figure imgf000049_0001
[0121] To a solution of 1 (15 g, 105.52 mmol, 13.04 mL) in DCM (150 mL) was added DIPEA (46.37 g, 358.77 mmol, 62.49 mL) and the solution was cooled to -78 °C. Tf2O (35.73 g, 126.62 mmol, 20.89 mL) was added dropwise. The mixture was warmed to 20 °C slowly and then stirred for 16 h. The reaction was quenched with cold water (300 mL), and the layers was separated. The aqueous phase was extracted with dichloromethane (50 mL). The combine organic layer was washed with 5% citric acid (2 x 50 mL) and brine (50 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with EA in PE from 0% to 8% to give 2 (25 g, 86.40% yield) as a light-yellow oil. ’H NMR (400 MHz, CDCl3- 5 3.80 (s, 3H), 2.81-2.68 (m, 4H), 2.08-1.98 (m, 2H). [0122] To a solution of 2 (20 g, 72.94 mmol) and BPD (22.23 g, 87.52 mmol) in dioxane (400 mL) was added KOAc (14.32 g, 145.87 mmol). The flask was extracted and backfilled with nitrogen. This process was repeated 3 times. Pd(dppf)Ch (2.67 g, 3.65 mmol) was added under nitrogen. The flask was extracted and backfilled with nitrogen. This process was repeated 3 times. The mixture was heated to 80 °C and stirred for 16 h. The mixture was filtered through a pad of celite, and the cake was washed with ethyl acetate (2 x 50 mL). The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with EA in PE from 0% to 9% to give 3 (22.9 g, 99.63% yield) as a light-yellow oil. 1H NMR (400 MHz, CDCl3- 5 3.73 (d, J = 0.7 Hz, 3H), 2.61 (t, J = 7.6 Hz, 4H), 1.94 (quin, J = 7.6 Hz, 2H), 1.37-1.32 (m, 12H).
[0123] To a solution of 3 (6.5 g, 30.01 mmol) and methyl 2-(4,4,5,5-tetramethyl-l,3,2- dioxaborolan-2-yl)cyclopentene-l -carboxylate (9.08 g, 36.01 mmol) in THF (160 mL) and H2O (40 mL) was added K3PO4 (12.74 g, 60.02 mmol). The flask was extracted and backfilled with nitrogen. This process was repeated 3 times. Pd(dppf)Ch (1.10 g, 1.50 mmol) was added under nitrogen. The flask was extracted and backfilled with nitrogen. This process was repeated 3 times. The mixture was heated to 80 °C and stirred for 3 h. The solution was poured into water (500 mL) and extracted with ethyl acetate (3 x 50 mL). The combined organic layer was washed with brine (50 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluted with EA in PE from 0% to 18% to give 4 (8.3 g, 90.30% yield) as a light-yellow thick oil. ’H NMR (400 MHz, CDCI3-< ) 5 9.36 (d, J = 2.0 Hz, 1H), 8.91 (d, J = 2.0 Hz, 1H), 4.03 (s, 3H), 3.53 (s, 3H), 3.05 (tt, J = 2.6, 7.6 Hz, 2H), 2.85 (tt, J = 2.6, 7.7 Hz, 2H), 2.19 (quin, J = 7.7 Hz, 2H).
[0124] To a suspension of Pd/C (1.56 g) in THF (150 mL) was added 4 (3 g, 9.80 mmol). The mixture was stirred under 15 psi of H2 at 20 °C for 16 h. The mixture was filtered through a pad of celite, and the cake was washed with a mixture of solvents of chloroform and methanol (3 x 50 mL, 10:1). The filtrate was concentrated under reduced pressure. The residue was treated with a mixture of solvents of PE and EA (30 mL, 1:1). The solid was collected by filtration, and the cake was dried in high vacuum to give 5 (2 g, 82.91% yield) as a light-yellow solid. ’H NMR (400 MHz, CDCl3-<5) 5 9.19 (d, J = 2.0 Hz, 1H), 8.80 (d, J = 1.8 Hz, 1H), 4.03 (s, 3H), 3.44-3.33 (m, 3H), 3.16-3.07 (m, 2H), 2.36-2.23 (m, 3H). [0125] To a suspension of 5 (2 g, 8.12 mmol) in AcOH (40 mL) was added SeCL (991.26 mg, 8.93 mmol, 971.83 uL) in one portion. The mixture was stirred at 120 °C for 16 h. After cooled to 20 °C, the mixture was filtered. The filtrate was concentrated under reduced pressure, and the residue was diluted with chloroform and methanol (50 mL, 10:1). The pH was adjusted to 8 with saturated aqueous NaHCCh, and the two layers were separated. The aqueous layer was extracted with chloroform and methanol (3 x 30 mL, 10:1). The combined organic layer was washed with saturated brine (30 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was treated with a mixture of solvents of PE and EA (30 mL, 1:1). The solid was collected by filtration, and the cake was dried in high vacuum to give 6 (1.2 g, 60.50% yield) as a brown solid. ’H NMR (400 MHz, DMSO- 6) 5 12.00 (br s, 1H), 8.87 (d, J = 1.4 Hz, 1H), 8.21 (s, 1H), 3.91 (s, 3H), 3.16 (br t, J = 7.3 Hz, 2H), 2.82 (br t, J = 7.2 Hz, 2H), 2.17-2.06 (m, 2H).
[0126] To a suspension of 6 (1.2 g, 4.91 mmol) in THF (36 mL) cooled at 0 °C. LiAlH4 (372.95 mg, 9.83 mmol) was added in portions while maintaining the temperature between 0-3°C during the addition. The mixture was stirred at 0 °C for 0.5 h. The reaction was quenched with water (0.37 mL). To the mixture was added 15% aqueous NaOH (0.37 mL) followed by water (1.11 mL) at 0 °C. The solid was filtered, and the cake was washed with methanol (3 x 15 mL). The filtrate was concentrated under reduced pressure to give 7 (1 g, 94.13% yield) as a light-yellow foam. ’H NMR (400 MHz, DMSO- 6) 5 8.23-8.17 (m, 1H), 7.57-7.52 (m, 1H), 4.61-4.53 (m, 2H), 3.14-3.06 (m, 2H), 2.81-2.71 (m, 2H), 2.10-1.99 (m, 2H).
[0127] To a suspension of 7 (1 g, 4.62 mmol) in DCM (20 mL) was added DMF (16.90 mg, 231.23 umol, 17.79 uL). The mixture was cooled at 0 °C. SOCh (1.10 g, 9.25 mmol, 670.96 uL) was added dropwise while maintaining the temperature between 0-3 °C during the addition. After addition, the mixture was allowed to warm to 20 °C and then stirred at 20 °C for 2 h. The mixture was concentrated under reduced pressure to remove dichloromethane and residual SOCI2. The residue was treated with dichloromethane (2 mL). The solid was collected by filtration, and then dried in high vacuum to give 8 (0.7 g, 64.50% yield) as a light brown solid. 1 H NMR (400 MHz, DMSO-^6) 5 12.08-11.91 (m, 1H), 8.53-8.42 (m, 1H), 7.85-7.80 (m, 1H), 4.97-4.92 (m, 1.2H), 4.67-4.63 (m, 0.8H), 3.24-3.12 (m, 2H), 2.86-2.77 (m, 2H), 2.19-2.04 (m, 2H).
[0128] To a suspension of 8 (104.01 mg, 443.20 umol) in acetonitrile (3 mL) was added N,6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (100 mg, 369.33 umol HC1) followed by DIPEA (286.40 mg, 2.22 mmol, 385.99 uL) and NaBr (114.01 mg, 1.11 mmol, 35.63 uL). The mixture was stirred at 80 °C for 2 h. After cooled to 20 °C, the mixture was filtered, and the cake was washed with acetonitrile (1 mL). The cake was purified by prep-HPLC and lyophilized to give Al (33.1 mg, 20.10% yield, 97.0% purity) as a white solid. ’H NMR (400 MHz, DMSO- e) 5 11.79-11.61 (m, 1H), 8.43-8.38 (m, 2H), 7.77 (d, J = 8.3 Hz, 1H), 7.63 (d, J = 1.5 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 3.65 (s, 2H), 3.14 (br t, J = 7.5 Hz, 2H), 2.93 (br s, 4H), 2.77 (d, J = 5.0 Hz, 6H), 2.57 (br d, J = 1.5 Hz, 4H), 2.46 (s, 3H), 2.31 (dd, J = 1.3, 2.6 Hz, 1H), 2.15-2.03 (m, 2H).
Example 2 Compound A2
Figure imgf000052_0001
[0129] To a solution of methyl 9 (2 g, 7.69 mmol) and methyl 2-(4,4,5,5-tetramethyl-
1, 3, 2-dioxaborolan-2-yl)cyclopentene-l -carboxylate (2.33 g, 9.23 mmol) in THF (60 mL) and H2O (15 mL) was added K3PO4 (3.27 g, 15.38 mmol). The mixture was extracted and backfilled with nitrogen. This process was repeated 3 times. Pd(dppf)Ch (281.38 mg, 384.55 umol) was added under nitrogen. The mixture was extracted and backfilled with nitrogen. This process was repeated 3 times. The mixture was heated to 80 °C and stirred for 3 h. The solution was poured into water (150 mL) and extracted with ethyl acetate (3 x 30 mL). The combined organic layer was washed with brine (30 mL), dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography on silica gel eluted with EA in PE from 0% to 18% to give 10 (2 g, 85.18% yield) as a light-yellow solid. ’H NMR (400 MHz, CDCl3- 5 8.71 (d, J = 1.6 Hz, 1H), 8.25 (dd, J = 1.6, 8.0 Hz, 1H), 7.32 (d, J = 7.9 Hz, 1H), 3.98 (s, 3H), 3.51 (s, 3H), 2.94-2.77 (m, 4H), 2.14 (t, J = 7.6 Hz, 2H).
[0130] To a suspension of Pd/C (1.39 g) in MeOH (60 mL) was added 10 (2 g, 6.55 mmol). The mixture was stirred under 15 psi of H2 at 20 °C for 16 h. The mixture was filtered through a pad of celite, and the cake was washed with a mixture of solvents of chloroform and methanol (3 x 50 mL, 10:1). The filtrate was concentrated under reduced pressure. The residue was treated with a mixture of solvents of PE and EA (20 mL, 5:1). The solid was collected by filtration, and the cake was dried in high vacuum to give 11 (1.4 g, 87.13% yield) as a light brown solid. ’H NMR (400 MHz, CDCl3- 5 11.58-11.49 (m, 1H), 8.57 (d, J = 1.4 Hz, 1H), 7.94 (dd, J = 1.5, 8.3 Hz, 1H), 7.62 (d, J = 8.3 Hz, 1H), 4.01-3.99 (m, 3H), 3.24-3.20 (m, 2H), 3.11 (br t, J = 7.5 Hz, 2H), 2.30 (br d, J = 2.9 Hz, 2H), 2.20-2.06 (m, 1H), 1.82 - 1.59 (m, 1H).
[0131] To a suspension of 11 (1.4 g, 5.71 mmol) in dioxane (28 mL) was added DDQ (1.43 g, 6.28 mmol) in portions at 20 °C. The mixture was stirred at 20 °C under nitrogen for 16 h. The reaction was quenched with saturated aqueous NaHCO3 (60 mL) at 0 °C. The resulting precipitate was collected by filtration. The cake was washed with water (3 x 10 mL) and dried in high vacuum. The crude product was treated with a mixture of solvents of PE and EA (10 mL, 5:1). The solid was collected by filtration, and the cake was dried in high vacuum to give 12 (0.9 g, 64.82% yield) as a light brown solid. ’H NMR (400 MHz, CDCl3- 5 11.33 (br s, 1H), 8.07 (d, J = 1.1 Hz, 1H), 7.87 (dd, J = 1.3, 8.3 Hz, 1H), 7.57 (d, J = 8.3 Hz, 1H), 3.99 - 3.96 (m, 3H), 3.19 (br t, J = 7.6 Hz, 2H), 3.06 (br t, J = 7.5 Hz, 2H), 2.32 - 2.22 (m, 2H).
[0132] To a suspension of 12 (0.9 g, 3.70 mmol) in THF (30 mL) cooled at 0 °C. LiAlH4 (280.81 mg, 7.40 mmol) was added in portions while maintaining the temperature between 0-3 °C during the addition. The mixture was stirred at 0 °C or 0.5 h. The reaction was quenched with water (0.28 mL). 15% aqueous NaOH (0.28 mL) followed by water (0.84 mL) at 0 °C were added. The resulting solid was filtered, and the cake was washed with methanol (3x 15 mL). The filtrate was concentrated under reduced pressure to give 13 (0.65 g, 81.62% yield) as a white solid. ’H NMR (400 MHz, DMSO- 6) 5 11.58 (br dd, J = 1.3, 2.4 Hz, 1H), 7.47 (d, J = 8.1 Hz, 1H), 7.32 (s, 1H), 7.10 (dd, J = 1.1, 8.1 Hz, 1H), 5.37 (br dd, J = 2.0, 3.3 Hz, 1H), 4.56 (s, 2H), 3.07 (br t, J = 7.5 Hz, 2H), 2.75 (br t, J = 7.3 Hz, 2H), 2.09 (t, J = 7.5 Hz, 2H). [0133] To a solution of 13 (150 mg, 696.87 umol) in DMSO (3 mL) was added TCT (154.21 mg, 836.25 umol) in portions at 10 °C. The mixture was stirred at 20 °C for 15 mins. The reaction was quenched with water (10 mL), and the resulting solid was filtered. The cake was washed with water (3 x 2 mL) and dried in high vacuum to give 14 (120 mg, 73.69% yield) as a white solid. ’H NMR (400 MHz, DMSO-r/6) 5 11.68 (s, 1H), 7.54 (d, J = 8.1 Hz, 1H), 7.37 (s, 1H), 7.23 (dd, J = 1.5, 8.1 Hz, 1H), 4.83 (s, 2H), 3.08 (br t, J = 7.6 Hz, 2H), 2.76 (br t, J = 7.2 Hz, 2H), 2.10 (t, J = 7.5 Hz, 2H).
[0134] To a suspension of 14 (100.00 mg, 427.91 umol) in acetonitrile (3 mL) was added N,6-dimethyl-5-piperazin-l-yl-pyridine-2-carboxamide (139.03 mg, 513.49 umol, HC1) followed by DIPEA (331.82 mg, 2.57 mmol, 447.20 uL) and NaBr (132.08 mg, 1.28 mmol, 41.28 uL). The mixture was stirred at 80 °C for 2 h. After cooled to 20 °C, the solid was collected by filtration. The crude product was treated with acetonitrile (3 mL) and filtered. The cake was washed with acetonitrile (3x 1 mL) and dried in high vacuum. The product was suspended in acetonitrile (5 mL) and deionized water (5 mL) and lyophilized for 12 h to give A2 (58.1 mg, 31.09% yield, 98.8% purity) as a white solid. ’H NMR (400 MHz, DMSO- 6) 5 11.54 (s, 1H), 8.42 (br d, J = 4.8 Hz, 1H), 7.79 (d, J = 8.2 Hz, 1H), 7.49 (t, J = 9.2 Hz, 2H), 7.33 (s, 1H), 7.17 (d, J = 7.9 Hz, 1H), 3.62 (s, 2H), 3.08 (br t, J = 7.3 Hz, 2H), 2.95 (br s, 4H), 2.85 - 2.71 (m, 5H), 2.64 - 2.54 (m, 4H), 2.49 (br s, 3H), 2.10 (quin, J = 7.4 Hz, 2H).
Example 3 Compound A3
Figure imgf000054_0001
80°C, 3 hrs
Figure imgf000055_0001
[0135] To a solution of 31 (2 g, 12.98 mmol) in MeCN (30 mL) was added NCS (2.25 g, 16.87 mmol) at 25 °C. The mixture was stirred at 80° C for 12 h. The mixture was poured into ice-water (60 mL) and extracted with EA (3 x 30 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiCL, PE:EA = 50:1 to 3:1) to provide 32 (1.3 g, 53.13% yield) as a yellow oil. ’H NMR: (400 MHz, DMSO-^6) 5 12.98 (br s, 1H), 7.98 (s, 1H), 2.22 (s, 3H).
[0136] To a solution of 32 (900 mg, 4.77 mmol) in MeCN (15 mL) was added pyridine (604.05 mg, 7.64 mmol, 616.37 uL) at 25 °C. The mixture was degassed and purged with N2 (3x) and then cooled to 0 °C. Tf2O (2.02 g, 7.16 mmol, 1.18 mL) was added to the mixture at 0 °C. The mixture was stirred at 25 °C for 1 h. The mixture was poured into ice-water (20 mL). The mixture was extracted with EA (3 x 20 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50:1 to 6:1) to obtain 33 (1.2 g, 78.42% yield) as a colorless oil. ’H NMR: (400 MHz, DMSO- (5) 5 8.87 (s, 1H), 2.51 (s, 3H).
[0137] To a solution of 3 (1.04 g, 4.12 mmol), 33 (1.2 g, 3.74 mmol) and K3PO4 (1.59 g, 7.49 mmol) in THF (40 mL) and H2O (10 mL) was added Pd(dppf)Ch (273.85 mg, 374.26 umol) at 25 °C. The mixture was degassed and purged with N2 (3x). The mixture was stirred at 80 °C for 12 h. The mixture was poured into ice-water (20 mL) and adjusted to pH=8 with NaHCCh- The mixture was extracted with EA (3 x 40 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product. The residue was purified by column chromatography (SiCh, PE:EA = 50:1 to 6:1) to give 34 (0.8 g, 71.09% yield) as a yellow solid. ’H NMR: (400 MHz, DMSO- 6) 5 8.86 (s, 1H), 3.47 (s, 3H), 2.86-2.78 (m, 2H), 2.74-2.66 (m, 2H), 2.40 (s, 3H), 2.00 (quin, J = 7.6 Hz, 2H).
[0138] To a solution of 34 (720 mg, 2.39 mmol) in AcOH (15 mL) was added Fe (1.34 g, 23.95 mmol). The mixture was stirred at 60 °C for 3 h. The mixture filtered and concentrated to give a residue. The crude product was triturated with EA (5 mL) at 25 °C for 30 mins. Compound 35 (260 mg, 46.26% yield) was obtained as a yellow solid. ’H NMR: (400 MHz, DMSO- e) 5 11.43 - 11.02 (m, 1H), 8.45 (s, 1H), 3.16 (br t, J = 7.6 Hz, 2H), 2.82 (br t, J = 7.3 Hz, 2H), 2.12 (quin, J = 7.5 Hz, 2H).
[0139] To a solution 19 (492.54 mg, 1.53 mmol) and 35 (240 mg, 1.02 mmol) in dioxane (10 mL) was added XPhos-Pd-G2 (80.46 mg, 102.27 umol) under N2. The mixture was stirred at 80 °C for 12 h under N2 atmosphere. The mixture was concentrated to give the crude product. The crude product was triturated with EA at 25 °C for 30 mins. The mixture was filtered. The cake was collected and dried under high vacuum to give a residue. Compound 36 (0.1 g, 42.47% yield) was obtained as a brown solid.
[0140] To a solution of 36 (100 mg, 434.29 umol) in DCM (2 mL) was added SOCI2 (103.33 mg, 868.58 umol, 63.01 uL). The mixture was stirred at 60 °C for 3 h. The mixture was concentrated to give a residue, which was used in the next step without further purification. Compound 37 (80 mg, 74.07% yield) was obtained as a yellow solid.
[0141] To a solution of 22 (88.37 mg, 321.66 umol, HC1) and 37 (80 mg, 321.66 umol) in MeCN (2 mL) were added DIEA (207.86 mg, 1.61 mmol, 280.14 uL) and NaBr (99.29 mg, 964.99 umol, 31.03 uL). The mixture was stirred at 80 °C for 3 h. The mixture was poured into ice-water (10 mL). The mixture was extracted with EA (3 x 10 mL). The combined organic phase was washed with brine, dried over Na2SO4 and concentrated to give the crude product. The crude product was purified by reverse-phase HPLC (0.1% NH3*H2O) to obtain A3 (7.7 mg, 5.31% yield) as a white solid. 1 H NMR: (400 MHz, DMSO- 6) 5 10.95 (br s, 1H), 8.40 (q, J = 4.3 Hz, 1H), 8.33 (s, 1H), 7.84 (d, J = 7.9 Hz, 1H), 7.55 (dd, J = 8.3, 10.5 Hz, 1H), 3.65 (s, 2H), 3.20 - 3.10 (m, 6H), 2.83 (br t, J = 7.3 Hz, 2H), 2.77 (d, J = 4.8 Hz, 3H), 2.57 (br s, 4H), 2.50 - 2.50 (m, 3H), 2.12 (quin, J = 7.5 Hz, 2H). LCMS (ESI+): 451.1 [M+H]+, RT: 1.634 min.
[0142] Prep-HPLC method: column: Waters Xbridge BEH C18 100 x 30 mm x 10 um; mobile phase: [water (NH4HCO3)-CH3CN] ; B%: 30%-50%,8 min. LC/MS: The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in O.Olmin, Flow rate was 1.0 mL/min. Mobile phase A was 0.04% trifluoroacetic acid in water, Mobile phase B was 0.02% trifluoroacetic acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1 x 50 mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.
Example 4 Compound A4
Figure imgf000057_0001
[0143] To a solution of 23B (2 g, 8.42 mmol) in AcOH (20 mF) was added Fe (2.35 g,
42.12 mmol) at 25 °C. The mixture was stirred at 100 °C for 3 h. The mixture was filtered, and the filtrate was concentrated to give a residue and obtain 24B (1.3 g, 74.39% yield) as a brown solid, which was used for the next step directly without further purification.
[0144] To a solution of 24B (1.4 g, 6.75 mmol) in THF (14 mL) was added NaHMDS (I M, 13.50 mL) at 0 °C and the mixture was stirred at 0 °C for 0.5 h. (Boc)2O (1.77 g, 8.10 mmol, 1.86 mL) was added to the mixture at 25 °C and then stirred at 25 °C for 3 h. The mixture was poured into aq. NH4CI (50 mL) and extracted with EA (3 x 25 mL). The combined mixture was washed with brine, dried over Na2SO4 and concentrated to give a residue. The residue was purified by column chromatography (SiCL, PE:EA = 1:0 to 50:1) to give 25B (1 g, 48.18% yield) as a white solid.
[0145] To a solution of 25B (0.1 g, 0.325 mmol) and TMEDA (94.4 mg, 0.813 mmol) in THF (1.5 mL) was added LDA (2 M, 0.41 mL) at -60 °C under N2. The mixture was stirred at -10 °C for 2 h. N-(benzenesulfonyl)-N- fluoro-benzenesulfonamide (0.154 g, 0.488 mmol) were added to the mixture at -78 °C. The mixture was stirred at 0 °C for 1 h. 14 additional vials were set up as described above. All of the 15 reactions were poured into NH4CI (50 mL) at 0 °C. The mixture was stirred at 0 °C for 20 mins. The mixture was extracted with EA (3 x 25 mL). The combined organic phase was concentrated to give the crude product. The residue was purified by column chromatography (SiCL, PE:EA = 100:1 to 20:1) to give 26B (0.9 g, 85.03% yield) as a white solid. ’H NMR: (400 MHz, DMSO- 6) 5 9.41-9.23 (m, 1H), 8.57 (d, J = 8.3 Hz, 1H), 1.44 (s, 9H).
[0146] A mixture of 3 (464.64 mg, 1.84 mmol), 26B (600 mg, 1.84 mmol) and K3PO4 (782.41 mg, 3.69 mmol) in THF (24 mL) and H2O (6 mL) was degassed and purged with N2 (3x). Ditert-butyl (cyclopentyl) phosphane; dichloropalladium;iron (240.23 mg, 368.59 pmol) was added to the mixture under N2. The mixture was stirred at 60 °C for 3 h under N2 atmosphere. The mixture was partitioned between water (10 mL) and EA (10 mL). The organic phase was separated, washed with EA (3 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCL, PE:EA = 50:1 to 2:1) to give 27B (400 mg, 58.53% yield) as a yellow oil. ’H NMR: (400 MHz, DMSO- e) 5 9.15 (br s, 1H), 8.59 (d, J = 8.4 Hz, 1H), 3.53-3.46 (m, 3H), 2.84-2.78 (m, 2H), 2.76- 2.68 (m, 2H), 2.00-1.91 (m, 2H), 1.42 (s, 9H).
[0147] A mixture of 27B (400 mg, 1.08 mmol) in HCl/dioxane (5 mL) was stirred at 25 °C for 12 h under N2 atmosphere. The mixture was filtered, and the filter cake was dried under high vacuum to give 26A (200 mg, 77.69% yield) as a white solid, which was used for the next step directly without further purification.
[0148] A mixture of 26A (220 mg, 921.87 pmol), 4,4,5,5-tetramethyl-2-vinyl-l,3,2 - dioxaborolane (283.96 mg, 1.84 mmol, 312.73 pL) and K3PO4 (391.37 mg, 1.84 mmol) in THF (12 mL) and H2O (2 mL) was degassed and purged with N2 (3x). Ditert- butyl(cyclopentyl)phosphane;dichloropalladium;iron (60.08 mg, 92.19 pmol) was added to the mixture under N2. The mixture was stirred at 80 °C for 12 h under N2 atmosphere. The mixture was partitioned between water (10 mL) and EA (10 mL). The organic phase was separated, washed with ethyl acetate (3 x 10 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiCh, PE:EA = 50:1 to 1:1) to give 27C (130 mg, 61.25% yield) as a brown solid.
[0149] To a solution of 27C (80 mg, 347.47 pmol) in THF (2.5 mL) was added dipotassium;oxide(dioxo)osmium;dihydrate (1.28 mg, 3.47 pmol) followed by a solution of NalCL (222.96 mg, 1.04 mmol, 57.76 pL) in H2O (1 mL) dropwise at 20 °C. The reaction was quenched by adding water (5 mL). The resulting precipitate was collected by filtration, and the cake was dried in high vacuum to give 28C (80 mg, 99.15% yield) as a light-yellow solid, which was used for the next step without further purification.
[0150] To a solution of 28C (94.65 mg, 344.52 pmol, HC1) in DCE (1.5 mL) and DMSO (1.5 mL) was added TEA (104.58 mg, 1.03 mmol, 143.86 pL) followed by AcOH (82.76 mg, 1.38 mmol, 78.89 pL) and 4-fluoro-6-oxo-5, 7,8,9- tetrahydrocyclopenta[c][l,5]naphthyridine-3-carbaldehyde (80 mg, 344.52 pmol). After stirred at 30 °C for 1 h, NaBH(OAc)s (182.54 mg, 861.29 pmol) was added in portions. The mixture was stirred at 30 °C for 15 h. The mixture was diluted with water (5 mL), extracted with dichloromethane (3 x 1 mL), dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by prep-HPLC (column: Phenomenex luna C 18 100 x 40 mm x 3 um; mobile phase: [H2O (0.2% FA)-CH3CN]; gradient: 5% -40% B over 8.0 min) and lyophilized to give A4 (17.6 mg, 95% purity) as a white solid. ’H NMR: (400 MHz, DMSO- d6) 5 2.05-2.17 (m, 2 H) 2.59 (br s, 4 H) 2.76 (d, J=4.75 Hz, 3 H) 2.79-2.87 (m, 2 H) 3.16 (br s, 6 H) 3.73 (s, 2 H) 7.54 (dd, J=10.32, 8.32 Hz, 1 H) 7.83 (d, J=8.00 Hz, 1 H) 8.34-8.49 (m, 2 H). LCMS (ESI+): 455.2 [M+H]+, RT: 1.575 min. [0151] LC/MS (The gradient was 5% B in 0.40 min and 5-95% B in 2.60 min, hold on 95% B in 1.00 min, and then 95-5% B in O.Olmin, the flow rate was 1.0 ml/min. Mobile phase A was 0.04% Trifluoroacetic Acid in water, mobile phase B was 0.02% Trifluoroacetic Acid in acetonitrile. The column used for chromatography was a Kinetex C18 2.1 x 50 mm, 5 um. Detection methods are diode array (DAD), and evaporative light scattering detection (ELSD). MS mode was positive electrospray ionization. MS range was 100-1000.
Example 5
Additional Compounds
[0152] Additional compounds of Formula (I) can be prepared using similar materials and methods described herein, such as those described herein.
Figure imgf000060_0001
Figure imgf000061_0001
Figure imgf000062_0001
Figure imgf000063_0001
acceptable salts thereof).
Example A PARP Assay
FP binding assay (PARP1, PARP2)
[0153] The PARP1 and PARP 2 protein and the PARPi-FL were purchased from BPS Bioscience. The assay buffer was 50 mM Tris pH 8.0, 0.001% Triton X-100, 10 mM MgCh, 150 mM NaCl. The compounds were diluted into top point concentration in 384PP-plate and transferred serially into an Optiplate-384F plate. Compound (20 nF) or DMSO was added to assay plate and then 10 uL of 40 nM PARP1 or PARP2 (diluted using assay buffer) was added. The assay plate was centrifuged at 1000 rpm for 1 min and then incubated for 30 min at rt. 6 nM PARPi-FL (diluted using assay buffer) (10 uL) was added to the plate (final concentration of PARP1 and PARP2 was 20 nM, and PARPi-FL was 3 nM). After centrifuging at 1000 rpm for 1 min, the assay plate was incubated at rt 4 h. The plates were read using Envision with Excitation filter. The data analysis was done by calculating the inhibition rate using mP value using the following equation. Inhibition (%) = (l-mpC-mpL)/mpH-mpL X100%. Proliferation Assay (PARP inhibitors) in DLD-1 wt and DLD-1 BRCA2
[0154] DLD-1 -wt and DLD-1 mutant cells are cultured in RPMI 1640+10%FBS+l%PS. The cells are harvested into culture media for 2-3 days. The cells are diluted into culture media (density 2-3 x 106) and 40 uL of cell suspension (50 cells/well for DLD- 1 wt and 50 cells/well for DLD-1 BRCA (-/-). The plates are covered and spun at rt at 1000 rpm, for 1 minute and then transferred. The plates are placed into 37 °C 5% CO2 incubator overnight. Test compounds are dissolved at 10 mM DMSO stock solution and then 40 uL of stock solution is transferred to a 384 PP-plate. A 10-point dilution is carried out by transferring 10 uL compound into 30 pL DMSO by using TECAN (EV0200) liquid handler. The plates are spun at rt at 1000 rpm for 1 minute and then shaken on a plate shaker for 2 minutes. Forty nL of diluted compound is transferred into the cell plate by using a liquid handler. After 7 days of incubation, a CTG detection assay is performed. The CTG detection assay is carried out by removing the plates from the incubators and then equilibrated at rt for 15 minutes. The cellTiter Gio reagents are thawed and equilibrated at rt. CellTiter-Glo reagent (30 pL) is added into each well, and the plates are placed at rt for 30 minutes followed by reading on EnVision. The inhibition activity is calculated using the formula: % Inhibition = 100 x (LumHC - LumSample) / (LumHC -LumLC).
[0155] The results of the assays are provided in Table 2. In Table 2, ‘A’ indicates an IC50 of < 0.01 pM, ‘B’ indicates an IC50 of > 0.01 pM and < 0.10 pM, and ‘C’ indicates an IC50 of > 0.10 pM. As shown by the results in Table 2, compounds of Formula (I), including pharmaceutically acceptable salts thereof, are effective PARP1 inhibitors.
Table 2
Figure imgf000064_0001
[0156] The results of the assays are provided in Table 3. In Table 3, ‘A’ indicates an IC50 of < 0.1 pM, ‘B’ indicates an IC50 of > 0.1 pM and < 1.0 pM, and ‘C’ indicates an IC50 of > 1.0 pM. As shown by the results in Table 1, compounds of Formula (I), including pharmaceutically acceptable salts thereof, are effective PARP1 inhibitors. Table 3
Figure imgf000065_0001
[0157] Although the foregoing has been described in some detail by way of illustrations and examples for purposes of clarity and understanding, it will be understood by those of skill in the art that numerous and various modifications can be made without departing from the spirit of the present disclosure. Therefore, it should be clearly understood that the forms disclosed herein are illustrative only and are not intended to limit the scope of the present disclosure, but rather to also cover all modification and alternatives coming with the true scope and spirit of the present disclosure.

Claims

Figure imgf000066_0003
Figure imgf000066_0001
pharmaceutically acceptable salt of any of the foregoing. m 1, wherein the compound
Figure imgf000066_0002
pharmaceutically acceptable salt thereof.
Figure imgf000066_0004
65 m 1, wherein the compound is
Figure imgf000067_0001
pharmaceutically acceptable salt thereof.
6. A pharmaceutical composition comprising a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.
7. Use of an effective amount of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 6 in the manufacture of a medicament for treating a cancer.
8. The use of Claim 7, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, a myelodysplastic syndrome, a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma, or an anaplastic thyroid carcinoma.
9. Use of an effective amount of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 6 in the manufacture of a medicament for inhibiting PARP1.
10. A compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, for use in treating a cancer.
11. The compound of Claim 10, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, a myelodysplastic syndrome, a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma, or an anaplastic thyroid carcinoma.
12. A compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, for use in inhibiting PARP1.
13. A method for treating a cancer comprising administering an effective amount of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 6 to a subject in need thereof.
14. A method for treating a cancer comprising contacting a cancer cell with an effective amount of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 6 to a subject having the cancer.
15. The method of Claim 13 or 14, wherein the cancer is selected from the group consisting of a lung cancer, a pancreatic cancer, a colon cancer, a myeloid leukemia, a thyroid cancer, a myelodysplastic syndrome, a bladder carcinoma, an epidermal carcinoma, a melanoma, a breast cancer, a prostate cancer, a head and neck cancers, an ovarian cancer, a brain cancer, a cancer of mesenchymal origin, a sarcoma, a teratocarcinoma, a neuroblastoma, a kidney carcinoma, a hepatoma, non-Hodgkin's lymphoma, multiple myeloma, or an anaplastic thyroid carcinoma.
16. A method for inhibiting PARP1 comprising contacting a cell with an effective amount of a compound of any one of Claims 1-5, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of Claim 6, wherein the cell is a cancer cell.
67
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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115232129A (en) * 2022-08-18 2022-10-25 上海闻耐医药科技有限公司 PARP1 selective inhibitor and preparation method and application thereof
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof

Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6391887B1 (en) * 1998-02-12 2002-05-21 Schering Aktiengesellschaft 3,4-Dihydroquinoline derivatives as nitrogen monoxide synthase (NOS) inhibitors
US20210040084A1 (en) * 2019-07-19 2021-02-11 Astrazeneca Ab Chemical compounds
WO2022225934A1 (en) * 2021-04-19 2022-10-27 Xinthera, Inc. Parp1 inhibitors and uses thereof

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US6391887B1 (en) * 1998-02-12 2002-05-21 Schering Aktiengesellschaft 3,4-Dihydroquinoline derivatives as nitrogen monoxide synthase (NOS) inhibitors
US20210040084A1 (en) * 2019-07-19 2021-02-11 Astrazeneca Ab Chemical compounds
WO2022225934A1 (en) * 2021-04-19 2022-10-27 Xinthera, Inc. Parp1 inhibitors and uses thereof

Non-Patent Citations (1)

* Cited by examiner, † Cited by third party
Title
DATABASE PUBCHEM SUBSTANCE 5 August 2021 (2021-08-05), ANONYMOUS : "2589531-76-8", XP093078974, retrieved from PUBCHEM Database accession no. 442104925 *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US11802128B2 (en) 2021-10-01 2023-10-31 Xinthera, Inc. Azetidine and pyrrolidine PARP1 inhibitors and uses thereof
US11939329B2 (en) 2022-01-21 2024-03-26 Xinthera, Inc. PARP1 inhibitors and uses thereof
US11795173B1 (en) 2022-04-28 2023-10-24 Xinthera, Inc. Substituted pyridines as PARP1 inhibitors
CN115232129A (en) * 2022-08-18 2022-10-25 上海闻耐医药科技有限公司 PARP1 selective inhibitor and preparation method and application thereof
CN115232129B (en) * 2022-08-18 2023-12-01 上海闻耐医药科技有限公司 PARP1 selective inhibitor and preparation method and application thereof

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