WO2021236771A1 - Methods and compositions for targeting pd-l1 - Google Patents

Methods and compositions for targeting pd-l1 Download PDF

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Publication number
WO2021236771A1
WO2021236771A1 PCT/US2021/033159 US2021033159W WO2021236771A1 WO 2021236771 A1 WO2021236771 A1 WO 2021236771A1 US 2021033159 W US2021033159 W US 2021033159W WO 2021236771 A1 WO2021236771 A1 WO 2021236771A1
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Prior art keywords
compound
alkyl
nitrogen
ring
membered
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PCT/US2021/033159
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English (en)
French (fr)
Inventor
Tongfei Wu
Pierre Jean-Marie Bernard Raboisson
Antitsa Dimitrova Stoycheva
Francois GONZALVEZ
Jerome Deval
Cheng Liu
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Aligos Therapeutics Inc
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Aligos Therapeutics Inc
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Priority to KR1020227043982A priority Critical patent/KR20230030056A/ko
Priority to CN202180049412.2A priority patent/CN115835907A/zh
Priority to EP21808539.7A priority patent/EP4153567A4/en
Priority to JP2022571280A priority patent/JP2023527315A/ja
Priority to AU2021275118A priority patent/AU2021275118A1/en
Priority to CA3182131A priority patent/CA3182131A1/en
Publication of WO2021236771A1 publication Critical patent/WO2021236771A1/en
Anticipated expiration legal-status Critical
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    • A61P35/00—Antineoplastic agents
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    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
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Definitions

  • the present disclosure related to compounds that can be useful as inhibitors of PD-1, PD-Ll or the PD-1/PD-Ll interaction.
  • pharmaceutical compositions of compounds described herein and uses of or methods of using the compounds for the treatment of PD-L1 related diseases including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.
  • PD-L1 related diseases including but not limited to liver diseases, cancer, hepatocellular carcinoma, viral diseases, or hepatitis B.
  • BACKGROUND The programmed cell death 1 (PD-1) immune checkpoint expressed on the surface of activated CD4 + and CD8 + T cells controls an inhibitory mechanism to prevent autoimmunity.
  • PD-1 programmed death-ligand 1
  • PD-L1 programmed death-ligand 1
  • IL-2 effector cytokine production
  • TNF- ⁇ TNF- ⁇
  • IFN- ⁇ inhibitory receptors and immune checkpoints
  • High expression of PD- L1 is exhibited by many types of cancers to escape tumor immune surveillance and has been associated with poorer prognosis.
  • PD-1-mediated immunosuppression is also linked to some viral infections, such as hepatitis B.
  • Figure 1A shows the absolute configuation of the formate salt of intermediate 1-4b.
  • Figure 1B shows the ORTEP crystal structure of the formate salt of intermediate 1-4b.
  • SUMMARY Some embodiments disclosed herein relate to a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • 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 HBV and/or HDV infection that can include administering to a subject identified as suffering from the HBV and/or HDV infection an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of treating a HBV and/or HDV infection.
  • Some embodiments disclosed herein relate to a method of inhibiting replication of HBV and/or HDV that can include contacting a cell infected with the HBV and/or HDV with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • Other embodiments described herein relate to a compound, or a pharmaceutically acceptable salt thereof, as described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for the use of inhibiting the replication HBV and/or HDV.
  • HCC Hepatocellular carcinoma
  • Figure 1A shows the absolute configuation of the formate salt of intermediate 1-4b.
  • Figure 1B shows the ORTEP crystal structure of the formate salt of intermediate 1-4b.
  • DETAILED DESCRIPTION [0013] Hepatocellular carcinoma (HCC) is the most common form of liver cancer. HCC can be caused by a variety of conditions, such as alcohol consumption, cirrhosis, and viral infections that cause hepatitis, such as hepatitis B virus, hepatitis C virus, and hepatitis D virus. The inflammation, fibrosis, and cirrhosis linked with these conditions can induce malignancies in affected liver cells.
  • HCC has relatively poor prognosis, with a five-year survival rate of about 30%, depending on if full surgical resection of the tumor is possible.
  • surgical resection is used.
  • most HCC are identified at later stages because of difficulties in diagnosing.
  • the tumors are unresectable and most patients are given systemic therapies.
  • the current standard of care in front line are multi-kinase inhibitors (including, for example, sorafenib and/or lenvatinib).
  • HBV can be acute and/or chronic. Acute HBV infection can be either asymptomatic or present with symptomatic acute hepatitis.
  • HBV can be transmitted by blood, semen, and/or another body fluid. This can occur through direct blood-to-blood contact, unprotected sex, sharing of needles, and from an infected mother to her baby during the delivery process.
  • the HBV surface antigen (HBsAg) is most frequently used to screen for the presence of this infection.
  • Currently available medications do not cure HBV and/or HDV infection. Rather, the medications suppress replication of the virus.
  • the hepatitis D virus is a DNA virus, also in the Hepadnaviridae family of viruses.
  • HDV can propagate only in the presence of HBV.
  • the routes of transmission of HDV are similar to those for HBV.
  • Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or in addition to chronic hepatitis B or hepatitis B carrier state (superinfection). Both superinfection and coinfection with HDV results in more severe complications compared to infection with HBV alone. These complications include a greater likelihood of experiencing liver failure in acute infections and a rapid progression to liver cirrhosis, with an increased risk of developing liver cancer in chronic infections.
  • hepatitis D In combination with hepatitis B, hepatitis D has the highest fatality rate of all the hepatitis infections, at 20%. There is currently no cure or vaccine for hepatitis D.
  • PD-1 programmed cell death 1, or programmed death 1
  • PD-1 protein (NCBI accession number NP_005009.2) is expressed from the cluster of differentiation 279 (CD279) gene (NCBI accession number NG_012110.1) or mRNA transcript (NCBI accession number NM_005018.3).
  • CD279 cluster of differentiation 279 gene
  • CD279 is the human CD279 transcript or gene on chromosome 2.
  • PD-1 and CD279 are often nominally interchangeable when considering the nucleic acid (DNA or RNA) or corresponding translated protein, or the sequences thereof.
  • Programmed cell death-ligand 1, or programmed death-ligand 1 (PD-L1), also known as B7 homolog 1 (B7-H1) is 272 amino acid long type I transmembrane protein found as a surface marker on many different cell types.
  • PD-L1 is a major ligand of PD-1 and results in inhibition of T cell cytotoxicity and cytokine production.
  • Cancer cells such as HCC cells take advantage of this immune checkpoint by upregulating PD-L1 expression, resulting in dysfunctional anti-tumor immunity by proximal T cells.
  • Viruses also have been observed to modulate the PD-1/PD-L1 pathway to inhibit immune host response.
  • Hepatitis B virus has been shown to upregulate PD-L1 in infected hepatocytes, and PD-1 in associated T cells.
  • PD- L1 protein (NCBI accession number NP_054862.1) is expressed from the cluster of differentiation 274 (CD274) transcript (NCBI accession number NM_014143.4).
  • PD-L1 is the human PD-L1 protein
  • CD274 is the human CD274 transcript or gene on chromosome 9. It should be understood that a person with ordinary skill in the art would view the terms PD-L1 and CD274 as often nominally interchangeable when considering the nucleic acid (DNA or RNA) or corresponding translated protein, or the sequences thereof. Definitions [0020] 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.
  • the indicated “optionally substituted” or “substituted” group may be substituted with one or more group(s) 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, isocyanato, thiocyanato, nitro, azido, silyl
  • group(s) such as 1, 2 or 3 groups
  • C a to C b 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 “C1 to C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH 3 -, CH 3 CH 2 -, CH 3 CH 2 CH 2 -, (CH 3 ) 2 CH-, CH 3 CH 2 CH 2 CH 2 -, CH 3 CH 2 CH(CH 3 )- and (CH 3 ) 3 C-. If no “a” and “b” are designated with regard to an alkyl, alkenyl, alkynyl, cycloalkyl cycloalkenyl, aryl, heteroaryl or heterocyclyl group, the broadest range described in these definitions is to be assumed.
  • alkyl refers to a straight or branched hydrocarbon chain that comprises a fully saturated (no double or triple bonds) hydrocarbon group.
  • the alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated).
  • the alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms.
  • the alkyl group could also be a lower alkyl having 1 to 6 carbon atoms.
  • the alkyl group of the compounds may be designated as “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.
  • 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.
  • alkenyl group may be unsubstituted or substituted.
  • alkynyl refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds.
  • the length of an alkynyl can vary.
  • the alkynyl can be a C 2-4 alkynyl, C 2-6 alkynyl or C 2-8 alkynyl.
  • 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 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 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 C6-C10 aryl group, or a C6 aryl group.
  • 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.
  • heteroaryl group can contain 4 to 14 atoms in the ring(s), 5 to 10 atoms in the ring(s) or 5 to 6 atoms in the ring(s).
  • heteroaryl includes fused ring systems where two rings, such as at least one aryl ring and at least one heteroaryl ring, or at least two heteroaryl rings, share at least one chemical bond.
  • heteroaryl rings include, but are not limited to, furan, furazan, thiophene, benzothiophene, phthalazine, pyrrole, oxazole, benzoxazole, 1,2,3-oxadiazole, 1,2,4- oxadiazole, thiazole, 1,2,3-thiadiazole, 1,2,4-thiadiazole, benzothiazole, imidazole, benzimidazole, indole, indazole, pyrazole, benzopyrazole, isoxazole, benzoisoxazole, isothiazole, triazole, benzotriazole, thiadiazole, tetrazole, pyridine, pyridazine, pyrimidine, pyrazine, purine, pteridine, quinoline, isoquinoline, quinazoline, quinoxaline, cinnoline and triazine.
  • heteroaryl group may be substituted or unsubstituted.
  • 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 quaternized.
  • Heterocyclyl groups may be unsubstituted or substituted.
  • heterocyclyl groups include but are not limited to, 1,3-dioxin, 1,3-dioxane, 1,4-dioxane, 1,2-dioxolane, 1,3-dioxolane, 1,4-dioxolane, 1,3-oxathiane, 1,4-oxathiin, 1,3-oxathiolane, 1,3-dithiole, 1,3-dithiolane, 1,4-oxathiane, tetrahydro-1,4-thiazine, 2H-1,2-oxazine, maleimide, succinimide, barbituric acid, thiobarbituric acid, dioxopiperazine, hydantoin, dihydrouracil, trioxane, hexahydro-1,3,5- triazine, imidazoline, imidazolidine, isox
  • aryl(alkyl) refer 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.
  • 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.
  • 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 1,3-thiazinan-4-yl(methyl).
  • “Lower alkylene groups” are straight-chained -CH 2 - tethering groups, forming bonds to connect molecular fragments via their terminal carbon atoms.
  • 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.
  • alkoxys are methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, iso-butoxy, sec-butoxy, tert-butoxy, phenoxy and benzoxy.
  • an alkoxy can be –OR wherein R is an unsubstituted C 1-4 alkyl.
  • An alkoxy may be substituted or unsubstituted.
  • acyl refers to a hydrogen an alkyl, an alkenyl, an alkynyl, a cycloalkyl, a cycloalkenyl, 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).
  • haloalkyl may be substituted or unsubstituted.
  • haloalkoxy refers to a O-alkyl group in which one or more of the hydrogen atoms are replaced by a halogen (e.g., mono-haloalkoxy, di- haloalkoxy and tri- haloalkoxy).
  • a “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 “sulfonyl” group refers to an “SO 2 R” 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.
  • a “trihalomethanesulfonyl” group refers to an “X 3 CSO 2 -” group wherein each X is a halogen.
  • a “trihalomethanesulfonamido” group refers to an “X 3 CS(O) 2 N(R A )-” group wherein each X is a halogen, and R A is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • the term “amino” as used herein refers to a –NH 2 group.
  • the term “hydroxy” refers to a –OH group.
  • a “cyano” group refers to a “-CN” group.
  • the term “azido” as used herein refers to a –N 3 group.
  • An “isocyanato” group refers to a “-NCO” group.
  • a “thiocyanato” group refers to a “-CNS” group.
  • An “isothiocyanato” group refers to an “ -NCS” group.
  • a “mercapto” group refers to an “-SH” group.
  • S-sulfonamido refers to a “-SO 2 N(R A R B )” group in which R A and R B can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R A and R B 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 “RSO 2 N(R A )-” group in which R and R A can be independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclyl, aryl(alkyl), heteroaryl(alkyl) or heterocyclyl(alkyl).
  • R and R A 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.
  • An O-carbamyl may be substituted or unsubstituted.
  • R and R A 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 R A 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.
  • a C-amido may be substituted or unsubstituted.
  • R and R A 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.
  • 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 e.g. haloalkyl
  • substituents there may be one or more substituents present.
  • haloalkyl may include one or more of the same or different halogens.
  • C 1 -C 3 alkoxyphenyl may include one or more of the same or different alkoxy groups containing one, two or three atoms.
  • 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)).
  • pharmaceutically acceptable salt refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound.
  • the 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 (for example, ammonium or triethylammonium salt), an alkali metal salt, such as a lithium, 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, C 1 -C 7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine and lysine.
  • a salt such as an ammonium salt (for example, ammonium or triethylammonium salt), an alkali metal salt, such as a lithium, 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 dicyclo
  • 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.
  • 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.
  • Embodiment 1 A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure: wherein: R 1a is selected from the group consisting of: Ring A 1a , Ring A 2a , Ring A 3a and Ring A 4a are independently selected from the group consisting of: a monocyclic C 5-7 cycloalkyl substituted with R 3a1 ; a bicyclic C 6-12 cycloalkyl substituted with R 3a2 ; a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen- containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom
  • Embodiment 2 [0077] The compound of Embodiment 1, wherein R 1a is Embodiment 3 [0078] The compound of Embodiment 2, wherein Ring A 1a is a monocyclic C5-7 cycloalkyl substituted with R 3a1 .
  • Embodiment 4 [0079] The compound of Embodiment 2, wherein Ring A 1a is a bicyclic C 6-12 cycloalkyl substituted with R 3a2 .
  • Embodiment 5 The compound of Embodiment 2, wherein Ring A 1a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 6 [0081] The compound of Embodiment 2, wherein Ring A 1a is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 7 [0082] The compound of Embodiment 2, wherein Ring A 1a is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 8 [0083] The compound of any one of Embodiments 2-7, wherein X 1a is N.
  • Embodiment 9 [0084] The compound of any one of Embodiments 2-7, wherein X 1a is CR 4a1 .
  • Embodiment 10 [0085] The compound of any one of Embodiments 2-9, wherein X 2a is N.
  • Embodiment 11 [0086] The compound of any one of Embodiments 2-9, wherein X 2a is CR 4a1 .
  • Embodiment 12 [0087] The compound of any one of Embodiments 2-11, wherein X 3a is N.
  • Embodiment 13 [0088] The compound of any one of Embodiments 2-11, wherein X 3a is CR 4a1 .
  • Embodiment 14 [0089] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is hydrogen.
  • Embodiment 15 [0090] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is halogen.
  • Embodiment 16 [0091] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is cyano.
  • Embodiment 17 [0092] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is an unsubstituted C 1-4 alkyl.
  • Embodiment 18 [0093] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 19 [0094] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is an unsubstituted C 1-4 alkoxy, such as methoxy.
  • Embodiment 20 [0095] The compound of Embodiment 9, 11 or 13, wherein R 4a1 is an unsubstituted C 1-4 haloalkoxy. [0096] Examples of include, but are not limited to, the following:
  • Embodiment 21 [0097] The compound of Embodiment 1, wherein R 1a is Embodiment 22 [0098] The compound of Embodiment 21, wherein Ring A 2a is a monocyclic C 5-7 cycloalkyl substituted with R 3a1 .
  • Embodiment 23 [0099] The compound of Embodiment 21, wherein Ring A 2a is a bicyclic C 6-12 cycloalkyl substituted with R 3a2 .
  • Embodiment 24 [0100] The compound of Embodiment 21, wherein Ring A 2a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 25 [0101] The compound of Embodiment 21, wherein Ring A 2a is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 26 [0102] The compound of Embodiment 21, wherein Ring A 2a is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 27 [0103] The compound of any one of Embodiments 21-26, wherein X 4a is NR 4a2 .
  • Embodiment 28 [0104] The compound of Embodiment 27, wherein R 4a2 is hydrogen.
  • Embodiment 29 [0105] The compound of Embodiment 27, wherein R 4a2 is an unsubstituted C 1-4 alkyl.
  • Embodiment 30 [0106] The compound of Embodiment 27, wherein R 4a2 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 31 [0107] The compound of any one of Embodiments 21-26, wherein X 4a is O.
  • Embodiment 32 [0108] The compound of any one of Embodiments 21-26, wherein X 4a is S.
  • Non-limiting examples of include the following: wherein each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 33 [0110] The compound of Embodiment 1, wherein R 1a is Embodiment 34 [0111] The compound of Embodiment 33, wherein Ring A 3a is a monocyclic C5-7 cycloalkyl substituted with R 3a1 .
  • Embodiment 35 [0112] The compound of Embodiment 33, wherein Ring A 3a is a bicyclic C 6-12 cycloalkyl substituted with R 3a2 .
  • Embodiment 36 [0113] The compound of Embodiment 33, wherein Ring A 3a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 37 [0114] The compound of Embodiment 33, wherein Ring A 3a is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 38 [0115] The compound of Embodiment 33, wherein Ring A 3a is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 39 [0116] The compound of any one of Embodiments 33-38, wherein X 5a is N.
  • Embodiment 40 [0117] The compound of any one of Embodiments 33-38, wherein X 5a is CR 4a3 .
  • Embodiment 41 [0118] The compound of Embodiment 40, wherein R 4a3 is halogen.
  • Embodiment 42 [0119] The compound of Embodiment 40, wherein R 4a3 is cyano.
  • Embodiment 43 [0120] The compound of Embodiment 40, wherein R 4a3 is an unsubstituted C 1-4 alkyl.
  • Embodiment 44 [0121] The compound of Embodiment 40, wherein R 4a3 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 45 [0122] The compound of Embodiment 40, wherein R 4a3 is an unsubstituted C 1-4 alkoxy, such as methoxy.
  • Embodiment 46 [0123] The compound of Embodiment 40, wherein R 4a3 is an unsubstituted C 1-4 haloalkoxy. [0124] Exemplary groups include, but are not limited to, the following: wherein each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 47 [0125] The compound of Embodiment 1, wherein R 1a is .
  • Embodiment 48 [0126] The compound of Embodiment 47, wherein Ring A 4a is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 49 [0127] The compound of Embodiment 47, wherein Ring A 4a is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 50 [0128] The compound of Embodiment 47, wherein Ring A 4a is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 51 [0129] The compound of any one of Embodiments 47-50, wherein X 6a is N.
  • Embodiment 52 [0130] The compound of any one of Embodiments 47-50, wherein X 6a is CR 4a3 .
  • Embodiment 53 [0131] The compound of any one of Embodiments 47-52, wherein X 7a is N.
  • Embodiment 54 [0132] The compound of any one of Embodiments 47-52, wherein X 7a is CR 4a3 . [0133] Examples of include, but are not limited to, the following: wherein each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 55 [0134] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is -OH.
  • Embodiment 56 [0135] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is -N(R m )R n .
  • Embodiment 57 [0136] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is -C 1-4 alkyl- N(R m )R n .
  • Embodiment 58 [0137] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is -OC 2-4 alkyl- N(R m )R n .
  • Embodiment 59 [0138] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 60 [0139] The compound of Embodiment 59, wherein n1 is 1.
  • Embodiment 61 [0140] The compound of Embodiment 59, wherein n1 is 2.
  • Embodiment 62 [0141] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 63 [0142] The compound of Embodiment 62, wherein n2 is 1.
  • Embodiment 64 [0143] The compound of Embodiment 62, wherein n2 is 2.
  • Embodiment 65 [0144] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 66 [0145] The compound of Embodiment 65, wherein n3 is 1.
  • Embodiment 67 [0146] The compound of Embodiment 65, wherein n3 is 2.
  • Embodiment 68 [0147] The compound of any one of Embodiments 65-67, wherein m1 is 1.
  • Embodiment 69 [0148] The compound of any one of Embodiments 65-67, wherein m1 is 2.
  • Embodiment 70 The compound of any one of Embodiments 65-69, wherein R W is an unsubstituted –C 1- 4 alkyl.
  • Embodiment 72 [0150] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is Embodiment 73 [0151] The compound of Embodiment 72, wherein n4 is 1.
  • Embodiment 74 [0152] The compound of Embodiment 72, wherein n4 is 2.
  • Embodiment 75 [0153] The compound of any one of Embodiments 72-74, wherein m2 is 1.
  • Embodiment 76 [0154] The compound of any one of Embodiments 72-74, wherein m2 is 2.
  • Embodiment 77 [0155] The compound of any one of Embodiments 72-76, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 79 [0157] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 80 [0158] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 81 [0159] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is .
  • Embodiment 82 [0160] The compound of Embodiment 3, 22 or 34, wherein R 3a1 is Embodiment 83 [0161] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is -OH.
  • Embodiment 84 [0162] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is -N(R m )R n .
  • Embodiment 85 [0163] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is -C 1-4 alkyl- N(R m )R n .
  • Embodiment 86 [0164] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is -OC 2-4 alkyl- N(R m )R n .
  • Embodiment 87 [0165] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is .
  • Embodiment 88 [0166] The compound of Embodiment 87, wherein n1 is 1.
  • Embodiment 89 [0167] The compound of Embodiment 87, wherein n1 is 2.
  • Embodiment 90 [0168] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is .
  • Embodiment 91 [0169] The compound of Embodiment 90, wherein n2 is 1.
  • Embodiment 92 [0170] The compound of Embodiment 90, wherein n2 is 2.
  • Embodiment 93 [0171] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is .
  • Embodiment 94 [0172] The compound of Embodiment 93, wherein n3 is 1.
  • Embodiment 95 [0173] The compound of Embodiment 93, wherein n3 is 2.
  • Embodiment 96 [0174] The compound of any one of Embodiments 93-95, wherein m1 is 1.
  • Embodiment 97 [0175] The compound of any one of Embodiments 93-95, wherein m1 is 2.
  • Embodiment 98 [0176] The compound of any one of Embodiments 93-97, wherein R W is an unsubstituted –C 1-4 alkyl.
  • Embodiment 100 [0178] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is Embodiment 101 [0179] The compound of Embodiment 100, wherein n4 is 1. Embodiment 102 [0180] The compound of Embodiment 100, wherein n4 is 2. Embodiment 103 [0181] The compound of any one of Embodiments 100-102, wherein m2 is 1. Embodiment 104 [0182] The compound of any one of Embodiments 100-102, wherein m2 is 2.
  • Embodiment 105 [0183] The compound of any one of Embodiments 100-104, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 107 [0185] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is Embodiment 108 [0186] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is .
  • Embodiment 109 [0187] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is .
  • Embodiment 110 [0188] The compound of Embodiment 4, 23 or 35, wherein R 3a2 is Embodiment 111 [0189] The compound of Embodiment 5, 24, 36 or 48, wherein R 3a3 is –R x1 .
  • Embodiment 112 [0190] The compound of Embodiment 109, wherein –R x1 is Embodiment 113 [0191] The compound of Embodiment 112, wherein n5 is 1.
  • Embodiment 114 [0192] The compound of Embodiment 112, wherein n5 is 2.
  • Embodiment 115 [0193] The compound of Embodiment 112, wherein –R x1 is .
  • Embodiment 116 [0194] The compound of Embodiment 115, wherein n6 is 1.
  • Embodiment 117 [0195] The compound of Embodiment 115, wherein n6 is 2.
  • Embodiment 118 [0196] The compound of any one of Embodiments 115-117, wherein m3 is 1.
  • Embodiment 119 [0197] The compound of any one of Embodiments 115-117, wherein m3 is 2.
  • Embodiment 120 [0198] The compound of Embodiment 112, wherein –R x1 is Embodiment 121 [0199] The compound of Embodiment 120, wherein n7 is 1.
  • Embodiment 122 [0200] The compound of Embodiment 120, wherein n7 is 2.
  • Embodiment 123 [0201] The compound of any one of Embodiments 120-122, wherein m4 is 1.
  • Embodiment 124 [0202] The compound of any one of Embodiments 120-122, wherein m4 is 2.
  • Embodiment 125 [0203] The compound of Embodiment 112, wherein –R x1 is .
  • Embodiment 126 [0204] The compound of Embodiment 125, wherein n8 is 1.
  • Embodiment 127 [0205] The compound of Embodiment 125, wherein n8 is 2.
  • Embodiment 128 [0206] The compound of Embodiment 112, wherein –R x1 is Embodiment 129 [0207] The compound of Embodiment 112, wherein –R x1 is Embodiment 130 [0208] The compound of Embodiment 112, wherein –R x1 is .
  • Embodiment 135 [0213] The compound of Embodiment 6, 25, 37 or 49, wherein R 3a6 is –R x1 .
  • Embodiment 136 [0214] The compound of Embodiment 135, wherein –R x1 is Embodiment 137 [0215] The compound of Embodiment 136, wherein n5 is 1.
  • Embodiment 138 [0216] The compound of Embodiment 136, wherein n5 is 2.
  • Embodiment 139 [0217] The compound of Embodiment 135, wherein –R x1 is .
  • Embodiment 140 [0218] The compound of Embodiment 139, wherein n6 is 1.
  • Embodiment 141 [0219] The compound of Embodiment 139, wherein n6 is 2.
  • Embodiment 142 [0220] The compound of any one of Embodiments 139-141, wherein m3 is 1.
  • Embodiment 143 [0221] The compound of any one of Embodiments 139-141, wherein m3 is 2.
  • Embodiment 144 [0222] The compound of Embodiment 135, wherein –R x1 is Embodiment 145 [0223] The compound of Embodiment 144, wherein n7 is 1.
  • Embodiment 146 [0224] The compound of Embodiment 144, wherein n7 is 2.
  • Embodiment 147 [0225] The compound of any one of Embodiments 144-146, wherein m4 is 1.
  • Embodiment 148 [0226] The compound of any one of Embodiments 144-146, wherein m4 is 2.
  • Embodiment 149 [0227] The compound of Embodiment 135, wherein –R x1 is .
  • Embodiment 150 [0228] The compound of Embodiment 149, wherein n8 is 1.
  • Embodiment 151 [0229] The compound of Embodiment 149, wherein n8 is 2.
  • Embodiment 152 [0230] The compound of Embodiment 135, wherein –R x1 is Embodiment 153 [0231] The compound of Embodiment 135, wherein –R x1 is Embodiment 154 [0232] The compound of Embodiment 135, wherein –R x1 is .
  • substituents selected from the group consisting of –halogen, –C alkyl, –OH, –N(R m ) n 1 -4 R , –C 1- 4 alkoxy, –C
  • Embodiment 159 [0237] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is -OH.
  • Embodiment 160 [0238] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is -N(R m )R n .
  • Embodiment 161 [0239] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is -C 1-4 alkyl- N(R m )R n .
  • Embodiment 162 [0240] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is -OC 2-4 alkyl- N(R m )R n .
  • Embodiment 163 [0241] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is .
  • Embodiment 164 [0242] The compound of Embodiment 163, wherein n1 is 1.
  • Embodiment 165 [0243] The compound of Embodiment 163, wherein n1 is 2.
  • Embodiment 166 [0244] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is .
  • Embodiment 167 [0245] The compound of Embodiment 166, wherein n2 is 1.
  • Embodiment 168 [0246] The compound of Embodiment 166, wherein n2 is 2.
  • Embodiment 169 [0247] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is .
  • Embodiment 170 [0248] The compound of Embodiment 169, wherein n3 is 1.
  • Embodiment 171 [0249] The compound of Embodiment 169, wherein n3 is 2.
  • Embodiment 172 [0250] The compound of any one of Embodiments 169-171, wherein m1 is 1.
  • Embodiment 173 [0251] The compound of any one of Embodiments 169-171, wherein m1 is 2.
  • Embodiment 174 The compound of any one of Embodiments 169-173, wherein R W is an unsubstituted –C 1-4 alkyl.
  • Embodiment 176 [0254] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is Embodiment 177 [0255] The compound of Embodiment 176, wherein n4 is 1. Embodiment 178 [0256] The compound of Embodiment 176, wherein n4 is 2. Embodiment 179 [0257] The compound of any one of Embodiments 176-178, wherein m2 is 1. Embodiment 180 [0258] The compound of any one of Embodiments 176-178, wherein m2 is 2.
  • Embodiment 181 [0259] The compound of any one of Embodiments 176-180, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 183 [0261] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is .
  • Embodiment 184 [0262] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is Embodiment 185 [0263] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is Embodiment 186 [0264] The compound of Embodiment 7, 26, 38 or 50, wherein R 3a9 is Embodiment 187 [0265] The compound of Embodiment 3, 22 or 34, wherein the monocyclic C5-7 cycloalkyl substituted with R 3a1 is selected from the group consisting of: , and , wherein asterisks indicate the position of the fused bond.
  • Embodiment 188 The compound of Embodiment 4, 23 or 35, wherein the bicyclic C 6-12 cycloalkyl substituted with R 3a2 is wherein asterisks indicate the position of the fused bond.
  • Embodiment 189 [0267] The compound of Embodiment 5, 24, 36 or 48, wherein the 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is selected from the group consisting of: wherein asterisks indicate the position of the fused bond, and R 3a4 and R 3a5 are
  • Embodiment 190 [0268] The compound of Embodiment 6, 25, 37 or 49, wherein the 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3a6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3a7 or R 3a8 , and wherein R 3a8 is present, R 3a8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is selected from the group consisting of:
  • Embodiment 191 The compound of Embodiment 7, 26, 38 or 50, wherein the 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3a9 or R 3a10 ; wherein R 3a10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens is selected from the group consisting of: wherein asterisks indicate the position of the fused bond, and R 3a9 or R 3a10 is present.
  • Embodiment 192 [0270] The compound of Embodiment 5, 24, 36 or 48, wherein R 3a4 is –halogen.
  • Embodiment 195 [0273] The compound of Embodiment 5, 24, 36 or 48, wherein R 3a4 is –OH.
  • Embodiment 197 [0275] The compound of Embodiment 5, 24, 36 or 48, wherein R 3a4 is –N(R m )R n .
  • Embodiment 198 [0276] The compound of Embodiment 5, 24, 36 or 48, wherein R 3a4 is –C 1-4 alkyl(R m )R n .
  • Embodiment 206 [0284] The compound of Embodiment 6, 25, 37 or 49, wherein R 3a7 is –halogen.
  • Embodiment 209 [0287] The compound of Embodiment 6, 25, 37 or 49, wherein R 3a7 is –OH.
  • Embodiment 211 [0289] The compound of Embodiment 6, 25, 37 or 49, wherein R 3a7 is –N(R m )R n .
  • Embodiment 212 [0290] The compound of Embodiment 6, 25, 37 or 49, wherein R 3a7 is –C 1-4 alkyl(R m )R n .
  • Embodiment 222 [0300] The compound of any one of Embodiments 1-221, wherein R 1b is .
  • Embodiment 223 [0301] The compound of Embodiment 222, wherein Ring A 1b is a monocyclic C5- 7 cycloalkyl substituted with R 3b1 .
  • Embodiment 224 [0302] The compound of Embodiment 222, wherein Ring A 1b is a bicyclic C 6-12 cycloalkyl substituted with R 3b2 .
  • Embodiment 225 [0303] The compound of Embodiment 222, wherein Ring A 1b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 226 [0304] The compound of Embodiment 222, wherein Ring A 1b is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3b6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R 3b8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 227 [0305] The compound of Embodiment 222, wherein Ring A 1b is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3b9 or R 3b10 ; wherein R 3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 228 [0306] The compound of any one of Embodiments 222-227, wherein X 1b is N.
  • Embodiment 229 [0307] The compound of any one of Embodiments 222-227, wherein X 1b is CR 4b1 .
  • Embodiment 230 [0308] The compound of any one of Embodiments 222-229, wherein X 2b is N.
  • Embodiment 231 [0309] The compound of any one of Embodiments 222-229, wherein X 2b is CR 4b1 .
  • Embodiment 232 [0310] The compound of any one of Embodiments 222-231, wherein X 3b is N.
  • Embodiment 233 [0311] The compound of any one of Embodiments 222-231, wherein X 3b is CR 4b1 .
  • Embodiment 234 [0312] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is hydrogen.
  • Embodiment 235 [0313] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is halogen.
  • Embodiment 236 [0314] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is cyano.
  • Embodiment 237 [0315] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is an unsubstituted C 1-4 alkyl.
  • Embodiment 238 [0316] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 239 [0317] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is an unsubstituted C 1-4 alkoxy, such as methoxy.
  • Embodiment 240 [0318] The compound of Embodiment 229, 231 or 233, wherein R 4b1 is an unsubstituted C 1-4 haloalkoxy. [0319] Examples of include, but are not limited to, the following:
  • Embodiment 241 [0320] The compound of any one of Embodiments 1-221, wherein R 1b is .
  • Embodiment 242 [0321] The compound of Embodiment 241, wherein Ring A 2b is a monocyclic C 5- 7 cycloalkyl substituted with R 3b1 .
  • Embodiment 243 [0322] The compound of Embodiment 241, wherein Ring A 2b is a bicyclic C 6-12 cycloalkyl substituted with R 3b2 .
  • Embodiment 244 [0323] The compound of Embodiment 241, wherein Ring A 2b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 245 [0324] The compound of Embodiment 241, wherein Ring A 2b is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R3b6; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R ba8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 246 [0325] The compound of Embodiment 241, wherein Ring A 2b is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3b9 or R 3b10 ; wherein R 3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 247 [0326] The compound of any one of Embodiments 241-246, wherein X 4b is NR 4b2 .
  • Embodiment 248 [0327] The compound of Embodiment 247, wherein R 4b2 is hydrogen.
  • Embodiment 249 [0328] The compound of Embodiment 247, wherein R 4b2 is an unsubstituted C 1-4 alkyl.
  • Embodiment 250 [0329] The compound of Embodiment 247, wherein R 4b2 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 251 [0330] The compound of any one of Embodiments 241-250, wherein X 4b is O.
  • Embodiment 252 [0331] The compound of any one of Embodiments 241-250, wherein X 4b is S.
  • Embodiment 253 [0333] The compound of any one of Embodiments 1-221, wherein R 1b is .
  • Embodiment 254 [0334] The compound of Embodiment 253, wherein Ring A 3b is a monocyclic C 5- 7 cycloalkyl substituted with R 3b1 .
  • Embodiment 255 [0335] The compound of Embodiment 253, wherein Ring A 3b is a bicyclic C 6-12 cycloalkyl substituted with R 3b2 .
  • Embodiment 256 [0336] The compound of Embodiment 253, wherein Ring A 3b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 257 [0337] The compound of Embodiment 253, wherein Ring A 3b is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3b6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R 3b8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 258 [0338] The compound of Embodiment 253, wherein Ring A 3b is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R3b9 or R3b10; wherein R3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 259 [0339] The compound of any one of Embodiments 253-258, wherein X 5b is N.
  • Embodiment 260 [0340] The compound of any one of Embodiments 253-258, wherein X 5b is CR 4b3 .
  • Embodiment 261 [0341] The compound of Embodiment 260, wherein R 4b3 is halogen.
  • Embodiment 262 [0342] The compound of Embodiment 260, wherein R 4b3 is cyano.
  • Embodiment 263 [0343] The compound of Embodiment 260, wherein R 4b3 is an unsubstituted C 1-4 alkyl.
  • Embodiment 264 [0344] The compound of Embodiment 260, wherein R 4b3 is an unsubstituted C 1-4 haloalkyl.
  • Embodiment 265 [0345] The compound of Embodiment 260, wherein R 4b3 is an unsubstituted C 1-4 alkoxy, such as methoxy.
  • Embodiment 266 [0346] The compound of Embodiment 260, wherein R 4b3 is an unsubstituted C 1-4 haloalkoxy.
  • Exemplary groups include, but are not limited to, the following: wherein each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 267 [0348] The compound of any one of Embodiments 1-221, wherein R 1b is .
  • Embodiment 268 [0349] The compound of Embodiment 267, wherein Ring A 4b is a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl.
  • Embodiment 269 [0350] The compound of Embodiment 267, wherein Ring A 4b is a 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen- containing bicyclic heterocyclyl is optionally substituted with R 3b6 ; wherein a carbon of the 6- 12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R 3b8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl.
  • Embodiment 270 [0351] The compound of Embodiment 267, wherein Ring A 4b is a 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3b9 or R 3b10 ; wherein R 3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen-containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens.
  • Embodiment 271 [0352] The compound of any one of Embodiments 267-270, wherein X 6b is N.
  • Embodiment 272 [0353] The compound of any one of Embodiments 267-270, wherein X 6b is CR 4b3 .
  • Embodiment 273 [0354] The compound of any one of Embodiments 267-272, wherein X 7b is N.
  • Embodiment 274 [0355] The compound of any one of Embodiments 267-272, wherein X 7b is CR 4b3 .
  • Examples of include, but are not limited to, the following: wherein each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 275 [0357] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is -OH.
  • Embodiment 276 [0358] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is -N(R m )R n .
  • Embodiment 277 [0359] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is -C 1-4 alkyl- N(R m )R n .
  • Embodiment 278 [0360] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is -OC 2-4 alkyl-N(R m )R n .
  • Embodiment 279 [0361] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is Embodiment 280 [0362] The compound of Embodiment 279, wherein n1 is 1. Embodiment 281 [0363] The compound of Embodiment 279, wherein n1 is 2.
  • Embodiment 282 [0364] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is Embodiment 283 [0365] The compound of Embodiment 282, wherein n2 is 1.
  • Embodiment 284 [0366] The compound of Embodiment 282, wherein n2 is 2.
  • Embodiment 285 [0367] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is .
  • Embodiment 286 [0368] The compound of Embodiment 285, wherein n3 is 1.
  • Embodiment 287 [0369] The compound of Embodiment 285, wherein n3 is 2.
  • Embodiment 288 [0370] The compound of any one of Embodiments 285-287, wherein m1 is 1.
  • Embodiment 289 [0371] The compound of any one of Embodiments 285-287, wherein m1 is 2.
  • Embodiment 290 [0372] The compound of any one of Embodiments 285-289, wherein R W is an unsubstituted –C 1-4 alkyl.
  • Embodiment 292 [0374] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is Embodiment 293 [0375] The compound of Embodiment 292, wherein n4 is 1.
  • Embodiment 294 [0376] The compound of Embodiment 292, wherein n4 is 2.
  • Embodiment 295 [0377] The compound of any one of Embodiments 292-294, wherein m2 is 1.
  • Embodiment 296 [0378] The compound of any one of Embodiments 292-294, wherein m2 is 2.
  • Embodiment 297 [0379] The compound of any one of Embodiments 292-296, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 299 [0381] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is .
  • Embodiment 300 [0382] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is .
  • Embodiment 301 [0383] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is .
  • Embodiment 302 [0384] The compound of Embodiment 223, 242 or 254, wherein R 3b1 is Embodiment 303 [0385] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is -OH.
  • Embodiment 304 [0386] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is -N(R m )R n .
  • Embodiment 305 [0387] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is -C 1-4 alkyl- N(R m )R n .
  • Embodiment 306 [0388] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is -OC2-4 alkyl-N(R m )R n .
  • Embodiment 307 [0389] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 308 [0390] The compound of Embodiment 307, wherein n1 is 1.
  • Embodiment 309 [0391] The compound of Embodiment 307, wherein n1 is 2.
  • Embodiment 310 [0392] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 311 [0393] The compound of Embodiment 310, wherein n2 is 1.
  • Embodiment 312 [0394] The compound of Embodiment 310, wherein n2 is 2.
  • Embodiment 313 [0395] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 314 [0396] The compound of Embodiment 313, wherein n3 is 1.
  • Embodiment 315 [0397] The compound of Embodiment 313, wherein n3 is 2.
  • Embodiment 316 [0398] The compound of any one of Embodiments 313-315, wherein m1 is 1.
  • Embodiment 317 [0399] The compound of any one of Embodiments 313-315, wherein m1 is 2.
  • Embodiment 318 [0400] The compound of any one of Embodiments 313-317, wherein R W is an unsubstituted –C 1-4 alkyl.
  • Embodiment 320 [0402] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is Embodiment 321 [0403] The compound of Embodiment 320, wherein n4 is 1.
  • Embodiment 322 [0404] The compound of Embodiment 320, wherein n4 is 2.
  • Embodiment 323 [0405] The compound of any one of Embodiments 320-322, wherein m2 is 1.
  • Embodiment 324 [0406] The compound of any one of Embodiments 320-322, wherein m2 is 2.
  • Embodiment 325 [0407] The compound of any one of Embodiments 320-324, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 327 [0409] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 328 [0410] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 329 [0411] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is .
  • Embodiment 330 [0412] The compound of Embodiment 224, 243 or 255, wherein R 3b2 is Embodiment 331 [0413] The compound of Embodiment 225, 244, 256 or 268, wherein R 3b3 is –R x1 .
  • Embodiment 332 [0414] The compound of Embodiment 331, wherein –R x1 is Embodiment 333 [0415] The compound of Embodiment 332, wherein n5 is 1.
  • Embodiment 334 [0416] The compound of Embodiment 332, wherein n5 is 2.
  • Embodiment 335 [0417] The compound of Embodiment 331, wherein –R x1 is .
  • Embodiment 336 [0418] The compound of Embodiment 335, wherein n6 is 1.
  • Embodiment 337 [0419] The compound of Embodiment 335, wherein n6 is 2.
  • Embodiment 338 [0420] The compound of any one of Embodiments 335-337, wherein m3 is 1.
  • Embodiment 339 [0421] The compound of any one of Embodiments 335-337, wherein m3 is 2.
  • Embodiment 340 [0422] The compound of Embodiment 331, wherein –R x1 is Embodiment 341 [0423] The compound of Embodiment 340, wherein n7 is 1. Embodiment 342 [0424] The compound of Embodiment 340, wherein n7 is 2. Embodiment 343 [0425] The compound of any one of Embodiments 340-342, wherein m4 is 1. Embodiment 344 [0426] The compound of any one of Embodiments 340-342, wherein m4 is 2. Embodiment 345 [0427] The compound of Embodiment 331, wherein –R x1 is .
  • Embodiment 346 [0428] The compound of Embodiment 345, wherein n8 is 1. Embodiment 347 [0429] The compound of Embodiment 345, wherein n8 is 2. Embodiment 348 [0430] The compound of Embodiment 331, wherein –R x1 is Embodiment 349 [0431] The compound of Embodiment 331, wherein –R x1 is Embodiment 350 [0432] The compound of Embodiment 331, wherein –R x1 is .
  • substituents selected from the group consisting of –halogen, –C alkyl, – m n 1 -4 OH, –N(R )R , –C 1- 4 alkoxy,
  • Embodiment 355 [0437] The compound of Embodiment 226, 245, 257 or 269, wherein R 3b6 is –R x1 .
  • Embodiment 356 [0438] The compound of Embodiment 355, wherein –R x1 is Embodiment 357 [0439] The compound of Embodiment 356, wherein n5 is 1.
  • Embodiment 358 [0440] The compound of Embodiment 356, wherein n5 is 2.
  • Embodiment 359 [0441] The compound of Embodiment 355, wherein –R x1 is .
  • Embodiment 360 [0442] The compound of Embodiment 359, wherein n6 is 1.
  • Embodiment 361 [0443] The compound of Embodiment 359, wherein n6 is 2.
  • Embodiment 362 [0444] The compound of any one of Embodiments 359-361, wherein m3 is 1.
  • Embodiment 363 [0445] The compound of any one of Embodiments 359-361, wherein m3 is 2.
  • Embodiment 364 [0446] The compound of Embodiment 355, wherein –R x1 is Embodiment 365 [0447] The compound of Embodiment 364, wherein n7 is 1.
  • Embodiment 366 [0448] The compound of Embodiment 364, wherein n7 is 2.
  • Embodiment 367 [0449] The compound of any one of Embodiments 364-366, wherein m4 is 1.
  • Embodiment 368 [0450] The compound of any one of Embodiments 364-366, wherein m4 is 2.
  • Embodiment 369 [0451] The compound of Embodiment 355, wherein –R x1 is Embodiment 370 [0452] The compound of Embodiment 369, wherein n8 is 1.
  • Embodiment 371 [0453] The compound of Embodiment 369, wherein n8 is 2.
  • Embodiment 372 The compound of Embodiment 355, wherein –R x1 is Embodiment 373 [0455] The compound of Embodiment 355, wherein –R x1 is Embodiment 374 [0456] The compound of Embodiment 355, wherein –R x1 is .
  • Embodiment 379 [0461] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is -OH.
  • Embodiment 380 [0462] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is - N(R m )R n .
  • Embodiment 381 [0463] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is -C 1-4 alkyl-N(R m )R n .
  • Embodiment 382 [0464] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is -OC 2- 4 alkyl-N(R m )R n .
  • Embodiment 383 [0465] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 384 [0466] The compound of Embodiment 383, wherein n1 is 1.
  • Embodiment 385 [0467] The compound of Embodiment 383, wherein n1 is 2.
  • Embodiment 386 [0468] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 387 [0469] The compound of Embodiment 386, wherein n2 is 1.
  • Embodiment 388 [0470] The compound of Embodiment 386, wherein n2 is 2.
  • Embodiment 389 [0471] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 390 [0472] The compound of Embodiment 389, wherein n3 is 1.
  • Embodiment 391 [0473] The compound of Embodiment 389, wherein n3 is 2.
  • Embodiment 392 [0474] The compound of any one of Embodiments 389-391, wherein m1 is 1.
  • Embodiment 393 [0475] The compound of any one of Embodiments 389-391, wherein m1 is 2.
  • Embodiment 394 [0476] The compound of any one of Embodiments 389-393, wherein R W is an unsubstituted –C 1-4 alkyl.
  • Embodiment 396 [0478] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is Embodiment 397 [0479] The compound of Embodiment 396, wherein n4 is 1. Embodiment 398 [0480] The compound of Embodiment 396, wherein n4 is 2. Embodiment 399 [0481] The compound of any one of Embodiments 396-398, wherein m2 is 1. Embodiment 400 [0482] The compound of any one of Embodiments 396-398, wherein m2 is 2.
  • Embodiment 401 [0483] The compound of any one of Embodiments 396-400, wherein R W1 is an unsubstituted –C 1-4 alkyl.
  • Embodiment 403 [0485] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 404 [0486] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 405 [0487] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is .
  • Embodiment 406 [0488] The compound of Embodiment 227, 246, 258 or 270, wherein R 3b9 is Embodiment 407 [0489] The compound of Embodiment 223, 242 or 254, wherein the monocyclic C 5-7 cycloalkyl substituted with R 3b1 is selected from the group consisting of: , wherein asterisks indicate the position of the fused bond.
  • Embodiment 408 [0490] The compound of Embodiment 224, 243 or 255, wherein the bicyclic C 6-12 cycloalkyl substituted with R 3b2 is wherein asterisks indicate the position of the fused bond.
  • Embodiment 409 The compound of Embodiment 225, 244, 255 or 268, wherein the 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b3 , wherein a carbon of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3b4 or R 3b5 , and wherein when R 3b5 is present, R 3b5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is selected from the group consisting of: and wherein asterisks indicate the position of the fused bond, and R 3b4 and R 3b5 are each optionally present.
  • Embodiment 410 The compound of Embodiment 226, 245, 257 or 269, wherein the 6-12 membered nitrogen-containing bicyclic heterocyclyl, wherein a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b6 ; wherein a carbon of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is optionally substituted with R 3b7 or R 3b8 , and wherein R 3b8 is present, R 3b8 is attached at the carbon atom adjacent to a nitrogen of the 6-12 membered nitrogen-containing bicyclic heterocyclyl is selected from the group consisting of: wherein asterisks indicate the position of the fused bond, R 3b7 and R 3b8 are each optionally present, and each of shown rings can be further substituted, including replacing the hydrogen of the shown NH moiety.
  • Embodiment 411 [0493] The compound of Embodiment 227, 246, 258 or 270, wherein the 5-7 membered oxygen-containing monocyclic heterocyclyl substituted with R 3b9 or R 3b10 ; wherein R 3b10 is attached at a carbon atom adjacent to an oxygen of the 5-7 membered oxygen- containing monocyclic heterocyclyl, and the 5-7 membered oxygen-containing monocyclic heterocyclyl does not include any ring nitrogens is selected from the group consisting of: wherein asterisks indicate the position of the fused bond, and R 3b9 or R 3b10 is present.
  • Embodiment 412 [0494] The compound of Embodiment 225, 244, 256 or 268, wherein R 3b4 is – halogen.
  • Embodiment 415 [0497] The compound of Embodiment 225, 244, 256 or 268, wherein R 3b4 is –OH.
  • Embodiment 417 [0499] The compound of Embodiment 225, 244, 256 or 268, wherein R 3b4 is – N(R m )R n .
  • Embodiment 418 [0500] The compound of Embodiment 225, 244, 256 or 268, wherein R 3b4 is –C 1-4 alkyl(R m )R n .
  • Embodiment 426 [0508] The compound of Embodiment 226, 245, 257 or 269, wherein R 3b7 is – halogen.
  • Embodiment 429 [0511] The compound of Embodiment 226, 245, 257 or 269, wherein R 3b7 is –OH.
  • Embodiment 431 [0513] The compound of Embodiment 226, 245, 257 or 269, wherein R 3b7 is – N(R m )R n .
  • Embodiment 432 [0514] The compound of Embodiment 226, 245, 257 or 269, wherein R 3b7 is –C 1-4 alkyl(R m )R n .
  • Embodiment 442 [0524] The compound of any one of Embodiments 56-58, 72, 80-82, 84-86, 100, 108-110, 131-134, 155-158, 160-162, 176, 184-186, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 292, 300-302, 304-306, 320, 328-330, 351-354, 375-378, 380-328, 396, 404-406, 413, 414, 416-418, 424, 425, 427, 427, 430-432, 437 and 438, wherein R m is hydrogen.
  • Embodiment 443 The compound of any one of Embodiments 56-58, 72, 80-82, 84-86, 100, 108-110, 131-134, 155-158, 160-162, 176, 184-186, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 292, 300-302, 304-306, 320, 328-330, 351-354, 375-378, 380-328, 396, 404-406, 413, 414, 416-418, 424, 425, 427, 427, 430-432, 437 and 438, wherein R m is –R x2 .
  • Embodiment 444 [0526] The compound of Embodiment 443, wherein –R x2 is Embodiment 445 [0527] The compound of Embodiment 444, wherein n5 is 1. Embodiment 446 [0528] The compound of Embodiment 444, wherein n5 is 2. Embodiment 447 [0529] The compound of Embodiment 443, wherein –R x2 is .
  • Embodiment 448 [0530] The compound of Embodiment 447, wherein n6 is 1.
  • Embodiment 449 [0531] The compound of Embodiment 447, wherein n6 is 2.
  • Embodiment 450 [0532] The compound of any one of Embodiments 447-449, wherein m3 is 1.
  • Embodiment 451 [0533] The compound of any one of Embodiments 447-449, wherein m3 is 2.
  • Embodiment 452 [0534] The compound of Embodiment 443, wherein –R x2 is Embodiment 453 [0535] The compound of Embodiment 452, wherein n7 is 1.
  • Embodiment 454 [0536] The compound of Embodiment 452, wherein n7 is 2.
  • Embodiment 455 [0537] The compound of any one of Embodiments 452-454, wherein m4 is 1.
  • Embodiment 456 [0538] The compound of any one of Embodiments 452-454, wherein m4 is 2.
  • Embodiment 457 [0539] The compound of Embodiment 443, wherein –R x2 is .
  • Embodiment 458 [0540] The compound of Embodiment 457, wherein n7 is 1.
  • Embodiment 459 [0541] The compound of Embodiment 457, wherein n7 is 2.
  • Embodiment 460 [0542] The compound of Embodiment 443, wherein –R x2 is Embodiment 461 [0543] The compound of Embodiment 443, wherein –R x2 is Embodiment 462 [0544] The compound of Embodiment 443, wherein –R x2 is Embodiment 463 [0545] The compound of any one of Embodiments 56-58, 72, 80-82, 84-86, 100, 108-110, 131-134, 155-158, 160-162, 176, 184-186, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 292, 300-302, 304-306, 320, 328-330, 351-354, 375-378, 380-328, 396, 404-406, 413, 414, 416-418, 424, 425, 427, 427, 430-432, 437 and 438, wherein R m
  • Embodiment 466 The compound of any one of Embodiments 56-58, 72, 80-82, 84-86, 100, 108-110, 131-134, 155-158, 160-162, 176, 184-186, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 292, 300-302, 304-306, 320, 328-330, 351-354, 375-378, 380-328, 396, 404-406, 413, 414, 416-418, 424, 425, 427, 427, 430-432, 437 and 438, wherein R m is ––Het a1 .
  • Embodiment 470 The compound of any one of Embodiments 56-58, 84-86, 131-134, 155- 158, 160-162, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 304-306, 351-354, 375-378, 380-382, 413, 414, 416-418, 424, 425, 427, 428, 430-432, 437 and 438, wherein R n is ––Het a1 .
  • Embodiment 471 The compound of any one of Embodiments 56-58, 84-86, 131-134, 155- 158, 160-162, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 304-306, 351-354, 375-378, 380-382, 413, 414, 416-418, 424, 425, 427, 428, 430-432, 437 and 438, wherein R m and R n are taken together along with the atom to which R m and R n are attached to form an optionally substituted 4-7 monocyclic heterocyclic ring.
  • the optionally substituted 4-7 monocyclic heterocyclic ring contains an additional nitrogen, such that the optionally substituted 4-7 monocyclic heterocyclic ring contains 2 or 3 total ring nitrogens.
  • Embodiment 472 [0554] The compound of any one of Embodiments 56-58, 84-86, 131-134, 155- 158, 160-162, 193, 194, 196-198, 204, 205, 207, 208, 210-212, 217, 218, 304-306, 351-354, 375-378, 380-382, 413, 414, 416-418, 424, 425, 427, 428, 430-432, 437 and 438, wherein R m and R n are taken together along with the atom to which R m and R n are attached to form an optionally substituted 7-10 bicyclic heterocyclic ring.
  • the optionally substituted 7-10 bicyclic heterocyclic ring contains 1, 2 or 3 heteroatoms selected from O (oxygen) and S (sulfur) along with a further nitrogen, such that the optionally substituted 7-10 bicyclic heterocyclic ring contains 2 or 3 total ring nitrogens.
  • Embodiment 473 [0555] The compound of Embodiment 471 or 472, wherein the heterocyclic ring is unsubstituted.
  • Embodiment 474 [0556] The compound of Embodiment 471 or 472, wherein heterocyclic ring is substituted.
  • Embodiment 476 [0558] The compound of any one of Embodiments 471-474, wherein the heterocyclic ring is selected from the group consisting of , , .
  • Embodiment 477 The compound of any one of Embodiments 471-474, wherein the heterocyclic ring is selected from the group consisting of ,
  • Embodiment 478 [0560] The compound of Embodiment 134 466 or 470, wherein –Het a1 is an optionally substituted 5-, 6- or 7-membered monocyclic heteroaryl.
  • Embodiment 479 [0561] The compound of Embodiment 134 466 or 470, wherein –Het a1 is an optionally substituted 4-, 5-, 6- or 7-membered monocyclic heterocyclyl.
  • Embodiment 480 [0562] The compound of Embodiment 134 466 or 470, wherein –Het a1 is an optionally substituted fused 8-, 9-, 10- or 11-membered bicyclic heteroaryl.
  • Embodiment 481 [0563] The compound of Embodiment 134 466 or 470, wherein –Het a1 is an optionally substituted fused 8-, 9-, 10- or 11-membered heterocyclyl.
  • Embodiment 482 [0564] The compound of any one of Embodiments 1-481, wherein R 2a is hydrogen.
  • Embodiment 483 [0565] The compound of any one of Embodiments 1-481, wherein R 2a is halogen.
  • Embodiment 484 [0566] The compound of any one of Embodiments 1-483, wherein R 2b is hydrogen.
  • Embodiment 485 [0567] The compound of any one of Embodiments 1-483, wherein R 2b is halogen.
  • Embodiment 486 [0568] The compound of any one of Embodiments 1-485, wherein R 2c is hydrogen.
  • Embodiment 487 [0569] The compound of any one of Embodiments 1-485, wherein R 2c is halogen.
  • Embodiment 488 [0570] The compound of any one of Embodiments 1-487, wherein R 2d is hydrogen.
  • Embodiment 489 [0571] The compound of any one of Embodiments 1-487, wherein R 2d is halogen.
  • Embodiment 490 [0572] The compound of any one of Embodiments 1-487, wherein R 2d is cyano.
  • Embodiment 491 [0573] The compound of any one of Embodiments 1-487, wherein R 2d is –CH 3 .
  • Embodiment 492 [0574] The compound of any one of Embodiments 1-487, wherein R 2d is –CH 2 CH 3 .
  • Embodiment 493 [0575] The compound of any one of Embodiments 1-487, wherein R 2d is –CH 2 OH.
  • Embodiment 494 [0576] The compound of any one of Embodiments 1-487, wherein R 2d is –OCH 3 .
  • Embodiment 495 [0577] The compound of any one of Embodiments 1-487, wherein R 2d is –SCH 3 .
  • Embodiment 496 [0578] The compound of any one of Embodiments 1-495, wherein R 2e is hydrogen.
  • Embodiment 497 [0579] The compound of any one of Embodiments 1-495, wherein R 2e is halogen.
  • Embodiment 498 [0580] The compound of any one of Embodiments 1-497, wherein R 2f is hydrogen.
  • Embodiment 499 [0581] The compound of any one of Embodiments 1-497, wherein R 2f is halogen.
  • Embodiment 500 [0582] The compound of any one of Embodiments 1-497, wherein R 2f is cyano.
  • Embodiment 501 [0583] The compound of any one of Embodiments 1-497, wherein R 2f is –CH 3 .
  • Embodiment 502 [0584] The compound of any one of Embodiments 1-497, wherein R 2f is –CH 2 CH 3 .
  • Embodiment 503 [0585] The compound of any one of Embodiments 1-497, wherein R 2f is –CH 2 OH.
  • Embodiment 504 [0586] The compound of any one of Embodiments 1-497, wherein R 2f is –OCH 3 .
  • Embodiment 505 [0587] The compound of any one of Embodiments 1-497, wherein R 2f is –SCH 3 .
  • Embodiment 506 [0588] The compound of any one of Embodiments 1-505, wherein R 2g is hydrogen.
  • Embodiment 507 [0589] The compound of any one of Embodiments 1-505, wherein R 2g is halogen.
  • Embodiment 508 [0590] The compound of any one of Embodiments 1-507, wherein R 2h is hydrogen.
  • Embodiment 509 [0591] The compound of any one of Embodiments 1-507, wherein R 2h is halogen.
  • Embodiment 510 A compound of Formula (I), or a pharmaceutically acceptable salt thereof, having the structure: wherein: R 1a is selected from the group consisting of: Ring A 1a , Ring A 2a , Ring A 3a and Ring A 4a are independently selected from the group consisting of: a monocyclic C 5-7 cycloalkyl substituted with R 3a1 ; a bicyclic C 6-12 cycloalkyl substituted with R 3a2 ; a 5-7 membered nitrogen-containing monocyclic heterocyclyl, wherein a nitrogen of the 5-7 membered nitrogen-containing monocyclic heterocyclyl is optionally substituted with R 3a3 , wherein a carbon of the 5-7 membered nitrogen- containing monocyclic heterocyclyl is optionally substituted with R 3a4 or R 3a5 , and wherein when R 3a5 is present, R 3a5 is attached at a carbon atom adjacent to a nitrogen of the 5-7 membered nitrogen-containing monocyclic
  • a compound of Formula (I) can be selected from:
  • Embodiment 511 [0595] The compound of any one of Embodiments 1-510, wherein a compound of Formula (I), or a pharmaceutically acceptable salt thereof, cannot be or a pharmaceutically acceptable salt thereof.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof cannot be a compound, or a pharmaceutically acceptable salt thereof, provide in WO 2020/257549.
  • a compound of Formula (I), or a pharmaceutically acceptable salt thereof cannot be a compound, or a pharmaceutically acceptable salt thereof, provide in WO 2018/119263.
  • R 2d cannot be fluoro.
  • R 2f cannot be fluoro.
  • R 2d cannot be –CH 3 .
  • R 2f cannot be –CH 3 .
  • Ring A 1a , A 2a , A 3a and/or A 4a cannot be a 5-membered oxygen- containing monocyclic heterocyclyl, such as wherein asterisks indicate the position of the fused bond.
  • Ring A 1b , A 2b , A 3b and/or A 4b cannot be a 5-membered oxygen-containing monocyclic heterocyclyl**, such as a nd/or wherein asterisks indicate the position of the fused bond.
  • R 1a cannot be such as wherein Ring A 1a is a 5-membered oxygen-containing monocyclic heterocyclyl (for example, and/or wherein asterisks indicate the position of the fused bond).
  • R 1b cannot be such as 1b wherein Ring A is a 5- membered oxygen-containing monocyclic heterocyclyl (for example, and/or wherein asterisks indicate the position of the fused bond).
  • R 1a cannot be inclu 1b ding .
  • R cannot be for example, Methods for the Preparation [0596] In this section, as in all other sections unless the context indicates otherwise, references to Formula (I), along with pharmaceutical acceptable salts thereof, include all other sub-groups and examples thereof as provided herein. The general preparations of some representative examples of compounds of Formula (I) are described herein, and are generally prepared from starting materials which are either commercially available or prepared by standard synthetic processes used by those skilled in the art.
  • R 1a -LG is defined as Br or Cl connected to the 5 or 6 aromatic rings of R 1a shown in above scheme. All other variables shown in General Scheme 1 are as provided herein.
  • the following reaction conditions can be used in each of the indicates reactions: (1) In the presence of suitable catalyst, such as bis(triphenylphosphine)palladium(II) dichloride, in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example K 3 PO 4 ) at a suitable temperature, such as approximately 90 °C; (2) In the presence of suitable base, such as DIPEA, in a suitable solvent, such as DCM, at a suitable temperature, for example, approximately 20 °C; (3) In the presence of suitable catalyst, such as for example, bis(triphenylphosphine)-palladium(II) dichloride, in a suitable solvent, such as1,4-dioxane, with a suitable base (for example, K
  • R 1a -LG is defined as Br or Cl connected to the 5 or 6 aromatic rings of R 1a shown in above scheme. All other variables shown in General Scheme 2 are as provided herein.
  • the following reaction conditions can be used in each of the indicates reactions: (1) In the presence of suitable catalyst, such as bis(triphenylphosphine)palladium(II) dichloride, in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example, K3PO4) at a suitable temperature (for example, approximately 90 °C); (2) In the presence of suitable base (for example, DIPEA) in a suitable solvent, such as DCM, at a suitable temperature, such as approximately 20 °C; (3) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent, such as 1,4-dioxane, with a suitable base (for example KOAc) at
  • reaction conditions can be used in each of the indicates reactions: (1) In the presence of suitable catalyst, such as bis(triphenylphosphine)palladium(II) dichloride, in a suitable solvent (for example,1,4- dioxane) with a suitable base, such as K 2 CO 3 , at a suitable temperature (for example approximately 90 °C); (2) In the presence of O 2 ,with suitable catalyst (for example, copper (II) acetate hydrate) in a suitable solvent (for example, DCM0 with a suitable base, such as pyridine, at a suitable temperature, such as approximately 20 °C; and (3) In the presence of appropriate reductive reagent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent (for example, DCM or MeOH) at a suitable temperature, such as approximately 20 °C.
  • suitable solvent for example,1,4- dioxane
  • suitable base such as K 2 CO 3
  • suitable temperature for example approximately 90 °C
  • reaction conditions can be used in each of the indicates reactions: (1) In the presence of suitable catalyst (for example, bis(triphenylphosphine)palladium(II) dichloride) in a suitable solvent (for example, 1,4- dioxane) with a suitable base, such as K 2 CO 3 , at a suitable temperature, such as approximately 90 °C; (2) In the presence of suitable acid, such as TFA or HCl, in a suitable solvent (for example, DCM or dioxane) at a suitable temperature, such as approximately 20 °C; (3) Different sets of reaction conditions may be used based on the coupling reagents for introducing R 3a3 : (3a) When the coupling reagent contains an aldehyde or a ketone as reactive group - in the presence of appropriate reductive reagent, such as sodium cyanoborohydride or sodium triacetoxyborohydride, in a suitable solvent (for example DCM or MeOH) at
  • reaction work-up refers to the series of manipulations required to isolate and purify the product(s) of a chemical reaction such as for example quenching, column chromatography, extraction).
  • heating the reaction mixture under stirring may enhance the reaction outcome. In some reactions microwave heating may be used instead of conventional heating to shorten the overall reaction time.
  • another sequence of the chemical reactions shown in the schemes herein may also provide a compound of Formula (I), or a pharmaceutically acceptable salt thereof.
  • intermediates and final compounds shown in the schemes herein may be further functionalized according to methods well-known by the person skilled in the art.
  • a primary or secondary amine group may be reductively alkylated by reaction with an aldehyde or a ketone in the presence of a suitable reducing reagent (for example, sodium triacetoxyborohydride (NaBH(AcO) 3 ) together with a suitable solvent (such as, DCM) at a suitable temperature (for example, room temperature); or alternatively in the presence of NaBH 3 CN together with a suitable solvent (for example, MeOH) at a suitable temperature, such as between room temperature and 50 °C.
  • a suitable reducing reagent for example, sodium triacetoxyborohydride (NaBH(AcO) 3
  • a suitable solvent such as, DCM
  • a suitable solvent for example, MeOH
  • compositions that comprise, consist essentially of, or consist of an effective amount of a compound described herein (such as a compound of Formula (I), or a pharmaceutically acceptable salt thereof) and a pharmaceutically acceptable carrier, excipient, or combination thereof.
  • a pharmaceutical composition described herein is suitable for human and/or veterinary applications.
  • an effective amount or “effective dose” is used to indicate an amount of an active compound, or pharmaceutical agent, that 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.
  • pharmaceutically acceptable salts includes relatively non-toxic, inorganic and organic acid, or base addition salts of compositions, including without limitation, analgesic agents, therapeutic agents, other materials, and the like.
  • Examples of pharmaceutically acceptable salts include those derived from mineral acids, such as hydrochloric acid and sulfuric acid, and those derived from organic acids, such as ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, and the like.
  • suitable inorganic bases for the formation of salts include the hydroxides, carbonates, and bicarbonates of ammonia, sodium, lithium, potassium, calcium, magnesium, aluminum, zinc, and the like. Salts may also be formed with suitable organic bases, including those that are non-toxic and strong enough to form such salts.
  • the class of such organic bases may include but are not limited to mono-, di-, and trialkylamines, including methylamine, dimethylamine, and triethylamine; mono-, di-, or trihydroxyalkylamines including mono-, di- , and triethanolamine; amino acids, including glycine, arginine and lysine; guanidine; N- methylglucosamine; N-methylglucamine; L-glutamine; N-methylpiperazine; morpholine; ethylenediamine; N-benzylphenethylamine; trihydroxymethyl aminoethane.
  • composition as used interchangeably herein are equivalent terms referring to a composition of matter for administration to a subject.
  • pharmaceutically acceptable means compatible with the treatment of a subject, and in particular, a human.
  • agent refers to an active agent that has biological activity and may be used in a therapy.
  • an “agent” can be synonymous with “at least one agent,” “compound,” or “at least one compound,” and can refer to any form of the agent, such as a derivative, analog, salt or a prodrug thereof.
  • the agent can be present in various forms, components of molecular complexes, and pharmaceutically acceptable salts (e.g., hydrochlorides, hydrobromides, sulfates, phosphates, nitrates, borates, acetates, maleates, tartrates, and salicylates).
  • the term “agent” can also refer to any pharmaceutical molecules or compounds, therapeutic molecules or compounds, matrix forming molecules or compounds, polymers, synthetic molecules and compounds, natural molecules and compounds, and any combination thereof.
  • subject as used herein has its ordinary meaning as understood in light of the specification and refers to an animal that is the object of treatment, inhibition, or amelioration, observation or experiment.
  • Animal has its ordinary meaning as understood in light of the specification and includes cold- and warm-blooded vertebrates and/or invertebrates such as fish, shellfish, or reptiles and, in particular, mammals.
  • “Mammal” has its ordinary meaning as understood in light of the specification, and includes but is not limited to mice, rats, rabbits, guinea pigs, dogs, cats, sheep, goats, cows, horses, primates, such as humans, monkeys, chimpanzees, or apes. In some embodiments, the subject is human. [0617] 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, enteral, oral, rectal, topical, sublingual, buccal, intraaural, epidural, epicutaneous, aerosol, parenteral delivery, including intramuscular, subcutaneous, intra-arterial, intravenous, intraportal, intra-articular, intradermal, peritoneal, intramedullary injections, intrathecal, direct intraventricular, intraperitoneal, intranasal or intraocular injections.
  • Pharmaceutical compositions will generally be tailored to the specific intended route of administration.
  • compositions can also be administered to isolated cells from a patient or individual, such as T cells, Natural Killer cells, B cells, macrophages, lymphocytes, stem cells, bone marrow cells, or hematopoietic stem cells.
  • the pharmaceutical compound can also be administered in a local rather than systemic manner, for example, via injection of the compound directly into an organ, tissue, cancer, tumor or infected area, often in a depot or sustained release formulation.
  • 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, tissue, cancer, tumor, or infected area.
  • 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.
  • a “carrier” refers to a compound, particle, solid, semi-solid, liquid, or diluent that facilitates the passage, delivery and/or incorporation of a compound to cells, tissues and/or bodily organs.
  • a lipid nanoparticle is a type of carrier that can encapsulate a compound, or a pharmaceutically acceptable salt thereof, as described herein to thereby protect the compound, or a pharmaceutically acceptable salt thereof, as described herein from degradation during passage through the bloodstream and/or to facilitate delivery to a desired organ, such as to the liver.
  • 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.
  • diluent in the art is a buffered aqueous solution such as, without limitation, phosphate buffered saline that mimics the composition of human blood.
  • excipient has its ordinary meaning as understood in light of the specification, and refers to inert substances, compounds, or materials added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition.
  • Excipients with desirable properties include but are not limited to preservatives, adjuvants, stabilizers, solvents, buffers, diluents, solubilizing agents, detergents, surfactants, chelating agents, antioxidants, alcohols, ketones, aldehydes, ethylenediaminetetraacetic acid (EDTA), citric acid, salts, sodium chloride, sodium bicarbonate, sodium phosphate, sodium borate, sodium citrate, potassium chloride, potassium phosphate, magnesium sulfate sugars, dextrose, fructose, mannose, lactose, galactose, sucrose, sorbitol, cellulose, serum, amino acids, polysorbate 20, polysorbate 80, sodium deoxycholate, sodium taurodeoxycholate, magnesium stearate, octylphenol ethoxylate, benzethonium chloride, thimerosal, gelatin, esters, ethers, 2-phenoxyethanol, urea, or vitamins
  • the amount of the excipient may be found in a pharmaceutical composition at a percentage of 0%, 0.1%, 0.2%, 0.3%, 0.4%, 0.5%, 0.6%, 0.7%, 0.8%, 0.9%, 1%, 2%, 3%, 4%, 5%, 6%, 7%, 8%, 9%, 10%, 20%, 30%, 40%, 50%, 60%, 70%, 80%, 90%, 95%, 100% w/w or any percentage by weight in a range defined by any two of the aforementioned numbers.
  • adjuvant refers to a substance, compound, or material that stimulates the immune response and increase the efficacy of protective immunity and is administered in conjunction with an immunogenic antigen, epitope, or composition.
  • Adjuvants serve to improve immune responses by enabling a continual release of antigen, up- regulation of cytokines and chemokines, cellular recruitment at the site of administration, increased antigen uptake and presentation in antigen presenting cells, or activation of antigen presenting cells and inflammasomes.
  • adjuvants include but are not limited to alum, aluminum salts, aluminum sulfate, aluminum hydroxide, aluminum phosphate, calcium phosphate hydroxide, potassium aluminum sulfate, oils, mineral oil, paraffin oil, oil-in-water emulsions, detergents, MF59®, squalene, AS03, ⁇ -tocopherol, polysorbate 80, AS04, monophosphoryl lipid A, virosomes, nucleic acids, polyinosinic:polycytidylic acid, saponins, QS-21, proteins, flagellin, cytokines, chemokines, IL-1, IL-2, IL-12, IL-15, IL-21, imidazoquinolines, CpG oligonucleotides, lipids, phospholipids, dioleoyl phosphatidylcholine (DOPC), trehalose dimycolate, peptidoglycans, bacterial extracts, lip
  • purity of any given substance, compound, or material as used herein refers to the actual abundance of the substance, compound, or material relative to the expected abundance.
  • the substance, compound, or material may be at least 80, 85, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99, or 100% pure, including all decimals in between.
  • Purity may be affected by unwanted impurities, including but not limited to side products, isomers, enantiomers, degradation products, solvent, carrier, vehicle, or contaminants, or any combination thereof.
  • Purity can be measured technologies including but not limited to chromatography, liquid chromatography, gas chromatography, spectroscopy, UV-visible spectrometry, infrared spectrometry, mass spectrometry, nuclear magnetic resonance, gravimetry, or titration, or any combination thereof.
  • Methods of Use [0625] Some embodiments disclosed herein related to selecting a subject or patient in need. In some embodiments, a patient is selected who is in need of treatment, inhibition, amelioration, prevention or slowing of diseases or conditions associated with PD-L1 dysregulation. In some embodiments, such diseases or conditions associated with PD-L1 dysregulation may include, for example, cancer, HCC, viral infections, or HBV.
  • a subject can be selected who has previously been treated for the disease or disorder described herein. In some embodiments, a subject can be selected who has previously been treated for being at risk for the disease or disorder described herein. In some embodiments, a subject can be selected who has developed a recurrence of the disease or disorder described herein. In some embodiments, a subject can be selected who has developed resistance to therapies for the disease or disorder described herein. In some embodiments, a subject can be selected who may have any combination of the aforementioned selection criteria. [0626] Compounds, and pharmaceutically acceptable salts thereof, disclosed herein can be evaluated for efficacy and toxicity using known methods.
  • a non-limiting list of potential advantages of a compound, or a pharmaceutically acceptable salt thereof, described herein include improved stability, increased safety profile, increased efficacy, increased binding to the target, increased specificity for the target (for example, a cancer cell or virally infected cell).
  • the terms “treating,” “treatment,” “therapeutic,” or “therapy” as used herein has its ordinary meaning as understood in light of the specification, and do not necessarily mean total cure or abolition of the disease or condition.
  • the term “treating” or “treatment” as used herein (and as well understood in the art) also means an approach for obtaining beneficial or desired results in a subject's condition, including clinical results.
  • Beneficial or desired clinical results can include, but are not limited to, alleviation or amelioration of one or more symptoms or conditions, diminishment of the extent of a disease, stabilizing (i.e., not worsening) the state of disease, prevention of a disease's transmission or spread, delaying or slowing of disease progression, amelioration or palliation of the disease state, diminishment of the reoccurrence of disease, and remission, whether partial or total and whether detectable or undetectable.
  • Treating” and “treatment” as used herein also include prophylactic treatment. Treatment methods comprise administering to a subject a therapeutically effective amount of an active agent. The administering step may consist of a single administration or may comprise a series of administrations.
  • compositions are administered to the subject in an amount and for a duration sufficient to treat the subject.
  • the length of the treatment period depends on a variety of factors, such as the severity of the condition, the age and genetic profile of the subject, the concentration of active agent, the activity of the compositions used in the treatment, or a combination thereof.
  • the effective dosage of an agent used for the treatment or prophylaxis may increase or decrease over the course of a particular treatment or prophylaxis regime. Changes in dosage may result and become apparent by standard diagnostic assays known in the art. In some instances, chronic administration may be required.
  • Some embodiments described herein relate to a method of treating, inhibiting, ameliorating, preventing, or slowing the disease or disorder described herein.
  • the methods include administering to a subject identified as suffering from the disease or disorder described herein an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • Other embodiments described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for treating, inhibiting ameliorating, preventing, or slowing the disease or disorder described herein.
  • Still other embodiments described herein relate to the use of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for treating, inhibiting ameliorating, preventing, or slowing the disease or disorder described herein.
  • Some embodiments described herein relate to a method for inhibiting replication of a cancer cell or a virus that can include contacting the cell or virus or administering to a subject identified as suffering from a cancer or a viral infection with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein.
  • inventions described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting replication of a cancer cell or virus. Still other embodiments described herein relate to an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein for inhibiting replication of a cancer cell or virus.
  • the cancer cell is an HCC cell.
  • the virus is hepatitis B.
  • Some embodiments described herein relate to a method for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus, that can include administering to a subject identified as suffering from a disease wherein inhibiting cell proliferation is desirable with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein.
  • inventions described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus. Still other embodiments described herein relate to an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein for inhibiting cell proliferation, such as inhibiting cell proliferation of a cancer cell or cell infected with a virus.
  • the cancer cell is an HCC cell.
  • the cell infected with a virus is infected with hepatitis B virus.
  • Some embodiments described herein relate to a method of inducing apoptosis of a cell (for example, a cancer cell or cell infected with a virus) that can include contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, as described herein.
  • inventions described herein relate to using an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein in the manufacture of a medicament for inducing apoptosis of a cell, such as a cancer cell or cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for inducing apoptosis of a cell, such as a cancer cell or cell infected with a virus.
  • the cancer cell is an HCC cell.
  • the cell infected with a virus is infected with hepatitis B virus.
  • Some embodiments described herein relate to a method of decreasing the viability of a cell (for example, a cancer cell or cell infected with a virus) that can include contacting the cell with an effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein, or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein.
  • inventions described herein relate to using a compound, or a pharmaceutically acceptable salt thereof, as described herein in the manufacture of a medicament for decreasing the viability of a cell, such as a cancer cell or cell infected with a virus. Still other embodiments described herein relate to the use of an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein or a pharmaceutical composition that includes an effective amount of a compound, or a pharmaceutically acceptable salt thereof, as described herein for decreasing the viability of a cell, such as a cancer cell or cell infected with a virus.
  • the cancer cell is an HCC cell.
  • the cell infected with a virus is infected with hepatitis B virus.
  • an effective therapeutic daily amount would be from about 0.005 mg /kg to 50 mg/kg. in particular 0.01 mg/kg to 50 mg/kg body weight, more in particular from 0.01 mg/kg to 25 mg/kg body weight, preferably from about 0.01 mg/kg to about 15 mg/kg, more preferably from about 0.01 mg/kg to about 10 mg/kg, even more preferably from about 0.01 mg/kg to about 1 mg/kg, most preferably from about 0.05 mg/kg to about 1 mg/kg body weight.
  • the effective amount of a compound, or a pharmaceutically acceptable salt thereof, described herein is dosed more than one time.
  • the compound, or a pharmaceutically acceptable salt thereof, described herein can be administered every 1, 2, 3, 4, 5, 6, 7 days, or 1, 2, 3, 4 weeks, or 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12 months, or 1, 2, 3, 4, 5 years, or any period or combination thereof within the range defined by any two aforementioned times.
  • at least one loading dose and at least one maintenance dose is administered to the subject, where the at least one loading dose is a higher dose of a compound, or a pharmaceutically acceptable salt thereof, described herein than the at least one maintenance dose.
  • the term “combination therapy” is intended to define therapies which comprise the use of a combination of two or more pharmaceutical compounds/agents or therapies.
  • references to “combination therapy”, “combinations” and the use of compounds/agents “in combination” in this application may refer to compounds/agents that are administered as part of the same overall treatment regimen.
  • the dosage or timing of each of the two or more compounds/agents may differ: each may be administered at the same time or at different times.
  • the compounds/agents of the combination may be administered sequentially (e.g. before or after) or simultaneously, either in the same pharmaceutical formulation (i.e. together), or in different pharmaceutical formulations (i.e. separately).
  • Each of the two or more compounds/agents in a combination therapy may also differ with respect to the route of administration.
  • inhibitor refers to an enzyme inhibitor or receptor inhibitor which is a molecule that binds to an enzyme or receptor, and decreases and/or blocks its activity.
  • the term may relate to a reversible or an irreversible inhibitor.
  • Cancer may be treated with surgery, radiation therapy, chemotherapy, targeted therapies, immunotherapy or hormonal therapies. Any of these mentioned therapies may be used in conjunction with another therapy as a combination therapy.
  • Chemotherapeutic compounds include but are not limited to alemtuzumab, altretamine, azacitidine, bendamustine, bleomycin, bortezomib, busulfan, cabazitaxel, capecitabine, carboplatin, carmofur, carmustine, chlorambucil, chlormethine, cisplatin, cladribine, clofarabine, cyclophosphamide, cytarabine, dacarbazine, dactinomycin, daunorubicin, decitabine, denosumab, docetaxel, doxorubicin, epirubicin, estramustine, etoposide, everolimus, floxuridine, fludarabine, fluorouracil, fotemustine, gemcitabine, gemtuzumab, hydroxycarbamide, ibritumomab, idarubicin, ifosfamide, ir
  • protein kinase inhibitor refers to inhibitors of protein kinases, serine/threonine kinases, tyrosine kinases, or dual-specificity kinases for the treatment of cancer or other illness.
  • the protein kinase inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide.
  • the protein kinase inhibitor includes but is not limited to acalabrutinib, adavosertib, afatinib, alectinib, axitinib, binimetinib, bosutinib, brigatinib, cediranib, ceritinib, cetuximab, cobimetinib, crizotinib, cabozantinib, dacomitinib, dasatinib, entrectinib, erdafitinib, erlotinib, fostamatinib, gefitinib, ibrutinib, imatinib, lapatinib, lenvatinib, lestaurtinib, lortatinib, masitinib, momelotinib, mubritinib, neratinib, nilotinib, ninte
  • checkpoint inhibitor refers to an immunotherapy that targets immune checkpoints to stimulate immune function.
  • the checkpoint inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide.
  • the immune checkpoint is the PD- 1/PD-L1 checkpoint.
  • the PD-1 checkpoint includes but is not limited to nivolumab, pembrolizumab, spartalizumab, cemiplimab, camrelizumab, sintilimab, tislelizumab, toripalimab, AMP-224 or AMP-514, or any combination thereof.
  • the PD-L1 checkpoint inhibitor includes but is not limited to atezolizumab, avelumab, durvalumab, KN035, AUNP12, CA-170, or BMS-986189, or any combination thereof.
  • the immune checkpoint is the CTLA-4 checkpoint.
  • the CTLA-4 checkpoint inhibitor includes but is not limited to ipilimumab or tremilimumab, or any combination thereof.
  • the term “VEGF inhibitor” refers to inhibitors of vascular endothelial growth factor (VEGF) or a VEGF receptor (VEGFR).
  • the VEGF inhibitor is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide.
  • the VEGF inhibitor includes but is not limited to aflibercept, axitinib, bevacizumab, brivanib, cabozantinib, cediranib, lenvatinib, linifinib, nintedanib, pazopanib, ponatinib, ramucirumab, regorafenib, semaxanib, sorafenib, sunitinib, tivozanib, toceranib, or vandetanib, or any combination thereof.
  • antiviral medication refers to a pharmaceutical composition administered to treat a viral infection.
  • the viral infection is caused by adenovirus, Ebola virus, coronavirus, Epstein-Barr virus (EBV), Friend virus, hantavirus, hepatitis B virus (HBV), hepatitis C virus (HCV), herpes simplex virus, human immunodeficiency virus (HIV), human metapneumovirus, human papillomavirus (HPV), influenza virus, Japanese encephalitis virus, Kaposi’s sarcoma-associated herpesvirus, lymphocytic choriomeningitis virus, parainfluenza virus, rabies virus, respiratory syncytial virus, rhinovirus, varicella zoster virus.
  • Ebola virus coronavirus
  • EBV Epstein-Barr virus
  • HBV hepatitis B virus
  • HCV hepatitis C virus
  • herpes simplex virus herpes simplex virus
  • HCV human metapneumovirus
  • HPV
  • the antiviral medication is a small molecule, compound, polysaccharide, lipid, peptide, polypeptide, protein, antibody, nucleoside, nucleoside analog, nucleotide, nucleotide analog, nucleic acid, or oligonucleotide.
  • the antiviral medication is an interferon, a capsid assembly modulator, a sequence specific oligonucleotide, an entry inhibitor, or a small molecule immunomodulatory.
  • the antiviral medication includes but is not limited to AB-423, AB-506, ABI-H2158, ABI-HO731, acyclovir, adapromine, adefovir, alafenamide, amantadine, asunaprevir, baloxavir marboxil, beclabuvir, boceprevir, brivudine, cidofovir, ciluprevir, clevudine, cytarabine, daclatasvir, danoprevir, dasabuvir, deleobuvir, dipivoxil, edoxudine, elbasvir, entecavir, faldaprevir, famciclovir, favipiravir, filibuvir, fomivirsen, foscarnet, galidesivir, ganciclovir, glecaprevir, GLS4, grazoprevir, idoxuridine, imiquimod, IFN- ⁇ , inter
  • % w/w or “% wt/wt” as used herein has its ordinary meaning as understood in light of the specification and refers to a percentage expressed in terms of the weight of the ingredient or agent over the total weight of the composition multiplied by 100.
  • % v/v or “% vol/vol” as used herein has its ordinary meaning as understood in the light of the specification and refers to a percentage expressed in terms of the liquid volume of the compound, substance, ingredient, or agent over the total liquid volume of the composition multiplied by 100.
  • Step 1 A mixture of 3-Bromo-2-chlorophenol (110 g, 530 mmol), Pd(dppf)Cl2 (38.8 g, 53.0 mmol), KOAc (146 g, 1.48 mol) and Bis(pinacolato)diboron (148 g, 583 mmol) in dioxane (1220 mL) was degassed and purged with N2 (3x). The mixture was stirred at 90 °C for 16 hrs. The two batches of the same reaction were combined to work up. The reaction was cooled to 20 °C and then filtered.
  • Step 2 A mixture of Intermediate 1 (81.0 g, 318 mmol), 3-Bromo-2- chlorophenol (72.6 g, 350 mmol), K3PO4 (203 g, 955 mmol), Pd(dppf)Cl2 (11.6 g, 15.9 mmol) in a solution of dioxane (1620 mL) and H 2 O (540 mL) was degassed and purged with N 2 (3x). The mixture was stirred at 90 °C for 16 hrs. The reaction was cooled to 20 °C and concentrated to give a residue. The residue was dissolved in ethyl acetate (1000 mL) and H 2 O (500 mL), and then the mixture was filtered.
  • ethyl acetate 1000 mL
  • H 2 O 500 mL
  • Step 1 A mixture of Intermediate 4b-1 (41.0 g, 161 mmol), 3-Bromo-2- chlorophenol (32.3 g, 169 mmol), K3PO4 (103 g, 483 mmol), Pd(dppf)Cl2 (5.89 g, 8.05 mmol) in dioxane (800 mL) and H2O (160 mL) was degassed and purged with N 2 (3x) and then was stirred at 90 °C for 16 h.
  • Step 2 To a solution of Intermediate 4b-2 (44.0 g, 184 mmol) and DIPEA (90.6 g, 701 mmol, 122 mL) in DCM (1200 mL) was added slowly Tf2O (122 g, 433 mmol, 71.5 mL) at 0 ⁇ 5 °C.
  • Step 3 A mixture of Intermediate 4b-3 (44.0 g, 87.5 mmol), KOAc (34.4 g, 350 mmol), Pd(dppf)Cl2 (9.61 g, 13.1 mmol) and Bis(pinacolato)diboron (45.6 g, 179 mmol) in dioxane (600 mL) was degassed and purged with N 2 (3x), and then the mixture was stirred at 90 °C for 16 h. The mixture was cooled to 25 °C and filtered. The filter cake was washed with DCM (2 x 50 mL). The filtrate was concentrated to the crude product.
  • the crude reside (20 mg) was purified by prep- HPLC (acid condition; Column: Phenomenex luna C18100*40 mm*3 um; Condition: water (0.225%FA)-ACN; Begin B:0; End B:60; Gradient Time (min):10; 100% B Hold Time (min):2; Flow Rate (mL/min): 25; Injections:1) to give Compound D-1 (5.49 mg) as a white solid of formate salt.
  • Example 6 Preparation of Compound E-1 [0668] A mixture of crude Compound D-1 (15 mg) and LiOH•H 2 O (10 mg, 245 ⁇ mol) in mixture of H 2 O (0.5 mL), THF (1 mL) and MeOH (1.5 mL) was stirred at 40 °C for 2 hrs. The mixture was concentrated under reduced pressure to remove THF. The residue was adjusted to pH ⁇ 3 with 1N aq. HCl, and then was purified by prep-HPLC, to provide Compound E-1 (3.9 mg) as a white solid of HCl salt.
  • Example 7 Preparation of Compound F-1 [0669] A mixture of Compound B-7 (20 mg, 41.20 ⁇ mol), ethyl glyoxalate (17 mg, 82 ⁇ mol, 50% purity) in MeOH (1 mL) was stirred at 20 °C for 14 hrs. NaBH 3 CN (13 mg, 206 ⁇ mol, 5 eq) was added, and the mixture was stirred at 20 °C for 1 hour.
  • Example 8 Preparation of Compound G-1 [0670] A mixture of Compound F-1 (15 mg, 23 ⁇ mol) and LiOH•H 2 O (2 mg, 46 ⁇ mol) in mixture of H 2 O (0.2 mL), THF (0.4 mL) and MeOH (0.6 mL) was stirred at 20 °C for 2 hrs. The mixture was adjusted to pH 5 ⁇ 6 with 1N HCl.
  • Example 9 Preparation of Compound H-1 [0671] A mixture of Compound B-6 (50 mg, 96 ⁇ mol) and ethyl glyoxalate (59 mg) in MeOH (0.5 mL) was stirred at 20 °C for 1 hour. NaBH 3 CN (33 mg, 515 umol) was added into the mixture. The mixture was stirred at 20 °C for 2 hrs. Additional ethyl glyoxalate (98 mg) and NaBH 3 CN (18.06 mg, 288 ⁇ mol) was added into the mixture. The mixture was stirred at 20°C for 5 hrs. The mixture was diluted with H 2 O (3 mL) and extracted with ethyl acetate (4 x 3 mL).
  • Example 11 Preparation of Compound J-1 [0677] A mixture of Compound B-6 (50 mg, 95.80 ⁇ mol ), Boc-L-aspartic acid 4- tert-butyl ester (69 mg, 240 ⁇ mol) and DIEA (66.75 ⁇ L, 383 ⁇ mol,) in DCM (2 mL) was stirred at 20 °C for 1 hour. To the mixture was added HATU (102 mg, 268.25 ⁇ mol), and the mixture was stirred at 20 °C for 2 hrs. The mixture was diluted with H 2 O (5 mL) and extracted with DCM (3 x 5 mL).
  • Example 13 Preparation of Compound K-2 [0680] A mixture of Compound B-1 (50 mg, 96 ⁇ mol ), 2-Cl-pyrimidine (14.26 mg, 4.79 ⁇ L, 125 ⁇ mol) and DIEA (16.69 uL, 95.80 ⁇ mol) in NMP (0.5 mL) was stirred at 110 °C for 12 hours. The mixture was diluted with H 2 O (3 mL) and extracted with EtOAc (3 x 2 mL).
  • Methyl carbonochloridate (39.13 g, 414 mmol) was added, followed by TEA (41.91 g, 414 mmol) added dropwise at 0 °C. The mixture was stirred at 0 °C for 1.5 h. Further methyl carbonochloridate (26.9 g, 285 mmol) was added, followed by TEA (41.91 g, 414.13 mmol) added dropwise at 0 °C. The mixture was stirred at 30 °C for 15 h and then concentrated under reduced pressure. The mixture was diluted with 1N aq. NaOH (300 mL) and extracted with EtOAc (2 x 200mL).
  • the crystal was a colorless needle with the following dimensions: 0.30 ⁇ 0.04 ⁇ 0.04 mm 3 .
  • Figures 1A and 1B shows the absolute configuration structure and ORTEP crystal structure of the formate salt of intermediate 1-4b. [0688]
  • the intermediates shown in Table S1-1 were prepared by an analogous reaction protocol as was used for the preparation of Intermediates i-4a and i-4b using the appropriate starting materials.
  • SFC Method B Column: Chiralpak ND-3100 x 4.6mm I.D., 3 ⁇ m; Mobile phase: A: CO 2 ; B: Ethanol (0.05% DEA); Gradient: from 5% to 40% of B in 4 min and hold 40% for 2.5 min, then 5% of B for 1.5 min; Flow rate: 2.8mL/min; Column temp.: 35 °C; ABPR: 1500psi.
  • SFC Method D Column: UniChiral AD 100 ⁇ 4.6mm I.D., 3 ⁇ m; Mobile phase: A: CO 2 ; B: iso-propanol (0.05% DEA); Gradient: from 5% to 40% of B in 4.5min and hold 40% for 0.5 min, then 5% of B for 1 min; Flow rate: 2.8mL/min Column temperature: 40 °C.
  • SFC Method F Column: Chrialpak IG 50 ⁇ 4.6mm I.D., 3 ⁇ m; Mobile phase: A: CO 2 ; B: 40% of Methanol (0.05% DEA); Gradient: from 5% to 40% of B in 2.5min and hold 40% for 0.5 min, then 5% of B for 1.5 min; Flow rate: 4mL/min Column temperature: 35 °C.
  • Example 19 Preparation of Compound L-1 [0703] A mixture of Intermediate i-6b (89 mg, 263 ⁇ mol), Intermediate 4 (50 mg, 105 ⁇ mol), K 2 CO 3 (44 mg, 316 ⁇ mol) and Pd(dppf)Cl2 (7.7 mg, 11 ⁇ mol) in dioxane (2 mL) and H 2 O (0.2 mL) was stirred at 110 °C for 2 h under N 2 atmosphere. The mixture was filtered and concentrated under reduced pressure to give a residue. The residue was further purified by prep-HPLC to provide Compound L-1 (4.78 mg) as an off-white solid with 1 eq of formate. [0704] The compounds shown in Table S1-3 were prepared by an analogous reaction protocol as was used for the preparation of Compound L-1 using the appropriate starting materials. Table Sl-3
  • Example 20 Preparation of Compound M-1A and M-1B [0705] To a solution of Compound L-4 (40 mg, 51.96 ⁇ mol) in EtOH (6 mL) was added LiOH•H 2 O (0.01 M, 5.20 mL). The mixture was stirred at 40 °C for 18 h. The mixture was concentrated under reduced pressure to remove EtOH. The residue was extracted with EtOAC (3 x 15 mL). The combined organic layers were washed with brine (20 mL), dried over Na 2 SO 4 , filtered and concentrated under reduced pressure to give a residue. The residue was adjusted to pH ⁇ 3 with 1N aqueous HCl. The combined aqueous mixture was purified by prep-HPLC.
  • Example 25 Preparation of Compound O-2B [0718] To a solution of Compound O-2A (330 mg, 460 ⁇ mol) in EtOH (3 mL), THF (2 mL) and H 2 O (1 mL) was added LiOH•H 2 O (193 mg, 4.60 mmol). The mixture was stirred at 40 °C for 2 h. The mixture was concentrated to remove EtOH and THF. The aqueous residue was diluted with H 2 O (1 mL), and the pH was adjusted to ⁇ 6 with 4 M aqueous HCl. The residue was purified by prep-HPLC. Compound O-2B (144 mg, 99% purity) was obtained as an off-white solid 1 eq of formate.
  • Example A LCMS Liquid chromatography/Mass spectrometry
  • HPLC High Performance Liquid Chromatography
  • MS Mass Spectrometer
  • SQL Single Quadrupole Detector
  • MSD Mass Selective Detector
  • RT room temperature
  • BEH bridged ethylsiloxane/silica hybrid
  • DAD Diode Array Detector
  • HSS High Strength silica
  • Q-Tof Quadrupole Time-off light mass spectrometers "CLND”, ChemiLuminescent Nitrogen Detector, "ELSD” Evaporative Light Scanning Detector.
  • Table A LCMS Method Codes
  • PDL1 and PD1 protein are 0.3 nM and 2.5 nM, respectively.
  • Anti-6xHis Acceptor beads final concentration 20 ug/ml
  • Streptavidin Donor beads final concentration 20 ug/mL
  • the plates were sealed with foil and incubated in the dark for additional 1 h or overnight before reading on an Envision reader.
  • the IC 50 s were determined by fitting the curves using a four-parameter equation in Graphpad Prism 8.
  • Example C PDL1 Dimerization Assay [0722] Serially diluted compounds were added to plate wells with the final concentration of DMASO at 1%.
  • PDL1-6xHis and PDL1-strep proteins were diluted in assay buffer (25 mM Hepes pH 7.4, 150mM NaCl, 0.005% Tween 20, BSA 0.01%), added to the wells, and mixed well with the compounds. The plates were incubated for 2 h at room temperature. Anti-6xHis Acceptor beads were added to the wells and the plates were further incubated for 1 h at room temperature. Strep-tactin Donor beads were added to the wells at reduced light. After additional 1 h incubation in the dark, the plates were read on a Envision reader.
  • Example D PD-1/PD-L1 NFAT Reporter Assay [0723] Cellular activity of the compounds was assessed using a co-culture reporter assay in which TCR-mediated NF-AT activity of Jurkat T cells is constitutively inhibited by the engagement of PD-1 by PD-L1 expressing CHO cells.
  • CHO cells expressing surface-bound anti-CD3 antibodies and PD-L1 were first seeded overnight and treated with the compounds.
  • Jurkat cells overexpressing PD-1 and a luciferase construct under NF-AT promoter were then immediately seeded on the monolayer of CHO cells. The co-culture was then incubated for 6 hrs at 37 °C. Luciferase activity was assessed by adding the ONE-Glo reagent and measuring luminescence with a plate reader.

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US20230002413A1 (en) 2023-01-05
AU2021275118A1 (en) 2022-12-01
EP4153567A4 (en) 2024-06-26
JP2023527315A (ja) 2023-06-28
EP4153567A1 (en) 2023-03-29
CN115835907A (zh) 2023-03-21
CA3182131A1 (en) 2021-11-25
KR20230030056A (ko) 2023-03-03
US11760764B2 (en) 2023-09-19
TW202208320A (zh) 2022-03-01

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