MEK immuno-oncology inhibitors and their therapeutic uses

Abstract

The present disclosure provides compounds represented by general formula (III), including pharma- ceutically acceptable salts thereof or synthetic intermediates thereof, compositions containing such compounds, and methods for designing, developing, manufacturing, and preparing such compounds. The compounds act as MEK inhibitors and can exhibit one or more beneficial therapeutic effects, including the treatment of cancer.

Description

[Technical Field]

[0001] The present invention relates to the fields of chemistry and medicine. More specifically, the present invention relates to MEK inhibitors, MEK immuno-oncology inhibitors, techniques for designing and synthesizing such MEK inhibitors, MEK immuno-oncology compositions comprising MEK inhibitors, MEK immuno-oncology inhibitors, and methods of treating disease, comprising administering a MEK inhibitor.

[0002] 2. Description of Related Art In healthy cells, mitogen-activated protein kinase (MAPK) pathways use parallel signaling streams to decode complex extracellular stimuli and drive cellular programs that promote proliferation, differentiation, survival, motility, apoptosis, and stress response. The RAS-RAF-MEK-ERK cascade is one of three distinct MAPK pathways and the one most frequently exploited in cancer. Gain of function mutations in RAS (KRAS, NRAS, HRAS) or RAF (ARAF, BRAF, CRAF / RAF1) are common in cancer. RAS mutations alone represent up to 95% of pancreatic cancers (KRAS), 20–30% of melanomas (NRAS), 40% of non-small cell lung cancers (KRAS), and 45% of colorectal cancers (KRAS). Patients with these tumor types often face poor prognosis and limited treatment options, leading to intense research into how to generate active drugs against this pathway. As a central node in the MAPK signaling pathway, MEK has been an attractive drug target for over 20 years. However, in clinical settings, MEK inhibitors have struggled with class-effect toxicity and acquired resistance. In addition, regulatory approval has been primarily limited to RAF mutant disease. Clinical setbacks in the RAS mutant setting may be due to the mechanistic blind spot of first-generation MEK inhibitors, which leads to increased pathway reactivation, which in turn requires sustained target engagement, limiting drug tolerance. Therefore, new approaches to target MEK with greater tolerance and broader activity are urgently needed.

[0003] MEK1 and MEK2 (MEK) are closely related dual-specificity kinases that are activated by upstream mediators, including RAF (ARAF, BRAF, RAF1 [also known as CRAF]), KSR (KSR1, KSR2), and RAS (KRAS, NRAS, HRAS). Upon activation by phosphorylation on two serine residues, pMEK then facilitates the phosphorylation of ERK1 and ERK2 (pERK), which results in the regulation of multiple downstream targets. Inappropriate activation of this pathway is associated with multiple oncogenic cellular processes, including proliferation, survival, growth, tumor metabolism, migration, and immune evasion. Multiple targeted agents have been and continue to be developed with the goal of reducing MAPK pathway activity at each level, from RAS to ERK. Clinical proof-of-concept has been achieved for several drugs in this field, including KRAS. G12C , BRAF V600E / K Common challenges for drugs that block this core homeostatic pathway include clinically limiting toxicity due to persistent on-target inhibition, specific target mutations (e.g., KRAS G12C or BRAFV 600E / K These include a narrow subset of treatable patients based on tumors exhibiting phenotypic resistance, and acquired or adaptive resistance that limits the clinical utility of emerging drugs.

[0004] Previous MEK inhibitors suffer from one or more significant drawbacks. First-generation MEK inhibitors counteract pathway reactivation by sustaining drug occupancy in the allosteric pocket of MEK throughout the dosing cycle (i.e., chronic inhibition). This is generally achieved by endowing the drug with a long half-life and dosing at regular intervals, or by creating a drug with an intermediate half-life and dosing more frequently. Both approaches result in chronic suppression of the MAPK pathway by sustaining active steady-state drug trough levels. Second-generation MEK inhibitors resist pathway reactivation by preventing RAF activation of MEK itself, yet still possess long half-lives and associate with the allosteric pocket in MEK in a unique manner that results in chronic pathway ablation. This continued disruption of this core biological pathway leads to at least three well-documented challenges for first- and second-generation MEK inhibitors: (1) Tolerability: Clinically limiting class-effect safety issues (Heinzerling 2019), (2) Acquired / adaptive resistance: Selective pressure for escape mutations (Corcoran 2011), and (3) Clinical utility: Reduced drug-drug combination potential due to limitations in drug-related safety and toxicity. Thus, first-generation MEK inhibitors suffer from multiple shortcomings: (1) persistent on-target occupancy drives acquired and / or adaptive resistance and dose-limiting toxicity, (2) mechanistic drug-target interactions fail to effectively control pathway reactivation (e.g., CRAF bypass), and (3) limited clinical utility for drug combinations due to high baseline drug-related toxicity.

[0005] A common feature of nearly all MEK inhibitors is their allosteric target interaction, which is highly selective for MEK and non-ATP-competitive, and is commonly referred to as a type III allosteric inhibitor. First-generation MEK inhibitors, exemplified by trametinib, cobimetinib, binimetinib, and selumetinib, persistently suppress MAPK pathway activity through chronic occupancy of MEK1 and MEK2. However, they exhibit dose-limiting class effect toxicity and are sensitive to pathway reactivation events. Second-generation MEK inhibitors, exemplified by VS-6766 (CH5126766 with a mean terminal half-life of 53.6 hours, Guo et al. Lancet Oncol. 2020 Nov;21(11):1478-1488), exhibit mechanistic resistance to pathway reactivation, but they also persistently suppress MAPK pathway activity through chronic occupancy of MEK1 and MEK2 and therefore have class-effect toxicity similar to first-generation inhibitors. Table 1 summarizes certain characteristics of MEK inhibitors for the treatment of RAS mutant diseases. [Table 1]

[0006] Thus, there remains an unmet need for improved MEK inhibitor compounds, e.g., MEK inhibitor compounds with shorter half-lives, such compounds with shorter half-lives in mouse liver microsome and / or human liver microsome stability studies. Summary of the Invention

[0007] The compounds disclosed in the present application have been discovered to exhibit surprising and unexpected biological effects. In some embodiments, the chemical compounds of the present application are useful as dual MEK inhibitors that exhibit surprising and unexpected biological effects.

[0008] In some embodiments, the compounds are MEK inhibitor compounds characterized by unexpectedly short in vivo half-lives, including novel dual MEK inhibitors with unprecedentedly short half-lives, useful for cyclically inhibiting and relieving MEK and ERK activity. Unlike previous MEK inhibitors, Applicants have discovered compounds that can be used in treatment regimens designed to maximize drug exposure at Cmax while achieving near-zero drug trough within a 12- to 24-hour cycle. In some embodiments, the compounds disclosed herein can be administered on a schedule to drive profound cyclic inhibition of the MAPK pathway in a subject.

[0009] Some embodiments include a compound having the chemical structure of formula (IV): [ka] (IV) or a pharmaceutically acceptable salt thereof, wherein R6 is hydrogen, fluoro, or chloro; and R 13 is ethyl or -NR A R B and R A is hydrogen and R B is methyl and Z2 is -NR 5 R 5’ , [ka] , or [ka] and R 5 is C1-C6 alkyl, and R 5’ is C1-C6 alkyl. 5 is methyl. In some embodiments, R 5’ is methyl. In some embodiments, R 5’is ethyl. In some embodiments, Z2 is -NR 5 R 5’ In some embodiments, R 13 is -NR A R B In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, R 13 is ethyl. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, Z2 is [ka] In some embodiments, R 13 is ethyl. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, R 13 is -NR A R B In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, Z2 is [ka] In some embodiments, R 13 is ethyl. In some embodiments, R 13 is -NR A R B In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof. In some embodiments, the compound is [ka] or a pharmaceutically acceptable salt thereof.

[0010] Some embodiments are compounds having the structure of Formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein R 2 is L and R 6 is selected from the group consisting of H, fluoro, chloro, or bromo; R 7is H and R 13 optionally substituted amine, C1-C6 alkyl, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R is selected from the group consisting of heteroaryl, and L; 3 is chloro, X is —O—, and Y is [ka] and L is -Z1-Z2, Z1 is -CH2-, and Z2 is -NR 5 R 5’ , optionally substituted C3-C8 heterocyclyl, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), and each R 5 and R 5’ is an independently selected optionally substituted C1-C6 alkyl. In some embodiments, Z2, is -NR 5 R 5’ In some embodiments, R 5 is methyl. In some embodiments, R 5’ is methyl. In some embodiments, R 5’ In some embodiments, Z2 is [ka] In some embodiments, Z2 is optionally substituted [ka] wherein n is 1, 2, 3, or 4. In some embodiments, n is 1. In some embodiments, R 13 is -NR A R B and R A and R B are each independently hydrogen or C 1~6 In some embodiments, R A is hydrogen and R B is methyl. In some embodiments, R 13 is C1-C6 alkyl. In some embodiments, R 13 is ethyl. In some embodiments, R 6 is fluoro. In some embodiments, R 6 is chloro. In some embodiments, R 6 is H.

[0011] Some embodiments are compounds having the structure of Formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein R 2 is L and R 6 is selected from the group consisting of H, fluoro, chloro, or bromo; R 7 is H and R 13 is C1-C6 alkyl, and R 3 is chloro, X is —O—, and Y is [ka] and L is -Z1-Z2, Z1 is -CH2-, and Z2 is -NR 5 R 5’ and each R 5 and R 5’ is independently selected from optionally substituted C1-C6 alkyl.

[0012] Some embodiments are compounds having the structure of Formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein R 2 is halogen, H, deuterium, hydroxyl, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R is selected from the group consisting of heteroaryl, and L; 6is H, halogen, deuterium, hydroxyl, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R is selected from the group consisting of heteroaryl, and L; 7 is selected from the group consisting of deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R is selected from the group consisting of heteroaryl, and L; 13optionally substituted C1-C6 alkyl, optionally substituted amino, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R is selected from the group consisting of heteroaryl, and L; 3 is chloro, bromo, or iodo, and X is —O—, C(R 5 )2, CH(R 5 ), CH2, [ka] , [ka] , or [ka] and Y is [ka] , C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , or [ka] L is -Z1-Z2 or -Z1-Z2-Z3, and Z1 is -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, or -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10heteroaryl), and Z2 is selected from the group consisting of -NR 5 R 5’ , -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), and Z3 is selected from the group consisting of -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), and each R 5 and R 5’ are independently selected from optionally substituted C1-C6 alkyl, H, deuterium, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10Aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C 10 The present invention relates to compounds in which the aryl is selected from the group consisting of: heteroaryl;

[0013] In some embodiments, the design of certain compounds is based on the R 3 This is based in part on Applicant's discovery that a specific halogen atom change from fluorine (F) to chlorine (Cl) at position R in formula (III) is a key site substitution that unexpectedly serves to further reduce metabolic stability upon exposure to mouse or human microsomes. 3 This change from F to Cl in was not trivial, as exemplified by an important example within the same targeted drug class of MEK inhibitors: binimetinib and selumetinib are US FDA-registered MEK inhibitors that differ by a single halogen: F in binimetinib is changed to Cl in selumetinib. Selumetinib (more than 6.2 hours - National Center for Biotechnology Information (2023). CID 10127622, ​​PubChem Compound Summary for Selumetinib. Retrieved January 5, 2023, from https: / / pubchem.ncbi.nlm.nih.gov / compound / Selumetinib) exhibits a drug half-life in human plasma that is approximately two-fold longer than binimetinib (3.5 hours - National Center for Biotechnology Information (2023). CID 10288191, PubChem Compound Summary for Binimetinib. Retrieved January 5, 2023, from https: / / pubchem.ncbi.nlm.nih.gov / compound / Binimetinib). Many drug-like properties are associated with R 3 Although the concentration varied unpredictably among newly synthesized analogs of formula (III) bearing Cl at the site of action, Applicants consistently observed lower microsomal metabolic stability, a key desirable attribute for short-lived dual MEK inhibitors designed to enable BID dosing.

[0014] Some embodiments relate to pharmaceutical compositions comprising a compound described herein and a pharmaceutically acceptable salt thereof. Some embodiments relate to methods of treating cancer. In some embodiments, the method comprises administering to a subject in need thereof an effective amount of a compound described herein or a pharmaceutical composition thereof. Some embodiments relate to the use of a compound described herein for the treatment of cancer. Some embodiments relate to the use of a compound described herein for the treatment of cancer. Some embodiments relate to the use of a compound described herein, such as 4-((dimethylamino)methyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 244), 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 252), 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 253), 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 254), 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 255), 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 25 The present invention relates to a compound selected from the group consisting of -((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 253), and 4-((dimethylamino)methyl)-3-(3-(ethylsulfonamido)-2-fluorobenzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 269). In some embodiments, the compound is 4-((dimethylamino)methyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 244). In some embodiments, the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 253). In some embodiments, the compound is 4-((dimethylamino)methyl)-3-(3-(ethylsulfonamido)-2-fluorobenzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 269).

[0015] Some embodiments include 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (compound 245), 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (compound 246), 6-chloro-3-(2-fluoro-3-((2,2,2-trifluoroethyl)sulfonamide )benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 247), 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 249), 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 2 54), 3-(2-chloro-3-(ethylsulfonamido)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 255), 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 256), 6-chloro-3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 257), The present invention relates to a compound selected from the group consisting of 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 257), 3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 258), and 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 274).In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 245). In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 246). In some embodiments, the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (Compound 249). In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 254). In some embodiments, the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 245). In some embodiments, the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 256). In some embodiments, the compound is 6-chloro-3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate (Compound 257). In some embodiments, the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (compound 274).

[0016] Some embodiments are 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(azetidin-1-ylmethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl) 6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, and 4-(azetidin-1-ylmethyl)-6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate.In some embodiments, the compound is 4-(azetidin-1-ylmethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0017] Some embodiments include 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(3-(ethylsulfonamido)-2-fluorobenzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-fluoro-3 -((N-methylsulfamoyl)amino)benzyl)-4-((methyl(prop-2-yn-1-yl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(((cyanomethyl)(methyl)amino)methyl 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-(methyl(sulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H- The present invention relates to a compound selected from the group consisting of chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(3-((ethylsulfonyl)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, and 3-(3-((tert-butylsulfinyl)amino)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.In some embodiments, the compound is 3-(3-(ethylsulfonamido)-2-fluorobenzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-((methyl(prop-2-yn-1-yl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 4-(((cyanomethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-(methyl(sulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. In some embodiments, the compound is 3-(3-((tert-butylsulfinyl)amino)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate. [Brief explanation of the drawings]

[0018] [Figure 1] The pharmacokinetics of exemplary compounds of the present disclosure are illustrated in comparison to analog compounds. [Figure 2A] 1 illustrates a graph of pERK:total ERK (activated) in an A549 lung cancer model. [Figure 2B]Graph of pERK:total ERK (activated) in A375 model. [Figure 2C] 1 illustrates a graph of pERK:total ERK in the SK-MEL-2 melanoma model. [Figure 3] 1 illustrates a graph of a Colon 26 syngeneic CRC tumor mouse model (BID) study. [Figure 4] 1 illustrates a graph of a Colon 26 syngeneic CRC tumor mouse model (QD) study. [Figure 5] 1 illustrates a table of compounds of the present disclosure. DETAILED DESCRIPTION OF THE INVENTION

[0019] In some embodiments, MEK inhibitors are provided. Various embodiments of these compounds include compounds having the structure of Formula I, as described herein, or pharmaceutically acceptable salts thereof. In some embodiments, prodrugs, metabolites, stereoisomers, hydrates, solvates, polymorphs, and pharmaceutically acceptable salts of the compounds disclosed herein are provided.

[0020] In certain aspects, provided herein are therapeutic methods or uses for the treatment, prevention, or amelioration of a disease or condition in a subject, comprising administering to the subject at least one compound disclosed herein. In some embodiments, provided are therapeutic methods or uses for the treatment, prevention, or amelioration of cancer, comprising administering a compound having the structure of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) described herein. In some embodiments, provided are therapeutic methods or uses for the treatment of cancer cachexia, comprising administering a compound having the structure of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) described herein.

[0021] definition Unless expressly defined otherwise, technical and / or scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. In the event that there are multiple definitions for terms herein, those in this section prevail unless expressly stated otherwise. As used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. Conventional methods of mass spectrometry, NMR, HPLC, protein chemistry, biochemistry, and pharmacology are employed unless otherwise indicated. The use of either the conjunction "or" or "and" means "and / or" unless otherwise stated. Furthermore, the term "including," as well as other forms of "include," "includes," and "included," are not limiting. As used herein, regardless of transitional phrases or the body of a claim, the terms "comprise(s)" and "comprising" are to be construed as having an open-ended meaning. That is, these terms should be interpreted synonymously with the phrases "having at least" or "including at least." When used in the context of a process, the term "comprising" means that the process includes at least the recited steps, but may include additional steps. When used in the context of a compound, composition, or device, the term "comprising" means that the compound, composition, or device includes at least the recited features or components, but may also include additional features or components.

[0022] While the present disclosure has been illustrated and described in detail in the foregoing description, such description is to be considered illustrative or exemplary and not restrictive. The present disclosure is not limited to the disclosed embodiments. Variations of the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the present disclosure and the appended claims.

[0023] With respect to the use of virtually any plural and / or singular term herein, those skilled in the art can convert from the plural to the singular and / or from the singular to the plural as appropriate to the context and / or application. Various singular / plural permutations may be expressly indicated herein for clarity. The indefinite article "a" or "an" does not exclude a plurality. The mere fact that certain measures are recited in mutually different dependent claims does not indicate that a combination of these measures cannot be used to advantage.

[0024] All references cited herein are incorporated by reference in their entirety. To the extent that publications and patents or patent applications incorporated by reference conflict with the disclosure contained herein, the present specification is intended to supersede and / or supersede such conflicting material.

[0025] Unless otherwise defined, all terms (including technical and scientific terms) should be given their ordinary and customary meanings to those skilled in the art and should not be limited to any special or customized meaning unless otherwise expressly defined herein. Note that the use of a particular terminology when describing a particular feature or aspect of the present disclosure should not be construed as meaning that the terminology has been redefined herein to be limited to include any specific characteristic of the feature or aspect of the present disclosure to which the terminology pertains.

[0026] Where a range of values ​​is provided, it is understood that the upper and lower limits, and each intervening value between the upper and lower limits of the range, are encompassed within an embodiment.

[0027] As used herein, the term "prodrug" refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some cases, they may be easier to administer than the parent drug. They may be bioavailable, for example, by oral administration, whereas the parent drug is not. Prodrugs may also have improved solubility in pharmaceutical compositions over the parent drug. An example of a prodrug is a compound that is administered as an ester ("prodrug") to facilitate transport across cell membranes where water solubility is detrimental to mobility, but is then metabolically hydrolyzed to the active carboxylic acid once inside the cell where water solubility is beneficial. A further example of a prodrug may be a peptide, which is a short peptide (polyamino acid) bonded to an acid group, where the peptide is metabolized to reveal the active moiety. Conventional procedures for the selection and preparation of suitable prodrug derivatives are described, for example, in *Design of Prodrugs* (edited by H. Bundgaard, Elsevier, 1985), which is incorporated herein by reference in its entirety.

[0028] Metabolites of the compounds disclosed herein include active species produced upon introduction of the compounds into the biological milieu.

[0029] Compounds disclosed herein that have at least one chiral center can exist as racemates or as individual enantiomers, or as enantiomer-enriched mixtures of enantiomers. It should be noted that all such isomers and mixtures thereof are within the scope of the present invention. Furthermore, crystalline forms of the compounds disclosed herein may exist as alternative polymorphs. Such polymorphs are included within one embodiment of the present invention. In addition, some of the compounds of the present invention may form solvates with water (i.e., hydrates) or common organic solvents. Such solvates are included within one embodiment of the present invention.

[0030] As used herein, the term "pharmaceutically acceptable salt" refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with an inorganic acid, such as a 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 an aliphatic or aromatic carboxylic or sulfonic acid, such as acetic acid, succinic acid, lactic acid, malic acid, tartaric acid, citric acid, ascorbic acid, nicotinic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt, for example, an ammonium salt, an alkali metal salt, for example, a sodium or potassium salt, an alkaline earth metal salt, for example, a calcium or magnesium salt, a salt of an organic base, for example, dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamines, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids, for example, arginine and lysine.

[0031] When the preparation of a pharmaceutical formulation involves intimate mixing of a pharmaceutical excipient with an active ingredient in salt form, it may be desirable to use pharmaceutical excipients that are non-basic, i.e., either acidic or neutral excipients.

[0032] In various embodiments, the compounds disclosed herein may be used alone, in combination with other compounds disclosed herein, or in combination with one or more other agents active in the therapeutic areas described herein.

[0033] As used herein, the term "halogen atom" means any one of the radiostable atoms of column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and iodine being preferred.

[0034] As used herein, the term "ester" refers to an ester of the formula -(R) n refers to a chemical moiety having the formula -COOR', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), and n is 0 or 1.

[0035] As used herein, the term "amide" refers to a group of the formula -(R) n -C(O)NHR' or -(R) n It refers to a chemical moiety having the formula -NHC(O)R', where R and R' are independently selected from the group consisting of alkyl, cycloalkyl, aryl, heteroaryl (bonded through a ring carbon), and heteroalicyclic (bonded through a ring carbon), and n is 0 or 1. An amide can be an amino acid or peptide molecule that is attached to a molecule of the invention, thereby forming a prodrug.

[0036] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified. Procedures and specific groups used to achieve this purpose are known to those skilled in the art and can be found in references such as Greene and Wuts, Protective Groups in Organic Synthesis, 3 rd Ed., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0037] As used herein, the term "aromatic" refers to an aromatic group having at least one ring with a conjugated pi-electron system, including both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl (e.g., pyridine) groups. This term includes monocyclic or fused-ring polycyclic (i.e., rings that share adjacent pairs of carbon atoms) groups. The term "carbocyclic" refers to a compound containing one or more covalently closed ring structures, in which the atoms forming the backbone of the ring are all carbon atoms. Thus, this term distinguishes carbocyclic rings from heterocyclic rings, in which the ring backbone contains at least one atom other than carbon. The term "heteroaromatic" refers to an aromatic group containing at least one heterocyclic ring.

[0038] As used herein, "C" refers to a group of integers where "a" and "b" are integers. a ~C b" refers to the number of carbon atoms in an alkyl, alkenyl, or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, aryl, heteroaryl, or heterocyclyl group. That is, an alkyl, alkenyl, alkynyl, cycloalkyl ring, aryl ring, heteroaryl ring, or heterocyclyl ring can contain from "a" to "b" (inclusive) carbon atoms. Thus, for example, a "C1 to C4 alkyl" group or a "C1-C4 alkyl" group refers to all alkyl groups having one to four carbons, i.e., CH3-, CH3CH2-, CH3CH2CH2-, (CH3)2CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)-, and (CH3)3C-. Similarly, for example, a cycloalkyl group can contain "a" to "b" total atoms (inclusive); for example, a C3-C8 cycloalkyl group can contain 3 to 8 carbon atoms in the ring(s). When "a" and "b" are not specified with respect to alkyl, cycloalkyl, or cycloalkenyl, the broadest range described by those definitions is to be assumed. Similarly, a "4- to 7-membered heterocyclyl" group refers to all heterocyclyl groups having 4 to 7 total ring atoms, such as azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, and morpholine. As used herein, the term "C1-C6" includes C1, C2, C3, C4, C5, and C6, as well as the range defined by either of the two above numbers. For example, C1-C6 alkyl includes C1, C2, C3, C4, C5, and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, etc. Similarly, C3-C8 carbocyclyl or cycloalkyl includes hydrocarbon rings containing 3, 4, 5, 6, 7, and 8 carbon atoms, or a range defined by either of the two numbers, for example, C3-C7 cycloalkyl or C5-C6 cycloalkyl. As another example, a 3- to 10-membered heterocyclyl includes 3, 4, 5, 6, 7, 8, 9, or 10 ring atoms, or a range defined by either of the two above numbers, for example, a 4- to 6-membered or 5- to 7-membered heterocyclyl.

[0039] As used herein, "alkyl" refers to a hydrocarbon group in which the straight or branched hydrocarbon chain is fully saturated (having no double or triple bonds). The alkyl group can have 1 to 20 carbon atoms. (Whenever it appears herein, a numerical range such as "1 to 20" refers to each integer within the given range; for example, "1 to 20 carbon atoms" means that the alkyl group can contain up to 20 carbon atoms and can consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc.; however, this definition also encompasses appearances of the term "alkyl" without a specified numerical range.) An alkyl group can also be a medium-sized alkyl having 1 to 10 carbon atoms. An alkyl group can also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of a compound can be designated as "C1-C4 alkyl" or similar designation. By way of example only, "C1-C4 alkyl" indicates that there are 1 to 4 carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, isopropyl, n-butyl, isobutyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0040] Alkyl groups can be substituted or unsubstituted. When substituted, the substituent(s) can individually and independently be selected from the group consisting of alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocabonyl, and the like. and one or more groups selected from the group consisting of carbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Whenever a substituent is described as "optionally substituted," this group can be substituted with one of the above substituents.

[0041] As used herein, "alkenyl" refers to an alkyl group containing one or more double bonds in the straight or branched hydrocarbon chain. Alkenyl groups can be unsubstituted or substituted. When substituted, the substituent(s) can be selected from the same groups disclosed above for alkyl group substitution. Alkenyl groups can have 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkenyl" when no numerical range is specified. Alkenyl groups can also be medium-sized alkenyls having 2 to 9 carbon atoms. Alkenyl groups can also be lower alkenyls having 2 to 4 carbon atoms. The alkenyl group of a compound is defined as "C 2~4 Alkenyl" or similar names. By way of example only, "C 2~4"Alkenyl" indicates that there are 2 to 4 carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-1-yl, propen-2-yl, propen-3-yl, buten-1-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1-methyl-propen-1-yl, 2-methyl-propen-1-yl, 1-ethyl-ethen-1-yl, 2-methyl-propen-3-yl, buta-1,3-dienyl, buta-1,2-dienyl, and buta-1,2-dien-4-yl. Typical alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, pentenyl, hexenyl, and the like.

[0042] As used herein, "alkynyl" refers to an alkyl group containing one or more triple bonds in the straight or branched hydrocarbon chain. Alkynyl groups can be unsubstituted or substituted. When substituted, the substituent(s) can be selected from the same groups disclosed above for alkyl group substitution. Alkynyl groups can have 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkynyl" when no numerical range is specified. Alkynyl groups can also be medium-sized alkynyls having 2 to 9 carbon atoms. Alkynyl groups can also be lower alkynyls having 2 to 4 carbon atoms. The alkynyl group of a compound is defined as "C 2~4 By way of example only, "C" may be designated as "alkynyl" or similar names. 2~4 "Alkynyl" indicates that there are 2 to 4 carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-1-yl, propyn-2-yl, butyn-1-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are not limited to, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and the like.

[0043] As used herein, "heteroalkyl" refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur, in the chain backbone. Heteroalkyl groups can have 1 to 20 carbon atoms, although this definition also covers occurrences of the term "heteroalkyl" when no numerical range is specified. Heteroalkyl groups can also be medium size heteroalkyls, having 1 to 9 carbon atoms. Heteroalkyl groups can also be lower heteroalkyls, having 1 to 4 carbon atoms. The heteroalkyl group of a compound is defined as "C 1~4 A heteroalkyl group may be designated "heteroalkyl" or similar designations. A heteroalkyl group may contain one or more heteroatoms. By way of example only, "C 1~4 "Heteroalkyl" indicates that the heteroalkyl chain has 1 to 4 carbon atoms, and, in addition, one or more heteroatoms in the backbone of the chain.

[0044] As used herein, "aryl" refers to a carbocyclic (all carbon) ring or two or more fused rings (rings sharing two adjacent carbon atoms) having a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene, and azulene. Aryl groups can be substituted or unsubstituted. When substituted, hydrogen atoms are independently replaced by alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, and the like. and aryl groups, including aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, substituents on the aryl group can form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0045] As used herein, "heteroaryl" refers to a monocyclic or polycyclic aromatic ring system (a ring system having a fully delocalized pi-electron system) that is one or more fused rings containing one or more heteroatoms, i.e., elements other than carbon, including, but not limited to, nitrogen, oxygen, and sulfur. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazinone, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine, and triazine. Heteroaryl groups can be substituted or unsubstituted. When substituted, hydrogen atoms are independently selected from alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl and aryl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. When substituted, the substituents on the heteroaryl group can form a non-aromatic ring fused to the aryl group, including cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0046] As used herein, "aralkyl" or "arylalkyl" refers to an aryl group connected as a substituent via an alkylene group. The alkylene and aryl groups of the aralkyl may be substituted or unsubstituted. Examples include, but are not limited to, benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphthylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0047] As used herein, a "heteroaralkyl" or "heteroarylalkyl" is a heteroaryl group connected as a substituent via an alkylene group. The alkylene and heteroaryl groups of a heteroaralkyl may be substituted or unsubstituted. Examples include, but are not limited to, 2-thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazolylalkyl, and imidazolylalkyl, as well as substituted benzo-fused analogs thereof. In some cases, the alkylene group is a lower alkylene group.

[0048] As used herein, "alkylene" refers to a branched or straight-chain fully saturated diradical chemical group (i.e., alkanediyl) containing only carbon and hydrogen attached to the rest of the molecule through two points of attachment. Alkylene groups can have from 1 to 20 carbon atoms, although this definition also covers occurrences of the term "alkylene" when no numerical range is specified. Alkylene groups can also be medium-sized alkylenes having from 1 to 9 carbon atoms. Alkylene groups can also be lower alkylenes having from 1 to 4 carbon atoms. An alkylene group is also referred to as a "C 1~4 By way of example only, "C 1~4"Alkylene" indicates that there are 1 to 4 carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethane-1,1-diyl, propylene, propane-1,1-diyl, propane-2,2-diyl, 1-methyl-ethylene, butylene, butane-1,1-diyl, butane-2,2-diyl, 2-methyl-propane-1,1-diyl, 1-methyl-propylene, 2-methyl-propylene, 1,1-dimethyl-ethylene, 1,2-dimethyl-ethylene, and 1-ethyl-ethylene.

[0049] As used herein, "alkenylene" refers to a straight or branched chain diradical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond attached to the rest of the molecule through two points of attachment. Alkenylene groups can have from 2 to 20 carbon atoms, although this definition also covers occurrences of the term "alkenylene" when no numerical range is specified. Alkenylene groups can also be medium-sized alkenylenes having from 2 to 9 carbon atoms. Alkenylene groups can also be lower alkenylenes having from 2 to 4 carbon atoms. An alkenylene group is defined as "C 2~4 By way of example only, "C 2~4 "Alkenylene" indicates that there are 2 to 4 carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethene-1,1-diyl, propenylene, propen-1,1-diyl, prop-2-ene-1,1-diyl, 1-methyl-ethenylene, but-1-enylene, but-2-enylene, but-1,3-dienylene, butene-1,1-diyl, but-1,3-dien-1,1-diyl, but-2-ene- -1,1-diyl, but-3-ene-1,1-diyl, 1-methyl-prop-2-ene-1,1-diyl, 2-methyl-prop-2-ene-1,1-diyl, 1-ethyl-ethenylene, 1,2-dimethyl-ethenylene, 1-methyl-propenylene, 2-methyl-propenylene, 3-methyl-propenylene, 2-methyl-propen-1,1-diyl, and 2,2-dimethyl-ethen-1,1-diyl.

[0050] As used herein, "alkylidene" refers to a divalent group that is attached to a carbon of another group, forming a double bond, e.g., ═CR'R'', and alkylidene groups include, but are not limited to, methylidene (═CH) and ethylidene (═CHCH). As used herein, "arylalkylidene" refers to an alkylidene group where either R' or R'' is an aryl group. Alkylidene groups can be substituted or unsubstituted.

[0051] As used herein, "alkoxy" refers to a group of the formula -OR, where R is alkyl and is defined above, such as, for example, methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n-butoxy, isobutoxy, sec-butoxy, tert-butoxy, amoxy, and tert-amoxy. Alkoxy can be substituted or unsubstituted.

[0052] As used herein, "alkylthio" refers to a group of the formula -SR, where R is alkyl and is defined above, such as, for example, methyl mercapto, ethyl mercapto, n-propyl mercapto, 1-methylethyl mercapto (isopropyl mercapto), n-butyl mercapto, isobutyl mercapto, sec-butyl mercapto, and tert-butyl mercapto. Alkylthio can be substituted or unsubstituted.

[0053] As used herein, "aryloxy" and "arylthio" refer to RO- and RS-, respectively, where R is aryl, such as, but not limited to, phenyl. Both aryloxy and arylthio can be substituted or unsubstituted.

[0054] As used herein, "acyl" refers to -C(=O)R, where R is hydrogen, C, as defined herein. 1~6 Alkyl, C 2~6 Alkenyl, C2~6 Alkynyl, C 3~7 refers to —C(═O)R, which is carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0055] As used herein, "cycloalkyl" refers to a fully saturated (no double bonds) monocyclic or polycyclic hydrocarbon ring system. When composed of more than one ring, the rings may be joined together in a fused, bridged, or spiro-connected fashion. Cycloalkyl groups include C3 to C6 10 and in other embodiments, C3 to C6. The cycloalkyl group can be unsubstituted or substituted. Typical cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. When substituted, the substituent(s) may be alkyl or may be selected from those set forth above for substitution of alkyl groups, unless otherwise indicated. When substituted, the substituents on the cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including aryl and heteroaryl.

[0056] As used herein, "cycloalkenyl" refers to a cycloalkyl group containing one or more double bonds within the ring, provided that if more than one is present, they cannot form a completely delocalized pi-electron system within the ring (otherwise the group would be an "aryl" as defined herein). When composed of two or more rings, the rings can be connected together in a fused, bridged, or spiro-connected manner. A cycloalkenyl group can be unsubstituted or substituted. When substituted, the substituent(s) may be alkyl or selected from the groups disclosed above for alkyl group substitution, unless otherwise indicated. When substituted, substituents on a cycloalkenyl group can form an aromatic ring fused to the cycloalkenyl group, including aryl and heteroaryl.

[0057] As used herein, "cycloalkynyl" refers to a cycloalkyl group containing one or more triple bonds in the ring. When composed of two or more rings, the rings can be linked together in a fused, bridged, or spiro-connected manner. A cycloalkynyl group can be unsubstituted or substituted. When substituted, the substituent(s) can be alkyl or selected from the groups disclosed above for alkyl group substitution, unless otherwise indicated. When substituted, substituents on a cycloalkynyl group can form an aromatic ring fused to the cycloalkynyl group, including aryl and heteroaryl.

[0058] As used herein, "heteroalicyclic" or "heteroalicyclyl" refers to a stable 3- to 18-membered ring consisting of carbon atoms and one to five heteroatoms selected from the group consisting of nitrogen, oxygen, and sulfur. A "heteroalicyclic" or "heteroalicyclyl" can be a monocyclic, bicyclic, tricyclic, or tetracyclic ring system that can be linked together in a fused, bridged, or spiro-connected fashion; the nitrogen, carbon, and sulfur atoms in a "heteroalicyclic" or "heteroalicyclyl" can be optionally oxidized; the nitrogen can be optionally quaternized; and the ring can also contain one or more double bonds, provided that one or more double bonds do not form a fully delocalized pi-electron system throughout the entire ring. A heteroalicyclyl group can be unsubstituted or substituted. When substituted, the substituent(s) may be one or more groups independently selected from the group consisting of alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, heteroaralkyl, (heteroalicyclyl)alkyl, hydroxy, protected hydroxyl, alkoxy, aryloxy, acyl, ester, mercapto, alkylthio, arylthio, cyano, halogen, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, protected C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Examples of such "heteroalicyclic" or "heteroalicyclyl" include, but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl N-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone.When substituted, the substituents on a heteroalicyclyl group can form an aromatic ring fused to the heteroalicyclyl group, which includes aryl and heteroaryl.

[0059] As used herein, the term "(cycloalkenyl)alkyl" refers to a cycloalkenyl group connected as a substituent via an alkylene group. The alkylene and cycloalkenyl of a (cycloalkenyl)alkyl may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0060] As used herein, the term "(cycloalkynyl)alkyl" refers to a cycloalkynyl group connected as a substituent via an alkylene group. The alkylene and cycloalkynyl of a (cycloalkynyl)alkyl may be substituted or unsubstituted. In some cases, the alkylene group is a lower alkylene group.

[0061] As used herein, the term "O-carboxy" refers to the group "RC(=O)O-" where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. O-carboxy can be substituted or unsubstituted.

[0062] As used herein, the term "C-carboxy" refers to the group "-C(=O)R" where R can be the same as defined for O-carboxy. C-carboxy can be substituted or unsubstituted.

[0063] As used herein, the term "trihalomethanesulfonyl" refers to an "X3CSO2-" group where X is a halogen.

[0064] As used herein, the term "cyano" refers to a "-CN" group.

[0065] As used herein, the term "cyanato" refers to an "-OCN" group.

[0066] As used herein, the term "isocyanato" refers to an "-NCO" group.

[0067] As used herein, the term "thiocyanato" refers to a "-SCN" group.

[0068] As used herein, the term "isothiocyanato" refers to the group "-NCS."

[0069] As used herein, the term "sulfinyl" refers to the group "-S(=O)-R" where R can be the same as defined for O-carboxy. Sulfinyl can be substituted or unsubstituted.

[0070] As used herein, the term "sulfonyl" refers to the group "-S02R" where R can be the same as defined for O-carboxy. Sulfonyl can be substituted or unsubstituted.

[0071] As used herein, the term "S-sulfonamide" refers to "-SONR A R B " group, where R A and R B may be the same as defined for O-carboxy, "-SONR A R B " group. The S-sulfonamide can be substituted or unsubstituted.

[0072] As used herein, the term "N-sulfonamide" refers to "-SO2N(R A )(RB ) group, wherein R, R A , and R B may be the same as defined for O-carboxy, "-SO2N(R A )(R B ) group. The sulfonyl can be substituted or unsubstituted.

[0073] As used herein, the term "trihalomethanesulfonamide" refers to an "X3CSON(R)-" group, where X is a halogen and R can be the same as defined for O-carboxy. Trihalomethanesulfonamides can be substituted or unsubstituted.

[0074] As used herein, the term "O-carbamyl" refers to "-OC(=O)NR A R B " group, R A and R B may be the same as defined for O-carboxy, such as "-OC(=O)NR A R B " group. O-carbamyl can be substituted or unsubstituted.

[0075] As used herein, the term "N-carbamyl" refers to "ROC(=O)NR A - group, where R and R A may be the same as defined for O-carboxy, "ROC(=O)NR A - group. N-carbamyl can be substituted or unsubstituted.

[0076] As used herein, the term "O-thiocarbamyl" refers to "-OC(=S)-NR A R B " group, where R A and R B may be the same as defined for O-carboxy, such as "-OC(=S)-NR A RB " group. O-thiocarbamyl can be substituted or unsubstituted.

[0077] As used herein, the term "N-thiocarbamyl" refers to "ROC(=S)NR A - group, where R and R A may be the same as defined for O-carboxy, "ROC(=S)NR A - group. N-thiocarbamyl can be substituted or unsubstituted.

[0078] As used herein, the term "C-amide" refers to "-C(=O)NR A R B " group, where R A and R B may be the same as defined for O-carboxy, such as "-C(=O)NR A R B " group. The C-amide may be substituted or unsubstituted.

[0079] As used herein, the term "N-amide" refers to "RC(=O)NR A - group, where R and R A may be the same as defined for O-carboxy, "RC(=O)NR A N-amides refer to a "-" group. N-amides can be substituted or unsubstituted.

[0080] As used herein, the term "amino" refers to "-NR A R B " group, where R A and R B each independently represents hydrogen as defined herein, C 1~6 Alkyl, C 2~6 Alkenyl, C 2~6 Alkynyl, C 3~7 Carbocyclyl, C 6~10 aryl, 5- to 10-membered heteroaryl, and 5- to 10-membered heterocyclyl; A RB " refers to the group.

[0081] As used herein, the term "aminoalkyl" refers to an amino group connected via an alkylene group.

[0082] As used herein, the term "ester" refers to the group "-C(=O)OR" where R can be the same as defined for O-carboxy. Esters can be substituted or unsubstituted.

[0083] As used herein, the term "lower aminoalkyl" refers to an amino group connected via a lower alkylene group. A lower aminoalkyl may be substituted or unsubstituted.

[0084] As used herein, the term "lower alkoxyalkyl" refers to an alkoxy group connected via a lower alkylene group. A lower alkoxyalkyl may be substituted or unsubstituted.

[0085] As used herein, the term "acetyl" refers to the group -C(=O)CH3.

[0086] As used herein, the term "trihalomethanesulfonyl" refers to a X3CS(=O)2- group where X is a halogen.

[0087] As used herein, the term "O-carbamyl" refers to -OC(=O)-NR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. O-carbamyl can be substituted or unsubstituted.

[0088] As used herein, the term "N-carbamyl" refers to the ROC(=O)NH- group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. N-carbamyl can be substituted or unsubstituted.

[0089] As used herein, the term "O-thiocarbamyl" refers to -OC(=S)-NR, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. O-thiocarbamyl can be substituted or unsubstituted.

[0090] As used herein, the term "N-thiocarbamyl" refers to the ROC(=S)NH- group, where R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. N-thiocarbamyl can be substituted or unsubstituted.

[0091] As used herein, the term "perhaloalkyl" refers to an alkyl group in which all of the hydrogen atoms have been replaced by halogen atoms.

[0092] As used herein, the term "halogen" or "halo" refers to any one of the radiostable atoms in column 7 of the periodic table of the elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and iodine being preferred.

[0093] As used herein, the term "carbocyclyl" refers to a non-aromatic cyclic ring or ring system containing only carbon atoms in the ring system backbone. When a carbocyclyl is a ring system, two or more rings can be linked together in a fused, bridged, or spiro-connected fashion. A carbocyclyl can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. Thus, carbocyclyl includes cycloalkyl, cycloalkenyl, and cycloalkynyl. A carbocyclyl group can have 3 to 20 carbon atoms, although this definition also covers occurrences of the term "carbocyclyl" when no numerical range is specified. A carbocyclyl group can also be a medium-sized carbocyclyl having 3 to 10 carbon atoms. A carbocyclyl group can also be a carbocyclyl having 3 to 6 carbon atoms. A carbocyclyl group is defined as "C 3~6 Examples of carbocyclyl rings include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclohexenyl, 2,3-dihydro-indene, bicycle[2.2.2]octanyl, adamantyl, and spiro[4.4]nonanyl.

[0094] As used herein, the term "(cycloalkyl)alkyl" refers to a cycloalkyl group connected as a substituent via an alkylene group. The alkylene and cycloalkyl of a (cycloalkyl)alkyl may be substituted or unsubstituted. Examples include, but are not limited to, cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, and cycloheptylmethyl. In some cases, the alkylene group is a lower alkylene group.

[0095] As used herein, the term "cycloalkyl" refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0096] As used herein, the term "cycloalkenyl" refers to a carbocyclyl ring or ring system having at least one double bond, where no ring in the ring system is aromatic. An example is cyclohexenyl.

[0097] As used herein, the term "heterocyclyl" refers to a 3-, 4-, 5-, 6-, 7-, and 8-membered or larger ring in which carbon atoms, together with one to three heteroatoms, comprise the ring. A heterocyclyl can optionally contain one or more unsaturated bonds positioned in such a way that an aromatic pi-electron system does not result. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen.

[0098] Heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so that the definition includes oxo and thio systems, such as lactams, lactones, cyclic imides, cyclic thioimides, and cyclic carbamates.

[0099] As used herein, "heterocyclyl" refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls can be joined together in fused, bridged, or spiro-connected fashions. Heterocyclyls can have any degree of saturation, provided that at least one ring in the ring system is not aromatic. The heteroatom(s) can be present in either a non-aromatic or aromatic ring in the ring system. Heterocyclyl groups can have 3 to 20 ring members (i.e., the number of atoms comprising the ring backbone, including carbon atoms and heteroatoms), although this definition also covers occurrences of the term "heterocyclyl" when no numerical range is specified. Heterocyclyl groups can also be medium-sized heterocyclyls having 3 to 10 ring members. Heterocyclyl groups can also be heterocyclyls having 3 to 6 ring members. Heterocyclyl groups can also be designated as "3- to 6-membered heterocyclyl" or similar names. In preferred 6-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 to a maximum of 3 of O, N, or S, and in preferred 5-membered monocyclic heterocyclyls, the heteroatom(s) are selected from 1 or 2 heteroatoms selected from O, N, or S.Examples of heterocyclyl rings include azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, imidazolidinyl, morpholinyl, oxiranyl, oxepanyl, thiepanyl, piperidinyl, piperazinyl, dioxopiperazinyl, pyrrolidinyl, pyrrolidonyl, pyrrolidionyl, 4-piperidonyl, pyrazolinyl, pyrazolidinyl, 1,3-dioxinyl, 1,3-dioxanyl, 1,4-dioxinyl, 1,4-dioxanyl, 1,3-oxathianyl, 1,4-oxathiinyl, 1,4-oxathianyl, 2H-1,2-oxazinyl, trioxanyl, hexahydro-1,3-diox ...athiinyl, 1,4-oxathianyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl, 2H-1,2-oxathiinyl ,3,5-triazinyl, 1,3-dioxolyl, 1,3-dioxolanyl, 1,3-dithiolyl, 1,3-dithiolanyl, isoxazolinyl, isoxazolidinyl, oxazolinyl, oxazolidinyl, oxazolidinonyl, thiazolinyl, thiazolidinyl, 1,3-oxathiolanyl, indolinyl, isoindolinyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiophenyl, tetrahydrothiopyranyl, tetrahydro-1,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0100] As used herein, the term "(heterocyclyl)alkyl" refers to a heterocyclyl group connected, as a substituent, via an alkylene group. Examples include, but are not limited to, imidazolinylmethyl and indolinylethyl.

[0101] As used herein, the terms "purified," "substantially purified," and "isolated" refer to compounds disclosed herein that are free of other distinct compounds with which the compounds of the invention are normally associated in their natural state, and thus comprise at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% by weight of the mass of a given sample.

[0102] As used herein, a substituted group is based on or derived from an unsubstituted parent group in which one or more hydrogen atoms have been replaced with another atom or group. Unless otherwise indicated, when a group is considered to be "substituted," the group can be independently selected from C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, C1-C6 heteroalkyl, C3-C7 carbocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy), and C3-C7-carbocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkoxy). alkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-C1-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C 1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl(C1-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), halo, cyano, hydroxy, C1-C6 alkoxy, C1-C6 alkoxy(C1-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(C1-C6)alkyl (e.g., -CF3), halo(C1-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(C1-C6)alkyl, nitro, O-carbamyl, N-carbamyl,Substituted with one or more substituents selected from O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanoto, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=O). Whenever a group is described as "optionally substituted," that group can be substituted with the above substituents.

[0103] In some embodiments, substituted groups are individually and independently substituted with one or more substituents selected from C1-C4 alkyl, amino, hydroxy, and halogen.

[0104] It is understood that a particular radical naming convention can include either a monoradical or a diradical, depending on the context. For example, if a substituent requires two points of attachment to the rest of the molecule, the substituent is understood to be a diradical. For example, a substituent specified as alkyl, which requires two points of attachment, includes diradicals such as -CH2-, -CH2CH2-, and -CH2CH(CH3)CH2-, etc. Other radical naming conventions explicitly indicate that the radical is a diradical, such as an "alkylene" or "alkenylene."

[0105] Unless otherwise indicated, when a substituent is considered to be "optionally substituted," this means that the substituents may be individually and independently substituted with one or more groups selected from alkyl, alkenyl, alkynyl, cycloalkyl, aryl, heteroaryl, heteroalicyclic, hydroxyl, alkoxy, aryloxy, mercapto, alkylthio, arylthio, cyano, halo, carbonyl, thiocarbonyl, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C-amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, isocyanato, thiocyanato, isothiocyanato, nitro, silyl, trihalomethanesulfonyl, and amino, including mono- and di-substituted amino groups, and protected derivatives thereof. Protecting groups that may form the protective derivatives of the above substituents are known to those of skill in the art and may be found in references such as Greene and Wuts, supra.

[0106] As used herein, the term "agent" or "test agent" includes any substance, molecule, element, compound, entity, or combination thereof. This includes, but is not limited to, proteins, polypeptides, peptides or mimetics, small organic molecules, polysaccharides, and polynucleotides. It can be a natural product, a synthetic compound, or a chemical compound, or a combination of two or more substances. Unless otherwise specified, the terms "agent," "substance," and "compound" are used interchangeably herein.

[0107] As used herein, the term "analog" refers to a molecule that is structurally similar to a reference molecule but has been modified in a targeted and controlled manner by replacing specific substituents of the reference molecule with alternative substituents. Compared to the reference molecule, an analog will be expected by those skilled in the art to exhibit the same, similar, or improved utility. The synthesis and screening of analogs to identify variants of known compounds with improved characteristics (e.g., higher binding affinity to a target molecule) is a well-known technique in pharmaceutical chemistry.

[0108] As used herein, the term "mammal" is used in its ordinary biological sense, and thus specifically includes, but is not limited to, primates, including monkeys (chimpanzees, apes, monkeys) and humans, cows, horses, sheep, goats, pigs, rabbits, dogs, cats, rats, and mice, as well as many other species.

[0109] As used herein, the term "microbial infection" refers to the invasion of an organism by a pathogenic microorganism, whether the host organism is a vertebrate, invertebrate, fish, plant, bird, or mammal. This includes the excessive growth of microorganisms normally present in or on a mammal or other organism. More generally, a microbial infection can be any situation in which the presence of a microbial population(s) is damaging to the host mammal. Thus, a mammal "suffers" from a microbial infection when excessive numbers of microbial populations are present in or on the mammal, or when the effects of the presence of a microbial population(s) are damaging to the mammal's cells or other tissues. Specifically, this description applies to bacterial infections. The compounds of the preferred embodiments are also useful in treating microbial growth or contamination of cell culture or other media, or inanimate surfaces or objects, and it should be noted that this specification in no way limits the preferred embodiments to the treatment of only higher organisms, except as expressly specified in the claims.

[0110] As used herein, the term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0111] As used herein, the term "subject" refers to a human or non-human mammal, such as a dog, cat, mouse, rat, cow, sheep, pig, goat, non-human primate, or bird, such as a chicken, and any other vertebrate or invertebrate.

[0112] As used herein, the term "effective amount" or "therapeutically effective amount" refers to an amount of a therapeutic agent that is effective to some extent to alleviate one or more of the symptoms of a disease or condition or reduce the likelihood of their occurrence, including curing the disease or condition. "Cure" means that the symptoms of the disease or condition are eliminated, although certain long-term or permanent effects (e.g., extensive tissue damage) may exist even after a cure is achieved.

[0113] As used herein, the terms "treat," "treatment," or "treating" refer to administering a pharmaceutical composition for prophylactic and / or therapeutic purposes. The term "prophylactic treatment" refers to treating a subject who does not yet exhibit symptoms of the disease or condition, but who is susceptible to or otherwise at risk of a particular disease or condition, whereby the treatment reduces the likelihood that the patient will develop the disease or condition. The term "therapeutic treatment" refers to administering a treatment to a subject.

[0114] It is understood that if a compound disclosed herein has unsatisfied valences, the valences should be filled with hydrogen and / or deuterium.

[0115] It is understood that the compounds described herein may be isotopically labeled or labeled by other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with an isotope, such as deuterium, may provide certain therapeutic advantages resulting from greater metabolic stability, such as increased in vivo half-life or reduced dosing requirements. Each chemical element represented in a compound structure may include any isotope of that element. For example, in a compound structure, a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position in the compound where a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including, but not limited to, hydrogen-1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Therefore, reference to a compound herein encompasses all possible isotopic forms unless the context clearly dictates otherwise.

[0116] As used herein, the term "immune checkpoint inhibitor" refers to a molecule (e.g., a small molecule, peptide, polypeptide, protein, antibody, antibody fragment, etc.) that acts as an inhibitor (antagonist) of an immune checkpoint pathway. Inhibition of the pathway can include blocking the pathway through binding to a receptor or signaling molecule that is part of the immune checkpoint pathway.

[0117] As used herein, the term "about" refers to a quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length that varies by as much as 30, 25, 20, 15, 10, 9, 8, 7, 6, 5, 4, 3, 2, or 1% relative to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight, or length. When the term about precedes a value, it is not intended that the component be strictly limited to that value, but rather to include amounts that vary from that value.

[0118] compound Some embodiments provide a compound of formula (I): [ka]

[0119] In some embodiments, Formula (I) is a pharmaceutically acceptable salt described herein.

[0120] In some embodiments, Formula (I) is represented by Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id). [ka] , [ka] [ka] , [ka]

[0121] In some embodiments, Formula (Ia), Formula (Ib), Formula (Ic), or Formula (Id) is a pharmaceutically acceptable salt described herein.

[0122] Some embodiments provide a compound of formula (II): [ka]

[0123] In some embodiments, Formula (II) is a pharmaceutically acceptable salt described herein.

[0124] In some embodiments, Formula (II) is represented by Formula (IIa), Formula (IIb), or Formula (IIc). [ka] , [ka] , [ka] , [ka]

[0125] In some embodiments, Formula (IIa), Formula (IIb), Formula (IIc), and Formula (IId) can be pharmaceutically acceptable salts described herein.

[0126] Some embodiments provide a compound of formula (III): [ka]

[0127] In some embodiments, Formula (III) is a pharmaceutically acceptable salt described herein.

[0128] In some embodiments, ring A is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , or [ka] is.

[0129] In some embodiments of compounds of Formula (I) or (Ic), R 1 is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, O-aryl, O-heteroaryl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L.

[0130] In some embodiments, R 1 is not O-pyrimidinyl. 1 is not an ether-linked pyrimidyl.

[0131] In some embodiments of compounds of Formula (I), (Ia), (Ib), (II), (IIa), (IIb), or (III), R 2is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, O-aryl, O-heteroaryl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some embodiments, R 2 is L. In some further embodiments, R 2 is -CH3.

[0132] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IId), or (III), R 3is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some further embodiments, R 2 is L. In some further embodiments, R 2 is -CH3.

[0133] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), or (IIa), R 4is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L.

[0134] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), R 5 may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl. 5 is H, deuterium, halo, or optionally substituted C1-C6 alkyl.

[0135] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), or (IIc), R 5’may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl. 5’ is H, deuterium, halo, or optionally substituted C1-C6 alkyl.

[0136] In some embodiments of the compound of formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), or (III), R 6 is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some embodiments, R 6 is selected from the group consisting of H, or fluoro, chloro, or bromo.

[0137] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), R 7is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some embodiments, R 7 is F, Cl, or Br. In some embodiments, R 7 is Cl. In some embodiments, R 7 may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, and optionally substituted C2-C6 alkynyl. In some embodiments, R 7 is halo. In some embodiments, R 7 is H. In some embodiments, R 7 is selected from the group consisting of H, F, methyl, or methoxy. 7 is H or F.

[0138] In some embodiments of the compound of Formula (IIa), H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 R selected from heteroaryl 8 In some further embodiments, R 8 is selected from halo, H, deuterium, or CH3.

[0139] In some embodiments of compounds of Formula (Id), R 9 is hydrogen, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), or -CH2- (optionally substituted C3-C 10 In some further embodiments, Z2 may be selected from C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl, -NR 5 R 5’ , —CH2CH, or —CH2CN.

[0140] In some embodiments of compounds of Formula (Id), R 10 is hydrogen, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), or -CH2- (optionally substituted C3-C 10 In some further embodiments, Z2 may be selected from C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl, -NR 5 R 5’ , —CH2CH, or —CH2CN.

[0141] In some embodiments of the compound of Formula (II), R 11 are independently H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some further embodiments, R 11 is selected from halo, H, or CH3.

[0142] In some embodiments of the compound of Formula (III), R 13is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, or L. In some embodiments, R 13 is a C1-C6 alkyl.

[0143] In some embodiments of the compound of Formula (III), X is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] In some further embodiments, X is —CH 2 or —O—. In some further embodiments, X is —O—.

[0144] In some embodiments of compounds of Formula (Id) or (IId), X 1is N or CH.

[0145] In some embodiments of compounds of Formula (Id), n is 1, 2, 3, or 4.

[0146] In some embodiments of compounds of Formula (I), (Ia), (II), or (IIa), Y 1 is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] In some further embodiments, Y 1 is —CH or —O—. In some further embodiments, Y 1 is —O—. In some embodiments, Y 1 teeth, [ka] In some embodiments of compounds of Formula (I), (Ia), (II), or (IIa), Y 2 is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] In some embodiments, Y 2 is —O—. In some embodiments, Y 2 teeth, [ka] is.

[0147] In some embodiments of compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), L can be selected from -Z1-Z2. In some embodiments of compounds of Formula (III), L can be selected from -Z1-Z2-Z3.

[0148] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), Z is -CH-, -O-, -S-, S=O, -SO-, C=O, -CO-, -NO, -NH-, -CHCCH, -CHCN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -NHCH2CO-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), or -CH2- (optionally substituted C3-C 10 heteroaryl). In some further embodiments, Z1 is -CH2-.

[0149] In some embodiments of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), Z2 is hydrogen, deuterium, halo, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR2 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5 -, -NHCH2CO-, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -CH2R 5 -, -OR 5 -, -SR5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), or -CH2- (optionally substituted C3-C 10 In some further embodiments, Z2 may be selected from C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl, -NR 5 R 5 , -CH2CH, or -CH2CN. In some further embodiments, Z2 is an optionally substituted C3-C8 heterocyclyl. In some embodiments, Z2 is -NR 5 R 5’ In some embodiments, Z1 is -CH2- and Z2 is -NR 5 R 5’ is.

[0150] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), Z3 is hydrogen, deuterium, halo, -COH, -CO2H, -NO2, -CH2CCH, -CH2CN, -NR 5 R 5’ , -(CO)NH2, -(CO)NR 5 R 5’ , -SO2-NH2, -R 5CH3, -R 5 -COH, -R 5 CO2H, -R 5 NH2, -R 5 NH(COH), -R 5 (CO)NH2, -R 5 NH-SO2H, -R 5 SO2-NH2, -CH2R 5 , -OR 5 , -SO2R 5 -, -CO2R 5 , -NHR 5 , -NH(CO)R 5 , -(CO)NHR 5 , -NH-SO2R 5 , -SO2-NHR 5 , optionally substituted amino, optionally substituted C1-C4 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), or -CH2- (optionally substituted C3-C 10 heteroaryl).

[0151] In some embodiments, Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III) is a compound of a disclosed formula, e.g., Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), or (III), but [ka] , [ka] , and [ka] Except.

[0152] Some embodiments provide a compound of formula (IV): [ka] (IV)

[0153] In some embodiments, Formula (IV) is a pharmaceutically acceptable salt described herein.

[0154] In some embodiments of the compound of Formula (IV), R6 is hydrogen, fluoro, or chloro.

[0155] In some embodiments of the compound of Formula (IV), R 13 is ethyl or -NR A R B and R A is hydrogen and R B is methyl.

[0156] In some embodiments of the compound of Formula (IV), Z2 is -NR 5 R 5’ , [ka] , or [ka] is.

[0157] In some embodiments of the compound of Formula (IV), R 5 is a C1-C6 alkyl.

[0158] In some embodiments of the compound of Formula (IV), R 5’ is a C1-C6 alkyl.

[0159] In some embodiments of the compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV), the compound is selected from the compounds of Tables B, C, D, E, and pharmaceutically acceptable salts thereof. [Table 2-1] TIFF2025503606000081.tif164169 [Table 2-2] [Table 2-3] [Table 2-4] [Table 2-5] [Table 3-1] TIFF2025503606000087.tif84165 [Table 3-2] [Table 4] [Table 5]

[0160] In some embodiments, the pharmaceutically acceptable salt can be an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt can be an alkali metal salt. In some embodiments, the pharmaceutically acceptable salt can be an alkaline earth metal salt. In some embodiments, the pharmaceutically acceptable salt can be an ammonium salt.

[0161] synthesis The compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), and (IV) described herein, or pharmaceutically acceptable salts thereof, can be prepared in a variety of ways, including methods known to those skilled in the art. The routes shown and described herein are illustrative only and are not intended to, or should be construed to, limit the scope of the claims in any manner. Those skilled in the art will recognize modifications of the disclosed syntheses and will be able to devise alternative routes based on the disclosure herein. All such modifications and alternative routes are within the scope of the claims. Exemplary methods are described in the Examples below.

[0162] Method of preparation The compounds disclosed herein can be synthesized by the methods described below or by modifications of these methods. Modifications of the methodology, including, inter alia, temperature, solvents, reagents, etc., will be apparent to those skilled in the art. Generally, during any of the processes for the preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules of interest. This can be achieved using conventional protecting groups, such as those described in "Protective Groups in Organic Chemistry" (J.F.W. McOmie, ed., Plenum Press, 1973) and "Protective Groups in Organic Synthesis" by Greene & Wuts, John Wiley & Sons, 1991, both of which are incorporated herein by reference in their entirety. The protecting groups can be removed at a convenient subsequent stage using methods known in the art. Synthetic chemical transformations useful in the synthesis of applicable compounds are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers, 1989, or L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons, 1995, both of which are incorporated herein by reference in their entirety.

[0163] Where the processes for preparing the compounds disclosed herein result in mixtures of stereoisomers, such isomers can be separated by conventional techniques, such as preparative chiral chromatography. The compounds may be prepared in racemic form, or individual enantiomers may be prepared by stereoselective synthesis or by resolution. The compounds may be resolved into their component enantiomers by standard techniques, such as the formation of diastereomeric pairs by salt formation with optically active acids, such as (-)-di-p-toluoyl-d-tartaric acid and / or (+)-di-p-toluoyl-l-tartaric acid, followed by fractional crystallization and regeneration of the free base. The compounds may also be resolved using a chiral auxiliary to form diastereomeric derivatives, e.g., esters, amides, or ketals, followed by chromatographic separation and removal of the chiral auxiliary.

[0164] Pharmaceutical Compositions In another aspect, a pharmaceutical composition is disclosed, comprising a physiologically acceptable surfactant, carrier, diluent, excipient, lubricant, suspending agent, film-forming agent, and coating aid, or a combination thereof, and a compound disclosed herein. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical field and are described, for example, in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety. Preservatives, stabilizers, dyes, sweeteners, fragrances, and flavoring agents may be provided in the pharmaceutical composition. For example, sodium benzoate, ascorbic acid, and esters of p-hydroxybenzoic acid may be added as preservatives. In addition, antioxidants and suspending agents may be used. In various embodiments, alcohols, esters, and sulfated fatty alcohols may be used as surfactants; sucrose, glucose, lactose, starch, crystalline cellulose, mannitol, light anhydrous silicic acid, magnesium aluminate, magnesium aluminometasilicate, synthetic aluminum silicate, calcium carbonate, acid sodium carbonate, calcium hydrogen phosphate, and calcium carboxymethylcellulose may be used as excipients; magnesium stearate, talc, and hydrogenated oils may be used as lubricants; coconut oil, olive oil, sesame oil, peanut oil, and soybean may be used as suspending agents or lubricants; carbohydrates, such as cellulose acetate phthalate as a derivative of cellulose or sugar, or methyl acetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspending agents; and plasticizers, such as phthalate esters, may be used as suspending agents.

[0165] As used herein, the term "pharmaceutical composition" refers to a mixture of a compound disclosed herein with other chemical components, such as a diluent or carrier. A pharmaceutical composition facilitates administration of a compound to an organism. Multiple techniques for administering a compound exist in the art, including, but not limited to, oral, injection, aerosol, parenteral, and topical administration. Pharmaceutical compositions can also be obtained by reacting a compound with an inorganic or organic acid, such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid, etc.

[0166] As used herein, the term "carrier" refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example, dimethyl sulfoxide (DMSO) is a commonly used carrier that facilitates the uptake of many organic compounds into the cells or tissues of living organisms.

[0167] As used herein, the term "diluent" refers to a chemical compound diluted in water to dissolve the compound of interest and stabilize the compound in a biologically active form. Salts dissolved in buffer solutions are utilized as diluents in the art. One commonly used buffer solution is phosphate buffered saline, which mimics the salt conditions of human blood. Because buffer salts can control the pH of the solution at low concentrations, buffer diluents rarely alter the biological activity of the compound.

[0168] As used herein, the term "physiologically acceptable" refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0169] As used herein, "excipient" refers to an inert substance added to a pharmaceutical composition to provide the composition with, but not limited to, bulk, consistency, stability, binding ability, lubrication, disintegration ability, etc. A "diluent" is a type of excipient.

[0170] Also described for each compound described herein, and for each genus or subgenus of compounds described herein, are pharmaceutical compositions comprising the compound alone, or a mixture of the compound with other compounds of the genus or subgenus, or a mixture of the compound with an alternative compound described herein, or a mixture of the compound with one or more alternative pharmaceutically active compounds, and one or more pharmaceutically acceptable carriers, diluents, excipients, or combinations thereof. The pharmaceutical compositions described herein can be administered to a human patient by themselves, or they can be administered in pharmaceutical compositions in which they are mixed with other active ingredients, such as in combination therapy, or mixed with carriers, diluents, excipients, or combinations thereof. The appropriate formulation will depend on the route of administration selected. Techniques for formulating and administering the compounds described herein are known to those skilled in the art.

[0171] The pharmaceutical compositions disclosed herein can be prepared in any known manner, for example, by conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, encapsulating, or tabletting processes. In addition, the active ingredient is contained in an amount effective to achieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein can be provided as salts containing pharmaceutically compatible counterions.

[0172] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions in which they are mixed with other active ingredients, as in combination therapy, or mixed with a suitable carrier or excipient(s). Techniques for formulating and administering the compounds of the present application can be found in "Remington's Pharmaceutical Sciences," Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0173] Suitable routes of administration may include, for example, oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injection, and intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injection. The compounds may also be administered in sustained- or controlled-release dosage forms, including depot injections, osmotic pumps, pills, transdermal (including electrotransport) patches, and the like, for prolonged and / or regular pulse administration at a predetermined rate.

[0174] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, for example, by means of conventional mixing, dissolving, granulating, dragee-making, pulverizing, emulsifying, encapsulating, entrapping, or tabletting processes.

[0175] Therefore, pharmaceutical compositions for use according to the present invention can be formulated in a conventional manner using one or more physiologically acceptable carriers, including excipients and adjuvants that facilitate the processing of active compounds into pharmaceutically usable preparations.Appropriate formulations depend on the selected route of administration.Any well-known techniques, carriers, and excipients can be used as suitable and understood in the art, for example, in Remington's Pharmaceutical Sciences, supra.

[0176] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for dissolution or suspension in liquid prior to injection, or emulsions. Suitable excipients include, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, and cysteine ​​hydrochloride. In addition, if desired, injectable pharmaceutical compositions may contain small amounts of non-toxic auxiliary substances, such as wetting agents and pH buffering agents. Physiologically compatible buffers include, but are not limited to, Hank's solution, Ringer's solution, or physiological saline buffer. If desired, absorption-enhancing preparations (e.g., liposomes) can be used.

[0177] For transmucosal administration, penetrants appropriate to the barrier to be permeated can be used in the formulation.

[0178] Pharmaceutical formulations for parenteral administration, for example, by bolus injection or continuous infusion, include aqueous solutions of the active compound in water-soluble form. In addition, suspensions of the active compound can be prepared as appropriate oily injection suspensions. Suitable lipophilic solvents or vehicles include fatty oils, such as sesame oil, or other organic oils, such as soybean, grapefruit, or almond oil, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions can contain substances that increase the viscosity of the suspension, such as sodium carboxymethylcellulose, sorbitol, or dextran. Optionally, the suspension can also contain suitable stabilizers or agents that increase the solubility of the compound, allowing for the preparation of highly concentrated solutions. Formulations for injection can be provided in unit dosage form, for example, in ampoules or multi-dose containers, with added preservatives. The compositions can take the form of suspensions, solutions, or emulsions in oily or aqueous vehicles, and can contain formulatory agents such as suspending, stabilizing, and / or dispersing agents. Alternatively, the active ingredient may be in powder form for constitution with a suitable vehicle, eg, sterile pyrogen-free water, before use.

[0179] For oral administration, the compounds can be easily formulated by combining the active compound with pharmaceutically acceptable carriers well known in the art. Such carriers allow the compounds of the present invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions, etc., for oral ingestion by the patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compound with a solid excipient, optionally grinding the resulting mixture, and, if desired, adding suitable excipients, processing the granular mixture to obtain tablets or dragee cores. Suitable excipients are, in particular, sugars, including fillers such as lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as corn starch, wheat starch, rice starch, potato starch, gelatin, tragacanth gum, methylcellulose, hydroxypropylmethylcellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrants such as cross-linked polyvinylpyrrolidone, agar, or alginic acid or its salts, such as sodium alginate, can be added. The dragee core is provided with a suitable coating. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or dragee coating to identify the active compound dose or to characterize different combinations thereof. For this purpose, concentrated sugar solutions can be used, which can optionally contain gum arabic, talc, polyvinylpyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, a lacquer solution, and a suitable organic solvent or solvent mixture. Dyes or pigments can be added to the tablet or dragee coating to identify the active compound dose or to characterize different combinations thereof.

[0180] Pharmaceutical preparations that can be used orally include push-fit capsules made of gelatin, and soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. Push-fit capsules can contain a mixture of active ingredients and fillers, such as lactose, binders, such as starch, and / or lubricants, such as talc or magnesium stearate, and optionally stabilizers. In soft capsules, the active compound can be dissolved or suspended in a suitable liquid, such as fatty oils, liquid paraffin, or liquid polyethylene glycol. In addition, stabilizers can be added. All preparations for oral administration should be in dosages suitable for such administration.

[0181] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0182] For administration by inhalation, the compound for use according to the present invention is conveniently delivered in the form of aerosol spray presentation from a pressurized pack or nebulizer, using a suitable propellant, for example, dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas.In the case of pressurized aerosol, dosage unit can be determined by providing a valve to deliver a metered amount.Capsules and cartridges for use in inhalers or insufflators, for example, gelatin capsules and cartridges, can be formulated to contain a powder mix of the compound and a suitable powder base, for example, lactose or starch.

[0183] Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses including intraocular, intranasal, and intraauricular delivery. Suitable penetrants for these uses are generally known in the art. Pharmaceutical compositions for intraocular delivery include aqueous ophthalmic solutions of the active compound in water-soluble form, such as eye drops, or aqueous ophthalmic solutions of the active compound in gellan gum (Shedden et al., Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2):101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticles, small drug-containing polymer particles suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol., 10(1):29-45 (1994)); lipid-soluble formulations (Alm et al., J. Ocul. Pharmacol., 10(1):29-45 (1994)); al., Prog. Clin. Biol. Res., 312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Sci., 52(1):101-6 (1999)); and intraocular inserts. All of the above references are incorporated herein by reference in their entirety. Such suitable pharmaceutical formulations are most frequently and preferably formulated to be sterile, isotonic, buffered formulations for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays, which are often prepared to mimic nasal secretions in many respects and ensure the maintenance of normal ciliary action. As disclosed in Remington's Pharmaceutical Sciences, 18th Ed., Mack Publishing Co., Easton, PA (1990), which is incorporated herein by reference in its entirety and is well known to those skilled in the art, suitable formulations are most often and preferably isotonic, weakly buffered formulations that maintain a pH of 5.5 to 6.5, and most often and preferably contain antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application within the ear. Common solvents for such otic formulations include glycerin and water.

[0184] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, eg, suppositories or retention enemas containing conventional suppository bases such as cocoa butter or other glycerides.

[0185] In addition to the above-mentioned formulations, the compound can also be formulated as a depot preparation.Such long-acting preparations can be administered by implantation (for example, subcutaneously or intramuscularly) or by intramuscular injection.Thus, for example, the compound can be formulated with suitable polymer or hydrophobic materials (for example, as an emulsion in an acceptable oil) or ion exchange resins, or can be formulated as a sparingly soluble derivative, for example, as a sparingly soluble salt.

[0186] For hydrophobic compounds, a suitable pharmaceutical carrier may be a cosolvent system comprising benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. A common cosolvent system used is the VPD cosolvent system, which is a solution of 3% w / v benzyl alcohol, 8% w / v of the nonpolar surfactant Polysorbate 80™, and 65% w / v polyethylene glycol 300, made up by volume in absolute ethanol. Of course, the proportions of a cosolvent system may vary significantly without destroying its solubility and toxicity characteristics. Furthermore, the identity of the cosolvent components may vary; for example, other low-toxicity nonpolar surfactants may be used in place of POLYSORBATE 80™, the proportion of polyethylene glycol may vary, other biocompatible polymers, such as polyvinylpyrrolidone, may replace polyethylene glycol, and other sugars or polysaccharides may be substituted for dextrose.

[0187] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds can be used. Liposomes and emulsions are well-known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents, such as dimethyl sulfoxide, can also be used, although usually at the expense of greater toxicity. In addition, the compounds can be delivered using sustained-release systems, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known to those skilled in the art. Sustained-release capsules may release compounds for weeks up to over 100 days, depending on their chemical nature. Depending on the chemical nature and biological stability of the therapeutic reagent, additional strategies for protein stabilization can be employed.

[0188] Drugs intended for intracellular administration can be administered using techniques well known to those skilled in the art. For example, such drugs can be encapsulated in liposomes. All molecules present in aqueous solution at the time of liposome formation are incorporated into the aqueous interior. Both liposome contents are protected from the external microenvironment and are efficiently delivered into the cell cytoplasm because the liposome fuses with the cell membrane. Liposomes can be coated with tissue-specific antibodies. Liposomes are targeted to and selectively taken up by desired organs. Alternatively, small hydrophobic organic molecules can be directly administered intracellularly.

[0189] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical composition. Alternatively, or in addition, the pharmaceutical composition may be combined with other compositions containing other therapeutic or diagnostic agents.

[0190] Parenteral Pharmaceutical Compositions To prepare a parenteral pharmaceutical composition suitable for administration by injection (such as subcutaneous or intravenous), 0.1 mg to 120 mg of a water-soluble salt / soluble material itself / solubilized complex of the compound of the preferred embodiments is dissolved in sterile water and then mixed with 10 μL of 0.9% sterile saline. The mixture is incorporated into a unit dosage form suitable for administration by injection.

[0191] Injectable Pharmaceutical Compositions To prepare an injectable formulation, 0.1 mg to 100 mg of a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (III), or (IV), 2.0 mL of sodium acetate buffer solution (0.4 M), HCl (1 N), or NaOH (1 M) (pH) (qs to suitable pH), and water (distilled, sterile) (qs to 20 mL) are mixed. All of the above ingredients, except for water, are mixed and stirred, and if necessary, slightly heated. A sufficient amount of water is then added.

[0192] Oral Pharmaceutical Compositions To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 120 mg of the compound of one embodiment is mixed with 750 mg of starch. The mixture is incorporated into an oral dosage unit, such as a hard gelatin capsule, or 0.1 mg to 120 mg of the compound is granulated with a binder solution, such as a starch solution, a suitable diluent, such as microcrystalline cellulose, and a disintegrant, such as croscarmellose sodium, and the resulting mixture is dried, lubricated, and compressed into tablets suitable for oral administration.

[0193] Sublingual (hard lozenge) pharmaceutical compositions To prepare a pharmaceutical composition for buccal delivery, e.g., a hard lozenge, 0.1 mg to 120 mg of a compound of a preferred embodiment is mixed with 420 mg of powdered sugar / mannitol / xylitol, or such a sugar that provides a negative heat of solution to the system, 1.6 mL of light corn syrup, 2.4 mL of distilled water, and 0.42 mL of mint extract or other flavoring. The mixture is blended and poured into a mold to form a lozenge suitable for buccal administration.

[0194] Rapidly disintegrating sublingual tablets Rapidly disintegrating sublingual tablets are prepared by mixing 48.5% by weight of a compound of a preferred embodiment, 20% by weight of microcrystalline cellulose (KG-802), 24.5% by weight of either mannitol or modified dextrose, or a combination thereof, which promotes faster dissolution of the compressed tablet in the mouth, 5% by weight of low-substituted hydroxypropyl cellulose (50 μm), and 2% by weight of magnesium stearate. The tablets are prepared by direct compression (AAPS PharmSciTech. 2006;7(2):E41). The total weight of the compressed tablets is maintained at 150 mg. The formulation is prepared by mixing the above amount of a compound of a preferred embodiment with the total amount of microcrystalline cellulose (MCC) and mannitol / modified dextrose or a combination, and two-thirds of the amount of low-substituted hydroxypropyl cellulose (L-HPC) for 4.5 minutes using a three-dimensional manual mixer (Inversina, Bioengineering AG, Switzerland). All of the magnesium stearate (MS) and the remaining one-third of the L-HPC are added 30 seconds before the end of mixing.

[0195] Inhaled Pharmaceutical Compositions To prepare a pharmaceutical composition for inhalation delivery, 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 50 mg of anhydrous citric acid and 100 mL of 0.9% sodium chloride solution. The mixture is incorporated into an inhalation delivery unit, such as a nebulizer, suitable for inhalation administration.

[0196] Nebulizer Suspension Pharmaceutical Composition In another embodiment, a compound of the preferred embodiments (0.1 mg to 100 mg) is suspended in sterile water (100 mL) and Span 85 (1 g) is added, followed by dextrose (5.5 g) and ascorbic acid (10 mg). Benzalkonium chloride (3 mL of a 1:750 aqueous solution) is added and the pH is adjusted to 7 with phosphate buffer. The suspension is packaged in a sterile nebulizer.

[0197] Transdermal patch pharmaceutical composition To prepare a pharmaceutical composition for transdermal delivery, 0.1 mg to 100 mg of a compound of a preferred embodiment is embedded in or deposited on a patch having a single adhesive surface, and the resulting patch is then attached to the skin via the adhesive surface for transdermal administration.

[0198] Topical gel pharmaceutical composition To prepare a pharmaceutical topical gel composition, 0.1 mg to 100 mg of a compound of the preferred embodiments is mixed with 1.75 g of hydroxypropyl cellulose, 10 mL of propylene glycol, 10 mL of isopropyl myristate, and 100 mL of purified alcohol USP. The resulting gel mixture is then incorporated into a container, such as a tube, suitable for topical administration.

[0199] ophthalmic solution To prepare a pharmaceutical ophthalmic solution composition, 0.1 mg to 100 mg of a compound of the preferred embodiments is mixed with 0.9 g of NaCl in 100 mL of purified water and filtered using a 0.2 micron filter. The resulting isotonic solution is then incorporated into an ophthalmic delivery unit, such as an eye dropper, suitable for ophthalmic administration.

[0200] nasal spray solution To prepare a pharmaceutical nasal spray solution, 0.1 mg to 100 mg of a compound of the preferred embodiments is mixed with 30 mL of 0.05 M phosphate buffer solution (pH 4.4). The solution is placed in a nasal applicator designed to deliver a 100 μl spray for each application.

[0201] Immune checkpoint inhibitors In some embodiments, one or more immune checkpoint inhibitors may be co-administered with a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (III), or (IV). A review describing immune checkpoint pathways and blockade of such pathways with immune checkpoint inhibitor compounds is provided by Pardoll in Nature Reviews Cancer (April 2012), pp. 252-264, which is incorporated herein by reference in its entirety. Immune checkpoint inhibitor compounds exhibit anti-tumor activity by blocking one or more endogenous immune checkpoint pathways that down-regulate anti-tumor immune responses. Inhibition or blockade of immune checkpoint pathways typically involves inhibiting checkpoint receptor and ligand interactions with immune checkpoint inhibitor compounds to reduce or eliminate the down-regulatory signal and the resulting attenuation of the anti-tumor response.

[0202] In some embodiments of the present disclosure, immune checkpoint inhibitor compounds inhibit signaling interactions between immune checkpoint receptors and their corresponding ligands. Immune checkpoint inhibitor compounds can act by blocking activation of immune checkpoint pathways through the inhibition (antagonism) of immune checkpoint receptors (some example receptors include CTLA-4, PD-1, LAG-3, TIM-3, BTLA, and KIR) or through the inhibition of ligands of immune checkpoint receptors (some example ligands include PD-L1 and PD-L2). In such embodiments, the effect of the immune checkpoint inhibitor compound is to reduce or eliminate downregulation of certain aspects of the immune system's anti-tumor response in the tumor microenvironment.

[0203] The programmed death 1 (PD-1) protein is an inhibitory member of the extended CD28 / CTLA-4 family of T cell regulatory factors (Okazaki et al. (2002) Curr Opin Immunol 14:391779-82; Bennett et al. (2003) J. Immunol. 170:711-8; these references are incorporated herein by reference in their entireties). Other members of the CD28 family include CD28, CTLA-4, ICOS, and BTLA. PD-1 has been suggested to exist as a monomer lacking the unpaired cysteine ​​residue characteristic of other CD28 family members. PD-1 is expressed on activated B cells, T cells, and monocytes.

[0204] The PD-1 gene encodes a 55-kDa type I transmembrane protein (Agata et al. (1996) Int Immunol. 8:765-72; this document is incorporated herein by reference in its entirety). Although structurally similar to CTLA-4, PD-1 lacks the MYPPY motif that is important for B7-1 and B7-2 binding. Two ligands for PD-1, PD-L1 (B7-H1) and PD-L2 (B7-DC), have been identified and have been shown to downregulate T cell activation upon binding to PD-1 (Freeman et al. (2000) J. Exp. Med. 192:1027-34; Carter et al. (2002) Eur. J. Immunol. 32:634-43; this document is incorporated herein by reference in its entirety). Both PD-L1 and PD-L2 are B7 homologs that bind to PD-1 but not other CD28 family members. PD-L1 is abundant in a variety of human cancers (Dong et al. (2002) Nat. Med. 8:787-9; incorporated herein by reference in its entirety).

[0205] PD-1 is known as an immunoinhibitory protein that negatively regulates TCR signaling (Ishida, Y. et al. (1992) EMBOJ. 11:3887-3895; Blank, C. et al. (Epub 2006 Dec. 29) Immunol. Immunother. 56(5):739-745; these documents are incorporated herein by reference in their entirety). The interaction between PD-1 and PD-L1 can act as an immune checkpoint, which can result in, for example, a reduction in tumor-infiltrating lymphocytes, a reduction in T cell receptor-mediated proliferation, and / or immune evasion by cancer cells (Dong et al. (2003) J. Mol. Med. 81:281-7; Blank et al. (2005) Cancer Immunol. Immunother. 54:307-314; Konishi et al. (2004) Clin. Cancer Res. 10:5094-100; these references are incorporated herein by reference in their entireties). Immune suppression can be reversed by inhibiting the local interaction of PD-1 with PD-L1 or PD-L2, and the effect is additive when the interaction of PD-1 with PD-L2 is also blocked (Iwai et al. (2002) Proc. Nat'l. Acad. Sci. USA 99:12293-7; Brown et al. (2003) J. Immunol. 170:1257-66; these references are incorporated herein by reference in their entireties).

[0206] The immune checkpoint receptor cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) is expressed on T cells and is involved in signaling pathways that reduce the level of T cell activation. CTLA-4 is thought to be able to downregulate T cell activation through competitive binding and sequestration of CD80 and CD86. In addition, CTLA-4 downregulates T Reg It has been shown to be involved in enhancing the immunosuppressive activity of cells.

[0207] The immune checkpoint receptor programmed death 1 (PD-1) is expressed by activated T cells upon prolonged exposure to antigen. The association of PD-1 with its known binding ligands, PD-L1 and PD-L2, occurs primarily within the tumor microenvironment and results in downregulation of anti-tumor-specific T cell responses. Both PD-L1 and PD-L2 are known to be expressed on tumor cells. Expression of PD-L1 and PD-L2 on tumors correlates with reduced survival outcomes.

[0208] The immune checkpoint receptor T-cell membrane protein 3 (TIM-3) is expressed on Th1 and Tc1 cells but not on other T cells. Interaction of TIM-3 with its ligand, galectin-9, generates a Th1 cell death signal. TIM-3 has been reported to play a role in maintaining T cell exhaustion, and blockade of TIM-3 has been shown to restore the activity of exhausted T cells.

[0209] The immune checkpoint receptor B and T lymphocyte attenuator (BTLA) receptor is expressed on both resting and activated B and T cells. Activation of BTLA, when combined with its ligand, HVEM (herpesvirus entry mediator), leads to downregulation of both T cell activation and proliferation. HVEM is expressed by certain tumors (e.g., melanoma) and tumor-associated endothelial cells.

[0210] Immune checkpoint receptors known as killer cell immunoglobulin-like receptors (KIRs) are a polymorphic family of receptors expressed on NK cells and some T cells, and function as regulators of immune tolerance associated with natural killer (NK) cells. Blocking certain KIR receptors with inhibitor compounds can facilitate tumor destruction through increased NK cell activity.

[0211] In some embodiments of the present disclosure, the immune checkpoint inhibitor compound is a small organic molecule (molecular weight less than 1000 daltons), a peptide, a polypeptide, a protein, an antibody, an antibody fragment, or an antibody derivative. In some embodiments, the immune checkpoint inhibitor compound is an antibody. In some embodiments, the antibody is a monoclonal antibody, particularly a human monoclonal antibody or a humanized monoclonal antibody.

[0212] Monoclonal antibodies, antibody fragments, and antibody derivatives for blocking immune checkpoint pathways can be prepared by any of several methods known to those skilled in the art, including, but not limited to, somatic cell hybridization techniques and hybridoma methods. Hybridoma production is described in "Antibodies, A Laboratory Manual," Harlow and Lane, 1988, Cold Spring Harbor Publications, New York, which is incorporated herein by reference in its entirety. Human monoclonal antibodies can be identified and isolated by screening phage display libraries of human immunoglobulin genes by the methods described in, for example, U.S. Patent Nos. 5,223,409, 5,403,484, 5,571,698, 6,582,915, and 6,593,081, which are incorporated herein by reference in their entireties. Monoclonal antibodies may be prepared using the general methods described in US Pat. No. 6,331,415 (Cabilly), which is incorporated herein by reference in its entirety.

[0213] As an example, human monoclonal antibodies can be prepared using XenoMouse™ (Abgenix, Freemont, Calif.) or hybridomas of B cells from a XenoMouse, a mouse host with functional human immunoglobulin genes as described in U.S. Patent No. 6,162,963 (Kucherlapati), which is incorporated herein by reference in its entirety.

[0214] Methods for the preparation and use of immune checkpoint antibodies are described in the following illustrative publications: The preparation and therapeutic use of anti-CTLA-4 antibodies is described in U.S. Patent No. 7,229,628 (Allison), U.S. Patent No. 7,311,910 (Linsley), and U.S. Patent No. 8,017,144 (Korman), which are incorporated herein by reference in their entireties. The preparation and therapeutic use of anti-PD-1 antibodies is described in U.S. Patent No. 8,008,449 (Korman) and U.S. Patent Application No. 2011 / 0271358 (Freeman), which are incorporated herein by reference in their entireties. The preparation and therapeutic use of anti-PD-L1 antibodies is described in U.S. Patent No. 7,943,743 (Korman), which is incorporated herein by reference in its entirety. The preparation and therapeutic use of anti-TIM-3 antibodies is described in U.S. Patent No. 8,101,176 (Kuchroo) and U.S. Patent No. 8,552,156 (Tagayanagi), which are incorporated herein by reference in their entireties. The preparation and therapeutic use of anti-LAG-3 antibodies is described in U.S. Patent Application No. 2011 / 0150892 (Thudium) and WO 2014 / 008218 (Lonberg), which are incorporated herein by reference in their entireties. The preparation and therapeutic use of anti-KIR antibodies is described in U.S. Patent No. 8,119,775 (Moretta), which is incorporated herein by reference in its entirety. The preparation of antibodies that block the BTLA regulatory inhibitory pathway (anti-BTLA antibodies) is described in U.S. Patent No. 8,563,694 (Mataraza), which is incorporated herein by reference in its entirety.

[0215] In some embodiments, the one or more immune checkpoint inhibitors are inhibitors of PD-1, PD-L1, or CTLA-4. In some embodiments, the immune checkpoint inhibitor is a PD-1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a binding ligand of PD-1. In some embodiments, the immune checkpoint inhibitor is a PD-L1 inhibitor. In some embodiments, the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0216] In some embodiments, the one or more immune checkpoint inhibitors described herein comprise a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor. In some embodiments, the first and second immune checkpoint inhibitors are independently inhibitors of PD-1, PD-L1, or CTLA-4. In some embodiments, the first immune checkpoint inhibitor is a PD-1 inhibitor and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0217] In some embodiments, the immune checkpoint inhibitor is pembrolizumab, nivolumab, cemiplimab, atezolizumab, avelumab, pembrolizumab, pidilizumab, ipilimumab, BMS 936559, durvalumab, or any combination thereof. In some embodiments, the one or more immune checkpoint inhibitors may include an anti-PD-1 HuMAb, and may be selected from 17D8, 2D3, 4H1, 5C4 (also referred to herein as nivolumab), 4A1 1, 7D3, and 5F4, all of which are described in U.S. Patent No. 8,008,449, which is incorporated herein by reference in its entirety. In some embodiments, the anti-PD-1 HuMAb may be selected from 3G10, 12A4 (also referred to herein as BMS-936559), 10A5, 5F8, 10H10, 1B12, 7H1, 1 1E6, 12B7, and 13G4, all of which are described in U.S. Patent No. 7,943,743, which is incorporated herein by reference in its entirety.

[0218] In some embodiments, one or more immune checkpoint inhibitors may be incorporated into a pharmaceutically acceptable formulation. In some embodiments, one or more immune checkpoint inhibitors are incorporated into a pharmaceutically acceptable aqueous formulation. Examples of acceptable aqueous formulations include isotonic buffered saline solutions adjusted to pH 4.5 to 8, such as lactated Ringer's solution.

[0219] In some embodiments, the immune checkpoint inhibitor compound is incorporated into a pharmaceutically acceptable liposomal formulation, which is a passive or targeted liposomal formulation. Examples of methods for the preparation of suitable liposomal formulations of antibodies are described in U.S. Patent No. 5,399,331 (Loughrey), U.S. Patent No. 8,304,565 (Wu), and U.S. Patent No. 7,780,882 (Chang), which are incorporated herein by reference in their entireties.

[0220] In some embodiments, the one or more immune checkpoint inhibitors may be antibodies. In some embodiments, the antibodies are dry, lyophilized solids that are reconstituted with an aqueous reconstitution solvent prior to use. In some embodiments, the antibodies are incorporated into a pharmaceutically acceptable formulation, and the pharmaceutically acceptable formulation is injected directly into the tumor. In some embodiments, the immune checkpoint inhibitor antibodies are incorporated into a pharmaceutically acceptable formulation, and the pharmaceutically acceptable formulation is injected into the peritumoral region surrounding the tumor. The peritumoral region may contain anti-tumor immune cells. In some embodiments, the antibodies are incorporated into a pharmaceutically acceptable formulation, and the pharmaceutically acceptable formulation is administered by intravenous injection or infusion. In some embodiments, the immune checkpoint inhibitor antibodies are incorporated into a pharmaceutically acceptable formulation, and the pharmaceutically acceptable formulation is administered by subcutaneous or intradermal injection. In some embodiments, the antibodies are incorporated into a pharmaceutically acceptable formulation, and the pharmaceutically acceptable formulation is administered by intraperitoneal injection or lavage.

[0221] The precise amount of immune checkpoint inhibitor compound incorporated within a particular method or therapeutic combination of the present disclosure may vary depending on factors known in the art, such as the subject's physical and clinical condition, the method of administration, the contents of the formulation, the physical and chemical properties of the immune checkpoint inhibitor compound, and the intended dosing regimen or sequence. However, one of ordinary skill in the art can readily determine the appropriate amount with due consideration of such factors.

[0222] Method of Treatment / Use Embodiments disclosed herein relate to administering to a subject in need thereof an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising one or more compounds described herein (e.g., one or more compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof).

[0223] As disclosed elsewhere herein, some embodiments relate to treating a disease or condition, e.g., cancer, via administration of a compound or composition disclosed herein. Subjects in need of receiving a compound or composition disclosed herein to improve their health need not always be identified prior to receiving a first treatment with the compound or composition. For example, a subject may be predetermined to develop a disease or condition, e.g., cancer, before exhibiting any symptoms of the disease or condition. Alternatively, a subject may receive treatment prophylactically if the subject is at risk for or has not developed a disease or condition, e.g., cancer (e.g., when the patient exhibits symptoms of another disease or condition related to cancer). Thus, in some embodiments, a compound or composition may be administered to a subject after the subject has received an early stage diagnosis. In some embodiments, not all subjects are candidates for such administration, and identification of treatment subjects may be desirable. It is understood that patient selection depends on several factors within the skill of an ordinarily skilled physician. Accordingly, some embodiments disclosed herein further include identifying the subject as one who would benefit from administration of an effective amount of at least one compound or composition to increase lifespan extension, increase survival time, or increase longevity.

[0224] In another aspect, the present disclosure is directed to a method for the treatment, prevention, or prophylaxis of cancer, which can include administering to a subject in need thereof an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof). In certain embodiments, the cancer can be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, renal cancer, colorectal cancer, melanoma, or leukemia. In further or additional embodiments, the cancer is brain cancer or adrenocortical carcinoma. In further or additional embodiments, the cancer is breast cancer. In further or additional embodiments, the cancer is ovarian cancer. In further or additional embodiments, the cancer is pancreatic cancer. In further or additional embodiments, the cancer is gastric cancer. In further or additional embodiments, the cancer is prostate cancer. In further or additional embodiments, the cancer is renal cancer. In further or additional embodiments, the cancer is colorectal cancer. In further or additional embodiments, the cancer is myeloid leukemia. In further or additional embodiments, the cancer is glioblastoma. In further or additional embodiments, the cancer is follicular lymphoma. In further or additional embodiments, the cancer is pre-B acute leukemia. In further or additional embodiments, the cancer is chronic lymphocytic B leukemia. In further or additional embodiments, the cancer is mesothelioma. In further or additional embodiments, the cancer is small cell carcinoma. In further or additional embodiments, the cancer is melanoma.

[0225] Some embodiments relate to a method of inhibiting proliferation of cells with a RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is associated with a RAS mutation. Some embodiments relate to a method of inducing apoptosis in cells with a RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. Some embodiments relate to a method of inhibiting proliferation of cells having a KRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is associated with a KRAS mutation. Some embodiments relate to a method of inducing apoptosis in cells having a KRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. Some embodiments relate to a method of inhibiting proliferation of cells with an NRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is associated with an NRAS mutation. Some embodiments relate to a method of inducing apoptosis in cells with an RAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the cancer is associated with an NRAS mutation.Some embodiments relate to a method of inducing apoptosis in cells having a KRAS mutation, comprising administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the KRAS mutation is at codon 12, 13, 59, 61, and / or 146. In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H. In some embodiments, the mutant form of the KRAS protein has one or more amino acid substitutions selected from the group consisting of G12C, G12R, G12S, G12A, G12D, G12V, G13C, G13R, G13S, G13A, G13D, G13V, A59E, A59G, A59T, Q61K, Q61L, Q61R, Q61H, K117N, K117R, K117E, A146P, A146T, and A146V.

[0226] In certain embodiments, the cancer is resistant to treatment with a MEK protein kinase inhibitor. In other embodiments, the cancer is resistant to treatment with a RAF protein kinase inhibitor. In still further embodiments, the resistance is acquired resistance. In other embodiments, the resistance is de novo resistance. In further or additional embodiments, the cancer is resistant to an anti-cancer drug.

[0227] In some aspects, provided herein are compounds or pharmaceutical compositions and methods for treating cancer, comprising a therapeutically effective amount of a dual MEK protein kinase inhibitor. In some embodiments, administration of the dual MEK protein kinase inhibitor provides an increase in the area under the serum concentration-time curve (AUC) of the dual MEK protein kinase inhibitor. In some embodiments, the cancer is resistant to treatment with a RAF protein kinase inhibitor. In further embodiments, the cancer is resistant to a RAF protein kinase inhibitor, and the RAF protein kinase inhibitor comprises an A-RAF inhibitor, a B-RAF inhibitor, or a C-RAF inhibitor. In further embodiments, the cancer is resistant to a RAF protein kinase inhibitor, and the RAF protein kinase inhibitor comprises a B-RAF inhibitor.

[0228] In some embodiments, the resistant cancer is pancreatic cancer, melanoma, colon cancer, lung cancer, or gastric cancer. In further embodiments, the resistant cancer is pancreatic cancer. In additional embodiments, the resistant cancer is gastric cancer. In alternative embodiments, pharmaceutical combinations and methods are provided for resensitizing cancer cells to treatment in a patient having or suspected of having a cancer that is resistant to an anti-cancer agent, comprising administering to the patient a therapeutically effective amount of a dual MEK inhibitor disclosed herein.

[0229] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV), or a pharmaceutically acceptable salt thereof, is co-administered with a CTLA-4 receptor inhibitor compound. In some embodiments, a compound of Formula (I) is co-administered with a PD-1 or PD-L1 receptor inhibitor compound.

[0230] In some embodiments, the method comprises treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a LAG-3 receptor inhibitor compound. In some embodiments, the method comprises treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I) and a TIM-3 receptor inhibitor compound. In some embodiments, the method comprises treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a BTLA receptor inhibitor compound. In some embodiments, the method comprises treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a KIR receptor inhibitor compound. In some embodiments, the method comprises treating the subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a PD-L1 inhibitor compound. In some embodiments, the methods include treating the subject by co-administering therapeutically effective amounts of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a PD-L2 inhibitor compound.

[0231] In some embodiments of the present disclosure, a method comprises treating a subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and an immune checkpoint pathway blocking antibody. In some embodiments, a method comprises treating a subject by co-administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and an anti-CTLA-4 receptor antibody. In some embodiments, the method includes treating the subject by co-administering therapeutically effective amounts of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and an anti-PD-1 receptor antibody.

[0232] In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-LAG-3 receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-TIM-3 receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-BTLA receptor antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-KIR receptor antibody. In some embodiments, the anti-KIR receptor antibody is lirilumab. In some embodiments, the method comprises co-administering to a subject having a tumor therapeutically effective amounts of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-PD-1 antibody. In some embodiments, the anti-PD-1 antibody is lambrolizumab, pidilizumab, or nivolumab. In some embodiments, the method comprises co-administering to a subject having a tumor therapeutically effective amounts of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-PD-L1 antibody.In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-PD-L2 antibody. In some embodiments, the method comprises co-administering to a subject having a tumor a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an anti-CTLA-4 antibody. In some embodiments, the anti-CTLA-4 antibody is ipilimumab or tremelimumab.

[0233] In some embodiments, the methods include co-administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and an immune checkpoint inhibitor to treat, prevent, or ameliorate cancer or tumor in a subject by administering a compound of Formula (I) or a pharmaceutically acceptable salt thereof and an immune checkpoint inhibitor. In some embodiments, the subject has been refractory to previous treatment with an immune checkpoint inhibitor alone.

[0234] In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a PD-1 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a PD-L1 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a PD-L2 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a CTLA-4 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, a PD-1 inhibitor, and a CTLA-4 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a LAG-3 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a KIR inhibitor.In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a TIM-3 inhibitor. In some embodiments, a method for treating a subject having cancer or a tumor comprises administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, and a BTLA inhibitor.

[0235] In some embodiments, the method for treating a subject comprises treating the subject who has exhibited resistance to a PD-L1 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises treating the subject who has exhibited resistance to a PD-L1 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises treating a subject who has exhibited resistance to a PD-L2 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method comprises treating a subject who has exhibited resistance to a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof when the subject has developed resistance to two different immune checkpoint inhibitors. The two different immune inhibitors may be selected from a CTLA-4 receptor inhibitor, a PD-1 receptor inhibitor, a LAG-3 receptor inhibitor, a TIM-3 receptor inhibitor, a BTLA receptor inhibitor, a KIR receptor inhibitor, a PD-L1 inhibitor, or a PD-L2 inhibitor.In some embodiments, the method includes treating a subject who has exhibited resistance to a PD-1 inhibitor and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes treating a subject who has exhibited resistance to a PD-L1 inhibitor and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, the method includes treating a subject who has exhibited resistance to a PD-1 inhibitor, a PD-L1 inhibitor, and a CTLA-4 inhibitor by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof.

[0236] Some embodiments disclosed herein relate to a method of treating a mammal having a disease, which may include administering to a subject in need thereof an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof). Other embodiments disclosed herein relate to methods of treating a subject with cancer cachexia, which may include administering to the subject an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising a compound described herein, e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof).

[0237] Some embodiments described herein relate to the use of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof) in the manufacture of a medicament for ameliorating and / or treating cancer or a cancerous condition, e.g., cancer cachexia, which can include administering to a subject an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (Iib), (Iic), (Iid), (III), (IV) or a pharmaceutically acceptable salt thereof). Still other embodiments described herein relate to one or more compounds described herein (e.g., compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or pharmaceutically acceptable salts thereof), which can be used to ameliorate and / or treat cancer or a cancerous condition, e.g., cancer cachexia, by administering to a subject an effective amount of one or more compounds described herein or a pharmaceutically acceptable salt thereof.

[0238] Some embodiments disclosed herein relate to methods of ameliorating and / or treating cancer, which may include contacting cancer cells with an effective amount of one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (Iib), (Iic), (Iid), (III), (IV) or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition comprising one or more compounds described herein (e.g., a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof). In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof can act as an inhibitor of MEK. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof can act as an inhibitor of ERK. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (Iib), (Iic), (Iid), (III), or (IV) or a pharmaceutically acceptable salt thereof can act as a STAT3 (pSER-727) inhibitor. In some embodiments, compounds of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or pharmaceutically acceptable salts thereof may reduce inflammatory cachexia and muscle wasting.

[0239] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in a single dose, once daily. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in multiple doses, two or more times daily. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered once daily. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered twice daily. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered three times daily. In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered four times daily.

[0240] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof can inhibit abnormal cell growth. In some embodiments, the abnormal cell growth occurs in a mammal. A method for inhibiting abnormal cell growth can include administering an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (Iib), (Iic), (Iid), (III), or (IV) or a pharmaceutically acceptable salt thereof, wherein the abnormal cell growth is inhibited. A method for inhibiting abnormal cell growth in a mammal can include administering to the mammal a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof, wherein the amount of the compound is effective in inhibiting abnormal cell growth in the mammal.

[0241] In another aspect, the present invention is directed to a method of degrading, inhibiting the growth of, or killing cancer cells, comprising contacting the cells with a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof effective to degrade, inhibit the growth of, or kill the cells. In some embodiments, the cancer cells comprise brain cancer cells, breast cancer cells, lung cancer cells, ovarian cancer cells, pancreatic cancer cells, gastric cancer cells, prostate cancer cells, renal cancer cells, melanoma cells, or colorectal cancer cells.

[0242] In some embodiments, the cancer cells are degraded. In some embodiments, 1% of the cancer cells are degraded. In further or additional embodiments, 2% of the cancer cells are degraded. In further or additional embodiments, 3% of the cancer cells are degraded. In further or additional embodiments, 4% of the cancer cells are degraded. In further or additional embodiments, 5% of the cancer cells are degraded. In further or additional embodiments, 10% of the cancer cells are degraded. In further or additional embodiments, 20% of the cancer cells are degraded. In further or additional embodiments, 25% of the cancer cells are degraded. In further or additional embodiments, 30% of the cancer cells are degraded. In further or additional embodiments, 40% of the cancer cells are degraded. In further or additional embodiments, 50% of the cancer cells are degraded. In further or additional embodiments, 60% of the cancer cells are degraded. In further or additional embodiments, 70% of the cancer cells are degraded. In further or additional embodiments, 75% of the cancer cells are degraded. In further or additional embodiments, 80% of the cancer cells are degraded. In further or additional embodiments, 90% of the cancer cells are degraded. In further or additional embodiments, 100% of the cancer cells are degraded. In further or additional embodiments, essentially all of the cancer cells are degraded.

[0243] In some embodiments, the cancer cells are killed. In further or additional embodiments, 1% of the cancer cells are killed. In further or additional embodiments, 2% of the cancer cells are killed. In further or additional embodiments, 3% of the cancer cells are killed. In further or additional embodiments, 4% of the cancer cells are killed. In further or additional embodiments, 5% of the cancer cells are killed. In further or additional embodiments, 1.0% of the cancer cells are killed. In further or additional embodiments, 20% of the cancer cells are killed. In further or additional embodiments, 25% of the cancer cells are killed. In further or additional embodiments, 30% of the cancer cells are killed. In further or additional embodiments, 40% of the cancer cells are killed. In further or additional embodiments, 50% of the cancer cells are killed. In further or additional embodiments, 60% of the cancer cells are killed. In further or additional embodiments, 70% of the cancer cells are killed. In further or additional embodiments, 75% of the cancer cells are killed. In further or additional embodiments, 80% of the cancer cells are killed. In further or additional embodiments, 90% of the cancer cells are killed. In further or additional embodiments, 100% of the cancer cells are killed. In further or additional embodiments, essentially all of the cancer cells are killed.

[0244] In further or additional embodiments, cancer cell growth is inhibited. In further or additional embodiments, cancer cell growth is inhibited by about 1%. In further or additional embodiments, cancer cell growth is inhibited by about 2%. In further or additional embodiments, cancer cell growth is inhibited by about 3%. In further or additional embodiments, cancer cell growth is inhibited by about 4%. In further or additional embodiments, cancer cell growth is inhibited by about 5%. In further or additional embodiments, cancer cell growth is inhibited by about 10%. In further or additional embodiments, cancer cell growth is inhibited by about 20%. In further or additional embodiments, cancer cell growth is inhibited by about 25%. In further or additional embodiments, cancer cell growth is inhibited by about 30%. In further or additional embodiments, cancer cell growth is inhibited by about 40%. In further or additional embodiments, cancer cell growth is inhibited by about 50%. In further or additional embodiments, cancer cell growth is inhibited by about 60%. In further or additional embodiments, cancer cell growth is inhibited by about 70%. In further or additional embodiments, cancer cell growth is inhibited by about 75%. In further or additional embodiments, cancer cell growth is inhibited by about 80%. In further or additional embodiments, cancer cell growth is inhibited by about 90%. In further or additional embodiments, cancer cell growth is inhibited by about 100%.

[0245] In some embodiments, tumor size is reduced by administering a therapeutically effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof. In further or additional embodiments, the tumor size is reduced by at least 1%. In further or additional embodiments, the tumor size is reduced by at least 2%. In further or additional embodiments, the tumor size is reduced by at least 3%. In further or additional embodiments, the tumor size is reduced by at least 4%. In further or additional embodiments, the tumor size is reduced by at least 5%. In further or additional embodiments, the tumor size is reduced by at least 10%. In further or additional embodiments, the tumor size is reduced by at least 20%. In further or additional embodiments, the tumor size is reduced by at least 25%. In further or additional embodiments, the tumor size is reduced by at least 30%. In further or additional embodiments, the tumor size is reduced by at least 40%. In further or additional embodiments, the tumor size is reduced by at least 50%. In further or additional embodiments, the tumor size is reduced by at least 60%. In further or additional embodiments, the tumor size is reduced by at least 70%. In further or additional embodiments, the tumor size is reduced by at least 75%. In further or additional embodiments, the tumor size is reduced by at least 80%. In further or additional embodiments, the tumor size is reduced by at least 85%. In further or additional embodiments, the tumor size is reduced by at least 90%. In further or additional embodiments, the tumor size is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the tumor does not increase in size.

[0246] In some embodiments, tumor growth is reduced by administering a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof. In some embodiments, tumor growth is reduced by at least 1%. In some embodiments, tumor growth is reduced by at least 2%. In some embodiments, tumor growth is reduced by at least 3%. In some embodiments, tumor growth is reduced by at least 4%. In some embodiments, tumor growth is reduced by at least 5%. In some embodiments, tumor growth is reduced by at least 10%. In some embodiments, tumor growth is reduced by at least 20%. In some embodiments, tumor growth is reduced by at least 25%. In some embodiments, tumor growth is reduced by at least 30%. In some embodiments, tumor growth is reduced by at least 40%. In some embodiments, tumor growth is reduced by at least 50%. In some embodiments, tumor growth is reduced by at least 60%. In some embodiments, tumor growth is reduced by at least 70%. In some embodiments, tumor growth is reduced by at least 75%. In some embodiments, tumor growth is reduced by at least 75%. In some embodiments, tumor growth is reduced by at least 80%. In some embodiments, tumor growth is reduced by at least 90%. In some embodiments, tumor growth is reduced by at least 95%. In some embodiments, tumor growth is prevented.

[0247] Method of administration The compound or pharmaceutical composition may be administered to a patient by any suitable means. Non-limiting examples of administration methods include, inter alia, (a) oral administration, including administration in capsules, tablets, granules, sprays, syrups, or other such forms; (b) parenteral administration, such as rectal, vaginal, urethral, ​​ocular, nasal, or auricular administration, including administration as an aqueous suspension or oily preparation, or as a drip, spray, suppository, salve, or ointment; (c) injection, such as subcutaneous, intraperitoneal, intravenous, intramuscular, intradermal, orbital, intracapsular, intraspinal, or intrasternal administration, including infusion pump delivery; (d) local administration, such as direct injection in the renal or cardiac region, for example, by depot implantation; and topical administration, as deemed appropriate by those skilled in the art for contacting the compound of the present invention with biological tissue.

[0248] Pharmaceutical compositions suitable for administration include compositions containing the active ingredient in an amount effective to achieve its intended purpose. The therapeutically effective amount of the compounds disclosed herein required as a dose will depend on the route of administration, the type of animal, including humans, being treated, and the physical characteristics of the specific animal under consideration. The dose can be adjusted to achieve the desired effect and will depend on factors such as body weight, diet, concomitant medications, and other factors that will be recognized by those skilled in the medical field. More specifically, a therapeutically effective amount refers to an amount of compound effective to prevent, alleviate, or ameliorate the symptoms of, or prolong the survival of, the subject being treated. Determining a therapeutically effective amount is well within the capabilities of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0249] As is readily apparent to those skilled in the art, the useful in vivo dosage and specific mode of administration will vary depending on the age, weight, and mammalian species being treated, the specific compound used, and the specific use for which these compounds are used. The determination of effective dosage levels, i.e., the dosage levels required to achieve the desired result, can be achieved by those skilled in the art using conventional pharmacological methods. Typically, human clinical application of a product begins at a lower dosage level, and the dosage level is increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and administration routes of the compositions identified by this method using established pharmacological methods.

[0250] In non-human animal studies, application of a potential product is initiated at a higher dosage level, and the dosage is then decreased until the desired effect is no longer achieved or adverse side effects disappear. Dosages can range widely, depending on the desired effect and therapeutic indication. Typically, dosages can be about 1 microgram / kg to 200 mg / kg body weight, preferably about 180 micrograms / kg to 10 mg / kg body weight. Alternatively, dosages can be calculated based on the patient's surface area, as will be understood by those skilled in the art.

[0251] The exact formulation, route of administration, and dosage for the pharmaceutical compositions of the present invention can be chosen by the individual physician in view of the patient's condition. (See Fingl et al., 1975, in "The Pharmacological Basis of Therapeutics," which is incorporated herein by reference in its entirety, and see particularly Chapter 1, page 1.) Typically, the dose range of the composition administered to a patient can be about 0.5 to 1000 mg / kg of the patient's body weight. Dosage can be a single dosage, or a series of two or more dosages given over the course of one or more days, depending on the needs of the patient. In cases where human dosages for a compound have been established for at least some conditions, the present invention uses these same dosages, or dosages that are about 0.1% to 500%, more preferably about 25% to 250%, of the established human dosage. When a human dosage has not been established, such as is the case for a newly discovered pharmaceutical composition, a suitable human dosage may be determined based on an ED derived from in vitro or in vivo studies, qualified by toxicity and efficacy studies in animals. 50 or TD 50 The value may be inferred from the .times. ...

[0252] It should be noted that the attending physician would know how and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunction. Conversely, if the clinical response is not adequate (excluding toxicity), the attending physician would also know how to adjust treatment to higher levels. The magnitude of the administered dose in the management of the disorder of interest will vary depending on the severity of the condition being treated and the route of administration. The severity of the condition may, for example, be assessed, in part, by standard prognostic evaluation methods. Furthermore, the dose and perhaps dose frequency will vary depending on the age, weight, and response of the individual patient. Programs equivalent to those discussed above can be used in veterinary medicine.

[0253] While the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding dosage can be made. A daily dosing regimen for an adult human patient may be, for example, an oral dose of 0.1 mg to 2000 mg, preferably 1 mg to 500 mg, e.g., 5 to 200 mg, of each active ingredient. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of 0.01 mg to 100 mg, preferably 0.1 mg to 60 mg, e.g., 1 to 40 mg, of each active ingredient is used. When administering a pharmaceutically acceptable salt, the dosage may be calculated as the free base. In some embodiments, the composition is administered one to four times daily. Alternatively, the compositions of the present invention may be administered by continuous intravenous infusion, preferably at a dose of up to 1000 mg of each active ingredient per day. As will be appreciated by those skilled in the art, in certain circumstances, it may be necessary to administer the compounds disclosed herein in amounts exceeding, or even far exceeding, the preferred dosage ranges set forth above, particularly to effectively and aggressively treat aggressive diseases or infections. In some embodiments, the compounds will be administered for a period of continuous therapy, for example for a week or more, or for months or years.

[0254] In further or additional embodiments, the amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in the range of about 0.001 to about 1000 mg / kg body weight / day. In further or additional embodiments, the amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in the range of about 0.5 to about 50 mg / kg / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (Iib), (Iic), (Iid), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.001 to about 7 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.002 to about 6 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.005 to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.01 to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.02 to about 5 g / day. In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof may be administered in an amount of about 0.05 to about 2.5 g / day.In further or additional embodiments, the compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), (IV) or a pharmaceutically acceptable salt thereof may be administered at about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower end of the above ranges may exceed appropriate dosage levels.

[0255] Dosage and interval can be individually adjusted to provide a plasma level of the active moiety sufficient to maintain the modulating effect, or minimum effective concentration (MEC). The MEC varies for each compound but can be estimated from in vitro data. The dosage required to achieve the MEC will depend on individual characteristics and the route of administration. However, plasma concentrations can be determined using HPLC assays or bioassays.

[0256] Dosage intervals can also be determined using the MEC value. Compositions should be administered using a regimen that maintains plasma levels 10-90% above the MEC, preferably 30-90%, and most preferably 50-90%.

[0257] In cases of local administration or selective uptake, the effective local concentration of drug may not be related to plasma concentration.

[0258] The amount of composition administered will be dependent on the subject being treated, on the subject's weight, the severity of the affliction, the manner of administration, and the judgment of the prescribing physician.

[0259] The compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicity of a particular compound, or a subset of compounds sharing a particular chemical moiety, can be established by determining in vitro toxicity on a cell line, such as a mammalian, preferably a human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of a particular compound in an animal model, such as a mouse, rat, rabbit, or monkey, can be determined using known methods. The efficacy of a particular compound can be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition, including, but not limited to, cancer, cardiovascular disease, and various immune dysfunctions. Similarly, accepted animal models can be used to establish the efficacy of chemicals for treating such conditions. When selecting a model to determine efficacy, one skilled in the art can be guided by the state of the art to select the appropriate model, dose, route of administration, and regimen. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0260] The compositions may, if desired, be presented in a pack or dispenser device that can contain one or more unit dosage forms containing the active ingredient. The pack may, for example, comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also have a notice associated with the container in a form prescribed by a government agency regulating the manufacture, use, or sale of pharmaceuticals, reflecting the agency's approval of the drug form for human or veterinary administration. Such notice may, for example, be a label approved by the U.S. Food and Drug Administration for prescription drugs or an approved product insert. Compositions containing a compound of the present invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.

[0261] Administration and Pharmaceutical Compositions The compounds are administered in therapeutically effective dosages. While human dosage levels have not yet been specifically identified for the compounds described herein, generally, a daily dose can be from about 0.25 mg / kg to about 120 mg / kg body weight or more, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg body weight, or from about 1.5 mg / kg to about 10 mg / kg body weight. Thus, for administration to a 70 kg person, dosage ranges would be from about 17 mg / day to about 8000 mg / day, from about 35 mg / day or less to about 7000 mg / day or more, from about 70 mg / day to about 6000 mg / day, from about 100 mg / day to about 5000 mg / day, or from about 200 mg to about 3000 mg / day. Of course, the amount of active compound administered will depend on the subject and disease state being treated, the severity of the condition, the mode and schedule of administration, and the judgment of the attending physician.

[0262] Administration of the compounds disclosed herein or their pharmaceutically acceptable salts can be via any of the accepted modes of administration for agents that serve similar utilities, including, but not limited to, oral, subcutaneous, intravenous, intranasal, topical, transdermal, intraperitoneal, intramuscular, intrapulmonary, intravaginal, rectal, or intraocular. Oral and parenteral administration are customary in the treatment of indications that are the subject of preferred embodiments.

[0263] The above-mentioned useful compounds can be formulated into pharmaceutical compositions for use in treating these conditions. Standard pharmaceutical formulation techniques can be used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), which is incorporated by reference in its entirety. Thus, some embodiments include pharmaceutical compositions comprising: (a) a safe, therapeutically effective amount of a compound described herein (including its enantiomers, diastereoisomers, tautomers, polymorphs, and solvates) or a pharmaceutically acceptable salt thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient, or a combination thereof.

[0264] In addition to the above-mentioned useful selected compounds, the coming embodiment includes a composition containing a pharmaceutically acceptable carrier. The term "pharmaceutically acceptable carrier" or "pharmaceutically acceptable excipient" includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like. The use of such media and agents for pharmaceutically active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic compositions is contemplated. In addition, various adjuvants, such as those commonly used in the art, may be included. Considerations for including various components in pharmaceutical compositions are described, for example, in Gilman et al. (eds.) (1990); Goodman and Gilman's: The Pharmacological Basis of Therapeutics, 8th Ed., Pergamon Press, which is incorporated herein by reference in its entirety.

[0265] Some examples of substances that can function as pharmaceutically acceptable carriers or components thereof are sugars, such as lactose, glucose, and sucrose; starches, such as corn starch and potato starch; cellulose and its derivatives, such as sodium carboxymethylcellulose, ethylcellulose, and methylcellulose; powdered tragacanth; malt; gelatin; talc; solid lubricants, such as stearic acid and magnesium stearate; calcium sulfate; vegetable oils, such as peanut oil, cottonseed oil, sesame oil, olive oil, corn oil, and theobroma oil; polyols, such as propylene glycol, glycerin, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as TWEEN; wetting agents, such as sodium lauryl sulfate; colorants; flavorings; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0266] The choice of pharmaceutically acceptable carrier to be used in conjunction with the subject compounds is basically determined by the way the compound is to be administered.

[0267] The compositions described herein are preferably provided in unit dosage form. As used herein, a "unit dosage form" is a composition containing an amount of compound suitable for administration in accordance with good medical practice in a single dose to an animal, preferably a mammalian subject. However, preparing a single or unit dosage form does not mean that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated for administration once, twice, three or more times per day, may be administered as an infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or may be administered as a continuous infusion, and may be given more than once during the course of therapy, although single administration is specifically not excluded. Those skilled in the art will recognize that the formulations are not specifically intended for an entire course of therapy, and such decisions are left to those skilled in the art of therapy, rather than those skilled in the art of formulation.

[0268] The above-described useful compositions may be in any of a variety of suitable forms for various routes of administration, such as oral, intranasal, rectal, topical (including transdermal), intraocular, intracerebral, intracranial, intrathecal, intraarterial, intravenous, intramuscular, or other parenteral routes of administration. Those skilled in the art will appreciate that oral and intranasal compositions include compositions administered by inhalation and prepared using available methodologies. Depending on the specific route of administration desired, various pharmaceutically acceptable carriers known in the art may be used. Pharmaceutically acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropic agents, surfactants, and encapsulating materials. Optional pharmaceutically active materials that do not substantially interfere with the inhibitory activity of the compound may be included. The amount of carrier used with the compound is sufficient to provide a practical amount of material for administration per unit dose of the compound. Techniques and compositions for making dosage forms useful in the methods described herein are described in the following references: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman et al., Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004), all of which are incorporated herein by reference.

[0269] Various oral dosage forms can be used, including solid forms such as tablets, capsules, granules, and bulk powders. Tablets can be compressed tablets, powder tablets, enteric-coated tablets, sugar-coated tablets, film-coated tablets, or multiple compressed tablets, and contain suitable binders, lubricants, diluents, disintegrants, colorants, flavorings, flow-inducing agents, and melting agents. Liquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions, and / or suspensions reconstituted from non-effervescent granules and effervescent preparations reconstituted from effervescent granules, and contain suitable solvents, preservatives, emulsifiers, suspending agents, diluents, sweeteners, melting agents, colorants, and flavorings.

[0270] Pharmaceutically acceptable carriers suitable for preparing unit dosage forms for oral administration are well known in the art.Tablets typically contain conventional pharmaceutically compatible adjuvants as inert diluents, such as calcium carbonate, sodium carbonate, mannitol, lactose, and cellulose; binders such as starch, gelatin, and sucrose; disintegrants such as starch, alginic acid, and croscarmellose; lubricants such as magnesium stearate, stearic acid, and talc.Lubricants such as silicon dioxide can be used to improve the flow characteristics of powder mixtures.Coloring agents, such as FD&C dyes, can be added for appearance.Sweeteners and flavoring agents, such as aspartame, saccharin, menthol, peppermint, and fruit flavors, are useful adjuvants for chewable tablets.Capsules typically contain one or more of the solid diluents disclosed above. The selection of carrier components depends on secondary considerations such as minor taste, cost, and shelf stability, and can be readily made by one skilled in the art.

[0271] Oral compositions also include liquid solutions, emulsions, and suspensions. Pharmaceutically acceptable carriers suitable for preparing such compositions are well known in the art. Typical components of carriers for syrups, elixirs, emulsions, and suspensions include ethanol, glycerol, propylene glycol, polyethylene glycol, liquid sucrose, sorbitol, and water. For suspensions, typical suspending agents include methylcellulose, sodium carboxymethylcellulose, AVICEL RC-591, tragacanth, and sodium alginate, typical wetting agents include lecithin and polysorbate 80, and typical preservatives include methylparaben and sodium benzoate. Oral liquid compositions may also contain one or more components, such as sweeteners, flavoring agents, and coloring agents disclosed above.

[0272] Such compositions may also be coated by conventional methods, typically with a pH or time-dependent coating, so that the subject compounds are released in the gastrointestinal tract in the vicinity of the desired local application or over a variable period of time to prolong the desired effect. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinyl acetate phthalate, hydroxypropylmethylcellulose phthalate, ethylcellulose, Eudragit coatings, waxes, and shellac.

[0273] The compositions described herein may optionally include other pharmaceutically active agents.

[0274] Other compositions useful for achieving systemic delivery of the subject compound include sublingual, buccal, and intranasal dosage forms.Such compositions typically contain soluble fillers, such as sucrose, sorbitol, and mannitol; and binders, such as acacia, microcrystalline cellulose, carboxymethylcellulose, and hydroxypropylmethylcellulose.Also, the glidants, lubricants, sweeteners, colorants, antioxidants, and flavoring agents disclosed above may be included.

[0275] Liquid compositions formulated for topical ophthalmic use are formulated so that they can be administered topically to the eye. Comfort should be maximized as much as possible, but often formulation considerations (e.g., drug stability) may require less than optimal comfort. If comfort cannot be maximized, the liquid should be formulated so that it is acceptable to patients for topical ophthalmic use. In addition, ophthalmically acceptable liquids should either be packaged for single use or contain preservatives to prevent contamination over multiple uses.

[0276] For ophthalmic use, solutions or medicaments are often prepared using physiological saline solution as the primary vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. Formulations may also contain conventional pharmaceutically acceptable preservatives, stabilizers, and surfactants.

[0277] Preservatives that can be used in the pharmaceutical compositions disclosed herein include, but are not limited to, benzalkonium chloride, PHMB, chlorobutanol, thimerosal, phenylmercuric acetate, and phenylmercuric nitrate. A useful surfactant is, for example, Tween 80. Similarly, various useful vehicles can be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropylmethylcellulose, poloxamer, carboxymethylcellulose, hydroxyethylcellulose, and purified water.

[0278] Tonicity adjusting agents may be added as needed or conveniently, including, but not limited to, salts, particularly sodium chloride, potassium chloride, mannitol, and glycerin, or any other suitable ophthalmically acceptable tonicity adjusting agent.

[0279] Various buffers and means for adjusting pH can be used as long as the resulting preparation is ophthalmologically acceptable. For many compositions, the pH is 4 to 9. Buffers therefore include acetate buffer, citrate buffer, phosphate buffer, and borate buffer. Acids or bases can be used to adjust the pH of these formulations as needed.

[0280] In a similar vein, ophthalmically acceptable antioxidants include, but are not limited to, sodium disulfite, sodium thiosulfate, acetylcysteine, butylhydroxyanisole, and butylhydroxytoluene.

[0281] Another excipient component that may be included in the ophthalmic preparation is a chelating agent. A useful chelating agent is edetate disodium, although other chelating agents may also be used instead or in conjunction therewith.

[0282] For topical use, creams, ointments, gels, solutions, suspensions, etc. containing the compounds disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, cosolvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0283] For intravenous administration, the compounds and compositions described herein can be dissolved or dispersed in a pharmaceutically acceptable diluent, such as saline or dextrose solution. Suitable excipients can be included to achieve the desired pH, including, but not limited to, NaOH, sodium carbonate, sodium acetate, HCl, and citric acid. In various embodiments, the pH of the final composition ranges from 2 to 8, or preferably from 4 to 7. Antioxidant excipients can include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylates, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition can include sodium or potassium phosphate, citric acid, tartaric acid, gelatin, and carbohydrates, such as dextrose, mannitol, and dextran. Additional acceptable excipients are described in Powell, et al., Compendium of Excipients for Parenteral Formulations, PDA J Pharm Sci and Tech 1998, 52 238-311, and Nema et al., Excipients and Their Role in Approved Injectable Products: Current Usage and Future Directions, PDA J Pharm Sci and Tech 2011, 65 287-332, both of which are incorporated herein by reference in their entirety. Antibacterial agents may also be included to achieve a bacteriostatic or fungistatic solution, including, but not limited to, phenylmercuric nitrate, thimerosal, benzethonium chloride, benzalkonium chloride, phenol, cresol, and chlorobutanol.

[0284] Compositions for intravenous administration may be provided to the caregiver in another solid form that is reconstituted immediately prior to administration with a suitable diluent, such as sterile water, saline, or dextrose in water. In other embodiments, the compositions are provided in a solution ready for parenteral administration. In still other embodiments, the compositions are provided in a solution that is further diluted before administration. In embodiments involving administering a combination of a compound described herein and another agent, the combination may be provided to the caregiver as a mixture, or the caregiver may mix the two agents prior to administration, or the two agents may be administered separately.

[0285] The actual dose of the active compounds described herein will depend on the particular compound and the condition being treated, and the selection of an appropriate dose is well within the knowledge of one of ordinary skill in the art.

[0286] Second (or other additional) medication In some embodiments, the second therapeutic agent is an anti-inflammatory agent. In some embodiments, the second therapeutic agent is a nonsteroidal anti-inflammatory agent. In some embodiments, the second therapeutic agent is an anti-cancer agent.

[0287] In some embodiments, the method comprises administering an effective amount of a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof in combination with an amount of a chemotherapeutic agent, wherein the amounts of the combination and the chemotherapeutic agent together are effective in inhibiting abnormal cell growth. Many chemotherapeutic agents are currently known in the art and can be used in combination. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens. Also described is a method for inhibiting abnormal cell growth in a mammal, the method comprising administering to the mammal an amount of a MEK protein kinase inhibitor and / or a Raf protein kinase inhibitor in combination with radiation therapy, wherein this amount of a MEK protein kinase inhibitor and / or a Raf protein kinase inhibitor in combination with radiation therapy is effective in inhibiting abnormal cell growth or treating a hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapies described herein.

[0288] In some embodiments, the present disclosure also relates to a method for inhibiting abnormal cell growth in a mammal, which may include administering a compound of Formula (I), (Ia), (Ib), (Ic), (II), (IIa), (IIb), (IIc), (III), or (IV) or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from antiangiogenic agents, signal transduction inhibitors, and antiproliferative agents. Antiangiogenic agents, such as MMP-2 (matrix metalloproteinase 2) inhibitors, MMP-9 (matrix metalloproteinase 9) inhibitors, and COX-11 (cyclooxygenase 11) inhibitors, may be used in conjunction with the compounds of the present invention and the pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREX™ (alecoxib), valdecoxib, and rofecoxib.Examples of useful matrix metalloproteinase inhibitors are disclosed in WO96 / 33172 (published October 24, 1996), WO96 / 27583 (published March 7, 1996), European Patent Application No. 97304971.1 (filed July 8, 1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO98 / 07697 (published February 26, 1998), and WO98 / 0 3516 (published January 29, 1998), WO98 / 34918 (published August 13, 1998), WO98 / 34915 (published August 13, 1998), WO98 / 33768 (published August 6, 1998), WO98 / 30566 (published July 16, 1998), European Patent Publication No. 606,046 (published July 13, 1994), European Patent Publication No. 931,788 (published July 28, 1999) WO90 / 05719 (published May 31, 1990), WO99 / 52910 (published October 21, 1999), WO99 / 52889 (published October 21, 1999), WO99 / 29667 (published June 17, 1999), PCT International Patent Application No. PCT / IB98 / 01113 (filed July 21, 1991), European Patent Application No. 99302232.1 (filed March 1999), No. 5,863,949 (issued January 26, 1999), U.K. Patent Application No. 9912961.1 (filed June 3, 1999), U.S. Provisional Patent Application No. 60 / 148,464 (filed August 12, 1999), U.S. Patent No. 5,863,949 (issued January 26, 1999), U.S. Patent No. 5,861,510 (issued January 19, 1999), and European Patent Publication No. 780,386 (published June 25, 1997). Some MMP-2 and MMP-9 inhibitors have little or no activity inhibiting MMP-1, and some selectively inhibit MMP-2 and / or MMP-9 relative to other matrix metalloproteases (Le., MAP-1, NEMP-3, MMP-4, MMP-5, MMP-6, MMP-7, MMP-8, MMP-10, MMP-11, and MMP-13). Some specific examples of M1v1P inhibitors useful in the present invention are AG-3340, RU32-3555, and RS13-0830.

[0289] In some embodiments, a compound of Formula (I), (Ia), (Ib), (Ic), (Id), (II), (IIa), (IIb), (IIc), (IId), (III), or (IV) or a pharmaceutically acceptable salt thereof is administered with at least one additional therapeutic agent. In some embodiments, the therapeutic agent is taxol, bortezol, or both. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, antiangiogenic agents, and antitumor agents. In further or additional embodiments, the antitumor agent is selected from the group consisting of alkylating agents, antimetabolites, epiclophyllotoxime, antitumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitory agents, hormone / antihormonal therapies, and bamatopoietic growth factors.

[0290] Many chemotherapeutic agents are currently known in the art and may be used in combination with the compounds and compositions of the present disclosure. In some embodiments, the chemotherapeutic agent is selected from the group consisting of antimitotic agents, alkylating agents, antimetabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, antihormones, angiogenesis inhibitors, and antiandrogens.

[0291] In some embodiments, the combination is administered in combination with an additional therapy. In further or additional embodiments, the additional therapy is radiation therapy, chemotherapy, surgery, or any combination thereof. In further or additional embodiments, the combination is administered in combination with at least one additional therapeutic agent. In further or additional embodiments, the therapeutic agent is selected from the group consisting of cytotoxic agents, anti-angiogenic agents, and anti-tumor agents. In further or additional embodiments, the anti-tumor agent is selected from the group consisting of alkylating agents, antimetabolites, epidophyllotoxins, anti-tumor enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitory agents, hormone / anti-hormonal therapeutic agents, and hematopoietic growth factors.

[0292] In some embodiments, the second therapeutic agent is an agent for co-regulating the RAF pathway. In some embodiments, the second therapeutic agent is a RAF inhibitor. In some embodiments, the RAF inhibitor is vemurafenib, dabrafenib, encorafenib, XL-281, LGX-818, CEP-32496, or ARQ-736.

[0293] In some embodiments, the second therapeutic agent is selected from aspirin, diflunisal, salsalate, acetaminophen, ibuprofen, dexibuprofen, naproxen, fenoprofen, ketoprofen, dexketoprofen, flurbiprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac, etodolac, ketorolac, diclofenac, aceclofenac, nabumetone, enolic acids, piroxicam, meloxicam, tenoxicam, droxicam, lornoxicam, isoxicam, mefenamic acid, meclofenamic acid, flufenamic acid, tolfenamic acid, sulfonanilides, clonixin, licofelone, dexamethasone, and prednisone.

[0294] In some embodiments, the second therapeutic agent is selected from mechlorethamine, cyclophosphamide, melphalan, chlorambucil, ifosfamide, busulfan, N-nitroso-N-methylurea (MNU), carmustine (BCNU), lomustine (CCNU), semustine (MeCCNU), fotemustine, streptozotocin, dacarbazine, mitozolomide, temozolomide, thiotepa, mitomycin, diaziquone (AZQ), cisplatin, carboplatin, and oxaliplatin.

[0295] In some embodiments, the second therapeutic agent is selected from vincristine, vinblastine, vinorelbine, vindesine, vinflunine, paclitaxel, docetaxel, etoposide, teniposide, tofacitinib, ixabepilone, irinotecan, topotecan, camptothecin, doxorubicin, mitoxantrone, and teniposide.

[0296] In some embodiments, the second therapeutic agent is selected from actinomycin, bleomycin, plicamycin, mitomycin, daunorubicin, epirubicin, idarubicin, pirarubicin, aclarubicin, mitoxantrone, cyclophosphamide, methotrexate, 5-fluorouracil, prednisolone, folinic acid, methotrexate, melphalan, capecitabine, mechlorethamine, uramustine, melphalan, chlorambucil, ifosfamide, bendamustine, 6-mercaptopurine, and procarbazine.

[0297] In some embodiments, the second therapeutic agent is selected from cladribine, pemetrexed, fludarabine, gemcitabine, hydroxyurea, nelarabine, cladribine, clofarabine, itarabine, decitabine, cytarabine, cytarabine liposomal, pralatrexate, floxuridine, fludarabine, colchicine, thioguanine, cabazitaxel, larotaxel, ortataxel, tesetaxel, aminopterin, pemetrexed, pralatrexate, raltitrexed, pemetrexed, carmofur, and floxuridine.

[0298] In some embodiments, the second therapeutic agent is selected from azacitidine, decitabine, hydroxycarbamide, topotecan, irinotecan, belotecan, teniposide, aclarubicin, epirubicin, idarubicin, amrubicin, pirarubicin, valrubicin, zorubicin, mitoxantrone, pixantrone, mechlorethamine, chlorambucil, prednimustine, uramustine, estramustine, carmustine, lomustine, fotemustine, nimustine, ranimustine, carboquone, thiotepa, triaziquone, and triethylenemelamine.

[0299] In some embodiments, the second therapeutic agent is nedaplatin, satraplatin, procarbazine, dacarbazine, temozolomide, altretamine, mitobronitol, pipobroman, actinomycin, bleomycin, plicamycin, aminolevulinic acid, methyl aminolevulinate, efaproxiral, talaporfin, temoporfin, verteporfin, alvocidib, seliciclib, palbociclib, bortezomib, carfilzomib , anagrelide, masoprocol, olaparib, belinstat, panobinostat, romidepsin, vorinostat, idelalisib, atrasentan, bexarotene, testolactone, amsacrine, trabectedin, alitretinoin, tretinoin, demecolcine, elsamitrucin, etoglucide, lonidamine, lucantone, mitoguazone, mitotane, oblimersen, omacetaxine mepesuccinate, and eribulin.

[0300] In some embodiments, the second therapeutic agent is selected from the group consisting of azathioprine, mycophenolate, leflunomide, teriflunomide, tacrolimus, cyclosporine, pimecrolimus, avetimus, gusperimus, lenalidomide, pomalidomide, thalidomide, anakinra, sirolimus, everolimus, ridaforolimus, temsirolimus, umirolimus, zotarolimus, eculizumab, adalimumab, afelimumab, and thalidomide. and ocrelizumab.

[0301] In some embodiments, the second therapeutic agent is pascolizumab, gomiliximab, lumiliximab, teneliximab, toralizumab, acelizumab, galiximab, gavilimomab, ruplizumab, belimumab, blisibimod, ipilimumab, tremelimumab, bertilimumab, lerdelimumab, metelimumab, natalizumab, tocilizumab, odulimomab, basiliximab , daclizumab, inolimomab, zolimomab, atrolizumab, cedelizumab, fontolizumab, maslimomab, morolimumab, pexelizumab, reslizumab, rovelizumab, siplizumab, talizumab, terimomab, bapaliximab, bepalimomab, abatacept, belatacept, pegsunercept, aflibercept, alefacept, and rilonacept.

[0302] Accordingly, some aspects described herein relate to the following numbered alternatives:

[0303] 1. A compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 , R 6 , R 7 , and R 13are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 3 is chloro, bromo, or iodo; X is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and Y is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and L is -Z1-Z2 or -Z1-Z2-Z3, Z1, Z2, and Z3 are independently -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Each R 5 and R 5’ are independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C 10 A compound selected from heteroaryl.

[0304] 2.R 6 The compound according to alternative 1, wherein is H, deuterium, hydroxyl, or halo.

[0305] 3.R 6 The compound according to alternative 1 or 2, wherein is H or halo.

[0306] 4. The compound according to any one of alternatives 1-3, wherein halo is selected from fluoro, chloro, or bromo.

[0307] 5.R 7 The compound according to any one of alternatives 1 to 4, wherein is L.

[0308] 6. The compound according to alternative 5, wherein L is -Z1-Z2.

[0309] 7. The compound according to alternative 6, wherein Z1 is -CH2-.

[0310] 8. Z2 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl, -NR 5 R 5’8. The compound according to alternative 6 or 7, wherein the R is selected from -CH 2 CCH, or -CH 2 CN.

[0311] 9. The compound according to alternative 5, wherein L is -Z1-Z2-Z3.

[0312] 10. Z1 is -CH2- and Z2 is -NR 5 R 5’ , -NHCH2CO-, C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl; Z3 is selected from the group consisting of H, deuterium, halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C8 heteroaryl; 10 The compound according to alternative 9, wherein the aryl is selected from the group consisting of: aryl, or -CH2- (optionally substituted aryl).

[0313] 11.R 3 The compound according to any one of alternatives 1-10, wherein is chloro.

[0314] 12.R 3 The compound according to any one of alternatives 1-10, wherein is bromo.

[0315] 13.R 3 The compound according to any one of alternatives 1-10, wherein is iodo.

[0316] 14.R 2 is L.

[0317] 15. The compound according to alternative 14, wherein L is -Z1-Z2.

[0318] 16. The compound according to alternative 15, wherein Z1 is -CH2- or -NH-.

[0319] 17.X is CH2 or [ka] 17. The compound according to any one of alternatives 1-16, wherein

[0320] 18.Y is CH2 or [ka] The compound according to any one of alternatives 1-17, wherein

[0321] 19. The compound according to alternative 1, wherein the compound is selected from the compounds of Table B, C, D, or E.

[0322] 20. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 , R 6 , R 7 , and R 13 are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 3 is chloro, bromo, or iodo; X is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and Y is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and L is -Z1-Z2 or -Z1-Z2-Z3, Z1, Z2, and Z3 are independently -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Each R 5 and R 5’ are independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C 10 The pharmaceutical composition of claim 1, wherein the aryl is selected from the group consisting of:

[0323] 21.R 621. The pharmaceutical composition of alternative 20, wherein is H, deuterium, hydroxyl, or halo.

[0324] 22.R 6 22. The pharmaceutical composition according to alternative 20 or 21, wherein is H or halo.

[0325] 23. The pharmaceutical composition according to any one of alternatives 20-22, wherein halo is selected from chloro or bromo.

[0326] 24.R 7 24. The pharmaceutical composition of any one of alternatives 20-23, wherein is L.

[0327] 25. The pharmaceutical composition according to alternative 24, wherein L is -Z1-Z2.

[0328] 26. The pharmaceutical composition according to alternative 25, wherein Z1 is -CH2-.

[0329] 27. Z2 is optionally substituted C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl, -NR 5 R 5’ 27. The pharmaceutical composition of alternative 25 or 26, wherein the aryl group is selected from -CH2CCH, -CH2CN, -CH2CCH, or -CH2CN.

[0330] 28. The pharmaceutical composition according to alternative 24, wherein L is -Z1-Z2-Z3.

[0331] 29. Z1 is -CH2- and Z2 is -NR 5 R 5’ , -NHCH2CO-, C3-C8 cycloalkyl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C8 heteroaryl; Z3 is selected from the group consisting of H, deuterium, halo, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C8 heteroaryl; 10aryl, or -CH2- (optionally substituted aryl).

[0332] 30.R 3 30. The pharmaceutical composition of any one of alternatives 20-29, wherein is chloro.

[0333] 31.R 3 30. The pharmaceutical composition of any one of alternatives 20-29, wherein is bromo.

[0334] 32.R 3 30. The pharmaceutical composition of any one of alternatives 20-29, wherein is iodine.

[0335] 33.R 13 33. The pharmaceutical composition of any one of alternatives 30-32, wherein is L.

[0336] 34. The pharmaceutical composition according to alternative 33, wherein L is -Z1-Z2.

[0337] 35. The pharmaceutical composition according to alternative 34, wherein Z1 is -CH2- or -NH-.

[0338] 36.X is CH2 or [ka] 36. The pharmaceutical composition of any one of alternatives 20 to 35, wherein

[0339] 37.Y is CH2 or [ka] 37. The pharmaceutical composition of any one of alternatives 20 to 36, wherein

[0340] 38. The pharmaceutical composition according to alternative 20, wherein the compound is selected from the compounds of Tables B, C, D, or E.

[0341] 39. The pharmaceutical composition of any one of alternatives 20-38, further comprising one or more immune checkpoint inhibitors.

[0342] 40. The pharmaceutical composition of alternative 40, wherein the immune checkpoint inhibitor is an inhibitor of PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3.

[0343] 41. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-1 inhibitor.

[0344] 42. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-L1 inhibitor.

[0345] 43. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-L2 inhibitor.

[0346] 44. The pharmaceutical composition according to alternative 39 or 40, wherein the immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0347] 45. The pharmaceutical composition of alternative 39 or 40, comprising a first immune checkpoint inhibitor and a second immune checkpoint inhibitor, wherein the first immune checkpoint inhibitor is different from the second immune checkpoint inhibitor.

[0348] 46. ​​The pharmaceutical composition of alternative 39 or 40, wherein the first and second immune checkpoint inhibitors are, independently, inhibitors of PD-1, PD-L1, PD-L2, PD-L3, PD-L4, CTLA-4, LAG3, B7-H3, B7-H4, KIR, or TIM3.

[0349] 47. The pharmaceutical composition of alternative 39 or 40, wherein the first immune checkpoint inhibitor is a PD-1 inhibitor and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0350] 48. The pharmaceutical composition of alternative 39 or 40, wherein the first immune checkpoint inhibitor is a PD-L1 inhibitor and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0351] 49. The pharmaceutical composition of alternative 39 or 40, wherein the first immune checkpoint inhibitor is a PD-L2 inhibitor and the second immune checkpoint inhibitor is a CTLA-4 inhibitor.

[0352] 50. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is an antibody.

[0353] 51. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-1 antibody.

[0354] 52. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-L1 antibody.

[0355] 53. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a PD-L2 antibody.

[0356] 54. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is a CTLA-4 antibody.

[0357] 55. The pharmaceutical composition of alternative 39 or 40, wherein the immune checkpoint inhibitor is nivolumab, pembrolizumab, pidilizumab, ipilimumab, BMS936559, atezolizumab, durvalumab, or any combination thereof.

[0358] 56. A method for treating a mammal having a disease or disorder, comprising administering to the mammal a therapeutically effective amount of a compound according to any one of alternatives 1-19 or a pharmaceutical composition according to any one of alternatives 20-55.

[0359] 57. A method for treating a disease or disorder, comprising administering to a subject suffering from said disease or disorder an effective amount of a compound according to any one of alternatives 1-19 or a pharmaceutical composition according to any one of alternatives 20-55.

[0360] 58. A method for treating a disease, comprising administering to a subject suffering from said disease an effective amount of a compound according to any one of alternatives 1 to 19 or a pharmaceutical composition according to any one of alternatives 20 to 55.

[0361] 59. The method of any one of alternatives 56-58, wherein the disease is cancer.

[0362] 60. A method for treating cancer cachexia in a mammal having cancer, comprising administering an effective amount of a compound according to any one of alternatives 1-19 or a pharmaceutical composition according to any one of alternatives 20-55.

[0363] 61. A compound according to any one of alternatives 1 to 19 or a pharmaceutical composition according to any one of alternatives 20 to 55, or a method according to any one of alternatives 56 to 60.

[0364] 62. A compound according to any one of alternatives 1 to 19 or a pharmaceutical composition according to any one of alternatives 20 to 55, or a method according to any one of alternatives 56 to 60.

[0365] 63. The method of any one of alternatives 56-60, wherein the compound of any one of alternatives 1-19 or the pharmaceutical composition of any one of alternatives 20-55 is administered in multiple doses, two or more times daily.

[0366] 64. The method of alternative 59, wherein the cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, gastric cancer, prostate cancer, renal cancer, colorectal cancer, or leukemia. In further or additional embodiments, the fibrosing disorder is scleroderma, polymyositis, systemic lupus erythematosus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis, or pulmonary fibrosis.

[0367] 65. Method alternative 59 or 64, wherein the cancer is associated with a RAS mutation.

[0368] 66. Method alternative 65, wherein the RAS mutation is a KRAS mutation selected from the group consisting of G12C, G12S, G12R, G12F, G12L, G12N, G12A, G12D, G12V, G13C, G13S, G13D, G13V, G13P, S17G, P34S, A59E, A59G, A59T, Q61K, Q61L, Q61R, and Q61H.

[0369] 67. A compound having the chemical structure of formula (IV) [ka] (IV) or a pharmaceutically acceptable salt thereof, wherein: R6 is hydrogen, fluoro, or chloro; R 13 is ethyl or -NR A R B and R A is hydrogen and R B is methyl, Z2 is -NR 5 R 5’ , [ka] , or [ka] and R 5 is C1-C6 alkyl, R 5’ is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof.

[0370] 68.R 5 The compound according to alternative 67, wherein is methyl.

[0371] 69.R 5’ The compound according to alternative 68, wherein is methyl.

[0372] 70.R 5’ The compound according to alternative 68, wherein is ethyl.

[0373] 71.Z2 is -NR 5 R 5’ 71. The compound according to any one of alternatives 67-70, wherein

[0374] 72.R 13 But, -NR A R B 72. The compound according to any one of alternatives 67-71, wherein

[0375] 73. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0376] 74. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0377] 75. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0378] 76. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0379] 77. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0380] 78. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0381] 79.R 13 The compound according to any one of alternatives 67-71, wherein is ethyl.

[0382] 80. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0383] 81. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0384] 82. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0385] The 83 Z2, [ka] 71. The compound according to any one of alternatives 67-70, wherein

[0386] 84.R 13 The compound according to alternative 83, wherein is ethyl.

[0387] 85. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0388] 86. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0389] 87. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0390] 88.R 13 But, -NR A R B The compound according to alternative 83, wherein

[0391] 89. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0392] 90. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0393] 91. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0394] 92.Z2, [ka] 71. The compound according to any one of alternatives 67-70, wherein

[0395] 93.R 13 The compound according to alternative 92, wherein is ethyl.

[0396] 94.R 13 But, -NR A R B The compound according to alternative 92, wherein

[0397] 95. The compound is [ka] 95. The compound according to alternative 92 or 94, which is:

[0398] 96. The compound is [ka] 95. The compound according to alternative 92 or 94, which is:

[0399] 97. The compound is [ka] 95. The compound according to alternative 92 or 94, which is:

[0400] 98. A compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 But L, R 6 is selected from the group consisting of H, or fluoro, chloro, or bromo; R 7 is H, R 13 optionally substituted amine, C1-C6 alkyl, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10heteroaryl, and L; R 3 But it's Chloro. X is -O-, Y is, [ka] and L is -Z1-Z2, Z1 is -CH2-, Z2, -NR 5 R 5’ , optionally substituted C3-C8 heterocyclyl, -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 Aryl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Each R 5 and R 5’ is an independently selected optionally substituted C1-C6 alkyl.

[0401] 99.Z2, but -NR 5 R 5’ 99. The compound according to alternative 98, wherein

[0402] 100.R 5 The compound according to alternative 99, wherein is methyl.

[0403] 101.R 5’ The compound according to alternative 99, wherein is methyl.

[0404] 102.R 5’ The compound according to alternative 99, wherein is ethyl.

[0405] 103.Z2, [ka] 99. The compound according to alternative 98, wherein

[0406] 104.Z2 is optionally replaced [ka] 99. The compound according to alternative 98, wherein n is 1, 2, 3, or 4.

[0407] 105. The compound according to alternative 104, wherein n is 1.

[0408] 106.R 13 But, -NR A R B and R A and R B are each independently hydrogen or C 1~6 The compound according to any one of alternatives 98-105, wherein the compound is selected from alkyl.

[0409] 107.R A is hydrogen and R B The compound according to alternative 106, wherein is methyl.

[0410] 108.R 13 The compound according to any one of alternatives 98-105, wherein is C1-C6 alkyl.

[0411] 109.R 13 The compound according to alternative 108, wherein is ethyl.

[0412] 110.R 6 The compound according to any one of alternatives 98-109, wherein is fluoro.

[0413] 111.R 6 The compound according to any one of alternatives 98-109, wherein is chloro.

[0414] 112.R 6 The compound according to any one of alternatives 98-109, wherein is H.

[0415] 113. A compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 But L, R 6 is selected from the group consisting of H, or fluoro, chloro, or bromo; R 7 is H, R 13 is C1-C6 alkyl, R 3 But it's Chloro. X is -O-, Y is, [ka] and L is -Z1-Z2, Z1 is -CH2-, Z2 is -NR 5 R 5’ and Each R 5 and R 5’ is independently selected from optionally substituted C1-C6 alkyl.

[0416] 114. A compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof, wherein: R 2 is halogen, H, deuterium, hydroxyl, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 6 is H, halogen, deuterium, hydroxyl, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 7 is selected from the group consisting of deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 13 optionally substituted C1-C6 alkyl, optionally substituted amino, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 3 is chloro, bromo, or iodo; X is -O-, C(R 5 )2, CH(R 5 ), CH2, [ka] , [ka] , or [ka] and Y is, [ka] , C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , or [ka] and L is -Z1-Z2 or -Z1-Z2-Z3, Z1 is -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Z2, -NR 5 R 5’ , -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Z3 is -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C10 heteroaryl), Each R 5 and R 5’ are independently selected from optionally substituted C1-C6 alkyl, H, deuterium, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C 10 A compound selected from heteroaryl.

[0417] 115. [ka] A compound selected from the list consisting of:

[0418] 116. [ka] A compound selected from the list consisting of:

[0419] 117. A pharmaceutical composition comprising a compound according to any one of alternatives 67-116 or a pharmaceutically acceptable salt thereof.

[0420] 118. A method for treating cancer, comprising administering to a subject in need thereof an effective amount of a compound according to any one of alternatives 67-116 or a pharmaceutical composition thereof.

[0421] 119. Use of a compound according to any one of alternatives 67 to 116 for the treatment of cancer. 120. 4-((dimethylamino)methyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate, and 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0422] 121. The compound according to alternative 120, wherein the compound is 4-((dimethylamino)methyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0423] 122. The compound according to alternative 120, wherein the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0424] 123. The compound according to alternative 120, wherein the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0425] 124. A pharmaceutical composition comprising a compound according to alternative 1 and a pharmaceutically acceptable salt.

[0426] 125. 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-(ethylsulfonamido)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate, and A compound selected from the group consisting of 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0427] 126. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0428] 127. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0429] 128. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0430] 129. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0431] 130. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0432] 131. The compound according to alternative 126, wherein the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0433] 132. The compound according to alternative 126, wherein the compound is 6-chloro-3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0434] 133. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate.

[0435] 134. The compound according to alternative 126, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0436] 135. A pharmaceutical composition comprising a compound according to any one of alternatives 126-134 and a pharmaceutically acceptable salt.

[0437] 136. 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(azetidin-1-ylmethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, and A compound selected from the group consisting of 4-(azetidin-1-ylmethyl)-6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0438] 137. The compound according to alternative 136, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0439] 138. The compound according to alternative 136, wherein the compound is 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0440] 139. The compound according to alternative 136, wherein the compound is 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0441] 140. The compound according to alternative 136, wherein the compound is 4-(azetidin-1-ylmethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0442] 141. The compound according to alternative 136, wherein the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0443] 142. The compound according to alternative 136, wherein the compound is 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0444] 143. A pharmaceutical composition comprising a compound according to any one of alternatives 136-142 and a pharmaceutically acceptable salt.

[0445] 144. 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(3-(ethylsulfonamido)-2-fluorobenzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-((methyl(prop-2-yn-1-yl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-(((cyanomethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-(methyl(sulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, 4-((dimethylamino)methyl)-3-(3-((ethylsulfonyl)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate, and A compound selected from the group consisting of 3-(3-((tert-butylsulfinyl)amino)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0446] 145. The compound according to alternative 144, wherein the compound is 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0447] 146. The compound according to alternative 144, wherein the compound is 3-(3-(ethylsulfonamido)-2-fluorobenzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0448] 147. The compound according to alternative 144, wherein the compound is 3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-((methyl(prop-2-yn-1-yl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0449] 148. The compound according to alternative 144, wherein the compound is 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0450] 149. The compound according to alternative 144, wherein the compound is 4-(((cyanomethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0451] 150. The compound according to alternative 144, wherein the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-(methyl(sulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0452] 151. The compound according to alternative 144, wherein the compound is 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0453] 152. The compound according to alternative 144, wherein the compound is 3-(3-((tert-butylsulfinyl)amino)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate.

[0454] 153. A pharmaceutical composition comprising a compound according to any one of alternatives 144-152 and a pharmaceutically acceptable salt.

[0455] 154. A compound having the structure of formula (III): [ka] and pharmaceutically acceptable salts thereof. During the ceremony, R 2 , R 6 , R 7 , and R 13 are each independently H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C1-C6 alkoxy, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10 aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, and L; R 3 But it's Chloro. X is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and Y is C(R 5 )2, CH(R 5 ), CH2, -O-, [ka] , [ka] , or [ka] and L is -Z1-Z2 or -Z1-Z2-Z3, Z1, Z2, and Z3 are independently -CH2-, -O-, -S-, S=O, -SO2-, C=O, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR 5 R 5’ , -NH(CO)-, -(CO)NH-, -(CO)NR 5 R 5’ -, -NH-SO2-, -SO2-NH-, -R 5 CH2-, -R 5 O-, -R 5 S-, R 5 -S=O, -R 5 SO2-, R 5 -C=O, -R 5 CO2-, -R 5 NH-, -R 5 NH(CO)-, -R 5 (CO)NH-, -R 5 NH-SO2-, -R 5 SO2-NH-, -NHCH2CO-, -CH2R 5 -, -OR 5 -, -SR 5 -, S=OR 5 , -SO2R 5 -, C=OR 5 , -CO2R 5 -, -NHR 5 -, -NH(CO)R 5 -, -(CO)NHR 5 -, -NH-SO2R 5 -, -SO2-NHR 5 -, optionally substituted C1-C6 alkyl, optionally substituted C3-C8 cycloalkyl, optionally substituted C6-C 10aryl, optionally substituted C3-C8 heterocyclyl, optionally substituted C3-C 10 heteroaryl, -CH2- (optionally substituted aryl), -CH2- (optionally substituted C3-C8 cycloalkyl), and -CH2- (optionally substituted C3-C 10 heteroaryl), Each R 5 and R 5’ are independently selected from H, deuterium, optionally substituted C1-C6 alkyl, optionally substituted C2-C6 alkenyl, optionally substituted C2-C6 alkynyl, optionally substituted C3-C8 carbocyclyl, optionally substituted C6-C 10 Aryl, optionally substituted C3-C8 heterocyclyl, and optionally substituted C3-C 10 A compound selected from heteroaryl.

[0456] 155.R 2 The compound according to alternative 154 or a pharmaceutically acceptable salt thereof, wherein is CH2-Z2.

[0457] 156.Z2 is -NR 5 R 5’ or an optionally substituted C3-C8 heterocyclyl; or a pharmaceutically acceptable salt thereof.

[0458] 157.Z2 is -NR 5 R 5’ and R 5 and R 5’ each of which is an optionally substituted C1-C6 alkyl, and optionally R 5 and R 5’ are each Me, and optionally R 5 is Me and R 5’ 157. The compound or pharmaceutically acceptable salt according to alternative 155 or 156, wherein is Et.

[0459] 158. Z2 is an optionally substituted C3-C8 heterocyclyl, wherein the heterocycle is a nitrogen-containing heterocyclyl, and optionally Z2 is [ka] 157. The compound according to alternative 155 or 156, or a pharmaceutically acceptable salt thereof, wherein:

[0460] 159.Y is CH2 or [ka] 159. The compound or pharmaceutically acceptable salt according to any one of alternatives 154 to 158, wherein:

[0461] 160.Y is, [ka] 159. The compound according to alternative 159, or a pharmaceutically acceptable salt thereof, wherein:

[0462] 161.R 6 is H or halo, optionally wherein halo is selected from fluoro, chloro, or bromo, optionally wherein halo is fluoro or chloro, optionally wherein halo is chloro.

[0463] 162.R 7 or a pharmaceutically acceptable salt thereof.

[0464] 163. The compound according to any one of alternatives 154-162, or a pharmaceutically acceptable salt thereof, wherein X is O.

[0465] 164.R 13or a pharmaceutically acceptable salt thereof. The compound according to any one of alternatives 154-163, wherein is optionally substituted amino or optionally substituted C1-C6 alkyl.

[0466] 165.R 13 is NHMe or Et, and optionally R 13 165. The compound or pharmaceutically acceptable salt according to any one of alternatives 164, wherein is NHMe.

[0467] 166.The compound is [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] and, [ka] or a pharmaceutically acceptable salt thereof, selected from the group consisting of:

[0468] 167.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0469] 168.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0470] 169. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0471] 170.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0472] 171.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0473] 172.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0474] 173.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0475] 174.The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0476] 175. The compound is [ka] or a pharmaceutically acceptable salt thereof.

[0477] 176. A pharmaceutical composition comprising a therapeutically effective amount of at least one compound according to any one of alternatives 154-175 or a pharmaceutically acceptable salt thereof.

[0478] 177. A compound according to any one of alternatives 154-175 or a pharmaceutically acceptable salt thereof for use in the treatment of cancer. [Example]

[0479] General Procedure Additional embodiments are disclosed in more detail in the following examples, which are not intended to limit the scope of the claims in any way.

[0480] The materials used in the preparation of the compounds of formula (I), (Ia), (Ib), or (Ic) described herein can be made by known methods or are commercially available. In these reactions, it is also possible to use variants that are known to those skilled in the art but are not mentioned in more detail. Those skilled in the art are fully capable of preparing any of the compounds in light of the literature and this disclosure.

[0481] Those skilled in the art of organic chemistry will recognize that these manipulations can be readily performed without further instruction, i.e., are well within the scope and practice of one of ordinary skill in the art. These include reduction of carbonyl compounds to their corresponding alcohols, oxidation, acylation, aromatic substitution, both electrophilic and nucleophilic, etherification, esterification, and saponification. These manipulations are discussed in standard textbooks, such as March's Advanced Organic Chemistry (Wiley), and Carey and Sundberg, Advanced Organic Chemistry, which are incorporated herein by reference in their entireties.

[0482] Those skilled in the art will readily understand that certain reactions are best performed when other functional groups are masked or protected within the molecule, thus avoiding any undesired side reactions and / or increasing the yield of the reaction. Often, those skilled in the art use protecting groups to achieve such increased yields or to avoid undesired reactions. These reactions can be found in the literature and are well within the purview of those skilled in the art. Many examples of these manipulations can be found, for example, in T. Greene and P. Wuts, Protecting Groups in Organic Synthesis, 4th Ed., John Wiley & Sons (2007), which is incorporated herein by reference in its entirety.

[0483] The following exemplary schemes are provided for the reader's guidance and represent preferred methods for making the compounds exemplified herein. It will be apparent that these methods are not limiting and that other routes may be used to prepare these compounds. Such methods specifically include solid-phase-based chemistry, including combinatorial chemistry. Those skilled in the art will be fully capable of preparing these compounds by these methods in light of the literature and this disclosure. The numbering of compounds used in the synthetic schemes shown below is intended solely for these specific schemes and should not be construed or confused with the same numbering in other sections of this application.

[0484] The trademarks used herein are examples only and reflect illustrative materials used during the present invention. Those skilled in the art will recognize that variations in batches, manufacturing processes, etc. are to be expected. Therefore, the examples and the trademarks used therein are non-limiting and are not intended to be limiting, but merely illustrative of how one skilled in the art may select to implement one or more embodiments of the present invention.

[0485] The following illustrative schemes are provided for the reader's guidance and, collectively, represent exemplary methods for making the compounds provided herein. Additionally, other methods for preparing the compounds described herein will be readily apparent to those of skill in the art in view of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.

[0486] Example 1 General synthesis A [ka] Compound 2: To a solution of compound 1 and NBS (57.8 g, 321 mmol, 1.20 equiv.) in MeCN (1340 mL) under a nitrogen atmosphere, 1,1-azobis(cyclohexanecarbonitrile) (0.12 equiv.) was added. The resulting reaction mixture was stirred at 80° C. for 16 hours. The reaction mixture was cooled to room temperature and concentrated under reduced pressure to give an orange suspension. EtO was added, and the resulting suspension was stirred at room temperature for 18 hours. The suspension was filtered, and the residue was washed with some additional EtO. The combined organic layers were washed with saturated aqueous NaHCO and brine, dried over NaSO, filtered, and concentrated under reduced pressure to give benizul bromide compound 2 as a dark red oil, which crystallized upon standing.

[0487] Compound 3: A mixture of compound 2 (1.0 equiv.) and sodium iodide (1.0 equiv.) was stirred in THF (dry) for 30 minutes. In a separate flask, ethyl 3-oxobutanoate (1.10 equiv.) was dissolved in THF (dry), and lithium tert-butoxide (1.10 equiv.) was slowly added. The reaction mixture was stirred for 30 minutes and then slowly added to the bromide suspension. The resulting reaction mixture was stirred at room temperature for 16 hours. The reaction was quenched with water, and the product was extracted with EtOAc. The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give a dark brown oil. The oil was coated onto a hydromatrix and purified by column chromatography using the "flash" method (heptane / EtOAc = 1:0 → 7:3) to give compound 3 as a pale yellow oil.

[0488] Compound 4: To a solution of compound 3 (1.0 equivalent) in perchloric acid or methanesulfonic acid (10-20 equivalents) was added a resorcinol derivative (1.2 equivalents). The reaction mixture was stirred at room temperature for 1-18 hours. Water was added to the reaction mixture, and the product was filtered and washed with water and EtO. The residue was dried to give coumarin compound 4 as a solid.

[0489] Compound 5: To a solution of compound 4 (1.0 equiv.) in DMF (dry) (0.1-0.2 M) at 0°C under a N atmosphere was added 60% sodium hydride dispersion in mineral oil (1.60 equiv.). The reaction mixture was stirred for 10 minutes, after which dimethylcarbamoyl chloride (1.50-1.60 equiv.) was added. The reaction mixture was allowed to warm to room temperature and stirred for an additional 2-60 hours. Water was added to quench the reaction mixture. The suspension was filtered and washed with water and EtO. The residue was dried to give dimethylcarbamate compound 5 as a solid.

[0490] Compound 5: Dimethyl carbamate (1.0 equiv.) was suspended in methanol (0.2 M), and in some cases, some CHCl was added to obtain a solution. Argon was bubbled through the solution for 10 minutes. Then, 50% Raney® nickel slurry in water (1.0 equiv.) or 10% palladium on activated carbon (0.05 equiv.) was added. The resulting reaction mixture was purged with hydrogen and stirred at room temperature for 2-18 hours. The reaction mixture was filtered over diatomaceous earth and washed with MeCN, CHCl, and MeOH. The filtrate was concentrated under reduced pressure to obtain the primary amine as a solid.

[0491] Compound 7: To a cooled (0 °C) ice bath, a suspension of aniline compound 6 (1.0 equiv.) and pyridine (3.0 equiv.) in DMF (0.2 M) was added dropwise a solution of methylsulfamoyl chloride (2.5 equiv.) in MeCN (anhydrous) (0.2 M). After complete addition, the reaction mixture was allowed to warm to room temperature and stirred for 1-16 h. Water was added to the reaction mixture, and the resulting suspension was stirred for 1 h. The suspension was filtered and washed with water and EtO. The residue was dried to give the sulfamoyl as a solid.

[0492] Compound A: A solution of compound 7 (1.0 equiv.) in dry THF (0.06-0.10 M) under a nitrogen atmosphere was cooled to -78 °C, and 1 M LiHMDS (3.0 equiv.) in THF was slowly added. After complete addition, the resulting reaction mixture was diluted with some additional dry tetrahydrofuran, stirred for 30 min, and allowed to warm to 0 °C. This was added dropwise via cannula over 15 min to a cooled (-78 °C) solution of NCS or NBS (1.2 equiv.) in dry THF (0.04 M). The resulting reaction mixture was stirred at -78 °C for 1 h. At -78 °C, the reaction mixture was quenched with 1 M HCl and allowed to warm to room temperature. Some additional water was added, and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product, compound 7, was used directly.

[0493] Compound B.5: Compound A (1.0 equiv.) was suspended in MeOH (0.10-0.20 M). An amine (1-10 equiv.) was added. Optionally, 2-5 equiv. of EtN was added, and the reaction mixture was stirred at room temperature for 2-16 h. The reaction mixture was filtered and purified by preparative HPLC (method: preparative acid or preparative base) to give the desired amine B.5 as a solid after lyophilization or Genevac™.

[0494] Example 2 Synthesis of compound 244 [ka] Compound 244 was prepared in one step.

[0495] Step 1: Following the general synthesis of compound B.5, starting from 4-(chloromethyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and 2.0 M dimethylamine in MeOH. The product was combined with another batch and purified by column chromatography to give the title compound as a white solid after lyophilization.

[0496] 4-((Dimethylamino)methyl)-5-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.52min;m / z[M+H] + Calculated value = 525.2, Measured value = 525.2; 1 H NMR(400MHz,DMSO)δ9.37(s,1H),7.26(t,J=7.9Hz,1H),7.18-7.08(m,2H),6.94(s, 1H), 6.76 (s, 1H), 4.02 (s, 2H), 3.59 (s, 2H), 3.05 (s, 3H), 2.93 (s, 3H), 2.18 (s, 6H).

[0497] Example 3 Synthesis of compound 245 [ka] Compound 245 was prepared in one step.

[0498] Step 1: Following the general synthesis of procedure compound B.5, starting from 4-(bromomethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and N-ethylmethylamine in DCMDCM. After complete conversion, the reaction was concentrated under reduced pressure. The impure product was purified by column chromatography to give the title compound as a white solid.

[0499] 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-((ethyl(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.75min;m / z[M+H] + Calculated value=537.0 / 539.0, actual value=537.2 / 539.2;1H NMR(400MHz,DMSO)δ9.02(s,1H),8.12(d,J=8.8Hz,1H),7.38(d,J=8.0Hz,1H),7.29-7.08(m,4H),6.78-6.68(m,1H),4.09(s, 2H),3.60(s,2H),3.07(s,3H),2.94(s,3H),2.55(d,J=4.2Hz,3H),2.43(q,J=7.1Hz,2H),2.10(s,3H),0.98(t,J=7.1Hz,3H).

[0500] Example 4 Synthesis of compound 246 [ka] Compound 246 was prepared in two steps.

[0501] Step 1: Following the general synthesis of compound B.5., starting from 4-(bromomethyl)-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and N-Boc piperazine. The product was purified by preparative base elution. The desired fractions were combined and concentrated under reduced pressure to give the amine as a colorless oil.

[0502] Step 2: The amine was dissolved in 1,4-dioxane (3 mL), and HCl in dioxane (4 M, 16.7 equiv.) was added and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with DCMDCM. The residue was dissolved in MeCN / water and lyophilized to give the title compound as a white solid.

[0503] 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate hydrochloride Analytical: LCMS (Method T): t R =1.40min;m / z[M+H] + Calculated value=564.1 / 566.1, actual value=564.2 / 566.2;1H NMR(400MHz,DMSO)δ9.00(s,1H),8.73-8.68(m,1H),8.09(d,J=8.9Hz,1H),7.39(dd,J=8.1,1.5Hz,1H),7.30-7.24(m,2H),7.20 -7.12(m,2H),6.77(d,1H),4.07(s,2H),3.75(s,2H),3.07(s,3H),3.00-2.85(m,7H),2.72-2.62(m,4H),2.57(d,J=4.7Hz,3H).

[0504] Example 5 Synthesis of compound 249 [ka] Compound 249 was prepared in three steps.

[0505] Step 1: Following the procedure for the general synthesis of compound B.5, starting from the bromine compound and 2.0 M dimethylamine in MeOH, the impure product was purified by column chromatography to give the title compound as a white solid.

[0506] 3-(2-chloro-3-(ethylsulfonamido)benzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =0.95min;m / z[M+H] + Calculated value = 522.1, Measured value = 522.2; 1H NMR(400MHz,DMSO)δ9.69(s,1H),8.09(d,J=8.9Hz,1H),7.33(dd,J=8.0,1.5Hz,1H),7.24(d,J=2.3Hz,1H),7.20-7.07(m,2H),6.85( dd,J=7.8,1.5Hz,1H),4.11(s,2H),3.56(s,2H),3.14(q,J=7.3Hz,2H),3.07(s,3H),2.94(s,3H),2.18(s,6H),1.29(t,J=7.3Hz,3H).

[0507] Example 6 Synthesis of compound 252 [ka] Compound 252 was prepared in one step.

[0508] Step 1: Following the general synthesis of compound B.5, starting from 4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate (50 mg, 0.097 mmol) and 2.0 M dimethylamine in MeOH, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0509] 4-((Dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =0.89min;m / z[M+H] + Calculated value = 537.2, Measured value = 537.2; 1H NMR(400MHz,DMSO)δ9.38(s,1H),7.27(td,J=8.1,1.7Hz,1H),7.16(s,1H),6.99(t,J=7.9Hz,1H),6.84(d,J= 2.3Hz,1H),6.82-6.75(m,2H),4.03(s,2H),3.89(s,3H),3.74(s,2H),3.06(s,3H),2.93(s,3H),2.16(s,6H).

[0510] Example 7 Synthesis of compound 253 [ka] Compound 253 was prepared in one step.

[0511] Step 1: Following the general synthesis of compound B.5, starting from 4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate and 2.0 M dimethylamine in MeOH, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0512] 4-((Dimethylamino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methyl-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =0.85min;m / z[M+H] + Calculated value = 521.2, Measured value = 521.2; 1H NMR(400MHz,DMSO)δ9.36(s,1H),7.28(td,J=7.8,1.6Hz,1H),7.21(q,J=5.0Hz,1H),7.14(d,J=1.7Hz,1H),7.00(t,J=7.9Hz,1H),6.88( d,J=1.7Hz,1H),6.85-6.77(m,1H),4.07(s,2H),3.63(s,2H),3.12(s,3H),2.93(s,3H),2.52(d,J=5.0Hz,3H),2.37(s,3H),2.08(s,6H).

[0513] Example 8 Synthesis of compound 254 [ka] Compound 254 was prepared in one step.

[0514] Step 1: Following the general synthesis of compound B.5, starting from 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-(chloromethyl)-6-fluoro-2-oxo-2H-chromen-7-yldimethylcarbamate and piperazine, the impure product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0515] 3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =0.98min;m / z[M+H] + Calculated value = 582.2, Measured value = 582.2; 1H NMR(400MHz,DMSO)δ8.05(d,J=11.7Hz,1H),7.48(d,J=6.8Hz,1H),7.38(dd,J=8.1,1.5Hz,1H),7.13(t,J=7.9Hz,1H),6.74( dd,J=7.8,1.5Hz,1H),4.08(s,2H),3.58(s,2H),3.09(s,3H),2.95(s,3H),2.59(t,J=4.7Hz,3H),2.55(s,3H),2.35(s,4H).

[0516] Example 9 Synthesis of compound 255 [ka] Compound 255 was prepared in one step.

[0517] Step 1: Following the procedure for the general synthesis of compound B.5, starting from bromine using piperazine, the impure product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0518] 3-(2-chloro-3-(ethylsulfonamido)benzyl)-6-fluoro-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =1.02min;m / z[M+H] + Calculated value = 581.2, Measured value = 581.2; 1 H NMR(400MHz,DMSO)δ8.04(d,J=11.7Hz,1H),7.48(d,J=6.9Hz,1H),7.29(dd,J=8.2,1.5Hz,1H),7.04(t,J=7.9Hz,1H),6.61(d,J=7.7Hz,1 H),4.07(s,2H),3.58(s,2H),3.09(s,3H),3.01(q,J=7.3Hz,2H),2.95(s,3H),2.61(t,J=4.5Hz,4H),2.37(s,5H),1.24(t,J=7.3Hz,3H).

[0519] Example 10 Synthesis of compound 256 [ka] Compound 254 was prepared in one step.

[0520] Step 1: Following the general synthesis of compound B.5, starting from 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-4-(chloromethyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and piperazine, the impure product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0521] 6-chloro-3-(2-chloro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate hydrochloride Analysis: LCMS (Method R): t R =1.02min;m / z[M+H] + Calculated value = 598.1, Measured value = 598.2; 1 H NMR(400MHz,DMSO)δ9.05(s,1H),8.66(s,2H),8.21(s,1H),7.53(s,1H),7.40(d,J=7.9Hz,1H),7.30(d,J=5.2Hz,1H),7.15(t,J=7. 9Hz,1H),6.80(d,J=7.8Hz,1H),4.07(s,2H),3.77(s,2H),3.11(s,3H),2.95(s,3H),3.94(s,4H)2.68(s,4H),2.57(d,J=4.5Hz,3H).

[0522] Example 11 Synthesis of compound 257 [ka] Compound 257 was prepared in three steps.

[0523] Step 1: Following the procedure for the general synthesis of compound B.5, starting from bromine using piperazine, the impure product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0524] 6-chloro-3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate hydrochloride Analysis: LCMS (Method R): t R =1.05min;m / z[M+H] + Calculated value = 597.1, Measured value = 597.2; 1 H NMR(400MHz,DMSO)δ9.48(s,1H),9.04(s,2H),8.23(s,1H),7.53(s,1H),7.34(d,J=8.0Hz,1H),7.17(t,J=7.9Hz,1H),6.89(d,J=7 .7Hz,1H),4.09(s,2H),3.82(s,2H),3.16(q,J=7.4Hz,2H),3.11(s,3H),2.95(d,J=5.5Hz,7H),2.74(s,4H),1.30(t,J=7.3Hz,3H).

[0525] Example 12 Synthesis of compound 258 [ka] Compound 258 was prepared in three steps.

[0526] Step 1: Following the procedure for the general synthesis of compound B.5, starting from bromine using piperazine, the impure product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0527] 3-(2-chloro-3-(ethylsulfonamido)benzyl)-2-oxo-4-(piperazin-1-ylmethyl)-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R=1.00min;m / z[M+H] + Calculated value = 563.2, Measured value = 563.2; 1 H NMR(400MHz,DMSO)δ8.26(s,1H),8.10(d,J=8.9Hz,1H),7.31(d,J=8.1Hz,1H),7.25(d,J=2.3Hz,1H),7.17(dd,J=8.8,2.4Hz,1H),7.11(t,J=7. 9Hz,1H),6.74(d,J=7.7Hz,1H),4.08(s,2H),3.62(s,2H),3.08(d,J=3. 5Hz, 5H), 2.94 (s, 3H), 2.63 (s, 4H), 2.40 (s, 4H), 1.27 (t, J=7.3Hz, 3H).

[0528] Example 13 Synthesis of compound 261 [ka] Compound 261 was prepared in one step.

[0529] Step 1: Following the general synthesis of compound B.5, starting from 4-(bromomethyl)-6-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and N-methylethylamine, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0530] 4-((Ethyl(methyl)amino)methyl)-6-fluoro-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.73min;m / z[M+H] + Calculated value = 538.6, Measured value = 539.2; 1H NMR(400MHz,CDCl3)δ7.96(d,J=11.2Hz,1H),7.40(td,J=7.8,1.5Hz,1H),7 .19(d,J=6.7Hz,1H),7.01(t,J=8.0Hz,1H),6.87(d,J=7.7Hz,1H),6.60(s,1 H),4.42(d,J=5.6Hz,1H),4.15(s,2H),3.63(s,2H),3.15(s,3H),3.05(s,3H) ),2.76(d,J=5.3Hz,3H),2.48(s,2H),2.17(s,3H),1.25(s,1H),1.10(s,3H)

[0531] Example 14 Synthesis of compound 262 [ka] Compound 262 was prepared in two steps.

[0532] Step 1: Following the general synthesis of compound E.5., starting with 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and N-Boc piperazine. The product was purified by preparative base separation. The desired fractions were combined and concentrated under reduced pressure to give the amine (as a colorless oil).

[0533] Step 2: The amine was dissolved in 1,4-dioxane (3 mL), and HCl in dioxane (4 M, 16.7 equiv.) was added and stirred for 1 h at room temperature. The reaction mixture was concentrated under reduced pressure and co-evaporated twice with DCMDCM. The residue was dissolved in MeCN / water and lyophilized to give the title compound as a white solid.

[0534] Analysis: LCMS (Method S):t R =1.00min;m / z[M+H] +Calculated value=548.2, Actual value=548.2;1H NMR(400MHz,DMSO)δ9.37(s,1H),8.88(s,2H),8.09(d,J=8.8Hz,1H),7.32-7.19(m,3H),7.17(dd,J=8.9,2.4Hz,1H),7.00(t,J=7 .8Hz,1H),6.86-6.78(m,1H),4.04(s,2H),3.86(s,2H),3.07(s,3H),2.95(d,J=14.4Hz,7H),2.73(s,4H),2.54(d,J=2.8Hz,3H).

[0535] Example 15 Synthesis of compound 263 [ka] Compound 263 was prepared in one step.

[0536] Step 1: Following the general synthesis of compound B.5, starting from 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (and 2-fluoro-N-methylethan-1-amine). The product was purified by column chromatography to give (after lyophilization) the title compound as a white solid.

[0537] 3-(2-Fluoro-3-((N-methylsulfamoyl)amino)benzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =1.22min;m / z[M+H] + Calculated value = 539.2, Measured value = 539.2; 1H NMR(400MHz,DMSO)δ8.12(d,J=8.9Hz,1H),7.31-7.22(m,2H),7.14(dd,J=8.9,2.4Hz,1H),6.99(t,J=7.9Hz,1H),6.81(s,1H),4.59(t,J=4.7 Hz,1H),4.47(t,J=4.7Hz,1H),4.05(s,2H),3.80(s,2H),3.06(s,3H),2.93(s,3H),2.79(t,J=4.8Hz,1H),2.71(t,J=4.8Hz,1H),2.19(s,3H).

[0538] Example 16 Synthesis of compound 264 [ka] Compound 264 was prepared in three steps.

[0539] Step 1: Following the procedure for the general synthesis of compound B.5, starting from bromine and 2-fluoro-N-methylethan-1-amine, after complete conversion the impure product was purified by column chromatography to give the title compound as an off-white solid.

[0540] 3-(3-(ethylsulfonamido)-2-fluorobenzyl)-4-(((2-fluoroethyl)(methyl)amino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method R): t R =1.32min;m / z[M+H] + Calculated value = 538.2, Measured value = 538.2; 1H NMR(400MHz,DMSO)δ9.60(s,1H),8.12(d,J=8.9Hz,1H),7.29-7.18(m,2H),7.14(dd, J=8.8,2.3Hz,1H),7.01(t,J=8.0Hz,1H),6.90(t,J=7.4Hz,1H),4.58(t,J=4.8Hz,1H ),4.46(t,J=4.8Hz,1H),4.06(s,2H),3.81(s,2H),3.08(d,J=13.3Hz,5H),2.93(s,3 H),2.78(t,J=4.7Hz,1H),2.71(t,J=4.7Hz,1H),2.18(s,3H),1.26(t,J=7.3Hz,3H).

[0541] Example 17 Synthesis of compound 265 [ka] Compound 265 was prepared in one step.

[0542] Step 1: Following the general synthesis of compound B.5, starting from 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and N-methylprop-2-yn-1-amine, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0543] Example 18 Synthesis of Compound 266 [ka] Compound 266 was prepared in one step.

[0544] Step 1: Following the general synthesis of compound B.5, starting from 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and 2,2-difluoro-N-methylethan-1-amine, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0545] 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analytical: LCMS (Method R): t R =1.64 min;m / z[M+H] + Calculated value = 557.2, Measured value = 557.2; 1 H NMR(400MHz,DMSO)δ9.41(s,1H),8.09(d,J=8.9Hz,1H),7.38-7.23(m,2H),7.14(dd,J=8.8,2.4Hz,2H),6.98(t, J=8.0Hz,1H),6.79(s,1H),6.11(t,1H),4.05(s,2H),3.89(s,2H),3.06(s,3H),2.96-2.80(m,5H),2.24(s,3H).

[0546] Example 19 Synthesis of compound 267 [ka] Compound 267 was prepared in three steps.

[0547] Step 1: Following the procedure for the general synthesis of compound B.5, starting from 220 mg of 0.384 mmol of bromine and 2,2-difluoro-N-methylethan-1-amine, after complete conversion the impure product was purified by column chromatography to give the title compound as an off-white solid.

[0548] 4-(((2,2-difluoroethyl)(methyl)amino)methyl)-3-(3-(ethylsulfonamido)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analytical: LCMS (Method R): t R =1.69min;m / z[M+H] + Calculated value = 556.2, Measured value = 556.4; 1 H NMR(400MHz,DMSO)δ9.62(s,1H),8.09(d,J=8.9Hz,1H),7.24(q,J=3.0Hz,2H),7.14(dd,J=8.9,2.4Hz,1H),7.01(t,J=7.9Hz,1H),6.89( t,J=7.1Hz,1H),6.31-5.93(m,1H),4.06(s,2H),3.90(s,2H),3.17-3.02(m,5H),2.99-2.80(m,5H),2.24(s,3H),1.26(t,J=7.3Hz,3H).

[0549] Example 20 Synthesis of compound 268 [ka] Compound 268 was prepared in one step.

[0550] Step 1: Following the general synthesis of compound B.2, starting from 4-(bromomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (45 mg, 0.075 mmol, y: 40%) and 2-(methylamino)acetonitrile, 3.0 equivalents of Net3 were added. The product was purified by preparative base followed by preparative acid to give the title compound (3.8 mg, 0.007 mmol, y: 21%) as a white solid after lyophilization.

[0551] Example 21 Synthesis of compound 269 [ka] Compound 269 was prepared in one step.

[0552] Step 1: Following the general synthesis of compound B.5, starting from 4-(chloromethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-5-methoxy-2-oxo-2H-chromen-7-yldimethylcarbamate and 2.0 M dimethylamine in MeOH, the product was purified by column chromatography to give the title compound as a white solid after lyophilization.

[0553] Example 22 Synthesis of compound 271 [ka] Compound 271 was prepared in one step.

[0554] Step 1: To a solution of 3-(3-bromo-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (2.0 g, 4.19 mmol, 1.0 eq.) and (tributylstannyl)methanol (1.614 g, 5.03 mmol) (1.61 g, 5.03 mmol, 1.2 eq.) in 1,4-dioxane (0.1 M) under an inert atmosphere, Pd(Ph3p)4 (0.242 g, 0.209 mmol, 0.05 eq.) was added. The formed reaction mixture was stirred for 18 hours at 100 °C. The reaction mixture was filtered and washed with MeCN. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using the "Flash" method (heptane / EtOAc = 1:0 → 2:8). 40 mg of the still impure product was purified by preparative base to give the title compound (29 mg, 0.067 mmol, yield: 1.5%) as an off-white solid. Yield: The title compound was isolated as an off-white solid (1% over one step).

[0555] 4-((Dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.53min;m / z[M+H] + Calculated value=429.2, Actual value=429.2;1H NMR(400MHz,DMSO)δ8.07(d,J=8.8Hz,1H),7.33-7.27(m,1H),7.22(d,J=2.3Hz,1H),7.14(dd,J=8.8,2.4Hz,1H),7.08-6. 96(m,2H),5.23(t,J=5.7Hz,1H),4.55(d,J=5.5Hz,2H),4.04(s,2H),3.65(s,2H),3.06(s,3H),2.93(s,3H),2.19(s,6H).

[0556] Example 23 Synthesis of compound 272 [ka] Compound 272 was prepared in one step.

[0557] Step 1: Following the general synthesis of compound B.2, starting with 4-(bromomethyl)-3-(3-((ethylsulfonyl)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (45 mg, 0.075 mmol, y: 40%) and dimethylamine, 3.0 equivalents of Net3 were added. The product was purified by preparative base followed by preparative acid to give the title compound (3.8 mg, 0.007 mmol, y: 21%) as a white solid after lyophilization.

[0558] Yield: Compound 272 was isolated as a white solid (21% over one step).

[0559] Example 24 Synthesis of compound 273 [ka] Compound 273 was prepared in three steps.

[0560] Step 1: To a solution of 3-(3-bromo-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (2.0 g, 4.19 mmol, 1.0 equiv.) and (tributylstannyl)methanol (1.614 g, 5.03 mmol) (1.61 g, 5.03 mmol, 1.2 equiv.) in 1,4-dioxane (0.1 M) under an inert atmosphere, Pd(Ph3p)4 (0.242 g, 0.209 mmol, 0.05 equiv.) was added. The reaction mixture was stirred for 18 hours at 100 °C. The reaction mixture was filtered and washed with MeCN. The filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography using the "Flash" method (heptane / EtOAc = 1:0 → 2:8). The desired fractions were combined and concentrated under reduced pressure to give 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (1.46 g, 3.3 mmol, yield: 79%) as a clear oil.

[0561] Step 2: To a solution of 4-((dimethylamino)methyl)-3-(2-fluoro-3-(hydroxymethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (1.41 g, 3.29 mmol, 1.0 equiv.) in DCM (0.23 M) at 0 °C was slowly added a solution of thionyl chloride (0.48 ml, 6.58 mmol, 2.0 equiv.) in DCM (2 ml). The formed reaction mixture was stirred for 1 h and allowed to warm to room temperature. The reaction mixture was concentrated under reduced pressure and stripped twice with DCM to give 3-(3-(chloromethyl)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (1.68 g, 3.60 mmol, 109% yield) as an off-white solid.

[0562] Step 3: To a mixture of 3-(3-(chloromethyl)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (0.5 g, 1.12 mmol, 1.0 equiv.) in ethanol (absolute) (0.1 M) under N2 atmosphere, thiourea (0.102 g, 1.343 mmol, 1.2 equiv.) was added. The reaction mixture was stirred at 80° C. for 2 h and then at room temperature for 2 days. NaOHN (1.68 ml, 3.36 mmol, 3.0 equiv.) was added and stirred at 80° C. for 2 h. The reaction mixture was acidified with 1 M HCl. Some additional water was added, followed by DCM. The layers were separated using a phase separator, and the organic layer was concentrated under reduced pressure to give 4-((dimethylamino)methyl)-3-(2-fluoro-3-(mercaptomethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate and its dimer ((((disulfanediylbis(methylene))bis(2-fluoro-3,1-phenylene))bis(methylene))bis(4-((dimethylamino)methyl)-2-oxo-2H-chromene-3,7-diyl)bis(dimethylcarbamate)) (570 mg, 0.67 mmol, yield: 60%) as a yellow solid.

[0563] Step 4: (((disulfanediylbis(methylene))bis(2-fluoro-3,1-phenylene))bis(methylene))bis(4-((dimethylamino)methyl)-2-oxo-2H-chromene-3,7-diyl)bis(dimethylcarbamate) (0.57 g, 0.257 mmol, 1.0 equiv.) was dissolved in 0.11 M THF / 0.11 M water and cooled to 0° C. Tri-n-butylphosphine (0.071 ml, 0.283 mmol, 1.1 equiv.) was added slowly and stirred for 1 h at room temperature. Water and DCM were added and the layers were separated using a phase separator. The organic layer was concentrated under reduced pressure and the residue was purified by column chromatography using the "flash" method (DCM / MeOH=1:0→98:2). The desired fractions were combined and concentrated under reduced pressure to give 4-((dimethylamino)methyl)-3-(2-fluoro-3-(mercaptomethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (283 mg, 0.618 mmol, yield: 55%) as a clear oil.

[0564] Step 5: 4-((dimethylamino)methyl)-3-(2-fluoro-3-(mercaptomethyl)benzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (50 mg, 0.112 mmol, 1.0 equiv.) was dissolved in DMF (dry) (0.23 M), CsCO (36.6 mg, 0.112 mmol, 1.0 equiv.) and iodoethane (10.91 μL, 0.135 mmol, 1.2 equiv.) were added, and the mixture was stirred at room temperature for 1 h. Iodoethane (1.818 μL, 0.022 mmol, 0.2 equiv.) was added, and the mixture was stirred at room temperature for 30 min. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure to give 4-((dimethylamino)methyl)-3-(3-((ethylthio)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (43 mg, 0.058 mmol, yield: 52%) as a yellow oil.

[0565] Step 6: 4-((dimethylamino)methyl)-3-(3-((ethylthio)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (43 mg, 0.091 mmol, 1.0 equiv.) was dissolved in MeOH (0.06 M) / water (0.06 M), and oxone monopersulfate compound (55.9 mg, 0.091 mmol, 1.0 equiv.) was added and stirred for 1 h at room temperature. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layers were washed with brine, dried over Na2SO4, filtered, and concentrated under reduced pressure. The impure product was purified by preparative base followed by preparative acid to give the title compound (6.5 mg, 0.012 mmol, yield: 14%) as a white solid.

[0566] 4-((Dimethylamino)methyl)-3-(3-((ethylsulfonyl)methyl)-2-fluorobenzyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.60 min;m / z[M+H]+calculated value=505.2, actual value=505.2;1H NMR(400MHz,DMSO)δ8.08(d,J=8.8Hz,1H),7.35-7.27(m,1H),7.22(d,J=2.4Hz,1H),7.18-7.04(m,3H),4.52(s,2 H),4.07(s,2H),3.65(s,2H),3.12(q,J=7.5Hz,2H),3.06(s,3H),2.93(s,3H),2.18(s,6H),1.25(t,J=7.4Hz,3H).

[0567] Example 25 Synthesis of compound 274 [ka] Compound 274 was prepared in one step.

[0568] Step 1: 3-(3-Bromo-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate (50 mg, 0.105 mmol, 1.0 equiv.) was dissolved in toluene (dry) (0.2 M) and flushed with argon. Pd(dba) (4.80 mg, 5.24 μmol, 0.05 equiv.), t-BuXPhos (8.90 mg, 0.021 mmol, 0.2 equiv.), KCO (29.0 mg, 0.209 mmol, 2.0 equiv.), and 2-methylpropane-2-sulfinamide (25.4 mg, 0.209 mmol, 2.0 equiv.) were then added. The resulting reaction mixture was stirred at 50 °C for 17 h. The reaction mixture was flushed with argon, and Pd2(dba)3 (4.80 mg, 5.24 μmol, 0.05 equiv.) and t-BuXPhos (8.90 mg, 0.021 mmol, 0.2 equiv.) were added. The reaction mixture was stirred for 48 h at 50 °C. The impure product was purified by preparative base separation to give the title compound (40 mg, 0.076 mmol, yield: 72.7%) as a white solid. Yield: The title compound was isolated as a white solid (73% over one step).

[0569] 3-(3-((tert-Butylsulfinyl)amino)-2-fluorobenzyl)-4-((dimethylamino)methyl)-2-oxo-2H-chromen-7-yldimethylcarbamate Analysis: LCMS (Method T): t R =1.70min;m / z[M+H] + Calculated value=518.2, Actual value=518.2;1H NMR(400MHz,DMSO)δ8.08(d,J=8.8Hz,1H),7.61(s,1H),7.22(d,J=2.3Hz,1H),7.17-7.06(m,2H),6.97(t,J=7. 8Hz, 1H), 6.76 (t, J=7.0Hz, 1H), 4.04 (s, 2H), 3.65 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.18 (s, 6H), 1.25 (s, 9H).

[0570] Example 26 Synthesis of compound 278 [ka] Compound 278 was prepared in one step.

[0571] Step 1: Following the general synthesis of compound B.5, star...

Claims

1. A compound having the chemical structure of formula (IV), including pharmaceutically acceptable salts thereof: 【Chemistry 1】 During the ceremony, R ６ is hydrogen, fluoro, or chloro; R １３ is ethyl or -NR Ａ R Ｂ and R Ａ is hydrogen, and R Ｂ is methyl, Z ２ But, -NR ５ R ５’ , 【Chemistry 2】 or 【Transformation 3】 and R ５ But C １ ~C ６ is alkyl, R ５’ But C １ ~C ６ The compound, including pharmaceutically acceptable salts thereof, is alkyl.

2. R ５ 2. The compound of claim 1, wherein is methyl and R 5' is methyl or ethyl.

3. a) Z ２ But, -NR ５ R ５’ and R 13 is —NR A R B ; b) Z 2 is 【Chemistry 4】 and R 13 is —NR A R B ; c) Z 2 is —NR 5 R 5′ and R 13 is ethyl; d) Z 2 is 【Transformation 5】 and R 13 is —NR A R B .

4. The compound is 【Transformation 6】 or a pharmaceutically acceptable salt thereof; 【Transformation 7】 or a pharmaceutically acceptable salt thereof; 【Transformation 8】 or a pharmaceutically acceptable salt thereof; 【Chemistry 9】 or a pharmaceutically acceptable salt thereof; 【Chemistry 10】 2. The compound of claim 1, which is a compound selected from:

5. The compound is 【Chemistry 11】 or a pharmaceutically acceptable salt thereof.

6. The compound is 【Chemistry 12】 or a pharmaceutically acceptable salt thereof.

7. The compound is 【Chemistry 13】 or a pharmaceutically acceptable salt thereof.

8. The compound is 【Chemistry 14】 or a pharmaceutically acceptable salt thereof.

9. The compound is 【Chemistry 15】 or a pharmaceutically acceptable salt thereof.

10. The compound is 【Chemistry 16】 or a pharmaceutically acceptable salt thereof.

11. The compound is 【Chemistry 17】 or a pharmaceutically acceptable salt thereof.

12. A compound having the structure of formula (III): [Chemistry 18] and pharmaceutically acceptable salts thereof. During the ceremony, R ２ is L, R ６ is selected from the group consisting of H, or fluoro, chloro, or bromo; R ７ is H, R １３ optionally substituted amine, C １ ~C ６ Alkyl, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C １ ~C ６ Alkoxy, optionally substituted C ２ ~C ６ Alkenyl, optionally substituted C ２ ~C ６ Alkynyl, optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C ８ Heterocyclyl, optionally substituted C ３ ~C １０ heteroaryl, and L; R ３ But it's Chloro. X is —O—, Y is, 【Chemistry 19】 and L is -Z １ -Z ２ and Z １ But -CH ２ - and Z ２ , but -NR ５ R ５’ , optionally substituted C ３ ~C ８ Heterocyclyl, —CH ２ -, -O-, -S-, S=O, -SO ２ -, C=O, -CO ２ --, --NO ２ , —NH—, —CH ２ CCH, -CH ２ CN, -NH(CO)-, -(CO)NH-, -(CO)NR ５ R ５’ -, -NH-SO ２ -, -SO ２ -NH-, -R ５ CH ２ -, -R ５ O-, -R ５ S-, R ５ -S=O, -R ５ SO ２ -, R ５ -C=O, -R ５ CO ２ -, -R ５ NH-, -R ５ NH(CO)-, -R ５ (CO)NH-, -R ５ NH-SO ２ -, -R ５ SO ２ -NH-, -NHCH ２ CO-, -CH ２ R ５ -, -OR ５ -, -SR ５ -, S=O-R ５ , -SO ２ R ５ -, C=O-R ５ , -CO ２ R ５ --, --NHR ５ -, -NH(CO)R ５ -,-(CO)NHR ５ -, -NH-SO ２ R ５ -, -SO ２ -NHR ５ -, optional C replaced by １ ~C ６ Alkyl, optionally substituted C ３ ~C ８ Cycloalkyl, optionally substituted C ６ ~C １０ Aryl, optionally substituted C ３ ~C １０ Heteroaryl, —CH ２ -(optionally substituted aryl), -CH ２ - (optionally substituted C ３ ~C ８ cycloalkyl), and —CH ２ - (optionally substituted C ３ ~C １０ heteroaryl), Each R ５ and R ５’ is an independently selected optionally substituted C １ ~C ６ alkyl, H, deuterium, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 carbocyclyl, optionally substituted C 6 -C 10 aryl, optionally substituted C 3 -C 8 heterocyclyl, and optionally substituted C 3 -C 10 heteroaryl; or A compound having the structure of formula (III): 【Chemistry 20】 and pharmaceutically acceptable salts thereof. During the ceremony, R 2 is L; R 6 is selected from the group consisting of H, fluoro, chloro, or bromo; R 7 is H; R 13 is optionally substituted amine, C 1 -C 6 alkyl, H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C-amido, optionally substituted N-amido, optionally substituted ester, optionally substituted sulfonyl, optionally substituted S-sulfonamido, optionally substituted N-sulfonamido, optionally substituted sulfonate, optionally substituted O-thiocarbamyl, optionally substituted N-thiocarbamyl, optionally substituted N-carbamyl, optionally substituted O-carbamyl, optionally substituted urea, optionally substituted C 1 -C 6 alkoxy, optionally substituted C 2 -C 6 alkenyl, optionally substituted C 2 -C 6 alkynyl, optionally substituted C 3 -C 8 cycloalkyl, optionally substituted C 6 -C 10 is selected from the group consisting of aryl, optionally substituted C 3 -C 8 heterocyclyl, optionally substituted C 3 -C 10 heteroaryl, and L; R 3 is chloro; X is —O—, Y is, 【Chemistry 21】 and L is -Z 1 -Z 2 ; Z 1 is —CH 2 —; Z 2 is —NR 5 R 5′ optionally substituted C 3 -C 8 heterocyclyl, —CH 2 —, —O—, —S—, S═O, —SO 2 —, C═O, —CO 2 —, —NO 2 , —NH—, —CH 2 CCH, —CH 2 CN, —NH(CO)—, —(CO)NH—, —(CO)NR 5 R 5′ —, —NH—SO 2 —, —SO 2 —NH—, —R 5 CH 2 —, —R 5 O—, —R 5 S—, R 5 —S═O, —R 5 SO 2 —, R 5 —C═O, —R 5 CO 2 —, —R 5 NH—, —R 5 NH(CO)—, —R 5 (CO)NH—, —R 5 NH—SO 2 —, —R 5 SO 2 —NH—, —NHCH 2 CO—, —CH 2 R 5 —, —OR 5 —, —SR 5 —, S═O—R 5 , —SO 2 R 5 —, C═O—R 5 , —CO 2 R 5 —, —NHR 5 —, —NH(CO)R 5 —, —(CO)NHR 5 —, —NH—SO 2 R 5 —, —SO 2 —NHR 5 —, optionally substituted C 1 to C 6 alkyl, optionally substituted C 3 to C 8 cycloalkyl, optionally substituted C 6 to C 10 aryl, optionally substituted C 3 to C 10 heteroaryl, —CH 2 selected from the group consisting of -(optionally substituted aryl), -CH2-(optionally substituted C3-C8 cycloalkyl), and -CH2-(optionally substituted C3-C10 heteroaryl); each R 5 and R 5′ is independently selected from optionally substituted C 1 -C 6 alkyl; or A compound having the structure of formula (III): 【Chemistry 22】 and pharmaceutically acceptable salts thereof. During the ceremony, R 2 is L; R 6 is selected from the group consisting of H, fluoro, chloro, or bromo; R 7 is H; R 13 is C 1 -C 6 alkyl; R 3 is chloro; X is —O—, Y is, 【Chemistry 23】 and L is -Z 1 -Z 2 ; Z 1 is —CH 2 —; Z 2 is —NR 5 R 5′ ; Compounds wherein each R 5 and R 5' is independently an optionally substituted C 1 -C 6 alkyl.

13. A pharmaceutical composition comprising the compound of any one of claims 1 to 12 or a pharmaceutically acceptable salt thereof.

14. 13. Use of a compound according to any one of claims 1 to 12 in the manufacture of a medicament for the treatment of cancer.

Images