MEK inhibitors and their therapeutic uses.

Abstract

The present disclosure provides compounds, compositions containing such compounds, and methods of designing, developing, producing and preparing compounds represented by general Formula (I), including pharmaceutically acceptable salts thereof or a synthetic intermediate thereof. The compounds act as MEK inhibitors and are capable of displaying one or more beneficial therapeutic effects, including treating cancer.

Description

MEK INHIBITORS AND THERAPEUTIC USES THEREOFBACKGROUNDField

[0001] The present invention relates to the fields of chemistry and medicine. More particularly, the present invention relates to MEK inhibitors, techniques for designing and synthesizing such MEK inhibitors, compositions comprising MEK inhibitors, and methods of treating disease comprising administering MEK inhibitors.Description of the Related Technology

[0002] Cancer is among the most common causes of death in the United States. In the United States, cancer has accounted for approximately one of every four deaths. The 5- year relative survival rate forcancer patients diagnosed in 1996-2003 is approximately two- thirds, up from about one half in 1975-1977 (Cancer Facts & Figures, American Cancer Society: Atlanta, Ga. (2008)). The rate of new cancer cases decreased by an average 0.6% per year among men between 2000 and 2009, but stayed the same for women. From 2000 through 2009, death rates from all cancers combined decreased on average 1.8% per year among men and 1.4% per year among women. This improvement in survival reflects progress in diagnosing at an earlier stage as well as improvements in treatment, for which there remain a need. Discovering highly effective anticancer agents with low toxicity is a primary goal of cancer research.

[0003] Furthermore, cancer-related cachexia is a debilitating condition associated with loss of muscle mass, fatigue, weakness, and loss of appetite in cancer patients. Cachexia is also associated with severe clinical consequences including muscle weakness which can result in ambulation difficulties, and pulmonary complications. Cachexia is a significant contributing factor in the death of cancer patients.

[0004] Cachexia has been characterized, in part, by depletion of skeletal muscle mass that is not reversed by conventional nutritional support, leading to pronounced weight loss that severely impacts patient morbidity and mortality. Cachexia has been identified in more than 80% of patients with gastric, pancreatic, and esophageal cancer; approximately 70% of those with head and neck cancer; and approximately 60% of patients with lung,colorectal, and prostate cancer. See, Muscle (2012) 3, 245-51. Despite the impact of cachexia on mortality among cancer patients, effective therapies have not been developed to prevent or impede the progression of cachexia. For example, more than 85% of pancreatic cancer patients, including early stage patients, are estimated to lose an average of 14% of their pre illness weight. See, BMC Cancer, 2010 Jul. 8; 10:363. Cachectic pancreatic cancer patients are often weak and fatigued, and have a lower tolerance to therapy and more adverse outcomes to surgery. Consequently, cachexia is the main driver for mortality in pancreas cancer. Unfortunately, the 5-year survival rate for pancreatic cancer has not exceeded 6% for the last four decades, which is the lowest survival rate among all malignancies.

[0005] Substantial efforts have been invested in designing a treatment for the cachectic syndrome, but unfortunately there is no single, fully satisfactory treatment for reversing weight loss associated with cancer cachexia. The development of different therapeutic strategies has focused on two targets: counteracting anorexia and neutralizing metabolic disturbances. However, providing complete nutritional requirements by way of total parenteral nutrition does not abrogate weight loss instead, many drugs have been proposed and used in clinical trials, while others are still under investigation using experimental animals in order to revert metabolic alterations. See, Toledo, et al. 2014 PloS One. In one study, Selumetinib, an MEK inhibitor, was found to promote muscle gain in patients with cholangiocarcinoma. See, British Journal of Cancer, (2012), 106, 1583-1586. In another study, binimetinib, an MEK inhibitor, was found to promote muscle gain in patients with BTC. See, Inv New Drugs (2018) 36, 1037-1043.

[0006] In addition to its potential role in cachexia, MEK is a critical signaling intermediate in the MAPK / ERK pathway, which is inappropriately activated across a broad spectrum of human tumors, including those derived from lung, pancreas, ovary, skin and colon. While several MEK inhibitors have achieved regulatory approval to date, these MEK inhibitors have yet to deliver against clinical efficacy expectations. Indentification of a new class of MEK inhibitors that maximize pathologic reversal of the MAPK / ERK pathway, while limiting drug-related toxicity would have a significant impact on cancer patient morbidity and mortality.SUMMARY OF THE DISCLOSURE

[0007] The compounds disclosed in the present application have been discovered to exhibit surprising and unexpected biological effects. These compounds are MEK inhibitors that maximize pathologic reversal of the MAPK / ERK pathway, and are effective anti-cancer and anti-cancer cachexia agents suitable for use in anti-cancer and anti-cancer cachexia pharmaceutical formulations.

[0008] Some embodiments provide for a compound having the structure of Formula (I):including pharmaceutically acceptable salts thereof, wherein:R1, R2, R3, R4and R6are each independently selected from the group consisting of 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 substitutedN-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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2-, -R5O-, - R5S-, R5-S=O, - R5SO2-, R5-C=O, - R5C02-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, s=o- R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-S02R5-, - SCk-NHR3-, optionally substituted Ci to Ce alkyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted C6to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3 to CIO heteroaryl; and Y is CH2, NH or O, with the proviso that R1 is not pyrimidyl.

[0009] In some embodiments of Formula (I), the Ring A issome embodiments, R2is -CH3. In someembodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is - CH2-. In some embodiments, Z2is selected from optionally substituted C3 to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-and Z2is optionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, Zi is -C¾- and Z2is optionally substituted, wherein n is 1,2, 3 or 4. In some embodiments, Zi is -CH2- and Z2 is optionally substituted

[0010] Some embodiments provide a compound of Formula (la):including pharmaceutically acceptable salts thereof, wherein:R2, R3, R4and R6are each independently selected from the group consisting of 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted e to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2- -R5O-, - R5S- R5-S=O, - R5SO2- R5-C=O, - R5C02-, - R5NH- - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0- R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - SO2-NHR5-, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3 to C10 heteroaryl) ; each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl; and Y is CH2, NH or O, with the proviso that R1is not pyrimidyl.0011 In some embodiments of Formula (la), the Ring A issome embodiments, R2is -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is - CH2-. In some embodiments, Z2is selected from optionally substituted C3 to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2 ISoptionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, Zi is -CH2- and Z2 is optionally substituted, wherein n is 1, 2, 3 or 4. In some embodiments, Zi is -CH2- and Z2 is optionally substituted

[0012] Some embodiments provide a compound of Formula (lb):including pharmaceutically acceptable salts thereof, wherein:R2, R3, R4and R6are each independently selected from the group consisting of 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 Ci to C6 alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2- , -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, - (CO)NR5R5-, -NH-SO2-, -SO2-NH-, -R5CH2-, -R50-, - R5S-, R5-S=0, - R5S02-,R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0-R5, -SO2R5-, C=0-R\ -CO2R5-, - NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, -SO2-NHR5-, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2- (optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or - CH2-(optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to G alkenyl, optionally substituted C2to G, alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted G, to C10aryl, optionally substituted C3 to Cs heterocyclyl, or optionally substituted C3 to C10heteroaryl; and with the proviso that R1is not pyrimidyl.

[0013] In some embodiments of Formula (lb), the Ring A issome embodiments, R2is -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Z\is - CH2-. In some embodiments, Z2is selected from optionally substituted C3to G cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Z\is -CH2-, Z2 ISoptionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl).

[0014] Some embodiments provide a compound of Formula (Ic):including pharmaceutically acceptable salts thereof, wherein:R1, R2, R3, R4, and R6are each independently selected from the group consisting of 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, or L;L is -Z1-Z2 or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2-, -R5O-, - R5S-, R5-S=O, - R5SO2- R5-C=O. - R5CO2-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0- R5, -SO2R5-, C=0-R\ -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - S02-NHR3-, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, - CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, or optionally substituted C3 to C10heteroaryl; and Y is CH2, NH or 0, with the proviso that R1is not pyrimidyl.

[0015] In some embodiments of Formula (Ic), the Ring A issome embodiments, R2is -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is - CH2-. In some embodiments, Z2is selected from optionally substituted C3 to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2 ISoptionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, Zi ls -CH2-and Z2is optionally substituted, wherein n is an integer selected- I lfrom 1, 2, 3 and 4. In some embodiments, Zi is -CH2- and Z2 is optionally substituted

[0016] A compound of Formula (I), having the structure depicted in Formula (Id):including pharmaceutically acceptable salts thereof, wherein:R3and R4are each independently selected from the group consisting of 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 Ci to C6alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to C6alkenyl, optionally substituted C2 to Ce alkynyl,optionally substituted C3to Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, and L;R6is selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to Ce alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to C alkenyl, and optionally substituted C2 to C6alkynyl;R9and R10are each independently selected from hydrogen, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C3to Cg cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl);X1is selected from the group consisting of CH, B, N, or PO4; n is selected from 1, 2, 3, or 4; each R5and R5is independently selected from H, deuterium, optionally substituted Ci to C6alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, and optionally substituted C3 to C10 heteroaryl; and Y is CH2, NH, or 0, with the proviso that R1is not pyrimidyl.

[0017] In some embodiments, n is 1 or 2. In some embodiments, wherein X1is CH or N. In some embodiments, R9is selected from optionally substituted Ci to C6alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl. In some embodiments, R10is selected from optionally substituted Ci to C6alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl.

[0018] Some embodiments provide a compound of Formula (II):including pharmaceutically acceptable salts thereof, wherein:QA, QB, QC are independently C or N;R1, R2, R3, R6, and R7are each independently selected from the group consisting of 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 Ci to Cf, alkoxy, optionally substituted Ci to C(, alkyl, optionally substituted C2to Ci alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2-, -R5O-, - R5S-, R5-S=O, - R5SO2-, R5-C=O, - R5CO2-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, s=o- R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - S02-NHR3-, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, - CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3to C10heteroaryl);each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl;Y is CH2, NH or 0; andZ is C or N, with the proviso that R1is not pyrimidyl.

[0019] In some embodiments of Formula (II), R2is -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is -CH2-. In some embodiments, Z2is selected from optionally substituted C3to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, -NR5R5, - CH2CH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2 ISoptionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, Zi is -CH2- and Z2 is optionally substituted, wherein n an integer selected from is 1, 2, 3, and 4. In some embodiments, Zi is -CH2- and Z2 is optionally substituted

[0020] Some embodiments provide a compound of Formula (Ila):including pharmaceutically acceptable salts thereof, wherein:R2, R3,R6and R8are each independently selected from the group consisting of 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 Ci to alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, or L;L is -Z1-Z2 or -Z1-Z2-Z3;Zi, Z2, and Z3are independently selected from halo, -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5’, -NH(CO) -, -(CO)NH-, - (C0)NR5R5-, -NH-SO2-, -SO2-NH-, -R5CH2-, -R50-, - R5S-, R5-S=0, - R5S02-, R5- C=0, - R5C02-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02- -R5S02-NH-, - CH2R5-, -OR5-, -SR5-, S=0-R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, -SO2-NHR5-, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10heteroaryl); each of R5and R5is independently selected from H, deuterium, optionally substituted Ci to C6 alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl;Y is CH2, NH or 0; andZ is C or N.

[0021] In some embodiments of Formula (Ila), R2is -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is - CH2-. In some embodiments, Z2is selected from optionally substituted C3to C8 cycloalkyl,optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CCH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2is optionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, Zi is -CH2-and Z2is optionally substituted, wherein n is selected from 1, 2, 3 and 4. In some embodiments, Zi is -CH2-and Z2is optionally substituted

[0022] Some embodiments provide a structure depicted in Formula (lib):including pharmaceutically acceptable salts thereof, wherein:R2is L;R6is H, deuterium, halo, or optionally susbstituted Ci to C6alkyl;L is -Z1-Z2 or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2- -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2-, -R5O-, - R5S-, R5-S=O, - R5SO2- R5-C=O. - R5CO2-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0- R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - SCk-NHR3-, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl;Z is C or N.

[0023] In some embodiments of Formula (lib), L is -Z1-Z2. In some embodiments, Zi is -CH2-. In some embodiments, Z2is selected from optionally substituted C3 to C8 cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to Cs heteroaryl, -NR5R5, -CH2CCH, or -CH2CN. In some embodiments, R5is selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2is optionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In®- : ,>)nsome embodiments, Zi is -CH2- and Z2is optionally substituted V , wherein n is 1, 2, 3 or 4. In some embodiments, Zi is -CH2-and Z2is optionally substituted

[0024] In some embodiments, a compound of Formula (II) is represented by the structure of Formula (He):including pharmaceutically acceptable salts thereof, wherein:R1and R2are each independently selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally substituted C- amido, optionally substituted N-amido, optionally substituted ester, optionally substitutedsulfonyl, 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5’, -NH(CO) -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, -SO2-NH-, -R5CH2-, -R50-, - R5S-, R5-S=O, - R5SO2-, R5-C=O, - R5C02-, - R5NH-, - R5NH(CO)- , -R5(CO)NH-, -NHCH2C0-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0-R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH- SO2R5-, -SO2-NHR5-, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl); each R5and R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl; andZ is C or N, with the proviso that R1is not pyrimidyl.

[0025] In some embodiments, R2is not -CH3. In some embodiments, R2is L. In some embodiments, L is -Z1-Z2. In some embodiments, Zi is -CH2-. In some embodiments, Z2is selected from optionally substituted C3 to Cs cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, -NR5R5, -CH2CCH, or -CH2CN. In some embodiments, R5and R5are each selected from H or CH3. In some embodiments, L is -Z1-Z2-Z3. In some embodiments, Zi is -CH2-, Z2is selected from N or an optionally substituted C3to Cs heterocyclyl, and Z3is selected optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionallysubstituted C3to Cs cycloalkyl, optionally substituted C to C10aryl, optionally substituted C3to Cg heterocyclyl, optionally substituted C3 to C10heteroaryl.

[0026] In some embodiments, a compound of Formula (II) is represented by the structure of Formula (lid):including pharmaceutically acceptable salts thereof, wherein:R3is selected from the group consisting of 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 Ci to Ce alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl;R6is selected from the group consisting of H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6 alkoxy, optionally substituted Ci to C6 alkyl, optionally substituted C2to C6 alkenyl, and optionally substituted C2to C6 alkynyl;R8selected from H, deuterium, optionally substituted Ci to C6 alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl;R9and R10are each independently selected from hydrogen, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl); andX1is selected from the group consisting of CH, B, N.

[0027] In some embodiments, R3is selected from H, deuterium, halogen, Ci to C6alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl.

[0028] In som embodiments, R6is selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to Ce alkyl.

[0029] In some embodiments, R8is selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to Ce alkyl.

[0030] In some embodiments, R9is selected from H, deuterium, halogen, Ci to C6alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl.

[0031] In some embodiments, R10is selected from H, deuterium, halogen, Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to C6 alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl.

[0032] In some embodiments, a compound Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), or (lid) is selected from a compound of Table A. In some embodiments, a compound of Formula (I) or Formula (II) is selected from the group consisting of:and pharmaceutically acceptable salts thereof.

[0033] In some embodiments, the pharmaceutically acceptable salt is an alkaline metal salt or an ammonium salt.

[0034] Some embodiments provide a pharmaceutical composition comprising a therapeutically effective amount of at least one compound having the stmcture of the Formula (I):including pharmaceutically acceptable salts thereof, wherein:R1, R2, R3, R4, and R6are each independently selected from the group consisting of 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, -SO2-NH-, -R5CH2- -R5O-, - R5S- R5-S=O, - R5SO2-R5-C=O. - R5CO2-, - R5NH-, - R5NH(CO)- , -R5(C0)NH- - R5NH-S02- -R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0- R5, -SO2R5-, C=0-R\ -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - SCk-NHR3-, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, - CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, or optionally substituted C3 to C10heteroaryl; and Y is CH2, NH or 0, with the proviso that R1is not pyrimidyl.

[0035] Some embodiments provide a pharmaceutical composition comprising a therapeutically effective amount of at least one compound having the stmcture of the Formula (II):2.including pharmaceutically acceptable salts thereof, wherein:QA, QB, QC are independently C or N;R1, R2, R3, R6, and R7are each independently selected from the group consisting of 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to C6alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, or L;L is -Z1-Z2or -Z1-Z2-Z3;Zi, Z2, and Z3 are independently -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, - SO2-NH-, -R5CH2-, -R50-, - R5S-, R5-S=O, - R5SO2- R5-C=O, - R5CO2-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0- R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, - S02-NHR3-, optionally substituted C3to Cs cycloalkyl, optionally substituted C6to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, - CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2- (optionally substituted C3 to C10heteroaryl); each R5is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to C6 alkenyl, optionally substituted C2to C6 alkynyl, optionally substituted C3 to Cs carbocyclyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, or optionally substituted C3to C10heteroaryl;Y is CH2, NH or 0; andZ is C or N, with the proviso that R1is not pyrimidyl.

[0036] Some embodiments relate to a method of treating a mammal having a disease or disorder. In some embodiments, the method includes administering to the mammal a therapeutically effective amount of a compound as described herein. Some embodiments relate to a method of treating a mammal having a disease or disorder. In ome embodiments, the method includes administering to the mammal a therapeutically effective amount of a pharmaceutical composition as described herein. In some embodiments, the mammal is a human. In some embodiments, the method further includes administering to the mammal anadditional medicament. In some embodiments, the method includes administering to a subject suffering from said disease or disorder an effective amount of a compound of any one of the compounds as described herein or a pharmaceutically acceptable salt thereof.

[0037] Some embodiments relate to a method of trating a disease. In some embodiments, the method includes administering to a subject suffering from said disease an effective amount of a pharmaceutical composition as described herein. In some embodiments, the disease is cancer. In some embodiments, cancer is selected from the group consisting of brain cancer, breast cancer, lung cancer, non-small cell lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the fibrogenetic disorder is scleroderma, polymyositis, systemic lupus, rheumatoid arthritis, liver cirrhosis, keloid formation, interstitial nephritis or pulmonary fibrosis. In some embodiments, the cancer is associated with a RAS mutation. In some embodiments, 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. In some embodiments, the disease is cancer cachexia.

[0038] Some embodiments relate to a method of inhibiting proliferation of a cell. In some embodiments, the method includes contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein. In some embodiments, the cell has a RAS mutation.

[0039] Some embodiments relate to a method of inducing apoptosis in a cell. In some embodiments, the method includes contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0040] Some embodiments relate to a method of treating a subject with cancer resistant to treatment of a MEK protein kinase inhibitor. In some embodiments, the method includes contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0041] Some embodiments relate to a method of treating a subject with cancer resistant to treatment of a RAF protein kinase inhibitor. In some embodiments, the method includes contacting the cell with an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0042] Some embodiments relate to a method of treating cancer cachexia in a mammal with cancer. In some embodiments, the method includes administering an effective amount of a compound as described herein or a pharmaceutical composition as described herein.

[0043] In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd in a single dose. In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administered a single dose, once daily.

[0044] In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd in multiple doses, more than once per day. In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd twice a day. In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd three times a day. In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd as a dose between 0.1 mg and 2000 mg. In some embodiments, the compound as described herein or a pharmaceutical composition as described herein may be administerd as a dose between from about 0.001 to about 1000 mg / kg body weight / day.

[0045] In some embodiments, a compound as described herein a drug profile of RAF resistant, BID dosing, balance metabolism, and active between about 3 and about 6 hours.

[0046] In some embodiments, the compound as described herein interacts with a first region comprising LI 15, LI 18, V127, and M143 of an MEK Kinase.

[0047] In some embodiments, the compound interacts with a second region comprising K97 of an MEK Kinase.

[0048] In some embodiments, a compound as described herein interacts with a third region comprising S212, 1215 and M219 of an MEK Kinase.

[0049] In some embodiments, a method of developing molecules based on evaluation and balance of two downstream molecular targets is described herein.

[0050] In some embodiments, the method may include administering a compound targeting pERK (T202 / Y204) and pSTAT3(S727).

[0051] In some embodiments, a method for preventing re-activation of MEK by CRAF-bypass is described herein.

[0052] In some embodiments, the method may include administering an effective amount of any one of compounds or pharmaceutical composition as described herein.

[0053] In some embodiments, a method for designing a drug therapeutic window for dual RAF / MEK inhibitors is described herein.

[0054] In some embodiments, the method may include administering a therapeutic agent with a plasma half-life of less than 12 hours, QD or BID dosing, resistant to MEK reactivation by CRAF-bypass, and optimal metabolic balance between pERK and pSTAT3(S727) inhibition.BRIEF DESCRIPTION OF THE DRAWINGS

[0055] FIG. 1 illustrates pERK(T202 / Y204):total-ERK vs pSTAT3(S727):total- STAT3 ratio in A549 KRAS mutant lung cancer for Reference- 1, Reference-2, Compound (Cmpd)-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16.

[0056] FIG. 2 illustrates CRAF-bypass through elevated pMEK: total-MEK ratios in A549 KRAS mutant lung cancer following treatment with select reference MEK inhibitors.

[0057] FIG. 3 illustrates a gastrocnemius pharmacokinetic (PK) results from a single 2 hour timepoint in a C26 tumor model for Reference- 1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16.

[0058] FIG. 4 illustrates a tumor pharmacokinetic (PK) results from a single 2 hour timepoint in a C26 tumor model for Reference- 1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16.

[0059] FIG. 5 illustrates a plasma pharmacokinetic (PK) results from a single 2 hour timepoint in a C26 tumor model for Reference- 1, Reference-2, Compound-7, Compound-10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound-16.

[0060] FIG. 6 illustrates a liver pharmacokinetic (PK) results from a single 2 h timepoint in a C26 tumor model for Reference- 1, Reference-2, Compound-7, Compound- 10, Compound-9, Compound-11, Compound-12, Compound-13, Compound-14, Compound-15, and Compound- 16.

[0061] FIG. 7A illustrates a C26 tumor-bearing MTD study comparison between Reference- 1 and Compound- 9 100 mg / kg QD.

[0062] FIG. 7B illustrates a C26 tumor-bearing MTD study comparison between Compound 13 and Compound 14 100 mg / kg QD.

[0063] FIG. 8A illustrates a C26 tumor-bearing MTD study comparison between Reference- 1 and Compound- 9 at lOOmg / kg BID.

[0064] FIG. 8B illustrates a C26 tumor-bearing MTD study comparison between Compound- 13 and Compound- 14 100 mg / kg BID.

[0065] FIG. 9 illustrates an A549 (KRAS-G12S) pERK dose response.

[0066] FIG. 10 illustrates a graph of a colon-26 model for KRAS G12D CRC efficacy and safety.

[0067] FIG. 11A illustrates a graph of C-26 pharmacology study KRAS G12D CRC tumor growth; FIG. 1 IB illustrates a graph of C-26 pharmacology study KRAS G12D CRC weight loss.

[0068] FIG. 12 illustrates a graph of activity in a Colon-26 KRAS mutant CRC model.

[0069] FIG. 13 illustrates a graph of dual-RAF / MEK resistance to CRAF-bypass.

[0070] FIG. 14A illustrates a graph of a dual-RAF / MEK: CRAF-bypass time course for A459 KRAS pERK:total ERK; FIG. 14B illustrates pMEKdotal MEK in the NSCLC model A549 KRAS(G12S).

[0071] FIG. 15A illustrates a graph of pERKdotal ERK (activation) in the BRAF V600E mutant A375 melanoma model; FIG. 15B illustrates pERK: total ERK in the KRAS G12S mutant A549 model and paradoxical activation by a RAF inhibitor.

[0072] FIG. 16 illustrates a graph of a single dose pharmacokinetic profile in plasma.

[0073] FIG. 17 illustrates a graph of a single dose pharmacokinetic profile in the CRC model Colon-26 tumor.

[0074] FIG. 18 illustrates a graph of relative body weight corrected for the NSCLC model A549 tumor volume.DETAILED DESCRIPTION

[0075] 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.

[0076] In certain aspects, therapeutic methods or uses are providing herein for the treatement, prevention, or amelioration of a disease or condition in a subject, these methods comprising administering at least one compound disclosed herein to the subject. In some embodiments, therapeutic methods or uses are provided for the treatment, prevention or amelioration of cancer comprising administering of a compound having the structures of Formula (I), (la), (lb), (Ic), (Id) (II), (Ila), (lib), (lie), or (lid) as described herein. In some embodiments, therapeutic methods or uses are provided for the treatment of cancer cachexia comprising administering a compound having the structures of Formula (I), (la), (lb), (Ic), (Id) (II), (Ila), (lib), (lie), or (lid) as described herein.Definitions

[0077] Unless expressly defined otherwise, technical and / or scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art. In the event that there are a plurality of definitions for a term herein, those in this section prevail unless stated otherwise. As used in the specification and the appended claims, the singular forms “a,” “an,” and “the” include plural referents unless the context clearly dictates otherwise. Unless otherwise indicated, conventional methods of mass spectroscopy, NMR, HPLC, protein chemistry, biochemistry, and pharmacology are employed. The use of either the conjunction “or” or “and” means “and / or” unless stated otherwise. Furthermore, use of the term “including” as well as other forms, such as “include”, “includes,” and “included,” is not limiting. As used in this specification, whether in a transitional phrase or in the body of the claim, the terms “comprise(s)” and “comprising” are to be interpreted as having an open- ended meaning. That is, the terms are to 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.

[0078] While the 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 disclosure is not limited to the disclosed embodiments. Variations to the disclosed embodiments can be understood and effected by those skilled in the art in practicing the claimed disclosure, from a study of the disclosure and the appended claims.

[0079] With respect to the use of substantially any plural and / or singular terms herein, those having skill in the art can translate from the plural to the singular and / or from the singular to the plural as is appropriate to the context and / or application. The various singular / plural permutations may be expressly set forth herein for sake of clarity. The indefinite article “a” or “an” does not exclude a plurality. 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.

[0080] All references cited herein are incorporated herein by reference in their entirety. To the extent publications and patents or patent applications incorporated by reference contradict the disclosure contained in the specification, the specification is intended to supersede and / or take precedence over any such contradictory material.

[0081] Unless otherwise defined, all terms (including technical and scientific terms) are to be given their ordinary and customary meaning to a person of ordinary skill in the art, and are not to be limited to a special or customized meaning unless expressly so defined herein. It should be noted that the use of particular terminology when describing certain features or aspects of the disclosure should not be taken to imply that the terminology is being re-defined herein to be restricted to include any specific characteristics of the features or aspects of the disclosure with which that terminology is associated.

[0082] Where a range of values is provided, it is understood that the upper and lower limit, and each intervening value between the upper and lower limit of the range is encompassed within the embodiments.

[0083] The term “prodrug,” as used herein, refers to an agent that is converted into the parent drug in vivo. Prodrugs are often useful because, in some situations, they may be easier to administer than the parent drug. They may, for instance, be bioavailable by oral administration whereas the parent is not. The prodrug may also have improved solubility in pharmaceutical compositions over the parent drug. An example, without limitation, of a prodrug would be a compound which is administered as an ester (the “prodrug”) to facilitate transmittal across a cell membrane where water solubility is detrimental to mobility but which then is metabolically hydrolyzed to the carboxylic acid, the active entity, once inside the cell where water-solubility is beneficial. A further example of a prodrug might be a short peptide (polyaminoacid) 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, (ed. H. Bundgaard, Elsevier, 1985), which is hereby incorporated herein by reference in its entirety.

[0084] Metabolites of the compounds disclosed herein include active species that are produced upon introduction of the compounds into the biological milieu.

[0085] Compounds disclosed herein having at least one chiral center they may exist as a racemate or as each enantiomer, and may exist as enantiomeric-enriched mixtures of the enantimoers. It should be noted that all such isomers and mixtures thereof are included in the scope of the present invention. Furthermore, the crystalline forms for the compounds disclosed herein may exist as alternative polymorphs. Such polymorphs are included in 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 in one embodiment of the present invention.

[0086] The term “pharmaceutically acceptable salt,” as used herein, refers to a salt of a compound that does not cause significant irritation to an organism to which it is administered and does not abrogate the biological activity and properties of the compound. In some embodiments, the salt is an acid addition salt of the compound. Pharmaceutical salts can be obtained by reacting a compound with inorganic acids such as hydrohalic acid (e.g., hydrochloric acid or hydrobromic acid), sulfuric acid, nitric acid, phosphoric acid and the like. Pharmaceutical salts can also be obtained by reacting a compound with an organic acid such as aliphatic or aromatic carboxylic or sulfonic acids, for example acetic, succinic, lactic,malic, tartaric, citric, ascorbic, nicotinic, methanesulfonic, ethanesulfonic, p-toluensulfonic, salicylic or naphthalenesulfonic acid. Pharmaceutical salts can also be obtained by reacting a compound with a base to form a salt such as an ammonium salt, an alkali metal salt, such as a sodium or a potassium salt, an alkaline earth metal salt, such as a calcium or a magnesium salt, a salt of organic bases such as dicyclohexylamine, N-methyl-D-glucamine, tris(hydroxymethyl)methylamine, C1-C7 alkylamine, cyclohexylamine, triethanolamine, ethylenediamine, and salts with amino acids such as arginine, lysine, and the like.

[0087] If the manufacture of pharmaceutical formulations involves intimate mixing of the pharmaceutical excipients and the active ingredient in its salt form, then it may be desirable to use pharmaceutical excipients which are non-basic, that is, either acidic or neutral excipients.

[0088] In various embodiments, the compounds disclosed herein can 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.

[0089] The term “halogen atom,” as used herein, means any one of the radio stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0090] The term “ester,” as used herein, refers to a chemical moiety with formula -(R)n-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 where n is 0 or 1.

[0091] The term “amide,” as used herein, refers to a chemical moiety with formula -(R)n-C(0)NHR’ or -(R)n-NHC(0)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 where n is 0 or 1. An amide may be an amino acid or a peptide molecule attached to a molecule of the present invention, thereby forming a prodrug.

[0092] Any amine, hydroxyl, or carboxyl side chain on the compounds disclosed herein can be esterified or amidified. The procedures and specific groups to be used to achieve this end are known to those of skill in the art and can readily be found in referencesources such as Greene and Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley & Sons, New York, NY, 1999, which is incorporated herein in its entirety.

[0093] The term “aromatic,” as used herein, refers to an aromatic group which has at least one ring having a conjugated pi electron system and includes both carbocyclic aryl (e.g., phenyl) and heterocyclic aryl groups (e.g., pyridine). The term includes monocyclic or fused-ring polycyclic (i.e., rings which share adjacent pairs of carbon atoms) groups. The term “carbocyclic” refers to a compound which contains one or more covalently closed ring structures, and that the atoms forming the backbone of the ring are all carbon atoms. The term thus distinguishes carbocyclic from heterocyclic rings in which the ring backbone contains at least one atom which is different from carbon. The term “hetero aromatic” refers to an aromatic group which contains at least one heterocyclic ring.

[0094] As used herein, “Cato Cb” in which “a” and “b” are integers refer to the number of carbon atoms in an alkyl, alkenyl or alkynyl group, or the number of carbon atoms in the ring of a cycloalkyl, aryl, heteroaryl or heterocyclyl group. That is, the alkyl, alkenyl, alkynyl, ring of the cycloalkyl, ring of the aryl, ring of the heteroaryl or ring of the heterocyclyl can contain from “a” to “b”, inclusive, carbon atoms. Thus, for example, a “Ci to C4 alkyl” group or a “C1-C4 alkyl” group refers to all alkyl groups having from 1 to 4 carbons, that is, CH3-, CH3CH2-, CH3CH2CH2-, (CHs^CH-, CH3CH2CH2CH2-, CH3CH2CH(CH3)- and (CFbbC-. Likewise, for example, cycloalkyl group may contain from “a” to “b”, inclusive, total atoms, such as a C3-C8 cycloalkyl group, 3 to 8 carbon atoms in the ring(s). If no “a” and “b” are designated with regard to an alkyl, cycloalkyl, or cycloalkenyl, the broadest range described in these definitions is to be assumed. Similarly, a “4 to 7 membered heterocyclyl” group refers to all heterocyclyl groups with 4 to 7 total ring atoms, for example, azetidine, oxetane, oxazoline, pyrrolidine, piperidine, piperazine, morpholine, and the like. As used herein, the term “C1-C6” includes Ci, C2, C3, C4, C5 and C6, and a range defined by any of the two preceding numbers. For example, C1-C6 alkyl includes Ci, C2, C3, C4, C5 and C6 alkyl, C2-C6 alkyl, C1-C3 alkyl, etc. Similarly, C3-C8 carbocyclyl or cycloalkyl each includes hydrocarbon ring containing 3, 4, 5, 6, 7 and 8 carbon atoms, or a range defined by any of the two numbers, such as C3-C7 cycloalkyl or C5- C6cycloalkyl. As another example, 3 to 10 membered heterocyclyl includes 3, 4, 5, 6, 7, 8, 9,or 10 ring atoms, or a range defined by any of the two preceding numbers, such as 4 to 6 membered or 5 to 7 membered heterocyclyl.

[0095] As used herein, “alkyl” refers to a straight or branched hydrocarbon chain fully saturated (no double or triple bonds) hydrocarbon group. The alkyl group may have 1 to 20 carbon atoms (whenever it appears herein, a numerical range such as “1 to 20” refers to each integer in the given range; e.g., “1 to 20 carbon atoms” means that the alkyl group may consist of 1 carbon atom, 2 carbon atoms, 3 carbon atoms, etc., up to and including 20 carbon atoms, although the present definition also covers the occurrence of the term “alkyl” where no numerical range is designated). The alkyl group may also be a medium size alkyl having 1 to 10 carbon atoms. The alkyl group could also be a lower alkyl having 1 to 5 carbon atoms. The alkyl group of the compounds may be designated as “C1-C4 alkyl” or similar designations. By way of example only, “C1-C4 alkyl” indicates that there are one to four carbon atoms in the alkyl chain, i.e., the alkyl chain is selected from the group consisting of methyl, ethyl, propyl, iso-propyl, n-butyl, iso-butyl, sec-butyl, and t-butyl. Typical alkyl groups include, but are in no way limited to, methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tertiary butyl, pentyl, hexyl, ethenyl, propenyl, butenyl, and the like.

[0096] The alkyl group may be substituted or unsubstituted. When substituted, the substituent group(s) is(are) one or more group(s) individually and independently selected from 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, sulfenyl, sulfinyl, sulfonyl, haloalkyl, haloalkoxy, trihalomethanesulfonyl, trihalomethanesulfonamido, and amino, including mono- and di-substituted amino groups, and the protected derivatives thereof. Wherever a substituent is described as being “optionally substituted” that substituent may be substituted with one of the above substituents.

[0097] As used herein, “alkenyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more double bonds. An alkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from thesame groups disclosed above with regard to alkyl group substitution. The alkenyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkenyl” where no numerical range is designated. The alkenyl group may also be a medium size alkenyl having 2 to 9 carbon atoms. The alkenyl group could also be a lower alkenyl having 2 to 4 carbon atoms. The alkenyl group of the compounds may be designated as “C2-4 alkenyl” or similar designations. By way of example only, “C2-4 alkenyl” indicates that there are two to four carbon atoms in the alkenyl chain, i.e., the alkenyl chain is selected from the group consisting of ethenyl, propen-l-yl, propen-2-yl, propen-3-yl, buten-l-yl, buten-2-yl, buten-3-yl, buten-4-yl, 1 -methyl-propen- 1-yl, 2-methyl-propen- 1-yl, 1-ethyl- ethen-l-yl, 2-methyl-propen-3-yl, buta-l,3-dienyl, buta-l,2,-dienyl, and buta-l,2-dien-4-yl. Typical alkenyl groups include, but are in no way limited to, ethenyl, propenyl, butenyl, pentenyl, and hexenyl, and the like.

[0098] As used herein, “alkynyl” refers to an alkyl group that contains in the straight or branched hydrocarbon chain one or more triple bonds. An alkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be selected from the same groups disclosed above with regard to alkyl group substitution. The alkynyl group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term “alkynyl” where no numerical range is designated. The alkynyl group may also be a medium size alkynyl having 2 to 9 carbon atoms. The alkynyl group could also be a lower alkynyl having 2 to 4 carbon atoms. The alkynyl group of the compounds may be designated as “C2-4 alkynyl” or similar designations. By way of example only, “C2-4 alkynyl” indicates that there are two to four carbon atoms in the alkynyl chain, i.e., the alkynyl chain is selected from the group consisting of ethynyl, propyn-l-yl, propyn-2-yl, butyn-l-yl, butyn-3-yl, butyn-4-yl, and 2-butynyl. Typical alkynyl groups include, but are in no way limited to, ethynyl, propynyl, butynyl, pentynyl, and hexynyl, and the like.

[0099] As used herein, “heteroalkyl” refers to a straight or branched hydrocarbon chain containing one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur, in the chain backbone. The heteroalkyl group may have 1 to 20 carbon atoms although the present definition also covers the occurrence of the term “heteroalkyl” where no numerical range is designated. The heteroalkyl group may also be a medium size heteroalkyl having 1 to 9 carbon atoms. The heteroalkyl group couldalso be a lower heteroalkyl having 1 to 4 carbon atoms. The heteroalkyl group of the compounds may be designated as “CM heteroalkyl” or similar designations. The heteroalkyl group may contain one or more heteroatoms. By way of example only, “CM heteroalkyl” indicates that there are one to four carbon atoms in the heteroalkyl chain and additionally one or more heteroatoms in the backbone of the chain.

[0100] As used herein, “aryl” refers to a carbocyclic (all carbon) ring or two or more fused rings (rings that share two adjacent carbon atoms) that have a fully delocalized pi-electron system. Examples of aryl groups include, but are not limited to, benzene, naphthalene and azulene. An aryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) 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, 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 the protected derivatives thereof. When substituted, substituents on an aryl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0101] As used herein, “heteroaryl” refers to a monocyclic or multicyclic aromatic ring system (a ring system with fully delocalized pi-electron system), one or two or more fused rings that contain(s) one or more heteroatoms, that is, an element other than carbon, including but not limited to, nitrogen, oxygen and sulfur. Examples of heteroaryl rings include, but are not limited to, furan, thiophene, phthalazine, pyrrole, oxazole, thiazole, imidazole, pyrazole, isoxazole, isothiazole, triazole, thiadiazole, pyridine, pyridazine, pyrimidine, pyrazine and triazine. A heteroaryl group may be substituted or unsubstituted. When substituted, hydrogen atoms are replaced by substituent group(s) that is(are) one or more group(s) 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, 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 the protected derivatives thereof. When substituted, substituents on a heteroayl group may form a non-aromatic ring fused to the aryl group, including a cycloalkyl, cycloalkenyl, cycloalkynyl, and heterocyclyl.

[0102] As used herein, an “aralkyl” or “arylalkyl” refers to an aryl group connected, as a substituent, via an alkylene group. The alkylene and aryl group of an aralkyl may be substituted or unsubstituted. Examples include but are not limited to benzyl, substituted benzyl, 2-phenylethyl, 3-phenylpropyl, and naphtylalkyl. In some cases, the alkylene group is a lower alkylene group.

[0103] As used herein, a “heteroaralkyl” or “heteroarylalkyl” is heteroaryl group connected, as a substituent, via an alkylene group. The alkylene and heteroaryl group of heteroaralkyl may be substituted or unsubstituted. Examples include but are not limited to 2- thienylmethyl, 3-thienylmethyl, furylmethyl, thienylethyl, pyrrolylalkyl, pyridylalkyl, isoxazollylalkyl, and imidazolylalkyl, and their substituted as well as benzo-fused analogs. In some cases, the alkylene group is a lower alkylene group.

[0104] As used herein, a “alkylene” refers to a branched, or straight chain fully saturated di-radical chemical group containing only carbon and hydrogenthat is attached to the rest of the molecule via two points of attachment (i.e., an alkanediyl). The alkylene group may have 1 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkylene where no numerical range is designated. The alkylene group may also be a medium size alkylene having 1 to 9 carbon atoms. The alkylene group could also be a lower alkylene having 1 to 4 carbon atoms. The alkylene group may be designated as “Ci-4 alkylene” or similar designations. By way of example only, “CM alkylene” indicates that there are one to four carbon atoms in the alkylene chain, i.e., the alkylene chain is selected from the group consisting of methylene, ethylene, ethan-l,l-diyl, propylene, propan- 1,1-diyl, propan-2, 2-diyl, 1 -methyl-ethylene, butylene, butan- 1,1-diyl, butan-2,2-diyl, 2-methyl- propan- 1,1-diyl, 1 -methyl-propylene, 2-methyl-propylene, 1,1 -dimethyl-ethylene, 1,2- dimethyl-ethylene, and 1-ethyl-ethylene.

[0105] As used herein, “alkenylene” refers to a straight or branched chain di radical chemical group containing only carbon and hydrogen and containing at least one carbon-carbon double bond that is attached to the rest of the molecule via two points of attachment. The alkenylene group may have 2 to 20 carbon atoms, although the present definition also covers the occurrence of the term alkenylene where no numerical range is designated. The alkenylene group may also be a medium size alkenylene having 2 to 9 carbon atoms. The alkenylene group could also be a lower alkenylene having 2 to 4 carbon atoms. The alkenylene group may be designated as “C2-4 alkenylene” or similar designations. By way of example only, “C2 alkenylene” indicates that there are two to four carbon atoms in the alkenylene chain, i.e., the alkenylene chain is selected from the group consisting of ethenylene, ethen-l,l-diyl, propenylene, propen- 1,1-diyl, prop-2-en-l,l-diyl, 1-methyl- ethenylene, but-l-enylene, but-2-enylene, but-l,3-dienylene, buten- 1,1-diyl, but-l,3-dien- 1,1-diyl, but-2-en- 1,1-diyl, but-3-en- 1,1-diyl, l-methyl-prop-2-en- 1,1-diyl, 2-methyl-prop-2- en- 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.

[0106] As used herein, “alkylidene” refers to a divalent group, such as =CR’R”, which is attached to one carbon of another group, forming a double bond, alkylidene groups include, but are not limited to, methylidene (=CH2) and ethylidene (=CHCH3). As used herein, “arylalkylidene” refers to an alkylidene group in which either R’ and R’ ’ is an aryl group. An alkylidene group may be substituted or un substituted.

[0107] As used herein, “alkoxy” refers to the formula -OR wherein R is an alkyl is defined as above, e.g. methoxy, ethoxy, n-propoxy, 1-methylethoxy (isopropoxy), n- butoxy, iso-butoxy, sec-butoxy, tert-butoxy, amoxy, tert-amoxy and the like. An alkoxy may be substituted or unsubstituted.

[0108] As used herein, “alkylthio” refers to the formula -SR wherein R is an alkyl is defined as above, e.g. methylmercapto, ethylmercapto, n-propylmercapto, 1- methylethylmercapto (isopropylmercapto), n-butylmercapto, iso-butylmercapto, sec- butylmercapto, tert-butylmercapto, and the like. An alkylthio may be substituted or unsubstituted.

[0109] As used herein, “aryloxy” and “arylthio” refers to RO- and RS-, respectively, in which R is an aryl, such as but not limited to phenyl. Both an aryloxyl and arylthio may be substituted or unsubstituted.

[0110] As used herein, “acyl” refers to -C(=0)R, wherein R is hydrogen, Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein. Non-limiting examples include formyl, acetyl, propanoyl, benzoyl, and acryl.

[0111] As used herein, “cycloalkyl” refers to a completely saturated (no double bonds) mono- or multi- cyclic hydrocarbon ring system. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. Cycloalkyl groups may range from C3to C10, in other embodiments it may range from C3to Ce- A cycloalkyl group may be unsubstituted or substituted. Typical cycloalkyl groups include, but are in no way limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and the like. If substituted, the substituent(s) may be an alkyl or selected from those indicated above with regard to substitution of an alkyl group unless otherwise indicated. When substituted, substituents on a cycloalkyl group may form an aromatic ring fused to the cycloalkyl group, including an aryl and a heteroaryl.

[0112] As used herein, “cycloalkenyl” refers to a cycloalkyl group that contains one or more double bonds in the ring although, if there is more than one, they cannot form a fully delocalized pi-electron system in the ring (otherwise the group would be “aryl,” as defined herein). When composed of two or more rings, the rings may be connetected together in a fused, bridged or spiro-connected fashion. A cycloalkenyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwise indicated. When substituted, substituents on a cycloalkenyl group may form an aromatic ring fused to the cycloalkenyl group, including an aryl and a heteroaryl.

[0113] As used herein, “cycloalkynyl” refers to a cycloalkyl group that contains one or more triple bonds in the ring. When composed of two or more rings, the rings may be joined together in a fused, bridged or spiro-connected fashion. A cycloalkynyl group may be unsubstituted or substituted. When substituted, the substituent(s) may be an alkyl or selected from the groups disclosed above with regard to alkyl group substitution unless otherwiseindicated. When substituted, substituents on a cycloalkynyl group may form an aromatic ring fused to the cycloalkynyl group, including an aryl and a heteroaryl.

[0114] As used herein, “heteroalicyclic” or “heteroalicyclyl” refers to a stable 3- to 18 membered ring which consists of carbon atoms and from one to five heteroatoms selected from the group consisting of nitrogen, oxygen and sulfur. The “heteroalicyclic” or “heteroalicyclyl” may be monocyclic, bicyclic, tricyclic, or tetracyclic ring system, which may be joined together in a fused, bridged or spiro-connected fashion; and the nitrogen, carbon and sulfur atoms in the “heteroalicyclic” or “heteroalicyclyl” may be optionally oxidized; the nitrogen may be optionally quaternized; and the rings may also contain one or more double bonds provided that they do not form a fully delocalized pi-electron system throughout all the rings. Heteroalicyclyl groups may 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 the protected derivatives thereof. Examples of such “heteroalicyclic” or “heteroalicyclyl” include but are not limited to, azepinyl, acridinyl, carbazolyl, cinnolinyl, dioxolanyl, imidazolinyl, morpholinyl, oxiranyl, piperidinyl A-oxide, piperidinyl, piperazinyl, pyrrolidinyl, 4-piperidonyl, pyrazolidinyl, 2-oxopyrrolidinyl, thiamorpholinyl, thiamorpholinyl sulfoxide, and thiamorpholinyl sulfone. When substituted, substituents on a heteroalicyclyl group may form an aromatic ring fused to the heteroalicyclyl group, including an aryl and a heteroaryl.

[0115] 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.

[0116] As used herein, the term “(cycloalkynyl)alkyl” 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.

[0117] As used herein, the term “O-carboxy” refers to a “RC(=0)0-” group in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An 0- carboxy may be substituted or unsubstituted.

[0118] As used herein, the term “C-carboxy” refers to a “-C(=0)R” group in which R can be the same as defined with respect to O-carboxy. A C-carboxy may be substituted or unsubstituted.

[0119] As used herein, the term “trihalomethanesulfonyl” refers to an “X3CS02-“ group wherein X is a halogen.

[0120] As used herein, the term “cyano” refers to a “-CN” group.

[0121] As used herein, the term “cyanato” refers to an “-OCN” group.

[0122] As used herein, the term “isocyanato” refers to a “-NCO” group.

[0123] As used herein, the term “thiocyanato” refers to a “-SCN” group.

[0124] As used herein, the term “isothiocyanato” refers to an “-NCS” group.

[0125] As used herein, the term “sulfinyl” refers to a “-S(=0)-R” group in which R can be the same as defined with respect to O-carboxy. A sulfinyl may be substituted or unsubstituted.

[0126] As used herein, the term “sulfonyl” refers to an “-SO2R” group in which R can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted or unsubstituted.

[0127] As used herein, the term “S-sulfonamido” refers to a “-S02NRARB” group in which RA and RB can be the same as defined with respect to O-carboxy. An S-sulfonamido may be substituted or unsubstituted.

[0128] As used herein, the term “N-sulfonamido” refers to a “-S02N(RA)(RB)” group in which R, RA, and RB can be the same as defined with respect to O-carboxy. A sulfonyl may be substituted or unsubstituted.

[0129] As used herein, the term “trihalomethanesulfonamido” refers to an “X3CS02N(R)-“ group with X as halogen and R can be the same as defined with respect to O-carboxy. A trihalomethanesulfonamido may be substituted or unsubstituted.

[0130] As used herein, the term “0-carbamyl” refers to a “-0C(=0)NRARB” group in which RA and RB can be the same as defined with respect to O-carboxy. An O-carbamyl may be substituted or unsubstituted.

[0131] As used herein, the term “N-carbamyl” refers to an “ROC(=0)NRA group in which R and RA can be the same as defined with respect to O-carboxy. An N-carbamyl may be substituted or unsubstituted.

[0132] As used herein, the term “O-thiocarbamyl” refers to a “-OC(=S)-NRARB” group in which RA and RB can be the same as defined with respect to O-carboxy. An O-thiocarbamyl may be substituted or unsubstituted.

[0133] As used herein, the term “N-thiocarbamyl” refers to an “ROC(=S)NRA-“ group in which R and RA can be the same as defined with respect to O-carboxy. An N-thiocarbamyl may be substituted or unsubstituted.

[0134] As used herein, the term “C-amido” refers to a “-C(=0)NRARB” group in which RA and RB can be the same as defined with respect to O-carboxy. A C-amido may be substituted or unsubstituted.

[0135] As used herein, the term “N-amido” refers to a “RC(=0)NRA-“ group in which R and RA can be the same as defined with respect to O-carboxy. An N-amido may be substituted or unsubstituted.

[0136] As used herein, the term “amino” refers to a “-NRARB” group in which RA and RB are each independently selected from hydrogen, Ci-6alkyl, C2-6 alkenyl, C2-6 alkynyl, C3-7 carbocyclyl, Ce-io aryl, 5-10 membered heteroaryl, and 5-10 membered heterocyclyl, as defined herein.

[0137] As used herein, the term “aminoalkyl” refers to an amino group connected via an alkylene group.

[0138] As used herein, the term “ester” refers to a “-C(=0)OR” group in which R can be the same as defined with respect to O-carboxy. An ester may be substituted or unsubstituted.

[0139] 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.

[0140] 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.

[0141] As used herein, the term “acetyl” refers to a -C(=0)CH3, group.

[0142] As used herein, the term “trihalomethanesulfonyl” refers to a XsCS(=0)2- group where X is a halogen.

[0143] As used herein, the term “O-carbamyl” refers to a -OC(=0)-NR, in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O- carbamyl can be substituted or unsubstituted.

[0144] As used herein, the term “N-carbamyl” refers to a ROC(=0)NH- group, in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An N- carbamyl can be substituted or unsubstituted.

[0145] As used herein, the term “0-thiocarbamyl” refers to a -OC(=S)-NR, in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An O- thiocarbamyl can be substituted or unsubstituted.

[0146] As used herein, the term “N-thiocarbamyl” refers to an ROC(=S)NH- group, in which R can be hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, heteroalicyclyl, aralkyl, or (heteroalicyclyl)alkyl, as defined herein. An N-thiocarbamyl can be substituted or unsubstituted.

[0147] As used herein, the term “perhaloalkyl” refers to an alkyl group where all of the hydrogen atoms are replaced by halogen atoms.

[0148] As used herein, the term “halogen” or “halo,” refer to any one of the radio stable atoms of column 7 of the Periodic Table of the Elements, e.g., fluorine, chlorine, bromine, or iodine, with fluorine and chlorine being preferred.

[0149] 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 the carbocyclyl is a ring system, two or more rings may be joined together in a fused, bridged or spiro-connected fashion. Carbocyclyls may have any degree of saturation provided that at least one ring in a ring system is not aromatic. Thus, carbocyclyls include cycloalkyls, cycloalkenyls, and cycloalkynyls. The carbocyclyl group may have 3 to 20 carbon atoms, although the present definition also covers the occurrence of the term “carbocyclyl” where no numerical range is designated. The carbocyclyl group may also be a medium size carbocyclyl having 3 to 10 carbon atoms. The carbocyclyl group could also be a carbocyclyl having 3 to 6 carbon atoms. The carbocyclyl group may be designated as “C3-6 carbocyclyl” or similar designations. 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.

[0150] 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 cyclopropylmethyl, cyclobutylmethyl, cyclopropylethyl, cyclopropylbutyl, cyclobutylethyl, cyclopropylisopropyl, cyclopentylmethyl, cyclopentylethyl, cyclohexylmethyl, cyclohexylethyl, cycloheptylmethyl, and the like. In some cases, the alkylene group is a lower alkylene group.

[0151] As used herein, the term “cycloalkyl” refers to a fully saturated carbocyclyl ring or ring system. Examples include cyclopropyl, cyclobutyl, cyclopentyl, and cyclohexyl.

[0152] As used herein, the term “cyclo alkenyl” means a carbocyclyl ring or ring system having at least one double bond, wherein no ring in the ring system is aromatic. An example is cyclohexenyl.

[0153] As used herein, the term “heterocyclyl” refers to three-, four-, five-, six-, seven-, and eight- or more membered rings wherein carbon atoms together with from 1 to 3 heteroatoms constitute said ring. A heterocyclyl can optionally contain one or more unsaturated bonds situated in such a way, however, that an aromatic pi-electron system does not arise. The heteroatoms are independently selected from oxygen, sulfur, and nitrogen.

[0154] A heterocyclyl can further contain one or more carbonyl or thiocarbonyl functionalities, so as to make the definition include oxo- systems and thio- systems such as lactams, lactones, cyclic imides, cyclic thioimides, cyclic carbamates, and the like.

[0155] As used herein, “heterocyclyl” refers to a non-aromatic cyclic ring or ring system containing at least one heteroatom in the ring backbone. Heterocyclyls may be joined together in a fused, bridged or spiro-connected fashion. Heterocyclyls may have any degree of saturation provided that at least one ring in the ring system is not aromatic. The heteroatom(s) may be present in either a non-aromatic or aromatic ring in the ring system. The heterocyclyl group may have 3 to 20 ring members (i.e., the number of atoms making up the ring backbone, including carbon atoms and heteroatoms), although the present definition also covers the occurrence of the term “heterocyclyl” where no numerical range is designated. The heterocyclyl group may also be a medium size heterocyclyl having 3 to 10 ring members. The heterocyclyl group could also be a heterocyclyl having 3 to 6 ring members. The heterocyclyl group may be designated as “3-6 membered heterocyclyl” or similar designations. In preferred six membered monocyclic heterocyclyls, the heteroatom(s) are selected from one up to three of O, N or S, and in preferred five membered monocyclic heterocyclyls, the heteroatom(s) are selected from one or two heteroatoms selected from O, N, or S. Examples of heterocyclyl rings include, but are not limited to, 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, 2 / / -l,2-oxazinyl, trioxanyl, hexahydro-l,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-l,4-thiazinyl, thiamorpholinyl, dihydrobenzofuranyl, benzimidazolidinyl, and tetrahydroquinoline.

[0156] 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.

[0157] The terms “purified,” “substantially purified,” and “isolated” as used herein, refer to compounds disclosed herein being free of other, dissimilar compounds with which the compounds of the invention are normally associated in their natural state, so that the compounds of the invention comprise at least 0.5%, 1%, 5%, 10%, or 20%, and most preferably at least 50% or 75% of the mass, by weight, of a given sample.

[0158] Substituted groups are based upon or derived from the unsubstituted parent group in which there has been an exchange of one or more hydrogen atoms for another atom or group. Unless otherwise indicated, when a group is deemed to be “substituted,” the group is substituted with one or more substituents independently selected from C1-C6alkyl, Ci-Ce 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-Ci-C6-alkyl (optionally substituted with halo, C1-C6 alkyl, C1-C6 alkoxy, C1-C6 haloalkyl, and C1-C6haloalkoxy), 5-10 membered heterocyclyl (optionally substituted with halo, C1-C6 alkyl, Ci-Ce alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heterocyclyl-Ci-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, C1-C6 haloalkyl, and C1-C6 haloalkoxy), aryl(Ci-C6)alkyl (optionally substituted with halo, C1-C6 alkyl, Ci-Ce alkoxy, C1-C6 haloalkyl, and C1-C6 haloalkoxy), 5-10 membered heteroaryl (optionally substituted with halo, Ci-Ce alkyl, Ci-Ce alkoxy, C1-C6 haloalkyl, and C1-C6haloalkoxy), 5-10 membered heteroaryl(Ci-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(Ci-C6)alkyl (i.e., ether), aryloxy, sulfhydryl (mercapto), halo(Ci- C6)alkyl (e.g., -CF3), halo(Ci-C6)alkoxy (e.g., -OCF3), C1-C6 alkylthio, arylthio, amino, amino(Ci-C6)alkyl, nitro, O-carbamyl, N-carbamyl, O-thiocarbamyl, N-thiocarbamyl, C- amido, N-amido, S-sulfonamido, N-sulfonamido, C-carboxy, O-carboxy, acyl, cyanato, isocyanato, thiocyanato, isothiocyanato, sulfinyl, sulfonyl, and oxo (=0). Wherever a group is described as “optionally substituted” that group can be substituted with the above substituents.

[0159] In some embodiments, a substituted group is substituted with one or more substituent(s) individually and independently selected from C1-C4alkyl, amino, hydroxy, and halogen.

[0160] It is to be understood that certain radical naming conventions can include either a mono-radical or a di-radical, depending on the context. For example, where a substituent requires two points of attachment to the rest of the molecule, it is understood that the substituent is a di-radical. For example, a substituent identified as alkyl that requires two points of attachment includes di-radicals such as -CFh-, -CH2CH2-, -CFhCHiCFUlCFb-, and the like. Other radical naming conventions clearly indicate that the radical is a di-radical such as “alkylene” or “alkenylene.”

[0161] Unless otherwise indicated, when a substituent is deemed to be “optionally substituted,” it is meant that the substituent” is a group that may be substituted with one or more group(s) individually and independently 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 the protected derivatives thereof. The 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, above.

[0162] The term “agent” or “test agent,” as used herein, includes any substance, molecule, element, compound, entity, or a combination thereof. It includes, but is not limited to, e.g., protein, polypeptide, peptide or mimetic, small organic molecule, polysaccharide, polynucleotide, and the like. 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.

[0163] The term “analog,” as used herein, refers to a molecule that structurally resembles a reference molecule but which has been modified in a targeted and controlled manner, by replacing a specific substituent of the reference molecule with an alternate substituent. Compared to the reference molecule, an analog would be expected, by one skilled in the art, to exhibit the same, similar, or improved utility. Synthesis and screening of analogs, to identify variants of known compounds having improved characteristics (such ashigher binding affinity for a target molecule) is an approach that is well known in pharmaceutical chemistry.

[0164] The term “mammal,” as used herein, is used in its usual biological sense. Thus, it specifically includes, but is not limited to, primates, including simians (chimpanzees, apes, monkeys) and humans, cattle, horses, sheep, goats, swine, rabbits, dogs, cats, rats and mice but also includes many other species.

[0165] The term “microbial infection,” as used herein, refers to the invasion of the host organism, whether the organism is a vertebrate, invertebrate, fish, plant, bird, or mammal, by pathogenic microbes. This includes the excessive growth of microbes that are normally present in or on the body of 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 a host mammal. Thus, a mammal is “suffering” from a microbial infection when excessive numbers of a microbial population are present in or on a mammal’s body, or when the effects of the presence of a microbial population(s) is damaging the cells or other tissue of a mammal. Specifically, this description applies to a bacterial infection. Note that the compounds of preferred embodiments are also useful in treating microbial growth or contamination of cell cultures or other media, or inanimate surfaces or objects, and nothing herein should limit the preferred embodiments only to treatment of higher organisms, except when explicitly so specified in the claims.

[0166] The term “pharmaceutically acceptable carrier” or “pharmaceutically acceptable excipient,” as used herein, 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 are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., 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.

[0167] The term “subject,” as used herein, refers to a human or a non-human mammal, e.g., a dog, a cat, a mouse, a rat, a cow, a sheep, a pig, a goat, a non-human primate or a bird, e.g., a chicken, as well as any other vertebrate or invertebrate.

[0168] The term “effective amount” or a “therapeutically effective amount.” as used herein, refers to an amount of a therapeutic agent that is effective to relieve, to some extent, or to reduce the likelihood of onset of, one or more of the symptoms of a disease or condition, and includes curing a disease or condition. “Curing” means that the symptoms of a disease or condition are eliminated; however, certain long-term or permanent effects may exist even after a cure is obtained (such as extensive tissue damage).

[0169] The term “treat,” “treatment,” or “treating,” as used herein, refers 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 a 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 treatment to a subject.

[0170] It is to be understood that where compounds disclosed herein have unfilled valencies, then the valencies are to be filled with hydrogens and / or deuteriums.

[0171] It is understood that the compounds described herein can be labeled isotopically or by another other means, including, but not limited to, the use of chromophores or fluorescent moieties, bioluminescent labels, or chemiluminescent labels. Substitution with isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, such as, for example, increased in vivo half-life or reduced dosage requirements. Each chemical element as represented in a compound structure may include any isotope of said element. For example, in a compound structure a hydrogen atom may be explicitly disclosed or understood to be present in the compound. At any position of the compound that a hydrogen atom may be present, the hydrogen atom can be any isotope of hydrogen, including but not limited to hydrogen- 1 (protium), hydrogen-2 (deuterium), and hydrogen-3 (tritium). Thus, reference herein to a compound encompasses all potential isotopic forms unless the context clearly dictates otherwise.

[0172] The term “about,” as used herein, 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% to a reference quantity, level, value, number, frequency, percentage, dimension, size, amount, weight or length. When a value is preceded by the term about, the component is not intended to be limited strictly to that value, but it is intended to include amounts that vary from the value.Compounds

[0173] Some embodiments provide a compound of Formula (I):

[0174] In some embodiments, Formula (I) is a pharmaceutically acceptable salt as described herein.

[0175] In some embodiments, Formula (I) is represented by Formula (la), Formula (lb), Formula (Ic), or Formula (Id):(la) (lb)(Ic) (Id)

[0176] In some embodiments, Formula (la), Formula (lb), Formula (Ic), orFormula (Id) are a pharmaceutically acceptable salt as described herein.

[0177] In some embodiments, Ring A is

[0178] In some embodiments of the compounds of Formula (I) or (Ic), R1may be selected from 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl,optionally substituted C6to Cio aryl, optionally substituted C3 to Cg heterocyclyl, optionally substituted C3 to Cio heteroaryl, or L.

[0179] In some embodiments, R1is not O-pyrimidinyl. In some embodiments, R1is not an ether-linked pyrimidyl.

[0180] In some embodiments of the compounds of Formula (I), (la), or (lb), R2may be selected from 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 Ci to C6alkoxy, optionally substituted Ci to G alkyl, optionally substituted C2 to G, alkenyl, optionally substituted C2 to G, alkynyl, optionally substituted C3 to Cg cycloalkyl, optionally substituted G to Cio aryl, optionally substituted C3 to Cg heterocyclyl, optionally substituted C3 to Cio heteroaryl, or L. In some further embodiments, R2is L. In some further embodiments, R2is -CH3.

[0181] In some embodiments of the compounds Formula (I), (la), (lb), (Ic) or (Id), R3may be selected from 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 Ci to C6alkoxy, optionally substituted Ci to G, alkyl, optionally substituted C2 to G, alkenyl, optionally substituted C2 to G, alkynyl, optionally substituted C3 to Cg cycloalkyl, optionally substituted G, to Cio aryl, optionally substituted C3 to Cg heterocyclyl, optionally substituted C3 to Cio heteroaryl, or L.

[0182] In some embodiments of the compounds of Formula (I), (la), (lb), (Ic), or (Id), R4may be selected from 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 Ci to C6alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Cr, to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, or L.

[0183] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), R5may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl. In some embodiments, R5is H, deuterium, halo, or an optionally susbstituted Ci to Ce alkyl.

[0184] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), R5may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl. In some embodiments, R5is H, deuterium, halo, or an optionally susbstituted Ci to C6alkyl.

[0185] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), R6may be selected from H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl. In some embodiments, R6is H, deuterium, halo, or an optionally susbstituted Ci to Ce alkyl.

[0186] In some embodiments of the compounds of Formula (I) or (la), X may be selected from C(R5)2, CH(R5), CFh, -0-,, , . In some further embodiments, X is CFh or -0-. In some further embodiments, X is -0-.

[0187] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), L may be selected from -Z1-Z2. In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), L may be selected from -Z1-Z2-Z3.

[0188] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), Zi may be selected from -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, - CH2CCH, -CH2CN, -NR5R5’, -NH(CO) -, -(CO)NH-, -(CO)NR5R5’-, -NH-SO2-, -SO2-NH-, -R5CH2--R50-, - R5S- R5-S=0, -R5S02-R5-C=0, - R5C02-, - R5NH- - R5NH(CO)- , -NHCH2CO-, -R5(C0)NH- - R5NH-S02-, - R5S02-NH-, -CH2R5-, -OR5-, -SR5- S=0-R5, -S02R5-, C=0-R5. -C02R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH- S02R5-, -S02-NHR5-, optionally substituted Ci to Ce alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH2-(optionally substituted aryl), -CH2- (optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10 heteroaryl). In some further embodiments, Zi is -CH2-

[0189] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), Z2may be selected from hydrogen, deuterium, halo, -CH2-, -0-, -S-, S=0, -S02-, C=0, - C02-, -N02, -NH-, -CH2CCH, -CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NHCH2CO-, -NH-S02-, -S02-NH-, -R5CH2-, -R5O-, - R5S-, R5-S=O, -R5SO2-, R5- C=0, - R5C02-, - R5NH-, - R5NH(CO)- , -R5(C0)NH-, - R5NH-S02-, - R5S02-NH-, - CH2R5-, -OR5-, -SR5-, S=0-R5, -S02R5-, C=0-R5, -C02R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-S02R5-, -S02-NHR5-, optionally substituted Ci to C6alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10 heteroaryl). In some further embodiments, Z2is C3 to Cs cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to Cs heteroaryl, -NR5R5, - CH2CH, or -CH2CN. In some further embodiments, Z2is optionally substituted C3 to Cs heterocyclyl. In some embodiments, Z2is -CH2- and Z2is -NR5R5. In some embodiments, Z2is an optionally substituted C3 to Cs heterocycyl.

[0190] In some embodiments of the compounds of Formula (I), (la), (lb), or (Ic), Z3 may be selected from hydrogen, deuterium, halo, -COH, -C02H, -N02, -CH2CCH, - CH2CN, -NR5R5, -(CO)NH2, -(C0)NR5R5’, -SO2-NH2, -R5CH , -R5-COH, - R5CO2H, - R5NH2, - R5NH(COH) , -R5(CO)NH2, - R5NH-SO2H, - R5SO2-NH2, -CH2R5, -OR5, - S02R5-, -C02R5, -NHR5, -NH(CO)R5, - (CO)NHR5, -NH-S02R5, -S02-NHR5, optionally substituted amino, optionally substituted Ci to C4 alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10 heteroaryl).

[0191] In some embodiments of the compounds of Formula (Id), n is 1, 2, 3, or 4. In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 2 or 3. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, n is 4.

[0192] In some embodiments of the compounds of Formula (Id), X1may be selected from -CH, B, N, or PO4. In some embodiments, X1is -CO2-, N, or -SO2-. In some embodiments, X1is N.

[0193] In some embodiments of the compounds of Formula (Id), R9may be selected from hydrogen, deuterium, optionally substituted Ci to C6alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl). In some further embodiments, Z2 is C3to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, -NR5R5, -CFbCH, or -CH2CN.

[0194] In some embodiments of the compounds of Formula (Id), R10may be selected from hydrogen, deuterium, optionally substituted Ci to Cr>alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Cr>to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl). In some further embodiments, Z2 is C3to Cs cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to Cs heteroaryl, -NR5R5, -CFbCH, or -CH2CN.

[0195] In some embodiments, the optionally substituted C3to Cs heterocyclyl issome embodiments, n is 1, 2, 3 or 4. In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, the optionally substituted C3to Csheterocyclylsome embodiments, the optionally substituted C3to Cs heterocyclylsome embodiments, the optionally substituted C3toCs heterocyclyl isome embodiments, the optionally substituted C3toCs heterocyclyl is. In some embodiments, Z2 is

[0196] In some embodiments, Zi is -CH2- and Z2 is an optionally substituted C3 to Cs heterocyclyl, and Z3is an optionally substituted aryl. In some embodiments, Zi is - CH2- and Z2is an optionally substituted C3to Cs heterocyclyl, and Z3is hydrogen. In some embodiments, Zi is -CH2- and Z2 is an optionally substituted C3 to Cs heterocyclyl, and Z3 is an optionally substituted alkyl. In some embodiments, Zi is -CH2- and Z2 is an optionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments,

[0197] In some embodiments of the compounds of Formula (I), or (la), Y is CFh, NH or 0.

[0198] In some embodiments, Formula (I) is a compound of a disclosed formula, for example Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (Da), Formula (lib), Formula (lie), or Formula (lid) but excluding the, embodiments, Formula (I) is a compound of a disclosed formula, for example Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (Ila), Formula (lib), Formula (lie), or Formula (lid) but excluding R2as Ci to C(, alkyl. In some embodiments, Formula (I) is a compound of a disclosed formula, for example Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (Ila), Formula (lib). Formula (lie), or Formula (lid) but excluding R2as methyl. In some embodiments, Formula (I) is a compound of a disclosed formula, for example Formula (I), Formula (la), Formula (lb), Formula (Ic), Formula (Id), Formula (II), Formula (Ila), Formula (lib), Formula (lie), or Formula (lid) but excluding R2as ethyl.

[0199] Some embodiments provide a compound of Formula (II):

[0200] In some embodiments, Formula (II) is a pharmaceutically acceptable salt as described herein.

[0201] In some embodiments, Formula (II) is represented by Formula (Ila), Formula (lib). Formula (lie):

[0202] In some embodiments. Formula (Ila), Formula (lib), Formula (lie),Formula (lid) may be a pharmaceutically acceptable salt as described herein.

[0203] In some embodiments of Formula (II), QA, QB, QC are independently C orN.

[0204] In some embodiments of the compounds of Formula (II) or (lie), R1may be selected from 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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, or L.

[0205] In some embodiments, R1is not O-pyrimidinyl. In some embodiments, R1is not an ether-linked pyrimidyl.

[0206] In some embodiments of the compounds of Formula (II), (Ila), or (lib), R2may be selected from 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 Ci to C6alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, or L. In some further embodiments, R2is L. In some further embodiments, R2is -CH3.

[0207] In some embodiments of the compounds Formula (II), (Ila), or (lid), R3is 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 substitutedN-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 Ci to Ce alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Co alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, or L.

[0208] In some embodiments of the compounds of Formula (II) or (Ila), R4may be selected from 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 Ci to C6alkoxy, optionally substituted Ci to Ce alkyl, optionally substituted C2 to Ce alkenyl, optionally substituted C2 to Ce alkynyl, optionally substituted C3to Cs cycloalkyl, optionally substituted C6 to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, or L.

[0209] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (lie), R5is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R5is H, deuterium, halo, or an optionally susbstituted Ci to C6alkyl.

[0210] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (lie), R5is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl, optionally substituted C2 to C6 alkenyl, optionally substituted C2 to C6 alkynyl. In some embodiments, R5is H, deuterium, halo, or an optionally susbstituted Ci to C6alkyl.

[0211] In some embodiments of the compounds of Formula (II), (Ila), (lib), (lie), or (lid), R6is H, deuterium, hydroxyl, halogen, cyano, nitro, optionally substituted amino, optionally optionally substituted Ci to C6alkoxy, optionally substituted Ci to C6alkyl,optionally substituted C2to C6alkenyl, optionally substituted C2to C alkynyl. In some embodiments, R6is H, deuterium, halo, or an optionally susbstituted Ci to C6alkyl.

[0212] In some embodiments of the compounds of Formula (II) or (Ila), X isC(R5)2, CH(R5), CH2, -0-,, . In some further embodiments, X is CFhor -0-. In some further embodiments, X is -0-.

[0213] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (He), L is -Z1-Z2. In some embodiments of the compounds of Formula (II), (Ila) or (lib) -Zi- Z2-Z3.

[0214] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (lie), Zi is -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, -CH2CN, -NR¾5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, -SO2-NH-, -R5CH2-, -R50- , - R5S-, R5-S=0, -R5S02-R5-C=0, - R5C02- -R5NH-, - R5NH(CO)- , -R5(CO)NH-, - R5NH-S02- -R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0-R\ -SO2R5-, C=0-R5, -CO2R5- , -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, -SO2-NHR5-, optionally substituted C3 to Os cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), - CH2-(optionally substituted C3to Cx cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl). In some further embodiments, Zi is -CH2-.

[0215] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (lie), Z2is halo, -CH2-, -0-, -S-, S=0, -SO2-, C=0, -CO2-, -NO2, -NH-, -CH2CCH, - CH2CN, -NR5R5, -NH(CO) -, -(CO)NH-, -(CO)NR5R5-, -NH-SO2-, -SO2-NH-, - R5CH2-, -R50-, - R5S-, R5-S=0, -R5S02-, R5-C=0, - R5C02- -R5NH-, - R5NH(CO)- , -Rs(CO)NH-, - R5NH-S02- -R5S02-NH-, -CH2R5-, -OR5-, -SR5-, S=0-R5, -SO2R5-, C=0-R5, -CO2R5-, -NHR5-, -NH(CO)R5-, - (CO)NHR5-, -NH-SO2R5-, -SO2-NHR5-, optionally substituted C3 to Cs cycloalkyl, optionally substituted C6 to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10heteroaryl). In some further embodiments, Z2is C3 to Cs cycloalkyl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to Cs heteroaryl, - NR5R5, -CH2CH, or -CH2CN. In some further embodiments, Z2is optionally substituted C3to Cs heterocyclyl. In some embodiments, Zi is -CH2- and Z2is -NR5R5. In some embodiments, Z2an optionally an optionally substituted C3to C7heterocyclyl.

[0216] In some embodiments of the compounds of Formula (II), (Ila), (lib), or (lie), Z3is hydrogen, halo, -COH, -CO2H, -NO2, -CH2CCH, -CH2CN, -NR5R5, -(CO)NH2, -(CO)NR5R5, -SO2-NH2, -R5CH , -R5-COH, - R5C02H, - R5NH2, - R5NH(COH) , - R5(CO)NH2, - R5NH-S02H, - R5S02-NH2, -CH2R5, -OR5, -SO2R5-, -CO2R5, -NHR5, - NH(CO)R5, - (CO)NHR5, -NH-SO2R5, -SO2-NHR5, optionally substituted amino, optionally substituted Ci to C4alkyl, optionally substituted C3to Cs cycloalkyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3to Cs cycloalkyl) or -CH2-(optionally substituted C3to C10heteroaryl).

[0217] In some embodiments, Zi is -CH2- and Z2is an optionally substituted C3to Cs heterocyclyl, and Z3is an optionally substituted aryl. In some embodiments, Zi is - CH2- and Z2is an optionally substituted C3to Cs heterocyclyl, and Z3is hydrogen. In some embodiments, Zi is -CH2- and Z2is an optionally substituted C3to Cs heterocyclyl, and Z3is an optionally substituted alkyl. In some embodiments, Zi is -CH2- and Z2is an optionally substituted C3to Cs heterocyclyl, and Z3is -CH2-(optionally substituted aryl). In some embodiments, the optionally substituted C3to Cs heterocyclylsome embodiments, n is 1, 2, 3 or 4. In some embodiments, n is 1, 2 or 3. In some embodiments, n is 1 or 2. In some embodiments, n is 1. In some embodiments, n is 2. In some embodiments, n is 3. In some embodiments, the optionally substituted C3to Cs heterocyclylsome embodiments, the optionally substituted C3to Cs heterocyclyl is optionally substitutedsome embodiments, the optionally substituted C3to Cs heterocyclyl is optionally substituted. In some embodiments, theoptionally substituted C3to Cs heterocyclylsome embodiments, the optionally substituted C3to Cs heterocyclylsome embodiments, the optionally substituted C3to Cs heterocyclyl isIn some embodiments,some embodiments, the optionally substitutedC3 to Cs heterocyclyl i

[0218] In some embodiments of the compounds of Formula (II), R7is independently H, deuterium, optionally substituted Ci to Ce alkyl, optionally substituted C2to Ce alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted Ce to C10aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3to C10heteroaryl, or L. In some further embodiments, R7is selected from halo, H or CH3.

[0219] In some embodiments of the compounds of Formula (Ila), R8selected from H, deuterium, optionally substituted Ci to C6alkyl, optionally substituted C2to C6alkenyl, optionally substituted C2to Ce alkynyl, optionally substituted C3to Cs carbocyclyl, optionally substituted C6to C10aryl, optionally substituted C3to Cs heterocyclyl, optionally substituted C3to C10heteroaryl. In some further embodiments, R8is selected from halo, H, deuterium, or CH3.

[0220] In some embodiments of the compounds of Formula (Id), X1may be selected from -CH, -CO2-, N, or -SO2-. In some embodiments, X1is -CO2-, N, or -SO2-. In some embodiments, X1is N.

[0221] In some embodiments of the compounds of Formula (Id), R9may be selected from hydrogen, deuterium, optionally substituted Ci to C6alkyl, optionallysubstituted C3 to Cs cycloalkyl, optionally substituted C to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10 heteroaryl). In some further embodiments, Z2 is C3 to Cs cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to Cs heteroaryl, -NR5R5, - CH2CH, or -CH2CN.

[0222] In some embodiments of the compounds of Formula (Id), R10may be selected from hydrogen, deuterium, optionally substituted Ci to C6alkyl, optionally substituted C3 to Cs cycloalkyl, optionally substituted Ce to C10 aryl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to C10 heteroaryl, -CH2-(optionally substituted aryl), -CH2-(optionally substituted C3 to Cs cycloalkyl) or -CH2-(optionally substituted C3 to C10 heteroaryl). In some further embodiments, Z2 is C3 to Cs cycloalkyl, optionally substituted C3 to Cs heterocyclyl, optionally substituted C3 to Cs heteroaryl, -NR5R5, - CH2CH, or -CH2CN.

[0223] In some embodiments of the compounds of Formula (II), or (Ila), Y is CH2, NH or 0.

[0224] In some embodiments of the compounds of Formula (II), or (Ila), X is CH2or O.

[0225] In some embodiments of the compounds of Formula (II), (Ila), or (lid), Z is C or N.

[0226] In some embodiments, Formula (II) excludessome embodiments, Formula (II), (Ila),(lib), or (lie) excludes R2as CH3.

[0227] In some embodiments of the compounds of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib), or (lie) are selected from Compounds of Table A, and pharmaceutically acceptable salts thereof.

[0228] Table A. Exemplary Compounds of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), or (lid):Table A

[0229] In some embodiments, the pharmaceutically acceptable salt can be an alkaline 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 alkali earth metal salt. In some embodiments, the pharmaceutically acceptable salt can be an ammonium salt.Syntheses

[0230] Compounds of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or pharmaceutically acceptable salts thereof, described herein may be prepared in various ways, including those known to those skilled in the art. The routes shown and described herein are illustrative only and are not intended, nor are they to be construed, to limit the scope of the claims in any manner whatsoever. Those skilled in the art will be able to recognize modifications of the disclosed syntheses and to devise alternate routes based on thedisclosures herein; all such modifications and alternate routes are within the scope of the claims. Examples of methods are described in the Examples below.Methods of Preparation

[0231] The compounds disclosed herein may be synthesized by methods described below, or by modification of these methods. Ways of modifying the methodology include, among others, temperature, solvent, reagents etc., and will be obvious to those skilled in the art. In general, during any of the processes for preparation of the compounds disclosed herein, it may be necessary and / or desirable to protect sensitive or reactive groups on any of the molecules concerned. This may be achieved by means of conventional protecting groups, such as those described in Protective Groups in Organic Chemistry (ed. J.F.W. McOmie, Plenum Press, 1973); and Greene & Wuts, Protective Groups in Organic Synthesis, John Wiley & Sons, 1991, which are both hereby incorporated herein by reference in their entirety. The protecting groups may be removed at a convenient subsequent stage using methods known from the art. Synthetic chemistry transformations useful in synthesizing applicable compounds are known in the art and include e.g. 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, which are both hereby incorporated herein by reference in their entirety.

[0232] Where the processes for the preparation of the compounds disclosed herein give rise to mixtures of stereoisomers, such isomers may 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 an optically active acid, 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 by formation of diastereomeric derivatives such as esters, amides or ketals followed by chromatographic separation and removal of the chiral auxiliary.Pharmaceutical Compositions

[0233] In another aspect, pharmaceutical compositions are disclosed that comprise a physiologically acceptable surface active agents, carriers, diluents, excipients, smoothing agents, suspension agents, film forming substances, and coating assistants, or a combination thereof; and a compound disclosed herein. Acceptable carriers or diluents for therapeutic use are well known in the pharmaceutical art, 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, flavoring agents, and the like 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, sulfated aliphatic alcohols, and the like may be used as surface active agents; sucrose, glucose, lactose, starch, crystallized cellulose, mannitol, light anhydrous silicate, magnesium aluminate, magnesium methasilicate aluminate, synthetic aluminum silicate, calcium carbonate, sodium acid carbonate, calcium hydrogen phosphate, calcium carboxymethyl cellulose, and the like may be used as excipients; magnesium stearate, talc, hardened oil and the like may be used as smoothing agents; coconut oil, olive oil, sesame oil, peanut oil, soya may be used as suspension agents or lubricants; cellulose acetate phthalate as a derivative of a carbohydrate such as cellulose or sugar, or methylacetate-methacrylate copolymer as a derivative of polyvinyl may be used as suspension agents; and plasticizers such as ester phthalates and the like may be used as suspension agents.

[0234] The term “pharmaceutical composition,” as used herein, refers to a mixture of a compound disclosed herein with other chemical components, such as diluents or carriers. The pharmaceutical composition facilitates administration of the compound to an organism. Multiple techniques of 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 compounds with inorganic or organic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, salicylic acid and the like.

[0235] The term “carrier,” as used herein, refers to a chemical compound that facilitates the incorporation of a compound into cells or tissues. For example dimethyl sulfoxide (DMSO) is a commonly utilized carrier as it facilitates the uptake of many organic compounds into the cells or tissues of an organism.

[0236] The term “diluent,” as used herein, refers to chemical compounds diluted in water that will dissolve the compound of interest as well as stabilize the biologically active form of the compound. Salts dissolved in buffered solutions are utilized as diluents in the art. One commonly used buffered solution is phosphate buffered saline because it mimics the salt conditions of human blood. Since buffer salts can control the pH of a solution at low concentrations, a buffered diluent rarely modifies the biological activity of a compound.

[0237] The term “physiologically acceptable,” as used herein, refers to a carrier or diluent that does not abrogate the biological activity and properties of the compound.

[0238] As used herein, an “excipient” refers to an inert substance that is added to a pharmaceutical composition to provide, without limitation, bulk, consistency, stability, binding ability, lubrication, disintegrating ability etc., to the composition. A “diluent” is a type of excipient.

[0239] For each of the compounds described herein, and for each genus or sub genus of compounds described herein, also described are pharmaceutical compositions comprising the compound, alone or in a mixture with other compounds of the genus or sub genus, or with alternative compounds described herein, or with one or more alternative pharmaceutically active compounds, and one or more pharmaceutically acceptable carrier, diluent, excipient or combination thereof. The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or carriers, diluents, excipients or combinations thereof. Proper formulation is dependent upon the route of administration chosen. Techniques for formulation and administration of the compounds described herein are known to those skilled in the art.

[0240] The pharmaceutical compositions disclosed herein may be manufactured in any manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tableting processes. Additionally, the active ingredients are contained in an amount effective toachieve its intended purpose. Many of the compounds used in the pharmaceutical combinations disclosed herein may be provided as salts with pharmaceutically compatible counterions.

[0241] The pharmaceutical compositions described herein can be administered to a human patient per se, or in pharmaceutical compositions where they are mixed with other active ingredients, as in combination therapy, or suitable carriers or excipient(s). Techniques for formulation and administration of the compounds of the instant application may be found in “Remington’s Pharmaceutical Sciences,” Mack Publishing Co., Easton, PA, 18th edition, 1990.

[0242] Suitable routes of administration may, for example, include oral, rectal, transmucosal, topical, or intestinal administration; parenteral delivery, including intramuscular, subcutaneous, intravenous, intramedullary injections, as well as intrathecal, direct intraventricular, intraperitoneal, intranasal, or intraocular injections. The compounds can 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 timed, pulsed administration at a predetermined rate.

[0243] The pharmaceutical compositions of the present invention may be manufactured in a manner that is itself known, e.g., by means of conventional mixing, dissolving, granulating, dragee-making, levigating, emulsifying, encapsulating, entrapping or tabletting processes.

[0244] Pharmaceutical compositions for use in accordance with the present invention thus may be formulated in conventional manner using one or more physiologically acceptable carriers comprising excipients and auxiliaries which facilitate processing of the active compounds into preparations which can be used pharmaceutically. Proper formulation is dependent upon the route of administration chosen. Any of the well-known techniques, carriers, and excipients may be used as suitable and as understood in the art; e.g., in Remington’s Pharmaceutical Sciences, above.

[0245] Injectables can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solution or suspension in liquid prior to injection, or as emulsions. Suitable excipients are, for example, water, saline, dextrose, mannitol, lactose, lecithin, albumin, sodium glutamate, cysteine hydrochloride, and the like.In addition, if desired, the injectable pharmaceutical compositions may contain minor amounts of nontoxic auxiliary substances, such as wetting agents, pH buffering agents, and the like. Physiologically compatible buffers include, but are not limited to, Hanks’s solution, Ringer’s solution, or physiological saline buffer. If desired, absorption enhancing preparations (for example, liposomes), may be utilized.

[0246] For transmucosal administration, penetrants appropriate to the barrier to be permeated may be used in the formulation.

[0247] Pharmaceutical formulations for parenteral administration, e.g., by bolus injection or continuous infusion, include aqueous solutions of the active compounds in water- soluble form. Additionally, suspensions of the active compounds may 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 oils, or synthetic fatty acid esters, such as ethyl oleate or triglycerides, or liposomes. Aqueous injection suspensions may contain substances which increase the viscosity of the suspension, such as sodium carboxymethyl cellulose, sorbitol, or dextran. Optionally, the suspension may also contain suitable stabilizers or agents that increase the solubility of the compounds to allow for the preparation of highly concentrated solutions. Formulations for injection may be presented in unit dosage form, e.g., in ampoules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may 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, e.g., sterile pyrogen- free water, before use.

[0248] For oral administration, the compounds can be formulated readily by combining the active compounds with pharmaceutically acceptable carriers well known in the art. Such carriers enable the compounds of the invention to be formulated as tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspensions and the like, for oral ingestion by a patient to be treated. Pharmaceutical preparations for oral use can be obtained by combining the active compounds with solid excipient, optionally grinding a resulting mixture, and processing the mixture of granules, after adding suitable auxiliaries, if desired, to obtain tablets or dragee cores. Suitable excipients are, in particular, fillers such as sugars, including lactose, sucrose, mannitol, or sorbitol; cellulose preparations such as, for example,maize starch, wheat starch, rice starch, potato starch, gelatin, gum tragacanth, methyl cellulose, hydroxypropylmethyl-cellulose, sodium carboxymethylcellulose, and / or polyvinylpyrrolidone (PVP). If desired, disintegrating agents may be added, such as the cross-linked polyvinyl pyrrolidone, agar, or alginic acid or a salt thereof such as sodium alginate. Dragee cores are provided with suitable coatings. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses. For this purpose, concentrated sugar solutions may be used, which may optionally contain gum arabic, talc, polyvinyl pyrrolidone, carbopol gel, polyethylene glycol, and / or titanium dioxide, lacquer solutions, and suitable organic solvents or solvent mixtures. Dyestuffs or pigments may be added to the tablets or dragee coatings for identification or to characterize different combinations of active compound doses.

[0249] Pharmaceutical preparations which can be used orally include push-fit capsules made of gelatin, as well as soft, sealed capsules made of gelatin and a plasticizer, such as glycerol or sorbitol. The push-fit capsules can contain the active ingredients in admixture with filler such as lactose, binders such as starches, and / or lubricants such as talc or magnesium stearate and, optionally, stabilizers. In soft capsules, the active compounds may be dissolved or suspended in suitable liquids, such as fatty oils, liquid paraffin, or liquid polyethylene glycols. In addition, stabilizers may be added. All formulations for oral administration should be in dosages suitable for such administration.

[0250] For buccal administration, the compositions may take the form of tablets or lozenges formulated in conventional manner.

[0251] For administration by inhalation, the compounds for use according to the present invention are conveniently delivered in the form of an aerosol spray presentation from pressurized packs or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol the dosage unit may be determined by providing a valve to deliver a metered amount. Capsules and cartridges of, e.g., gelatin foruse in an inhaler or insufflator may be formulated containing a powder mix of the compound and a suitable powder base such as lactose or starch.

[0252] Further disclosed herein are various pharmaceutical compositions well known in the pharmaceutical art for uses that include 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 compounds in water-soluble form, such as eyedrops, or in gellan gum (Shedden et ah, Clin. Ther., 23(3):440-50 (2001)) or hydrogels (Mayer et al., Ophthalmologica, 210(2): 101-3 (1996)); ophthalmic ointments; ophthalmic suspensions, such as microparticulates, drug-containing small polymeric particles that are suspended in a liquid carrier medium (Joshi, A., J. Ocul. Pharmacol, 10(l):29-45 (1994)), lipid-soluble formulations (Aim et ah, Prog. Clin. Biol. Res., 312:447-58 (1989)), and microspheres (Mordenti, Toxicol. Scl, 52(1): 101-6 (1999)); and ocular inserts. All of the above-mentioned references, are incorporated herein by reference in their entireties. Such suitable pharmaceutical formulations are most often and preferably formulated to be sterile, isotonic and buffered for stability and comfort. Pharmaceutical compositions for intranasal delivery may also include drops and sprays often prepared to simulate in many respects nasal secretions to ensure 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 well-known to those skilled in the art, suitable formulations are most often and preferably isotonic, slightly buffered to maintain a pH of 5.5 to 6.5, and most often and preferably include antimicrobial preservatives and appropriate drug stabilizers. Pharmaceutical formulations for intraauricular delivery include suspensions and ointments for topical application in the ear. Common solvents for such aural formulations include glycerin and water.

[0253] The compounds may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.

[0254] In addition to the formulations described previously, the compounds may also be formulated as a depot preparation. Such long acting formulations may be administered by implantation (for example subcutaneously or intramuscularly) or byintramuscular injection. Thus, for example, the compounds may be formulated with suitable polymeric or hydrophobic materials (for example as an emulsion in an acceptable oil) or ion exchange resins, or as sparingly soluble derivatives, for example, as a sparingly soluble salt.

[0255] 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 co-solvent 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 to volume in absolute ethanol. Naturally, the proportions of a co-solvent system may be varied considerably without destroying its solubility and toxicity characteristics. Furthermore, the identity of the co-solvent components may be varied: for example, other low-toxicity nonpolar surfactants may be used instead of POLYSORBATE 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

[0256] Alternatively, other delivery systems for hydrophobic pharmaceutical compounds may be employed. Liposomes and emulsions are well known examples of delivery vehicles or carriers for hydrophobic drugs. Certain organic solvents such as dimethylsulfoxide also may be employed, although usually at the cost of greater toxicity. Additionally, the compounds may be delivered using a sustained-release system, such as semipermeable matrices of solid hydrophobic polymers containing the therapeutic agent. Various sustained-release materials have been established and are well known by those skilled in the art. Sustained-release capsules may, depending on their chemical nature, release the compounds for a few weeks up to over 100 days. Depending on the chemical nature and the biological stability of the therapeutic reagent, additional strategies for protein stabilization may be employed.

[0257] Agents intended to be administered intracellularly may be administered using techniques well known to those of ordinary skill in the art. For example, such agents may be encapsulated into liposomes. All molecules present in an aqueous solution at the time of liposome formation are incorporated into the aqueous interior. The liposomal contents are both protected from the external micro-environment and, because liposomes fuse with cell membranes, are efficiently delivered into the cell cytoplasm. The liposome may be coatedwith a tissue-specific antibody. The liposomes will be targeted to and taken up selectively by the desired organ. Alternatively, small hydrophobic organic molecules may be directly administered intracellularly.

[0258] Additional therapeutic or diagnostic agents may be incorporated into the pharmaceutical compositions. Alternatively or additionally, pharmaceutical compositions may be combined with other compositions that contain other therapeutic or diagnostic agents. Parenteral Pharmaceutical Composition

[0259] To prepare a parenteral pharmaceutical composition suitable for administration by injection (subcutaneous, intravenous, or the like), 0.1 mg to 120 mg of a water-soluble salt / soluble material itself / solubilized complex of a compound of a preferred embodiment is dissolved in sterile water and then mixed with 10 pL of 0.9% sterile saline. The mixture is incorporated into a dosage unit form suitable for administration by injection. Injectable Pharmaceutical Composition

[0260] To prepare an injectable formulation, 0.1 mg to 100 mg of a compound of Formula (I), (la), (lb), (Ic), (II), (Ila), (lib), or (lie), 2.0 mL of sodium acetate buffer solution (0.4 M), HC1 (1 N) or NaOH (1 M) (q.s. to suitable pH), water (distilled, sterile) (q.s. to 20 ml.) are mixed. All of the above ingredients, except water, are combined and stirred and if necessary, with slight heating if necessary. A sufficient quantity of water is then added.Oral Pharmaceutical Composition

[0261] To prepare a pharmaceutical composition for oral delivery, 0.1 mg to 120 mg of a compound of an 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 compound is granulated with binder solution such as starch solution along with suitable diluents such as microcrystalline cellulose or like, disintegrants such as croscaramellose sodium, dry the resultant mixture and add lubricant and compress into tablet which is suitable for oral administration.Sublingual (Hard Lozenge) Pharmaceutical Composition

[0262] To prepare a pharmaceutical composition for buccal delivery, such as 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 sugars that provide negative heat of solution to the system, 1.6 mL of light com syrup, 2.4 mL distilled water, and 0.42 mL mint extract orother flavorants. The mixture is blended and poured into a mold to form a lozenge suitable for buccal administration.Fast-Disintegrating Sublingual Tablet

[0263] A fast-disintegrating sublingual tablet is 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 combination that help dissolve the compressed tablet faster in the mouth, 5% by weight of low-substituted hydroxypropyl cellulose (50 pm), and 2% by weight of magnesium stearate. 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 amount of the compound of a preferred embodiment with the total quantity of microcrystalline cellulose (MCC) and mannitol / modified dextrose or combination, and two- thirds of the quantity of low-substituted hydroxypropyl cellulose (L-HPC) by using a three dimensional manual mixer (Inversina, Bioengineering AG, Switzerland) for 4.5 minutes. All of the magnesium stearate (MS) and the remaining one-third of the quantity of L-HPC are added 30 seconds before the end of mixing.Inhalation Pharmaceutical Composition

[0264] 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, which is suitable for inhalation administration. Nebulizer Suspension Pharmaceutical Composition

[0265] In another embodiment, a compound of a preferred embodiment (0.1 mg to 100 mg) is suspended in sterile water (100 mL); Span 85 (1 g) is added followed by addition of 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 sterile nebulizers.Transdermal Patch Pharmaceutical Composition

[0266] 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, apatch with a single adhesive face. The resulting patch is then attached to the skin via the adhesive face for transdermal administration.Topical Gel Pharmaceutical Composition

[0267] To prepare a pharmaceutical topical gel composition, 0.1 mg to 100 mg of a compound of a preferred embodiment 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 containers, such as tubes, which are suitable for topical administration.Ophthalmic Solution

[0268] To prepare a pharmaceutical ophthalmic solution composition, 0.1 mg to 100 mg of a compound of a preferred embodiment 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 ophthalmic delivery units, such as eye drop containers, which are suitable for ophthalmic administration.Nasal Spray Solution

[0269] To prepare a pharmaceutical nasal spray solution, 0.1 mg to 100 mg of a compound of a preferred embodiment is mixed with 30 mL of a 0.05M phosphate buffer solution (pH 4.4). The solution is placed in a nasal administrator designed to deliver 100 mΐ of spray for each application.Methods of Treatment / Uses

[0270] Aspects disclosed herein relate to administering to a subject in need an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds as described herein (such as one or more compounds of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof).

[0271] As disclosed elsewhere herein, some embodiments pertain to treating a disease or condition, such as cancer, through administration of a compound or composition as disclosed herein. A subject in neeed of receiving a compound or composition as disclosed herein to improve the subject’s health need not always be identified prior to receiving a firsttreatment with the compound or composition. For example, a subject may be predetermined that they will develop a disease or condition, such as cancer, prior to showing any signs of the disease or condition. Alternatively, the subject may receive treatment prophylactically if he or she is at risk or not developing a disease or condition, such as cancer, (e.g., once a patient shows symptoms of another disease or condition associated with a cancer). Accordingly, in some embodiments, the compound or composition may be adminsiterd to the subject after the subject receives an early stage diagnosis. In some embodiments, not every subject is a candidate for such administration and identification of treatment subjects may be desirable. It is understood that patient selection depends upon a number of factors within the skill of the ordinarily skilled physician. Thus, some embodiments disclosed herein further comprise identifying a subject as one that will benefit from administering an effective amount of at least one compound or composition to increase longevity, increase survival time or increase life span.

[0272] In other aspects, the present disclosure is directed to a method for the treatment, prevention or prophylaxis of cancer can include administering to a subject in need thereof an effective amount of one or more compound described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). In certain embodiments, the cancer may be selected from brain cancer, breast cancer, lung cancer, ovarian cancer, pancreatic cancer, stomach cancer, prostate cancer, renal cancer, colorectal cancer or leukemia. In further or additional embodiments, the cancer is brain cancer or ach-enocortical 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 stomach cancer. In further or additional emodiments, 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 lymphona. In further or additional embodiments, the cancer is pre-Bacute 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 line cancer.

[0273] Some embodiments relate to a method of inhibiting proliferation of a cell having a RAS mutation, comprising administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer has associated with a RAS mutation. Some embodiments relate to a method of inducing apoptosis in a cell in a cell having a RAS mutation, comprising administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). Some embodiments relate to a method of inhibiting proliferation of a cell having a KRAS mutation, comprising administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer has associated with a KRAS mutation. Some embodiments relate to a method of inducing apoptosis in a cell in a cell having a KRAS mutation, comprising administering a compound of Formula (I), (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). Some embodiments relate to a method of inhibiting proliferation of a cell having a NRAS mutation, comprising administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). In some embodiments, the cancer has associated with a NRAS mutation. Some embodiments relate to a method of inducing apoptosis in a cell in a cell having a RAS mutation, comprising administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). In some embodiments, the KRAS mutation is at codons 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.

[0274] In certain embodiments, the cancer is resistant to treatment of a MEK protein kinase inhibitor. In other embodimnets, the cancer is resistant to treatment of 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 anticancer agent.

[0275] In some aspects provided herein are a compounds or pharamceutical compositions and methods for treating cancer comprising a therapeutically effective amount of a dual-RAF / MEK protein kinase inhibitor. In some embodiments, the administration of the dual-RAF / MEK protein kinase inhibitor provides an increase in the area under the serum concentration time curve (AUC) of the dual-RAF / MEK protein kinase inhibitor. In some embodiments, the cancer is resistant to treatment of 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.

[0276] In some embodiments, the resistant cancer is pancreatic, melanoma, colon, lung, or stomach cancer. In further embodiments, the resistant cancer is pancreatic. In additional embodiments, the resistant cancer is stomach. In alternative embodiments, provided are pharmaceutical combinations and methods for resensitizing cancer cells to treatment in a patient having or suspected of having a cancer resistant to an anticancer agent, comprising the step of administering to the patient a therapeutically effective amount of a dual-MEK / RAF inhibitor as disclosed herein.

[0277] Some embodiments disclosed herein relate to a method of treating a mammal having a disease that can include administering to a subject in need thereof an effective amount of one or more compound described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes a compound described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof). Other embodiments disclosed herein relate to a method of treating a subject with cancer cachexia that can include administering to a subject an effective amount of one or more compounds described herein (such as a compound ofFormula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof), or a pharmaceutically acceptable salt of any of the foregoing), or a pharmaceutical composition that includes a compound described herein such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof).

[0278] Some embodiments described herein relate to using one or more compounds described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof), in the manufacture of a medicament for ameliorating and / or treating cancer or conditions of cancer, such as cancer cachexia, that can include administering to a subject an effective amount of one or more compounds described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof). Still other embodiments described herein relate to one or more compounds described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof) that can be used for ameliorating and / or treating cancer or conditions of cancer, such as cancer cachexia, by administering to a subject an effective amount of one or more compounds described herein, or a pharmaceutically acceptable salt thereof.

[0279] Some embodiments disclosed herein relate to methods of ameliorating and / or treating cancer that can include contacting a cancerous cell an effective amount of one or more compounds described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof), or a pharmaceutical composition that includes one or more compounds described herein (such as a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof). In some embodiments, a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, can act as an inhibitor of MEK. In some embodiments, a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, can act as an inhibitor of ERK. In some embodiments, a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (Re), (lid), or a pharmaceutically acceptable salt thereof, may act as a mitoSTAT3 inhibitor. In some embodiments, a compound of Formula (I), (la), (lb), (Ic), (Id),(II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may reduce inflammatory cachexia and muscle wasting.

[0280] In some embodiments, the compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered in a single dose, once daily. In some embodiments, the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered in multiple doses, more than once per day. In some embodiments, the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered once a day. In some embodiments, the compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered administered twice a day. In some embodiments, the compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered administered trice a day. In some embodiments, the compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may be administered administered four times a day.

[0281] In some aspects, a compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, may inhibit abnormal cell growth. In some embodiments, the abnormal cell growth occurs in a mammal. Methods for inhibiting abnormal cell growth may comprise administering an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ha), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, wherein abnormal cell growth is inhibited. Methods for inhibiting abnormal cell growth in a mammal may comprise administering to the mammal a compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, wherein the amounts of the compound is effective in inhibiting abnormal cell growth in the mammal.

[0282] In other aspects, the present invention is directed to a method for degrading, inhibiting the growth of or killing a cancer cell comprising contacting said cell with a compound of Formula (1), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (He), (lid), or a pharmaceutically acceptable salt thereof, effective to degrade, inhibit the growth of or to killsaid cell. In some embodiments, the cancer cells comprise brain, breast, lung, ovarian, pancreatic, stomach, prostate, renal, or colorectal cancer cells.

[0283] 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.

[0284] 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 = Page 70 -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 cellsare 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 farther or additional embodiments, essentially all of the cancer cells are killed.

[0285] In further or additional embodiments, the growth of the cancer cells is inhibited. In further or additional embodiments, the growth of the cancer cells is about 1% inhibited. In further or additional embodiments, the growth of the cancer cells is about 2% inhibited. In further or additional embodiments, the growth of the cancer cells is about 3% inhibited. In further or additional embodiments, the growth of the cancer cells is about 4% inhibited. In further or additional embodiments, the growth of the cancer cells is about 5% inhibited. In further or additional embodiments, the growth of the cancer cells is about 10% inhibited. In further or additional embodiments, the growth of the cancer cells is about 20% inhibited. In further or additional embodiments, the growth of the cancer cells is about 25% inhibited. In further or additional embodiments, the growth of the cancer cells is about 30% inhibited, hi further or additional embodiments, the growth of the cancer cells is about 40% inhibited. In further or additional embodiments, the growth of the cancer cells is about 50% inhibited. In further or additional embodiments, the growth of the cancer cells is about 60% inhibited. In further or additional embodiments, the growth of the cancer cells is about 70% inhibited. In further or additional embodiments, the growth of the cancer cells is about 75% inhibited. In further or additional embodiments, the growth of the cancer cells is about 80% inhibited. In further or additional embodiments, the growth of the cancer cells is about 90% inhibited. In further or additional embodiments, the growth of the cancer cells is about 100% inhibited.

[0286] In some embodiments, the size of a tumor is reduced by administering a therapeutically effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof. In further or additional embodiments, the size of a tumor is reduced by at least 1%. In further or additional embodiments, the size of a tumor is reduced by at least 2%. In further or additional embodiments, the size of a tumor is reduced by at least 3%. In further or additional embodiments, the size of a tumor is reduced by at least 4%. In further or additional embodiments, the size of a tumor is reduced by at least 5%. In further or additionalembodiments, the size of a tumor is reduced by at least 10%. In further or additional embodiments, the size of a tumor is reduced by at least 20%. In further or additional embodiments, the size of a tumor is reduced by at least 25%. In further or additional embodiments, the size of a tumor is reduced by at least 30%. In further or additional embodiments, the size of a tumor is reduced by at least 40%. In further or additional embodiments, the size of a tumor is reduced by at least 50%. In further or additional embodiments, the size of a tumor is reduced by at least 60%. In further or additional embodiments, the size of a tumor is reduced by at least 70%. In further or additional embodiments, the size of a tumor is reduced by at least 75%. In further or additional embodiments, the size of a tumor is reduced by at least 80%. In further or additional embodiments, the size of a tumor is reduced by at least 85%. In further or additional embodiments, the size of a tumor is reduced by at least 90%. In further or additional embodiments, the size of a tumor is reduced by at least 95%. In further or additional embodiments, the tumor is eradicated. In some embodiments, the size of a tumor does not increase.

[0287] In some embodiments, tumor proliferation is reduced by administering a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof. In some embodiments, tumor proliferation is reduced by at least 1 %. In some embodiments, tumor proliferation is reduced by at least 2 %. In some embodiments, tumor proliferation is reduced by at least 3 %. In some embodiments, tumor proliferation is reduced by at least 4 %. In some embodiments, tumor proliferation is reduced by at least 5 %. In some embodiments, tumor proliferation is reduced by at least 10 %. In some embodiments, tumor proliferation is reduced by at least 20 %. In some embodiments, tumor proliferation is reduced by at least 25 %. In some embodiments, tumor proliferation is reduced by at least 30 %. In some embodiments, tumor proliferation is reduced by at least 40 %. In some embodiments, tumor proliferation is reduced by at least 50 %. In some embodiments, tumor proliferation is reduced by at least 60 %. In some embodiments, tumor proliferation is reduced by at least 70 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 75 %. In some embodiments, tumor proliferation is reduced by at least 80 %. In some embodiments, tumor proliferation is reduced by at least 90 %. In someembodiments, tumor proliferation is reduced by at least 95 %. In some embodiments, tumor proliferation is prevented.Methods of Administration

[0288] The compounds or pharmaceutical compositions may be administered to the patient by any suitable means. Non-limiting examples of methods of administration include, among others, (a) administration though oral pathways, which administration includes administration in capsule, tablet, granule, spray, syrup, or other such forms; (b) administration through non-oral pathways such as rectal, vaginal, intraurethral, intraocular, intranasal, or intraauricular, which administration includes administration as an aqueous suspension, an oily preparation or the like or as a drip, spray, suppository, salve, ointment or the like; (c) administration via injection, subcutaneously, intraperitoneally, intravenously, intramuscularly, intradermally, intraorbitally, intracapsularly, intraspinally, intrastemally, or the like, including infusion pump delivery; (d) administration locally such as by injection directly in the renal or cardiac area, e.g., by depot implantation; as well as (e) administration topically; as deemed appropriate by those of skill in the art for bringing the compound of the invention into contact with living tissue.

[0289] Pharmaceutical compositions suitable for administration include compositions where the active ingredients are contained 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 human, being treated, and the physical characteristics of the specific animal under consideration. The dose can be tailored to achieve a desired effect, but will depend on such factors as weight, diet, concurrent medication and other factors which those skilled in the medical arts will recognize. More specifically, a therapeutically effective amount means an amount of compound effective to prevent, alleviate or ameliorate symptoms of disease or prolong the survival of the subject being treated. Determination of a therapeutically effective amount is well within the capability of those skilled in the art, especially in light of the detailed disclosure provided herein.

[0290] As will be readily apparent to one skilled in the art, the useful in vivo dosage to be administered and the particular mode of administration will vary depending upon the age, weight and mammalian species treated, the particular compounds employed,and the specific use for which these compounds are employed. The determination of effective dosage levels, that is the dosage levels necessary to achieve the desired result, can be accomplished by one skilled in the art using routine pharmacological methods. Typically, human clinical applications of products are commenced at lower dosage levels, with dosage level being increased until the desired effect is achieved. Alternatively, acceptable in vitro studies can be used to establish useful doses and routes of administration of the compositions identified by the present methods using established pharmacological methods.

[0291] In non-human animal studies, applications of potential products are commenced at higher dosage levels, with dosage being decreased until the desired effect is no longer achieved or adverse side effects disappear. The dosage may range broadly, depending upon the desired effects and the therapeutic indication. Typically, dosages may be between about 10 micro gram / kg and 100 mg / kg body weight, preferably between about 100 microgram / kg and 10 mg / kg body weight. Alternatively dosages may be based and calculated upon the surface area of the patient, as understood by those of skill in the art.

[0292] 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 e.g., Fingl el al. 1975, in “The Pharmacological Basis of Therapeutics”, which is hereby incorporated herein by reference in its entirety, with particular reference to Ch. 1, p. 1). Typically, the dose range of the composition administered to the patient can be from about 0.5 to 1000 mg / kg of the patient’s body weight. The dosage may be a single one or a series of two or more given in the course of one or more days, as is needed by the patient. In instances where human dosages for compounds have been established for at least some condition, the present invention will use those same dosages, or dosages that are between about 0.1% and 500%, more preferably between about 25% and 250% of the established human dosage. Where no human dosage is established, as will be the case for newly-discovered pharmaceutical compounds, a suitable human dosage can be inferred from ED50 or ID50 values, or other appropriate values derived from in vitro or in vivo studies, as qualified by toxicity studies and efficacy studies in animals.

[0293] It should be noted that the attending physician would know how to and when to terminate, interrupt, or adjust administration due to toxicity or organ dysfunctions.Conversely, the attending physician would also know to adjust treatment to higher levels if the clinical response were not adequate (precluding toxicity). The magnitude of an administrated dose in the management of the disorder of interest will vary with the severity of the condition to be treated and to the route of administration. The severity of the condition may, for example, be evaluated, in part, by standard prognostic evaluation methods. Further, the dose and perhaps dose frequency, will also vary according to the age, body weight, and response of the individual patient. A program comparable to that discussed above may be used in veterinary medicine.

[0294] Although the exact dosage will be determined on a drug-by-drug basis, in most cases, some generalizations regarding the dosage can be made. The daily dosage regimen for an adult human patient may be, for example, an oral dose of between 0.1 mg and 2000 mg of each active ingredient, preferably between 1 mg and 500 mg, e.g. 5 to 200 mg. In other embodiments, an intravenous, subcutaneous, or intramuscular dose of each active ingredient of between 0.01 mg and 100 mg, preferably between 0.1 mg and 60 mg, e.g. 1 to 40 mg is used. In cases of administration of a pharmaceutically acceptable salt, dosages may be calculated as the free base. In some embodiments, the composition is administered 1 to 4 times per day. Alternatively the compositions of the invention may be administered by continuous intravenous infusion, preferably at a dose of each active ingredient up to 1000 mg per day. As will be understood by those of skill in the art, in certain situations it may be necessary to administer the compounds disclosed herein in amounts that exceed, or even far exceed, the above-stated, preferred dosage range in order to effectively and aggressively treat particularly 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.

[0295] In further or additional embodiments the amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered in a range from about 0.001 to about 1000 mg / kg body weight / day. In further or additional embodiments, the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered the range of about 0.5 to about 50 mg / kg / day. In further or additional embodiments the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib),(IIc), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.001 to about 7 g / day. In further or additional embodiments the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.002 to about 6 g / day. In further or additional embodiments the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.005 to about 5 g / day. In further or additional embodiments, the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.01 to about 5 g / day. In further or additional embodiments, the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.02 to about 5 g / day. In further or additional embodiments, the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.05 to about 2.5 g / day. In further or additional embodiments, the amount a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, may be administered from about 0.1 to about 1 g / day. In further or additional embodiments, dosage levels below the lower limit of the aforesaid range may be more than adequate.

[0296] Dosage amount and interval may be adjusted individually to provide plasma levels of the active moiety which are sufficient to maintain the modulating effects, or minimal effective concentration (MEC). The MEC will vary for each compound but can be estimated from in vitro data. Dosages necessary to achieve the MEC will depend on individual characteristics and route of administration. However, HPLC assays or bioassays can be used to determine plasma concentrations.

[0297] Dosage intervals can also be determined using MEC value. Compositions should be administered using a regimen which maintains plasma levels above the MEC for 10-90% of the time, preferably between 30-90% and most preferably between 50-90%.

[0298] In cases of local administration or selective uptake, the effective local concentration of the drug may not be related to plasma concentration.

[0299] The amount of composition administered may 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.

[0300] Compounds disclosed herein can be evaluated for efficacy and toxicity using known methods. For example, the toxicology of a particular compound, or of a subset of the compounds, sharing certain chemical moieties, may be established by determining in vitro toxicity towards a cell line, such as a mammalian, and preferably human, cell line. The results of such studies are often predictive of toxicity in animals, such as mammals, or more specifically, humans. Alternatively, the toxicity of particular compounds in an animal model, such as mice, rats, rabbits, or monkeys, may be determined using known methods. The efficacy of a particular compound may be established using several recognized methods, such as in vitro methods, animal models, or human clinical trials. Recognized in vitro models exist for nearly every class of condition, including but not limited to cancer, cardiovascular disease, and various immune dysfunction. Similarly, acceptable animal models may be used to establish efficacy of chemicals to treat such conditions. When selecting a model to determine efficacy, the skilled artisan can be guided by the state of the art to choose an appropriate model, dose, and route of administration, and regime. Of course, human clinical trials can also be used to determine the efficacy of a compound in humans.

[0301] The compositions may, if desired, be presented in a pack or dispenser device which may contain one or more unit dosage forms containing the active ingredient. The pack may for example comprise metal or plastic foil, such as a blister pack. The pack or dispenser device may be accompanied by instructions for administration. The pack or dispenser may also be accompanied with a notice associated with the container in form prescribed by a governmental agency regulating the manufacture, use, or sale of pharmaceuticals, which notice is reflective of approval by the agency of the form of the drug for human or veterinary administration. Such notice, for example, may be the labeling approved by the U.S. Food and Drug Administration for prescription drugs, or the approved product insert. Compositions comprising a compound of the invention formulated in a compatible pharmaceutical carrier may also be prepared, placed in an appropriate container, and labeled for treatment of an indicated condition.Administration and Pharmaceutical Compositions

[0302] The compounds are administered at a therapeutically effective dosage. While human dosage levels have yet to be specifically identified for the compounds described herein, generally, a daily dose may be from about 0.25 mg / kg to about 120 mg / kg or more of body weight, from about 0.5 mg / kg or less to about 70 mg / kg, from about 1.0 mg / kg to about 50 mg / kg of body weight, or from about 1.5 mg / kg to about 10 mg / kg of body weight. Thus, for administration to a 70 kg person, the dosage range would be from about 17 mg per day to about 8000 mg per day, from about 35 mg per day or less to about 7000 mg per day or more, from about 70 mg per day to about 6000 mg per day, from about 100 mg per day to about 5000 mg per day, or from about 200 mg to about 3000 mg per day. The amount of active compound administered will, of course, be dependent on the subject and disease state being treated, the severity of the affliction, the manner and schedule of administration and the judgment of the prescribing physician.

[0303] Administration of the compounds disclosed herein or the pharmaceutically acceptable salts thereof can be via any of the accepted modes of administration for agents that serve similar utilities including, but not limited to, orally, subcutaneously, intravenously, intranasally, topically, transdermally, intraperitoneally, intramuscularly, intrapulmonarilly, vaginally, rectally, or intraocularly. Oral and parenteral administrations are customary in treating the indications that are the subject of the preferred embodiments.

[0304] The compounds useful as described above can be formulated into pharmaceutical compositions for use in treatment of these conditions. Standard pharmaceutical formulation techniques are used, such as those disclosed in Remington's The Science and Practice of Pharmacy, 21st Ed., Lippincott Williams & Wilkins (2005), incorporated by reference in its entirety. Accordingly, some embodiments include pharmaceutical compositions comprising: (a) a safe and therapeutically effective amount of a compound described herein (including enantiomers, diastereoisomers, tautomers, polymorphs, and solvates thereof), or pharmaceutically acceptable salts thereof; and (b) a pharmaceutically acceptable carrier, diluent, excipient or combination thereof.

[0305] In addition to the selected compound useful as described above, come embodiments include compositions 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 are commonly used in the art may be included. Considerations for the inclusion of various components in pharmaceutical compositions are described, e.g., 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.

[0306] Some examples of substances, which can serve as pharmaceutically- acceptable carriers or components thereof, are sugars, such as lactose, glucose and sucrose; starches, such as com starch and potato starch; cellulose and its derivatives, such as sodium carboxymethyl cellulose, ethyl cellulose, and methyl cellulose; 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 oil of theobroma; polyols such as propylene glycol, glycerine, sorbitol, mannitol, and polyethylene glycol; alginic acid; emulsifiers, such as the TWEENS; wetting agents, such sodium lauryl sulfate; coloring agents; flavoring agents; tableting agents, stabilizers; antioxidants; preservatives; pyrogen-free water; isotonic saline; and phosphate buffer solutions.

[0307] The choice of a pharmaceutically-acceptable carrier to be used in conjunction with the subject compound is basically determined by the way the compound is to be administered.

[0308] 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 a compound that is suitable for administration to an animal, preferably mammal subject, in a single dose, according to good medical practice. The preparation of a single or unit dosage form however, does not imply that the dosage form is administered once per day or once per course of therapy. Such dosage forms are contemplated to be administered once, twice, thrice or more per day and may be administered as infusion over a period of time (e.g., from about 30 minutes to about 2-6 hours), or administered as a continuous infusion, and may be given more than once during a course of therapy, though a single administration is not specificallyexcluded. The skilled artisan will recognize that the formulation does not specifically contemplate the entire course of therapy and such decisions are left for those skilled in the art of treatment rather than formulation.

[0309] The compositions useful as described above may be in any of a variety of suitable forms for a variety of routes for administration, for example, for oral, nasal, rectal, topical (including transdermal), ocular, intracerebral, intracranial, intrathecal, intra-arterial, intravenous, intramuscular, or other parental routes of administration. The skilled artisan will appreciate that oral and nasal compositions comprise compositions that are administered by inhalation, and made using available methodologies. Depending upon the particular route of administration desired, a variety of pharmaceutically-acceptable carriers well-known in the art may be used. Pharmaceutically-acceptable carriers include, for example, solid or liquid fillers, diluents, hydrotropies, surface- active agents, and encapsulating substances. Optional pharmaceutically-active materials may be included, which do not substantially interfere with the inhibitory activity of the compound. The amount of carrier employed in conjunction with the compound is sufficient to provide a practical quantity 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, all incorporated by reference herein: Modern Pharmaceutics, 4th Ed., Chapters 9 and 10 (Banker & Rhodes, editors, 2002); Lieberman el al, Pharmaceutical Dosage Forms: Tablets (1989); and Ansel, Introduction to Pharmaceutical Dosage Forms 8th Edition (2004).

[0310] Various oral dosage forms can be used, including such solid forms as tablets, capsules, granules and bulk powders. Tablets can be compressed, tablet triturates, enteric-coated, sugar-coated, film-coated, or multiple-compressed, containing suitable binders, lubricants, diluents, disintegrating agents, coloring agents, flavoring agents, flow- inducing agents, and melting agents. Eiquid oral dosage forms include aqueous solutions, emulsions, suspensions, solutions and / or suspensions reconstituted from non-effervescent granules, and effervescent preparations reconstituted from effervescent granules, containing suitable solvents, preservatives, emulsifying agents, suspending agents, diluents, sweeteners, melting agents, coloring agents and flavoring agents.

[0311] The pharmaceutically-acceptable carrier suitable for the preparation of unit dosage forms for peroral administration is well-known in the art. Tablets typicallycomprise 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 croscarmelose; lubricants such as magnesium stearate, stearic acid and talc. Glidants such as silicon dioxide can be used to improve flow characteristics of the powder mixture. Coloring agents, such as the 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 comprise one or more solid diluents disclosed above. The selection of carrier components depends on secondary considerations like taste, cost, and shelf stability, which are not critical, and can be readily made by a person skilled in the art.

[0312] Peroral compositions also include liquid solutions, emulsions, suspensions, and the like. The pharmaceutically-acceptable carriers suitable for preparation of 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 a suspension, typical suspending agents include methyl cellulose, sodium carboxymethyl cellulose, AVICEL RC-591, tragacanth and sodium alginate; typical wetting agents include lecithin and polysorbate 80; and typical preservatives include methyl paraben and sodium benzoate. Peroral liquid compositions may also contain one or more components such as sweeteners, flavoring agents and colorants disclosed above.

[0313] Such compositions may also be coated by conventional methods, typically with pH or time-dependent coatings, such that the subject compound is released in the gastrointestinal tract in the vicinity of the desired topical application, or at various times to extend the desired action. Such dosage forms typically include, but are not limited to, one or more of cellulose acetate phthalate, polyvinylacetate phthalate, hydroxypropyl methyl cellulose phthalate, ethyl cellulose, Eudragit coatings, waxes and shellac.

[0314] Compositions described herein may optionally include other drug actives.

[0315] Other compositions useful for attaining systemic delivery of the subject compounds include sublingual, buccal and nasal dosage forms. Such compositions typically comprise one or more of soluble filler substances such as sucrose, sorbitol and mannitol; and binders such as acacia, microcrystalline cellulose, carboxymethyl cellulose andhydroxypropyl methyl cellulose. Glidants, lubricants, sweeteners, colorants, antioxidants and flavoring agents disclosed above may also be included.

[0316] A liquid composition, which is formulated for topical ophthalmic use, is formulated such that it can be administered topically to the eye. The comfort should be maximized as much as possible, although sometimes formulation considerations (e.g. drug stability) may necessitate less than optimal comfort. In the case that comfort cannot be maximized, the liquid should be formulated such that the liquid is tolerable to the patient for topical ophthalmic use. Additionally, an ophthalmically acceptable liquid should either be packaged for single use, or contain a preservative to prevent contamination over multiple uses.

[0317] For ophthalmic application, solutions or medicaments are often prepared using a physiological saline solution as a major vehicle. Ophthalmic solutions should preferably be maintained at a comfortable pH with an appropriate buffer system. The formulations may also contain conventional, pharmaceutically acceptable preservatives, stabilizers and surfactants.

[0318] Preservatives that may 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. Likewise, various useful vehicles may be used in the ophthalmic preparations disclosed herein. These vehicles include, but are not limited to, polyvinyl alcohol, povidone, hydroxypropyl methyl cellulose, poloxamers, carboxymethyl cellulose, hydroxyethyl cellulose and purified water.

[0319] Tonicity adjustors may be added as needed or convenient. They include, but are not limited to, salts, particularly sodium chloride, potassium chloride, mannitol and glycerin, or any other suitable ophthalmically acceptable tonicity adjustor.

[0320] Various buffers and means for adjusting pH may be used so long as the resulting preparation is ophthalmically acceptable. For many compositions, the pH will be between 4 and 9. Accordingly, buffers include acetate buffers, citrate buffers, phosphate buffers and borate buffers. Acids or bases may be used to adjust the pH of these formulations as needed.

[0321] In a similar vein, an ophthalmically acceptable antioxidant includes, but is not limited to, sodium metabisulfite, sodium thiosulfate, acetylcysteine, butylated hydroxyanisole and butylated hydroxy toluene.

[0322] Other excipient components, which may be included in the ophthalmic preparations, are chelating agents. A useful chelating agent is edetate disodium, although other chelating agents may also be used in place or in conjunction with it.

[0323] For topical use, creams, ointments, gels, solutions or suspensions, etc., containing the compound disclosed herein are employed. Topical formulations may generally be comprised of a pharmaceutical carrier, co-solvent, emulsifier, penetration enhancer, preservative system, and emollient.

[0324] For intravenous administration, the compounds and compositions described herein may be dissolved or dispersed in a pharmaceutically acceptable diluent, such as a saline or dextrose solution. Suitable excipients may be included to achieve the desired pH, including but not limited to NaOH, sodium carbonate, sodium acetate, HC1, 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 may include sodium bisulfite, acetone sodium bisulfite, sodium formaldehyde, sulfoxylate, thiourea, and EDTA. Other non-limiting examples of suitable excipients found in the final intravenous composition may include sodium or potassium phosphates, citric acid, tartaric acid, gelatin, and carbohydrates such as dextrose, mannitol, and dextran. Further acceptable excipients are described in Powell, et ah, 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. Antimicrobial 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.

[0325] The compositions for intravenous administration may be provided to caregivers in the form of one more solids that are reconstituted with a suitable diluent such as sterile water, saline or dextrose in water shortly prior to administration. In other embodiments, the compositions are provided in solution ready to administer parenterally. Instill other embodiments, the compositions are provided in a solution that is further diluted prior to administration. In embodiments that include administering a combination of a compound described herein and another agent, the combination may be provided to caregivers as a mixture, or the caregivers may mix the two agents prior to administration, or the two agents may be administered separately.

[0326] The actual dose of the active compounds described herein depends on the specific compound, and on the condition to be treated; the selection of the appropriate dose is well within the knowledge of the skilled artisan.Second (or Other Additional) Agents

[0327] In some embodiments, the second therapeutic agent is anti-inflammatory agent. In some embodiments, the second therapeutic agent is a non-steroidal anti inflammatory agent. In some embodiments, the second therapeutic agent is anti-cancer agent.

[0328] In some embodiments, the methods comprise administering an effective amount of a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, in combination with an amount of a chemotherapeutic, wherein the amounts of the combination and the chemotherapeutic are together effective in inhibiting abnormal cell growth. Many chemotherapeutic s are presently known in the art and can be used in combination. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti- androgens. Also described are methods for inhibiting abnormal cell growth in a mammal comprising administering to the mammal an amount of a MEK protein kinase inhibitor and / or Raf protein kinase inhibitor in combination with radiation therapy, wherein the amounts of the MEK protein kinase inhibitor and / or Raf protein kinase inhibitor in combination with the radiation therapy effective in inhibiting abnormal cell growth or treating the hyperproliferative disorder in the mammal. Techniques for administering radiation therapy are known in the art, and these techniques can be used in the combination therapy described herein.

[0329] In some embodiments, the disclosure also relates to a method of inhibiting abnormal cell growth in a mammal which may comprises a compound of Formula (I), (la),(Ib), (Ic), (II), (Ila), (lib), (lie), or a pharmaceutically acceptable salt thereof, and an amount of one or more substances selected from anti-angiogenesis agents, signal transduction inhibitors, and antiproliferative agents. Anti-angiogenesis agents, such as MMP-2 (matrix- metalloprotienase 2) inhibitors, MMP-9 (matrix-metalloprotienase 9) inhibitors, and COX- 11 (cyclooxygenase 11) inhibitors, can be used in conjunction with a compound of the present invention and pharmaceutical compositions described herein. Examples of useful COX-II inhibitors include CELEBREXTM (alecoxib), valdecoxib, and rofecoxib. Examples of useful matrix metalloproteinase inhibitors are described in WO 96 / 33172 (published October 24,1996), WO 96 / 27583 (published March 7,1996), European Patent Application No. 97304971.1 (filed luly 8,1997), European Patent Application No. 99308617.2 (filed October 29, 1999), WO 98 / 07697 (published February 26,1998), WO 98 / 03516 (published lanuary29.1998), WO 98 / 34918 (published August 13,1998), WO 98 / 34915 (published August13.1998), WO 98 / 33768 (published August 6,1998), WO 98 / 30566 (published July 16, 1998), European Patent Publication 606,046 (published July 13,1994), European Patent Publication 931, 788 (published July 28,1999), WO 90 / 05719 (published May 31,1990), WO 99 / 52910 (published October 21,1999), WO 99 / 52889 (published October 21, 1999), WO 99 / 29667 (published June 17,1999), PCT International Application No. PCT / IB98 / 01113 (filed July 21,19911), European Patent Application No. 99302232.1 (filed March 25,1999), Great Britain Patent Application No. 9912961.1 (filed June 3, 1999), United States Provisional Application No. 60 / 148,464 (filed August 12,1999), United States Patent 5,863, 949 (issued January 26,1999), United States Patent 5,861, 510 (issued January 19,1999), and European Patent Publication 780,386 (published June 25, 1997). Some MMP-2 and MMP-9 inhibitors have little or no activity inhibiting MMP-1, while some selectively inhibit MMP-2 and / or AMP-9 relative to the other matrix-motalloproteinases (L e., MAP-1, NEMP-3, MMP-4, M7vlP-5, MMP-6, MMP- 7, MMP-8, MMP-10, MMP-11, and MMP-13). Some specific examples of MlvlP inhibitors useful in the present invention are AG-3340, RU 32- 3555, and RS 13-0830.

[0330] In some embodiments, a compound of Formula (I), (la), (lb), (Ic), (Id), (II), (Ila), (lib), (lie), (lid), or a pharmaceutically acceptable salt thereof, is administered with at least one additional therapeutic agent. In some embodiments, the therapeutic agent is a taxol, bortezornib or both. In further or additional embodiments, the therapeutic agent isselected from the group consisting of cytotoxic agents, anti-angiogenesis agents and anti neoplastic agents. In further or additional embodiments, the anti-neoplastic agents selected from the group of consisting of alkylating agents, anti-metabolites, epiclophyllotoxims; antineoplastic enzymes, topoisomerase inhibitors, procarbazine, mitoxantrone, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal / anti- hormonal therapeutic agents, and haematopoietic growth factors.

[0331] Many chemotherapeutic s are presently known in the art and can be used in combination with the compounds and compositions of the disclosure. In some embodiments, the chemotherapeutic is selected from the group consisting of mitotic inhibitors, alkylating agents, anti-metabolites, intercalating antibiotics, growth factor inhibitors, cell cycle inhibitors, enzymes, topoisomerase inhibitors, biological response modifiers, anti-hormones, angiogenesis inhibitors, and anti-androgens.

[0332] 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 of cytotoxic agents, anti-angiogenesis agents and anti-neopiastic agents. In further or additional embodiments, the anti-neoplastic agent is selected from the group of consisting of alkylating agents, anti-metabolites, epidophyllotoxins; antineoplastic enzymes, topoisomerase inhibitors, procarbazines, mitoxantrones, platinum coordination complexes, biological response modifiers and growth inhibitors, hormonal / anti-hormonal therapeutic agents, and haematopoietic growth factors.

[0333] In some embodiments, the second therapeutic is an agent for co-regulating MEKor RAF pathways. In some embodiments, the second therapeutic agent is a MEKor RAF inhibitor. In some embodiments, the RAF inhibitor is vemurafenib, dabrafenib, XL-281, LGX-818, CEP-32496. ARQ-736, MEK-162, Seliimednib, refametinib, E-6201, pimasertib, WX-554, and GDC -09? 5.

[0334] 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 acid; piroxicam; meloxicam; tenoxicam; droxicam; lomoxicam; isoxicam; mefenamic acid; meclofenamic acid; flufenamic acid; tolfenamic acid; sulfonanilides; clonixin; licofelone; dexamethasone; and prednisone.

[0335] 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; mytomycin; diaziquone (AZQ); cisplatin; carboplatin; and oxaliplatin.

[0336] 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.

[0337] In some embodiments, the second therapeutic agent is selected from actinomycin; bleomycin; plicamycin; mitomycin; daunombicin; epimbicin; idarubicin; pirarubicin; aclarubicin; mitoxantrone; cyclophosphamide; methotrexate; 5-fluorouracil; prednisolone; folinic acid; methotrexate; melphalan; capecitabine; mechlorethamine; uramustine; melphalan; chlorambucil; ifosfamide; bendamustine; 6-mercaptopurine; and procarbazine.

[0338] In some embodiments, the second therapeutic agent is selected from cladribine; pemetrexed; fludarabine; gemcitabine; hydroxyurea; nelarabine; cladribine; clofarabine; ytarabine; decitabine; cytarabine; cytarabine liposomal; pralatrexate; floxuridine; fludarabine; colchicine; thioguanine; cabazitaxel; larotaxel; ortataxel; tesetaxel; aminopterin; pemetrexed; pralatrexate; raltitrexed; pemetrexed; carmofur; and floxuridine.

[0339] In some embodiments, the second therapeutic agent is selected from azacitidine; decitabine; hydroxycarbamide; topotecan; irinotecan; belotecan; teniposide; aclarubicin; epimbicin; idarubicin; amrubicin; pirarubicin; valrubicin; zombicin; mitoxantrone; pixantrone; mechlorethamine; chlorambucil; prednimu stine; uramustine; estramustine; carmustine; lomustine; fotemustine; nimustine; ranimustine; carboquone; thioTEPA; triaziquone; and triethylenemelamine.

[0340] In some embodiments, the second therapeutic agent is selected from 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; belinostat; panobinostat; romidepsin; vorinosta; idelalisib; atrasentan; bexarotene; testolactone; amsacrine; trabectedin; alitretinoin; tretinoin; demecolcine; elsamitrucin; etoglucid; lonidamine; lucanthone; mitoguazone; mitotane; oblimersen; omacetaxine mepesuccinate; and eribulin.

[0341] In some embodiments, the second therapeutic agent is selected from azathioprine; Mycophenolic acid; leflunomide; teriflunomide; tacrolimus; cyclosporin; pimecrolimus; abetimus; gusperimus; lenalidomide; pomalidomide; thalidomide; anakinra; sirolimus; everolimus; ridaforolimus; temsirolimus; umirolimus; zotarolimus; eculizumab; adalimumab; afelimomab; certolizumab pegol; golimumab; infliximab; nerelimomab; mepolizumab; omalizumab; faralimomab; elsilimomab; lebrikizumab; ustekinumab; etanercept; otelixizumab; teplizumab; visilizumab; clenoliximab; keliximab; zanolimumab; efalizumab; erlizumab; obinutuzumab; rituximab; and ocrelizumab.

[0342] In some embodiments, the second therapeutic agent is selected from pascolizumab; gomiliximab; lumiliximab; teneliximab; toralizumab; aselizumab; galiximab; gavilimomab; ruplizumab; belimumab; blisibimod; ipilimumab; tremelimumab; bertilimumab; lerdelimumab; metelimumab; natalizumab; tocilizumab; odulimomab; basiliximab; daclizumab; inolimomab; zolimoma; atorolimumab; cedelizumab; fontolizumab; maslimomab; morolimumab; pexelizumab; reslizumab; rovelizumab; siplizumab; talizumab; telimomab; vapaliximab; vepalimomab; abatacept; belatacept; pegsunercept; aflibercept; alefacept; and rilonacept.EXAMPLESGeneral Procedures

[0343] Additional embodiments are disclosed in further detail in the following examples, which are not in any way intended to limit the scope of the claims.

[0344] Materials used in preparing compounds of Formula (I), (la), (lb), or (Ic), described herein may be made by known methods or are commercially available. In these reactions, it is also possible to make use of variants which are themselves known to those of ordinary skill in this art, but are not mentioned in greater detail. The skilled artisan given the literature and this disclosure is well equipped to prepare any of the compounds.

[0345] It is recognized that the skilled artisan in the art of organic chemistry can readily carry out manipulations without further direction, that is, it is well within the scope and practice of the skilled artisan to carry out these manipulations. These include reduction of carbonyl compounds to their corresponding alcohols, oxidations, acylations, aromatic substitutions, both electrophilic and nucleophilic, etherifications, esterification and saponification and the like. These manipulations are discussed in standard texts such as March’s Advanced Organic Chemistry (Wiley), Carey and Sundberg, Advanced Organic Chemistry (incorporated herein by reference in their entirety) and the like.

[0346] The skilled artisan will readily appreciate that certain reactions are best carried out when other functionality is masked or protected in the molecule, thus avoiding any undesirable side reactions and / or increasing the yield of the reaction. Often the skilled artisan utilizes protecting groups to accomplish such increased yields or to avoid the undesired reactions. These reactions are found in the literature and are also well within the scope of the skilled artisan. Examples of many 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), incorporated herein by reference in its entirety.

[0347] The following example schemes are provided for the guidance of the reader, and represent preferred methods for making the compounds exemplified herein. These methods are not limiting, and it will be apparent that other routes may be employed to prepare these compounds. Such methods specifically include solid phase based chemistries, including combinatorial chemistry. The skilled artisan is thoroughly equipped to prepare these compounds by those methods given the literature and this disclosure. The compound numberings used in the synthetic schemes depicted below are meant for those specific schemes only, and should not be construed as or confused with same numberings in other sections of the application.

[0348] Trademarks used herein are examples only and reflect illustrative materials used at the time of the invention. The skilled artisan will recognize that variations in lot, manufacturing processes, and the like, are expected. Hence the examples, and the trademarks used in them are non-limiting, and they are not intended to be limiting, but are merely an illustration of how a skilled artisan may choose to perform one or more of the embodiments of the invention.

[0349] The following example schemes are provided for the guidance of the reader, and collectively represent an example method for making the compounds provided herein. Furthermore, other methods for preparing compounds described herein will be readily apparent to the person of ordinary skill in the art in light of the following reaction schemes and examples. Unless otherwise indicated, all variables are as defined above.EXAMPLE 1General Synthesis A ethyl 3-oxobutanoate,1 , 1 '-Azobis(cyclohexanecarbonitrile)JC NRS Br-j .Nal, LiOteuNO 2 NO 2F MeCN, 80 °C, 16 h F THF, rt, 16 h1 2HO OHUΎNSHMQ Q Q perchloric acid dimethylcarbamyl rt, 18 hN0DMF, 0 °C - rt, 2 - 60 h2F5x = H, Me, Cl, F

[0350] Compound 2: To a solution of 2-Fluoro-3-nitrotoluene 1 (153.9 g, 268 mmol, 1.0 eq.) and NBS (57.8 g, 321 mmol, 1.20 eq.) in MeCN (1340 mL) under nitrogen atmosphere was added l,l-azobis(cyclohexanecarbonitrile) (8.0 g, 32.1 mmol, 0.12 eq.). The formed reaction mixture was stirred at 80 °C for 16 h. The reaction mixture was allowed to cool to rt and concentrated under reduced pressure to give an orange suspension. EtiO was added and the formed suspension was stirred for 18 hours at rt. The suspension was filtered and the residue was washed with some extra Et20. Combined organic layers were washed with aqueous saturated NaHCCE and brine, dried over NaiSCU, filtered and concentrated under reduced pressure to obtain a dark red oil that crystalized upon standing. The product was recry stallized using heptane to obtain l-(bromomethyl)-2-fluoro-3-nitrobenzene 2 (43.8 g, 186.7 mmol, yield: 70%, purity: 99%) as a white solid.

[0332] LCMS (Method K): tR = 1.95 min; m / z calculated for [M+H]+= 234.0, found = no mass; 1H NMR (400 MHz,DMSO) d 8.14 (td, J = 7.8, 7.3, 1.7 Hz, 1H), 8.01 - 7.93 (m, 1H), 7.50 - 7.40 (m, 1H), 4.81 (d, J = 1.4 Hz, 2H).

[0351] Compound 3: To a solution of ethyl 2-(2-fluoro-3-nitrobenzyl)-3- oxobutanoate 3 (1.0 eq.) in perchloric acid (10-20 eq.) the diol (1.20 eq.) was added. The formed reaction mixture was stirred for 1 - 18 h at rt. Water was added to the reaction mixture and the product was filtered, washed with water and Et20. The residue was dried to obtain the coumarin as a solid.

[0352] Compound 4: To a solution of the coumarin (1.0 eq.) in N,N-Dimethylformamide (dry) (0.13 - 0.2 M) at 0 °C under N2 atmosphere, sodium hydride 60% dispersion on mineral oil (1.60 eq.) was added. The formed reaction mixture was left to stir for 10 min before dimethyl carbamoyl chloride (1.50 - 1.60 eq.) was added. The formed reaction mixture was allowed to warm to room temperature and left to stir for 2 - 60 h. Water was added to quench the reaction mixture. The formed suspension was filtered, washed with water and Et20. The residue was dried to obtain the dimethylcarbamate as a solid.

[0353] Compound 5: The dimethylcarbamate (1.0 eq.) was suspended inMethanol (0.2 M), in some cases some CH2CI2 was added to get a solution. Argon was bubbled through the solution for lOmin. Then a 50% RaneyO-Nickel slurry in water (1.0 eq.) or 10% palladium on activated carbon (0.05 eq.) was added. The formed reaction mixture was purged with hydrogen and stirred for 2 - 18 h at rt. The reaction mixture was filtered over kieselguhr and washed with MeCN, CH2CI2 and MeOH. The filtrate was concentrated under reduced pressure to obtain the primary amine as a solid.

[0354] Compound 6: To an ice bath cooled (0 °C) suspension of the primary amine (1.0 eq.) and pyridine (3.00 eq.) in N,N-Dimethylformamide (0.2 M), a transparent solution of methylsulfamoyl chloride (2.50 eq.) in Acetonitrile (anhydrous) (0.2 M) was added dropwise. After complete addition the formed reaction mixture was allowed to warm up to room temperature and stirred for 1 - 16 h. Water was added to the reaction mixture and the formed suspension was stirred for 1 hour. The suspension was filtered, washed with water and Et20. The residue was dried to obtain the sulfamoyl as a solid.

[0355] Compound 7: A solution of the sulfamoyl (1.0 eq.) in Tetrahydrofuran (dry) (0.06 - 0.10 M) under nitrogen atmosphere was cooled to -78 °C and LiHMDS 1M in THF (3.00 eq.) was slowly added. After full addition the formed reaction mixture was insome cases diluted with some extra tetrahydrofuran (dry) and stirred for 30 min, allowed to warm to 0 °C. This was added to a cooled (-78 °C) solution of NCS or NBS (1.20 eq.) in Tetrahydrofuran (dry) (0.04 M), drop-wise via a canula over 15 minutes. The formed reaction mixture was stirred for 1 hour at -78 °C. At -78 °C the reaction mixture was quenched with HC1 1M and allowed to warm to rt. Some extra water wras added and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCE, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method flash ’ (heptane / EtOAc = 1:0 ® 0:1) to obtain the bromine or chlorine as a solid.EXAMPLE 2 General Synthesis BHO- -^onU

[0356] Compound B.l: To a solution of ethyl 2 - (2 - P uo ro -3-nitrohenzy l)-3- oxobutanoate 3 (6.54 g, 23.09 mmol, 1.0 eq.) in perchloric acid (29.8 mL, 346 mmol, 15.0 eq.), resorcinol (3.05 g, 27.7 mmol, 1.20 eq.) was added. The formed reaction mixture was stirred for 1 h at rt. Water was added to the reaction mixture and the product was filtered,washed with water and EtiO. The residue was dried overnight at 40 °C under reduced pressure to obtain 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl-2H-chromen-2-one (15.224 g, 45.8 mmol, yield: 112%) as an off-white solid.

[0357] LCMS (Method I): tR= 1.92 min; m / z calculated for [M+H]+= 330.1, found = 330.0; 1H NMR (400 MHz, DMSO) d 10.51 (s, 1H), 8.03 - 7.92 (m, 1H), 7.69 (d, J = 8.8 Hz, 1H), 7.60 - 7.51 (m, 1H), 7.32 (t, J = 8.0 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.72 (d, J = 2.4 Hz, 1H), 4.02 (s, 2H), 2.43 (s, 3H).

[0358] Compound B.2: To a suspension of 3-(2-fluoro-3-nitrobenzyl)-7- hydroxy-4-methyl-2H-chromen-2-one (3 g, 7.74 mmol, 1.0 eq.) in CH2CI2 (0.6 M) was added DIPEA (5 ml, 28.6 mmol, 3.70 eq.). MEM-C1 (1.8 ml, 15.90 mmol, 2.05 eq.) was added and the formed reaction mixture was stirred for 18 hours at rt. The reaction mixture was purified by column chromatography with method ‘flash’ (heptane / EtOAc 3:1 — > 1:3) to obtain 3-(2- fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-4-methyl-2H-chromen-2-one (2.71 g, 6.49 mmol, yield: 84%) as a colorless oil.

[0359] LCMS (Method I): tR= 2.08 min; m / z calculated for [M+H]+= 418.0, found = 418.0

[0360] Compound B.3: A solution of 3-(2-fluoro-3-nitrobenzyl)-7-((2- methoxyethoxy)methoxy)-4-methyl-2H-chromen-2-one (2.71 g, 6.49 mmol, 1.0 eq.) in Tetrahydrofuran (dry) (0.04 M) was cooled to -78 °C and LiHMDS (1 M in THF, 7.79 ml, 7.79 mmol, E20 eq.) was slowly added. The formed reaction mixture was stirred for 30 min at -78 °C prior to slow addition of NBS (1.156 g, 6.49 mmol, 1.0 eq.) dissolved in Tetrahydrofuran (dry) (75 ml). The formed yellow solution was stirred for 30 minutes at -78 °C. The reaction mixture was quenched with sat. aq. NH4CI at -78 °C and allowed to warm to rt. The product was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2$04, filtered and concentrated under reduced pressure to obtain a yellow oil. The impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc 1:0 — > 1:3) to obtain 4-(bromomethyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2- methoxyethoxy)methoxy)-2H-chromen-2-one (2.1 g, 4.23 mmol, yield: 65%) as an off-white fluffy solid.

[0361] LCMS (Method K): tR= 1.94 min; m / z calculated for [M+H]+= 496.0 / 498.0, found = 496.0 / 498.0

[0362] Compound B.4: 4-(bromomethyl)-3-(2-fluoro-3-nitrobenzyl)-7-((2- methoxyethoxy)methoxy)-2H-chromen-2-one (1.5 g, 3.02 mmol, 1.0 eq.) was suspended in dimethylamine (2.0 M in MeOH, 15 ml, 30.0 mmol, 10.0 eq.) at rt. The formed reaction mixture was stirred for 30 minutes at rt. The reaction mixture was concentrated under reduced pressure. The impure product was suspended in EtiO. The solids were filtered off and the residue was washed with Et20 and dried to obtain 4-((dimethylamino)methyl)-3-(2- fluoro-3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.27 g, 2.59 mmol, yield: 86%) an off-white solid.

[0363] LCMS (Method I): tR = 2.11 min; m / z calculated for [M+H]+= 461.1, found = 461.1

[0364] Compound B.5: To a mixture of 4-((dimethylamino)methyl)-3-(2-fluoro- 3-nitrobenzyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.27 g, 2.59 mmol, 1.0 eq.) in Methanol (0.26 M) was added Raney®-Nickel (50% slurry in water, 0.5 ml, 2.59 mmol, 1.0 eq.) and the formed reaction mixture was placed under a hydrogen atmosphere for 4h. The reaction mixture was diluted with MeOH and the formed solution was filtered. The filtrate was concentrated under reduced pressure and twice stripped with toluene to obtain 3- (3-amino-2-fluorobenzyl)-4-((dimethylamino)methyl)-7-((2-methoxyethoxy)methoxy)-2H- chromen-2-one (1.116 g, 2.59 mmol, yield: 100%) as a sticky solid.

[0365] LCMS (Method U): tR= 2.02 min; m / z calculated for [M+H]+= 430.8, found = 430.8

[0366] Compound B.6: To a solution of 3-(3-amino-2-fluorobenzyl)-4- ((dimethylamino)methyl)-7-((2-methoxyethoxy)methoxy)-2H-chromen-2-one (1.1 g, 2.56 mmol, 1.0 eq.) in N,N-Dimethylformamide (dry) (1.2 M) was added pyridine (0.413 ml, 5.11 mmol, 2.0 eq.) and a solution of methylsulfamoyl chloride (0.268 ml, 3.07 mmol, 1.2 eq.) in Acetonitrile (anhydrous) (1.2 M). The formed reaction mixture was stirred at rt for lh. 50% aq. NaHCCb was added to the reaction mixture and the product was extracted with EtOAc. The combined organic layers were washed with brine, dried over NaiSCE, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc 3:2 — > 1:9) to obtain sulfamide (1.35 g, 2.58 mmol, yield: 101%) as a yellow oil.

[0367] LCMS (Method U): tR= 1.94 min; m / z calculated for [M+H]+= 524.2, found = 524.1

[0368] Compound B.7: To a solution of sulfamide (910 mg, 1.738 mmol, 1.0 eq.) in Methanol / THF (1:1) (0.17 mL) was added sulfuric acid (1.5 ml, 28.1 mmol, 16 eq.). The formed reaction mixture was stirred at rt for lh. The reaction mixture was quenched in sat. aq. NaHCCL and extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method flash ’ (CH2CI2 / MeOH 1:0 ® 95:5). Desired fractions were combined and concentrated under reduced pressure. The residue was dissolved in MeCN / water and lyophilized to obtain phenol (510 mg, 1.171 mmol, yield: 67%) as a yellow solid.

[0369] LCMS (Method J): tR= 2.68 min; m / z calculated for [M+H]+= 436.1, found = 436.0EXAMPLE 3General Synthesis C

[0370] Compound C.2: A solution of Cl (3.0 g, 7.49 mmol) in Tetrahydrofuran (dry) (100 mL) under nitrogen atmosphere was cooled to -78 °C and LiHMDS 1M in THF (9.7 mL, 9.7 mmol, 1.3 eq.) was slowly added. After full addition the formed reaction mixture was stirred for 30 min at -78 °C and then for 30 min at 0 °C. Then, paraformaldehyde (3.4 g, 112 mmol, 15 eq.). The reaction mixture was stirred for 1 hour at 0 °C. Then, the reaction mixture was quenched with HC1 1M and allowed to warm to rt and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCL, filtered and concentrated under reduced pressure. The impure product was purified by flash column chromatography (heptane / EtOAc = 1:0 — > 3:7) to obtain C.2 (1.67 g, 3.41 mmol, purity: 88%, yield: 46%) as an off-white solid.

[0371] Compound C.3: Tert-Butyldimethylsilyl chloride (338 mg, 2.24 mmol) and imidazole (162 mg, 2.37 mmol) were dissolved in N,N-Dimethylformamide (20 mL) and 3-(2-fluoro-3-nitrobenzyl)-4-(2-hydroxyethyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (645 mg, 1.32 mmol) was added and mixture was stirred overnight. Then, the reactionmixture was quenched water and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCC, filtered and concentrated under reduced pressure. The impure product was purified by flash column chromatography (heptane / EtOAc = 1:0 — » 1:1) to obtain C.3 (502 mg, 0.92 mmol, yield: 70%) as a colorless oil.

[0372] Compound C.4: The C.3 (2.3 g, 4.22 mmol) was dissolved in 150 mL of MeOH and argon was bubbled through the solution for 10 min. Then, 50% Raney-Ni slurry in water (2 mL, 8.44 mmol) was added. The mixture was purged with hydrogen and stirred for 1.5 h at rt. Then the reaction was quenched by purging with argon and the mixture was filtered over celite and concentrated and stripped with EtOAc and DCM to afford C.4 (2.41 g, 4.21 mmol, purity: 90%, yield: 100%) as a brown oil.

[0373] Compound C.5: To an ice bath cooled (0 °C) suspension of the primary amine (1.0 eq.) and pyridine (3.00 eq.) in N,N-Dimethylformamide (0.2 M), a transparent solution of methylsulfamoyl chloride (2.50 eq.) in Acetonitrile (anhydrous) (0.2 M) was added dropwise. After complete addition the formed reaction mixture was allowed to warm up to room temperature and stirred for 1 - 16 h. Water was added to the reaction mixture and the formed suspension was stirred for 1 hour. The suspension was filtered, washed with water and Et20. The residue was dried to obtain the sulfamoyl as a solid. 727 mg, 5.61 mmol of C.4 afforded C.5 (1.97 g, 3.24 mmol, purity: 95%, yield: 87%) as an orange foam.

[0374] Compound 100: To a stirred solution of C,5 (1.97 g, 2.92 mmol) in 5 mL of 1,4-dioxane, 2 mL of 4N HC1 in 1,4-dioxane was added. After 30 min, the solvents were evaporated and stripped with DCM and purified by flash column chromatography (heptane / EtOAc = 1:0 0:1) to obtain 100 (1.45 g, 2.79 mmol, yield: 96%) as an off-white foam.

[0375] Analysis: LCMS (Method P): tR= 1.19 min; m / z calculated for [M+H]+= 494.1, found = 494.1;!H NMR 1H NMR (400 MHz, CDC13) d 7.65 (d, J = 8.7 Hz, 1H), 7.34 (dt, 1H), 7.14 - 7.07 (m, 2H), 7.02 - 6.90 (m, 2H), 6.81 - 6.73 (m, 1H), 4.79 (q, J = 5.3 Hz, 1H), 4.09 (s, 2H), 3.67 (t, J = 7.3 Hz, 2H), 3.17 - 3.08 (m, 5H), 3.03 (s, 3H), 2.75 (d, J = 5.3 Hz, 3H), 2.27 (s, 1H).

[0376] Compound 101: To an ice-cooled stirred solution of 100 (100 mg, 203 mmol) and carbon tetrabromide (161 mg, 0.487 mmol, 2.4 eq) in 4 mL of DCM was added triphenylphosphine (117 mg, 0.446 mmol 2.2 eq) and the reaction was allowed to warm to rtand stirred for 5h. The solvent was evaporated and the residue redissolved in 1 mL of DCM and purified with method ‘flash’ column chromatography (heptane / EtOAc = 1:0 — » 2:8) to obtain 101 (146 mg, 0.186 mmol, purity: 71% yield: 92%) as a white foam.EXAMPLE 4 General Synthesis D

[0377] Compound D.2: 2-chloro-3-fluoroisonicotinaldehyde hydrate (56.13 g, 316 mmol, 1.0 eq.) was dissolved in Methanol (630 ml) after which the solution was cooled to 0 °C. sodium borohydride (11.96 g, 316 mmol, 1.0 eq.) was added in a portion-wise fashion, the formed reaction mixture was stirred for 1 hour at rt. The reaction mixture was quenched in 1000 mL of an ice water slurry and slowly acidified. The reaction mixture was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04and concentrated under reduced pressure to obtain (2-chloro-3-fluoropyridin-4-yl)methanol (66.25 g, 410 mmol, 98 % yield) as an off white solid.

[0378] LCMS (Method K): tR = 1.20 min; mJz calculated for [M+H]+= 162.0, found = 162.0.

[0379] Compound D.3: (2-chloro-3-fluoropyridin-4-yl)methanol (30 g, 186 mmol, 1.0 eq.) was dissolved in anhydrous Tetrahydrofuran (460 ml) and placed under a nitrogen atmosphere and cooled to 0 °C. Lithium tert-butoxide (2.2 M, 89 ml, 195 mmol, 1.05 eq.) in THF was added dropwise, after which mesyl chloride (17.25 ml, 223 mmol, 1.20 eq.) was added dropwise. The formed reaction mixture was stirred for 1 hour at rt. The reaction mixture was added to a cooled (0 °C) solution of sodium iodide (27.8 g, 186 mmol, 1.0 eq.), Lithium tert-butoxide (93 ml, 204 mmol, 1.10 eq.) and Ethyl acetoacetate (47.2 ml, 371 mmol, 2.00 eq.) in 300 mL of anhydrous THF. The formed reaction mixture was stirred for 30 minutes at 0 °C and then for 3 hours at 50 °C. After cooling to rt, the reaction mixture was diluted with EtOAc and washed with 0.2 M LiCl and once using brine. The organic phase was dried over NaiSCL and concentrated under reduced pressure to obtain ethyl 2-((2- c h 1 o ro - 3 - P u o ro p y r i d i n - 4 - y 1 ) m e t h y 1 ) - 3 - o x o b u t a n o a t e (54.5 g, 199 mmol, 107% yield) as a yellow oil.

[0380] LCMS (Method K): tR = 1.91 and 2.12 min; m!z calculated for [M+H]+ = 274.1, found = 274.0.

[0381] Compound D.4: To a solution of ethyl 2-((2-chloro-3-fluoropyridin-4- yl)methyl)-3-oxobutanoate (51.2 g, 187 mmoll 1.0 eq.) in sulfuric acid (3-20 eq.) the diol 4 (2.00 eq.) was added. The formed reaction mixture was stirred for 2 - 18 h at rt. Water was added to the reaction mixture and the product was filtered, washed with water and Et20. The residue was recrystallized from EtOH:H20 8:2 to obtain the coumarin as a solid.

[0382] Compound D.5: To a solution of the coumarin (1.0 eq.) in N,N- Dimethylformamide (dry) (0.15 - 0.4 M) at 0 °C under N2 atmosphere, sodium hydride 60% dispersion on mineral oil (1.40 - 1.60 eq.) was added. The formed reaction mixture was left to stir for 10 - 20 min before dimethyl carbamoyl chloride (1.25 - 1.60 eq.) was added. The formed reaction mixture was allowed to warm to room temperature and left to stir for 1 - 24 h. Water was added to quench the reaction mixture. The formed suspension was stirred for 1hour, filtered, washed with water and heptane. The residue was dried to obtain the dimethylcarbamate as a solid.

[0383] Compound D.6: To a solution of the dimethylcarbamate (1.0 eq.) and tert- butyl carbamate (1.40 - 10.0 eq.) in 1,4-Dioxane (0.1 - 0.2 M) under nitrogen atmosphere were added Xantphos (0.10 - 0.20 eq.), ceasium carbonate (1.20 - 1.50 eq.) and PdOAc2 (0.10 eq.). after 5 additional minutes of nitrogen purging the formed reaction mixture was stirred for 18 hours at 90 °C. The reaction mixture was filtered over celite and washed with CH2CI2. The filtrated was concentrated under reduced pressure after which the residue was dissolved in CH2CI2 (0.3 - 0.5 M). TFA (0.30 - 10.00 eq.) were added and the formed reaction mixture was stirred for 1 hour at rt. The reaction mixture was concentrated under reduced pressure and twice co-evaporated with CH2CI2 to give an oil. The oil was purified by reversed phase chromatography method ‘ flash acid’ to obtain the amino pyridine as a solid.

[0384] Compound D.7: To an ice bath cooled (0 °C) suspension of the amino pyridine (1.0 eq.) and pyridine (3.00 eq.) in N,N-Dimethylformamide (0.2 - 0.30 M), a transparent solution of methylsulfamoyl chloride (2.50 eq.) in Acetonitrile (anhydrous) (0.2 M) was added dropwise. After complete addition the formed reaction mixture was allowed to warm-up to room temperature and stirred for 16 h. Water was added to the reaction mixture and the formed suspension was stirred for 1 hour. The suspension was filtered, washed with water and Et20. The residue was dried to obtain the sulfamoyl as a solid

[0385] Compound D.8: A solution of the sulfamoyl (1.0 eq.) in Tetrahydrofuran (dry) (0.06 M) under nitrogen atmosphere was cooled to -78 °C and LiHMDS 1M in THF (3.00 eq.) was slowly added. After full addition the formed reaction mixture was in some cases diluted with some extra tetrahydrofuran (dry) and stirred for 30 min, allowed to warm to 0 °C. This was added to a cooled (-78 °C) solution of NCS or NBS (1.20 eq.) in Tetrahydrofuran (dry) (0.04 M), drop-wise via a canula over 15 minutes. The formed reaction mixture was stirred for 1 hour at -78 °C. At -78 °C the reaction mixture was quenched with HC1 1M and allowed to warm to rt. Some extra water was added and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCE, filtered and concentrated under reduced pressure to obtain the bromine or chlorine as a solid.EXAMPLE 5General Synthesis EX = H, Me, Cl, F Y = Br, ClZ = different amines A = N, CHSulfonyl chloride, pyridineCH2CI2, rt, 2 -E.3X = H, Cl A = N, CHR = Et, propane, cyclopropane, isopropyl(methyl), cyclobutane, 3,3,3-trifluoropropane, 3,3,3,-trifluoroethaneR = Et, propane, cyclopropane, isopropyl(methyl), cyclobutane, 3,3,3-trifluoropropane, 3,3,3,-trifluoroethane

[0386] Compound E.2: The bromine or chlorine (1.0 eq.) was suspended in methanol (0.10 - 0.20 M). The amine (1 - 10 eq.) was added and the formed reaction mixture was stirred for 2 - 16 h at rt. The reaction mixture was filtered and purified by preparative HPLC (method: prep acid or prep base) to obtain the desired amine after freeze drying or Genevac™ as a solid.

[0387] Compound E.3: Di-methylamine E.2 (1.0 eq.) and pyridine (1.1 - 1.5 eq.) were dissolved in CH2CI2 (0.2 - 0.8 M). The sulfonyl chloride (1.2 - 1.7 eq.) was added and the formed reaction mixture was stirred at rt for 2 - 18 h. The reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography with method ‘flash’ (CPhCh / EtOAc = 1:0 —) 6:4) to obtain the sulfamoyl E.3 as a solid.

[0388] Compound E.4: A solution of the sulfamoyl E.3 (1.0 eq.) in Tetrahydrofuran (dry) (0.06 M) under nitrogen atmosphere was cooled to -78 °C and LiHMDS 1M in THF (1 - 3 eq.) was slowly added. After full addition the formed reaction mixture was in some cases diluted with some extra tetrahydrofuran (dry) and stirred for 30 min, allowed to warm to 0 °C. This was added to a cooled (-78 °C) solution of NCS or NBS (1.2 eq.) in Tetrahydrofuran (dry) (0.04 M), drop-wise via a canula over 15 minutes. The formed reaction mixture was stirred for 1 hour at -78 °C. At -78 °C the reaction mixture was quenched with H2SO4 1M and allowed to warm to rt. Some extra water was added and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCU, filtered and concentrated under reduced pressure to obtain the bromine or chlorine E.4 as a solid.

[0389] Compound E.5: The bromine or chlorine E.4 (1.0 eq.) was suspended in methanol (0.10 - 0.20 M). The amine (1 - 10 eq.) was added and the formed reaction mixture was stirred for 2 - 16 h at rt. The reaction mixture was filtered and purified by preparative HPLC (method: prep acid or prep base) to obtain the desired amine E.5 after freeze drying or Genevac™ as a solid.EXAMPLE 6General Synthesis F

[0390] The phenol F.l (1.0 eq.) and potassium carbonate (2.0 eq.) were dissolved in DMF (0.03 - 0.2 M). The acid chloride (1.0 eq.) was added and stirred for 1 - 18 hours at rt. The reaction mixtures were purified by preparative HPLC (method: “prep acid ” or “prep base ) to obtain the desired F.2 after freeze drying or Genevac™as a solid.EXAMPLE 7General Synthesis GG.1 G.2

[0391] Compound G.2 To a solutions of G.l (1.0 eq.) in DMF (0.1 - 0.2 M) were added the respective amines (1.5 eq.) and Et;¾N (2 - 5 eq.); each in one separate vial. The reaction mixtures were stirred for 2 - 18 h at rt. The reaction mixtures were then fdtered and purified by preparative HPLC (method: prep acid or prep base) to obtain the desired products G.2 as solids after evaporation under vacuum at 40 °C in a Genevac™.EXAMPLE 8Synthesis of Compound 102

[0392] Compound 102 was prepared in 5 steps:

[0393] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate 3 (48.9 g, 173 mmol) and resorcinol (1.04 eq.) following procedure General Synthesis A. After the filtration the residue was stirred in a aq. Sat. NaHCO, solution until bubbling had stopped. The suspension was again filtered washed with water, Et20 and dried to obtain the corresponding coumarin 5 (50.3 g, 153 mmol, yield: 98%) as a yellow solid.

[0394] Step 2: Following the procedure for the synthesis of Compound 4 to obtain the corresponding dimethylcarbamate 6 (70.7 g, 166 mmol, yield: 109%) as a yellow solid.

[0395] Step 3: Following the procedure for the synthesis of Compound 5, with Pd / C and EtOH / THF 1:2 (0.05 M) as solvents to obtain the corresponding primary amine 7 (50.83 g, 130 mmol, yield: 77%) as a light pink solid.

[0396] Step 4: Following the procedure for the synthesis of Compound 6 starting with 35 g, 90 mmol of 7. Methylsulfamoyl chloride was added in 2.5 eq. to obtain the corresponding sulfamoyl 8 (37.8 g, 76 mmol, yield: 84%) as a beige solid.

[0397] Step 5: Following procedure General Procedure E, using NBS and with the exception that IN H2SO4 was used instead of IN HC1, to obtain the title compound (23.9 g, 40.5 mmol, yield: 56%) as a white solid.

[0398] Yield: The title compound was isolated as a white solid (40% over 5 steps)

[0399] Analysis: LCMS (Method U): tR= 1.97 min; m / z calculated for [M+H20]+= 559.0 / 561.0, found = 559.0 / 561.0.EXAMPFE 9Synthesis of Compound 7

[0400] Compound 7 was prepared in 4 steps:

[0401] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrohenzyl)-3-oxobutanoate (48.9 g, 173 mmol) and resorcinol (1.04 eq.) following the general synthesis of Compound 4. After the filtration the residue was stirred in a aq. Sat. NaHCCF solution until bubbling had stopped. The suspension was again filtered washed with water, Et20 and dried to obtain the corresponding coumarin 5 (50.3 g, 153 mmol, yield: 98%) as a yellow solid.

[0402] Step 2: Following the general synthesis of Compound 5 to obtain the corresponding dimethylcarbamate (70.7 g, 166 mmol, yield: 109%) as a yellow solid.

[0403] Step 3: Following the general synthesis of Compound 6, with Pd / C and EtOH / THF 1:2 (0.05 M) as solvents to obtain the corresponding primary amine (50.83 g, 130 mmol, yield: 77%) as a light pink solid.

[0404] Step 4: Following the general synthesis of Compound 7 starting with 35 g, 90 mmol of 7. Methylsulfamoyl chloride was added in 2.5 eq. to obtain the title compound (37.8 g, 76 mmol, yield: 84%) as a beige solid.

[0405] Yield: The title compound was isolated as a beige solid (69% over 4 steps).

[0406] Analysis: LCMS (Method I): tR= 1.98 min; m / z calculated for [M+H]+= 464.1, found = 464.1; 1H NMR (400 MHz, CDC13) d 7.65 - 7.59 (m, 1H), 7.39 (td, J = 7.8, 1.7 Hz, 1H), 7.15 - 7.08 (m, 2H), 7.01 (t, J = 7.8 Hz, 1H), 6.95 (td, J = 7.9, 7.4, 1.8 Hz, 1H), 6.60 (d, J = 3.0 Hz, 1H), 4.44 (q, J = 5.4 Hz, 1H), 4.06 (s, 2H), 3.13 (s, 3H), 3.03 (s, 3H), 2.75 (d, J = 5.3 Hz, 3H), 2.44 (s, 3H).EXAMPLE 10 Synthesis of Compound 9

[0407] Compound 9 was prepared in 1 step:

[0408] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (22.22 g, 34.79 mmol) and dimethylamine 2M in MeOH, following the general synthesis of Compound E.2. After full conversion the reaction was concentrated under reduced pressure. 1M HC1 was added to the residue and the water layer was extracted with CH2CI2. The water layer was made basic with solid Na2C03. The basic water layer was extracted with CH2CI2. The organic layer from the basic extraction was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to obtain the title compound (13.23 g, 25.7 mmol, yield: 74%) as a light yellow solid.

[0409] Yield: Compound 9 was isolated as a light yellow solid (74% over 1 step)

[0410] Analysis: LCMS (Method T): tR= 1.53 min; m / z calculated for [M-H]+=507.2, found = 507.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.8 Hz, 1H), 7.28 (td, J = 8.0, 1.6 Hz, 1H), 7.25 - 7.18 (m, 2H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.90 - 6.77 (m, 1H), 4.04 (s, 2H), 3.64 (s, 2H), 3.06 (s, 3H), 2.93 (s, 3H), 2.52 (d, J = 4.9 Hz, 3H), 2.19 (s, 6H).EXAMPLE 11 Synthesis of Compound 10

[0411] Compound 10 was prepared in 2 steps:

[0412] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N- methyhulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.35 g, 0.59 mmol) and N-Boc piperazine, following the general synthesis of Compound E.2, with the addition that NEt3 (1.0 eq) was added. The product was purified by prep basic. Desired fractions were combined and concentrated under reduced pressure to obtain the amine (0.414 g, 0.486 mmol, yield: 82%, purity: 76%) as a colorless oil.

[0413] Step 2: The amine was dissolved in 1,4-dioxane (3 mL) and HC1 in dioxane (4M, 16.7 eq, 2.0 mL, 8.00 mmol) was added and stirred for 1 hour at rt. The reaction mixture was concentrated under reduced pressure and the twice co-evaporated with CH2CI2. The residue was dissolved in MeCN / water and lyophilized to obtain the title compound (304 mg, 0.49 mmol, yield: 102%) as a white solid.

[0414] Yield: Compound 10 was isolated as a white solid (84% over 2 steps).

[0415] Analysis: LCMS (Method S): tR= 1.00 min; m / z calculated for [M-H]+= 548.2, found = 548.2; 1H NMR (400 MHz, DMSO) d 9.37 (s, 1H), 8.88 (s, 2H), 8.09 (d, J = 8.8 Hz, 1H), 7.32 - 7.19 (m, 3H), 7.17 (dd, J = 8.9, 2.4 Hz, 1H), 7.00 (t, J = 7.8 Hz, 1H), 6.86 - 6.78 (m, 1H), 4.04 (s, 2H), 3.86 (s, 2H), 3.07 (s, 3H), 2.95 (d, J = 14.4 Hz, 7H), 2.73 (s, 4H), 2.54 (d, J = 2.8 Hz, 3H).EXAMPLE 12Synthesis of Compound 103

[0416] Compound 103 was prepared in 5 steps:

[0417] Step 1: To a solution of 3-(2-fluoro-3-nitrobenzyl)-7-hydroxy-4-methyl- 2H-chromen-2-one (700 mg, 2.126 mmol, 1.0 eq.) and 2-Bromopyrimidine (2467 mg, 15.52 mmol, 7.3 eq.) in N,N-Dimethylformamide (0.1 M) at room temperature was added potassium carbonate (588 mg, 4.25 mmol, 2.00 eq.) and the formed reaction mixture was stirred at 80 °C for 1 h. The solvent was evaporated under reduced pressure. Water was added and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCE, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc 4:1 — > 1:4) to obtain 3-(2-fluoro-3-nitrobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (470 mg, 1.154 mmol, yield: 51%) as a light yellow solid.

[0418] Step 2: To a suspension of 3-(2-fluoro-3-nitrobenzyl)-4-methyl-7- (pyrimidin-2-yloxy)-2H-chromen-2-one (470 mg, 1.154 mmol, 1.0 eq.) in N,N- Dimethylformamide (dry) (0.11 M) was added tin(II) chloride dihydrate (1302 mg, 5.77 mmol, 5.00 eq.). The formed reaction mixture was stirred at 70 °C for 1.5h. Reaction mixture was concentrated under reduced pressure and water was added to the residue. The product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain 3-(3-amino-2- fluorobenzyl)-4-methyl-7-(pyrimidin-2-yloxy)-2H-chromen-2-one (430 mg, 1.026 mmol, yield: 84%) as an orange oil.

[0419] Step 3: To a solution of 3-(3-amino-2-fluorobenzyl)-4-methyl-7- (pyrimidin-2-yloxy)-2H-chromen-2-one (430 mg, 1.026 mmol, 1.0 eq.) and pyridine (0.373 ml, 4.61 mmol, 4.50 eq.) in N,N-Dimethylformamide (dry) (0.1 M) at 0 °C was added a solution of methylsulfamoyl chloride (0.203 ml, 2.359 mmol, 2.30 eq.) in Acetonitrile (3 ml) and the formed reaction mixture was stirred at room temperature for 2 hours. Water wasadded and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain the sulfamoyl (493 mg, 0.912 mmol, yield: 89%) as an orange solid.

[0420] Step 4: The sulfamoyl (30 mg, 0.064 mmol, 1.0 eq.) was dissolved in Tetrahydrofuran (dry) (0.04 M), purged with argon and cooled to -78 °C. Then, LiHMDS (1 M in THF, 0.191 ml, 0.191 mmol, 3.00 eq.) was added and mixture was stirred for 30 min. A solution of N-bromosuccinimide (13.62 mg, 0.077 mmol, 1.20 eq.) in Tetrahydrofuran (dry) (0.5 ml) was added dropwise. Mixture was left to stir for 30 min at -78 °C. Water was added to the reaction mixture. The product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain the bromide (30 mg, 0.034 mmol, yield: 53%) as an orange solid.

[0421] Step 5: Starting with the bromine (0.02 g, 0.037 mmol) and piperazine, following procedure General Procedure P, with prep basic to obtain the title compound (11.1 mg, 0.02 mmol, yield: 54%) as a white solid.

[0422] Yield: The title compound was isolated as a white solid (11% over 5 steps)

[0423] Analysis: LCMS (Method P): tR= 1.12 min; m / z calculated for [M-H]+= 555.2, found = 555.2.EXAMPLE 13Synthesis of Compound 104

[0424] Compound 104 was prepared in 2 steps:

[0425] Step 1: Sulfamide, N-[3-fluoro-4-[[4-methyl-2-oxo-7-(2-pyrimidinyloxy)- 2H-l-benzopyran-3-yl]methyl]-2-pyridinyl]-N'-methyl- (20 mg, 0.042 mmol, 1.0 eq.) was dissolved in Tetrahydrofuran (dry) (0.02 M), purged with argon and cooled to -78 °C. Then, LiHMDS (1 M in THF, 0.169 ml, 0.169 mmol, 4.00 eq.) was added and mixture was stirred for 30 min. A solution of N-bromosuccinimide (9 mg, 0.051 mmol, 1.20 eq.) in Tetrahydrofuran (dry) (0.5 ml) was added dropwise. Mixture was left to stir for 30 min at -78 °C. 1M HC1 was added to the reaction mixture. The product was extracted with EtOAc.Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain the bromide (27 mg, 0.028 mmol, yield: 66%) as an orange oil.

[0426] Step 2: Starting with the bromine (0.02 g, 0.037 mmol) and piperazine, following the general synthesis of Compound G.2, with prep basic to obtain the title compound (7.8 mg, 0.0140 mmol, yield: 38%) as a white solid.

[0427] Yield: The title compound was isolated as a white solid (25% over 2 steps)

[0428] Analysis: LCMS (Method P): tR= 0.83 min; mJz calculated for [M-H]+=556.2, found = 556.2.

[0429] Compound 105 was prepared in 2 steps:

[0430] Step 1: 4-(bromomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.3 g, 0.553 mmol, 1.0 eq.) was dissolved in ammonia (0.5 M in THF, 20 mL, 10.0 mmol, 18 eq.) and stirred for 18 hours at rt. The reaction mixture was concentrated under reduced pressure to obtain 4-(aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H- chromen-7-yl dimethylcarbamate hydrobromide (331 mg, 0.592 mmol, yield: 107%) as an off-white solid.

[0431] Step 2: 4-(aminomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7 -yl dimethylcarbamate hydrobromide (40 mg, 0.072 mmol, 1.0 eq.) was dissolved in CH2CI2 (0.04 M). Et3N (0.08 mL, 0.572 mmol, 8.0 eq.) and Trimethylsilyl isocyanate (0.077 mL, 0.572 mmol, 8.0 eq.) were added and the formed reaction mixture was stirred for 18 hours at rt. The product was purified byprep acid to obtain the title compound (6.5 mg, 0.012 mmol, yield: 17%) as a white solid after lyophilization.

[0432] Yield: Compound 105 was isolated as a white solid (18% over 2 step)

[0433] Analysis: LCMS (Method T): tR= 1.20 min; m / z calculated for [M+H]+=522.2, found = 522.4.

[0434] Compound 106 was prepared in 3 steps:

[0435] Step 1: 4-(bromomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.3 g, 0.553 mmol, 1.0 eq.) was dissolved in ammonia (0.5 M in THF, 20 mL, 10.0 mmol, 18 eq.) and stirred for 18 hours at rt. The reaction mixture was concentrated under reduced pressure to obtain 4-(aminomethyl)-3-(2-fluoro-3-((N-methylsulfamoyl)amino)benzyl)-2-oxo-2H- chromen-7-yl dimethylcarbamate hydrobromide (331 mg, 0.592 mmol, yield: 107%) as an off-white solid.

[0436] Step 2: To a solution of 4-(aminomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7 -yl dimethylcarbamate hydrobromide (40 mg, 0.072 mmol, 1.0 eq.) and 2-((tert-butyldimethylsilyl)oxy)ethyl (4-nitrophenyl) carbonate (31.7 mg, 0.093 mmol, 1.3 eq.) in N,N-Dimethylformamide (dry) (2 mL) was added triethylamine (0.030 mL, 0.215 mmol, 3.0 eq.) and the formed reaction mixture was stirred at room temperature for 3 days. The mixture was diluted with EtOAc and water, the layers were separated and the aqueous layer was extracted with EtOAc once. The combined organic layer was washed with water twice and brine, dried over Na2S04 and concentrated. Water was added to the reaction mixture. The product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated underreduced pressure. The impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc 4:1 -> 1:4) to obtain 3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-4-(8,8,9,9-tetramethyl-3-oxo-4,7-dioxa-2-aza-8- siladecyl)-2H-chromen-7-yl dimethylcarbamate (25 mg, 0.033 mmol, yield: 46%) as a white solid.

[0437] Step 3: To a solution of 3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-4-(8,8,9,9-tetramethyl-3-oxo-4,7-dioxa-2-aza-8- siladecyl)-2H-chromen-7-yl dimethylcarbamate (25 mg, 0.037 mmol, 1.0 eq.) in Tetrahydrofuran (0.5 mL) was added hydrochloric acid (4N in dioxane, 0.092 mL, 0.367 mmol, 10 eq.) and the formed reaction mixture was stirred at room temperature for 30 minutes. The product was purified by prep basic to obtain the title compound (9.6 mg, 0.017 mmol, yield: 46%) as a white solid after lyophilization.

[0438] Yield: The title compound was isolated as a white solid (23% over 3 step).

[0439] Analysis: LCMS (Method T): tR= 1.25 min; m / z calculated for [M+H]+= 567.2, found = 567.4; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 7.94 (d, J = 8.9 Hz, 1H), 7.85 (t, J = 5.7 Hz, 1H), 7.32 - 7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.4 Hz, 1H), 6.97 (t, J = 8.0 Hz, 1H), 6.81 (s, 1H), 4.71 (t, J = 5.3 Hz, 1H), 4.41 (d, J = 5.6 Hz, 2H), 4.12 (s, 2H), 3.96 (t, J = 5.1 Hz, 2H), 3.50 (q, J = 5.2 Hz, 2H), 3.07 (s, 3H), 2.93 (s, 3H).EXAMPLE 16 Synthesis of Compound 107

[0440] Compound 107 was prepared in 1 step:

[0441] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H- chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and Ethane sulfony l chloride , following the general synthesis E.3 to obtain the title compound (46.8 mg, 0.10 mmol, yield: 37%) as a white solid.

[0442] Yield: Compound 107 was isolated as a white solid (37% over 1 step)

[0443] Analysis: LCMS (Method R): tR= 1.57 min; mJz calculated for [M+H20]+= 480.2, found = 480.1; 1H NMR (400 MHz, DMSO) 5 9.60 (s, 1H), 7.86 (d, J = 8.7 Hz, 1H), 7.29 - 7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.3 Hz, 1H), 7.03 (t, J = 7.9 Hz, 1H), 6.95 (td, J = 7.9, 7.5, 1.7 Hz, 1H), 3.99 (s, 2H), 3.15 - 3.02 (m, 5H), 2.93 (s, 3H), 2.45 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).EXAMPLE 17 Synthesis of Compound 108

[0444] Compound 108 was prepared in 4 steps:

[0445] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate (1.0 g, 3.53 mmol) and 4-methylbenzene-l,3-diol (1.20 eq.) following the general synthesis of Compound 4 to obtain the corresponding coumarin as an off white solid (1.32 g, 3.68 mmol, yield: 104%).

[0446] Step 2: Following procedure the general synthesis of Compound 5 to obtain the corresponding dimethylcarbamate (0.91 g, 2.06 mmol, yield: 54%) as a light yellow solid.

[0447] Step 3: Following the general synthesis of Compound 6. After filtration the product was purified by column chromatography with method ‘flash’ iCHiCb / McOH = 1:0 ® 95:5) to obtain the corresponding primary amine (0.54 g, 0.79 mmol, purity: 56% yield: 35%) as a light yellow solid.

[0448] Step 4: Following the general synthesis of Compound 7. After filtration 576 mg of impure compound was obtained. 50 mg was further purified by preparative LC (basic) to obtain the title compound (13.2 mg, 0.027 mmol, yield: 66%) after freeze drying as a white solid.

[0449] Yield: Compound 108 was isolated as a white solid (13% over 4 steps)

[0450] Analysis: LCMS (Method T): tR= 1.58 min; m / z calculated for [M-H]+= 476.1, found = 476.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 7.76 (s, 1H), 7.30 - 7.24 (m, 1H), 7.22 (s, 1H), 7.13 (s, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 3.96 (s, 2H), 3.09 (s, 3H), 2.94 (s, 3H), 2.44 (s, 3H), 2.23 (s, 3H).EXAMPLE 18 Synthesis of Compound 109

[0451] Compound 109 was prepared in 4 steps:

[0452] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate 3 (1.0 g, 3.53 mmol) and 4-chlorobenzene- 1 ,3-diol (1.20 eq.) following the general synthesis of Compound 4 to obtain the corresponding coumarin 5 (0.95 g, 2.57 mmol, yield: 73%) as an off white solid.

[0453] Step 2: Following the procedure of the general synthesis of Compound 5 to obtain the corresponding dimethylcarbamate (0.88 g, 1.95 mmol, yield: 75%) as a light yellow solid.

[0454] Step 3: Following the procedure of the general synthesis of Compound 6 to obtain the corresponding primary amine (0.51 g, 1.22 mmol, yield: 60%) as a light yellow solid.

[0455] Step 4: Following the procedure of the general synthesis of Compound 7 to obtain. After filtration, 588 mg of impure compound was obtained. 50 mg was further purified by preparative LC (basic) to obtain the title compound (28.9 mg, 0.027 mmol, yield: 44%) after freeze-drying as a white solid.

[0456] Yield: Compound 109 was isolated as a white solid (14% over 4 steps)

[0457] Analysis: LCMS (Method T): tR= 1.63 min; m / z calculated for [M-H]+= 496.1, found = 496.2; 1H NMR (400 MHz, DMSO) d 9.40 (s, 1H), 8.03 (s, 1H), 7.50 (s, 1H), 7.28 (td, J = 7.9, 1.8 Hz, 1H), 7.10 (s, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.0 Hz, 1H), 3.97 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.45 (s, 3H).EXAMPLE 19Synthesis of Compound 19

[0458] Compound 19 was prepared in 1 step:

[0459] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (23.9 g, 44.1 mmol) and azetidine, following procedure of the general synthesis of Compound E.2, with the addition that DIPEA (2.0 eq) was added during the reaction. After full conversion the reaction mixture was concentrated under reduced pressure. The residue was purified by column chromatography with method ‘flash’ (heptane / EtOAc = 1:0 — > 0:1). Desired fractions were combined and concentrated under reduced pressure to obtain the title compound (11.8 g, 22.17 mmol, yield: 50%) as an off white solid.

[0460] Yield: Compound 19 was isolated as an off white solid (50% over 1 step).

[0461] Analysis: LCMS (Method T): tR= 1.53 min; m / z calculated for [M-H]+= 519.2, found = 519.2; 1H NMR (400 MHz, CDC13) d 8.01 (d, J = 8.8 Hz, 1H), 7.38 (td, J = 7.8, 1.6 Hz, 1H), 7.15 - 7.03 (m, 2H), 6.99 (t, J = 8.1 Hz, 1H), 6.86 (t, J = 7.7 Hz, 1H), 6.68 (s, 1H), 4.58 (q, J = 5.3 Hz, 1H), 4.15 (s, 2H), 3.60 (s, 2H), 3.12 (s, 3H), 3.03 (s, 3H), 2.73 (d, J = 5.3 Hz, 3H), 2.26 (s, 6H).EXAMPLE 20Synthesis of Compound 21

[0462] Compound 21 was prepared in 1 step:

[0463] Step 1: Starting with 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (50 mg, 0.094 mmol) and piperazine, following the geneal synthesis of Compound E.2. The impure product was combined with other batches and purified by prep basic to obtain the title compound (22 mg, 0.037 mmol, yield: 39%) after freeze drying as a white solid.

[0464] Yield: Compound 21 was isolated as a white solid (65% over 1 step).

[0465] Analysis: LCMS (Method R): tR= 1.43 min; m / z calculated for [M+H]+= 582.2, found = 582.2; 1H NMR (400 MHz, DMSO) d 8.30 (s, 1H), 8.27 (s, 1H), 7.48 (s, 1H), 7.31 - 7.19 (m, 2H), 6.99 (t, J = 7.9 Hz, 1H), 6.83 (t, J = 7.2 Hz, 1H), 4.03 (s, 2H), 3.70 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.64 (t, J = 4.6 Hz, 4H), 2.53 (d, J = 2.9 Hz, 3H), 2.40 (s, 4H).EXAMPLE 21Synthesis of Compound 110

[0466] Compound 110 was prepared in 4 steps:

[0467] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3- oxobutanoate (1.18 g, 4.31 mmol) and 4-methylbenzene-l,3-diol (1.20 eq.) following procedure of the general synthesis of Compound D.4. After complete reaction water was added and the formed suspension was filtered. The residue co-evaporated with Et20. The residue was dried overnight at 40 °C under reduced pressure to obtain the corresponding coumarin (1.7 g, 4.53 mmol, yield: 105%, purity: 89%) as a beige solid.

[0468] Step 2: Following the procedure of the geneal synthesis of Compound D.5 to obtain the corresponding dimethylcarbamate (1.94 g, 4.32 mmol, yield: 95%, purity: 90%) as beige solid.

[0469] Step 3: Following the procedure of the geneal synthesis of Compound D.6 starting with 0.9 g, 2.22 mmol of compound D.5. The deprotection with TFA was not performed. The reaction mixture was filtered and concentrated under reduced pressure. The impure product was combined with another batch and purified by column chromatographywith method ‘flash' (CELCL / MeOH 1:0 — > 94:6) to obtain the corresponding primary amine D.6 (0.22 g, 0.303 mmol, yield: 14%, purity: 53%) as a brown solid.

[0470] Step 4: Following the procedure of the geneal synthesis of Compound D.7 After full conversion the reaction mixture was quenched with water and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over NaiSCL, filtered and concentrated under reduced pressure. The impure product was diluted with CH2CI2 and purified by column chromatography with method ‘flash’’ (CELCL / MeOH 1:0 ® 96:4) to give 141 mg of a yellow oil. 25 mg of the impure product was purified by prep basic to obtain the title compound (13.7 mg, 0.029 mmol, yield: 59%) after lyophilization as a white solid.

[0471] Yield: Compound 110 was isolated as a white solid (8% over 4 steps).

[0472] Analysis: LCMS (Method T): tR= 1.58 min; m / z calculated for [M-H]+= 479.1, found = 479.2; 1H NMR (400 MHz, DMSO) d 10.34 (s, 1H), 7.89 (s, 1H), 7.78 (s, 1H), 7.23 (s, 1H), 6.94 (s, 1H), 6.77 (s, 1H), 4.00 (s, 2H), 3.10 (s, 3H), 2.94 (s, 3H), 2.46 (s, 3H), 2.23 (s, 3H).EXAMPLE 22Svnthesis of Compound 111

[0473] Compound 111 was prepared in 4 steps:

[0474] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3- oxobutanoate (15.0 g, 46.0 mmol) and 4-chlorobenzene-l ,3-diol (1.20 eq.) following the procedure of the geneal synthesis of Compound D.4. After complete reaction water was added and the formed suspension was filtered. The residue co-evaporated with EtOH and triturated in EtOH / Et20. The solids were filtered off to obtain the corresponding coumarin (4.8 g, 13.55 mmol, yield: 29%) as a white solid.

[0475] Step 2: Following the procedure the geneal synthesis of Compound D.5 to obtain the corresponding dimethylcarbamate (5.48 g, 11.86 mmol, yield: 87%, purity: 92%) as a light yellow solid.

[0476] Step 3: Following the procedure of the geneal synthesis of Compound D.6 starting with 1.0 g, 2.35 mmol of compound D.5. The deprotection with TFA was not performed. The reaction mixture was filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc 9:1 ® 1:4) to obtain the corresponding primary amine (0.12 g, 0.281 mmol, yield: 12%) as a beige solid.

[0477] Step 4: Following procedure the geneal synthesis of Compound D.7 starting with 400 mg, 0.789 mmol of primary amine. After full conversion the reaction mixture was quenched with water. The product was extract with EtOAc, combined organic layers were washed with brine, dried over NaiSCU, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘flash’ (CFhCh / MeOFI = 1:0 — > 96:4). The impure product was purified by prep basic to obtain the title compound (27.5 mg, 0.054 mmol, yield: 7%) after lyophilization as a white solid.

[0478] Yield: Compound 111 was isolated as a white solid (0.2% over 4 steps).

[0479] Analysis: LCMS (Method T): tR= 1.20 min; m / z calculated for [M+H]+= 499.1, found = 499.2; 1H NMR (400 MHz, DMSO) d 10.34 (s, 1H), 8.04 (s, 1H), 7.95 - 7.86 (m, 1H), 7.51 (s, 1H), 6.95 (s, 1H), 6.81 (s, 1H), 4.01 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.47 (s, 3H).EXAMPLE 23 Synthesis of Compound 112

[0480] Compound 112 was prepared in 3 step:

[0481] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3- oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 eq.) following the geneal synthesis of Compound D.4. Instead of perchloric acid, sulfuric acid was used. After complete conversion the reaction mixture was cooled (0 °C) and quenched with sat. aq. NaHC03untilbasic pH. The formed white suspension was washed with water, Et20 and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off-white solid.

[0482] Step 2: Following the procedure of the geneal synthesis of Compound D.5 to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0483] Step 3: To an solution of dimethylcarbamate (200 mg, 0.512 mmol, 1.0 eq.) and cyclopropanesulfonamide (93 mg, 0.768 mmol, 1.5 eq.) in 1,4-Dioxane (extra dry) (0.1 M) under N2 atmosphere were added Xantphos (59.2 mg, 0.102 mmol, 0.2 eq.), cesium carbonate (250 mg, 0.768 mmol, 1.5 eq.) and PdOAc2 (11.49 mg, 0.051 mmol, 0.1 eq.). The formed reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered over a celite plug eluting with CH2CI2. The filtrate was concentrated and purified by column chromatography with method ‘ flash ’ (CH2Cl2 / EtOAc = 1:0 — > 6:4). The impure product was further purified by prep basic to obtain the title compound (89 mg, 0.208 mmol, yield: 41%) after lyophilization as a white solid.

[0484] Yield: Compound 112 was isolated as a white solid (39% over 3 steps).

[0485] Analysis: LCMS (Method R): tR= 1.43 min; m / z calculated for [M+H]+= 476.1, found = 476.2; 1H NMR (400 MHz, DMSO) d 10.62 (s, 1H), 7.94 (d, J = 5.1 Hz, 1H), 7.88 (d, J = 8.8 Hz, 1H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (d, J = 6.0 Hz, 1H), 4.02 (s, 2H), 3.17 (s, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.48 (s, 3H), 1.16 - 0.93 (m, 4H).

[0486] Compound 113 was prepared in 1 step:

[0487] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H- chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and Cyclopropanesulfonyl chloride, following the geneal synthesis of Compound E.3 to obtain the title compound (71.4 mg, 0.15 mmol, yield: 56%) as a white solid.

[0488] Yield: Compound 113 was isolated as a white solid (56% over 1 step).

[0489] Analysis: LCMS (Method R): tR= 1.58 min; mJz calculated for [M+H20]+= 492.4, found = 492.1; 1H NMR (400 MHz, DMSO) 5 9.58 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.19 (dd, J = 8.7, 2.3 Hz, 1H), 7.09 - 6.94 (m, 2H), 3.99 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.64 (tt, J = 7.9, 4.8 Hz, 1H), 2.45 (s, 3H), 1.00 - 0.80 (m, 4H).EXAMPLE 25 Synthesis of Compound 114

[0490] Compound 114 was prepared in 3 step:

[0491] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3- oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 eq.) following the geneal synthesis of Compound D.4. Instead of perchloric acid, sulfuric acid was used. After complete conversion the reaction mixture was cooled (0 °C) and quenched with sat. aq. NaHC03till basic pH. The formed white suspension was washed with water, Et20 and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off white solid.

[0492] Step 2: Following the procedure of the geneal synthesis of Compound D.5 to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0493] Step 3: To an solution of dimethylcarbamate (100 mg, 0.256 mmol, 1.0 eq.) and isopropylsulfonamide (47 mg, 0.384 mmol, 1.5 eq.) in 1,4-Dioxane (extra dry) (0.1 M) under N2 atmosphere were added Xantphos (29.6 mg, 0.051 mmol, 0.2 eq.), cesium carbonate (125 mg, 0.384 mmol, 1.5 eq.) and PdOAc2 (5.7 mg, 0.026 mmol, 0.1 eq.). The formed reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered over a celite plug eluting with CH2CI2. The filtrate was concentrated and purified by column chromatography with method ‘flash’ (CH2Cl2 / EtOAc = 1:0 — > 6:4). The impure product was further purified by prep basic to obtain the title compound (37 mg, 0.077 mmol, yield: 30%) after lyophilization as a white solid.

[0494] Yield: Compound 114 was isolated as a white solid (29% over 3 steps).

[0495] Analysis: LCMS (Method R): tR= 1.47 min; m / z calculated for [M+H]+= 478.1, found = 478.2; 1H NMR (400 MHz, DMSO) 5 10.49 (s, 1H), 8.05 - 7.82 (m, 2H), 7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.8, 2.3 Hz, 1H), 6.88 (s, 1H), 4.08 - 3.86 (m, 3H), 3.07 (s, 3H), 2.93 (s, 3H), 2.47 (s, 3H), 1.31 (d, J = 6.8 Hz, 6H).

[0496] Compound 115 was prepared in 1 step:

[0497] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H- chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and 2-Propanesulfonyl chloride, following the geneal synthesis of Compound E.3. Reaction time was 3 days and the product was purified by column chromatography with method ‘ flash ’ (ChbCh / EtOAc = 1:0 — » 6:4). to obtain the title compound (35.8 mg, 0.074 mmol, yield: 27%) as a white solid.

[0498] Yield: Compound 115 was isolated as a white solid (27% over 1 step).

[0499] Analysis: LCMS (Method R): tR= 1.62 min; m / z calculated for [M+H]+= 477.1, found = 477.2; 1H NMR (400 MHz, DMSO) d 9.58 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.31 - 7.22 (m, 2H), 7.19 (dd, J = 8.8, 2.3 Hz, 1H), 7.02 (t, J = 7.9 Hz, 1H), 6.97 - 6.88 (m, 1H), 3.98 (s, 2H), 3.22 (p, J = 6.8 Hz, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.45 (s, 3H), 1.27 (d, J = 6.8 Hz, 6H)

[0500] Compound 116 was prepared in 1 step:

[0501] Step 1: Starting with 4-(bromomethylj-6-chloro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (45 mg, 0.075 mmol, py:40%) and N-Methylbenzylamine, following the geneal synthesis of Compound E.2, with addition of Net3 3.0 eq. The product was purified by prep basic to obtain the title compound (12.8 mg, 0.021 mmol, y: 66%) after freeze drying as a white solid.

[0502] Yield: Compound 116 was isolated as a white solid (66% over 1 step).

[0503] Analysis: LCMS (Method T): tR= 1.98 min; mJz calculated for [M+H]+= 617.2 / 619.2, found = 617.4 / 619.4; 1H NMR (400 MHz, DMSO) d 9.41 (s, 1H), 8.25 (s, 1H), 7.47 (s, 1H), 7.37 - 7.21 (m, 6H), 7.15 (s, 1H), 6.97 (t, J = 7.9 Hz, 1H), 6.80 (t, J = 7.2 Hz, 1H), 4.05 (s, 2H), 3.76 (s, 2H), 3.56 (s, 2H), 3.11 (s, 3H), 2.95 (s, 3H), 2.52 (d, J = 4.0 Hz, 3H), 2.06 (s, 3H).

[0504] Compound 117 was prepared in 1 step:

[0505] Step 1: Starting with 4-(bromomethyl)-6-chloro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (45 mg, 0.075 mmol, py:40%) and N-Methylpropylamine, following the geneal synthesis of Compound E.2, with addition of Net33.0 eq. The product was purified by prep basic followed by prep acid to obtain the title compound (3.8 mg, 0.007 mmol, y: 21%) after freeze drying as a white solid.[05061 Yield: Compound 117 was isolated as a white solid (21% over 1 step).

[0507] Analysis: LCMS (Method T): tR= 1.94 min; m / z calculated for [M+H]+= 569.2 / 571.2, found = 569.4 / 571.4; 1H NMR (400 MHz, DMSO) d 9.41 (s, 1H), 8.29 (s, 1H), 7.48 (s, 1H), 7.28 (t, J = 7.7 Hz, 1H), 7.15 (s, 1H), 6.98 (t, J = 7.9 Hz, 1H), 6.81 (t, J = 7.2 Hz, 1H), 4.04 (s, 2H), 3.71 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H), 2.52 (s, 3H), 2.35 (t, J = 7.0 Hz, 2H), 2.06 (s, 3H), 1.44 (h, J = 7.3 Hz, 2H), 0.82 (t, J = 7.3 Hz, 3H).

[0508] Compound 117 was prepared in 1 step:

[0509] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H- chromen-7-yl dimethylcarbamate (0.1 g, 0.27 mmol) and cyclobutanesulfonyl chloride, following the geneal synthesis of Compound E.3. Reaction mixture was purified with method ‘ prep base ’ to obtain the title compound (8.0 mg, 0.016 mmol, yield: 6%) after lyophilization as a white solid.

[0510] Yield: Compound 117 was isolated as a white solid (6% over 1 step).

[0511] Analysis: LCMS (Method R): tR= 1.65 min; m / z calculated for [M+H]+= 489.1, found = 489.4; 1H NMR (400 MHz, DMSO) d 9.51 (s, 1H), 7.86 (d, J = 8.8 Hz, 1H), 7.28 - 7.15 (m, 3H), 7.06 - 6.88 (m, 2H), 3.98 (s, 2H), 3.90 (p, J = 8.2 Hz, 1H), 3.07 (s, 3H), 2.93 (s, 3H), 2.45 (s, 3H), 2.36 - 2.13 (m, 4H), 1.97 - 1.80 (m, 2H).EXAMPLE 30 Synthesis of Compound 119

[0512] Compound 119 was prepared in 1 step:

[0513] Step 1: Starting with 3-((2-amino-3-fluoropyridin-4-yl)methyl)-4-methyl- 2-oxo-2H-chromen-7-yl dimethylcarbamate (0.05 g, 0.135 mmol) and Ethane sulfony l chloride, following the geneal synthesis of Compound E.3. Reaction mixture was purified with method ‘prep base’ to obtain the title compound (3.6 mg, 0.007 mmol, yield: 6%) after lyophilization as a white solid.

[0514] Yield: Compound 119 was isolated as a white solid (6% over 1 step).

[0515] Analysis: LCMS (Method R): tR= 1.42 min; m / z calculated for [M+H]+=464.1, found = 464.2; 1H NMR (400 MHz, DMSO) d 10.54 (s, 1H), 8.01 - 7.80 (m, 2H),7.27 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.8, 2.4 Hz, 1H), 6.88 (s, 1H), 4.02 (s, 2H), 3.63 - 3.42 (m, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.47 (s, 3H), 1.26 (t, J = 7.4 Hz, 3H).

[0516] Compound 120 was prepared in 3 steps:

[0517] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-4-methyl-2-oxo-2H- chromen-7-yl dimethylcarbamate (0.516 g, 1.115 mmol) and ethane sulfony l chloride, following the geneal synthesis of Compound E.3 to obtain the sulfamoyl (320 mg, 0.678 mmol, yield: 61%) as a white solid.

[0518] Step 2: Following the procedure of the geneal synthesis of Compound E.4 using NBS. After extraction the impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc = 1:0 — > 0:1) to obtain the corresponding bromine compound (324 mg, 0.53 mmol, yield: 79%, purity: 89%) as a white solid.

[0519] Step 3: Following the procedure of the geneal synthesis of Compound E.5 starting with 10 mg, 0.016 mmol of the bromine compound and dimethylamine 2M in MeOH. The impure product was purified by prep basic followed by SFC CEL-2 gradient to obtain the title compound (2.8 mg, 0.005 mmol, yield: 33%) as a white solid.

[0520] Yield: Compound 120 was isolated as a white solid (16% over 3 steps).

[0521] Analysis: LCMS (Method T): tR= 1.61 min; m / z calculated for [M+H]+= 506.2, found = 506.4; 1H NMR (400 MHz, CDC13) d 8.01 (d, J = 8.8 Hz, 1H), 7.44 (td, J = 7.7, 1.2 Hz, 1H), 7.14 - 7.05 (m, 2H), 7.01 (t, J = 7.9 Hz, 1H), 6.90 (t, J = 7.2 Hz, 1H), 6.49 - 6.43 (m, 1H), 4.16 (s, 2H), 3.60 (s, 2H), 3.16 (q, J = 7.4 Hz, 3H), 3.13 (s, 2H), 3.04 (s, 3H), 2.27 (s, 6H), 1.40 (t, J = 7.4 Hz, 3H).EXAMPLE 32Synthesis of Compound 121

[0522] Compound 121 was prepared in 1 step:

[0523] Step 1: Starting with phenol (20 mg, 0.046 mmol) and 4- Morpholinecarbonyl chloride, following the geneal synthesis of Compound F.2. Purification with method ‘prep base ’ to obtain the title compound (16 mg, 0.029 mmol, yield: 64%) as a white solid after lyophilization.

[0524] Yield: Compound 121 was isolated as a white solid (64% over 1 step).

[0525] Analysis: LCMS (Method P): tR= 1.39 min; m / z calculated for [M+H]+= 549.2, found = 549.1; 1H NMR (400 MHz, CDC13) d 8.03 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 7.9, 1.6 Hz, 1H), 7.14 - 7.05 (m, 2H), 7.00 (td, J = 8.0, 1.2 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.61 (d, J = 3.2 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 4.15 (s, 2H), 3.77 (dd, J = 5.5, 4.0 Hz, 4H), 3.70 (d, J = 7.4 Hz, 2H), 3.60 (d, J = 12.2 Hz, 4H), 2.76 (d, J = 5.3 Hz, 3H), 2.28 (s, 6H).EXAMPLE 33Synthesis of Compound 122

[0526] Compound 122 was prepared in 1 step:

[0527] Step 1: Starting with phenol (20 mg, 0.046 mmol) and 4- Morpholinecarbonyl chloride, following the geneal synthesis of Compound F.2. Purification with method ‘prep base ’ to obtain the title compound (16 mg, 0.029 mmol, yield: 64%) as a white solid after lyophilization.

[0528] Yield: Compound 122 was isolated as a white solid (64% over 1 step).

[0529] Analysis: LCMS (Method P): tR = 1.39 min; m / z calculated for [M+H]+= 549.2, found = 549.1; 1H NMR (400 MHz, CDC13) d 8.03 (d, J = 8.8 Hz, 1H), 7.39 (td, J =7.9, 1.6 Hz, 1H), 7.14 - 7.05 (m, 2H), 7.00 (td, J = 8.0, 1.2 Hz, 1H), 6.92 - 6.84 (m, 1H), 6.61 (d, J = 3.2 Hz, 1H), 4.43 (t, J = 5.3 Hz, 1H), 4.15 (s, 2H), 3.77 (dd, J = 5.5, 4.0 Hz, 4H), 3.70 (d, J = 7.4 Hz, 2H), 3.60 (d, J = 12.2 Hz, 4H), 2.76 (d, J = 5.3 Hz, 3H), 2.28 (s, 6H).

[0530] Compound 123 was prepared in 1 step.

[0531] Step 1: Starting at general synthesis step D.4 (155 mg, 0.356 mmol) was dissolved in MeCN (1.8 mL) and DMAP (130 mg, 1.07 mmol, 3 eq) and dimethylthiocarbamoyl chloride (66 mg, 0.53 mmol, 1.5 eq) were added. This mixture was stirred overnight at rt and for 4 h at 40 °C. The reaction as such was purified with method “ prep acid ” to give the title compound (163 mg, 0.31 mmol, yield: 86%) as a white solid after lyophilzation.

[0532] Analysis: LCMS (Method R): tR= 0.951 min; m / z calculated for [M-H]+= 523.2, found = 523.4; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.08 (d, J = 8.9 Hz, 1H), 7.33 - 7.16 (m, 3H), 7.11 (dd, J = 8.8, 2.4 Hz, 1H), 7.00 (t, J = 7.9 Hz, 1H), 6.84 (t, J = 7.1 Hz, 1H), 4.05 (s, 2H), 3.65 (s, 2H), 3.41 - 3.30 (m, 6H), 2.55 - 2.52 (m, 3H), 2.20 (s, 6H).EXAMPLE 35Synthesis of Compound 124

[0533] Compound 124 was prepared in 1 step:

[0534] Step 1: Starting with 4-(chloromethyl)-3-((3-fluoro-2-((N- methybulfamoyl)amino)pyridin-4-yl)methyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (390 mg g, 0.391 mmol, purity: 50%) and dimethylamine 2M in MeOH, following the genealsynthesis of Compound E.2. The product was purified with method “ prep aci ’ to obtain the title compound (80 g, 0.155 mmol, yield: 40%) as an off white solid after lyophilization.

[0535] Yield: Compound 124 was isolated as an off white solid (40% over 1 step).

[0536] Analysis: LCMS (Method R): tR- 0.80 min; m / z calculated for [M-H]+- 508.2, found = 508.4; 1H NMR (400 MHz, DMSO) d 10.34 (s, 1H), 8.09 (d, J = 8.9 Hz, 1H), 7.90 (d, J = 5.1 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.8, 2.4 Hz, 1H), 6.96 (s, 1H), 6.79 (t, J = 5.1 Hz, 1H), 4.07 (s, 2H), 3.66 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.20 (s, 6H).EXAMPLE 36 Synthesis of Compound 125

[0537] Compound 125 was prepared in 3 step:

[0538] Step 1: Starting from ethyl 2-((2-chloro-3-fluoropyridin-4-yl)methyl)-3- oxobutanoate (10.0 g, 24.12 mmol) and resorcinol (2.00 eq.) following the geneal synthesis of Compound D.4. Instead of perchloric acid, sulfuric acid was used. After complete conversion the reaction mixture was cooled (0 °C) and quenched with sat. aq. NaHC03 till basic pH. The formed white suspension was washed with water, Et20 and dried to obtain the corresponding coumarin (8.61 g, 23.4 mmol, yield: 97%, purity: 87%) as an off white solid.

[0539] Step 2: Following the procedure of the geneal synthesis of Compound D.5 to obtain the corresponding dimethylcarbamate (9.33 g, 23.16 mmol, yield: 99%) as a beige solid.

[0540] Step 3: To an solution of dimethylcarbamate (200 mg, 0.512 mmol, 1.0 eq.) and cyclobutanesulfonamide (104 mg, 0.768 mmol, 1.5 eq.) in 1,4-Dioxane (extra dry) (0.1 M) under N2 atmosphere were added Xantphos (59.2 mg, 0.102 mmol, 0.2 eq.), cesium carbonate (250 mg, 0.768 mmol, 1.5 eq.) and PdOAc2 (11.5 mg, 0.051 mmol, 0.1 eq.). The formed reaction mixture was stirred at 100 °C for 16 hours. The reaction mixture was filtered over a celite plug eluting with CH2CI2. The filtrate was concentrated and purified by prepbasic to obtain the title compound (53 mg, 0.107 mmol, yield: 21%) after lyophilization as a white solid.

[0541] Yield: Compound 125 was isolated as a white solid (20% over 3 steps).

[0542] Analysis: LCMS (Method L): tR= 3.71 min; m / z, calculated for [M+H]+= 490.2, found = 490.1; 1H NMR (400 MHz, DMSO) d 10.53 (bs, 1H), 8.00 - 7.79 (m, 2H), 7.26 (d, J = 2.3 Hz, 1H), 7.20 (dd, J = 8.7, 2.3 Hz, 1H), 6.84 (s, 1H), 4.50 (bs, 1H), 4.00 (s,2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.48 - 2.34 (m, 5H), 2.29 - 2.17 (m, 2H), 2.01 - 1.83 (m, 2H).EXAMPLE 37Synthesis of Compound 126

[0543] Compound 125 was prepared in 1 step:

[0544] Step 1: Starting with phenol (20 mg, 0.046 mmol) and diethylcarbamyl chloride, following the geneal synthesis of Compound F.2. Purification with method ‘prep base ’ to obtain the title compound (9.7 mg, 0.018 mmol, yield: 39%) as a white solid after lyophilization.

[0545] Yield: Compound 125 was isolated as a white solid (39% over 1 step)

[0546] Analysis: LCMS (Method P): tR= 1.65 min; m / z calculated for [M+H]+=535.2, found = 535.1; no HNMR, compound was made in library.EXAMPLE 38Synthesis of Compound 127

[0547] Compound 126 was prepared in 1 step:

[0548] Step 1: Starting with phenol (20 mg, 0.046 mmol) and 4-Methyl-l- piperazinecarbonyl chloride, following the geneal synthesis of Compound F.2. Purification with method ‘prep base ’ to obtain the title compound (17.8 mg, 0.032 mmol, yield: 70%) as a white solid after lyophilization.

[0549] Yield: Compound 126 was isolated as a white solid (70% over 1 step).

[0550] Analysis: LCMS (Method P): tR= 1.33 min; m / z calculated for [M+H]+=562.2, found = 562.1; no HNMR, compound was made in library.

[0551] Compound 128 was prepared in 1 step:

[0552] Step 1: Starting with phenol (50 mg, 0.115 mmol) and azetidine-1- carbonyl chloride, following the geneal synthesis of Compound F.2, DMAP (0.6 eq.) and Et3N (1.1 eq.) were added and the reaction was performed in CH2CI2 (0.11 M). After full conversion the reaction mixture was concentrated and water was added to the residue. The product was extracted with CH2CI2. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified with method ‘prep base ’ to obtain the title compound (6 mg, 0.012 mmol, yield: 10%) as a white solid after lyophilization.

[0553] Yield: Compound 128 was isolated as a white solid (10% over 1 step).

[0554] Analysis: LCMS (Method T): tR= 1.44 min; m / z calculated for [M+H]+=519.2, found = 519.1; 1H NMR (400 MHz, CDC13) d 8.00 (d, J = 8.8 Hz, 1H), 7.39 (td, J = 7.9, 1.6 Hz, 1H), 7.15 - 7.05 (m, 2H), 7.03 - 6.96 (m, 1H), 6.90 - 6.83 (m, 1H), 6.61 (s, 1H), 4.44 (q, J = 5.4 Hz, 1H), 4.25 (s, 2H), 4.15 (s, 4H), 3.59 (s, 2H), 2.75 (d, J = 5.3 Hz, 3H), 2.36 (p, J = 7.7 Hz, 2H), 2.27 (s, 6H).EXAMPLE 40Synthesis of Compound 129

[0555] Compound 129 was prepared in 1 step:

[0556] Step 1: To a solution of Phenol derivate (50 mg, 0,115 mmol, 1.0 eq.) and 2-Bromopyrimidine (30 mg, 0,19 mmol, 1.6 eq.) in N,N-Dimethylformamide (dry) (2 ml) was added potassium carbonate (26 mg, 0,19 mmol, 1.6 eq.) The formed reaction mixture was stirred for 5 hours at 80 °C. Water was added and the product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified with method ‘prep base ’ to obtain the title compound (8.0 mg, 0.016 mmol, yield: 14%) as a white solid after lyophilization.

[0557] Yield: The title compound was isolated as a white solid (14% over 1 step).

[0558] Analysis: LCMS (Method T): tR = 1.34 min; m / z calculated for [M+H]+= 514.2, found = 514.1; 1H NMR (400 MHz, CDC13) d 8.60 (d, J = 4.7 Hz, 2H), 8.11 (d, J = 8.8 Hz, 1H), 7.40 (td, J = 7.8, 1.6 Hz, 1H), 7.22 (d, J = 2.4 Hz, 1H), 7.17 (dd, J = 8.8, 2.4 Hz,1H), 7.12 (t, J = 4.8 Hz, 1H), 7.01 (t, J = 8.0 Hz, 1H), 6.91 - 6.81 (m, 1H), 6.61 (s, 1H), 4.43(q, J = 5.4 Hz, 1H), 4.17 (s, 2H), 3.62 (s, 2H), 2.77 (d, J = 5.2 Hz, 3H), 2.29 (s, 6H).EXAMPLE 41Synthesis of Compound 130

[0559] Compound 130 was prepared in 4 steps:

[0560] Step 1: Starting from ethyl 2-(2-fluoro-3-nitrobenzyl)-3-oxobutanoate (2.0 g, 7.06 mmol) and 4-fluorobenzene-l,3-diol (1.20 eq.) following the geneal synthesis ofCompound 4 to obtain the corresponding coumarin compound (2.85 g, 8.13 mmol, yield: 115%) as an off white solid.

[0561] Step 2: Following the procedure of the geneal synthesis of Compound 5. With a reaction time of 2.5 days, to obtain the corresponding dimethylcarbamate (2.28 g, 5.01 mmol, purity: 92%, yield: 61%) as a beige solid.

[0562] Step 3: Following the procedure of the geneal synthesis of Compound 6 to obtain the corresponding primary amine (1.28 g, 3.11 mmol, yield: 57%) as a light yellow solid.

[0563] Step 4: Following the procedure of the geneal synthesis of Compound 7. After filtration the impure product was purified by flash column chromatography (CH2Cl2 / MeOH = 1:0 — > 97:3) to obtain the title compound (1.043 g, 2.15 mmol, yield: 65%) as an off white solid.

[0564] Yield: Compound 130 was isolated as an off white solid (26% over 4 steps).

[0565] Analysis: LCMS (Method R): tR= 1.55 min; m / z calculated for [M-H]+ISO.', found = 480.2; 1H NMR (400 MHz, DMSO) d 9.37 (s, 1H), 7.86 (d, J = 11.2 Hz, 1H), 7.49 (d, J = 6.8 Hz, 1H), 7.28 (td, J = 7.8, 1.6 Hz, 1H), 7.21 (q, J = 5.1 Hz, 1H), 7.01 (t, J = 7.9 Hz, 1H), 6.91 - 6.83 (m, 1H), 3.98 (s, 2H), 3.08 (s, 3H), 2.94 (s, 3H), 2.53 (s, 3H), 2.43 (s, 3H).EXAMPLE 42Synthesis of Compound 131

[0566] Compound 131 was prepared in 1 step:

[0567] Step 1: Starting with 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (20 mg, 0.038 mmol) and azetidine, following procedure the geneal synthesis of Compound E.2, with addition of potassium carbonate 3.0 eq. The impure product was combined with otherbatches and purified by prep basic to obtain the title compound (44 mg, 0.076 mmol, yield: 65%) after freeze drying as a white solid.

[0568] Yield: The title compound was isolated as a white solid (65% over 1 step)

[0569] Analysis: LCMS (Method R): tR= 0.95 min; m / z calculated for [M+H]+=553.1, found = 553.2; 1H NMR (400 MHz, DMSO) d 9.39 (s, 1H), 8.20 (s, 1H), 7.48 (s, 1H), 7.33 - 7.19 (m, 2H), 7.00 (t, J = 8.0 Hz, 1H), 6.81 (t, J = 7.1 Hz, 1H), 4.09 (s, 2H), 3.82 (s, 2H), 3.16 (t, J = 6.9 Hz, 4H), 3.10 (s, 3H), 2.95 (s, 3H), 2.53 (d, J = 4.8 Hz, 3H), 1.91 (p, J = 7.0 Hz, 2H).

[0570] Compound 132 was prepared in 3 steps:

[0571] Step 1: Starting with 3-(3-amino-2-fluorobenzyl)-6-chloro-4-methyl-2- oxo-2H-chromen-7-yl dimethylcarbamate (0.320 g, 0.585 mmol) and ethane sulfony l chloride, following the geneal synthesis of Compound E.3. During work-up the reaction mixture was combined with another batch to obtain the sulfamoyl (350 mg, 0.704 mmol, yield: 92%) as a white solid.

[0572] Step 2: Following the procedure of the geneal synthesis of Compound E.4 using NBS. After extraction the impure product was purified by column chromatography with method ‘flash’ (heptane / EtOAc = 1:0 ® 0:1) followed by prep acid to obtain the corresponding bromine (65 mg, 0.113 mmol, yield: 19%) as a beige solid.

[0573] Step 3: Following the procedure of the geneal synthesis of Compound E.5 using dimethylamine 2M in MeOH. The reaction mixture was quenched with water and the product was extracted with CH2CI2. Combined organic layers were dried over Na2S04, filtered and concentrated under reduced pressure. The residue was purified by prep acid to obtain the title compound (39 mg, 0.073 mmol, yield: 65%) as a white solid after lyophilization.

[0574] Yield: Compound 132 was isolated as a white solid (11% over 3 steps).

[0575] Analysis: LCMS (Method V): tR= 3.92 min; m / z calculated for [M+H]+= 540.1 / 542.1, found = 540.1 / 542.1; 1H NMR (400 MHz, DMSO) d 9.67 (s, 1H), 8.21 (s, 1H), 7.48 (s, 1H), 7.25 (td, J = 7.8, 1.7 Hz, 1H), 7.03 (t, J = 7.8 Hz, 1H), 6.98 - 6.88 (m, 1H), 4.05 (s, 2H), 3.66 (s, 2H), 3.14 - 3.07 (m, 5H), 2.95 (s, 3H), 2.18 (s, 6H), 1.26 (t, J = 7.3 Hz, 3H).EXAMPLE 44Synthesis of Compound 133

[0576] Compound 133 was prepared analogously to compound 225 with the chloride instead of the bromide.

[0577] Step-1: 6-chloro-4-(chloromethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (300 mg, 0.564 mmol) and triethylamine (236 uL, 1.69 mmol, 3 eq) was stirred at 40 °C in DCM (7 mL) and tert-butyl glycinate (308 uL, 2.25 mmol, 4 eq) was added. The next day, water was added and the product was extracted with DCM (2x). The combined extract was dried over brine and sodium sulfate and evaporated. The residue was redissolved in 1 mL of DCM and purified by column chromatography with method ‘ prep base’ to obtain the intermediate tert- butylester (126 mg, 0.20 mmol, yield: 35%).

[0578] Step-2: The intermediate of the previous step (126 mg, 0.20 mmol) was stirred in 2 mL of DCM and 2 mL of 4 N HC1 in dioxane (58 mmol, 287 eq). The next day, the volatiles were evaporated and the residue was stripped with DCM and the crude product was redissolved in MeCN and purifined with method ‘ prep base ’ to give the title compound (94 mg, 0.16 mmol, yield: 81 ) as an off-white solid.EXAMPLE 45Synthesis of Compound 134

[0579] Ccompound 134 was prepared in 1 step:

[0580] Step 1: Starting with 4-(chloromethyl)-6-fluoro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (30 mg, 0.058 mmol) and piperazine, following the geneal synthesis of Compound E.2. With the addition of Et3N 3.0 eq. The impure product was purified by prep basic to obtain the title compound (17.3 mg, 0.029 mmol, yield: 51%) after freeze drying as a white solid.

[0581] Yield: Compound 134 was isolated as a white solid (51% over 1 step)

[0582] Analysis: LCMS (Method T): tR = 1.39 min; mlz calculated for [M+H]+= 566.2, found = 566.4; 1H NMR (400 MHz, DMSO) d 8.04 (d, J = 11.8 Hz, 1H), 7.47 (d, J = 6.9 Hz, 1H), 7.28 (td, J = 7.9, 1.7 Hz, 1H), 7.24 - 7.12 (m, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.1 Hz, 1H), 4.03 (s, 2H), 3.66 (s, 2H), 3.08 (s, 3H), 2.94 (s, 3H), 2.63 - 2.55 (m, 4H), 2.55 - 2.52 (m, 3H), 2.41 - 2.28 (m, 4H).EXAMPLE 46Synthesis of Compound 135

[0583] Compound 135 was prepared in 1 step:

[0584] Step 1: Starting with 4-(chloromethyl)-6-fluoro-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (50 mg, 0.097 mmol) and dimethylamine 2M in MeOH, following the geneal synthesis of Compound E.2. The product was combined with another batch and purified by prep basic to obtain the title compound (9.1 mg, 0.017 mmol, yield: 18%) after freeze drying as a white solid.

[0585] Yield: The title compound was isolated as a white solid (18% over 1 step).

[0586] Analysis: LCMS (Method T): tR= 1.63 min; mJz calculated for [M+H]+=525.2, found = 525.2; 1H NMR (400 MHz, DMSO) d 9.38 (s, 1H), 8.00 (d, J = 11.7 Hz, 1H), 7.46 (d, J = 6.9 Hz, 1H), 7.32 - 7.25 (m, 1H), 7.18 (s, 1H), 6.99 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 7.2 Hz, 1H), 4.04 (s, 2H), 3.63 (s, 2H), 3.08 (s, 3H), 2.94 (s, 3H), 2.54 - 2.51 (m, 3H), 2.18(s, 6H).EXAMPLE 47 Synthesis of Compound 136

[0587] Compound 136 was prepared in 1 step:

[0588] Step 1: Starting with 4-(bromomethyl)-6-chloro-3-((3-fluoro-2-((N- methylsulfamoyl)amino)pyridin-4-yl)methyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (151 mg, 0.055 mmol, purity: 21%) and dimethylamine 2M in MeOH (109 eq.), following the geneal synthesis of Compound E.2. The reaction was performed neat. The product was purified by prep acid to obtain the title compound (12 mg, 0.022 mmol, yield: 40%) after lyophilization as a light yellow solid.

[0589] Yield: Compound 136 was isolated as a light yellow solid (40% over 1 step)

[0590] Analysis: LCMS (Method V): tR= 2.96 min; mJz calculated for [M+H]+= 542.1, found = 542.1; 1H NMR (400 MHz, DMSO) d 8.22 (s, 1H), 7.89 (d, J = 5.2 Hz, 1H),7.50 (s, 1H), 6.78 (t, J = 5.1 Hz, 1H), 4.07 (s, 2H), 3.67 (s, 2H), 3.10 (s, 3H), 2.95 (s, 3H),2.51 (s, 3H), 2.20 (s, 6H).

[0591] Compound 205 was prepared in 3 steps:

[0592] Step 1: To a solution of 3-((2-chloro-3-fluoropyridin-4-yl)methyl)-4- methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.5 g, 1.279 mmol, 1.0 eq.) and ethanesulfonamide (1.41 g, 12.92 mmol, 10.1 eq.) in 1,4-dioxane (0.1 M) under inert atmosphere were added Xantphos (0.148 g, 0.256 mmol, 0.2 eq.), cesium carbonate (0.625 g, 1.919 mmol, 1.5 eq.) and PdOAc2 (0.049 g, 0.218 mmol, 0.17 eq.). The formed reaction mixture was stirred for 24 hours at 100 °C. The reaction mixture was filtered over celite and washed with H2O and CH2CI2. The layers of the filtrate were separated and the organic layer was washed with brine. Dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘flash’ (CthCh / MeOH = 1:0 — > 9:1). The still impure product was purified by prep basic to obtain 3-((2-(ethylsulfonamido)-3-fluoropyridin-4-yl)methyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (32 mg, 0.068 mmol, yield: 5.3%) as an off-white solid.

[0593] Step 2: Following the procedure of the geneal synthesis of Compound E.4 using NBS. The reaction was quenched with IN H2SO4 and the THF was removed under reduced pressure. The product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure to obtain the corresponding bromine (42 mg, 0.046 mmol, yield: 64%, purity: 59%) as a sticky yellow solid.

[0594] Step 3: Following the procedure of the geneal synthesis of Compound E.5 starting with 33 mg, 0.040 mmol of bromine and dimethylamine 2M in MeOH. The impure product was purified prep acid to obtain the title compound (8.4 mg, 0.016 mmol, yield: 40%) as a white solid.

[0595] Yield: Compound 205 was isolated as a white solid (1% over 3 steps).

[0596] Analysis: LCMS (Method L): tR= 2.32 min; mJz calculated for [M+H]+=519.2, found = 519.2; 1H NMR (400 MHz, DMSO-d6) d 8.25 (s, 1H), 8.08 (d, J = 8.9 Hz,1H), 7.78 (s, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.15 (dd, J = 8.8, 2.4 Hz, 1H), 6.57 (s, 1H), 4.03 (s, 2H), 3.65 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.21 (s, 7H), 0.92 (d, J = 41.0 Hz, 4H).EXAMPLE 49 Synthesis of Compound 137

[0597] Compound 137 was prepared in 3 steps:

[0598] Step 1: To a solution of 3-((2-chloro-3-fluoropyridin-4-yl)methyl)-4- methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (0.5 g, 1.279 mmol, 1.0 eq.) and ethanesulfonamide (1.41 g, 12.92 mmol, 10.1 eq.) in 1,4-dioxane (0.1 M) under inert atmosphere were added Xantphos (0.148 g, 0.256 mmol, 0.2 eq.), cesium carbonate (0.625 g, 1.919 mmol, 1.5 eq.) and PdOAc2 (0.049 g, 0.218 mmol, 0.17 eq.). The formed reaction mixture was stirred for 24 hours at 100 °C. The reaction mixture was filtered over celite and washed with H2O and CH2CI2. The layers of the filtrate were separated and the organic layer was washed with brine. Dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method1flash ’ (CH2Cl2 / MeOH = 1:0 — > 9:1). The still impure product was purified by prep basic to obtain 3-((2-(ethylsulfonamido)-3-fluoropyridin-4-yl)methyl)-4-methyl-2-oxo-2H-chromen-7-yl dimethylcarbamate (32 mg, 0.068 mmol, yield: 5.3%) as an off-white solid.

[0599] Step 2: Following the procedure of the geneal synthesis of Compound E.4 using NBS. The reaction was quenched with IN H2SO4 and the THF was removed under reduced pressure. The product was extracted with EtOAc. Combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to obtain the corresponding bromine (42 mg, 0.046 mmol, yield: 64%, purity: 59%) as a sticky yellow solid.

[0600] Step 3: Following the procedure of the geneal synthesis of Compound E.5 starting with 106 mg, 0.078 mmol of bromine and dimethylamine 2M in MeOH. The impure product was purified twice with prep acid to obtain the title compound (23 mg, 0.044 mmol, yield: 57%) as a white solid.

[0601] Yield: Compound 137 was isolated as a white solid (1% over 3 steps)

[0602] Analysis: LCMS (Method L): tR= 2.38 min; m / z calculated for [M+H]+=521.2, found = 521.2; 1H NMR (400 MHz, DMSO-d6) d 8.09 (d, J = 8.8 Hz, 1H), 7.87 (d, J = 5.0 Hz, 1H), 7.24 (d, J = 2.3 Hz, 1H), 7.16 (dd, J = 8.7, 2.4 Hz, 1H), 6.76 (s, 1H), 4.06 (s, 2H), 3.91 (s, 1H), 3.66 (s, 2H), 3.07 (s, 3H), 2.93 (s, 3H), 2.54 (s, 1H), 2.20 (s, 6H), 1.29 (d, J = 6.8 Hz, 6H).

[0603] Compound 138 was prepared in 2 steps:

[0604] Step 1: Starting with 4-(bromomethyl)-3-(2-fluoro-3-((N- methylsulfamoyl)amino)benzyl)-2-oxo-2H-chromen-7-yl dimethylcarbamate (100 mg, 0.184 mmol) and tert-butyl 2,5-diazabicyclo[2.2.1 ]heptane-2-carboxylate, following the geneal synthesis of Compound E.2, with the exception that the reaction was performed in CH2CI2 and Et3N (1.8 eq) was added. After full conversion water was added and the product was extracted with CH2CI2. Combined organic layers were washed with brine, dried over Na2S04, filtered and concentrated under reduced pressure. The impure product was purified by column chromatography with method ‘ flash ’ (heptane / EtOAc = 1:0 — > 1:9). Desired fractions were combined and concentrated under reduced pressure to ...