Hepcidin mimetic compounds and uses thereof

Abstract

The present disclosure provides small molecule compounds that are hepcidin mimetics. In addition, the present disclosure also encompasses pharmaceutical compositions that include the small molecule compounds and a pharmaceutically acceptable carrier, excipient or vehicle. The present disclosure also encompasses kits that include the small molecule compounds or the pharmaceutical compositions. The present disclosure also encompasses methods of using the hepcidin mimetic compounds.

Description

HEPCIDIN MIMETIC COMPOUNDS AND USES THEREOFCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefit of priority to U. S. Provisional Application No.63 / 716,485, filed November 5, 2024, U. S. Provisional Application No. 63 / 799,025, filed May 2, 2025, and U. S. Provisional Application No. 63 / 871,471, filed August 27, 2025, the disclosures of each of which are incorporated herein by reference in their entireties.INTRODUCTION

[0002] Hepcidin (also referred to as LEAP-1), a peptide hormone produced by the liver, is a regulator of iron homeostasis in humans and other mammals. Hepcidin acts by binding to its receptor, the iron export channel ferroportin, causing its internalization and degradation. Human hepcidin is a 25-amino acid peptide (Hep25). See Krause et al. (2000) FEBS Lett 480:147-150, and Park et aL (2001) J Biol Chem 276:7806-7810. The structure of the bioactive 25-amino acid form of hepcidin is a simple hairpin with 8 cysteines that form 4 disulfide bonds as described by Jordan et al. J Biol Chem 284:24155-67. The N terminal region is required for iron-regulatory function, and deletion of 5 N-terminal amino acid residues results in a loss of iron-regulatory function. See Nemeth et al. (2006) Blood 107:328-33.

[0003] Abnormal hepcidin activity is associated with iron metabolism disorders and diseases, including hereditary hemochromatosis (HH) and iron-loading anemias. Hereditary hemochromatosis is a genetic iron overload disease that is mainly caused by hepcidin deficiency, or in some cases by hepcidin resistance. This allows excessive absorption of iron from the diet and development of iron overload. Clinical manifestations of HH may include liver disease (e.g., hepatic cirrhosis and hepatocellular carcinoma), diabetes, and heart failure. Currently, the only treatment for HH is regular phlebotomy, which is very burdensome for the patients. Iron-loading anemias are hereditary anemias with ineffective erythropoiesis such as P-thalassemia, which are accompanied by severe iron overload. Complications from iron overload are the main cause of morbidity and mortality for these patients. Hepcidin deficiency is the main cause of iron overload in non-transfused patients and contributes to iron overload in transfused patients. The current treatment for iron overload in these patients is iron chelation, which is burdensome, sometimes ineffective, and accompanied by frequent side effects. Abnormal hepcidin activity is also associated with diseases and disorders associated with high calorie diets. Increased total body fat levels have been found to be correlated with abnormal hepcidin levels and abnormal iron homeostasis.

[0004] Polycythemia vera (PV) is characterized by the World Health Organization as a myeloproliferative neoplasm. As PV is a disease characterized by increased erythropoiesis, it has been shown in animal models that high doses of hepcidin peptide mimetics can ameliorate this disease by diminishing erythropoiesis.

[0005] Hepcidin has several limitations that hinder its use as a drug, including a difficult synthesis process due in part to aggregation and precipitation of the protein during folding, which in turn leads to high cost of goods. There is need for compounds having hepcidin-like activity coupled with additional beneficial physical properties.SUMMARY

[0006] Hepcidin mimetics work by biologically mimicking the peptide hormone hepcidin. Compounds that are hepcidin mimetics are compounds that have the same or similar biological activity as hepcidin.

[0007] The present disclosure provides small molecule compounds that are hepcidin mimetics, having hepcidin-like activity and other advantageous properties. The present disclosure describes the preparation of hepcidin mimetic compounds. In addition, the present disclosure also encompasses pharmaceutical compositions, kits and methods of using hepcidin mimetic compounds.

[0008] Aspects of the present disclosure include compounds of formula (I):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;n is 0 or 1;B is selected fromX is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0009] In some embodiments, Raof the compound of formula (I) is phenyl or substituted phenyl. In some embodiments, R8of the compound of formula (I) is H. In some embodiments, R9of the compound of formula (I) is H. In some embodiments, B of the compound of formula (I) isO. In some embodiments, B of the compound of formulaUxwherein X is -CR11-. In some embodiments, B of the compound of formula (I) is O,wherein X is -NH-. In some embodiments, R14of the compound of formula (I) is R16, and R16is selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0010] Aspects of the present disclosure include compounds of formula (II):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;B is selected fromX is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0011] Aspects of the present disclosure include compounds of the formula (III):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR14is R16or -C(O)NH-R16;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0012] Aspects of the present disclosure include compounds of the formula (I II A):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;Y is CR13;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0013] Aspects of the present disclosure include compounds of formula (IV):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR14is R16or -C(O)NH-R16;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0014] In some embodiments, R8of the compound of formula (IV) is H. In some embodiments, R9of the compound of formula (IV) is H. In some embodiments, X of the compound of formula (IV) is -CR11-. In some embodiments, X of the compound of formula (IV) is -NH-. In some embodiments, m of the compound of the formula (IV) is 0. In some embodiments, m of the compound of the formula (IV) is 1. In some embodiments, R14of the compound of formula (IV) is R16, and R16is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0015] In some embodiments, the compound of any of formulae (I) to (IV) has an EC50of 50 nM or less, 25 nm or less, 10 nM or less, or 5 nM or less in the NanoLuc assay or T47D assay (see, e.g., Example 4).

[0016] In some embodiments, the compound is selected from:

[0017] Aspects of the present disclosure include compounds of formula (IA):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R7is selected from H, alkyl and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR16is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0018] In some embodiments, R3is methyl or methoxy.

[0019] In some embodiments, R7is H or methyl.

[0020] In some embodiments, R12and R13are each independently H or methyl.

[0021] In some embodiments, R16is heteroaryl or substituted heteroaryl.

[0022] In some embodiments, R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl.

[0023] In some embodiments, the compound is selected from:EV

[0024] Aspects of the present disclosure include compounds of formula (IB):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19and R20are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0025] Aspects of the present disclosure include compounds of formula (IC):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19, R20and R21are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0026] In certain embodiments of formula (IB) or formula (IC), the compound is selected from:

[0027] Aspects of the present disclosure include compounds of formula (ID):whereinR3is haloalkyl; andR22is selected from pyridinyl, pyrimidinyl, pyridazinyl, [1,2,4]triazolo[1,5-a]pyridinyl, and [1,2,4]triazolo[1,5-a]pyrazinyl, wherein R22is optionally substituted with one or more groups selected from halo, haloalkyl, alkyl, and alkoxy, and combinations thereof.

[0028] In some embodiments, R3is difluoroethyl.

[0029] In some embodiments, the compound is selected from:

[0030] Aspects of the present disclosure include compounds of formula (V):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;p is 0 or 1;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0031] Aspects of the disclosure include compounds of formula (VI):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0032] Aspects of the disclosure include compounds of formula (VII):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0033] Aspects of the disclosure include compounds of formula (VIII):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, amino, substituted amino, carboxyl ester, amino acyl, cyano, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 or 2.

[0034] In some embodiments, Raof the compound of any of formulae (V) to (VIII) is phenyl or substituted phenyl. In some embodiments, Raof the compound of any of formulae (V) to (VIII) is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl. In some embodiments, R8of the compound of any of formulae (V) to (VIII) is H. In some embodiments, R9of the compound of any of formulae (V) to (VIII) is H. In some embodiments, p and m of the compound of any of formulae (V) to (VIII) are 1 and 0, respectively. In some embodiments, A of the compound of any of formulae (V) to (VIII) is heterocycloalkyl or substituted heterocycloalkyl. In some embodiments, A of thecompound of any of formulae (V) to (VIII) is piperazinyl, substituted piperazinyl, piperidinyl, or substituted piperidinyl. In some embodiments, X of the compound of any of formulae (V) to (VIII) is NH. In some embodiments, R10of the compound of any of formulae (V) to (VIII) is aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some embodiments, R10of the compound of any of formulae (V) to (VIII) is pyridinyl, substituted pyridinyl, benzimidazolyl substituted benzimidazolyl, phenyl, or substituted phenyl. In some embodiments, R10of the compound of any of formulae (V) to (VIII) is alkyl or substituted alkyl. In some embodiments, R10of the compound of any of formulae (V) to (VIII) is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl. In some embodiments, R10of the compound of any of formulae (V) to (VIII) is carboxyl ester.

[0035] In some embodiments, A of the compound of any of formulae (V) to (VIII) is substituted piperazinyl or substituted piperidinyl, where the substituted piperazinyl or substituted piperidinyl includes a substituent selected from alkyl, alkoxyl, and alkyl amine.

[0036] In some embodiments, the compound of any of formulae (V) to (VIII) has an EC50of 50 nM or less, 25 nm or less, 10 nM or less, or 5 nM or less in the NanoLuc assay (see, e.g., Example 4).

[0037] In some embodiments, the compound is selected from:

[0038] Aspects of the present disclosure include a compound of formula (VA):whereinR3is selected from H, hydroxyl, alkyl, substituted alkyl, alkoxy and substituted alkoxy;R6bis selected from H, alkyl and substituted alkyl;R7is selected from H, alkyl and substituted alkyl;each R10is independently selected from H, alkyl, substituted alkyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andR18is selected from H, alkyl and substituted alkyl.

[0039] In some embodiments, R3is methoxy or substituted methoxy.

[0040] In some embodiments, R7is H or methyl.

[0041] In some embodiments, R10is selected from substituted alkyl, cycloalkyl and substituted aryl.

[0042] In some embodiments, R18is H or methyl.

[0043] In some embodiments, the compound is selected from:

[0044] Aspects of the present disclosure include a pharmaceutical composition comprising a compound according to the present disclosure, and a pharmaceutically acceptable carrier, excipient or vehicle.

[0045] Aspects of the present disclosure include a method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of the present disclosure.

[0046] Aspects of the present disclosure include a method for treating a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject.

[0047] Aspects of the present disclosure include a method for treating a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject. In some embodiments, the disease or disorder is a disease of iron metabolism. In some embodiments, the disease of iron metabolism is an iron overload disease. In some embodiments, the disease or disorder is a hemochromatosis, a thalassemia, or a polycythemia vera.

[0048] In some embodiments, the compound is compound 494, 495, 504, 612, 620, 622, 623, or 797.

[0049] Aspects of the present disclosure include a method for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject. In some embodiments, the disease or disorder associated with a high calorie diet is selected from obesity, diet-induced obesity, steatosis (fatty liver disease), hepatic stenosis, iron overload disease, iron deficiency disorder, hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, alpha thalassemia, β-thalassemia, sideroblastic anemia, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia, anemia of chronic disease, anemia of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease, erythropoietin resistance, iron deficiency of obesity, other anemias, benign or malignant tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, hereditary hemochromatosis, and Alzheimer's disease.

[0050] Aspects of the present disclosure further include kits. According to some embodiments, the kits comprise a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound.BRIEF DESCRIPTION OF THE FIGURES

[0051] Figures 1A-1D provide the results of an in vivo assay to test whether the compounds of the invention can function as a hepcidin mimetic. The in vivo test determines the ability of the compounds to decrease free iron (Fe2+) in serum. (See Example 7). Serum iron results are shown in Figure 1A for Compounds 495, 494, and 504. All compounds show significant reduction of iron levels after oral administration; and oral dose-response was tested and observed for Compound 504. Figure IB shows in vivo serum iron time course results for Compounds 612, 622, and 623 when orally dosed at 7.5 mg / kg. These compounds also exhibit significant reduction of iron levels after oral dosing. Figure 1C shows in vivo serum iron time course results for Compounds 620 and 623 when orally administered at 30 mg / kg, which shows these compounds exhibit significant reduction of iron levels after oral dosing. Figure ID shows in vivo serum iron time course results for Compound 797 when orally administered at 30 mg / kg, which shows this compound exhibits significant reduction of iron levels after oral dosing.

[0052] Figures 2A and 2B show the serum iron analysis for oral doses of a compound of the present disclosure (e.g., a compound of Formula (ID)) in dogs and monkeys, respectively. As discussed in Example 7, these results indicate a dose response for mean serum iron reduction, with >70% reduction observed for all compound doses.DEFINITIONS

[0053] The following terms have the following meanings unless otherwise indicated. Any undefined terms have their art recognized meanings.

[0054] "Alkyl" refers to monovalent saturated aliphatic hydrocarbyl groups having from 1 to 10 carbon atoms and such as 1 to 6 carbon atoms, or 1 to 5, or 1 to 4, or 1 to 3 carbon atoms. This term includes, by way of example, linear and branched hydrocarbyl groups such as methyl (CH3-), ethyl (CH3CH2-), n-propyl (CH3CH2CH2-), isopropyl ((CH₃)₂CH-), n-butyl (CH3CH2CH2CH2-), isobutyl ((CH3)2CHCH2-), sec-butyl ((CH3)(CH3CH2)CH-), t-butyl ((CH3)3C-), n-pentyl (CH3CH2CH2CH2CH2-), and neopentyl ((CH₃)₃CCH₂-). In some instances, one or more hydrogens in an alkyl group may be replaced with deuterium (D).

[0055] The term "substituted alkyl" refers to an alkyl group as defined herein wherein one or more carbon atoms in the alkyl chain (except the Ci carbon atom) have been optionally replaced with aheteroatom such as -O-, -N-, -S(O)n- (where n is 0 to 2), -NR- (where R is hydrogen or alkyl) and having from 1 to 5 substituents selected from the group consisting of alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-aryl, -SO2-heteroaryl, and -NRaRb, wherein R and R may be the same or different and are chosen from hydrogen, optionally substituted alkyl, cycloalkyl, alkenyl, cycloalkenyl, alkynyl, aryl, heteroaryl and heterocyclic. Substituted alkyl may also include alkyl groups where one or more hydrogen atoms have been replaced with deuterium (D), such as -CD3, -CHD2, -CH2D, and the like.

[0056] "Alkylene" refers to divalent aliphatic hydrocarbyl groups preferably having from 1 to 6 and more preferably 1 to 3 carbon atoms that are either straight-chained or branched, and which are optionally interrupted with one or more groups selected from -O-, -NR10-, -NR10C(O)-, -C(O)NR10- and the like. This term includes, by way of example, methylene (-CH2-), ethylene (-CH2CH2-), n-propylene (-CH2CH2CH2-), iso-propylene (-CH2CH(CH3)-), (-C(CH3)2CH2CH2-), (-C(CH3)2CH2C(O)-),(-C(CH3)2CH2C(O)NH-), (-CH(CH3)CH2-), and the like. In some instances, one or more hydrogens in an alkylene group may be replaced with deuterium (D), such as -CHD- or -CD2-.

[0057] "Substituted alkylene" refers to an alkylene group having from 1 to 3 hydrogens replaced with substituents as described for carbons in the definition of "substituted" below.

[0058] The term "alkane" refers to alkyl group and alkylene group, as defined herein.

[0059] The term "alkylaminoalkyl", "alkylaminoalkenyl" and "alkylaminoalkynyl" refers to the groups R'NHR"- where R' is alkyl group as defined herein and R" is alkylene, alkenylene or alkynylene group as defined herein.

[0060] The term "alkaryl" or "aralkyl" refers to the groups -alkylene-aryl and -substituted alkylenearyl where alkylene, substituted alkylene and aryl are defined herein.

[0061] "Alkoxy" refers to the group -O-alkyl, wherein alkyl is as defined herein. Alkoxy includes, by way of example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, t-butoxy, sec-butoxy, n-pentoxy, and the like. The term "alkoxy" also refers to the groups alkenyl-O-, cycloalkyl-O-, cycloalkenyl-O-, and alkynyl-O-, where alkenyl, cycloalkyl, cycloalkenyl, and alkynyl are as defined herein.

[0062] The term "substituted alkoxy" refers to the groups substituted alkyl-O-, substituted alkenyl-O-, substituted cycloalkyl-O-, substituted cycloalkenyl-O-, and substituted alkynyl-O- where substitutedalkyl, substituted alkenyl, substituted cycloalkyl, substituted cycloalkenyl and substituted alkynyl are as defined herein.

[0063] The term "alkoxyamino" refers to the group -NH-alkoxy, wherein alkoxy is defined herein.

[0064] The term "haloalkoxy" refers to the groups alkyl-O- wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group and include, by way of examples, groups such as trifluoromethoxy, and the like.

[0065] The term "haloalkyl" refers to a substituted alkyl group as described above, wherein one or more hydrogen atoms on the alkyl group have been substituted with a halo group. Examples of such groups include, without limitation, fluoroalkyl groups, such as trifluoromethyl, difluoromethyl, trifluoroethyl and the like.

[0066] The term "alkylalkoxy" refers to the groups -alkylene-O-alkyl, alkylene-O-substituted alkyl, substituted alkylene-O-alkyl, and substituted alkylene-O-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0067] The term "alkylthioalkoxy" refers to the group -alkylene-S-alkyl, alkylene-S-substituted alkyl, substituted alkylene-S-alkyl and substituted alkylene-S-substituted alkyl wherein alkyl, substituted alkyl, alkylene and substituted alkylene are as defined herein.

[0068] "Alkenyl" refers to straight chain or branched hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 4 carbon atoms and having at least 1 and preferably from 1 to 2 sites of double bond unsaturation. This term includes, by way of example, bi-vinyl, allyl, and but-3-en-l-yl. Included within this term are the cis and trans isomers or mixtures of these isomers.

[0069] The term "substituted alkenyl" refers to an alkenyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-aryl and -SO₂-heteroaryl.

[0070] "Alkynyl" refers to straight or branched monovalent hydrocarbyl groups having from 2 to 6 carbon atoms and preferably 2 to 3 carbon atoms and having at least 1 and preferably from 1 to 2 sites of triple bond unsaturation. Examples of such alkynyl groups include acetylenyl (-CECH), and propargyl (-CHJC CH).

[0071] The term "substituted alkynyl" refers to an alkynyl group as defined herein having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO₂-alkyl, -SO₂-substituted alkyl, -SO₂-aryl, and -SO₂-heteroaryl.

[0072] "Alkynyloxy" refers to the group -O-alkynyl, wherein alkynyl is as defined herein. Alkynyloxy includes, by way of example, ethynyloxy, propynyloxy, and the like.

[0073] "Acyl" refers to the groups H-C(O)-, alkyl-C(O)-, substituted alkyl-C(O)-, alkenyl-C(O)-, substituted alkenyl-C(O)-, alkynyl-C(O)-, substituted alkynyl-C(O)-, cycloalkyl-C(O)-, substituted cycloalkyl-C(O)-, cycloalkenyl-C(O)-, substituted cycloalkenyl-C(O)-, aryl-C(O)-, substituted aryl-C(O)-, heteroaryl-C(O)-, substituted heteroaryl-C(O)-, heterocyclyl-C(O)-, and substituted heterocyclyl-C(O)-, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein. For example, acyl includes the "acetyl" group CH3C(O)-

[0074] "Acylamino" refers to the groups -NR20C(O)alkyl, -NR20C(O)substituted alkyl, -NR20C(O)cycloalkyl, -NR20C(O)substituted cycloalkyl, -NR20C(O)cycloalkenyl, -NR20C(O)substituted cycloalkenyl, -NR20C(O)alkenyl, -NR20C(O)substituted alkenyl, -NR20C(O)alkynyl, -NR20C(O)substituted alkynyl, -NR20C(O)aryl, -NR20C(O)substituted aryl, -NR20C(O)heteroaryl, -NR20C(O)substituted heteroaryl, -NR20C(O)heterocyclic, and -NR20C(O)substituted heterocyclic, wherein R20is hydrogen or alkyl and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0075] "Aminocarbonyl" or the term "aminoacyl" refers to the group -C(O)NR21R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl,substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0076] "Aminocarbonylamino" refers to the group -NR21C(O)NR22R23where R21, R22, and R23are independently selected from hydrogen, alkyl, aryl or cycloalkyl, or where two R groups are joined to form a heterocyclyl group.

[0077] The term "alkoxycarbonylamino" refers to the group -NRC(O)OR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclyl wherein alkyl, substituted alkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0078] The term "acyloxy" refers to the groups alkyl-C(O)O-, substituted alkyl-C(O)O-, cycloalkyl-C(O)O-, substituted cycloalkyl-C(O)O-, aryl-C(O)O-, heteroaryl-C(O)O-, and heterocyclyl-C(O)O- wherein alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, aryl, heteroaryl, and heterocyclyl are as defined herein.

[0079] "Aminosulfonyl" refers to the group -SO2NR21R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, substituted heterocyclic and where R21and R22are optionally joined together with the nitrogen bound thereto to form a heterocyclic or substituted heterocyclic group and alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic and substituted heterocyclic are as defined herein.

[0080] "Sulfonylamino" refers to the group -NR21SO2R22, wherein R21and R22independently are selected from the group consisting of hydrogen, alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, aryl, substituted aryl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic and where R21and R22are optionally joined together with the atoms bound thereto to form a heterocyclic or substituted heterocyclic group, and wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0081] "Aryl" or "Ar" refers to a monovalent aromatic carbocyclic group of from 6 to 18 carbon atoms having a single ring (such as is present in a phenyl group) or a ring system having multiple condensed rings (examples of such aromatic ring systems include naphthyl, anthryl and indanyl) whichcondensed rings may or may not be aromatic, provided that the point of attachment is through an atom of an aromatic ring. This term includes, by way of example, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, naphthyl, benzoimidazolyl, benzoisoxazolyl, triazolopyridinyl, quinolinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, pyrazolopyridinyl, benzooxazolyl, and the like. Unless otherwise constrained by the definition for the aryl substituent, such aryl groups can optionally be substituted with from 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, oxo, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO₂-substituted alkyl, -SO₂-aryl, -SO₂-heteroaryl and trihalomethyl.

[0082] "Aryloxy" refers to the group -O-aryl, wherein aryl is as defined herein, including, by way of example, phenoxy, naphthoxy, and the like, including optionally substituted aryl groups as also defined herein.

[0083] "Amino" refers to the group -NH2.

[0084] The term "substituted amino" refers to the group -NRR where each R is independently selected from the group consisting of hydrogen, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, alkenyl, substituted alkenyl, cycloalkenyl, substituted cycloalkenyl, alkynyl, substituted alkynyl, aryl, heteroaryl, and heterocyclyl provided that at least one R is not hydrogen.

[0085] The term "azido" refers to the group -N3.

[0086] "Carboxyl," "carboxy" or "carboxylate" refers to -CO2H or salts thereof.

[0087] "Carboxyl ester" or "carboxy ester" or the terms "carboxyalkyl" or "carboxylalkyl" refers to the groups -C(O)O-alkyl, -C(O)O-substituted alkyl, -C(O)O-alkenyl, -C(O)O-substitutedalkenyl, -C(O)O-alkynyl, -C(O)O-substituted alkynyl, -C(O)O-aryl, -C(O)O-substitutedaryl, -C(O)O-cycloalkyl, -C(O)O-substituted cycloalkyl, -C(O)O-cycloalkenyl, -C(O)O-substituted cycloalkenyl, -C(O)O-heteroaryl, -C(O)O-substituted heteroaryl, -C(O)O-heterocyclic,and -C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0088] "(Carboxyl ester)oxy" or "carbonate" refers to the groups -O-C(O)O-alkyl, -O-C(O)O-substituted alkyl, -O-C(O)O-alkenyl, -O-C(O)O-substituted alkenyl, -O-C(O)O-alky nyl, -O-C(O)O-substituted alkynyl, -O-C(O)O-aryl, -O-C(O)O-substituted aryl, -O-C(O)O-cycloalkyl, -O-C(O)O-substituted cycloalkyl, -O-C(O)O-cycloalkenyl, -O-C(O)O-substituted cycloalkenyl, -O-C(O)O-heteroaryl, -O-C(O)O-substituted heteroaryl, -O-C(O)O-heterocyclic, and -O-C(O)O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0089] "Cyano" or "nitrile" refers to the group -CN.

[0090] "Cycloalkyl" refers to cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple cyclic rings including fused, bridged, and spiro ring systems. Examples of suitable cycloalkyl groups include, for instance, adamantyl, cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl and the like. Such cycloalkyl groups include, by way of example, single ring structures such as cyclopropyl, cyclobutyl, cyclopentyl, cyclooctyl, and the like, or multiple ring structures such as adamantanyl, and the like.

[0091] The term "substituted cycloalkyl" refers to cycloalkyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0092] "Cycloalkenyl" refers to non-aromatic cyclic alkyl groups of from 3 to 10 carbon atoms having single or multiple rings and having at least one double bond and preferably from 1 to 2 double bonds.

[0093] The term "substituted cycloalkenyl" refers to cycloalkenyl groups having from 1 to 5 substituents, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, keto, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl.

[0094] "Cycloalkynyl" refers to non-aromatic cycloalkyl groups of from 5 to 10 carbon atoms having single or multiple rings and having at least one triple bond.

[0095] "Cycloalkoxy" refers to -O-cycloalkyl.

[0096] "Cycloalkenyloxy" refers to -O-cycloalkenyl.

[0097] Halo" or "halogen" refers to fluoro, chloro, bromo, and iodo.

[0098] "Hydroxy" or "hydroxyl" refers to the group -OH.

[0099] "Heteroaryl" refers to an aromatic group of from 1 to 15 carbon atoms, such as from 1 to 10 carbon atoms and 1 to 10 heteroatoms selected from the group consisting of oxygen, nitrogen, and sulfur within the ring. Such heteroaryl groups can have a single ring (such as, pyridinyl, imidazolyl or furyl) or multiple condensed rings in a ring system (for example as in groups such as, indolizinyl, quinolinyl, benzofuran, benzimidazolyl or benzothienyl), wherein at least one ring within the ring system is aromatic. To satisfy valence requirements, any heteroatoms in such heteroaryl rings may or may not be bonded to H or a substituent group, e.g., an alkyl group or other substituent as described herein. In certain embodiments, the nitrogen and / or sulfur ring atom(s) of the heteroaryl group are optionally oxidized to provide for the N-oxide (N-> O), sulfinyl, or sulfonyl moieties. This term includes, by way of example, pyridinyl, pyrrolyl, indolyl, thiophenyl, and furanyl. Unless otherwise constrained by the definition for the heteroaryl substituent, such heteroaryl groups can be optionally substituted with 1 to 5 substituents, or from 1 to 3 substituents, selected from acyloxy, hydroxy, thiol, acyl, alkyl, alkoxy, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, substituted alkyl, substituted alkoxy, substituted alkenyl, substituted alkynyl, substituted cycloalkyl, substituted cycloalkenyl, amino, substituted amino, aminoacyl, acylamino, alkaryl, aryl, aryloxy, azido, carboxyl, carboxylalkyl, cyano, halogen, nitro, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, aminoacyloxy, oxyacylamino, thioalkoxy, substituted thioalkoxy, thioaryloxy, thioheteroaryloxy, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl and -SO2-heteroaryl, and trihalomethyl.

[0100] The term "heteroaralkyl" refers to the groups -alkylene-heteroaryl where alkylene and heteroaryl are defined herein. This term includes, by way of example, pyridylmethyl, pyridylethyl, indolylmethyl, and the like.

[0101] "Heteroaryloxy" refers to -O-heteroaryL

[0102] "Heterocycle," "heterocyclic," "heterocycloalkyl," and "heterocyclyl" refer to a saturated or unsaturated group having a single ring or multiple condensed rings, including fused bridged and spiro ring systems, and having from 3 to 20 ring atoms, including 1 to 10 hetero atoms. These ring atoms are selected from nitrogen, sulfur, or oxygen, where, in fused ring systems, one or more of the rings can be cycloalkyl, aryl, or heteroaryl, provided that the point of attachment is through the non-aromatic ring. In certain embodiments, the nitrogen and / or sulfur atom(s) of the heterocyclic group are optionally oxidized to provide for the N-oxide, -S(O)-, or-SO2- moieties. To satisfy valence requirements, anyheteroatoms in such heterocyclic rings may or may not be bonded to one or more H or one or more substituent group(s), e.g., an alkyl group or other substituent as described herein.

[0103] Examples of heterocycles and heteroaryls include, but are not limited to, azetidine, pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, indolizine, isoindole, indole, dihydroindole, indazole, purine, quinolizine, isoquinoline, quinoline, phthalazine, naphthylpyridine, quinoxaline, quinazoline, cinnoline, pteridine, carbazole, carboline, phenanthridine, acridine, phenanthroline, isothiazole, phenazine, isoxazole, phenoxazine, phenothiazine, imidazolidine, imidazoline, piperidine, piperazine, indoline, phthalimide, 1,2,3,4-tetrahydroisoquinoline, 4, 5,6,7-tetrahydrobenzo[b]thiophene, thiazole, thiazolidine, thiophene, benzo[b]thiophene, morpholinyl, thiomorpholinyl (also referred to as thiamorpholinyl), 1,1-dioxothiomorpholinyl, piperidinyl, pyrrolidine, tetrahydrofuranyl, and the like.

[0104] Unless otherwise constrained by the definition for the heterocyclic substituent, such heterocyclic groups can be optionally substituted with 1 to 5, or from 1 to 3 substituents, selected from alkoxy, substituted alkoxy, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, acyl, acylamino, acyloxy, amino, substituted amino, aminoacyl, aminoacyloxy, oxyaminoacyl, azido, cyano, halogen, hydroxyl, oxo, thioketo, carboxyl, carboxylalkyl, thioaryloxy, thioheteroaryloxy, thioheterocyclooxy, thiol, thioalkoxy, substituted thioalkoxy, aryl, aryloxy, heteroaryl, heteroaryloxy, heterocyclyl, heterocyclooxy, hydroxyamino, alkoxyamino, nitro, -SO-alkyl, -SO-substituted alkyl, -SO-aryl, -SO-heteroaryl, -SO2-alkyl, -SO2-substituted alkyl, -SO2-aryl, -SO2-heteroaryl, and fused heterocycle.

[0105] "Heterocyclyloxy" refers to the group -O-heterocyclyl.

[0106] The term "heterocyclylthio" refers to the group heterocyclic-S-.

[0107] The term "heterocyclene" refers to the diradical group formed from a heterocycle, as defined herein.

[0108] The term "hydroxyamino" refers to the group -NHOH.

[0109] "Nitro" refers to the group -NO2.

[0110] "Oxo" refers to the atom (=0).

[0111] "Sulfonyl" refers to the group -SO2-alkyl, -SO2-substituted alkyl, -SO2-alkenyl, -SO2-substituted alkenyl, -SO2-cycloalkyl, -SO2-substituted cylcoalkyl, -SO2-cycloalkenyl, -SO2-substituted cylcoalkenyl, -SO2-aryl, -SO2-substituted aryl, -SO2-heteroaryl, -SO2-substituted heteroaryl, -SO2-heterocyclic, and -SO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substitutedheterocyclic are as defined herein. Sulfonyl includes, by way of example, methyl-SO2-, phenyl-SO2-, and 4-methylphenyl-SO2-.

[0112] "Sulfonyloxy" refers to the group -OSO2-alkyl, -OSO2-substituted alkyl, -OSO2-alkenyl, -OSO2-substituted alkenyl, -OSO2-cycloalkyl, -OSO2-substituted cylcoalkyl, -OSO2-cycloalkenyl, -OSO2-substituted cylcoalkenyl, -OSO2-aryl, -OSO2-substituted aryl, -OSO2-heteroaryl, -OSO2-substituted heteroaryl, -OSO2-heterocyclic, and -OSO2-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0113] "Sulfate" or "sulfate ester" refers the group -O-SO2-OH, -O-SO2-O-alkyl, -O-SO2-O-substituted alkyl, -O-SO2-O-alkenyl, -O-SO2-O-substituted alkenyl, -O-SO2-O-cycloalkyl, -O-SO2-O-substituted cylcoalkyl, -O-SO2-O-cycloalkenyl, -O-SO2-O-substituted cylcoalkenyl, -O-SO2-O-aryl, -O-SO2-O-substituted aryl, -O-SO2-O-heteroaryl, -O-SO2-O-substituted heteroaryl, -O-SO2-O-heterocyclic, and -O-SO2-O-substituted heterocyclic, wherein alkyl, substituted alkyl, alkenyl, substituted alkenyl, alkynyl, substituted alkynyl, cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, aryl, substituted aryl, heteroaryl, substituted heteroaryl, heterocyclic, and substituted heterocyclic are as defined herein.

[0114] The term "aminocarbonyloxy" refers to the group -OC(O)NRR where each R is independently hydrogen, alkyl, substituted alkyl, aryl, heteroaryl, or heterocyclic wherein alkyl, substituted alkyl, aryl, heteroaryl and heterocyclic are as defined herein.

[0115] "Thiol" refers to the group -SH.

[0116] "Thioxo" or the term "thioketo" refers to the atom (=S).

[0117] "Alkylthio" or the term "thioalkoxy" refers to the group -S-alkyl, wherein alkyl is as defined herein. In certain embodiments, sulfur may be oxidized to -S(O)-. The sulfoxide may exist as one or more stereoisomers.

[0118] The term "substituted thioalkoxy" refers to the group -S-substituted alkyl.

[0119] The term "thioaryloxy" refers to the group aryl-S- wherein the aryl group is as defined herein including optionally substituted aryl groups also defined herein.

[0120] The term "thioheteroaryloxy" refers to the group heteroaryl-S- wherein the heteroaryl group is as defined herein including optionally substituted aryl groups as also defined herein.

[0121] The term "thioheterocyclooxy" refers to the group heterocyclyl-S- wherein the heterocyclyl group is as defined herein including optionally substituted heterocyclyl groups as also defined herein.

[0122] In addition to the disclosure herein, the term "substituted," when used to modify a specified group or radical, can also mean that one or more hydrogen atoms of the specified group or radical are each, independently of one another, replaced with the same or different substituent groups as defined below.

[0123] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for substituting for one or more hydrogens (any two hydrogens on a single carbon can be replaced with =0, =NR70, =N-OR70, =N2or =S) on saturated carbon atoms in the specified group or radical are, unless otherwise specified, -R60, halo, =0, -OR70, -SR70, -NR80R80,trihalomethyl, -CN, -OCN, -SCN, -NO, -NO2, =N2, -N3, -SO2R70, -S020“M+, -SO2OR70, -OSO2R70, -OSO2O“ M+, -OSO2OR70, -P(O)(O’)2(l\ / l+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)O“ M+, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)O⁻ M+, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2- M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C(NR70)NR80R80, where R60is selected from the group consisting of optionally substituted alkyl, cycloalkyl, heteroalkyl, heterocycloalkylalkyl, cycloalkylalkyl, aryl, arylalkyl, heteroaryl and heteroarylalkyl, each R70is independently hydrogen or R60; each R80is independently R70or alternatively, two R80s, taken together with the nitrogen atom to which they are bonded, form a 5-, 6- or 7-membered heterocycloalkyl which may optionally include from 1 to 4 of the same or different additional heteroatoms selected from the group consisting of O, N and S, of which N may have -H or C3-C3alkyl substitution; and each M+is a counter ion with a net single positive charge. Each M+may independently be, for example, an alkali ion, such as K+, Na+, Li+; an ammonium ion, such as+N(R60)4; or an alkaline earth ion, such as [Ca2+]o.s, [Mg2+]o.s, or [Ba2+]o.s ("subscript 0.5 means that one of the counter ions for such divalent alkali earth ions can be an ionized form of a compound of the invention and the other a typical counter ion such as chloride, or two ionized compounds disclosed herein can serve as counter ions for such divalent alkali earth ions, or a doubly ionized compound of the invention can serve as the counter ion for such divalent alkali earth ions). As specific examples, -NR80R80is meant to include -NH2, -NH-alkyl, N-pyrrolidinyl, N-piperazinyl, 4A / -methyl-piperazin-l-yl and / V-morpholinyl.

[0124] In addition to the disclosure herein, substituent groups for hydrogens on unsaturated carbon atoms in "substituted" alkene, alkyne, aryl and heteroaryl groups are, unless otherwise specified, -R60, halo, -O M+, -OR70, -SR70, -S’l\ / I+, -NR80R80,trihalomethyl, -CF3, -CN, -OCN, -SCN, -NO, -NO2, -N3, -SO2R70, -SO3’M+, -SO3R70, -OSO2R70, -OSO3“ M+, -OSO3R70, -PO3'2(M+)2, -P(O)(OR70)O-M+, -P(O)(OR70)2, -C(O)R70, -C(S)R70, -C(NR70)R70, -CO2-M+, -CO2R70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OCO2-M+, -OCO2R70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70CO2- M+, -NR70CO2R70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C(NR70)NR80R80, where R60, R70, R80and M+are as previously defined, provided that in case of substituted alkene or alkyne, the substituents are not -O’M‘, -OR70, -SR70, or -S"M+.

[0125] In addition to the groups disclosed with respect to the individual terms herein, substituent groups for hydrogens on nitrogen atoms in "substituted" heteroalkyl and cycloheteroalkyl groups are, unless otherwise specified, -R60, -O M+, -OR70, -SR70, -S’M+, -NR80R80,trihalomethyl, -CF3, -CN, -NO, -NO2, -S(O)2R70, -S(O)2O M+, -S(O)2OR70, -OS(O)2R70, -OS(O)2O‘M+, -OS(O)2OR70, -P(O)(O )2(M+)2, -P(O)(OR70)O M+, -P(O)(OR70)(OR70), -C(O)R70, -C(S)R70, -C(NR70)R70, -C(O)OR70, -C(S)OR70, -C(O)NR80R80, -C(NR70)NR80R80, -OC(O)R70, -OC(S)R70, -OC(O)OR70, -OC(S)OR70, -NR70C(O)R70, -NR70C(S)R70, -NR70C(O)OR70, -NR70C(S)OR70, -NR70C(O)NR80R80, -NR70C(NR70)R70and -NR70C(NR70)NR80R80, where R60, R70, R80and M+are as previously defined.

[0126] In addition to the disclosure herein, in a certain embodiment, a group that is substituted has 1, 2, 3, or 4 substituents, 1, 2, or 3 substituents, 1 or 2 substituents, or 1 substituent.

[0127] It is understood that in all substituted groups defined above, polymers arrived at by defining substituents with further substituents to themselves (e.g., substituted aryl having a substituted aryl group as a substituent which is itself substituted with a substituted aryl group, which is further substituted by a substituted aryl group, etc.) are not intended for inclusion herein. In such cases, the maximum number of such substitutions is three. For example, serial substitutions of substituted aryl groups specifically contemplated herein are limited to substituted aryl-(substituted aryl)-substituted aryl.

[0128] Unless indicated otherwise, the nomenclature of substituents that are not explicitly defined herein are arrived at by naming the terminal portion of the functionality followed by the adjacent functionality toward the point of attachment. For example, the substituent "arylalkyloxycarbonyl" refers to the group (aryl)-(alkyl)-O-C(O)-.

[0129] As to any of the groups disclosed herein which contain one or more substituents, it is understood, of course, that such groups do not contain any substitution or substitution patterns which are sterically impractical and / or synthetically non-feasible. In addition, the subject compounds include all stereochemical isomers arising from the substitution of these compounds.

[0130] The term "pharmaceutically acceptable salt" means a salt which is acceptable for administration to a patient, such as a mammal (salts with counterions having acceptable mammalian safety for a given dosage regime). Such salts can be derived from pharmaceutically acceptable inorganic or organic bases and from pharmaceutically acceptable inorganic or organic acids. "Pharmaceuticallyacceptable salt" refers to pharmaceutically acceptable salts of a compound, which salts are derived from a variety of organic and inorganic counter ions well known in the art and include, by way of example only, sodium, potassium, calcium, magnesium, ammonium, tetraalkylammonium, and the like; and when the molecule contains a basic functionality, salts of organic or inorganic acids, such as hydrochloride, hydrobromide, formate, tartrate, besylate, mesylate, acetate, maleate, oxalate, and the like.

[0131] The term "salt thereof" means a compound formed when a proton of an acid is replaced by a cation, such as a metal cation or an organic cation and the like. Where applicable, the salt is a pharmaceutically acceptable salt, although this is not required for salts of intermediate compounds that are not intended for administration to a patient. By way of example, salts of the present compounds include those wherein the compound is protonated by an inorganic or organic acid to form a cation, with the conjugate base of the inorganic or organic acid as the anionic component of the salt.

[0132] "Solvate" refers to a complex formed by combination of solvent molecules with molecules or ions of the solute. The solvent can be an organic compound, an inorganic compound, or a mixture of both. Some examples of solvents include, but are not limited to, methanol, W, / V-dimethylformamide, tetrahydrofuran, dimethylsulfoxide, and water. When the solvent is water, the solvate formed is a hydrate.

[0133] "Stereoisomer" and "stereoisomers" refer to compounds that have same atomic connectivity but different atomic arrangement in space. Stereoisomers include cis-trans isomers, E and Z isomers, enantiomers, and diastereomers.

[0134] "Tautomer" refers to alternate forms of a molecule that differ only in electronic bonding of atoms and / or in the position of a proton, such as enol-keto and imine-enamine tautomers, or the tautomeric forms of heteroaryl groups containing a -N=C(H)-NH- ring atom arrangement, such as pyrazoles, imidazoles, benzimidazoles, triazoles, and tetrazoles. A person of ordinary skill in the art would recognize that other tautomeric ring atom arrangements are possible.

[0135] It will be appreciated that the term "or a salt or solvate or stereoisomer thereof" is intended to include all permutations of salts, solvates and stereoisomers, such as a solvate of a pharmaceutically acceptable salt of a stereoisomer of subject compound.

[0136] While it may be possible for the compounds of the subject invention to be administered as the raw chemical, it is also possible to present them as a pharmaceutical composition. Accordingly, provided herein are pharmaceutical compositions which comprise one or more of certain compounds disclosed herein, or one or more pharmaceutically acceptable salts, esters, prodrugs, amides, or solvates thereof, together with one or more pharmaceutically acceptable carriers thereof and optionally one ormore other therapeutic ingredients. Other therapeutic ingredients may include one or more excipients and / or one or more vehicles. The carrier(s) must be "acceptable" in the sense of being compatible with the other ingredients of the formulation and not deleterious to the recipient thereof. 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. The pharmaceutical compositions disclosed herein may be manufactured in any manner known in the art, e.g., by means of conventional mixing, dissolving, granulating, drageemaking, levigating, emulsifying, encapsulating, entrapping or compression processes.

[0137] "Pharmaceutically effective amount" and "therapeutically effective amount" refer to an amount of a compound sufficient to treat a specified disorder or disease or one or more of its symptoms and / or to prevent the occurrence of the disease or disorder. In reference to tumorigenic proliferative disorders, a pharmaceutically or therapeutically effective amount comprises an amount sufficient to, among other things, cause the tumor to shrink or decrease the growth rate of the tumor.

[0138] Patient" refers to human and non-human subjects, especially mammalian subjects.

[0139] The term "treating" or "treatment" as used herein means the treating or treatment of a disease or medical condition in a patient, such as a mammal (particularly a human) that includes: (a) preventing the disease or medical condition from occurring, such as, prophylactic treatment of a subject; (b) ameliorating the disease or medical condition, such as, eliminating or causing regression of the disease or medical condition in a patient; (c) suppressing the disease or medical condition, for example by, slowing or arresting the development of the disease or medical condition in a patient; or (d) alleviating a symptom of the disease or medical condition in a patient.

[0140] As used herein the term "isolated" is meant to describe a compound of interest that is in an environment different from that in which the compound naturally occurs. "Isolated" is meant to include compounds that are within samples that are substantially enriched for the compound of interest and / or in which the compound of interest is partially or substantially purified.

[0141] As used herein, the term "substantially purified" refers to a compound that is removed from its natural environment and is at least 60% free, at least 75% free, at least 80% free, at least 85% free, at least 90% free, at least 95% free, at least 98% free, or more than 98% free, from other components with which it is naturally associated.

[0142] The term "physiological conditions" is meant to encompass those conditions compatible with living cells, e.g., predominantly aqueous conditions of a temperature, pH, salinity, etc. that are compatible with living cells.

[0143] Before the present invention is further described, it is to be understood that this invention is not limited to particular embodiments described, as such may, of course, vary. It is also to be understood that the terminology used herein is for the purpose of describing particular embodiments only, and is not intended to be limiting, since the scope of the present invention will be limited only by the appended claims.

[0144] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit unless the context clearly dictates otherwise, between the upper and lower limit of that range and any other stated or intervening value in that stated range, is encompassed within the invention. The upper and lower limits of these smaller ranges may independently be included in the smaller ranges, and are also encompassed within the invention, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both of the limits, ranges excluding either or both of those included limits are also included in the invention.

[0145] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination. All combinations of the embodiments pertaining to the invention are specifically embraced by the present invention and are disclosed herein just as if each and every combination was individually and explicitly disclosed, to the extent that such combinations embrace subject matter that are, for example, compounds that are stable compounds (i.e., compounds that can be made, isolated, characterized, and tested for biological activity). In addition, all sub-combinations of the various embodiments and elements thereof (e.g., elements of the chemical groups listed in the embodiments describing such variables) are also specifically embraced by the present invention and are disclosed herein just as if each and every such sub-combination was individually and explicitly disclosed herein.

[0146] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any methods and materials similar or equivalent to those described herein can also be used in the practice or testing of the present invention, the preferred methods and materials are now described. All publications mentioned herein are incorporated herein by reference to disclose and describe the methods and / or materials in connection with which the publications are cited.

[0147] It must be noted that as used herein and in the appended claims, the singular forms "a," "an," and "the" include plural referents unless the context clearly dictates otherwise. It is further noted that the claims may be drafted to exclude any optional element. As such, this statement is intended toserve as antecedent basis for use of such exclusive terminology as "solely," "only" and the like in connection with the recitation of claim elements, or use of a "negative" limitation.

[0148] It is appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, may also be provided in combination in a single embodiment. Conversely, various features of the invention, which are, for brevity, described in the context of a single embodiment, may also be provided separately or in any suitable sub-combination.

[0149] The publications discussed herein are provided solely for their disclosure prior to the filing date of the present application. Nothing herein is to be construed as an admission that the present invention is not entitled to antedate such publication by virtue of prior invention. Further, the dates of publication provided may be different from the actual publication dates which may need to be independently confirmed.DETAILED DESCRIPTION

[0150] The present disclosure provides hepcidin mimetic compounds and methods of using such compounds to treat iron-related diseases and diseases associated with high calorie diets. This disclosure also encompasses pharmaceutical compositions using such compounds and kits comprising such compounds.COMPOUNDS

[0151] Aspects of the present disclosure include compounds of formula (I):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;n is 0 or 1;B is selected fromxO -Xk S ^-x^ NR;and -CH?-;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0152] The substituents related to compounds of formula (I) are described in more detail below.

[0153] In certain embodiments, Rais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, Rais cycloalkyl or substituted cycloalkyl, such as C3.8cycloalkyl or C3.8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, Rais heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, Rais aryl or substituted aryl, such as C5.8aryl or C5.8substituted aryl, such as a C5aryl or C5substituted aryl, or a C6aryl or C6substituted aryl. In certain embodiments, Rais heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or Cssubstituted heteroaryl.

[0154] In certain embodiments, Rais a phenyl or substituted phenyl. In certain embodiments, Rais thiophenyl or substituted thiophenyl. In certain embodiments, Rais cyclopentyl or substituted cyclopentyl. In certain embodiments, Rais cyclopentenyl or substituted cyclopentenyl. In certain embodiments, Rais tetrahydro-2H-pyranyl or 3,6-dihydro-2H-pyranyl, or substituted tetrahydro-2H-pyranyl or substituted 3,6-dihydro-2H-pyranyl. In certain embodiments, Rais cyclohexyl or substituted cyclohexyl. In certain embodiments, Rais cyclohexenyl or substituted cyclohexenyl. In certain embodiments, Rais cycloheptenyl or substituted cycloheptenyl. In certain embodiments, Rais benzofuranyl or substituted benzofuranyl.

[0155] In certain embodiments, the substituent on Rais alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, the substituent on Rais alkyl, such as methyl. In certain embodiments, the substituent on Rais substituted alkyl, such as substituted methyl (e.g., trifluoromethyl). In certain embodiments, the substituent on Rais alkoxy, such as methoxy or ethoxy. In certain embodiments, the substituent on Rais substituted alkoxy, such as substituted methoxy (e.g., fluoromethoxy). In certain embodiments, the substituent on Rais halo, such as fluoro. In certain embodiments, the substituent on Rais cycloalkyl, such as cyclopropyl.

[0156] In certain embodiments, RSais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, R6ais H. In certain embodiments, R6ais alkyl or substituted alkyl, such as Ci-6alkyl or Ci-6substituted alkyl, or C1-4 alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R6ais methyl. In certain embodiments, RSais alkoxy or substituted alkoxy, such as Ci-e alkoxy or Ci-g substituted alkoxy, or C1.4 alkoxy or C1.4 substituted alkoxy, or C1-3 alkoxy or C1-3 substituted alkoxy. In certain embodiments, R6ais methoxy.

[0157] In certain embodiments, Rebis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, Rsbis H. In certain embodiments, Rsbis alkyl or substituted alkyl, such as Ci.salkyl or Ci.ssubstituted alkyl, or C1.4 alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, Rebis methyl. In certain embodiments, R6bis alkoxy orsubstituted alkoxy, such as Ci-6 alkoxy or Ci-s substituted alkoxy, or C1-4 alkoxy or C1-4 substituted alkoxy, or C1-3 alkoxy or C1.3 substituted alkoxy. In certain embodiments, R6bis methoxy.

[0158] In certain embodiments, R7and R8are each independently selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent.

[0159] In certain embodiments, R7is selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein R8is absent. In certain embodiments, R7is H. In certain embodiments, R7is alkyl or substituted alkyl, such as Ci.g alkyl or Ci.g substituted alkyl, or C1-4 alkyl or C1.4 substituted alkyl, or Ci-3 alkyl or C1.3 substituted alkyl. In certain embodiments, R7is methyl. In certain embodiments, R7is 2-(trimethylsilyl)ethoxy)methyl. In certain embodiments, R7is hydroxyethyl. In certain embodiments, R7is methoxyethyl. In certain embodiments, R7is substituted alkyl, such as -CD3, -CHF2, or -CH2F. In certain embodiments, R7is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0160] In certain embodiments, R8is selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein R7is absent. In certain embodiments, R8is H. In certain embodiments, R8is alkyl or substituted alkyl, such as Ci.6alkyl or Ci.6substituted alkyl, or C1-4 alkyl or C1.4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R8is methyl. In certain embodiments, R8is 2-(trimethylsilyl)ethoxy)methyl. In certain embodiments, R8is hydroxyethyl. In certain embodiments, R8is methoxyethyl. In certain embodiments, R7is substituted alkyl, such as -CD3, -CHF2, or -CH2F. In certain embodiments, R8is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0161] In certain embodiments, R9is selected from H, alkyl, and substituted alkyl. In certain embodiments, R9is H. In certain embodiments, R9is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1.4 alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl.

[0162] In certain embodiments, R10is selected from H, alkyl, and substituted alkyl. In certain embodiments, R10is H. In certain embodiments, R10is alkyl or substituted alkyl, such as C1-6 alkyl or C1-6 substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1.3 alkyl or C1-3 substituted alkyl.

[0163] In certain embodiments, n is 0 or 1. In certain embodiments, n is 0. In certain embodiments, n is 1.

[0164] In certain embodiments, B is selected fromMM NR}, and -CH2-. In certain embodiments, B isIn certain embodiments, Bis MM S-. In certain embodiments, B is MM NR. In certain embodiments, B is -CH2-.

[0165] In certain embodiments, X is selected from -NH-, -NR17-, and -CR11-. In certain embodiments, X is -NH-. In certain embodiments, X is -NR17-. In certain embodiments, X is -CR11-.

[0166] In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

[0167] In certain embodiments, R11is selected from H, alkyl, and substituted alkyl. In certain embodiments, R11is H. In certain embodiments, R11is alkyl or substituted alkyl, such as Ci-g alkyl or Ci-g substituted alkyl, or Ci-4alkyl or Ci-4substituted alkyl, or Ci.3alkyl or Ci.3substituted alkyl.

[0168] In certain embodiments, R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

[0169] In certain embodiments, R12is absent. For example, as described below, in some instances, R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In some of these instances (e.g., where R13and R16together with the atom to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl), R12may be absent.

[0170] In certain embodiments, R12is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R12is H. In certain embodiments, R12is hydroxyl. In certain embodiments, R12is amino or substituted amino. In certain embodiments, R12is alkyl or substituted alkyl, such as Ci.6alkyl or Ci.6substituted alkyl, or Ci.4alkyl or Ci.4 substituted alkyl, or Ci-3alkyl or Ci-3substituted alkyl. In certain embodiments, R12is methyl. In certain embodiments, R12is cycloalkyl or substituted cycloalkyl, such as C3.g cycloalkyl or C3.s substituted cycloalkyl, such as a C3-6cycloalkyl or C36substituted cycloalkyl, or a C3-5cycloalkyl or C3-5substituted cycloalkyl. In certain embodiments, R12is heterocycloalkyl or substituted heterocycloalkyl, such as C3.gheterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or Cs-g substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R12is aryl or substituted aryl, such as C5-8aryl or C5.8substituted aryl, such as a C5aryl or C5substituted aryl, or a Cg aryl or Cg substituted aryl. In certain embodiments, R12is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or C6substituted heteroaryl.

[0171] In certain embodiments, R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R13is H. In certain embodiments, R13is hydroxyl. In certain embodiments, R13is amino or substituted amino. In certain embodiments, R13is alkyl or substituted alkyl, such as Ci-g alkyl or Ci-g substituted alkyl, or C1.4 alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R13is methyl. In certain embodiments, R13is alkenyl or substituted alkenyl, such as C2.6alkenyl or C2.g substituted alkenyl, or C2.4alkenyl or C2.4substituted alkenyl, or C2.3 alkenyl or C2.3 substituted alkenyl, or C2alkenyl or C2substituted alkenyl. In certain embodiments, R13is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8substituted cycloalkyl, such as a C3-B cycloalkyl or C3.g substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R13is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3 Sheterocycloalkyl or C3-s substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R13is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5aryl or C5substituted aryl, or a Cg aryl or Cg substituted aryl. In certain embodiments, R13is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a Cg heteroaryl or Cg substituted heteroaryl.

[0172] In certain embodiments, R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl. In certain embodiments, R12and R13together with the atom to which they are attached form a cyclopropyl. In certain embodiments, R12and R13together with the atom to which they are attached form a cyclobutyl. In certain embodiments, R12and R13together with the atom to which they are attached form a cyclopentyl. In certain embodiments, R12and R13together with the atom to which they are attached form a cyclohexyl.

[0173] In certain embodiments, is R14is R16or -C(O)NH-R16. In certain embodiments, R14is R16. In certain embodiments, R14is -C(O)NH-R16.

[0174] In certain embodiments, R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0175] In certain embodiments, R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R16is carboxyl ester. In certain embodiments, R16is alkyl or substituted alkyl, such as Ci.salkyl or Ci.ssubstituted alkyl, or Ci-4alkyl or Ci-4substituted alkyl, or Ci.3alkyl or Ci.3substituted alkyl. In certain embodiments, R16is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4alkenyl or C2-4substituted alkenyl, or C2-3alkenyl or C2-3substituted alkenyl, or C2 alkenyl or C2 substituted alkenyl. In certain embodiments, R16is cycloalkyl or substituted cycloalkyl, such as C3.8cycloalkyl or C3.8substituted cycloalkyl, such as a C3.g cycloalkyl or C3.g substituted cycloalkyl, or a C3.5cycloalkyl or C3.5substituted cycloalkyl. In certain embodiments, R16is heterocycloalkyl or substituted heterocycloalkyl, such as C3.8heterocycloalkyl or C3.8substituted heterocycloalkyl, such as a C3.sheterocycloalkyl or C3.6substituted heterocycloalkyl, or a C3.5heterocycloalkyl or C3.5substituted heterocycloalkyl. In certain embodiments, R16is aryl or substituted aryl, such as C5.8aryl or C5.8substituted aryl, such as a C5aryl or C5substituted aryl, or a C6aryl or C6substituted aryl. In certain embodiments, R16is heteroaryl or substituted heteroaryl, such as C5.8heteroaryl or C5.8substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a Csheteroaryl or C6substituted heteroaryl.

[0176] In certain embodiments, R16is cyclohexyl or substituted cyclohexyl. In certain embodiments, R16is cyclopentyl or substituted cyclopentyl.

[0177] In certain embodiments, R16is piperidinyl or substituted piperidinyl. In certain embodiments, R16is piperazinyl or substituted piperazinyl.

[0178] In certain embodiments, R16is phenyl or substituted phenyl. In certain embodiments, R16is pyrrolyl or substituted pyrrolyl. In certain embodiments, R16is imidazolyl or substituted imidazolyl. In certain embodiments, R16is pyrazolyl or substituted pyrazolyl. In certain embodiments, R16is pyridinyl or substituted pyridinyl. In certain embodiments, R16is pyrimidinyl or substituted pyrimidinyl. In certain embodiments, R16is pyridazinyl or substituted pyridazinyl. In certain embodiments, R16is pyrazinyl or substituted pyrazinyl. In certain embodiments, R16is oxazolyl or substituted oxazolyl. In certainembodiments, R16is thiazolyl or substituted thiazolyl. In certain embodiments, R16is isoxazolyl or substituted isoxazolyl. In certain embodiments, R16is piperidinyl or substituted piperidinyl.

[0179] In certain embodiments, R16is benzimidazolyl or substituted benzimidazolyl. In certain embodiments, R16is hydrogenated benzimidazolyl or substituted hydrogenated benzimidazolyl. In certain embodiments, R16is benzoxazolyl or substituted benzoxazolyl. In certain embodiments, R16is benzisoxazolyl or substituted benzisoxazolyl. In certain embodiments, R16is phenylisoxazolyl or substituted phenylisoxazolyl. In certain embodiments, R16is benzoisothiazolyl or substituted benzoisothiazolyl. In certain embodiments, R16is benzothiazolyl or substituted benzothiazolyl. In certain embodiments, R16is imidazopyridinyl or substituted imidazopyridinyl. In certain embodiments, R16is hydrogenated isoquinolinyl or substituted hydrogenated isoquinolinyl. In certain embodiments, R16is hydrogenated imidazopyridinyl or substituted hydrogenated imidazopyridinyl. In certain embodiments, R16is indazolyl or substituted indazolyl.

[0180] In certain embodiments, R16is alkyl alkanoate or substituted alkyl alkanoate. In certain embodiments, R16is amidyl or substituted amidyl.

[0181] In certain embodiments, R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl. In these embodiments, R12may be absent. In certain embodiments, R13and R16together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl, such as C3-8cycloalkyl or C3-8substituted cycloalkyl, such as a C3-6cycloalkyl or C3-6substituted cycloalkyl, or a C3.5cycloalkyl or C3.5substituted cycloalkyl. In certain embodiments, R13and R16together with the atom to which they are attached form a heterocycloalkyl or substituted heterocycloalkyl, such as C3.8heterocycloalkyl or C3.8substituted heterocycloalkyl, such as a C3.sheterocycloalkyl or C3.6substituted heterocycloalkyl, or a C3.5heterocycloalkyl or C3.5substituted heterocycloalkyl. In certain embodiments, R13and R16together with the atom to which they are attached form an aryl or substituted aryl, such as C5-s aryl or C5-8 substituted aryl, such as a C5aryl or C5substituted aryl, or a C6aryl or C6substituted aryl. In certain embodiments, R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl, such as C5.8heteroaryl or C5-8 substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or Cssubstituted heteroaryl.

[0182] In certain embodiments, R13and R16together with the atom to which they are attached form a phenyl or substituted phenyl. In these embodiments, R12may be absent. In certain embodiments, R13and R16together with the atom to which they are attached form a pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, pyridazinyl, substituted pyridazinyl,benzoisoxazolyl, substituted benzoisoxazolyl, triazolopyridinyl, substituted triazolopyridinyl, quinolinyl, substituted quinolinyl, imidazopyridinyl, substituted imidazopyridinyl, imidazopyridazinyl, substituted imidazopyridazinyl, imidazopyrimidinyl, substiuted imidazopyrimidinyl, pyrazolopyridinyl, substituted pyrazolopyridinyl, benzooxazolyl, substituted benzooxazolyl, benzothiazolyl, substituted benzothiazolyl, benzothiadiazolyl, substituted benzothiadiazolyl, triazolopyrimidinyl, substituted triazolopyrimidinyl, tetrahydro-2H-pyranyl, substituted tetrahydro-2H-pyranyl, isothiazolyl, substituted isothiazolyl, pyrazinyl, substituted pyrazinyl, tetrazolo[l,5-a]pyridinyl, substituted tetrazolo[l,5-a]pyridinyl, pyrazolyl, substituted pyrazolyl, quinazolinyl, substituted quinazolinyl, l,l-dioxido-2,3-dihydrobenzo[b]thiophenyl, substituted l,l-dioxido-2,3-dihydrobenzo[b]thiophenyl, l,l-dioxidobenzo[b]thiophenyl, substituted 1,1-dioxidobenzo[b]thiophenyl, imidazo[l,2-a]pyrazinyl, substituted imidazo[l,2-a]pyrazinyl, triazinyl, substituted triazinyl, dihydropyridazinyl, substituted dihydropyridazinyl, triazolo[l,5-a]pyrazinyl, substituted triazolo[l,5-a]pyrazinyl, thiadiazolyl, substituted thiadiazolyl, triazolyl, substituted triazolyl, isoxazolyl, substituted isoxazolyl, pyrazolo[l,5-a]pyrimidinyl, substituted pyrazolo[l,5-a]pyrimidinyl, 2,3-dihydrofuro[3,2-b]pyridinyl, substituted 2,3-dihydrofuro[3,2-b]pyridinyl, pyrido[3,4-b]pyrazinyl, substituted pyrido[3,4-b]pyrazinyl, isoquinolinyl, substituted isoquinolinyl, [l,2,4]triazolo[l,5-a]pyridinyl, and substituted [l,2,4]triazolo[l,5-a]pyridinyl.

[0183] In certain embodiments, R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl. In certain embodiments, R15is alkyl or substituted alkyl, such as Ci6alkyl or Ci6substituted alkyl, or Ci-4alkyl or Ci_4substituted alkyl, or C1-3 alkyl or C1.3 substituted alkyl. In certain embodiments, R15is cyano. In certain embodiments, R15is alkenyl or substituted alkenyl, such as C2-6 alkenyl or C2-6 substituted alkenyl, or C2-4 alkenyl or C2-4 substituted alkenyl, or C2-3 alkenyl or C2-3 substituted alkenyl. In certain embodiments, R15is alkynyl or substituted alkynyl, such as C2-e alkynyl or C2-6 substituted alkynyl, or C2-4alkynyl or C2-4 substituted alkynyl, or C2-3 alkynyl or C2-3 substituted alkynyl.

[0184] In certain embodiments, R17is selected from alkyl and substituted alkyl, such as Ci-s alkyl or C1-6 substituted alkyl, or Ci-4alkyl or C1.4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R17is methyl.

[0185] Aspects of the present disclosure include compounds of formula (II):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;B is selected from -xO, -XS;-XNR, and -CH2-;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0186] The substituents related to compounds of formula (II) are defined in relation to formula (I) herein.

[0187] Aspects of the present disclosure include compounds of formula (III):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0188] The substituents related to compounds of formula (III) are defined in relation to formula (I) herein.

[0189] Aspects of the present disclosure include compounds of the formula (I II A):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;Y is CR13;R12is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13and R16together with the atom to which they are attached from a heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0190] The substituents related to compounds of formula (IIIA) are defined in relation to formula (I) herein.

[0191] Aspects of the present disclosure include compounds of formula (IV):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R16is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, carboxyl ester, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

[0192] The substituents RSa, Rsb, R7, R8, R9, R10, X, m, R11, R12, R13, R14, R16, and R17related to compounds of formula (IV) are as defined in relation to formula (I) herein.

[0193] The substituents R1, R2, R3, R4and R5related to compounds of formula (IV) are described in more detail below.

[0194] In certain embodiments, R1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl.

[0195] In certain embodiments, R1is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R1is H. In certain embodiments, R1is halo (e.g., F, Cl, Br, I). In certain embodiments, R1is hydroxy. In certain embodiments, R1is amino or substituted amino. In certain embodiments, R1is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci.g substituted alkyl, or Ci-4alkyl or Ci.4substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R1is alkoxy. In certain embodiments, R1is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0196] In certain embodiments, R2is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R2is H. Incertain embodiments, R2is halo (e.g., F, Cl, Br, I). In certain embodiments, R2is hydroxy. In certain embodiments, R2is amino or substituted amino. In certain embodiments, R2is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6substituted alkyl, or Ci-4alkyl or Ci.4substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R2is alkoxy. In certain embodiments, R2is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0197] In certain embodiments, R5is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R5is H. In certain embodiments, R5is halo (e.g., F, Cl, Br, I). In certain embodiments, R5is hydroxy. In certain embodiments, R5is amino or substituted amino. In certain embodiments, R5is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-s substituted alkyl, or C1-4 alkyl or Ci.4substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R5is alkoxy. In certain embodiments, R5is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0198] In certain embodiments, R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0199] In certain embodiments, R3is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R3is H. In certain embodiments, R3is halo (e.g., F, Cl, Br, I). In certain embodiments, R3is hydroxy. In certain embodiments, R3is amino or substituted amino. In certain embodiments, R3is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-g substituted alkyl, or Ci.4alkyl or Ci-4substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R3is alkoxy or substituted alkoxy. In certain embodiments, R3is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-s cycloalkyl or C3-6substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3is methyl. In certain embodiments, R3is methoxy.

[0200] In certain embodiments, R3is methyl or methoxy. In certain embodiments, R3is methyl. In certain embodiments, R3is alkoxy, such as methoxy or ethoxy. In certain embodiments, R3is methoxy. In certain embodiments, R3is ethoxy. In certain embodiments, R3is alkyl or substituted alkyl. In certain embodiments, R3is substituted alkyl, such as trifluoromethyl, 1,1-difluoroethyl, and the like. In certain embodiments, R3is halo (e.g., chloro or fluoro). In certain embodiments, R3is substituted alkoxy, such as substituted methoxy (e.g., fluoromethoxy, difluoromethoxy, and the like). In certain embodiments, R3Illis cycloalkyl, such as cyclopropyl. In certain embodiments, R3is substituted cycloalkyl, such as 1-methylcyclopropyl, l-(trifluoromethyl)cyclopropyl, 2,2-difluorocyclopropyl, and the like.

[0201] In certain embodiments, R4is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R4is H. In certain embodiments, R4is halo (e.g., F, Cl, Br, I). In certain embodiments, R4is hydroxy. In certain embodiments, R4is amino or substituted amino. In certain embodiments, R4is alkyl or substituted alkyl, such as Ci-g alkyl or Ci-g substituted alkyl, or Ci.4alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1.3 substituted alkyl. In certain embodiments, R4is alkoxy or substituted alkoxy. In certain embodiments, R4is cycloalkyl or substituted cycloalkyl, such as C3-s cycloalkyl or C3-s substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0202] In some embodiments, R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R3and R4together with the atom to which they are attached form an aryl or substituted aryl, such as C5-s aryl or C5-8 substituted aryl, such as a C5aryl or C5substituted aryl, or a Cg aryl or Cg substituted aryl. In certain embodiments, R3and R4together with the atom to which they are attached form a heteroaryl or substituted heteroaryl, such as C5-s heteroaryl or C5-s substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a Cg heteroaryl or Cg substituted heteroaryl.

[0203] Aspects of the present disclosure include compounds of formula (I) to formula (IV), wherein the compound has an EC50 of 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 45 nM or less, 40 nM or less, 35 nM or less, 30 nM or less, 25 nm or less, 20 nM or less, 15 nM or less, 10 nm or less, or 5 nm or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.5 nM or less, or 0.1 nM or less in the NanoLuc assay. In certain embodiments, the NanoLuc assay is conducted as described in Example 4 of the present disclosure. In certain embodiments, the compound has an EC5o of 50 nM or less. In certain embodiments, the compound has an EC50 of 25 nM or less. In certain embodiments, the compound has an EC50 of 10 nM or less. In certain embodiments, the compound has an EC50 of 5 nM or less.wherein the compound is selected from: Compounds of formula (I) to formula (IV),frZlSZT

[0205] Aspects of the present disclosure include compounds of formula (IA):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R7is selected from H, alkyl and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR16is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0206] The substituents R7, R12, R13, and R16related to compounds of formula (IA) are as defined in relation to formula (I) herein. The substituent R3related to compounds of formula (IA) are as defined in relation to formula (IV) herein.

[0207] In certain embodiments, R3is methyl or methoxy. In certain embodiments, R3is methyl. In certain embodiments, R3is methoxy. In certain embodiments, R3is ethoxy. In certain embodiments, R3is halo (e.g., chloro or fluoro). In certain embodiments, R3is alkyl or substituted alkyl. In certain embodiments, R3is substituted alkyl, such as trifluoromethyl, 1,1-difluoroethyl, and the like. In certain embodiments, R3is substituted alkoxy, such as substituted methoxy (e.g., fluoromethoxy, difluoromethoxy, and the like). In certain embodiments, R3is cycloalkyl, such as cyclopropyl. In certain embodiments, R3is substituted cycloalkyl, such as substituted cyclopropyl (e.g., 2,2-difluorocyclopropyl, 1-methylcyclopropyl, 1-trifluoromethylcyclopropyl, and the like).

[0208] In certain embodiments, R7is H or methyl.

[0209] In certain embodiments, R7is substituted alkyl, such as -CD3.

[0210] In certain embodiments, R12and R13are each independently H or methyl. In certain embodiments, R12and R13are each H. In certain embodiments, R12and R13are each methyl.

[0211] In certain embodiments, R16is heteroaryl or substituted heteroaryl, such as, but not limited to phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, benzoimidazolyl, benzoisoxazolyl, triazolopyridinyl, quinolinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, pyrazolopyridinyl, benzooxazolyl, or substituted versions thereof.

[0212] In certain embodiments, R16is heteroaryl or substituted heteroaryl, such as, but not limited to pyridinyl, oxazolyl, benzoimidazolyl, imidazopyridinyl, or benzooxazolyl, or substituted versions thereof.

[0213] In certain embodiments, R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl, such as, but not limited to, phenyl, pyridinyl, pyrimidinyl, pyridazinyl, oxazolyl, benzoimidazolyl, benzoisoxazolyl, triazolopyridinyl, quinolinyl, imidazopyridinyl, imidazopyridazinyl, imidazopyrimidinyl, pyrazolopyridinyl, benzooxazolyl, or substituted versions thereof.

[0214] In certain embodiments, R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl, such as, but not limited to, pyridinyl, pyrimidinyl, pyridazinyl, benzoimidazolyl, triazolopyridinyl, imidazopyridinyl, or substituted versions thereof.

[0215] In certain embodiments, R13and R16together with the atom to which they are attached form a pyridinyl, substituted pyridinyl, pyrimidinyl, substituted pyrimidinyl, pyridazinyl, substituted pyridazinyl, benzoisoxazolyl, substituted benzoisoxazolyl, triazolopyridinyl, substituted triazolopyridinyl, quinolinyl, substituted quinolinyl, imidazopyridinyl, substituted imidazopyridinyl, imidazopyridazinyl, substituted imidazopyridazinyl, imidazopyrimidinyl, substiuted imidazopyrimidinyl, pyrazolopyridinyl, substituted pyrazolopyridinyl, benzooxazolyl, substituted benzooxazolyl, benzothiazolyl, substitutedbenzothiazolyl, benzothiadiazolyl, substituted benzothiadiazolyl, triazolopyrimidinyl, substituted triazolopyrimidinyl, tetrahydro-2H-pyranyl, substituted tetrahydro-2H-pyranyl, isothiazolyl, substituted isothiazolyl, pyrazinyl, substituted pyrazinyl, tetrazolo[l,5-a]pyridinyl, substituted tetrazolo[l,5-a]pyridinyl, pyrazolyl, substituted pyrazolyl, quinazolinyl, substituted quinazolinyl, l,l-dioxido-2,3-dihydrobenzo[b]thiophenyl, substituted l,l-dioxido-2,3-dihydrobenzo[b]thiophenyl, 1,1-dioxidobenzo[b]thiophenyl, substituted l,l-dioxidobenzo[b]thiophenyl, imidazo[l,2-a]pyrazinyl, substituted imidazo[l,2-a]pyrazinyl, triazinyl, substituted triazinyl, dihydropyridazinyl, substituted dihydropyridazinyl, triazolo[l,5-a]pyrazinyl, substituted triazolo[l,5-a]pyrazinyl, thiadiazolyl, substituted thiadiazolyl, triazolyl, substituted triazolyl, isoxazolyl, substituted isoxazolyl, pyrazolo[l,5-a]pyrimidinyl, substituted pyrazolo[l,5-a]pyrimidinyl, 2,3-dihydrofuro[3,2-b]pyridinyl, substituted 2,3-dihydrofuro[3,2-b]pyridinyl, pyrido[3,4-b]pyrazinyl, substituted pyrido[3,4-b]pyrazinyl, isoquinolinyl, substituted isoquinolinyl, [l,2,4]triazolo[l,5-a] pyridinyl, and substituted [l,2,4]triazolo[l,5-a] pyridinyl.

[0216] In certain embodiments, the compound of formula (IA) is selected from:9izlZ. VI

[0217] Aspects of the present disclosure include compounds of formula (IB):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19and R20are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0218] Aspects of the present disclosure include compounds of formula (IC):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19, R20and R21are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0219] In certain embodiments of formula (IB) or formula (IC), R3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl. In certain embodiments, R3is halo (e.g., chloro or fluoro). In certain embodiments, R3is alkyl or substituted alkyl, such as Ci-3 alkyl or C1.3 substituted alkyl. For example, R3can be alkyl, such as methyl, ethyl, or propyl (e.g., n-propyl or isopropyl). In some cases, R3is substituted alkyl, such as trifluoromethyl or 1,1-difluoroethyl, and the like. In certain embodiments, R3is alkoxy or substituted alkoxy. In certain embodiments, R3is alkoxy, such as methoxy or ethoxy. In certain embodiments, R3is substituted alkoxy, such as substituted methoxy (e.g., fluoromethoxy, difluoromethoxy, and the like). In certain embodiments, R3is cycloalkyl, such as cyclopropyl. In certain embodiments, R3is substituted cycloalkyl, such as substituted cyclopropyl (e.g., 2,2-difluorocyclopropyl, 1-methylcyclopropyl, 1-trifluoromethylcyclopropyl, and the like).

[0220] In certain embodiments of formula (IB) or formula (IC), R19, R20and R21are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

[0221] In certain embodiments of formula (IB) or formula (IC), R19is selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, R19is H. In certain embodiments, R19is halo (e.g., fluoro or chloro). In certain embodiments, R19is alkyl or substituted alkyl, such as Ci-3 alkyl or C1.3 substituted alkyl. For example, R19can be alkyl, such as methyl, ethyl, or propyl (e.g., n-propyl or isopropyl). In some cases, R19is methyl. In certain embodiments, R19is substituted alkyl, such as trifluoromethyl, difluoromethyl, methoxymethyl, and the like. In certain embodiments, R19is alkoxy or substituted alkoxy. In certain embodiments, R19is alkoxy, such as methoxy, ethoxy, cyclopropoxy, and the like. In certain embodiments, R19is methoxy. In certain embodiments, R19is substituted alkoxy, such as 2,2,2-trifluoroethoxy, difluoromethoxy, 2-fluoroehtoxy, and the like.

[0222] In certain embodiments of formula (IB) or formula (IC), R20is selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, R20is H. In certain embodiments, R20is halo (e.g., fluoro or chloro). In certain embodiments, R20is alkyl or substituted alkyl, such as Ci-3 alkyl or C1.3 substituted alkyl. For example, R20can be alkyl, such as methyl, ethyl, or propyl (e.g., n-propyl or isopropyl). In some cases, R20is methyl. In certain embodiments, R20is substituted alkyl, such as trifluoromethyl, difluoromethyl, methoxymethyl, and the like. In certain embodiments, R20is alkoxy or substituted alkoxy. In certain embodiments, R20is alkoxy, such as methoxy, ethoxy, cyclopropoxy, and the like. In certain embodiments, R20is methoxy. In certain embodiments, R20is substituted alkoxy, such as 2,2,2-trifluoroethoxy, difluoromethoxy, 2-fluoroehtoxy, and the like.

[0223] In certain embodiments of formula (IB) or formula (IC), R21is selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, R21is H. In certain embodiments, R21is halo (e.g., fluoro or chloro). In certain embodiments, R21is alkyl or substituted alkyl, such as Ci-3 alkyl or C1-3 substituted alkyl. For example, R21can be alkyl, such as methyl, ethyl, or propyl (e.g., n-propyl or isopropyl). In some cases, R21is methyl. In certain embodiments, R21is substituted alkyl, such as trifluoromethyl, difluoromethyl, methoxymethyl, and the like. In certain embodiments, R21is alkoxy or substituted alkoxy. In certain embodiments, R21is alkoxy, such as methoxy, ethoxy, cyclopropoxy, and the like. In certain embodiments, R21is methoxy. In certain embodiments, R20is substituted alkoxy, such as 2,2,2-trifluoroethoxy, difluoromethoxy, 2-fluoroehtoxy, and the like.

[0225] Aspects of the present disclosure include compounds of formula (ID):whereinR3is haloalkyl; andR22is selected from pyridinyl, pyrimidinyl, pyridazinyl, [l,2,4]triazolo[l,5-o]pyridinyl, and [1.2.4]triazolo[l,5-o]pyrazinyl, wherein R22is optionally substituted with one or more groups selected from halo, haloalkyl, alkyl, and alkoxy, and combinations thereof.

[0226] In certain embodiments of formula (ID), R3is selected from haloalkyl. For example, R3can be Ci-6 alkyl substituted with halo (e.g., chloro or fluoro). In certain embodiments, R3is C1.3 alkyl (e.g., methyl, ethyl, or propyl) substituted with halo (e.g., chloro or fluoro). In some cases, R3is haloalkyl, such as trifluoromethyl or 1,1-difluoroethyl, and the like. In certain embodiments, R3is difluoroethyl, such as 1,1-difluoroethyl.

[0227] In certain embodiments, R22is selected from pyridinyl, pyrimidinyl, pyridazinyl,[1.2.4]triazolo[l,5-o]pyridinyl, and [l,2,4]triazolo[l,5-o]pyrazinyl, wherein R22is optionally substituted with one or more groups selected from halo, haloalkyl, alkyl, and alkoxy. In some cases, R22is pyridinyl. In some cases, R22is pyrimidinyl. In some cases, R22is pyridazinyl. In some cases, R22is [1.2.4]triazolo[l,5-o]pyridinyl. In some cases, R22is and [l,2,4]triazolo[l,5-o]pyrazinyl. In some cases, R22is unsubstituted. In some cases, R22is substituted with one or more groups selected from halo, haloalkyl, alkyl, and alkoxy. In some cases, R22is substituted with one or more groups, such as 1 to 4 groups, or 1 to 3 groups, or 1 to 2 groups (e.g., 1, 2, 3 or 4 groups), where the groups are selected from halo, haloalkyl, alkyl, and alkoxy. In some cases, the substituent on R22is halo (e.g., chloro or fluoro). In some cases, the substituent on R22is haloalkyl (e.g., difluoromethyl), In some cases, the substituent on R22is alkyl (e.g., Ci-e alkyl or C1-3 alkyl, such as methyl). In some cases, the substituent on R22is alkoxy (e.g., methoxy). If R22has more than one substituent (e.g., 2, 3, or 4 substituents), then the substituents may be the same or different. In some cases, R22has 2 substituents, where both substituents are the same. For example, in some cases, R22has 2 substituents, where both substituents are halo (e.g., fluoro). In some cases, R22has 2 substituents, where both substituents are alkoxy (e.g., methoxy). In some cases,R22has more than one substituent (e.g., 2, 3, or 4 substituents), where the substituents are different from each other. For example, in some cases R22has 2 substituents, where one substituent is alkyl (e.g., methyl) and the other substituent is halo (e.g., chloro).

[0228] In certain embodiments of formula (ID), the compound is selected from:

[0229] Aspects of the present disclosure include compounds of formula (V):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;p is 0 or 1;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0230] The substituents related to compounds of formula (V) are described in more detail below.

[0231] In certain embodiments, Rais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, Rais cycloalkyl or substituted cycloalkyl, such as C3.8cycloalkyl or C3.8 substituted cycloalkyl, such as a C3.scycloalkyl or C3.6substituted cycloalkyl, or a C3.5cycloalkyl or C3.5substituted cycloalkyl. In certain embodiments, Rais heterocycloalkyl or substituted heterocycloalkyl, such as C3-s heterocycloalkyl or C3.8substituted heterocycloalkyl, such as a C3.6heterocycloalkyl or C3.6substituted heterocycloalkyl, or a C3.5heterocycloalkyl or C3.5substituted heterocycloalkyl. In certain embodiments, Rais aryl or substituted aryl, such as C5-s aryl or C5-s substituted aryl, such as a C5aryl or C5substituted aryl, or a C6aryl or C6substituted aryl. In certain embodiments, Rais heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or Cssubstituted heteroaryl. In certain embodiments, Rais a phenyl or substituted phenyl.

[0232] In certain embodiments, Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, RSais H. In certain embodiments, RSais alkyl or substituted alkyl, such as Ci.salkyl or Ci.ssubstituted alkyl, or Ci_4alkyl or Ci.4substituted alkyl, or Ci.3alkyl or Ci.3substituted alkyl. In certain embodiments, Reais methyl. In certain embodiments, RSais alkoxy orsubstituted alkoxy, such as Ci-6 alkoxy or Ci-s substituted alkoxy, or C1-4 alkoxy or C1-4 substituted alkoxy, or C1-3 alkoxy or C1.3 substituted alkoxy. In certain embodiments, R6ais methoxy.

[0233] In certain embodiments, Rsbis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy. In certain embodiments, Rsbis H. In certain embodiments, Rsbis alkyl or substituted alkyl, such as Ci-e alkyl or Ci-e substituted alkyl, or C1-4 alkyl or C1.4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R6bis methyl. In certain embodiments, Rsbis alkoxy or substituted alkoxy, such as Ci-6 alkoxy or Ci-g substituted alkoxy, or C1-4 alkoxy or C1-4 substituted alkoxy, or Ci-3 alkoxy or C1-3 substituted alkoxy. In certain embodiments, Rsbis methoxy.

[0234] In certain embodiments, R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent.

[0235] In certain embodiments, R7is selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein R8is absent. In certain embodiments, R7is H. In certain embodiments, R7is alkyl or substituted alkyl, such as Ci-6alkyl or Ci.ssubstituted alkyl, or C1-4 alkyl or C1. substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R7is methyl. In certain embodiments, R7is 2-(trimethylsilyl)ethoxy)methyl. In certain embodiments, R7is hydroxyethyl. In certain embodiments, R7is methoxyethyl.

[0236] In certain embodiments, R8is selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein R7is absent. In certain embodiments, R8is H. In certain embodiments, R8is alkyl or substituted alkyl, such as Ci6alkyl or Ci6substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, alkyl or C1-3 substituted alkyl. In certain embodiments, R8is methyl. In certain embodiments, R8is 2-(trimethylsilyl)ethoxy)methyl. In certain embodiments, R8is hydroxyethyl. In certain embodiments, R8is methoxyethyl.

[0237] In certain embodiments, R9is selected from H, alkyl, and substituted alkyl. In certain embodiments, R9is H. In certain embodiments, R9is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci-6 substituted alkyl, or C1.4 alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl.

[0238] In certain embodiments, p is 0 or 1. In certain embodiments, p is 0. In certain embodiments, p is 1.

[0239] In certain embodiments, X is selected from N and NH. In certain embodiments, X is N. In certain embodiments, X is NH.

[0240] In certain embodiments, m is 0 or 1. In certain embodiments, m is 0. In certain embodiments, m is 1.

[0241] In certain embodiments, A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl. In certainembodiments, A is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, A is cycloalkenyl or substituted cycloalkenyl, such as C3-10 cycloalkenyl or C3-10 substituted cycloalkenyl, such as C3-8 cycloalkenyl or C3-8 substituted cycloalkenyl, such as a C3-6 cycloalkenyl or C3-6 substituted cycloalkenyl, or a C3-5 cycloalkenyl or C3-5 substituted cycloalkenyl. In certain embodiments, A is heterocycloalkyl or substituted heterocycloalkyl, such as C3-10 heterocycloalkyl or C3-10 substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl.

[0242] In certain embodiments, A is diazaspiroalkyl or substituted diazaspiroalkyl. In certain embodiments, A is diazaspirooctanyl or substituted diazaspirooctanyl. In certain embodiments, A is diazaspirononanyl or substituted diazaspirononanyl. In certain embodiments, A is diazaspirodecanyl or substituted diazaspirodecanyl.

[0243] In certain embodiments, A is diazaspiro[3.5]nonanyl or substituted diazaspiro[3.5]nonanyl. In certain embodiments, A is diazaspiro[4.5]decanyl or substituted diazaspiro[4.5]decanyl. In certain embodiments, A is diazaspiro[3.4]octanyl or substituted diazaspiro[3.4]octanyl.

[0244] In certain embodiments, A is azabicycloalkyl or substituted azabicycloalkyl. In certain embodiments, A is azabicyclohexanyl or substituted azabicyclohexanyl. In certain embodiments, A is azabicyclo[3.1.0]hexanyl or substituted azabicyclo[3.1.0]hexanyl.

[0245] In certain embodiments, A is piperidinyl or substituted piperidinyl. In certain embodiments, A is piperazinyl or substituted piperazinyl. In certain embodiments, A is piperidinyl azetidinyl or substituted piperidinyl azetidinyl. In certain embodiments, A is cyclobutenyl or substituted cyclobutenyl.

[0246] In certain embodiments, each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl. In certain embodiments, R10is H. In certain embodiments, R10is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci6substituted alkyl, or C1-4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R10is methyl. In certain embodiments, R10is ethyl. In certain embodiments, R10is propyl. In certain embodiments, R10is isopropyl. In certain embodiments, R10is tertbutyl. In certain embodiments, R10is isobutyl. In certain embodiments, each R10is cyano. In certain embodiments, R10is amino or substituted amino. In certain embodiments, R10is carboxyl ester. Incertain embodiments, R10is amino acyl. In certain embodiments, R10is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R10is heterocycloalkyl or substituted heterocycloalkyl, such as C3-8 heterocycloalkyl or C3-8 substituted heterocycloalkyl, such as a C3-6 heterocycloalkyl or C3-6 substituted heterocycloalkyl, or a C3-5 heterocycloalkyl or C3-5 substituted heterocycloalkyl. In certain embodiments, R10is aryl or substituted aryl, such as C5-8 aryl or C5-8 substituted aryl, such as a C5aryl or C5substituted aryl, or a Cg aryl or Cg substituted aryl. In certain embodiments, R10is heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-s substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or Cg substituted heteroaryl.

[0247] In certain embodiments, R10is substituted alkyl, such as 2-benzoimidazolyl-l-oxo-ethyl, difluoromethyl, trifluoromethyl, methyl acetate, methyl isobutyrate, methyl pivalate, hydroxymethyl, hydroxyethyl, methoxymethyl, methyl carboxylate, isopropyl carboxylate, tert-butyl-carboxylate, acetic acid, cyanomethyl, benzyl, substituted benzyl, phenoxyethyl, acetamide, and the like.

[0248] In certain embodiments, R10is phenyl or substituted phenyl. In certain embodiments, R10is pyridinyl or substituted pyridinyl. In certain embodiments, R10is benzimidazolyl or substituted benzimidazolyl. In certain embodiments, R10is pyridin-2-yl or substituted pyridin-2-yl. In certain embodiments, R10is pyridin-4-yl or substituted pyridin-4-yl. In certain embodiments, R10is cyclopropyl or substituted cyclopropyl. In certain embodiments, R10is cyclobutyl or substituted cyclobutyl. In certain embodiments, R10is cyclopentyl or substituted cyclopentyl. In certain embodiments, R10is cyclohexyl or substituted cyclohexyl. In certain embodiments, R10is naphthalenyl or substituted naphthalenyl. In certain embodiments, R10is triazolyl or substituted triazolyl. In certain embodiments, R10is naphthyridinyl or substituted naphthyridinyl.

[0249] In certain embodiments, q is 1 to 5. In certain embodiments, q is 1. In certain embodiments, q is 2. In certain embodiments, q is 3. In certain embodiments, q is 4. In certain embodiments, q is 5.

[0250] In certain embodiments, p is 1 and m is 0.

[0251] Aspects of the present disclosure include compounds of formula (VI):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0252] The substituents related to compounds of formula (VI) are defined in relation to formula (V) herein.

[0253] Aspects of the present disclosure include compounds of formula (VII):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

[0254] The substituents R6a, R6b, R7, R8, R9, X, m, A, R10and q related to compounds of formula (VII) are as defined in relation to formula (V) herein.

[0255] The substituents R1, R2, R3, R4and R5related to compounds of formula (VII) are described in more detail below.

[0256] In certain embodiments, R1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl.

[0257] In certain embodiments, R1is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R1is H. In certain embodiments, R1is halo (e.g., F, Cl, Br, I). In certain embodiments, R1is hydroxyl. In certain embodiments, R1is amino or substituted amino. In certain embodiments, R1is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci.g substituted alkyl, or Ci-4alkyl or Ci.4substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl. In certain embodiments, R1is alkoxy. In certain embodiments, R1is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-s substituted cycloalkyl, such as a C3-s cycloalkyl or C3-e substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0258] In certain embodiments, R2is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R2is H. In certain embodiments, R2is halo (e.g., F, Cl, Br, I). In certain embodiments, R2is hydroxyl. In certain embodiments, R2is amino or substituted amino. In certain embodiments, R2is alkyl or substituted alkyl, such as Ci-6 alkyl or Ci.g substituted alkyl, or Ci-4alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R2is alkoxy. In certain embodiments, R2is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0259] In certain embodiments, R5is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R5is H. In certain embodiments, R5is halo (e.g., F, Cl, Br, I). In certain embodiments, R5is hydroxyl. In certain embodiments, R5is amino or substituted amino. In certain embodiments, R5is alkyl or substituted alkyl, such as C1-6 alkyl or Ci-6substituted alkyl, or Ci-4alkyl or Ci.4substituted alkyl, or C1.3 alkyl or C1.3 substituted alkyl. In certain embodiments, R5is alkoxy. In certain embodiments, R5is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0260] In certain embodiments, R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl.

[0261] In certain embodiments, R3is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R3is H. In certain embodiments, R3is halo (e.g., F, Cl, Br, I). In certain embodiments, R3ishydroxyl. In certain embodiments, R3is amino or substituted amino. In certain embodiments, R3is alkyl or substituted alkyl, such as Ci-e alkyl or Ci-e substituted alkyl, or C1. alkyl or C1.4 substituted alkyl, or C1.3 alkyl or C1-3 substituted alkyl. In certain embodiments, R3is alkoxy or substituted alkoxy. In certain embodiments, R3is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-6 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl. In certain embodiments, R3is methyl. In certain embodiments, R3is methoxy.

[0262] In certain embodiments, R4is selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl. In certain embodiments, R4is H. In certain embodiments, R4is halo (e.g., F, Cl, Br, I). In certain embodiments, R4is hydroxyl. In certain embodiments, R4is amino or substituted amino. In certain embodiments, R4is alkyl or substituted alkyl, such as Ci-s alkyl or Ci-s substituted alkyl, or C1.4 alkyl or C1-4 substituted alkyl, or C1-3 alkyl or C1.3 substituted alkyl. In certain embodiments, R4is alkoxy or substituted alkoxy. In certain embodiments, R4is cycloalkyl or substituted cycloalkyl, such as C3-8 cycloalkyl or C3-8 substituted cycloalkyl, such as a C3-6 cycloalkyl or C3-5 substituted cycloalkyl, or a C3-5 cycloalkyl or C3-5 substituted cycloalkyl.

[0263] In some embodiments, R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl. In certain embodiments, R3and R4together with the atom to which they are attached form an aryl or substituted aryl, such as C5-8 aryl or C58 substituted aryl, such as a C5aryl or C5substituted aryl, or a C6aryl or C6substituted aryl. In certain embodiments, R3and R4together with the atom to which they are attached form a heteroaryl or substituted heteroaryl, such as C5-8 heteroaryl or C5-8 substituted heteroaryl, such as a C5heteroaryl or C5substituted heteroaryl, or a C6heteroaryl or C6substituted heteroaryl.

[0264] Aspects of the present disclosure include compounds of formula (VIII):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 or 2.

[0265] The substituents R6a, R6b, R7, R8, R9, A, R10and q related to compounds of formula (VIII) are as defined in relation to formula (V) herein.

[0266] The substituents R1, R2, R3, R4and R5related to compounds of formula (VIII) are as defined in relation to formula (VII) herein.

[0267] Aspects of the present disclosure include compounds of formula (V) to formula (VIII), where the compound has an EC5o of 100 nM or less, 90 nM or less, 80 nM or less, 70 nM or less, 60 nM or less, 50 nM or less, 45 nM or less, 40 nM or less, 35 nM or less, 30 nM or less, 25 nm or less, 20 nM or less, 15 nM or less, 10 nm or less, or 5 nm or less, 4 nM or less, 3 nM or less, 2 nM or less, 1 nM or less, 0.5 nM or less, or 0.1 nM or less in the NanoLuc assay. In certain embodiments, the NanoLuc assay is conducted as described in Example 4 of the present disclosure. In certain embodiments, the compound has an EC5o of 50 nM or less. In certain embodiments, the compound has an EC5o of 25 nM or less. In certain embodiments, the compound has an ECso of 10 nM or less. In certain embodiments, the compound has an EC5o of 5 nM or less.

[0268] Aspects of the present disclosure include compounds of formula (V) to formula (VIII), wherein the compound is selected from:

[0269] Aspects of the present disclosure include compounds of formula (VA):whereinR3is selected from H, hydroxyl, alkyl, substituted alkyl, alkoxy and substituted alkoxy;R6bis selected from H, alkyl and substituted alkyl;R7is selected from H, alkyl and substituted alkyl;each R10is independently selected from H, alkyl, substituted alkyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andR18is selected from H, alkyl and substituted alkyl.

[0270] The substituents R3, R5b, R7, and R10related to compounds of formula (VA) are as defined in relation to formula (V) herein.

[0271] The substituent R18related to compounds of formula (VA) is described in more detail below.

[0272] In certain embodiments, R3is methoxy or substituted methoxy.

[0273] In certain embodiments, R7is H or methyl. In certain embodiments, R7is H. In certain embodiments, R7is methyl.

[0274] In certain embodiments, R10is selected from substituted alkyl, cycloalkyl and substituted aryl. In certain embodiments, R10is substituted alkyl, such as substituted methyl. In certain embodiments, R10is cycloalkyl, such as cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl. In certain embodiments, R10is substituted aryl, such as substituted phenyl.

[0275] In certain embodiments, R18is selected from H, alkyl and substituted alkyl. In certain embodiments, R18is H. In certain embodiments, R18is alkyl or substituted alkyl, such as Ci-6alkyl or Ci-6substituted alkyl, or Ci-4alkyl or Ci-4substituted alkyl, or C1-3 alkyl or C1-3 substituted alkyl.

[0276] In certain embodiments, R18is H or methyl. In certain embodiments, R18is H. In certain embodiments, R18is methyl.

[0277] In certain embodiments, the compound of formula (VA) is selected from:FORMULATIONS

[0278] The compounds of the present disclosure can be formulated in a variety of different ways. The compound is formulated in a manner compatible with the compound, the condition to be treated, and the route of administration to be used.

[0279] In some embodiments, provided is a pharmaceutical composition that includes any of the compounds of the present disclosure and a pharmaceutically acceptable carrier, excipient or vehicle.

[0280] The compound can be provided in any suitable form, e.g., in the form of a pharmaceutically acceptable salt, and can be formulated for any suitable route of administration, e.g., oral, topical or parenteral administration. Where the compound is provided as a liquid injectable (such as in those embodiments where they are administered intravenously or directly into a tissue,.e.g, subcutaneously or intramuscular), the compound can be provided as a ready-to-use dosage form, or as a reconstitutable storage-stable powder or liquid composed of pharmaceutically acceptable carriers and excipients. Where the compound is provided as a solid composition, the compound can be provided as a ready-to-use dosage form such as in the form of powders, granules, pellets, tablets, capsules, chewable tablets, dispersible tablets, troches, and lozenges.

[0281] In some embodiments, a compound of the invention may be suitable for oral administration and formulation. In Example 7, human liver microsome stability assay data is provided, and metabolic stability influences the oral bioavailability and plasma half-life of a compound. Metabolic stability assays measure intrinsic clearance and determine the extent to which a drug will be metabolized, is

[0282] Methods for formulating compounds can be adapted from those readily available. For example, compounds can be provided in a pharmaceutical composition comprising a therapeutically effective amount of a compound and a pharmaceutically acceptable carrier, excipient or vehicle. The pharmaceutical composition may optionally include other additives (e.g., buffers, stabilizers, preservatives, and the like). In some embodiments, the formulations are suitable for administration to a mammal, such as those that are suitable for administration to a human.

[0283] Aspects of the present disclosure include a pharmaceutical composition comprising a compound of the present disclosure and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (I), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (IA), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (II), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (III), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (IIIA), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (IV), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (V), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (VA), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (VI), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (VII), and a pharmaceutically acceptable carrier, excipient or vehicle. Aspects of the present disclosure include a pharmaceutical composition comprising a compound of formula (VIII), and a pharmaceutically acceptable carrier, excipient or vehicle.METHODS OF TREATMENT

[0284] The compounds of the present disclosure find use in treatment of a condition or disease in a subject. By "treatment" is meant that at least an amelioration of the symptoms associated with the condition afflicting the host is achieved, where amelioration is used in a broad sense to refer to at leasta reduction in the magnitude of a parameter, e.g. symptom, associated with the condition being treated. As such, treatment also includes situations where the pathological condition, or at least symptoms associated therewith, are completely inhibited, e.g., prevented from happening, or stopped, e.g. terminated, such that the host no longer suffers from the condition, or at least the symptoms that characterize the condition. Thus treatment includes: (i) prevention, that is, reducing the risk of development of clinical symptoms, including causing the clinical symptoms not to develop, e.g., preventing disease progression to a harmful state; (ii) inhibition, that is, arresting the development or further development of clinical symptoms, e.g., mitigating or completely inhibiting an active disease; and / or (iii) relief, that is, causing the regression of clinical symptoms.

[0285] In some embodiments, provided are methods that include administering to a subject an effective amount (e.g., a therapeutically effective amount) of any of the compounds of the present disclosure. The subject to be treated can be one that is in need of therapy, where the subject to be treated is one amenable to treatment using a compound of the present disclosure. Accordingly, a variety of subjects may be amenable to treatment using the compounds disclosed herein. Generally, such subjects are "mammals", with humans being of interest. Other subjects can include domestic pets (e.g., dogs and cats), livestock (e.g., cows, pigs, goats, horses, and the like), rodents (e.g., mice, guinea pigs, and rats, e.g., as in animal models of disease), as well as non-human primates (e.g., chimpanzees and monkeys).

[0286] In certain aspects, provided are methods of delivering a drug to a subject, the method including administering to the subject a pharmaceutical composition including any of the compounds of the present disclosure, where the administering is effective to release a therapeutically effective amount of the compound to a subject.

[0287] In some embodiments, multiple doses of a compound are administered. The frequency of administration of a compound can vary depending on any of a variety of factors, e.g., severity of the symptoms, condition of the subject, etc. For example, in some embodiments, a compound is administered once per month, twice per month, three times per month, every other week (qow), once per week (qw), twice per week (biw), three times per week (tiw), four times per week, five times per week, six times per week, every other day (qod), daily (qd), twice a day (qid), or three times a day (tid).Methods of Treating Iron-related Diseases

[0288] The iron-regulatory hormone hepcidin determines plasma iron concentrations and total body iron content. Hepcidin is secreted by hepatocytes and functions by controlling the activity of the cellular iron exporter ferroportin, which delivers iron to plasma from intestinal iron absorption and fromiron stores. Ferroportin is a transmembrane protein that transports iron from the inside of the cell to the outside of the cell (i.e. into the blood). Ferroportin is the only known iron exporter and plays a critical role in iron homeostasis. Hepcidin concentration in plasma is increased by iron loading and inflammation and is suppressed by erythropoietic stimulation and during pregnancy. Hepcidin deficiency causes iron overload in hemochromatosis and anemias with ineffective erythropoiesis. Thus, hepcidin mimetics that can bind to ferroportin and trigger its internalization and degradation can be modulators of plasma iron concentration and / or total body iron content, thereby having the potential to treat iron-related disorders associated with dysregulated hepcidin and / or ferroportin levels.

[0289] In certain aspects, provided are methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of the present disclosure. In certain embodiments, binding a ferroportin modulates ferroportin and induces ferroportin internalization and degradation.

[0290] In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of the present disclosure are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (I) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (IA)-(IC) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (II) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (III) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (IIIA) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (IV) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (V) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (VA) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (VI) are provided. In certain embodiments, methods of binding a ferroportin or inducingferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (VII) are provided. In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of formula (VIII) are provided.

[0291] In certain embodiments, methods of binding a ferroportin or inducing ferroportin internalization and degradation or methods to treat a disease of iron metabolism, comprises orally administering a Compound of the invention. In some embodiments, a Compound for oral administration exhibits a rate of clearance in a human liver microsome (HLM) assay (see Examples) that is less than 15 ml / min / kg. In certain embodiments, a Compound for oral administration exhibits not only a rate of clearance in an HLM assay that is less than 15 ml / min / kg, but also an EC50 potency in a Nanoluc assay or T47D assay (see Examples) that is less than 20 nM. In certain embodiments, a Compound for oral administration to treat a disease of iron metabolism comprises oral administration of Compound 494, 495, 504, 612, 620, 622, or 623.

[0292] In certain aspects, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (IA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (II) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (III) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (IIIA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (IV) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (V) orpharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (VA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (VI) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (VII) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of formula (VIII) or pharmaceutically acceptable salt or solvate thereof to the subject.

[0293] In certain aspects, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (IA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (II) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (III) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (IIIA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (IV) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorderassociated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (V) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (VA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (VI) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (VII) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods to treat a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of formula (VIII) or pharmaceutically acceptable salt or solvate thereof to the subject.

[0294] In certain embodiments, the disease or disorder is a disease of iron metabolism. In certain embodiments, the disease of iron metabolism is an iron overload disease, iron deficiency disorder, hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, alpha thalassemia, 0-thalassemia, sideroblastic anemia, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia, anemia of chronic disease, anemia of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease, erythropoietin resistance, iron deficiency of obesity, other anemias, benign or malignant tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, hereditary hemochromatosis, and Alzheimer's disease. In certain embodiments, the disease or disorder is a hemochromatosis, a thalassemia, or a polycythemia vera.Methods of Treating Diseases Associated with High Calorie Diets

[0295] In certain aspects, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (IA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (II) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (III) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (IIIA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (IV) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (V) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (VA) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (VI) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound offormula (VII) or pharmaceutically acceptable salt or solvate thereof to the subject. In certain embodiments, provided are methods for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of formula (VIII) or pharmaceutically acceptable salt or solvate thereof to the subject.

[0296] While abnormal hepcidin activity is associated with iron overload diseases, metabolic dysfunction-associated fatty liver disease (MAFLD) and iron overload frequently coexist and potentiate the risk of hepatic fibrosis. Accordingly, the instant hepcidin mimetics have the potential to restore iron homeostasis thereby providing a potential treatment for high calorie related disorders. In certain embodiments, the disease or disorder associated with a high calorie diet is selected from obesity, diet-induced obesity, steatosis (fatty liver disease), and hepatic stenosis.KITS

[0297] Aspects of the present disclosure further include kits. In certain embodiments, the kits comprise a compound of the present disclosure or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (I) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (IA) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (II) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (III) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (IIIA) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (IV) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (V) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (VA) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (VI) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (VII) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound. In certain embodiments, the kits comprise a compound of formula (VIII) or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound.

[0298] In addition to the above components, the kits may also include instructions for practicing the above described kits. The instructions included in the kits may be recorded on a suitable recording medium. For example, the instructions may be printed on a substrate, such as paper or plastic, etc. As such, the instructions may be present in the kits as a package insert, in the labeling of the container of the kit or components thereof (i.e., associated with the packaging or sub-packaging) etc. In other embodiments, the instructions are present as an electronic storage data file present on a suitable computer readable storage medium, e.g., portable flash drive, DVD, CD-ROM, diskette, etc. In yet other embodiments, the actual instructions are not present in the kit, but means for obtaining the instructions from a remote source, e.g. via the internet, are provided. An example of this embodiment is a kit that includes a web address where the instructions can be viewed and / or from which the instructions can be downloaded. As with the instructions, the means for obtaining the instructions is recorded on a suitable substrate.EXAMPLES

[0299] The following examples are put forth so as to provide those of ordinary skill in the art with a complete disclosure and description of how to make and use the present invention, and are not intended to limit the scope of what the inventors regard as their invention nor are they intended to represent that the experiments below are all or the only experiments performed. Efforts have been made to ensure accuracy with respect to numbers used (e.g. amounts, temperature, etc.) but some experimental errors and deviations should be accounted for. Unless indicated otherwise, parts are parts by weight, molecular weight is weight average molecular weight, temperature is in degrees Celsius, and pressure is at or near atmospheric. By "average" is meant the arithmetic mean. Standard abbreviations may be used, e.g., bp, base pair(s); kb, kilobase(s); pl, picol iter(s); s or sec, second(s); min, minute(s); h or hr, hour(s); aa, amino acid(s); kb, kilobase(s); bp, base pair(s); nt, nucleotide(s); i.m., intramuscular(ly); i.p., intraperitoneal(ly); s.c., subcutaneous(ly); and the like.General Synthetic Procedures

[0300] Many general references providing commonly known chemical synthetic schemes and conditions useful for synthesizing the disclosed compounds are available (see, e.g., Smith and March, March's Advanced Organic Chemistry: Reactions, Mechanisms, and Structure, Fifth Edition, Wiley-Interscience, 2001; or Vogel, A Textbook of Practical Organic Chemistry, Including Qualitative Organic Analysis, Fourth Edition, New York: Longman, 1978).

[0301] Compounds as described herein can be purified by any purification protocol known in the art, including chromatography, such as HPLC, preparative thin layer chromatography, flash column chromatography and ion exchange chromatography. Any suitable stationary phase can be used, including normal and reversed phases as well as ionic resins. In certain embodiments, the disclosed compounds are purified via silica gel and / or alumina chromatography. See, e.g., Introduction to Modern Liquid Chromatography, 2nd Edition, ed. L. R. Snyder and J. J. Kirkland, John Wiley and Sons, 1979; and Thin Layer Chromatography, ed E. Stahl, Springer-Verlag, New York, 1969.

[0302] During any of the processes for preparation of the subject compounds, 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 as described in standard works, such as J. F. W. McOmie, "Protective Groups in Organic Chemistry", Plenum Press, London and New York 1973, in T. W. Greene and P. G. M. Wuts, "Protective Groups in Organic Synthesis", Third edition, Wiley, New York 1999, in "The Peptides"; Volume 3 (editors: E. Gross and J. Meienhofer), Academic Press, London and New York 1981, in "Methoden der organischen Chemie", Houben-Weyl, 4thedition, Vol. 15 / 1, Georg Thieme Verlag, Stuttgart 1974, in H.-D. Jakubke and H. Jescheit, "Aminosauren, Peptide, Proteine", Verlag Chemie, Weinheim, Deerfield Beach, and Basel 1982, and / or in Jochen Lehmann, "Chemie der Kohlenhydrate: Monosaccharide and Derivate", Georg Thieme Verlag, Stuttgart 1974. The protecting groups may be removed at a convenient subsequent stage using methods known from the art.

[0303] The subject compounds can be synthesized via a variety of different synthetic routes using commercially available starting materials and / or starting materials prepared by conventional synthetic methods. A variety of examples of synthetic routes that can be used to synthesize the compounds disclosed herein are described in the schemes below.EXAMPLE 1Syntheses of Hepcidin Mimetic CompoundsScheme 1. Synthesis of compound 101.Step 1: N-methoxy-N-methyl-2-(p-tolyl)acetamide.

[0304] To a solution of 2-(p-tolyl)acetic acid (50.00 g, 332.95 mmol, 1.0 eq) in THF (500 mL) at rt was added CDI (70.18 g, 432.83 mmol, 1.3 eq) the mixture was stirred 1 hr, then a solution of N- methoxymethanamine (51.96 g, 532.72 mmol, 1.6 eq, HCI) in ACN (500 mL) and TEA (67.38 g, 665.89 mmol, 92.68 mL, 2.0 eq) at rt was added to the mixture, the result mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was disolved into H2O (400 mL), and extracted with EtOAc (400 mLx2). The combined organic layers were washed with HCI(2 N, 400 mLx2), Na2CO3(sat. aq., 200 mLx2), brine (200 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford N-methoxy-N-methyl-2-(p-tolyl)acetamide (120 g, 88% yield) as a colourless oil. LCMS calculated for C11H15NO2: m / z = 194; found: m / z = 195 (M+H).Step 2: 2-(p-tolyl)-1-(2-pyridyl)ethanone.

[0305] To a solution of 2-bromopyridine (29.43 g, 186.30 mmol, 17.76 mL, 1.2 eq) in THF (300 mL) at -70°C under N2 was added dropwised n-BuLi (2.5 M, 77.62 mL, 1.25 eq). The mixture was stirred at - 70°C for 0.5 h. Then a solution of N-methoxy-N-methyl-2-(p-tolyl)acetamide (30.00 g, 155.25 mmol, 1.0eq) in THF (100 m L) -70°C under N2was added dropwised to the reaction mixture. After addition, the resulting mixture was warmed to rt and stirred for 3.5 hr. The reaction mixture was poured slowly into NH4CI aq (500 mL) at 0°C. Then it was extracted with EtOAc (200 mLx2). The combined organic layers were washed with brine (200 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to afford 2-(p-tolyl)-1-(2-pyridyl)ethanone (20 g, 60% yield) as a white solid. LCMS calculated for C14H13NO: m / z = 211; found: m / z = 212 (M+H).Step 3: 2-bromo-l-(pyridin-2-yl)-2-(p-tolyl)ethan-l-one.

[0306] To a mixture of 2-(p-tolyl)-1-(2-pyridyl)ethanone (20 g, 94.67 mmol, 1.0 eq) in AcOH (200 mL) and HBr (100 mL) at rt was added Br2(30.26 g, 189.34 mmol, 9.75 mL, 2 eq). The mixture was stirred for 2 h at 20°C. The reaction mixture was poured slowly into MTBE (100 mL) at 0°C. Then the suspension was filtered and the filter cake was isolated and dried under vacuum to provide to 2-bromo-2-(p-tolyl)-1-(2-pyridyl)ethanone (30 g, 84% yield) as a yellow solid. LCMS calculated for C14H11BrNO: m / z = 289; found: m / z = 290 (M+H).Step 4: (4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methanol.

[0307] To a solution of 2-bromo-2-(p-tolyl)-1-(2-pyridyl)ethanone (1 g, 3.45 mmol, 1.0 eq) and 2-hydroxyacetamidine (380.98 mg, 3.45 mmol, 1.0 eq, HCI) in EtOH (20 mL) at rt was added K2CO3 (1.43 g, 10.34 mmol, 3.0 eq). The mixture was heated to 80 °C and stirred 1 hr. The reaction mixture was then cooled to rt, diluted with H2O (30 mL), and then extracted with EtOAc (2 x 40 mL). The combined organic layers were washed with brine (100 mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanol (0.4 g, 44% yield) as a black oil. LCMS calculated for C16H15N3O: m / z = 265; found: m / z = 266 (M+H).Core-6: 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde.

[0308] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanol (0.4 g, 1.51 mmol, 1.0 eq) in THF (20 ml) at rt was added MnO2(655.39 mg, 7.54 mmol, 5.0 eq). The mixture was stirred at 80 °C for 6 hr. The mixture was heated to 80 °C and stirred 1 hr. The reaction mixture was then cooled to rt, diluted with H2O (30 ml), and then Then the suspension was filtered and the filtrate was dried under vacuum to provide 5-(p-tolyl)-4-(2-pyridyl)-lH-imidazole-2-carbaldehyde (0.3 g, 76% yield) as a black oil. LCMS calculated for C16H13N3O: m / z = 263; found: m / z = 264 (M+H).Compound 101: l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazine.

[0309] To a solution of 4-(p-tolyl)-5-(2-pyridyl)-lH-imidazole-2-carbaldehyde (50 mg, 189.90 pmol, 1.0 eq) and l-(4-pyridyl)piperazine (31.00 mg, 189.90 pimol, 1.0 eq) in THF (1 mL) at rt was added AcOH (11.40 mg, 189.90 pmol, 10.87 pL, 1.0 eq) and NaBH(OAc)3(120.74 mg, 569.71 pmol, 3.0 eq). The result mixture was stirred for 2 hr. The reaction mixture was purified by prep-HPLC (FA condition), column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H20(0.2% FA)-ACN];gradient:l%-20% B over 8.0 min to give l-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]-4-(4-pyridyl)piperazine (8.9 mg, 11% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 5 12.73 - 12.18 (m, 1H), 8.69 - 8.36 (m, 1H), 8.26 - 8.11 (m, 3H), 7.85 - 7.66 (m, 1H), 7.55 - 7.34 (m, 2H), 7.19 (d, J = 8.0, 3H), 6.82 (br d, J = 6.0, 2H), 3.66 (s, 2H), 3.35 (br s, 6H), 2.66 - 2.60 (m, 4H), 2.34 (s, 3H); LCMS calculated for C25H25N5O: m / z = 411; found: m / z = 412 (M+H).Scheme 2. Synthesis of compound 102.Step 1: tert-butyl 3-isopropyl-4-(pyridin-4-yl)piperazine-l-carboxylate.

[0310] To a solution of tert-butyl 3-isopropylpiperazine-l-carboxylate (50.00 mg, 218.98 pmol, 1.0 eq) and 4-bromopyridine (34.60 mg, 218.98 pmol, 1.0 eq) in dioxane (2 mL) at rt was added RuPhos (10.22 mg, 21.90 pmol, 0.1 eq), t-BuONa (42.09 mg, 437.96 pmol, 2.0 eq) and Pd₂(dba)₃ (10.03 mg, 10.95 pmol, 0.05 eq). The mixture was heated to 100 °C and stirred 4 hr. The reaction mixture was cooled to rt and concentrated in vacuum to remove most of dioxane. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl 3-isopropyl-4-(pyridin-4-yl)piperazine-l-carboxylate (50.00 mg, 60% yield) as a white solid. LCMS calculated for C17H27N3O2: m / z = 305; found: m / z = 306 (M+H).Step 2: 2-isopropyl-l-(pyridin-4-yl)piperazine.

[0311] To a solution of tert-butyl 3-isopropyl-4-(pyridin-4-yl)piperazine-l-carboxylate (50.00 mg, 163.71 pmol, 1.0 eq) in EtOAc (0.2 mL) at rt was added HCI / EtOAc (4 M, 2 mL, 48.87 eq). The resulting reaction mixture was stirred at rt for 1 hr. The reaction mixture was concentrated in vacuum to remove most of the EtOAc. The filtrate was concentrated under vacuum to afford crude 2-isopropyl-l-(pyridin-4-yl)piperazine (35.00 mg, HCI) as a white solid. LCMS calculated for C12H19N3: m / z = 205; found: m / z = 206 (M+H).Compound 102: 2-isopropyl-4-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine(Example 106).

[0312] To a solution of 5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazole-2-carbaldehyde (40.00 mg, 151.92 pmol, 1.0 eq) and 2-isopropyl-l-(pyridin-4-yl)piperazine (35.00 mg, 144.77 pmol, 1.0 eq, HCI) in MeOH (2 ml) at rt was added NaOAc (62.31 mg, 759.61 pmol, 5.0 eq) and NaBH(OAc)3 (64.40 mg, 303.84 pmol, 2.0 eq). The resulting reaction mixture was stirred at rt for 12 hr. The mixture was purified by prep-HPLC(FA condition column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to afford 2-isopropyl-4-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine (4.30 mg, 6 % yield) as a white solid.NMR (400 MHz, MeOD-d4) 68.59 - 8.49 (m, 2H), 8.07 (d, J = 7.2, 2H), 7.78 - 7.65 (m, 1H), 7.45 (br d, J = 8.0, 1H), 7.36 (d, J = 8.0, 2H), 7.28 (dd, J = 5.2, 7.0, 1H), 7.22 (d, J = 8.0, 2H), 7.11 (br d, J = 7.2, 2H), 4.14 - 3.88 (m, 2H), 3.84 - 3.62 (m, 2H), 3.56 - 3.40 (m, 1H), 3.26 - 3.04 (m, 2H), 2.84 - 2.67 (m, 1H), 2.39 (s, 3H), 2.36 - 2.19 (m, 2H), 1.00 (d, J = 6.4, 3H), 0.81 (d, J = 6.8, 3H).; LCMS calculated for C28H32N6: m / z = 452; found: m / z = 453 (M+H).Scheme 3. Synthesis of compound 103.Step 1: tert-butyl 2-(hydroxymethyl)-4-(pyridin-4-yl)piperazine-l-carboxylate.

[0313] To a solution of 4-bromopyridine (500 mg, 3 mmol, 1.0 eq) tert-butyl 2-(hydroxymethyl)piperazine-l-carboxylate (685 mg, 3 mmol, 1.0 eq) in dioxane (10 mL) was added Pd2(dba)3 (290 mg, 300 pmol, 0.1 eq), Cs2CO3(2.06 g, 6 mmol, 2 eq) and RuPhos (295 mg, 600 pmol, 0.2 eq) at rt. The mixture was heated to 90 °C and stirred for 12hr. The reaction mixture was then cooled to rt and diluted with H2O 50 mL and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 0 / 1) to afford tert-butyl 2-(hydroxymethyl)-4-(pyridin-4-yl)piperazine-l-carboxylate(680 mg, 49% yield) as a brown solid. LCMS calculated for C15H23N3O3: m / z = 293; found: m / z = 294 (M+H).Step 2: (4-(pyridin-4-yl)piperazin-2-yl)methanol.

[0314] tert-butyl 2-(hydroxymethyl)-4-(pyridin-4-yl)piperazine-l-carboxylate (630 mg, 1 mmol, 1.0 eq) was added in HCI / EtOAc (5 mL) at rt and stirred for 2hr. The reaction mixture was concentrated under reduced pressure to afford (4-(pyridin-4-yl)piperazin-2-yl)methanol (570 mg, crude) as a brown solid. LCMS calculated for C10H15N3O: m / z = 193; found: m / z = 194 (M+H).Compound 103: (l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazin-2-yl)methanol.

[0315] To a solution of (4-(pyridin-4-yl)piperazin-2-yl)methanol (58 mg, 300 pmol, 1.0 eq) 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (80 mg, 300 pmol, 1.0 eq) in MeOH (1 mL) was added TEA (62 mg, 600 pmol, 2.0 eq) at rt. The mixture was stirred for 11 hr. NaBH3CN (39 mg, 600 pmol, 2.0 eq) was added into above mixture at rt and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna Ci8100x40mmx3 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:25%-50% B over 8.0 min) to afford (l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazin-2-yl)methanol (7.9 mg, 5% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 68.54 (d, J = 4.4, 1H), 8.45-8.43 (s, 0.7 HJ8.10 (d, J = 7.6, 2H), 7.68 (t, J =7.6, 1H), 7.44-7.33 (m, 3H), 7.28-7.17 (m, 3H), 7.14-7.06 (m, 2H), 4.16 (d, J = 14.4, 1H), 4.01 (d, J = 2.8, 1H), 3.96-3.85 (m, 1H), 3.84-3.75 (m, 3H), 3.60 (d, J = 8.0, 1H), 3.54-3.44 (m, 1H), 3.03 (d, J = 4.0, 1H), 2.77 (d, J =8.2, 1H), 2.63 (d, J =12.4, 1H), 2.37 (s, 3H). LCMS calculated for C26H28N6O: m / z = 440; found: m / z = 441 (M+H).Scheme 4. Synthesis of compound 104.Step 1: tert-butyl l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane-7-carboxylate.

[0316] To a solution of tert-butyl l,7-diazaspiro[3.5]nonane-7 -carboxylate (250.0 mg, 1.1 mmol, 1.0 eq) and 4-bromopyridine (209.4 mg, 1.3 mmol, 1.2 eq) in dioxane (5 mL) at rt was added NaOtBu (116.7 mg, 1.2 mmol, 1.1 eq), Pd2(dba)3(101.1 mg, 110.4 pmol, 0.1 eq) and RuPhos (103.1 mg, 220.9 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and combined with another batch (50 mg). The combined mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane-7-carboxylate (260 mg, 65% yield) as a yellow oil. LCMS calculated for Ci7H25N3O2: m / z = 303; found: m / z = 304 (M+H).

[0317] Step 2: l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane.

[0318] To a solution of tert-butyl l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane-7-carboxylate (230 mg, 758.0 pmol, 1.0 eq) in HCI / EtOAc (4 M, 5 mL) at rt was stirred for 2 hr. The reaction mixture was concentrated in vacuum to afford l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane (230 mg, crude) as a yellow solid.

[0319] Compound 104: 7-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane.

[0320] To a solution of l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane (60.0 mg, 295.1 ptmol, 1.0 eq) and 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (77.7 mg, 295.1 pmol, 1.0 eq) in MeOH (2 mL) at rt was added TEA (59.7 mg, 590.3 pmol, 2.0 eq). The mixture was stirred for 12 hr. Then NaBH₃CN (37.1 mg, 590.3 pmol, 2.0 eq) at rt was added to mixture. The resulting mixture was stirred for 1 hr. The reaction mixture was combined with another batch (25 mg). The mixture was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um; mobile phase: [Hz0(0.2% FA)-ACN];gradient:l%-30% B over 8.0 min) to afford 7-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)-l,7-diazaspiro[3.5]nonane (8.5 mg, 8% yield) as a yellow solid. H NMR (400 MHz, MeOD-d4) 68.59 - 8.52 (m, 1H), 8.43 (br s, 1H), 8.02 (br s, 2H), 7.73 - 7.66 (m, 1H), 7.44 (d, J = 8.0, 1H), 7.36 (d, J = 7.6, 2H), 7.31 - 7.17 (m, 3H), 6.90 - 6.84 (m, 1H), 6.62 - 6.44 (m, 0.3H), 5.57 - 5.52 (m, 0.5H), 5.04 - 4.95 (m, 1H), 4.19 -4.04 (m, 1H), 3.86 - 3.72 (m, 2H), 3.50 - 3.42 (m, 1H), 3.20 - 3.13 (m, 1H), 3.12 - 3.02 (m, 1H), 2.85 - 2.79 (m, 1H), 2.56 - 2.20 (m, 8H), 2.00 - 1.97 (m, 1H), 2.12 - 1.88 (m, 1H), 1.30 (br s, 1H); LCMS calculated for C28H3ON6: m / z = 450; found: m / z = 451 (M+H).Scheme 5. Synthesis of compound 105.Step 1: tert-butyl 3-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate.

[0321] To a solution of 4-bromopyridine (358.6 mg, 2.3 mmol, 1.0 eq) and tert-butyl 3- methylpiperazine-l-carboxylate (0.5 g, 2.5 mmol, 1.1 eq) in dioxane (10 mL) at rt was added tBuONa (239.9 mg, 2.5 mmol, 1.1 eq), Pd2(dba)3(207.8 mg, 226.9 pmol, 0.1 eq) and RuPhos (211.8 mg, 453.9 pmol, 0.2 eq). The resulting reaction mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and poured into H2O (30 mL), extracted with EtOAc (3 x 30 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl 3-methyl-4-(pyridin-4- yl)piperazine-l-carboxylate (0.48 g, 76% yield) as a brown solid.Step 2: 2-methyl-l-(pyridin-4-yl)piperazine.

[0322] To a solution of tert-butyl 3-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate (0.35 g, 1.26 mmol, 1.0 eq) in DCM (5 mL) at rt was added TFA (1 mL). The mixture was stirred for 1 hr. The reaction mixture was poured into NaHCO3(aq, 15 mL), extracted with DCM (3 x 10 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated uner vacuum to afford 2-methyl-l- (pyridin-4-yl)piperazine (160 mg, crude) as a yellow solid.Compound 105: 2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4- yl)piperazine.

[0323] To a solution of 2-methyl-l-(pyridin-4-yl)piperazine (60.6 mg, 341.8 pmol, 1.0 eq) and 4- (pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (90 mg, 341.8 pmol, 1.0 eq) and AcOH (20.5 mg, 341.8 pmol, 1.0 eq) in MeOH (2 mL) at rt was stirred for 8 h. Then NaBH3CN (42.9 mg, 683.6 pmol, 2.0 eq) at rt was added to the mixture. The resulting reaction mixture was stirred for 5 hr. The reaction mixture was poured into NaHCO3(10 mL), extracted with EtOAc (3 x 20 mL), dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Waters Xbridge Prep OBD Ci8150*40mm*10um; mobile phase: [H20(0.05% NH3H2O+10mM NH4HCO3)- ACN];gradient:30%-70% B over 8.0 min) to afford 2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine. (1.4 mg, 1% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 6 8.63 - 8.45 (m, 1H), 8.09 (d, J = 6.8, 2H), 7.82 - 7.60 (m, 1H), 7.54 - 7.29 (m, 3H), 7.29 - 7.18 (m, 3H), 6.80 (d, J = 6.8, 2H), 4.24 (br s, 1H), 3.73 - 3.64 (m, 3H), 3.24 - 3.16 (m, 1H), 3.07 (br d, J = 11.2, 1H), 2.90 (br d, J = 11.6, 1H), 2.48 - 2.41 (m, 1H), 2.37 (s, 3H), 2.33 - 2.26 (m, 1H), 1.27 (d, J = 6.8, 3H); LCMS calculated for C26H28N6: m / z = 424; found: m / z = 425 (M+H).Scheme 6. Synthesis of compound 106.step 1Compound 106: l-((4-(4-methoxyphenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazine.

[0324] To a solution of 5-(4-methoxyphenyl)-4-(pyridin-2-yl)-lH-imidazole-2-carbaldehyde (0.1 g, 358.1 tmol, 1.0 eq), l-(pyridin-4-yl)piperazine (58.4 mg, 358.1 pmol, 1.0 eq) and AcOH (21.50 mg, 358.1 pmol, 1.0 eq) in MeOH (3.0 mL) at rt was stirred for 12 hr. NaBH3CN (45.0 mg, 716.2 pmol, 2.0 eq) at rt was added to the mixture. The resulting reaction mixture was stirred for 12 hr. The reaction mixture was poured into NaHCO3(10 mL), extracted with EtOAc (3 x 10 mL), dried with anhydrous NazSO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [HjO(0.2% FA)-ACN];gradient:l%-25% B over 8.0 min) to afford 1-((4-(4-methoxyphenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazine. (5.6 mg, 4% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 68.49 (br d, J = 3.6, 1H), 8.22 (s, 1H), 8.15 (br d, J = 6.4, 2H), 7.74 - 7.67 (m, 1H), 7.62 - 7.46 (m, 3H), 7.24 - 7.14 (m, 1H), 6.93 (d, J = 8.8, 2H), 6.84 (br d, J = 6.4, 2H), 3.78 (s, 3H), 3.64 (s, 2H), 3.35 (br d, J = 4.8, 4H), 2.66 - 2.56 (m, 4H); LCMS calculated for C25H26N6O: m / z = 426; found: m / z = 427 (M+H).Scheme 7. Synthesis of compound 107.Step 1: tert-butyl 3-(l-(pyridin-4-yl)piperidin-3-yl)azetidine-l-carboxylate.hoc

[0325] To a solution of tert-butyl 3-(piperidin-3-yl)azetidine-l-carboxylate (200 mg, 832.1 pmol, 1.0 eq) and 4-bromopyridine (157.7 mg, 998.5 pmol, 1.2 eq) in dioxane (3 mt) at rt was added NaOtBu (87.9 mg, 1.6 mmol, 1.1 eq), Pd₂(dba)₃ (76.2 mg, 83.2 pmol, 0.1 eq) and RuPhos (77.6 mg, 166.4 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and combined with another batch (30 mg). The combined mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl 3-(l-(pyridin-4-yl)piperidin-3-yl)azetidine-l-carboxylate (270 mg, 89% yield) as a yellow oil. LCMS calculated for CI8H27N3O2: m / z = 317; found: m / z = 318 (M+H).Step 2: 4-(3-(azetidin-3-yl)piperidin-l-yl)pyridine.

[0326] A mixture of tert-butyl 3-(l-(pyridin-4-yl)piperidin-3-yl)azetidine-l-carboxylate (100 mg, 315 tmol, 1.0 eq) in HCI / EtOAc (3 mL) at rt was stirred for 2 hr. The reaction mixture was concentrated in vacuum to afford 4-(3-(azetidin-3-yl)piperidin-l-yl)pyridine (80 mg, crude) as a yellow solid.Compound 107: 2-(2-((3-(l-(pyridin-4-yl)piperidin-3-yl)azetidin-l-yl)methyl)-5-(p-tolyl)-lH-imidazol-4-yl)pyridine.

[0327] To a solution of 4-(3-(azetidin-3-yl)piperidin-l-yl)pyridine (80 g, 368.1 pmol, 1.0 eq) and 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (96.9 mg, 368.1 pmol, 1.0 eq) in MeOH (2 mL) at rt was added TEA (74.5 mg, 736.2 pmol, 2.0 eq). The mixture was stirred for 12 hr. NaBH₃CN (46.2 mg, 736.2 pmol, 2.0 eq) at rt was added to mixture. The resulting mixture was stirred for 1 hr. The reaction mixture was combined with another batch (15 mg). The combined mixture was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:l%-25% B over 8.0 min) to afford 2-(2-((3-( l-(pyridin-4-yl)pi peridi n-3-yl )azetidin-l-yl Jmethyl )-5-(p-tolyl)-l H-imidazol-4-yl)pyridine (18.5 mg, 10% yield) as a yellow solid.1H NMR (400 MHz, MeOH-d4) 68.56 (br d, J = 4.4, 1H), 8.49 (br s, 1H), 8.06 (d, J = 7.6, 2H), 7.73 - 7.64 (m, 1H), 7.43 (d, J = 8.0, 1H), 7.35 (d, J = 8.0, 2H), 7.31 - 7.16 (m, 3H), 7.11 (br d, J = 7.6, 2H), 4.17 (s, 2H), 4.13 - 3.94 (m, 4H), 3.87 - 3.69 (m, 2H), 3.28 - 3.19 (m, 1H), 3.01 - 2.89 (m, 1H), 2.67 - 2.52 (m, 1H), 2.37 (s, 3H), 1.95 - 1.77 (m, 3H), 1.69 - 1.49 (m, 1H), 1.41 - 1.21 (m, 1H); LCMS calculated for C29H32N6: m / z = 464; found: m / z = 465 (M+H).Scheme 8. Synthesis of compound 108.steplCompound 108: l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-ylmethyl)piperazine.

[0328] To a solution of 5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazole-2-carbaldehyde (60.0 mg, 227.9 pmol, 1.0 eq) and l-(pyridin-4-ylmethyl)piperazine (40.4 mg, 227.9 pimol, 1.0 eq) in MeOH (2.0 ml) at rt was added AcOH (13.7 mg, 227.9 pmol, 1.0 eq). The mixture was stirred for 12 hr. NaBH₃CN (28.6 mg, 455.8 pmol, 2.0 eq) at rt was added to the mixture and stirred for 0.5 hr. The reaction mixture was poured into NaHCO3(10 ml), extracted with EtOAc (3 x 10 ml) dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna Cig 100*30mm*3um;mobile phase: [H20(0.2% FA)-ACN];gradient:l%-25% B over 8.0 min) to afford l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-ylmethyl)piperazine (9.2 mg, 9% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 5 12.94 - 11.76 (m, 1H), 8.61 - 8.42 (m, 3H), 8.20 (s, 1H), 7.71 (br t, J = 7.2, 1H), 7.47 (br d, J = 8.0, 2H), 7.30 (d, J = 6.0, 2H), 7.23 - 7.13 (m, 3H), 3.57 (s, 2H), 3.48 (s, 2H), 2.53 (br s, 4H), 2.40 (br s, 4H), 2.32 (s, 3H); LCMS calculated for C26H28NS: m / z = 424; found: m / z = 425 (M+H).Scheme 9. Synthesis of compound 109.Step 1: tert-butyl (S)-3-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate.

[0329] To a solution of 4-BROMOPYRIDINE (1.0 g, 6 mmol, 1.0 eq) tert-butyl (S)-3-methylpiperazine-l-carboxylate (1.27 g, 6 mmol, 1.0 eq) in dioxane (10 mL) was added t-BuONa (913mg, 9 mmol, 1.5 eq), RuPhos (590 mg, 1.2 mol, 0.2 eq) and Pd2(dba)3 (580 mg, 600 nmol, 0.1 eq) at rt. The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was then cooled to rt, poured into H2O (50 ml) and extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l / O to 0 / 1) to afford tertbutyl (S)-3-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate (1.18g, 67% yield) as a brown solid. LCMS calculated for C15H23N3O2: m / z = 277; found: m / z = 278 (M+H).Step 2: (S)-2-methyl-l-(pyridin-4-yl)piperazine.

[0330] To a solution of tert-butyl (3S)-3-methyl-4-(4-pyridyl)piperazine-l-carboxylate (1.08 g, 3.89 mmol, 1 eq) in DCM (5 ml) was added TFA (5 mL) at rt and stirred for 2h. The reaction mixture was concentrated under reduced pressure to afford (S)-2-methyl-l-(pyridin-4-yl)piperazine (1.1 g, crude) as a brown solid. LCMS calculated for C10H15N3: m / z = 177; found: m / z = 178 (M+H).Compound 109: (S)-2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine.

[0331] To a solution of (2S)-2-methyl-l-(4-pyridyl)piperazine (471 mg, 2.6 mmol, 1.0 eq) in MeOH (10 ml) was added TEA (538 mg, 5.32 mmol, 2.0 eq) and 4-(pyridin-2-yl)-5-(p-tolyl)-l H-im idazole-2- carbaldehyde (700 mg, 2.66 mmol, 1.0 eq) at rt. The mixture was stirred at rt for 12 hr. Then NaBH₃CN (335 mg, 5.32 mmol, 2.0 eq) was added into above mixture at rt and stirred for lh. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC(column: 2_Phenomenex Gemini Cis 75*40mm*3um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-50% B over 8.0 min) to afford (S)-2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH- imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine (168.2 mg, 15% yield) as a light yellow solid.1H NMR (400 MHz, MeOD-d4) 68.54 (s, 1H), 8.09 (d, J = 6.4, 2H), 7.78-7.61 (m, 1H), 7.50-7.30 (m, 3H), 7.29-7.17 (m, 3H), 6.79 (d, J = 6.4, 2H), 4.23 (s, 1H), 3.73-3.63 (m, 3H), 3.19 (m, 1H), 3.07 (m, 1H), 2.90 (m, 1H),2.44 (m, 1H), 2.37 (s, 3H), 2.33-2.26 (m, 1H), 1.26 (d, J = 6.4, 3H). LCMS calculated for C26H28N6: m / z = 424; found: m / z = 425 (M+H).Scheme 10. Synthesis of compound 110.-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate.

[0332] To a solution of 4-BROMOPYRIDINE (1.0 g, 6.3 mmol, 1.0 eq) and tert-butyl (R)-3- methylpiperazine-l-carboxylate (1.27 g, 6.3 mmol, 1.0 eq) in dioxane (10 mt) at rt was added t-BuONa (669 mg, 7.0 mmol, 1.1 eq), RuPhos (590.7 mg, 1.3 mol, 0.2 eq) and Pd2(dba)3(579.6 mg, 632.9 pmol, 0.1 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was then cooled to rt, poured into H2O (50 mt) and extracted with EtOAc (3 x 25 ml). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l: O to 0:1) to afford tert-butyl (R)-3-methyl-4-(pyridin-4-yl)piperazine-l-carboxylate (1.12 g, 64% yield) as a yellow solid. LCMS calculated for Ci5H23N3O2: m / z = 277; found: m / z = 278 (M+H).Step 2: (R)-2-methyl-l-(pyridin-4-yl)piperazine.

[0333] To a solution of tert-butyl (3S)-3-methyl-4-(4-pyridyl)piperazine-l-carboxylate (1.08 g, 3.89 mmol, 1 eq) in DCM (6 mt) was added TFA (5 mL) at rt and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure to afford (R)-2-methyl-l-(pyridin-4-yl)piperazine (0.5 g, crude) as a brown oil.Compound 110: (R)-2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine.

[0334] To a solution of (R)-2-methyl-l-(pyridin-4-yl)piperazine (269.3 mg, 1.5 mmol, 1.0 eq) and 4- (pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (0.4 g, 1.5 mmol, 1.0 eq) in MeOH (10 mL) at rt was added TEA (768.6 mg, 7.6 mmol, 5 eq), the mixture was stirred for 12 hr, then NaBH3CN (190.9 mg, 3.0 mmol, 2 eq) at rt was added to the mixture, the resulting mixture was stirred for 1 hr. The reaction mixture was combined with another batch (100 mg), the combined mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex Gemini Cis 250*50mm*15um;mobile phase: [H20(0.04%HCI)-ACN];gradient:l%-40% B over 10.0 min) to afford (R)-2-methyl-4-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-l-(pyridin-4-yl)piperazine (71.5 mg, 9% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 68.80 - 8.73 (m, 1H), 8.37 - 8.25 (m, 3H), 7.88 - 7.77 (m, 2H), 7.55 (d, J = 8.0, 2H), 7.42 (d, J = 8.0, 2H), 7.34 (d, J = 7.6 Hz, 2H), 4.70 (s, 2H), 4.48 (br d, J = 15.2, 1H), 4.16 - 3.40 (m, 6H), 2.46 (s, 3H), 1.58 (br d, J = 6.8, 3H). LCMS calculated for C26H28Ne: m / z = 424; found: m / z = 425 (M+H).Scheme 11. Synthesis of compound 111.6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate.

[0335] To a solution of tert-butyl ((lR,5S,6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (250 mg, 1.2 mmol, 1.0 eq) and 4-bromopyridine (199.2 mg, 1.2 mmol, 1.0 eq) in dioxane (8 mL) at rt was added NaOtBu (133.3 mg, 1.4 mmol, 1.1 eq), Pd2(dba)3(115.4 mg, 126.1 ptmol, 0.1 eq) and RuPhos (117.6 mg, 252.2 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and combined with another batch (50 mg). The combined mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl ((lR,5S,6s)-3-(pyridin-4-yl)-3- azabicyclo[3.1.0]hexan-6-yl)carbamate (530 mg, 81% yield) as a yellow oil.LCMS calculated for CI5H2IN3O2: m / z = 275; found: m / z = 276 (M+H).Step 2: (lR,5S,6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-amine.

[0336] A solution of tert-butyl ((lR,5S,6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-yl)carbamate (110 mg, 399.5 pmol, 1.0 eq) in HCI / EtOAc (4M, 2 mL) at rt was stirred for 2 hr. The reaction mixture was concentrated in vacuum to afford (lR,5S,6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-amine (90 mg, crude) as a yellow solid.Compound 111: (lR,5S,6s)-N-((4,5-diphenyl-lH-imidazol-2-yl)methyl)-3-(pyridin-4-yl)-3- azabicyclo[3.1.0]hexan-6-amine.

[0337] To a solution of (lR,5S,6s)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-amine (90 mg, 389.0 pmol, 1.0 eq) and 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (135.2 mg, 513.6 pmol, 1.0 eq) in MeOH (2 mL) at rt was added TEA (103.9 mg, 1 mmol, 2.0 eq). The mixture was stirred for 11 hr. NaBH3CN (64.5 mg, 1.0 mmol, 2.0 eq) at rt was added to mixture. The mixture was stirred for 1 hr. The mixture was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to afford (lR,5S,6s)-N-((4,5-diphenyl-lH-imidazol-2-yl)methyl)-3-(pyridin-4-yl)-3-azabicyclo[3.1.0]hexan-6-amine (7.7 mg, 4% yield) as a yellow solid.1H NMR (400 MHz, MeOH-d4) 68.58 (d, 7 = 4.4, 1H), 8.17 (s, 1H), 8.08 (d, J = 7.6, 2H), 7.74 - 7.67 (m, 1H), 7.45 - 7.35 (m, 3H), 7.33 - 7.22 (m, 3H), 6.78 (d, J = 7.6, 2H), 4.07 (s, 2H), 3.75 - 3.70 (m, 2H), 3.70 - 3.65 (m, 2H), 2.39 (s, 3H), 2.10 (t, J = 2.4 Hz, 1H), 1.98 (br s, 2H); LCMS calculated for C26H25N5: m / z = 407; found: m / z = 408 (M+H).Scheme 12. Synthesis of compound 112.Step 1: tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate.Boc

[0338] To a solution of tert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (430 mg, 1.9 mmol, 1.0 eq) and 4-bromopyridine (300 mg, 1.9 mmol, 1.0 eq) in dioxane (5 mL) at rt was added NaOtBu (548 mg, 5.7 mmol, 3.0 eq), Pd2(dba)3(174 mg, 190 pmol, 0.1 eq) and RuPhos (177 mg, 380 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and combined with another batch (50 mg). The combined mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 30 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (DCM: MeOH = 10:1) to afford tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (380 mg, 75% yield) as a yellow oil. LCMS calculated for CI7H25N3O2: m / z = 303; found: m / z = 304 (M+H).Step 2: 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane.

[0339] To a solution of tert-butyl 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane-2-carboxylate (330.0 mg, 1.1 mmol, 1.0 eq) in DCM (3 mL) was added TFA (0.6 mL) at rt and stirred for 1 hr. The reaction mixture was concentrated in vacuum to afford 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane (330 mg, crude) as a yellow oil.Compound 112: 2-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-7-(pyridin-4-yl)-2,7- diazaspiro[3.5]nonane.

[0340] To a solution of 7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane (62 mg, 304 pmol, 1.0 eq) and 4- (pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (80 mg, 304 pmol, 1.0 eq) in MeOH (1 mL) at rt was added TEA (92 mg, 912 pmol, 3.0 eq). The mixture was stirred for 11 hr. Then NaBH₃CN (38 mg, 608 pmol, 2.0 eq) was added at rt and stirred for 1 hr. The reaction mixture was combined with another batch (10 mg). The mixture was was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna Cig 100*30mm*3um;mobile phase: [H? O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to afford 2-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-7-(pyridin-4-yl)-2,7-diazaspiro[3.5]nonane (18.1 mg, 11% yield) as a colorless gum.1H NMR (400 MHz, MeOD-d4) 68.52-8.57 (m, 1 H), 8.36 (s, 2 H), 8.06 (d, J = 7.6, 2 H), 7.68 (m, 1 H), 7.42 (d, J = 8.0, 1 H), 7.35 (d, J = 8.0, 2 H), 7.25 (m, 1 H), 7.21 (d, J = 8.0, 2 H), 7.13 (d, J = 7.6, 2 H), 3.93 (s, 2 H), 3.63- 3.70 (m, 4 H), 3.46 (s, 4 H), 2.37 (s, 3 H), 1.90-1.96 (m, 4 H); LCMS calculated for C2gH3oN6: m / z = 450; found: m / z = 451 (M+H).Scheme 13. Synthesis of compound 113.Step 1: tert-butyl 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane-l-carboxylate.

[0341] To a solution of 4-bromopyridine (300 mg, 2 mmol, 1.0 eq), tert-butyl 1,8-diazaspiro[4.5]decane-l-carboxylate (450 mg, 2 mmol, 1.0 eq) in dioxane (10 mL) at rt was added t-BuONa (274 mg, 4 mmol, 2.0 eq), RuPhos (178 mg, 400 ptmol, 0.2 eq) and Pd2(dba)3(174 mg, 200 pmol, 0.1 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was then cooled to rt and diluted with H2O (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=l: O to 0:1) to afford tert-butyl 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane-l-carboxylate (500 mg, 71% yield) as a brown solid. LCMS calculated for C18H27N3O2: m / z = 317; found: m / z = 318 (M+H).Step 2: 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane.

[0342] Tert-butyl 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane-l-carboxylate (450 mg, 1.5 mmol, 1.0 eq) was added in HCI / EtOAc (5 mL) at rt and stirred for 1 hr. The reaction mixture was concentratedunder reduced pressure to afford 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane (500 mg, crude) as a yellow solid.Compound 113: l-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-8-(pyridin-4-yl)-l,8- diazaspiro[4.5]decane.

[0343] To a solution of 8-(pyridin-4-yl)-l,8-diazaspiro[4.5]decane (58 mg, 265 pmol, 1.0 eq), 4- (pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (70 mg, 265 pmol, 1.0 eq) in MeOH (2 mL) at rt was added TEA (85 mg, 836 pmol, 2.0 eq). The mixture was stirred for 11 hr. Then NaBH3CN (53 mg, 836 pmol, 2 eq) was added into above mixture at rt and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna Cis 100x40mmx3 um;mobile phase: [HzO(0.2% FA)-ACN];gradient:25%-50% B over 8.0 min) to afford l-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)methyl)-8-(pyridin-4-yl)-l,8- diazaspiro[4.5]decane (11.6 mg, 8% yield) as a yellow gum.1H NMR (400 MHz, MeOD-d4) 68.54-8.50 (m, 1H), 8.37 (s, 2H), 8.07 (d, J = 7.6, 2H), 7.67 (m, 1H), 7.39 (d, J = 8.0, 1H), 7.32 (d, J = 8.0, 2H), 7.26 (m, 1H), 7.20 (d, J = 8.0, 2H), 7.15 (d, J = 7.6, 2H), 4.34-4.23 (m, 2H), 3.85 (s, 2H), 3.30-3.25 (m, 2H), 2.98 (t, J = 7.2 Hz, 2H), 2.37 (s, 3H), 2.11-2.02 (m, 2H), 1.97-1.84 (m, 4H), 1.71 (m, 2H). LCMS calculated for C29H32N6: m / z = 464; found: m / z = 465 (M+H).Scheme 14. Synthesis of compound 114.Step 1: tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate.

[0344] To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (400.0 mg, 1.6 mmol, 1.1 eq) and 4-bromopyridine (239.0 mg, 1.5 mmol, 1.0 eq) in dioxane (10 mL) at rt was added NaOtBu (160.0 mg, 1.7 mmol, 1.1 eq), Pd2(dba)3(138.6 mg, 151 ptmol, 0.1 eq) and RuPhos (141.2 mg, 302 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred for 12 hr. The reaction mixture was cooled to rt and combined with another batch (50 mg). The combined mixture was poured into H2O (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (460 mg, 68% yield) as a yellow oil.NMR (400 MHz, MeOH-d4) 68.08 (d, J = 6.4, 2H), 6.85 (d, J = 6.8, 2H), 3.58-3.37 (m, 6H), 3.24 (s, 2H), 1.84 (t, J = 7.2, 2H), 1.69-1.59 (m, 4H), 1.46 (s, 9H); LCMS calculated for CI8H27N3O2: m / z = 317; found: m / z = 318 (M+H).Step 2: 8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane.

[0345] To a solution of tert-butyl 2,8-diazaspiro[4.5]decane-2-carboxylate (430.0 mg, 1.3 mmol, 1.0 eq) in HCI / EtOAc (4M, 10 mL) at rt was stirred for 2 hr. The reaction mixture was concentrated in vacuum to afford 8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane (300 mg, crude) as a yellow solid.Compound 114: 2-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane.

[0346] To a solution of 8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane (100.0 mg, 460 pmol, 1.5 eq) in MeOH (2 mL) at rt was added 4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazole-2-carbaldehyde (80.8 mg, 307 pmol, 1.0 eq) and TEA (93.1 mg, 920 pmol, 3.0 eq). The mixture was stirred for 12 hr. Then the mixture was added NaBHsCN (38.6 mg, 613.6 pmol, 2.0 eq) at rt and stirred for 1 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H20(0.2% FA)-ACN];gradient:l%-30% B over 8.0 min) to afford 2-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-8-(pyridin-4-yl)-2,8-diazaspiro[4.5]decane (39.0 mg, 24% yield) as a colorless gum.1H NMR (400 MHz, MeOD-d4) 68.57-8.53 (m, 1H), 8.07 (d, J = 8.0, 2H), 7.69 (m, 1H), 7.44 (d, J = 8.0, 1H), 7.36 (d, J = 8.0, 2H), 7.27 (m, 1H), 7.21 (d, J = 8.0, 2H), 7.13 (d, J = 8.0, 2H), 3.97 (s, 2H), 3.78-3.63 (m, 4H), 3.00 (t, J = 7.2, 2H), 2.85 (s, 2H), 2.37 (s, 3H), 1.89 (t, J = 7.2, 2H), 1.82-1.73 (m, 4H); LCMS calculated for C29H32N6: m / z = 464; found: m / z = 465 (M+H).Scheme 15. Synthesis of compound 115.Step 1: tert-butyl 6-(pyridin-4-yl)-2,6-diazaspiro[3.4]octane-2-carboxylate.

[0347] To a solution of 4-bromopyridine (300 mg, 1.90 mmol, 1.0 eq) and tert-butyl 2,7-diazaspiro[3.4]octane-2-carboxylate (403.09 mg, 1.90 mmol, 1.0 eq) in dioxane (5 m L) at rt was added t-BuONa (364.95 mg, 3.80 mmol, 2.0 eq) and BINAP (118.23 mg, 189.88 pmol, 0.1 eq) and Pd?(dba)3 (173.88 mg, 189.88 pmol, 0.1 eq). The mixture was heated to 100 °C and stirred 8 hr. The reaction mixture was cooled to rt and poured into HjO (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 0:1) to afford tert-butyl 7-(4-pyridyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (0.3 g, 54 % yield) as a yellow oil. LCMS calculated for C16H23N3O2: m / z = 289; found: m / z = 290 (M+H).

[0348] Step 2: 6-(pyridin-4-yl)-2,6-diazaspiro[3.4]octane.

[0349] To a solution of tert-butyl 7-(4-pyridyl)-2,7-diazaspiro[3.4]octane-2-carboxylate (0.3 g, 1.04 mmol, 1.0 eq) in HCI / EtOAc (3 ml) at rt. The mixture was stirred for 2 hr. The reaction mixture was poured into H2O (10 mL) adjust PH to 9, and extracted with EtOAc(10 mLx3). The combined organic layers were washed with brine(10 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-(4-pyridyl)-2,5-diazaspiro[3.4]octane (0.2 g, 85.47% yield) was obtained as a yellow oil. LCMS calculated for C11H15N3: m / z = 189; found: m / z = 190 (M+H).Compound 115: l-(2-(lH-benzo[d]imidazol-2-yl)propan-2-yl)-3-((4-(4-methoxyphenyl)-5-(pyridin-2-yl)- lH-imidazol-2-yl)methyl)urea.

[0350] To a solution of 6-(4-pyridyl)-2,6-diazaspiro[3.4]octane (40 mg, 211.35 pmol, 1.0 eq) and 4- (p-tolyl)-5-(2-pyridyl)-lH-imidazole-2-carbaldehyde (55.65 mg, 211.35 pmol, 1.0 eq) in MeOH (1 mL) at rt was added NaBH(OAc)3(39.84 mg, 634.06 pmol, 3.0 eq) and NaOAc (86.69 mg, 1.06 mmol, 5.0 eq). The mixture was stirred at 20 °C for 12 hr. The reaction mixture was purified by prep-HPLC (FA condition), column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:l%-22% B over 8.0 min to give 2-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]-7-(4- pyridyl)-2,7-diazaspiro[3.4]octane (3.6 mg, 4% yield) as white solid.1H NMR (400 MHz, MeOD-d4) 68.57 (br d, J = 4.4 Hz, 1H), 8.46 (s, 2H), 8.13 (d, J = 7.2 Hz, 2H), 7.79 - 7.65 (m, 1H), 7.46 (br d, J = 8.0 Hz, 1H), 7.38 (br d, J = 8.0 Hz, 2H), 7.33 - 7.18 (m, 3H), 6.86 (br d, J = 7.2 Hz, 2H), 4.04 (s, 2H), 3.74 (br d, J = 14.4 Hz, 6H), 3.62 (br t, J = 6.8 Hz, 2H), 2.47 - 2.30 (m, 5H); LCMS calculated for C28H29N5: m / z = 435; found: m / z = 436 (M+H).Scheme 16. Synthesis of compound 116.Step 1: tert-butyl N-[3-(2-aminoanilino)-2-hydroxy-3-oxo-propyl]carbamate.

[0351] To a solution of benzene-l,2-diamine (5.00 g, 46.24 mmol, 1.0 eq) and 3-(tert- butoxycarbonylamino)-2-hydroxy-propanoic acid (9.49 g, 46.24 mmol, 1.0 eq) in THF (50 mL) at rt was added HOBt (6.25 g, 46.24 mmol, 1.0 eq) and EDCI (8.86 g, 46.24 mmol, 1.0 eq), DIEA (11.95 g, 92.47 mmol, 16.11 mL, 2.0 eq). The mixture was stirred for 12hr. The residue was poured into HjO (200 mL) and extracted with EtOAc (3 x 100 mL). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with PE: EtOAc = 3:1 (40 mL) at rt for 30 min. The resulting slurry was filtered and the solid was collected and dried under vacuum to afford tert-butyl N-[3-(2-aminoanilino)-2-hydroxy-3-oxo- propyl]carbamate (7 g, 51% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 59.01 (s, 1 H), 7.22 (br d, 7=7.6, 1 H), 6.91 (td, 7=7.6, 1.2, 1 H), 6.69 - 6.79 (m, 2 H), 6.51 - 6.61 (m, 1 H), 5.79 (br d, 7=5.6, 1 H), 4.80 (s, 2 H), 4.03 - 4.17 (m, 1 H), 3.33 - 3.38 (m, 1 H), 3.19 (dt, 7=13.6, 6.8, 1 H), 1.39 (s, 9 H); LCMS calculated for C14H21N3O4: m / z = 295; found: m / z = 296 (M+H).Step 2: tert-butyl N-[2-(lH-benzimidazol-2-yl)-2-hydroxy-ethyl]carbamate.

[0352] To a solution of AcOH (5 mL) at rt was added tert-butyl N-[3-(2-aminoanilino)-2-hydroxy-3-oxo-propyl]carbamate (0.50 g, 1.69 mmol, 1.0 eq). The mixture was heated to 80 °C and stirred 1 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to afford tert-butyl N-[2-(lH-benzimidazol-2-yl)-2-hydroxy-ethyl]carbamate (0.50 g, 1.62 mmol, 95% yield) as a white solid. LCMS calculated for C14H19N3O3: m / z = 277; found: m / z = 278 (M+H).Step 3: 2-amino-l-(lH-benzimidazol-2-yl)ethanol

[0353] To a solution of tert-butyl N-[2-(lH-benzimidazol-2-yl)-2-hydroxy-ethyl]carbamate (0.50 g, 1.80 mmol, 1.0 eq) in EtOAc (1 mL) at rt was added HCI / EtOAc (4 M, 5 mL, 11.09 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford 2-amino-l-(lH-benzimidazol-2-yl)ethanol (0.4 g, 93% yield) as a white solid. LCMS calculated for C9H11N3O: m / z = 177; found: m / z = 178 (M+H).Compound 116: l-(lH-benzimidazol-2-yl)-2-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]ethanol.

[0354] To a solution of 4-(p-tolyl)-5-(2-pyridyl)-lH-imidazole-2-carbaldehyde (0.07 g, 265.86 pmol, 1.0 eq) and 2-amino-l-(lH-benzimidazol-2-yl)ethanol (56.81 mg, 265.86 pmol, 1.0 eq, HCI) in MeOH (2 mL) at rt was added NaOAc (43.62 mg, 531.73 pmol, 2.0 eq). The mixture was stirred for 2 hr. Then at rt was added NaBH(OAc)3(281.74 mg, 1.33 mmol, 5.0 eq), the mixture was stirred for 11 h. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:l%-40% B over 8.0 min) to afford 1-(1 H-benzim idazol-2-yl )-2-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]ethanol (19.8 mg, 16 yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 68.49 (br s, 1 H), 8.17 (s, 1 H), 7.70 (td, 7=7.6, 1.6, 1 H), 7.42 - 7.58 (m, 5 H), 7.16 - 7.21 (m, 3 H), 7.08 - 7.15 (m, 2 H), 4.90 (dd, 7=7.2, 4.4, 1 H), 3.82 - 3.89 (m, 2 H), 3.06 - 3.10 (m, 1 H), 2.95 (dd, 7=12.0, 7.2, 1 H), 2.33 (s, 3 H); LCMS calculated for C25H24N5O: m / z = 424; found: m / z = 425 (M+H).Scheme 17. Synthesis of compound 117.Step 1: tert-butyl N-[4-(4-pyridyl)piperazin-l-yl]carbamate.

[0355] To a solution of tert-butyl N-piperazin-l-ylcarbamate (0.1 g, 496.86 pmol, 1.0 eq) and 4-bromopyridine (78.50 mg, 496.86 pmol, 1.0 eq) in dioxane (2 mt) at rt was added Pd2(dba)3 (45.50 mg, 49.69 pmol, 0.1 eq), t-BuONa (143.25 mg, 1.49 mmol, 3.0 eq) and RuPhos (46.37 mg, 99.37 pmol, 0.2 eq). The mixture was heated to 100 °C and stirred 12 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=20 / l to 0 / 1) to afford tert-butyl N-[4-(4-pyridyl)piperazin-l-yl]carbamate (80 mg, 57% yield) as a white solid. LCMS calculated for C15H26N4O2: m / z = 294; found: m / z = 295 (M+H).Step 2: 4-(4-pyridyl)piperazin-l-amine.

[0356] To a solution of tert-butyl N-[4-(4-pyridyl)piperazin-l-yl]carbamate (0.08 g, 287.41 pmol, 1.0 eq) in EtOAc (0.2 mL) was added HCI / EtOAc (4 M, 2 mL, 27.83 eq) at rt. The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford 4-(4-pyridyl)piperazin-l-amine (60 mg, 95% yield) as a yellow solid. LCMS calculated for CioHisN^: m / z = 194; found: m / z = 195 (M+H).Compound 117: (Z)-l-[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]-N-[4-(4-pyridyl)piperazin-l-

[0357] To a solution of 4-(p-tolyl)-5-(2-pyridyl)-lH-imidazole-2-carbaldehyde (30 mg, 113.94 pmol, 1.0 eq) and 4-(4-pyridyl)piperazin-l-amine (24.46 mg, 113.94 pmol, 1.0 eq, HCI) in MeOH (2 mL) at rt was added NaOAc (18.69 mg, 227.88 pmol, 2.0 eq) and NaBH3CN (35.80 mg, 569.71 pmol, 5.0 eq). The mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (FA condition column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to afford (Z)-l-[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]-N-[4-(4-pyridyl)piperazin-l-yl]methanimine (8.8 mg, 17% yield) as a white solid.1H NMR (400 MHz, DMSO-dg) 68.48 (br d, J = 4.4, 1H), 8.43 (br s, 1H), 8.11 (d, 7 = 7.2, 2H), 7.65 (dt, J = 1.6, 7.6, 1H), 7.49 (s, 1H), 7.39 (d, J = 8.0, 1H), 7.31 (d, J = 8.0, 2H), 7.25 - 7.19 (m, 1H), 7.15 (d, J = 8.0, 2H), 7.09 (d, J = 7.2, 2H), 3.89 - 3.79 (m, 4H), 3.49 - 3.37 (m, 4H), 2.31 (s, 3H); LCMS calculated for C25H25N7: m / z = 423; found: m / z = 424 (M+H).Scheme 18. Synthesis of compound 118.steplScheme 18. Synthesis of compound 118.

[0343] To a mixture of 5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazole-2-carbaldehyde (0.05 g, 189.90 pmol, 1.0 eq), 4-(piperidin-4-yl )pyridine (30.81 mg, 189.90 pmol, 1.0 eq) in MeOH (2 mL) at rt was added AcOH (11.40 mg, 189.90 pmol, 10.87 pL, 1.0 eq), The resulting reaction mixture was stirred at rt for 12 hr. Then NaBH(OAc)3 (80.50 mg, 379.80 pmol, 2.0 eq) was added at rt, the result mixture was stirred for 2 hr. The mixture was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:l%-35% B over 8.0 min) to afford l-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)-4-(pyridin-4-yl)piperazine(1.80 mg, 2% yield) as a white solid.1H NMR (400 MHz, MeOD) 6 1.85 - 2.01 (m, 4 H), 2.37 (s, 3 H), 2.59 (td, 7=11.2, 2.50, 2 H), 2.73 (tt, 7=11.6, 3.89, 1 H), 3.28 -3.31 (m, 2 H), 3.96 (s, 2 H), 7.22 (d, 7=8.0, 2 H), 7.27 (ddd, 7=7.6, 5.00, 0.88, 1 H), 7.33 - 7.40 (m, 4 H), 7.45 (d, 7=8.0, 1 H), 7.70 (td, 7=7.6, 1.75, 1 H), 8.32 (br s, 1 H), 8.40 - 8.47 (m, 2 H), 8.56 (d, 7=4.8, 1 H); LCMS calculated for C25H26N5: m / z = 410; found: m / z = 411 (M+H).Scheme 19. Synthesis of compound 119.

[0344] To a solution of 2-(tert-butoxycarbonylamino)acetic acid (14.03 g, 80.09 mmol, 1.0 eq) and 2- bromo-l-(2-pyridyl)ethanone;hydrobromide (22.50 g, 80.09 mmol, 1.0 eq) in ACN (500 mL) at rt was added DIEA (20.70 g, 160.17 mmol, 27.90 mL, 2.0 eq). The mixture was stirred for 2hr. The reaction mixture was poured into H2O (300 mL), and extracted with EtOAc(300 mLx3). The combined organic layers were washed with brine(300 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford [2-oxo-2-(2-pyridyl)ethyl] 2-(tert-butoxycarbonylamino)acetate (97.96 g, 90% yield) was obtained as a brown solid.1H NMR (400 MHz, DMSO-d6) 68.76 (d, J = 4.4, 1H), 8.12 - 8.01 (m, 1H), 7.99 (s, 1H), 7.74 (dd, J = 6.4, 7.2, 1H), 7.30 (br t, J = 6.0, 1H), 5.65 (s, 2H), 3.88 (d, J = 6.4 Hz, 2H), 1.40 (s, 9H); LCMS calculated for Ci4Hi8N2O5: m / z = 294; found: m / z = 295 (M+H).Step 2: tert-butyl ((4-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)carbamate.

[0345] To a solution of [2-oxo-2-(2-pyridyl)ethyl] 2-(tert-butoxycarbonylamino)acetate (32.50 g, 110.43 mmol, 1.0 eq) in P-XYLENE (200 mL) at rt was added NH4OAc (34.05 g, 441.72 mmol, 4.0 eq). The mixture was stirred at 150 °C for 2hr. The combined mixture was concentrated in vacuum to remove most of the P-XYLENE. The reaction mixture was poured into H2O (100 mL), and extracted withEtOAc(100 m Lx3). The combined organic layers were washed with brine(100 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 2:1) to afford tert-butyl N-[[4-(2-pyridyl)-lH-imidazol- 2-yl]methyl]carbamate (43 g, 40% yield) was obtained as a brown oil.1H NMR (400 MHz, DMSO-dg) 6 12.00 (br s, 1H), 8.60 - 8.41 (m, 1H), 7.93 - 7.66 (m, 2H), 7.56 (br s, 1H), 7.36 - 7.11 (m, 2H), 4.20 (br d, J = 6.0, 1H), 3.17 (d, J = 5.2, 1H), 1.47 - 1.32 (m, 9H); LCMS calculated for C14HI8N4O2: m / z = 287; found: m / z = 288 (M+H).Step 3: tert-butyl ((5-bromo-4-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)carbamate.

[0346] To a solution of tert-butyl N-[[4-(2-pyridyl)-lH-imidazol-2-yl]methyl]carbamate (12.60 g, 45.93 mmol, 1.0 eq) in DCM (80 ml) was cooled to 0°C and added NBS (9.81 g, 55.12 mmol, 1.2 eq). The mixture was stirred for 2hr. The mixture was heated to rt and poured into H2O (100 mL), and extracted with EtOAc(100 mLx3). The combined organic layers were washed with brine(100 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The crude product was triturated with PE: EtOAc = 3:1 (400 mL) at rt for 30 min. The resulting slurry was filtered and the solid was collected and dried under vacuum to afford tert-butyl N-[[5-bromo-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]carbamate (20.5 g, 42% yield) was obtained as a white solid. LCMS calculated for Ci4Hi7BrN4O2: m / z = 352; found: m / z = 353 (M+H).Step 4: tert-butyl ((5-bromo-4-(pyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)carbamate.

[0347] To a solution of tert-butyl N-[[5-bromo-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]carbamate (5.20 g, 14.72 mmol, 1.0 eq) in THF (30 mL) was cooled to 0°C and added NaH (883.32 mg, 22.08 mmol, 60% purity, 1.5 eq). The mixture was stirred for 1 h. Then was added SEM-CI (2.95 g, 17.67 mmol, 3.13 mL, 1.2 eq) at 0°C. The mixture was heated to rt and stirred for 1 h.

[0348] The reaction mixture was quenched with NH4CI (aq, 50 mL) and H2O (50 mL). The mixture was extracted with EtOAc(50 mLx2) and the combined extracts were dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel columnchromatography (PE: EtOAc = 1:0 to 15:1) to afford tert-butyl N-[[5-bromo-4-(2-pyridyl)-l-(2- trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (15 g, 70% yield) was obtained as a white solid. H NMR (400 MHz, DMSO-d6) 68.60 (d, J = 4.0, 1H), 7.96 - 7.89 (m, 1H), 7.86 (dd, J = 2.0, 7.6 Hz, 1H), 7.42 (br s, 1H), 7.30 (ddd, J = 1.2, 4.8, 7.2, 1H), 5.45 (s, 2H), 4.36 (br d, J = 5.6, 2H), 3.61 (s, 2H), 1.42 (s, 9H), 0.91 (t, J = 8.0, 2H), 0.00 (s, 9H); LCMS calculated for C20H3iBrN4O3Si: m / z = 482; found: m / z = 483 (M+H).Step 5: tert-butyl ((5-(4-cyclopropylphenyl)-4-(pyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-

[0349] To a solution of tert-butyl N-[[5-bromo-4-(2-pyridyl)-l-(2-trirnethylsilylethoxyrnethyl)imidazol-2- yl]methyl]carbamate (1.00 g, 2.07 mmol, 1.0 eq) and (4-cyclopropylphenyl)boronic acid (335.06 mg, 2.07 mmol, 1.0 eq) in dioxane (10 ml) and H2O (2 mL) at rt was added Pd(dppf)CI2(151.34 mg, 206.84 pmol, 0.1 eq) and Cs2CO3(1.35 g, 4.14 mmol, 2.0 eq). The mixture was heated to 100 °C and stirred 4 hr. The reaction mixture was cooled to rt and poured into H2O (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 1:1) to afford tert-butyl N-[[5-(4-cyclopropylphenyl)-4-(2-pyridyl)- l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.8 g, 60% yield) was obtained as a yellow oil. LCMS calculated for C29H4oN403Si: m / z = 521; found: m / z = 522 (M+H).Step 6: (4-(4-cyclopropylphenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methanamine.

[0350] To a solution of tert-butyl N-[[5-(4-cyclopropylphenyl)-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.30 g, 576.11 pmol, 1.0 eq) in HCI / EtOAc (3 ml) at rt. The mixture was stirred for 2hr. The reaction mixture was poured into H2O (10 mL) adjust PH to 9, and extracted with EtOAc(10 mLx3). The combined organic layers were washed with brine(10 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford [5-(4- cyclopropylphenyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.12 g, 71% yield) was obtained as a yellow oil.1H NMR (400 MHz, DMSO-d6) 88.51 (br d, J = 4.4, 1H), 8.32 (s, 1H), 7.72 (dt, J = 1.6, 7.8 Hz, 1H), 7.56 (br d, J = 8.0, 1H), 7.47 (d, J = 8.4, 2H), 7.21 (ddd, J = 0.8, 4.8, 7.6, 1H), 7.08 (d, J = 8.4, 2H), 3.88 (s, 2H), 1.98 - 1.89 (m, 1H), 1.01 - 0.93 (m, 2H), 0.74 - 0.67 (m, 2H); LCMS calculated for C18HI8N4: m / z = 290; found: m / z = 291 (M+H).Compound 119: l-((lH-benzo[d]imidazol-2-yl)methyl)-3-((4-(4-cyclopropylphenyl)-5-(pyridin-2-yl)-lH- imidazol-2-yl)methyl)urea.

[0351] To a solution of [4-(4-cyclopropylphenyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.05 g, 172.20 pmol, 1.0 eq) in THF (1 mL) at rt was added CDI (27.92 mg, 172.20 pmol, 1.0 eq) and DIEA (66.77 mg, 516.60 pmol, 89.98 pL, 3.0 eq). The mixture was stirred for 30 min. Then was added 1H- benzimidazol-2-ylmethanamine (25.34 mg, 172.20 pmol, 1.0 eq). The mixture was stirred for 12 h. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep- HPLC (column: Phenomenex Luna C1880*30mm*3um;mobile phase: [H20(0.2%FA)-ACN];gradient:15%-45% B over 8.0 min) to afford l-(lH-benzimidazol-2-ylmethyl)-3-[[4-(4-cyclopropylphenyl)-5-(2-pyridyl)- lH-imidazol-2-yl]methyl]urea (0.01 g, 11% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 68.51 (br d, J = 2.4, 1H), 8.20 (s, 1H), 7.71 (dt, J = 1.6, 7.6, 1H), 7.64 - 7.42 (m, 5H), 7.24 - 7.18 (m, 1H), 7.16 - 7.10 (m, 2H), 7.07 (d, J = 8.4, 2H), 6.85 (br t, J = 5.2, 1H), 6.70 (br t, J = 5.6, 1H), 4.47 (d, J = 5.6, 2H), 4.35 (d, J = 5.6, 2H), 2.02 - 1.86 (m, 1H), 1.06 - 0.88 (m, 2H), 0.76 - 0.64 (m, 2H); LCMS calculated for C27H25N7O: m / z = 463; found: m / z = 464 (M+H).Scheme 20. Synthesis of compound 120.120Compound 120: 3-(lH-benzo[d]imidazol-2-yl)-N-((4-(4-cyclopropylphenyl)-5-(pyridin-2-yl)-lH-imidazol- 2-yl)methyl)propanamide.

[0352] To a solution of [4-(4-cyclopropylphenyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.04 g, 137.76 pmol, 1.0 eq) and 3-(lH-benzimidazol-2-yl)propanoic acid (26.20 mg, 137.76 pmol, 1.0 eq) in THF (1 mL) at rt was added PYBOP (78.86 mg, 151.54 pmol, 1.1 eq) and DIEA (35.61 mg, 275.52 pmol, 47.99 pL, 2.0 eq). The mixture was stirred for 2hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H20(0.04% HCI)-ACN];gradient:10%-50% B over 8.0 min) to afford 3-( 1 H- benzimidazol-2-yl)-N-[[4-(4-cyclopropylphenyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide (13.2 mg, 18% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6 15.15 - 14.81 (m, 1H), 9.04 (t, J = 5.6, 1H), 8.74 (d, J = 4.4, 1H), 7.94 (dt, J = 1.2, 7.6, 1H), 7.78 (dd, J = 3.2, 6.0, 2H), 7.58 - 7.50 (m, 3H), 7.47 (d, J = 2.4, 1H), 7.46 - 7.44 (m, 1H), 7.27 (d, J = 8.4, 2H), 4.67 (br d, J = 5.6, 2H), 3.42 (t, J = 6.8, 2H), 3.08 (br t, J = 7.2, 2H), 2.11 - 2.01 (m, 1H), 1.13 - 1.04 (m, 2H), 0.86 - 0.77 (m, 2H); LCMS calculated for C₂₈H₂₆N₆O: m / z = 462; found: m / z = 463 (M+H).Scheme 21. Synthesis of compound 121.ystep 1Compound 121: ethyl (((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)carbamoyl)glycinate.

[0353] To a solution of [4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.20 g, 756.65 pmol, 1.0 eq) in THF (2 ml) at rt was added DIEA (195.58 mg, 1.51 mmol, 263.59 pL, 2.0 eq). The mixture was stirred for 10 min. The reaction mixture was then cooled to 0°C, then was added ethyl 2-isocyanatoacetate (97.69 mg, 756.65 pmol, 86.38 ptL, 1.0 eq) at 0°C. The reaction mixture was heated to rt and stirred for 2 hr. The reaction mixture was poured into H2O (10 mL), and extracted with EtOAc(10 m Lx3). The combined organic layers were washed with brine(10 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude. ethyl 2-[[4-(p-tolyl)-5-(2-pyridyl)-lH-im idazol-2-yl]methylcarbamoylamino]acetate (0.2 g, 67% yield) was obtained as a brown oil.1H NMR (400 MHz, DMSO-d6) 612.70 - 11.86 (m, 1H), 8.51 (br d, J = 1.6, 1H), 7.71 (br s, 1H), 7.46 (br d, J = 8.0, 3H), 7.25 -7.14 (m, 3H), 6.69 (s, 1H), 6.52 (br s, 1H), 4.30 (d, J = 5.6, 2H), 4.08 (q, J = 7.2, 2H), 3.80 (d, J = 6.0, 2H), 2.33 (s, 3H), 1.18 (t, J = 7.2, 3H); LCMS calculated for C21H23N5O3: m / z = 393; found: m / z = 394 (M+H).Scheme 22. Synthesis of compound 122.Step 1: tert-butyl ((5-(4-(methyl-d3)phenyl)-4-(pyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)carbamate.

[0354] To a solution of tert-butyl N-[[5-bromo-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (1 g, 2.06 mmol, 1.0 eq) and [4-(trideuteriomethyl)phenyl]boronic acid (287.44 mg, 2.06 mmol, 1.0 eq) in dioxane (10 ml) and H2O (2 mL) at rt was added Pd(dppf)Cl₂ (151.34 mg, 206.84 pmol, 0.1 eq) and Cs₂CO₃ (1.35 g, 4.14 mmol, 2.0 eq). The mixture was heated to 100 °C and stirred for 4hr. The reaction mixture was cooled to rt and poured into H2O (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 1:1) to afford d tert-butyl N-[[4-(2-pyridyl)-5-[4-(trideuteriomethyl)phenyl]-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.8 g, 77% yield) was obtained as a yellow oil. LCMS calculated for C27H35D3N4O3Si: m / z = 497; found: m / z = 498 (M+H).Step 2: (4-(4-(methyl-d3)phenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methanamine.

[0355] To a solution of tert-butyl N-[[4-(2-pyridyl)-5-[4-(trideuteriomethyl)phenyl]-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.4 g, 803.67 pmol, 1.0 eq) in HCI / EtOAc (4 mL) at rt. The mixture was stirred for 4hr. The reaction mixture was poured into H2O (10 mL) adjust PH to 9, and extracted with EtOAc(10 mLx3). The combined organic layers were washed with brine(10 m Lx2), dried over Na2SO4, filtered and concentrated under reduced pressure to afford crude [4-(2-pyridyl)-5-[4-(trideuteriomethyl)phenyl]-lH-imidazol-2-yl]methanamine (0.32 g, crude) was obtained as a brown oil. LCMS calculated for Ci6Hi3D3N4: m / z = 267; found: m / z = 268 (M+H).Compound 122: 3-(lH-benzo[d]imidazol-2-yl-4,5,6,7-d4)-N-((4-(4-(methyl-d3)phenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)propanamide.

[0356] To a solution of 3-(4,5,6,7-tetradeuterio-lH-benzimidazol-2-yl)propanoic acid (29.06 mg, 149.62 pmol, 1.0 eq) and [5-(2-pyridyl)-4-[4-(trideuteriomethyl)phenyl]-lH-imidazol-2-yl]methanamine (0.04 g, 149.62 pmol, 1.0 eq) in THF (2 mL) at rt was added PYBOP (85.65 mg, 164.58 pmol, 1.1 eq) and DIEA (58.01 mg, 448.86 pmol, 78.18 pL, 3.0 eq). The mixture was stirred for 2hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [Ha0(0.2% FA)-ACN];gradient:l%-35% B over 8.0 min) to afford N-[[5-(2-pyridyl)-4-[4-(trideuteriomethyl)phenyl]-lH-imidazol-2-yl]methyl]-3-(4, 5,6,7-tetradeuterio-lH-benzimidazol-2-yl)propanamide (13.3 mg, 18% yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 6 = 8.55 (br d, J = 4.8, 1H), 8.19 (s, 1H), 7.76 (br t, J = 7.2, 1H), 7.64 - 7.43 (m, 3H), 7.32 - 7.18 (m, 3H), 4.45 (br d, J = 5.6, 2H), 3.15 (br t, J = 7.6, 2H), 2.78 (br t, J = 7.2, 2H); LCMS calculated for C26H17D7N6O: m / z = 443; found: m / z = 444 (M+H).Scheme 23. Synthesis of compound 123.35% yield 123Compound 123: l-((lH-benzo[d]imidazol-2-yl)methyl)-3-((4-(4-(methyl-d3)phenyl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)urea.

[0357] To a solution of [5-(2-pyridyl)-4-[4-(trideuteriomethyl)phenyl]-lH-imidazol-2-yl]methanamine (0.03 g, 112.22 pmol, 1.0 eq) and lH-benzimidazol-2-ylmethanamine (16.52 mg, 112.22 pmol, 1.0 eq) in THF (1 mL) at was added CDI (18.20 mg, 112.22 pmol, 1 eq) and DIEA (43.51 mg, 336.65 pmol, 58.64 pL, 3.0 eq). The mixture was stirred for 10 hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 80*30mm*3um;mobile phase: [H2O(0.2%FA)-ACN];gradient:5%-35% B over 8.0 min) to afford 1-(1H- benzimidazol-2-ylmethyl)-3-[[5-(2-pyridyl)-4-[4-(trideuteriomethyl)phenyl]-lH-imidazol-2-yl]methyl]urea (19.2 mg, 35% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6 13.25 - 11.33 (m, 1H), 8.50 (br s, 1H), 8.17 (s, 1H), 7.74 - 7.65 (m, 1H), 7.45 (br d, J = 8.0, 4H), 7.22 - 7.16 (m, 3H), 7.15 -7.09 (m, 2H), 6.83 (br t, J = 5.6, 1H), 6.68 (br t, J = 5.6, 1H), 4.46 (d, J = 5.6, 2H), 4.35 (d, J = 5.6, 2H); LCMS calculated for C25H20D3N7O: m / z = 440; found: m / z = 441 (M+H).Scheme 24. Synthesis of compound 124.Step 1: tert-butyl ((4-(4-methylcyclohex-l-en-l-yl)-5-(pyridin-2-yl)-l-((2-(trimethylsilyl)ethoxy)methyl)- lH-imidazol-2-yl)methyl)carbamate.

[0358] To a solution of tert-butyl N-[[5-bromo-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (800.00 mg, 1.65 mmol, 1.0 eq) and 4,4,5,5-tetramethyl-2-(4-methylcyclohexen-l-yl)-l,3,2-dioxaborolane (551.34 mg, 2.48 mmol, 1.5 eq) in dioxane (2 mL) and H2O (0.5 mL) at rt was added Pd(dppf)CI2(121.07 mg, 165.47 pmol, 0.1 eq) and Cs2CO3(1.08 g, 3.31 mmol, 2 eq). The mixture was heated to 100 °C and stirred for 4hr. The reaction mixture was cooled to rt and poured into H2O (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc - 20:1 to 1:1) to afford tert-butyl N-[[5-(4-methylcyclohexen-l-yl)-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.58 g, 70% yield) was obtained as a yellow oil.1H NMR (400 MHz, METHANOL-d4)68.52 (br d, J = 4.4, 1H), 8.28 (s, 1H), 7.84 - 7.73 (m, 1H), 7.69 (br d, J = 7.6, 1H), 7.28 - 7.19 (m, 1H), 5.88 (br s, 1H), 5.32 (s, 2H), 4.44 (s, 2H), 3.56 (br t, J = 8.0, 2H), 2.46 - 2.05 (m, 4H), 1.91 - 1.76 (m, 3H), 1.44 (s, 9H), 1.04 (br d, J = 6.0, 3H), 0.98 - 0.89 (m, 2H), 0.00 (s, 9H); LCMS calculated for C27H42N4O3Si: m / z = 498; found: m / z = 499 (M+H).Step 2: (4-(4-methylcyclohex-l-en-l-yl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methanamine.

[0359] To a solution of tert-butyl N-[[5-(4-methylcyclohexen-l-yl)-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (530.00 mg, 1.06 mmol, 1.0 eq) in HCI / EtOAc (2 ml) at rt. The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to afford [5-(4-methylcyclohexen-l-yl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.23 g, 80 % yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 58.52 (d, J = 4.4, 1H), 8.29 (s, 1H), 7.79 - 7.69 (m, 2H), 7.23 - 7.12 (m, 1H), 5.89 (br d, J = 2.0, 1H), 3.82 (s, 2H), 2.34 (br s, 2H), 2.23 (br d, J = 16.4, 1H), 1.83 - 1.67 (m, 3H), 1.31 (br s, 1H), 1.00 (d, J = 6.0, 3H); LCMS calculated for C16H20N4: m / z = 268; found: m / z = 269 (M+H).Compound 124: l-((lH-benzo[d]imidazol-2-yl)methyl)-3-((4-(4-methylcyclohex-l-en-l-yl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)urea.

[0360] To a solution of [4-(4-methylcyclohexen-l-yl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.05 g, 164.03 pmol, 1.0 eq, HCI) and lH-benzimidazol-2-ylmethanamine (24.14 mg, 164.03 pimol, 1.0 eq) in THF (3 mL) at rt was added CDI (26.60 mg, 164.03 imol, 1.0 eq) and DIEA (63.60 mg, 492.10 ptmol, 85.71 pL, 3.0 eq). The mixture was stirred for 12hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um;mobile phase: [H2O(0.1%TFA)-ACN];gradient:15%-45% B over 8.0 min) to afford 1-(1H-benzimidazol-2-ylmethyl)-3-[[4-(4-methylcyclohexen-l-yl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (10.9 mg, 13% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-dg) 68.74 - 8.66 (m, 1H), 7.96 (br t, J = 7.6, 1H), 7.75 - 7.65 (m, 3H), 7.53 - 7.39 (m, 3H), 7.32 (br s, 1H), 7.17 (br s, 1H), 6.07 (br s, 1H), 4.65 (br d, J = 5.2, 2H), 4.52 (br d, J = 5.2, 2H), 2.34 - 2.17 (m, 3H), 1.88 - 1.71 (m, 3H), 1.42 - 1.31 (m, 1H), 1.02 (br d, J = 6.0, 3H); LCMS calculated for C25H27N7O: m / z = 441; found: m / z = 442 (M+H).Scheme 25. Synthesis of compound 125.Step 1: tert-butyl ((4-(pyridin-2-yl)-5-(4-(trifluoromethyl)phenyl)-l-((2-(trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)carbamate.

[0361] To a solution of tert-butyl N-[[5-bromo-4-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (1.00 g, 2.07 mmol, 1.0 eq) and [4-(trifluoromethyl)phenyl]boronic acid (589.26 mg, 3.10 mmol, 1.5 eq) in dioxane (20 mL) and H2O (4 mL) at rt was added Pd(dppf)CI2 (151.34 mg, 206.84 pmol, 0.1 eq), Cs2CO3(1.35 g, 4.14 mmol, 2.0 eq). The mixture was heated to 100 °C and stirred for 4hr. The reaction mixture was poured into H2O (20 mL) and filtered through the celite. The cake was washed by EtOAc (10 m Lx2). The filtrate was extracted with EtOAc (20 m Lx2). The combined organic layers were washed with brine (20 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 1:1) to afford tert-butyl N-[[4-(2-pyridyl)-5-[4-(trifluoromethyl)phenyl]-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (0.8 g, 70% yield) was obtained as yellow oil. LCMS calculated for C27H35F3N4O3Si: m / z = 548; found: m / z = 549 (M+H).Step 2: (5-(pyridin-2-yl)-4-(4-(trifluoromethyl)phenyl)-lH-imidazol-2-yl)methanamine.

[0362] To a solution of tert-butyl N-[[4-(2-pyridyl)-5-[4-(trifluoromethyl)phenyl]-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbarnate (0.50 g, 911.29 pmol, 1.0 eq) in EtOAc (5ml) at rt was added HCI / EtOAc (4 M, 5.00 ml_, 21.9 eq). The mixture was stirred for lhr. The reaction mixture was concentrated under reduced pressure to afford crude product [5-(2-pyridyl)-4-[4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl]methanamine (350 mg, crude, HCI) was obtained as yellow solid, which was used into the next step without further purification. LCMS calculated for C16H13F3N4: m / z = 318; found: m / z = 319 (M+H).Compound 125: 3-(lH-benzo[d]imidazol-2-yl-4,5,6,7-d4)-N-((5-(pyridin-2-yl)-4-(4-(trifluoromethyl)phenyl)-lH-imidazol-2-yl)methyl)propanamide.

[0363] To a solution of [5-(2-pyridyl)-4-[4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl]methanamine (0.10 g, 281.88 pmol, 1.0 eq, HCI) in THF (2 ml) at rt was added 3-(4,5,6,7-tetradeuterio-lH-benzimidazol-2-yl)propanoic acid (60.22 mg, 310.07 pmol, 1.1 eq) HOBt (45.71 mg, 338.26 pmol, 1.2 eq) and EDCI (64.84 mg, 338.26 pmol, 1.2 eq) DIEA (109.29 mg, 845.65 pmol, 147.30 pL, 3 eq). The mixture was stirred for 12hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H20(0.2% FA)-ACN];gradient:10%-50% B over 8.0 min) to afford N-[[5-(2-pyridyl)-4-[4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl]methyl]-3-(4,5,6,7-tetradeuterio-lH-benzimidazol-2-yl)propanamide (9.6 mg, 6% yield)was obtained as a white solid.1H NMR (400 MHz, METHANOL-d4) δ 8.57 (d, J = 4.0, 1H), 7.85 - 7.74 (m, 1H), 7.68 (s, 4H), 7.49 (d, J = 8.0, 1H), 7.36 - 7.28 (m, 1H), 4.57 (s, 3H), 3.28 (t, J = 7.2, 2H), 2.88 (s, 2H); LCMS calculated for C26H17D4F3N6O: m / z = 494; found: m / z = 495 (M+H).Scheme 26. Synthesis of compound 126.5% yield 126Compound 126: 3-(lH-benzo[d]imidazol-2-yl)-N-((5-(pyridin-2-yl)-4-(4-(trifluoromethyl)phenyl)-lH-imidazol-2-yl)methyl)propanamide.

[0364] To a solution of [5-(2-pyridyl)-4-[4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl]methanamine (0.10 g, 281.88 pmol, 1.0 eq, HCI) in THF (2 mL) at rt was added 3-(lH-benzimidazol-2-yl)propanoic acid (58.98 mg, 310.07 pmol, 1.1 eq), HOBt (45.71 mg, 338.26 pmol, 1.2 eq) and EDCI (64.84 mg, 338.26 pmol, 1.2 eq), DIEA (109.29 mg, 845.65 pmol, 147.30 pL, 3.0 eq). The mixture was stirred for 12h. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC(column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-50% B over 8.0 min) to afford 3-(lH-benzimidazol-2-yl)-N-[[5-(2-pyridyl)-4-[4-(trifluoromethyl)phenyl]-lH-imidazol-2-yl]methyl]propanamide (7.5 mg, 5% yield) was obtained as a white solid.1H NMR (400 MHz, METHANOL-d4) 58.57 (dd, J = 0.8, 4.8, 1H), 7.78 (dt, J = 1.6, 7.6, 1H), 7.68 (s, 4H), 7.49 (d, J = 8.0, 1H), 7.46 - 7.40 (m, 2H), 7.33 (ddd, J = 1.2, 4.8, 7.6, 1H), 7.22 - 7.14 (m, 2H), 4.57 (s, 2H), 3.31 - 3.25 (m, 2H), 2.91 - 2.84 (m, 2H); LCMS calculated for C26H21F3N6O: m / z = 490; found: m / z = 491 (M+H).Scheme 27. Synthesis of compound 127.Step 1: tert-butyl 4-(4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)piperidine-l-carboxylate.

[0365] To a solution of 2-bromo-2-(p-tolyl)-1-(2-pyridyl)ethanone (0.60 g, 2.07 mmol, 1.0 eq) and tertbutyl 4-carbamimidoylpiperidine-l-carboxylate (470.03 mg, 2.07 mmol, 1.0 eq) in EtOH (5 mL) at rt wasadded K2CO3 (571.58 mg, 4.14 mmol, 2.0 eq). The mixture was heated to 80 °C and stirred for lhr. The reaction mixture was cooled to rt and concentrated under reduced pressure to remove most of the EtOH. The residue was poured into H2O (30 ml), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 1:1) to afford tert-butyl 4-(4-(pyridin-2-yl )-5-(p-tolyl)-lH-im idazol-2-yl)piperidine-l-carboxylate (0.25 g, 35% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 12.36 - 11.99 (m, 1H), 8.58 (br d, J = 3.2, 1H), 7.81 - 7.30 (m, 4H), 7.26 - 7.08 (m, 3H), 4.01 (br d, J = 10.8, 2H), 3.02 - 2.78 (m, 3H), 2.31 (s, 3H), 1.89 (br d, J = 10.4, 2H), 1.76 - 1.60 (m, 2H), 1.41 (s, 9H); LCMS calculated for C25H30N4O2: m / z = 418; found: m / z = 419 (M+H).Step 2: 2-(2-(piperidin-4-yl)-5-(p-tolyl)-lH-imidazol-4-yl)pyridine.

[0366] To a solution of tert-butyl 4-[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]piperidine-l-carboxylate (0.05 g, 119.47 pmol, 1.0 eq) in HCI / EtOAc (3 ml) at rt. The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to give 2-[2-(4-piperidyl)-5-(p-tolyl)-l H-imidazol-4-yl]pyridine (0.15 g, 98 % yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 58.50 (br s, 1H), 8.39 (s, 1H), 7.76 - 7.67 (m, 1H), 7.55 (br d, J = 1.6, 1H), 7.46 (d, J = 8.0, 2H), 7.26 - 7.11 (m, 3H), 3.30 - 3.20 (m, 2H), 3.00 (ddd, J = 4.0, 7.2, 10.8, 1H), 2.87 (dt, J = 2.0, 12.1, 2H), 2.33 (s, 3H), 2.06 (br dd, J = 3.2, 13.9, 2H), 1.98 - 1.84 (m, 2H); LCMS calculated for C20H22N4: m / z = 318; found: m / z = 319 (M+H).Compound 127: 2-(lH-benzo[d]imidazol-2-yl)-l-(4-(4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2-yl)piperidin-l-yl)ethan-l-one.

[0367] To a solution of 2-[2-(4-piperidyl)-5-(p-tolyl)-lH-imidazol-4-yl]pyridine (60.43 mg, 170.29 pmol, 1.0 eq, HCI) and 2-(lH-benzimidazol-2-yl)acetic acid (0.03 g, 170.29 pmol, 1.0 eq) in THF (2 mL) at rt was added DIEA (66.02 mg, 510.87 pmol, 88.98 pL, 3.0 eq) and PYBOP (88.62 mg, 170.29 pmol, 1.0 eq). The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*5um;mobile phase: [H20(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to afford.2-(lH-benzimidazol-2-yl)-l-[4-[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]-l-piperidyl]ethanone (14 mg, 12 % yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) δ 12.38 - 11.99 (m, 2H), 8.66 - 8.29 (m, 1H), 8.17 (s, 1H), 7.70 (br s, 1H), 7.67 - 7.27 (m, 5H), 7.71 - 7.09 (m, 5H), 4.43 (br d, J = 14.0, 1H), 4.18 (br d, J = 12.8, 1H), 4.11 - 3.97 (m, 2H), 3.11 - 2.98 (m, 2H), 2.89 - 2.78 (m, 1H), 2.33 (s, 3H), 2.05 - 1.93 (m, 2H), 1.90 - 1.62 (m, 2H); LCMS calculated for C29H28N6O: m / z = 476; found: m / z = 477 (M+H).Scheme 28. Synthesis of compound 128.Step 1: ethyl 2-(5-methyl-lH-benzo[d]imidazol-2-yl)acetate.

[0368] To a solution of 4-methylbenzene-l,2-diamine (2.00 g, 16.37 mmol, 1.0 eq) and ethyl 3-ethoxy-3-imino-propanoate (3.20 g, 16.37 mmol, 1.0 eq, HCI) in EtOH (10 mL)at rt. The mixture was heated to 80 °C and stirred for 12hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to remove most of the EtOH. The residue was poured into H2O (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 1:0 to 1:1) to afford ethyl 2-(5-methyl-lH-benzimidazol-2-yl)acetate (3 g, 83% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-ds) 6 12.44 - 11.94 (m, 1H), 7.38 (br d, J = 8.0, 1H), 7.29 (br s, 1H), 6.97 (d, J = 8.0, 1H), 4.13 (q, J = 6.8, 2H), 3.92 (s, 2H), 2.39 (s, 3H), 1.20 (t, J = 1.1, 3H); LCMS calculated for C12H14N2O2: m / z = 218; found: m / z = 219 (M+H).Step 2: 2-(5-methyl-lH-benzo[d]imidazol-2-yl)acetic acid.

[0369] To a solution of ethyl 2-(5-methyl-lH-benzimidazol-2-yl)acetate (1.00 g, 4.58 mmol, 1.0 eq) in THF (10 mL) and H2O (2 mL) at rt was added LiOH. H2O (384.54 mg, 9.16 mmol, 2.0 eq). The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to give 2-(5-methyl-lH- benzimidazol-2-yl)acetic acid (0.8 g, 94 yield) was obtained as a yellow solid. LCMS calculated for C10H10N2O2: m / z = 190; found: m / z = 191 (M+H).Compound 128: 2-(5-methyl-lH-benzo[d]imidazol-2-yl)-N-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2- yl)methyl)acetamide.

[0370] To a solution of 2-(5-methyl-lH-benzimidazol-2-yl)acetic acid (17.99 mg, 94.58 pmol, 1.0 eq) and [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (25.00 mg, 94.58 pmol, 1 eq) in THF (0.5 mL) at rt was added PYBOP (54.14 mg, 104.04 pmol, 1.1 eq) and DIEA (36.67 mg, 283.74 pmol, 49.42 pL, 33.0 eq). The mixture was stirred for 12hr. The reaction mixture was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H20(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min)to afford 2-(5- methyl-lH-benzimidazol-2-yl)-N-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]acetamide (13.3 mg, 20%yield) was obtained as a white solid.1H NMR (400 MHz, DMSO-d6) 58.87 (t, J = 5.6, 1H), 8.52 (br d, J = 4.0, 1H), 8.14 (s, 1H), 7.72 (dt,7 = 1.6, 7.6, 1H), 7.52 (br d, J = 8.0, 1H), 7.46 (d, 7 = 8.0, 2H), 7.29 - 7.17 (m, 4H), 7.08 (s, 1H), 7.01 - 6.89 (m, 1H), 4.48 (d, J = 5.6, 2H), 3.86 (s, 2H), 2.36 (d, J = 2.4, 6H); LCMS calculated for C26H24N6O: m / z = 436; found: m / z = 437 (M+H).Scheme 29. Synthesis of compound 129.Step 1: tert-butyl (2-((2-amino-4-methylphenyl)amino)-2-oxoethyl)carbamate.

[0371] To a solution of 4-methylbenzene-l,2-diamine (2.00 g, 16.37 mmol, 1.0 eq) and 2-(tert- butoxycarbonylamino)acetic acid (2.87 g, 16.37 mmol, 1.0 eq) in THF (20 mL) at rt was added HOBt (2.65 g, 19.65 mmol, 1.2 eq) and EDCI (3.77 g, 19.65 mmol, 1.2 eq), DIEA (6.35 g, 49.11 mmol, 8.55 mL, 3.0 eq). The mixture was stirred for 12hr. The reaction mixture was poured into H2O (30 mL), and extracted with EtOAc(30 mLx3). The combined organic layers were washed with brine(30 mLx2), dried over Na2SO4, filtered and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 1:1) to afford tert-butyl N-[2-(2-amino-4-methyl- anilino)-2-oxo-ethyl]carbamate (2.2 g, 48% yield) was obtained as a brown solid. LCMS calculated for C14H21N3O3: m / z = 279; found: m / z = 280 (M+H).Step 2: tert-butyl ((5-methyl-lH-benzo[d]imidazol-2-yl)methyl)carbamate.

[0372] To a solution of tert-butyl N-[2-(2-amino-4-methyl-anilino)-2-oxo-ethyl]carbamate (1.00 g, 3.58 mmol, 1.0 eq) in AcOH (10 mL) at rt. The reaction mixture was heated to 80 °C and stirred for 2 hr. The reaction mixture was then cooled to rt and concentrated under reduced pressure to afford crude tertbutyl N-[(5-methyl-lH-benzimidazol-2-yl)methyl]carbamate (0.8 g, 85% yield) was obtained as a yellow oil. LCMS calculated for C14H19N3O2 = 261; found: m / z = 262 (M+H).Step 3: 5-methyl-lH-benzo[d]imidazol-2-yl)methanamine.

[0373] To a solution of tert-butyl N-[(5-methyl-lH-benzimidazol-2-yl)methyl]carbamate (0.50 g, 1.91 mmol, 1.0 eq) in HCI / EtOAc (8 mL) at rt. The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to give crude (5-methyl-lH-benzimidazol-2-yl)methanamine (0.3 g, 79% yield, HCI) was obtained as a pink solid. LCMS calculated for C9H11N3 = 161; found: m / z = 162 (M+H).Compound 129: l-((5-methyl-lH-benzo[d]imidazol-2-yl)methyl)-3-((4-(pyridin-2-yl)-5-(p-tolyl)-lH- imidazol-2-yl)methyl)urea.

[0374] To a solution of (5-methyl-lH-benzimidazol-2-yl)methanamine (26.29 mg, 132.99 pmol, 1.0 eq, HCI) and [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (40 mg, 132.99 pmol, 1.0 eq, HCI) in THF (1 mL) at rt was added CDI (21.56 mg, 132.99 pmol, 1.0 eq) and DIEA (51.56 mg, 398.96 pmol, 69.49 pL, 3.0 eq). The mixture was stirred for 12hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H? O(0.2% FA)-ACN];gradient:20%-50% B over 8.0 min) to afford l-[(5-methyl-lH- benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (13.5 mg, 20% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) 612.54 - 11.92 (m, 1H), 8.51 (br s, 1H), 8.14 (s, 1H), 7.75 - 7.66 (m, 1H), 7.46 (br d, J = 8.0, 2H), 7.34 (br d, J = 8.0, 1H), 7.26 - 7.13 (m, 4H), 6.94 (d, J = 8.0, 1H), 6.80 (br t, J = 5.6, 1H), 6.67 (br t, J = 5.6, 1H), 4.44 (d, J = 5.6, 2H), 4.35 (d, J = 5.2, 2H), 2.38 (s, 3H), 2.33 (s, 3H); LCMS calculated for C26H25N7O = 451; found: m / z = 452 (M+H).Scheme 30. Synthesis of compound 130.4% yield 130Compound 130: l-(2-(lH-benzo[d]imidazol-2-yl)ethyl)-3-((4-(pyridin-2-yl)-5-(p-tolyl)-lH-imidazol-2- yl)methyl)urea.

[0375] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.03 g, 113.50 pmol, 1.0 eq) in DCM (1 mL) at rt was added DSC (58.15 mg, 226.99 pmol, 2.0 eq) and NMI (18.64 mg, 226.99 pmol, 18.09 pL, 2.0 eq).for 30 min, then was added 2-(lH-benzimidazol-2-yl)ethanamine (36.59 mg, 226.99 nmol, 2.0 eq) and NMI (18.64 mg, 226.99 pmol, 18.09 pL, 2.0 eq). The mixture was stirred for 12hr. It was filtrate and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [Ha0(0.2% FA)- ACN];gradient:5%-35% B over 8.0 min) to afford l-[2-(lH-benzimidazol-2-yl)ethyl]-3-[[5-(p-tolyl)-4-(2- pyridyl)-lH-imidazol-2-yl]methyl]urea (3.2 mg, 4% yield) was obtained as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ8.50 (br d, J = 3.6, 1H), 8.14 (s, 1H), 7.70 (s, 1H), 7.56 - 7.39 (m, 5H), 7.25 - 7.08 (m, 5H), 6.47 (br s, 1H), 6.32 (br s, 1H), 5.09 - 4.92 (m, 3H), 4.30 (br d, J = 5.2, 2H), 2.97 (br d, J = 6.4, 2H), 2.32 (s, 3H); LCMS calculated for C26H25N7O: m / z = 451; found: m / z = 452 (M+H).Scheme 31. Synthesis of compound 131.Step 1: Synthesis of tert-butyl (l-((2-hydroxyphenyl)amino)-2-methyl-l-oxopropan-2-yl)carbamate

[0376] To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (500 mg, 2.46 mmol, 1.0 eq) and DIEA (635.93 mg, 4.92 mmol, 857.05 pL, 2.0 eq) in THF (10 mL) at rt was added CMPI (754.25 mg, 2.95 mmol, 1.2 eq) and 2-aminophenol (322.17 mg, 2.95 mmol, 1.2 eq), the mixture was stirred for 12 hr. The reaction mixture was combined with another batch (50 mg). The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (40 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 2:1) to afford tert-butyl N-[2-(2- hydroxyanilino)-l,l-dimethyl-2-oxo-ethyl]carbamate (0.14 g, 17% yield) as a brown solid. LCMS calculated for C15H22N2O4: m / z = 294; found: m / z = 295 (M+H).Step 2: Synthesis of tert-butyl(2-(benzo[d]oxazol-2-yl)propan-2-yl)carbamate

[0377] To a solution of tert-butyl N-[2-(2-hydroxyanilino)-l,l-dimethyl-2-oxo-ethyl]carbamate (120 mg, 407.68 pmol, 1.0 eq) and PPh3(235.25 mg, 896.91 pmol, 2.2 eq) in THF (2 mL) at 0°C under N2was added DIAD (181.36 mg, 896.91 pmol, 173.88 pL, 2.2 eq). The resulting reaction mixture was then warmed to rt and stirred for 5 hr. The reaction mixture was combined with another batch (10 mg). The reaction mixture was diluted with water (5 mL) and extracted with ethyl acetate (3x5 mL). The combined organic layers were washed with brine (10 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by prep-TLC (SiO2, PE: EA = 2:1) to afford tertbutyl N-[l-(l,3-benzoxazol-2-yl)-l-methyl-ethyl]carbamate (0.11 g, 90% yield) as a yellow solid. LCMS calculated for C15H20N2O3: m / z = 276; found: m / z = 277 (M+H).Step 3: Synthesis of 2-(benzo[d]oxazol-2-yl) propan-2-amine

[0378] A solution of tert-butyl N-[l-(l,3-benzoxazol-2-yl)-l-methyl-ethyl]carbamate (0.11 g, 398.07 pmol, 1.0 eq) in HCI / EtOAc (4 M, 1.1 mL) at rt was stirred for 1 hr. The reaction mixture was concentrated under vacuum to afford 2-(l,3-benzoxazol-2-yl)propan-2-amine (90 mg, 95% yield, HCI) as a yellow solid. LCMS calculated for C10H12N2O: m / z = 176; found: m / z - 177 (M+H).Compound 131: Synthesis of l-(2-(benzo[d]oxazol-2-yl) propan-2-yl)-3-((4-(pyridin-2-yl)-5-(p-tolyl)-lH- imidazol-2-yl) methyl) urea.

[0379] To a solution of [4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (50 mg, 166.23 pmol, 1.0 eq, HCI) in DCM (1 mL) at rt was added DSC (42.58 mg, 166.23 pmol, 1.0 eq) and NMI (13.65 mg, 166.23 pmol, 13.25 pL, 1.0 eq). The mixture was stirred for 30 min. Then 2-(l,3-benzoxazol-2-yl)propan- 2-amine (35.35 mg, 166.23 pmol, 1.0 eq, HCI) and NMI (13.65 mg, 166.23 pmol, 13.25 pL, 1.0 eq) was added. The resulting reaction mixture was heated to 80 °C and stirred for 2 hr. The reaction mixture was cooled to rt and combined with another batch (20 mg). The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:20%-50% B over 8.0 min) to afford l-[l-(l,3-benzoxazol-2-yl)-l- methyl-ethyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (26 mg, 22% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 6 12.04 - 12.42 (m, 1 H), 8.34 - 8.58 (m, 1 H), 7.58 - 7.82 (m, 3 H), 7.45 (br d, 7=7.6, 2 H), 7.26 - 7.38 (m, 3 H), 7.19 (br s, 3 H), 6.90 - 7.03 (m, 1 H), 6.39 (t, 7=5.2, 1 H), 4.20 (d, 7=5.2, 2 H), 2.33 (br s, 3 H), 1.65 (s, 6 H); LCMS calculated for C27H26N6O2: m / z = 466; found: m / z = 467 (M+H).Scheme 32. Synthesis of compound 132.Step 1: Synthesis of tert-butyl (l-((2-amino-6-fluorophenyl) amino)-2-methyl-l-oxopropan-2-yl) carbamate

[0380] To a solution of 2-(tert-butoxycarbonylamino)-2-methyl-propanoic acid (0.5 g, 2.46 mmol, 1.0 eq) and 3-fluorobenzene-l,2-diamine (372.37 mg, 2.95 mmol, 1.2 eq) in THF (10 mL) at rt was added HOBt (332.43 mg, 2.46 mmol, 1.0 eq), EDCI (471.62 mg, 2.46 mmol, 1.0 eq) and DIEA (635.93 mg, 4.92 mmol, 857.05 pL, 2.0 eq). The mixture was stirred for 12 hr. The reaction mixture was combined with another batch (100 mg). The reaction mixture was diluted with H2O (20 mL) and extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (40 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 2:1) to afford tert-butyl N-[2-(2-amino-6-fluoro-anilino)-l, 1-dimethyl-2-oxo-ethyl]carbamate (0.6 g, 65% yield) as a yellow solid. LCMS calculated for C15H22FN3O3: m / z = 311; found: m / z = 312 (M+H).Step 2: Synthesis of tert-butyl (2-(7-fluoro-lH-benzo[d]imidazol-2-yl) propan-2-yl) carbamate

[0381] A solution of tert-butyl N-[2-(2-amino-6-fluoro-anilino)-l,l-dimethyl-2-oxo-ethyl]carbamate (0.3 g, 963.54 pmol, 1.0 eq) in AcOH (18 M, 2.91 mL) was heated to 80 °C and stirred for 1 hr. The reaction mixture was cooled to rt and concentrated under vacuum to afford tert-butyl N-[l-(7-fluoro-lH-benzimidazol-2-yl)-l-methyl-ethyl] carbamate (0.28 g, 99% yield) as a brown solid. LCMS calculated for C15H20FN3O2: m / z = 293; found: m / z = 294 (M+H).Step 3: Synthesis of 2-(benzo[d]oxazol-2-yl) propan-2-amine

[0382] A solution of tert-butyl N-[l-(7-fluoro-lH-benzimidazol-2-yl)-l-methyl-ethyl] carbamate (0.28 g, 954.54 pmol, 1.0 eq) in HCI / EtOAc (4 M, 3 mL) at rt was stirred for 1 hr. The reaction mixture wasconcentrated under vacuum to afford 2-(7-fluoro-lH-benzimidazol-2-yl) propan-2-amine (0.21 g, 95% yield, HCI) as a pink solid. LCMS calculated for C10H12FN3: m / z = 193; found: m / z = 194 (M+H).Compound 132: Synthesis of l-(2-(7-fluoro-lH-benzo[d]imidazol-2-yl) propan-2-yl)-3-((5-(pyridin-2-yl)-4- (p-tolyl)-l H-imidazol-2-yl) methyl) urea.

[0383] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (50 mg, 166.23 pmol, 1.0 eq, HCI) in DCM (1 mL) at rt was added DSC (42.58 mg, 166.23 pmol, 1.0 eq) and NMI (13.65 mg, 166.23 pmol, 13.25 pL, 1.0 eq). The mixture was stirred for 30 min. Then 2-(7-fluoro-lH-benzimidazol-2-yl) propan-2-amine (38.18 mg, 166.23 pmol, 1.0 eq, HCI) and NMI (13.65 mg, 166.23 pmol, 13.25 pL, 1.0 eq) was added. The resulting reaction mixture was heated to 80 °C and stirred for 3 hr. The reaction mixture was cooled to rt and combined with another batch (40 mg). The reaction mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: 3_Phenomenex Luna C18 75*30mm*3um; mobile phase: [H2O(0.1% TFA)-ACN];gradient:10%-40% B over 8.0 min) to afford 1-[1- (7-fluoro-lH-benzimidazol-2-yl)-l-methyl-ethyl]-3-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (32 mg, 35% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 68.64 - 8.73 (m, 1 H), 7.73 - 7.91 (m, 1 H), 7.29 - 7.49 (m, 6 H), 7.08 - 7.27 (m, 3 H), 6.92 - 7.03 (m, 1 H), 6.71 (t, 7=5.6, 1 H), 4.48 (br d, 7=5.2, 2 H), 2.41 (s, 3 H), 1.53 - 1.76 (m, 6 H); LCMS calculated for C27H26FN7O: m / z = 483; found: m / z = 484 (M+H).Scheme 33. Synthesis of compound 133.Step 1: Synthesis of tert-butyl ((4-(cyclohex-l-en-l-yl)-5-(pyridin-2-yl)-l-((2- (trimethylsilyl)ethoxy)methyl)-lH-imidazol-2-yl)methyl)carbamate

[0384] To a solution of tert-butyl N-[[4-bromo-5-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl) imidazol-2-yl]methyl]carbamate (700 mg, 1.45 mmol, 1.0 eq) in dioxane (10 mL) and H2O (3 mL) at rt was added cyclohexen-l-ylboronic acid (218.85 mg, 1.74 mmol, 1.2 eq), Cs2CO3(943.48 mg, 2.90mmol, 2.0 eq) and Pd(dppf)CI2(105.94 mg, 144.79 pmol, 0.1 eq). The resulting reaction mixture was heated to 100 °C and stirred for 4 hr under N2atmosphere. The reaction mixture was cooled to rt and poured into H2O (20 mL), and then the mixture was extracted with ethyl acetate (3x20 mL). The combined organic layers were washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 2:1) to afford tert-butyl N-[[4-(cyclohexen-l-yl)-5-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (530 mg, 75% yield) as a yellow oil. LCMS calculated for C26H37N3O3Si: m / z = 484; found: m / z = 485 (M+H).Step 2: Synthesis of (4-(cyclohex-l-en-l-yl)-5-(pyridin-2-yl)-lH-imidazol-2-yl)methanamineA solution of tert-butyl N-[[4-(cyclohexen-l-yl)-5-(2-pyridyl)-l-(2-trimethylsilylethoxymethyl)imidazol-2-yl]methyl]carbamate (480 mg, 990.29 pmol, 1.0 eq) in HCI / EtOAc (5 mL) at rt was stirred for 1 hr. The reaction mixture was concentrated under vacuum to afford [4-(cyclohexen-l-yl)-5-(2-pyridyl)-lH- imidazol-2-yl]methanamine (260 mg, 894.11 pmol, 90% yield, HCI) as a yellow solid. LCMS calculated for C15H18N4: m / z = 254; found: m / z = 255 (M+H).Step 3: Synthesis of l-((lH-benzo[d]imidazol-2-yl)methyl)-3-((4-(cyclohex-l-en-l-yl)-5-(pyridin-2-yl)-lH- imidazol-2-yl)methyl)urea

[0385] To a solution of [4-(cyclohexen-l-yl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (230 mg, 904.34 pmol, 1.0 eq) and lH-benzimidazol-2-ylmethanamine (133.10 mg, 904.34 nmol, 1.0 eq) in THF (3 ml) at rt was added CDI (145.64 mg, 904.34 pmol, 1.0 eq) and DIEA (292.20 mg, 2.26 mmol, 393.80 pL, 2.5 eq). The mixture was stirred for 12 hr. The reaction mixture was filtered and the filter was concentrated to give a residue. The residue was purification by pre-HPLC(column: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H20(0.04% HCI)-ACN];gradient:10%-30% B over 8.0 min) to afford 1-(lH-benzimidazol-2-ylmethyl)-3-[[4-(cyclohexen-l-yl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (80 mg, 14% yield) as a yellow solid. LCMS calculated for C24H25N7O: m / z = 427; found: m / z = 428 (M+H).Compound 133: Synthesis of l-((lH-benzo[d]imidazol-2-yl)methyl)-3-((4-cyclohexyl-5-(pyridin-2-yl)-lH-imidazol-2-yl)methyl)urea.

[0386] To a solution of l-(lH-benzimidazol-2-ylmethyl)-3-[[5-(2-pyridyl)-4-(l,2,3,6-tetrahydropyridin-4-yl)-lH-imidazol-2-yl]methyl]urea (20 mg, 46.68 pmol, 1.0 eq) in MeOH (1 mL) at rt was added Pd(OH>2 (6.55 mg, 9.34 pmol, 20% purity, 0.2 eq) under N2. The suspension was degassed under vacuum and purged with H2several times. The mixture was stirred under H2(15 psi) for 12 hr. The reaction mixture was filtered and concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:l%-40% B over 8.0 min)and twice purified by prep-HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to afford 1-(1H-benzimidazol-2-ylmethyl)-3-[[4-(4-piperidyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (1 mg, 4% yield) as a white solid.1H NMR (400 MHz, MeOD-d4) 68.57 (br d, 7=4.0, 1 H), 8.36 - 8.51 (m, 2 H), 7.82 (br t, 7=7.6, 1 H), 7.67 (br d, 7=8.4, 1 H), 7.50 (dd, 7=6.0, 3.2, 2 H), 7.14 - 7.24 (m, 2 H), 4.61 (br s, 2 H), 4.42 (s, 2 H), 3.35 - 3.42 (m, 1 H), 2.13 - 2.39 (m, 1 H), 1.69 - 1.92 (m, 5 H), 1.50 - 1.64 (m, 2 H), 1.40 - 1.47 (m, 1 H), 1.29 - 1.34 (m, 1 H); LCMS calculated for C24H27N7O: m / z = 429; found: m / z = 430 (M+H).Scheme 34. Synthesis of compound 134.Step 1: ethyl 2-(5-methoxy-lH-benzimidazol-2-yl)acetate.

[0387] To a solution of 4-methoxybenzene-l,2-diamine (2.00 g, 14.48 mmol, 1.0 eq) in EtOH (30 mL) at rt was added ethyl 3-ethoxy-3-imino-propanoate;hydrochloride (2.97 g, 15.20 mmol, 1.05 eq). The mixture was heated to 120 °C and stirred 12 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a residue. The residue was purified by silica gel column chromatography (PE: EtOAc = 20:1 to 1:1) to afford ethyl 2-(5-methoxy-lH-benzimidazol-2-yl)acetate (3 g, 88% yield) as a gray solid. LCMS calculated for C12H14N2O3: m / z = 235; found: m / z = 236 (M+H).Step 2: 2-(5-methoxy-lH-benzimidazol-2-yl)acetic acid.

[0388] To a solution of ethyl 2-(5-methoxy-lH-benzimidazol-2-yl)acetate (0.50 g, 2.13 mmol, 1.0 eq) in MeOH (5 mL) and H2O (1 mL) at rt was added LiOH. H2O (179.14 mg, 4.27 mmol, 2.0 eq). The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to afford 2-(5- methoxy-lH-benzimidazol-2-yl)acetic acid (0.5 g, crude) as a yellow oil. LCMS calculated for C10H10N2O3: m / z = 207; found: m / z = 208 (M+H).Compound 134: 2-(5-methoxy-lH-benzimidazol-2-yl)-N-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]acetamide.

[0389] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (40.00 mg, 132.99 pmol, 1.0 eq, HCI) and 2-(5-methoxy-lH-benzimidazol-2-yl)acetic acid (51.41 mg, 199.48 pmol, 1.5 eq) in THF (1 mL) at rt was added PYBOP (69.20 mg, 132.99 pmol, 1.0 eq) and DIEA (34.37 mg, 265.97 pmol, 46.33 pL, 2.0 eq). The mixture was stirred for 12hr. The reaction mixture was concentrated under reduced pressure to give a residue. The residue was purified by prep-HPLC (olumn: Phenomenex luna C18 100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-45% B over 8.0 min) to afford 2-(5- methoxy-lH-benzimidazol-2-yl)-N-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]acetamide (30.9 mg, 37% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 58.77 - 8.89 (m, 1 H), 8.60 (br d, 7=4.0, 1 H), 7.79 (td, 7=7.6, 1.6, 1 H), 7.50 (br d, 7=2.0, 2 H), 7.44 - 7.48 (m, 2 H), 7.31 - 7.35 (m, 1 H), 7.11 (d, J=7.6, 2 H), 7.09 (d, 7=2.0, 1 H), 6.98 (dd, 7=8.8, 2.4, 1 H), 4.60 (br d, 7=5.2, 2 H), 4.09 (s, 3 H), 3.83 (s, 2 H), 2.39 (s, 3 H); LCMS calculated for C26H24N6O2: m / z = 453; found: m / z = 454 (M+H).Scheme 35. Synthesis of compound 135.Step 1: tert-butyl 2-(2-ethoxy-l-methyl-2-oxo-ethyl)benzimidazole-l-carboxylate.boc

[0390] To a solution of tert-butyl 2-(2-ethoxy-2-oxo-ethyl)benzimidazole-l-carboxylate (0.10 g, 328.58 pmol, 1.0 eq) in THF (10 mL) at -78°C under Na(g) was added dropwise LDA (2.0 M, 492.87 pL, 3.0 eq). Then the mixture was stirred at -78°C for 30 min. After that Mel (69.96 mg, 492.87 pmol, 30.68 pL, 1.5 eq) at -78°C under N 2(g) was added dropwise to the mixture. The resulting reaction mixture was then warmed to rt and stirred for 11.5 hr. The residue was poured into H2O (50 mL) and extracted with EtOAc (3 x 40 mL). The combined organic phase was washed with brine (20 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum to provide crude tert-butyl 2-(2-ethoxy-l-methyl-2-oxo- ethyl)benzimidazole-l-carboxylate (0.10 g, 76% yield) as a yellow solid. LCMS calculated for C17H22N2O4: m / z = 318; found: m / z = 319 (M+H).Step 2: 2-(lH-benzimidazol-2-yl)propanoic acid.

[0391] To a solution of tert-butyl 2-(2-ethoxy-l-methyl-2-oxo-ethyl)benzimidazole-l-carboxylate (0.10 g, 314.10 pmol, 1.0 eq) in MeOH (1 mL) and H? O (0.2 mL) at rt was added UOH. H2O (26.36 mg, 628.21 pmol, 2.0 eq). The mixture was stirred for 2hr. The reaction mixture was concentrated under reduced pressure to afford crude 2-(lH-benzimidazol-2-yl)propanoic acid (0.06 g, 252.37 imol, 80% yield) as a white solid. LCMS calculated for C10H10N2O2: m / z = 190; found: m / z = 191 (M+H).Compound 135: 2-(lH-benzimidazol-2-yl)-N-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide.

[0392] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (25.00 mg, 94.58 pmol, 1.0 eq) and 2-(lH-benzimidazol-2-yl)propanoic acid (26.98 mg, 141.87 pmol, 1.5 eq) in THF (1 mL) at rt was added PYBOP (49.22 mg, 94.58 pimol, 1.0 eq) and DIEA (24.45 mg, 189.16 pmol, 32.95 piL, 2.0 eq). The mixture was stirred for 12hr. The residue was purified by prep-HPLC (FA condition column:Phenomenex Luna C18 100*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:15%-45% B over 8.0 min) to afford 2-(lH-benzimidazol-2-yl)-N-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide (7.5 mg, 11% yield, HCI) as a white solid.1H NMR (400 MHz, MeOD) 6 12.22 - 12.74 (m, 2 H) 8.76 (br t, 7=5.2, 1 H), 8.32 - 8.66 (m, 1 H), 8.18 (s, 1 H), 7.70 (br t, 7=7.2, 1 H), 7.28 - 7.54 (m, 4 H), 7.20 (br d, 7=8.0, 4 H), 7.06 (br s, 2 H), 4.46 - 4.56 (m, 1 H), 4.34 - 4.44 (m, 1 H), 4.06 (q, J=7.2, 1 H), 2.35 (s, 3 H), 1.55 (d, J=7.2, 3 H); LCMS calculated for C26H24N6O: m / z = 436; found: m / z = 437 (M+H).Scheme 36. Synthesis of compound 136.Step 1: tert-butyl N-[2-(2-amino-4-chloro-anilino)-2-oxo-ethyl]carbamate.

[0393] To a solution of 4-chlorobenzene-l,2-diamine (2.00 g, 14.03 mmol, 1.0 eq) and 2-(tert-butoxycarbonylamino)acetic acid (2.46 g, 14.03 mmol, 1 eq) in THF (20 mL) at rt was added HOBt (1.90 g, 14.03 mmol, 1.0 eq) and EDCI (2.69 g, 14.03 mmol, 1.0 eq), DIEA (3.63 g, 28.05 mmol, 4.89 mL, 2.0 eq). The mixture was stirred for 12hr. The residue was poured into H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with PE: EtOAc = 3:1 (20 mL) at rt for 30 min. The resulting slurry was filtered and the solid was collected and dried under vacuum to afford tert-butyl N-[2-(2-amino-4-chloro-anilino)-2-oxo-ethyl]carbamate (1.5 g, 35% yield) as a white solid. LCMS calculated for C13H18CIN3O3: m / z = 299; found: m / z = 301 (M+H).Step 2: tert-butyl N-[(5-chloro-lH-benzimidazol-2-yl)methyl]carbamate.

[0394] To a solution of AcOH (5 mt) at rt was added dtert-butyl N-[2-(2-amino-4-chloro-anilino)-2-oxo-ethylcarbamate (0.5 g, 1.67 mmol, 1 eq). The mixture was heated to 80 °C and stirred 2 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to afford tert-butyl N-[(5-chloro-lH-benzimidazol-2-yl)methyl]carbamate (0.50 g, 85% yield) as a gray solid. LCMS calculated for CI3H16CIN3O2: m / z = 281; found: m / z = 282 (M+H).Step 3: (5-chloro-lH-benzimidazol-2-yl)methanamine.

[0395] To a solution of tert-butyl N-[(5-chloro-lH-benzimidazol-2-yl)methyl]carbamate (0.50 g, 1.77 mmol, 1.0 eq) in EtOAc (1 mL) at rt was added HCI / EtOAc (4 M, 5 mL, 11.27 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford (5-chloro-lH- benzimidazol-2-yl)methanamine (0.45 g, 1.65 mmol, 93% yield, HCI) as a white solid. LCMS calculated for C8H8CIN3: m / z = 181; found: m / z = 183 (M+H).Compound 136: l-[(5-chloro-lH-benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2- yl]methyl]urea.

[0396] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (40.00 mg, 132.99 pmol, 1.0 eq, HCI) and (5-chloro-lH-benzimidazol-2-yl)methanamine (29.00 mg, 132.99 pmol, 1.0 eq, HCI) in THF (1 mL) at rt was added CDI (21.56 mg, 132.99 pmol, 1.0 eq) and DIEA (85.94 mg, 664.93 imol, 115.82 pL, 5.0 eq). The mixture was stirred for 12hr. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H20(0.04% HCI)-ACN];gradient:l%- 30% B over 8.0 min) to afford l-[(5-chloro-lH-benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH- imidazol-2-yl]methyl]urea (5.2 mg, 4 yield) as a white solid.1H NMR (400 MHz, DMSO-de) 511.69 - 12.88 (m, 2 H), 8.34 - 8.72 (m, 1 H), 8.26 (br s, 1 H), 7.30 - 7.79 (m, 6 H), 7.09 - 7.28 (m, 4 H), 6.87 (br s, 1 H), 6.71 (br t, 7=5.2, 1 H), 4.46 (d, 7=5.6, 2 H), 4.35 (d, 7=5.6, 2 H), 2.34 (s, 3 H); LCMS calculated for C25H22CIN7O: m / z = 472; found: m / z = 474 (M+H).Scheme 37. Synthesis of compound 137.Step 1: tert-butyl N-[2-(2-amino-5-methoxy-anilino)-2-oxo-ethyl]carbamate.

[0397] To a solution of 4-methoxybenzene-l,2-diamine (2.00 g, 14.48 mmol, 1.0 eq) and 2-(tert-butoxycarbonylamino)acetic acid (2.54 g, 14.48 mmol, 1.0 eq) in THF (20 mL) at rt was added DIEA (3.74 g, 28.95 mmol, 5.04 mL, 2.0 eq) and HOBt (1.96 g, 14.48 mmol, 1.0 eq), EDCI (2.77 g, 14.48 mmol, 1.0 eq). The mixture was stirred for 12hr. The residue was poured into H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 1 / 1) to afford tert-butyl N-[2-(2-amino-5-methoxy-anilino)-2-oxo-ethyl]carbamate (3 g, 49% yield) as a white solid. LCMS calculated for Ci4H2iN3O4: m / z = 296; found: m / z = 297 (M+H).Step 2: tert-butyl N-[(5-methoxy-lH-benzimidazol-2-yl)methyl]carbamate.

[0398] To a solution of AcOH (5 mt) at rt was added tert-butyl N-[2-(2-amino-5-methoxy-anilino)-2-oxo-ethyl]carbamate (1.00 g, 3.39 mmol, 1.0 eq). The mixture was heated to 80 °C and stirred 2 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 0 / 1) to afford ttert-butyl N-[(5-methoxy-lH-benzimidazol-2-yl)methyl]carbamate (0.50 g, 42% yield) as a white solid. LCMS calculated for C14H19N3O3: m / z = 278; found: m / z = 279 (M+H).Step 3: (5-methoxy-lH-benzimidazol-2-yl)methanamine.

[0399] To a solution of tert-butyl N-[(5-methoxy-lH-benzimidazol-2-yl)methyl]carbamate (0.30 g, 1.08 mmol, 1.0 eq) in EtOAc (1 mL) at rt was added HCI / EtOAc (4 M, 5 mL, 11.27 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford (5-methoxy-lH- benzimidazol-2-yl)methanamine (0.20 g, 86% yield, HCI) as a purple solid. LCMS calculated for C9H11N3O: m / z = 178; found: m / z = 179 (M+H).Compound 137: l-[(5-methoxy-lH-benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea.

[0400] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (40.00 g, 132.99 pmol, I.0 eq, HCI) and (5-methoxy-lH-benzimidazol-2-yl)methanamine (28.41 mg, 132.99 pmol, 1.0 eq, HCI) in THF (1 mL) at rt was added CDI (21.56 mg, 132.99 pmol, 1.0 eq) and DIEA (85.94 mg, 664.93 pmol, 115.82 pL, 5.0 eq). The mixture was stirred for 12hr. The reaction mixture was purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H20(0.04% HCI)-ACN];gradient:l%- 30% B over 8.0 min) to afford l-[(5-methoxy-lH-benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)- lH-imidazol-2-yl]methyl]urea (3.3 mg, 6 yield) as a white solid.1H NMR (400 MHz, DMSO-dg) 6 12.45 - II.55 (m, 1H), 8.65 - 8.32 (m, 1H), 7.76 - 7.65 (m, 1H), 7.61 - 7.26 (m, 4H), 7.23 - 7.13 (m, 3H), 6.97 (br s, 1H), 6.82 (br s, 1H), 6.75 (dd, J = 2.4, 8.8, 1H), 6.68 (br t, J = 5.2, 1H), 4.42 (d, J = 5.6, 2H), 4.35 (d, J = 5.6, 2H), 3.75 (s, 3H), 2.33 (s, 3H); LCMS calculated for C26H25N7O2: m / z = 468; found: m / z = 469 (M+H).Scheme 38. Synthesis of compound 138.Step 1: tert-butyl N-[2-[2-amino-4-(trifluoromethyl)anilino]-2-oxo-ethyl]carbamate.

[0401] To a solution of 4-(trifluoromethyl)benzene-l,2-diamine (2.00 g, 11.35 mmol, 1.0 eq) and 2-(tert-butoxycarbonylamino)acetic acid (1.99 g, 11.35 mmol, 1.0 eq) in THF (20 mL) at rt was added EDCI (2.18 g, 11.35 mmol, 1.0 eq) and HOBt (1.53 g, 11.35 mmol, 1.0 eq) and DIEA (2.94 g, 22.71 mmol, 3.96 mL, 2.0 eq). The mixture was stirred for 12 hr. The residue was poured into H2O (100 mL) and extracted with EtOAc (3 x 50 mL). The combined organic phase was washed with brine (100 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with PE: EtOAc = 3:1 (20 mL) at rt for 30 min. The resulting slurry was filtered and the solid was collected and dried under vacuum to afford tert-butyl N-[2-[2-amino-4-(trifluoromethyl)anilino]-2-oxo-ethyl]carbamate (1.5 g, 39% yield) as a white solid. LCMS calculated for C14H18F3N3O3: m / z = 334; found: m / z = 335 (M+H).Step 2: tert-butyl N-[[5-(trifluoromethyl)-lH-benzimidazol-2-yl]methyl]carbamate.

[0402] To a solution of AcOH (5 mL) at rt was added tert-butyl N-[2-[2-amino-4-(trifluoromethyl)anilino]-2-oxo-ethyl]carbamate (0.50 g, 1.50 mmol, 1.0 eq). The mixture was heated to 80 °C and stirred 2 hr. The reaction mixture was cooled to rt and concentrated under reduced pressureto afford tert-butyl N-[[5-(trifluoromethyl)-lH-benzimidazol-2-yl]methyl]carbamate (0.50 g, 95% yield) as a white solid. LCMS calculated for C14H16F3N3O2: m / z = 316; found: m / z = 317 (M+H).Step 3: [5-(trifluoromethyl)-lH-benzimidazol-2-yl]methanamine.

[0403] To a solution of tert-butyl N-[[5-(trifluoromethyl)-lH-benzimidazol-2-yl]methyl]carbamate (0.5 g, 1.59 mmol, 1.0 eq) in EtOAc (1 mL) at rt was added HCI / EtOAc (4 M, 5 m L, 11.27 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford [5- (trifluoromethyl)-lH-benzimidazol-2-yl]methanamine (0.45 g, 99% yield, HCI) as a white solid. LCMS calculated for CgHgFjNa: m / z = 216; found: m / z = 217 (M+H).Compound 138: l-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]-3-[[5-(trifluoromethyl)-lH- benzimidazol-2-yl]methyl]urea.

[0404] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.04 g, 132.99 pmol, 1.0 eq, HCI) and [5-(trifluoromethyl)-lH-benzimidazol-2-yl]methanamine (33.46 mg, 132.99 pmol, 1.0 eq, HCI) in THF (1 mL) at rt was added CDI (21.56 mg, 132.99 pmol, 1.0 eq) and DIEA (85.94 mg, 664.93 pmol, 115.82 pL, 5.0 eq). The mixture was stirred for 12hr. The reaction mixture was purified by prep- HPLC (column: Phenomenex Luna C18 100*30mm*3um;mobile phase: [H20(0.2% FA)-ACN];gradient:10%-40% B over 8.0 min) to afford l-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]-3- [[5-(trifluoromethyl)-lH-benzimidazol-2-yl]methyl]urea (5.2 mg, 4 yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 611.96 - 12.97 (m, 2 H), 8.32 - 8.71 (m, 1 H), 8.18 (s, 1 H), 7.76 - 7.88 (m, 1 H), 7.59 - 7.74 (m, 2 H), 7.46 (br d, 7=8.4, 4 H), 7.15 - 7.25 (m, 3 H), 6.90 (br s, 1 H), 6.73 (t, 7=5.2, 1 H), 4.52 (d, 7=5.6, 2 H), 4.36 (d, 7=5.6, 2 H), 2.33 (s, 3 H); LCMS calculated for C26H22F3N7O: m / z = 506; found: m / z = 507 (M+H).Scheme 39. Synthesis of compound 139.step 4 139Step 1: tert-butyl N-[2-(2-aminoanilino)-l,l-dimethyl-2-oxo-ethyl]carbamate.

[0405] To a solution of benzene-l,2-diamine (1.00 g, 9.25 mmol, 1.0 eq) and 2-(tertbutoxycarbonylamino)-2-methyl-propanoic acid (1.88 g, 9.25 mmol, 1.0 eq) in THF (10 mL) at rt was added EDCI (1.77 g, 9.25 mmol, 1.0 eq) and HOBt (1.25 g, 9.25 mmol, 1.0 eq), DIEA (2.39 g, 18.49 mmol, 3.22 mL, 2.0 eq). The mixture was stirred for 12hr. The residue was poured into H2O (50 mL) and extracted with EtOAc (3 x 20 mL). The combined organic phase was washed with brine (50 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The crude product was triturated with PE: EtOAc = 3:1 (20 mL) at rt for 30 min. The resulting slurry was filtered and the solid was collected and dried under vacuum to afford tert-butyl N-[2-(2-aminoanilino)-l,l-dimethyl-2-oxo-ethyl]carbamate (0.5 g, 18% yield) as a white solid. LCMS calculated for C15H23N3O3: m / z = 293; found: m / z = 294 (M+H).Step 2: tert-butyl N-[l-(lH-benzimidazol-2-yl)-l-methyl-ethyl]carbamate.

[0406] To a solution of AcOH (5 mL) at rt was added tert-butyl N-[2-(2-aminoanilino)-l,l-dimethyl-2-oxo-ethyl]carbamate (0.50 g, 1.70 mmol, 1.0 eq). The mixture was heated to 80 °C and stirred 2 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to afford tert-butyl N-[l-(lH-benzimidazol-2-yl)-l-methyl-ethyl]carbamate (0.45 g, 95% yield) as a white solid. LCMS calculated for CI5H2IN3O2: m / z = 275; found: m / z = 276 (M+H).Step 3: 2-(lH-benzimidazol-2-yl)propan-2-amine.

[0407] To a solution of ert-butyl N-[l-(lH-benzimidazol-2-yl)-l-methyl-ethyl]carbamate (0.45 g, 1.63 mmol, 1.0 eq) in EtOAc (1 mL) at rt was added HCI / EtOAc (4 M, 5 mL, 11.27 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford 2-(lH-benzimidazol-2-yl)propan-2-amine (0.34 g, 98% yield, HCI) as a purple solid. LCMS calculated for C10H13N3: m / z = 175; found: m / z = 176 (M+H).Compound 139: l-[(5-chloro-lH-benzimidazol-2-yl)methyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea.

[0408] To a solution of [5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methanamine (0.02 g, 66.49 pmol, 1.0 eq, HCI) in DCM (1 mL) at rt was added DSC (17.03 mg, 66.49 pmol, 1.0 eq) and NMI (5.46 mg, 66.49 pmol, 5.30 |iL, 1.0 eq). The mixture was stirred for 1 hr. Then at rt was added 2-(lH-benzimidazol-2-yl)propan-2-amine (14.08 mg, 66.49 pmol, 1.0 eq, HCI) and NMI (5.46 mg, 66.49 pmol, 5.30 pL, 1.0 eq) The resulting reaction mixture was heated to 80 °C and stirred for 1 hr. The reaction mixture was then cooled to rt, purified by prep-HPLC (column: Phenomenex luna C18100*40mm*5 um;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-45% B over 8.0 min) to afford l-[l-(lH-benzimidazol-2-yl)-l-methyl-ethyl]-3-[[5-(p-tolyl)-4-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea (8.7 mg, 9% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 68.32 - 8.69 (m, 1 H), 8.14 (s, 1 H), 7.71 (br t, 7=7.2, 1 H), 7.27 - 7.61 (m, 5 H), 7.19 (br d, 7=8.0, 3 H), 7.10 (dd, 7=6.0, 3.2, 2 H), 6.82 (s, 1 H), 6.50 (s, 1 H), 4.27 (d, 7=5.2, 2 H), 2.34 (s, 3 H), 1.66 (s, 6 H); LCMS calculated for C27H27N7O: m / z = 465; found: m / z = 466 (M+H).Scheme 40. Synthesis of compound 140.step 1 step 2Step 1: 3-ethoxy-4-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]cyclobut-3-ene-l, 2-dione.

[0409] To a solution of [4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]rnethanamine (50.00 mg, 166.23 pmol, 1.0 eq, HCI) and 3, 4-diethoxycyclobut-3-ene-l, 2-dione (28.29 mg, 166.23 pmol, 24.34 pL, 1.0 eq) in EtOH (2 mL) at rt was added DIEA (64.45 mg, 498.69 pmol, 86.86 pL, 3 eq). The mixture was stirred for 12 hr. The mixture was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:30%-57% B over 8.0 min) to afford 3-ethoxy-4-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]cyclobut-3-ene-l, 2-dione. (3 mg, 5% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 68.43 - 8.60 (m, 1 H), 7.68 - 7.75 (m, 1 H), 7.45 (br d, 7=7.88 Hz, 3 H), 7.15 -7.28 (m, 3 H), 4.84 (br s, 1 H), 4.66 (q, 7=7.05 Hz, 3 H), 2.33 (s, 3 H), 1.30 - 1.43 (m, 3 H); LCMS calculated for C21H18N4O3: m / z = 375; found: m / z = 376 (M+H).Compound 140: 3-(lH-benzimidazol-2-ylmethylamino)-4-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]cyclobut-3-ene-l, 2-dione.

[0410] To a solution of 3-ethoxy-4-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]cyclobut-3-ene-1, 2-dione (60.00 mg, 154.47 pmol, 1.0 eq) and lH-benzimidazol-2-ylmethanamine (22.73 mg, 154.47 pmol, 1.0 eq) in MeOH (1 mL) at rt was added DIEA (19.96 mg, 154.47 pmol, 26.91 pL, 1.0 eq). The mixture was stirred for 12hr. The mixture was purified by prep-HPLC (column: Waters Xbridge BEH C18 100*30mm*10um;mobile phase: [H2O(10mM NH4HCO3)-ACN];gradient:25%-65% B over 8.0 min) to afford 3-(lH-benzimidazol-2-ylmethylamino)-4-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methylamino]cyclobut-3-ene-l, 2-dione (6.7 mg, 3% yield) as a white solid.1H NMR (400 MHz, DMSO- d6) 6 12.29 - 12.82 (m, 2 H), 8.32 - 8.72 (m, 1 H), 8.22 (s, 1 H), 7.70 (br s, 3 H), 7.28 - 7.62 (m, 5 H), 7.08 - 7.26 (m, 5 H), 4.80 - 5.11 (m, 4 H), 2.33 (s, 3 H); LCMS calculated for C28H23N7O2: m / z = 489; found: m / z = 490 (M+H).Scheme 41. Synthesis of compounds 141 and 217.Step 1: (2R)-2-(lH-benzimidazol-2-yl)-N-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propenamide (Compound 141).

[0411] The 2-(lH-benzimidazol-2-yl)-N-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide 20.00 mg was purified by prep-HPLC (column: DAICEL CHIRALCEL OD(250mm*30mm,10um);mobile phase: [CO2-IPA(0.1%NH3H2O)]; B%:45%, isocratic elution mode) to afford (2R)-2-(lH-benzimidazol-2-yl)- N-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide (6.5 mg, 31% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 612.87 - 12.12 (m, 2H), 8.86 - 8.72 (m, 1H), 8.69 - 8.31 (m, 1H), 7.70 (br s, 1H), 7.53 - 6.96 (m, 10H), 4.58 - 4.31 (m, 2H), 4.12 - 4.01 (m, 1H), 2.36 (s, 3H), 1.56 (d, J = 7.2, 3H); LCMS calculated for C26H24N6O: m / z = 437; found: m / z = 438 (M+H).Compound 217: (2S)-2-(lH-benzimidazol-2-yl)-N-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide.

[0412] (2S)-2-(lH-benzimidazol-2-yl)-N-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]propanamide (5.5 mg, 27% yield) as a white solid.1H NMR (400 MHz, DMSO-d6) 6 12.67 - 12.24 (m, 2H), 8.77 (brt, 7 = 5.2, 1H), 8.69 - 8.27 (m, 1H), 7.79 - 7.69 (m, 1H), 7.61 - 6.86 (m, 9H), 4.56 - 4.33 (m, 2H), 4.06 (q, J = 7.2, 1H), 2.36 (s, 3H), 1.56 (d, J = 7.2, 3H); LCMS calculated for C26H24N6O: m / z = 437; found: m / z = 438 (M+H).Scheme 42. Synthesis of compound 142.Step 1: lH-imidazo[4,5-c]pyridin-2-ylmethanamine.

[0413] To a solution of tert-butyl N-(lH-imidazo[4,5-c]pyridin-2-ylmethyl)carbamate (0.15 g, 604.16 pmol, 1.0 eq) in EtOAc (0.2 ml) at rt was added HCI / EtOAc (4 M, 2 mL, 13.24 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford 1H-imidazo[4,5-c]pyridin-2-ylmethanamine (0.1 g, 95% yield, HCI) as a yellow solid. LCMS calculated for C7H8N4: m / z = 148; found: m / z = 149 (M+H).Compound 142: l-(lH-imidazo[4,5-c]pyridin-2-ylmethyl)-3-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methyl]urea.

[0414] To a solution of [4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (50 mg, 166.23 pmol, 1.0 eq, HCI) and lH-imidazo[4,5-c]pyridin-2-ylmethanamine (30.69 mg, 166.23 pmol, 1.0 eq, HCI) in THF (2 mL) at rt was added CDI (26.95 mg, 166.23 pmol, 1.0 eq) and DIEA (42.97 mg, 332.46 pmol, 57.91 pL,2.0 eq). The mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was purified by prep-HPLC (FA condition column:3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.2% FA)-ACN];gradient:5%-35% B over 8.0 min) to afford l-(lH-imidazo[4,5-c]pyridin-2-ylmethyl)-3-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2- yl]methyl]urea (18.4 mg, 24% yield, 96.6% purity) as a white solid.1H NMR (400 MHz, DMSO) 58.78 (s, 1H), 8.48 (br s, 1H), 8.39 (br s, 1H), 8.28 (br d, J = 5.6, 1H), 7.71 - 7.49 (m, 2H), 7.46 - 7.07 (m, 6H), 4.67 (br s, 2H), 4.52 (s, 2H), 2.41 (s, 3H); LCMS calculated for C25H25N8O: m / z = 438; found: m / z = 439 (M+H).Scheme 43. Synthesis of compound 143.Step 1: tert-butyl ((lS,2R)-2-(((5-(pyridin-2-yl )-4-(p-tolyl)-lH-im idazol-2- yl)methyl)carbamoyl)cyclohexyl)carbamate.

[0415] To a solution of (lR,2S)-2-((tert-butoxycarbonyl)amino)cyclohexane-l-carboxylic acid (90 mg, 369.9 pmol, 1.0 eq) in DCM (2 mt) at rt was added DIEA (95.6 mg, 739.8 pmol, 2.0 eq), HOBt (75 mg, 554.9 pmol, 1.5 eq) and EDCI (106.4 mg, 554.9 pmol, 1.5 eq). The mixture was stirred for 0.5 hr. Then (5- (pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methanamine (97.8 mg, 367 pmol, 1.0 eq) at rt was added. The resulting mixture was stirred for 3 hr. The reaction mixture was combined with another batch (10 mg). The combined mixture was poured into Sat. NaHCOj (30 mt) and extracted with DCM (3 x 15 mL). The combined organic phase was dried with anhydrous Na2SO4, filtered and concentrated under vacuum to afford tert-butyl ((lS,2R)-2-(((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)carbamoyl) cyclohexyl)carbamate (150 mg, crude) as a yellow solid.1H NMR (400 MHz, DMSO-dg) 68.52 (br d, J = 4.8, 1H), 7.75 - 7.63 (m, 1H), 7.44 (br d, J = 7.6, 1H), 7.36 (d, J = 8.0, 2H), 7.29 - 7.23 (m, 1H), 7.19 (d, J = 8.0, 2H), 4.77 - 4.49 (m, 2H), 4.32 (br d, J = 16.0, 1H), 4.12 (br s, 1H), 2.63 - 2.51 (m, 1H), 2.36 (s, 3H), 1.91 - 1.70 (m, 3H), 1.67 - 1.54 (m, 3H), 1.54 - 1.45 (m, 1H), 1.31 (s, 9H); LCMS calculated for C28H35N5O3: m / z = 489; found: m / z = 490 (M+H).Compound 143: (lS,2R)-2-amino-N-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)cyclohexane-l- carboxamide.

[0416] A mixture of tert-butyl ((lS,2R)-2-(((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)carbamoyl) cyclohexyl)carbamate (130 mg, 265.5 pmol, 1.0 eq) in HCI / EtOAc (4M, 2 mL) at rt was stirred for 0.5 hr. The reaction mixture was combined with another batch (20 mg). The combined mixture was concentrated under vacuum. The residue was purified by prep-HPLC (column: Phenomenex luna C18 100*30mm*3 urn; mobile phase: [H2O (0.2% FAJ-ACN]; gradient: l%-30% B over 8.0 min) to afford (lS,2R)-2-amino-N-((5-(pyridin-2-yl)-4-(p-tolyl)-lH-imidazol-2-yl)methyl)cyclohexane-l- carboxamide (7.9 mg, 7% yield) as a yellow solid.1H NMR (400 MHz, DMSO-d6) 69.11 (br s, 1H), 8.51 (br d, J = 4.4, 1H), 8.40 (s, 1H), 7.76 - 7.63 (m, 1H), 7.55 - 7.36 (m, 3H), 7.27 - 7.09 (m, 3H), 4.57 - 4.50 (m, 1H), 4.32 - 4.23 (m, 1H), 3.41 (br s, 1H), 2.80 - 2.69 (m, 1H), 2.32 (s, 3H), 1.96 - 1.77 (m, 2H), 1.74 - 1.52 (m, 4H), 1.41 - 1.23 (m, 2H); LCMS calculated for C23H27ON5: m / z = 389; found: m / z = 390 (M+H).Scheme 44. Synthesis of compound 144.step 1 step 2Step 1: lH-imidazo[4,5-c]pyridin-2-ylmethanamine.

[0417] To a solution of tert-butyl N-[(5-methylimidazo[4,5-c]pyridin-2-yl)methyl]carbamate (0.05 g, 190.62 pmol, 1 eq) in EtOAc (0.2 mL) was added HCI / EtOAc (4 M, 2 mL, 41.97 eq). The mixture was stirred for 2 hr. The reaction mixture was concentrated under reduced pressure to afford (5- methylimidazo[4,5-c]pyridin-2-yl)methanamine (35 mg, 95% yield, HCI) as a yellow solid. LCMS calculated for CgHi2N4: m / z = 164; found: m / z = 165 (M+H).Compound 144: l-[(5-methylimidazo[4,5-c]pyridin-2-yl)methyl]-3-[[4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol- 2-yl]methyl]urea.

[0418] To a solution of [4-(p-tolyl)-5-(2-pyridyl)-lH-imidazol-2-yl]methanamine (50 mg, 166.23 pmol, 1 eq, HCI) and (5-methylimidazo[4,5-c]pyridin-2-yl)methanamine (33.02 mg, 166.23 pmol, 1 eq, HCI) in THF (2 mL) at rt was added GDI (26.95 mg, 166.23 pimol, 1 eq) and DIEA (42.97 mg, 332.46 pmol, 57.91 pL, 2 eq). The mixture was stirred for 12 hr. The reaction mixture was concentrated under reduced pressure to give a residue. The reaction mixture was purified by prep-HPLC (HCI condition column: 3_Phenomenex Luna C1875*30mm*3um;mobile phase: [H2O(0.04% HCI)-ACN];gradient:l%-30% B over 8.0 min) to afford l-[(5-methylimidazo[4,5-c]pyridin-2-yl)methyl]-3-[[4-(p-tolyl)-5-(2-pyridyl)-lH- imidazol-2-yl]methyl]urea (2.4 mg, 16% yield, 98.7% purity) as a white solid.1H NMR (400 MHz, DMSO) 6 9.23 (s, 1H), 8.74 (d, J = 4.8, 1H), 8.55 (d, J = 6.8, 1H), 8.04 (d, J = 6.8, 1H), 7.99 - 7.91 (m, 1H), 7.61 - 7.51 (m, 2H), 7.48 - 7.36 (m, 4H), 4.75 (d, J = 10.4, 4H), 4.45 (s, 3H), 2.45 (s, 3H); LCMS calculated for C25H26N8O: m / z = 454; found: m / z = 455 (M+H).Scheme 45. Synthesis of compound 145.

[0419] To a solution of pyridine-3,4-diamine (5.0 g, 45.82 mmol, 1.0 eq) and 2-(tert- butoxycarbonylamino)acetic acid (8.03 g, 45.82 mmol, 1.0 eq) in THF (200 mL) at rt was added EDCI (8.78 g, 45.82 mmol, 1.0 eq) and HOBt (6.19 g, 45.82 mmol, 1.0 eq), DIEA (11.84 g, 91.63 mmol, 15.96 mL, 2.0 eq). The mixture was stirred for 12hr. The residue was poured into H2O (500 mL) and extracted with EtOAc (3 x 200 mL). The combined organic phase was washed with brine (200 mL), dried with anhydrous Na2SO4, filtered, and concentrated under vacuum. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 0 / 1) to afford tert-butyl N-[2-[(3-amino-4-pyridyl)amino]-2-oxo-ethyl]carbamate (3.6 g, 30 % yield)) as a yellow solid. LCMS calculated for Ci2Hi8N4O3: m / z = 266; found: m / z = 267 (M+H).Step 2: tert-butyl N-(3H-imidazo[4,5-c]pyridin-2-ylmethyl)carbamate.

[0420] To a solution of tert-butyl N-[2-[(3-amino-4-pyridyl)amino]-2-oxo-ethyl]carbamate (3.2 g, 12.02 mmol, 1.0 eq) in DMF (16 mL) at rt was added AcOH (503.52 mg, 8.38 mmol, 480.00 pL, 0.1 eq). The mixture was heated to 130 °C and stirred 12 hr. The reaction mixture was cooled to rt and concentrated under reduced pressure to give a residue. The residue was purified by column chromatography (SiO2, Petroleum ether / Ethyl acetate=10 / l to 0 / 1) to afford tert-butyl N-(3H-imidazo[4,5-c]pyridin-2-ylmethyl)carbamate (1.5 g, 45% yield) as a yellow solid. LCMS calculated for C12H16N4O2: m / z = 248; found: m / z = 249 (M+H).Step 3: tert-butyl 2-[(tert-butoxycarbonylamino)methyl]imidazo[4,5-c]pyridine-...

Claims

CLAIMSWHAT is CLAIMED is:

1. A compound of formula (I):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;Rebis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;n is 0 or 1;B is selected fromX is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

2. The compound of Claim 1, wherein Rais phenyl or substituted phenyl.

3. The compound of Claim 1, wherein R8is H.

4. The compound of Claim 1, wherein R9is H.

5. The compound of Claim 1, wherein6. The compound of Claim 5, wherein X is -CR11-.

7. The compound of Claim 5, wherein X is -NH-.

8. The compound of Claim 1, wherein R14is R16, and R16is selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

9. The compound of Claim 1, wherein the compound is of formula (II):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;B is selected fromX is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl;R14is R16or -C(O)NH-R16;R15is selected from alkyl, substituted alkyl, cyano, alkenyl, substituted alkenyl, alkynyl, and substituted alkynyl;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

10. The compound of Claim 1, wherein the compound is of formula (III):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl,aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR14is R16or -C(O)NH-R16;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

11. The compound of Claim 1, wherein the compound is of formula (IIIA):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;Y is CR13;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

12. The compound of Claim 1, wherein the compound is of formula (IV):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, cycloalkyl, and substituted cycloalkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;R10is selected from H, alkyl, and substituted alkyl;X is selected from -NH-, -NR17-, and -CR11-;m is 0 or 1;R11is selected from H, alkyl, and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR14is R16or -C(O)NH-R16;R16is selected from carboxyl ester, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl; andR17is selected from alkyl and substituted alkyl.

13. The compound of Claim 12, wherein R8is H.

14. The compound of Claim 12, wherein R9is H.

15. The compound of Claim 12, wherein X is -CR11-.

16. The compound of Claim 12, wherein X is -NH-.

17. The compound of Claim 12, wherein m is 0.

18. The compound of Claim 12, wherein m is 1.

19. The compound of Claim 12, wherein R14is R16, and R16is selected from alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl.

20. The compound of any one of Claims 1-19, wherein the compound has an EC50of 50nM or less in a NanoLuc assay (as described in Example 4).

21. The compound of any one of Claims 1-19, wherein the compound has an EC50of 25nM or less in the NanoLuc assay.

22. The compound of any one of Claims 1-19, wherein the compound has an EC5o of lOnM or less in the NanoLuc assay.

23. The compound of any one of Claims 1-19, wherein the compound has an EC50of 5nM or less in the NanoLuc assay.

24. The compound of Claim 1, selected from:520523524Z£9whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R7is selected from H, alkyl and substituted alkyl;R12is absent or selected from H, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R13is selected from H, alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, or R12and R13together with the atom to which they are attached form a cycloalkyl or substituted cycloalkyl; andR16is selected from alkyl, substituted alkyl, alkenyl, substituted alkenyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl, or R13and R16together with the atom to which they are attached form a cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl or substituted heteroaryl.

26. The compound of Claim 25, wherein R3is methyl or methoxy.

27. The compound of Claim 25, wherein R7is H or methyl.

28. The compound of Claim 25, wherein R12and R13are each independently H or methyl.

29. The compound of Claim 25, wherein R16is heteroaryl or substituted heteroaryl.

30. The compound of Claim 25, wherein R13and R16together with the atom to which they are attached form a heteroaryl or substituted heteroaryl.

31. The compound of Claim 25, selected from:9£90179817932. A compound of formula (IB):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19and R20are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

33. A compound of formula (IC):whereinR3is selected from halo, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl and substituted cycloalkyl;R19, R20and R21are each independently selected from H, halo, alkyl, substituted alkyl, alkoxy, and substituted alkoxy.

34. The compound of Claim 32 or 33, wherein R3is methoxy.

35. The compound of Claim 32 or 33, wherein R3is cyclopropyl or substituted cyclopropyl.

36. The compound of Claim 32 or 33, wherein R3is substituted C1-3 alkyl.

37. The compound of Claim 32 or 33, wherein R19or R20is methoxy.

38. The compound of Claim 32 or 33, wherein one or both of R19and R20are halo.

39. The compound of Claim 32 or 33, selected from:

40. A compound of formula (ID):whereinR3is haloalkyl; andR22is selected from pyridinyl, pyrimidinyl, pyridazinyl, [l,2,4]triazolo[l,5-o]pyridinyl, and [l,2,4]triazolo[l,5-o]pyrazinyl, wherein R22is optionally substituted with one or more groups selected from halo, haloalkyl, alkyl, and alkoxy, and combinations thereof.

41. The compound of Claim 40, wherein R3is difluoroethyl.

42. The compound of Claim 40, selected from:

43. A pharmaceutical composition comprising a compound of any one of Claims 1 to 42, and a pharmaceutically acceptable carrier, excipient or vehicle.

44. A method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of any one of Claims 1 to 42.

45. A method for treating a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claims 1 to 42 or pharmaceutically acceptable salt or solvate thereof to the subject.

46. A method for treating a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of any one of Claims 1 to 42 or pharmaceutically acceptable salt or solvate thereof to the subject.

47. The method of Claim 46, wherein the disease or disorder is a disease of iron metabolism.

48. The method of Claim 47, wherein the disease of iron metabolism is an iron overload disease.

49. The method of Claim 46, wherein the disease or disorder is a hemochromatosis, a thalassemia, or a polycythemia vera.

50. A method for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claims 1 to 42 or pharmaceutically acceptable salt or solvate thereof to the subject.

51. The method of Claim 50, wherein the disease or disorder associated with a high calorie diet is selected from obesity, diet-induced obesity, steatosis (fatty liver disease), hepatic stenosis, iron overload disease, iron deficiency disorder, hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, alpha thalassemia, P-thalassemia, sideroblastic anemia, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia,anemia of chronic disease, anemia of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease, erythropoietin resistance, iron deficiency of obesity, other anemias, benign or malignant tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, hereditary hemochromatosis, and Alzheimer's disease.

52. A kit comprising a compound of any one of Claims 1 to 42 or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound.

53. A compound of formula (V):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;p is 0 or 1;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

54. The compound of Claim 53, wherein the compound is of formula (VI):whereinRais selected from cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl;R6ais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

55. The compound of Claim 53, wherein the compound is a compound of formula (VII):VIIv)whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;X is selected from N and NH;m is 0 or 1;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 to 5.

56. The compound of Claim 53, wherein the compound is a compound of formula (VIII):whereinR1, R2, and R5are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, cycloalkyl, and substituted cycloalkyl;R3and R4are each independently selected from H, halo, hydroxyl, amino, substituted amino, alkyl, substituted alkyl, alkoxy, substituted alkoxy, cycloalkyl, and substituted cycloalkyl; or R3and R4together with the atoms to which they are attached form an aryl, substituted aryl, heteroaryl or substituted heteroaryl;Reais selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R6bis selected from H, alkyl, substituted alkyl, alkoxy, and substituted alkoxy;R7and R8are each independently selected from H, alkyl, and substituted alkyl, wherein one of R7and R8is absent;R9is selected from H, alkyl, and substituted alkyl;A is selected from cycloalkyl, substituted cycloalkyl, cycloalkenyl, substituted cycloalkenyl, heterocycloalkyl, and substituted heterocycloalkyl;each R10is independently selected from H, alkyl, substituted alkyl, cyano, amino, substituted amino, carboxyl ester, amino acyl, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andq is 1 or 2.

57. The compound of any one of Claims 53-56, wherein Rais phenyl or substituted phenyl.

58. The compound of any one of Claims 53-56, wherein Rais cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl.

59. The compound of any one of Claims 53-58, wherein R8is H.

60. The compound of any one of Claims 53-59, wherein R9is H.

61. The compound of any one of Claims 53-60, wherein p is 1 and m is 0.

62. The compound of any one of Claims 53-61, wherein A is heterocycloalkyl or substituted heterocycloalkyl.

63. The compound of Claim 62, wherein A is piperazinyl, substituted piperazinyl, piperidinyl, or substituted piperidinyl.

64. The compound of any one of Claims 53-63, wherein X is NH.

65. The compound of any one of Claims 53-64, wherein R10is aryl, substituted aryl, heteroaryl or substituted heteroaryl.

66. The compound of Claim 65, wherein R10is pyridinyl, substituted pyridinyl, benzimidazolyl substituted benzimidazolyl, phenyl, or substituted phenyl.

67. The compound of any one of Claims 53-64, wherein R10is alkyl or substituted alkyl.

68. The compound of any one of Claims 53-64, wherein R10is cycloalkyl, substituted cycloalkyl, heterocycloalkyl, or substituted heterocycloalkyl.

69. The compound of any one of Claims 53-64, wherein R10is carboxyl ester.

70. The compound of any one of Claims 53-69, wherein the compound has an EC50of 50nM or less in a NanoLuc assay (as described in Example 4).

71. The compound of any one of Claims 53-69, wherein the compound has an EC50of 25nM or less in the NanoLuc assay.

72. The compound of any one of Claims 53-69, wherein the compound has an EC50of 10nM or less in the NanoLuc assay.

73. The compound of any one of Claims 53-69, wherein the compound has an EC50of 5nM or less in the NanoLuc assay.

74. The compound of Claim 53, selected from:1799Z.990Z.9frZ.

975. A compound of formula (VA):whereinR3is selected from H, hydroxyl, alkyl, substituted alkyl, alkoxy and substituted alkoxy;R6bis selected from H, alkyl and substituted alkyl;R7is selected from H, alkyl and substituted alkyl;each R10is independently selected from H, alkyl, substituted alkyl, carboxyl ester, cycloalkyl, substituted cycloalkyl, heterocycloalkyl, substituted heterocycloalkyl, aryl, substituted aryl, heteroaryl, and substituted heteroaryl; andR18is selected from H, alkyl and substituted alkyl.

76. The compound of Claim 75, wherein R3is methoxy or substituted methoxy.

77. The compound of Claim 75, wherein R7is H or methyl.

78. The compound of Claim 75, wherein R10is selected from substituted alkyl, cycloalkyl and substituted aryl.

79. The compound of Claim 75, wherein R18is H or methyl.

80. The compound of Claim 75, selected from:8Z.

981. A pharmaceutical composition comprising a compound of any one of Claims 53-80, and a pharmaceutically acceptable carrier, excipient or vehicle.

82. A method of binding a ferroportin or inducing ferroportin internalization and degradation, comprising contacting the ferroportin with a compound of any one of Claim 53-80.

83. A method for treating a disease of iron metabolism in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claim 53-80 or pharmaceutically acceptable salt or solvate thereof to the subject.

84. A method for treating a disease or disorder associated with dysregulated hepcidin signaling in a subject in need thereof, comprising administering an effective amount of the compound of any one of Claim 53-80 or pharmaceutically acceptable salt or solvate thereof to the subject.

85. The method of Claim 84, wherein the disease or disorder is a disease of iron metabolism.

86. The method of Claim 85, wherein the disease of iron metabolism is an iron overload disease.

87. The method of Claim 84, wherein the disease or disorder is a hemochromatosis, a thalassemia, or a polycythemia vera.

88. The method of Claim 87, wherein the compound is compound 494, 495, 504, 612, 620, 622, 623, or 797.

89. The method of Claim 84, wherein the disease or disorder is associated with dysregulated iron metabolism and is selected from obesity, diet-induced obesity, steatosis (fatty liver disease), hepatic stenosis, iron overload disease, iron deficiency disorder, hemochromatosis, HFE mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, thalassemia, thalassemia intermedia, alpha thalassemia, β-thalassemia, sideroblastic anemia, African iron overload, hyperferritinemia, ceruloplasmin deficiency, atransferrinemia, congenital dyserythropoietic anemia, anemia of chronic disease, anemia of inflammation, anemia of infection, hypochromic microcytic anemia, iron- deficiency anemia, iron-refractory iron deficiency anemia, anemia of chronic kidney disease, erythropoietin resistance, iron deficiency of obesity, other anemias, benign or malignant tumors that overproduce hepcidin or induce its overproduction, conditions with hepcidin excess, Friedreich ataxia, gracile syndrome, Hallervorden-Spatz disease, Wilson's disease, pulmonary hemosiderosis, hepatocellular carcinoma, cancer, hepatitis, cirrhosis of liver, pica, chronic renal failure, insulin resistance, diabetes, atherosclerosis, neurodegenerative disorders, multiple sclerosis, Parkinson's disease, Huntington's disease, hereditary hemochromatosis, and Alzheimer's disease.

90. A method for treating a disease or disorder associated with a high calorie diet in a subject in need thereof, comprising administering an effective amount of a compound of any one of Claim 53-80 or pharmaceutically acceptable salt or solvate thereof to the subject.

91. A kit comprising a compound of any one of Claim 53-80 or pharmaceutically acceptable salt or solvate thereof, and a packaging containing the compound.

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