METHOD FOR THE USE OF PYRIMIDINES AS FERROPORTIN HIBITORS

Abstract

The subject matter described herein is directed to ferroportin inhibitor compounds of Formula (I) and pharmaceutical salts thereof, methods of preparing the compounds, pharmaceutical compositions comprising the compounds, and methods of administering the compounds for prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis, and also kidney injuries.

Description

METHODS OF USE FOR PYRIMIDINES AS FERROPORTIN INHIBITORS CROSS REFERENCE TO RELATED APPLICATIONS [1] This application claims the benefit of and priority to U.S. Provisional Application No.63 / 016,874, filed on April 28, 2020, and U.S. Provisional Application No. 63 / 127,830, filed on December 18, 2020, the contents of each of which are hereby incorporated by reference in their entirety. FIELD [2] The subject matter described herein is directed to ferroportin inhibitor compounds, methods of making the compounds, their pharmaceutical compositions, and their use in the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis, and also kidney injuries. BACKGROUND [3] In nearly all organisms, iron is an essential trace element. In humans, iron is a critical component for oxygen transport, oxygen uptake, cell functions such as mitochondrial electron transport, cognitive functions, and energy metabolism. Iron is present in enzymes, hemoglobin and myoglobin, as well as in depots in the form of ferritin and hemosiderin. With respect to hemoglobin, approximately half of all iron is present as heme iron, bound in the hemoglobin of the erythrocytes. The human body contains on average approximately 4 to 5 g iron. The iron requirement of a human adult is between 0.5 to 1.5 mg per day, whereas infants and women during pregnancy require 2 to 5 mg of iron per day. [4] In a healthy human adult, the normal daily loss of iron of about 1 mg is usually replaced via food intake. Iron balance is primarily regulated by recycling and iron recovery from hemoglobin of aging erythrocytes and the duodenal absorption of dietary iron in the form of divalent as well as trivalent iron ions. [5] Absorption is regulated by the organism depending on the iron requirement and the size of the iron depot. Usually, Fe(III) compounds are dissolved in the stomachat a sufficiently acidic pH value and thus made available for absorption. The absorption of the iron is carried out in the upper small intestine by mucosal cells. Trivalent non- heme iron is first reduced in the intestinal cell membrane to Fe(II) for absorption, for example by ferric reductase (membrane-bound duodenal cytochrome b), so that it can then be transported into the intestinal cells by means of the transport protein DMT1 (divalent metal transporter 1). In contrast, heme iron enters the enterocytes through the cell membrane without any change. In the enterocytes, iron is either stored in ferritin as depot iron, or released into the blood by the transport protein ferroportin. The divalent iron transported into the blood by ferroportin is converted into trivalent iron by oxidases (ceruloplasmin, hephaestin). The trivalent iron is then transported to its destination in the organism by transferrin. (“Balancing acts: molecular control of mammalian iron metabolism," M.W. Hentze, Cell, 1:17, 2004, 285-297). Hepcidin plays a central role in this process because it is the essential regulating factor of iron absorption. The hepcidin- ferroportin system directly regulates iron metabolism. [6] Iron uptake and storage is regulated by hepcidin. Hepcidin Antimicrobial Peptide (HAMP; also known as LEAP-1; further referred to as Hepcidin) is a 25 amino acid peptide (Krause et al., FEBS Lett.480, 147-150, 2000). Hepcidin has a hairpin structure with 8 cysteines that form 4 disulfide bridges (Jordan et al., J Biol Chem.284, 24155–24167, 2009). The N-terminus appears to be important for the iron-regulatory function since deletion of the first 5 amino acids resulted in complete loss of bioactivity (Nemeth et al., Blood, 107, 328-333, 2006). Hepcidin is produced in the liver and functions as the master iron regulatory hormone controlling intestinal iron uptake, and also regulates iron storage in other organs (Ganz, Hematol. Am. Soc. Hematol. Educ. Program, 29-35, 5072006; Hunter et al., J. Biol. Chem.277, 37597-37603, 2002; Park et al., J. Biol. Chem.276, 7806-7810, 2001). Hepcidin limits iron-uptake by binding to the iron transport molecule ferroportin and causing its degradation (Sebastiani et al., Front. Pharmacol. 7, 160, 2016). [7] The formation of hepcidin is regulated in direct correlation to the organism’s iron level, i.e., if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed; if iron and oxygen levels are low, or in case of increased erythropoiesis, less hepcidin is formed. In the small intestinal mucosal cells and in the macrophages hepcidinbinds with the transport protein ferroportin, which conventionally transports the phagocytotically recycled iron from the interior of the cell into the blood. [8] Ferroportin is an iron transporter that plays a key role in regulating iron uptake and distribution in the body and thus in controlling iron levels in the blood. The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids which is formed in the liver, spleen, kidneys, heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal epithelial cells. Ferroportin bound in this way thus acts to export the iron into the blood. In this case, it is most probable that ferroportin transports iron as Fe2+. If hepcidin binds to ferroportin, ferroportin is transported into the interior of the cell, where its breakdown takes place so that the release of the phagocytotically recycled iron from the cells is then almost completely blocked. If the ferroportin is inactivated, for example by hepcidin, so that it is unable to export the iron which is stored in the mucosal cells, the stored iron is lost with the natural shedding of cells via the stools. The absorption of iron in the intestine is therefore reduced, when ferroportin is inactivated or inhibited, for example by hepcidin. [9] A decrease of hepcidin results in an increase of active ferroportin, thus allowing an enhanced release of stored iron and an enhanced iron uptake, e.g., from the food, resulting in an increase in serum iron levels, i.e., iron overload. Iron overload causes many diseases and undesired medical conditions. Iron overload can be treated by removal of the iron from the body. This treatment includes regularly scheduled phlebotomies (bloodletting). For patients unable to tolerate routine blood draws, there are chelating agents available for use. A disadvantage in the treatment of iron overload by chelation therapy is the removal of the chelated iron from the body when the iron overload has already occurred instead of preventing the occurrence of the disorder.

[0010] What is therefore needed and not effectively addressed by the art are compounds that act as ferroportin inhibitors that have desired efficacy and therapeutic potential. This problem as well as others stemming from iron imbalance are addressed by the subject matter described herein. BRIEF SUMMARY

[0011] In certain embodiments, the subject matter described herein is directed toinhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0012] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0013] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0014] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0015] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with hemochromatosis comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0016] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with a disease related to or caused by a hemoglobinopathy comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0017] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0018] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with sickle cell disease comprising administeringto the subject an effective amount of a compound of Formula I’ or Formula I.

[0019] In certain embodiments, the subject matter described herein is directed to methods of treating a subject afflicted with sickle cell anemia comprising administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0020] In certain embodiments, the subject matter described herein is directed to methods of treating a subject wherein the treating comprises inhibiting iron transport mediated by ferroportin in the subject by administering to the subject an effective amount of a compound of Formula I’ or Formula I.

[0021] Other embodiments are also described. DETAILED DESCRIPTION

[0022] Described herein are ferroportin inhibitor compounds of Formula I’ and Formula I, methods of making the compounds, pharmaceutical compositions comprising the compounds and their use in the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis. Ferroportin is the iron transport protein responsible for the uptake of the released iron via the intestine and its transfer into the blood circulation, where ultimately the iron is delivered to the appropriate tissues and organs. Inactivation or inhibition of the ferroportin reduces or prevents the export of the iron, thereby reducing the absorption of iron in the intestine and ultimately the amount of iron in the body. These compounds, compositions and methods can be used for an effective therapy for the prophylaxis and treatment of iron metabolism disorders which are associated with increased iron levels. It is desirable to provide compounds, compositions and methods that exhibit few side effects, have very low toxicity and good bioavailability and compatibility.

[0023] Iron overload has been associated with a variety of diseases (Blanchette et al., Expert Rev. Hematol.9, 169-186, 2016). Hereditary hemochromatosis is the most common inherited disease in Europe and is caused by lack of, or insensitivity to, hepcidin (Powell et al., The Lancet 388, 706-716, 2016). The clinical manifestation of hemochromatosis are hepatic cirrhosis, diabetes, and skin pigmentation (Powell et al., The Lancet 388, 706-716, 2016). While this disease canbe managed by phlebotomy, this approach may be cumbersome and does not treat the cause of the disease.

[0024] Iron-loading anemias such as beta-thalassemia are also associated with reduced hepcidin levels (Origa et al., Haematologica 92, 583-588, 2007). Treatment of this disease with hepcidin mimetics may not only address the iron overload, but has also been shown to improve the ineffective erythropoiesis that occurs in this disease (Casu et al., Blood 128, 265-276, 2016). This may be of major benefit for thalassemia patients who may be less dependent on blood transfusions, which can contribute to the iron overload in these patients.

[0025] Myelofibrosis, myelodysplastic syndrome, and sickle cell disease are diseases that are also characterized by ineffective erythropoiesis and that may require frequent blood transfusions (Carreau et al., Blood Rev.30, 349-356, 2016; Temraz et al., Crit. Rev. Oncol. Hematol.91, 64-73, 2014; Walter et al., Acta Haematol.122, 174-183, 2009). Reduced hepcidin levels have been described in some of these patients (Cui et al., Leuk. Res.38, 545-550, 2014; Santini et al., PLoS ONE 6, e23109, 2011). Hepcidin mimetics may also be beneficial in these patients.

[0026] Polycythemia vera is a disease characterized by increased erythropoiesis. It has been shown in animal models that high doses of hepcidin mimetics can ameliorate this disease by diminishing erythropoiesis (Casu et al., Blood 128, 265- 276, 2016).

[0027] Reduction of iron uptake and thereby serum iron levels may even be beneficial in diseases where iron load is normal, such as kidney diseases (Walker and Agarwal, Nephrol.36, 62-70, 2016), infections with iron-dependent bacteria (Arezes et al., Cell Host Microbe 17, 47-57, 2015), and polymicrobial sepsis (Zeng et al., Anesthesiology, 122, 374-386, 2015).

[0028] Hepcidin itself is limited in its use as a drug because of its complex structure which requires a complicated manufacturing, and also its limited in vivo duration of action. Continuous efforts have been made to search for hepcidin mimetics and chemical compounds that could be used to increase hepcidin levels.

[0029] A common approach relates to small hepcidin-derived or hepcidin-like peptides, which can be produced affordably, and can be used to treat hepcidin-relateddiseases and disorders such as those described herein. Such so-called mini-hepcidins are rationally designed small peptides that mimic hepcidin activity and may be useful for the treatment of iron overload, and also iron overload related disease symptoms.

[0030] Such mini-hepcidin peptides are described for example in WO 2010 / 065815 A2 and WO 2013 / 086143 A1. WO 2015 / 157283 A1 and the corresponding US 9,315,545 B2 describe hepcidin mimetic peptides and the use thereof in hepcidin-related disorders, such as iron overload, beta-thalassemia, hemochromatosis etc. and cover a development compound M012 of the company Merganser Biotech, having been under evaluation in a Phase 1 clinical program as a potentially transformative therapy for a number of hematological diseases including beta-thalassemia, low risk myelodysplasia and polycythemia vera.

[0031] WO 2014 / 145561 A2 and WO 2015 / 200916 A2 describe further small hepcidin peptide analogues and the use thereof in the treatment or prevention of a variety of hepcidin-related diseases, including iron overload diseases and iron- loading anemias, and further related disorders. Further, WO 2015 / 042515 A1 relates to hepcidin and its peptide fragments, which are particularly intended for treating renal ischemia reperfusion injury or acute kidney injury. Further, mini-hepcidin analogs are described for example by Preza et al., J. Clin. Invest., 121 (12), 4880- 4888, 2011 or in CN 104011066 and in WO 2016 / 109363 A1.

[0032] Ferroportin inhibitors as well as compounds that have hepcidin-like activity are needed that also possess additional beneficial properties such as improved solubility, stability, and / or potency. An advantage of the ferroportin inhibitor compounds of Formula I described herein is their preparation in sufficient yields by the synthetic routes disclosed herein.

[0033] The presently disclosed subject matter will now be described more fully hereinafter. However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will come to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the specific embodiments disclosed and that modifications and other embodiments are intended to be includedwithin the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in this field. All publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, including but not limited to defined terms, term usage, described techniques, or the like, this application controls. I. Definitions

[0034] As used in the present specification, the following words, phrases and symbols are generally intended to have the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0035] A dash (“that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NH2is attached through the carbon atom. A dash at the front or end of a chemical group is a matter of convenience; chemical groups may be depicted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specified point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implied by the order in which a chemical group is written or named.

[0036] The prefix “Cu-Cv” indicates that the following group has from u to v carbon atoms. For example, “C1-C6 alkyl” indicates that the alkyl group has from 1 to 6 carbon atoms.

[0037] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 50%. In certain other embodiments, the term “about” includes the indicated amount ± 20%. In certain other embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the term “about” includes the indicated amount ± 1%. In certain other embodiments, the term“about” includes the indicated amount ± 0.5% and in certain other embodiments, 0.1%. Such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural references unless the context clearly dictates otherwise. Thus, e.g., reference to “the compound” includes a plurality of such compounds and reference to “the assay” includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0038] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 12 carbon atoms (i.e., C1-C12alkyl), 1 to 8 carbon atoms (i.e., C1-C8alkyl), 1 to 6 carbon atoms (i.e., C1-C6alkyl), 1 to 4 carbon atoms (i.e., C1-C4alkyl), or 1 to 3 carbon atoms (i.e., C1-C3alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec- butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a specific number of carbons is named by chemical name or identified by molecular formula, all positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2) and tert- butyl (i.e., -C(CH3)3); and “propyl” includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0039] Certain commonly used alternative chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., arylalkyl or aralkyl, the last mentioned group contains the atom by which the moiety is attached to the rest of the molecule.

[0040] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-C20 alkenyl), 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), 2 to 6 carbon atoms (i.e., C2-C6 alkenyl) or 2 to 4 carbon atoms (i.e., C2-C4alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0041] “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C2-C20 alkynyl), 2 to 8 carbon atoms (i.e., C2-C8 alkynyl), 2 to 6 carbon atoms (i.e., C2-C6 alkynyl) or 2 to 4 carbon atoms (i.e., C2-C4alkynyl). The term “alkynyl” also includes those groups having one triple bond and one double bond.

[0042] The term “alkylene” by itself or as part of another substituent means a divalent radical derived from an alkane, such as, methylene —CH2—, ethylene — CH2CH2—, and the like. As an example, a “hydroxy-methylene” refers to HO—CH2—*, where * is the attachment point to the molecule.

[0043] “Alkoxy” refers to the group “alkyl-O-” (e.g., C1-C3alkoxy or C1-C6alkoxy). Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n- butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0044] “Alkoxy-alkyl” refers to the group “-alkyl-alkoxy”. The term “C1-C3 alkoxy- C1-C3alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to three carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to three carbons. The term, “C1-C6alkoxy-C1-C3alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to six carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to six carbons. The term, “C1-C3alkoxy-C1-C6alkyl” refers to a one to six carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to three carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to three carbons. Non-limiting examples of alkoxy-alkyl are -CH2OCH3, -CH2OC(CH3)3, and -C(CH3)2CH2OCH3.

[0045] “Alkylthio” refers to the group “alkyl-S-”. “Alkylthioalkyl” refers to the group -alkyl-S-alkyl, such as -C1-C3-alkyl-S-C1-C3 alkyl. A non-limiting example of alkylthioalkyl is -CH2CH2SCH3. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “alkyl-S(O)2-”. “Alkylsulfonylalkyl” refers to -alkyl- S(O)2-alkyl.

[0046] “Acyl” refers to a group -C(O)Ry, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may beoptionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl and benzoyl.

[0047] “Amido” refers to both a “C-amido” group which refers to the group - C(O)NRyRzand an “N-amido” group which refers to the group -NRyC(O)Rz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or Ryand Rzare taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0048] “Amino” refers to the group -NRyRzwherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0049] “Amidino” refers to -C(NRy)(NRz2), wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0050] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including fused systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-C20aryl), 6 to 12 carbon ring atoms (i.e., C6-C12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-C10 aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless of the point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of the point of attachment.

[0051] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”, such as (C6-C10aryl)-C1-C3 alkyl. As used herein, “(C6-C10 aryl)-C1-C3 alkyl” refers to a one to three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by an aryl group having six to ten carbon atoms, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an aryl group having six to ten carbon atoms. A non-limiting example of arylalkyl is benzyl.

[0052] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -O-C(O)NRyRzand an “N-carbamoyl” group which refers to the group -NRyC(O)ORz, wherein Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0053] “Carboxyl ester” or “ester” refer to both -OC(O)Rxand -C(O)ORx, wherein Rxis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0054] “Carboxylic acid-alkyl” refers to an -alkyl-carboxylic acid group. As used herein, “carboxylic acid-C1-C6 alkyl” refers to a one to six carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by a carboxylic acid group in particular, one hydrogen on one carbon of the alkyl chain is replaced by a carboxylic acid group. A non-limiting example of a carboxylic acid-alkyl is -CH2C(O)OH.

[0055] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp3carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-C20cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C12cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-C8 cycloalkyl), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C6cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bridged and / or fused rings, such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentan-1-yl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and the like. Further, the term cycloalkyl is intended to encompass any ring or ring system comprising a non-aromatic alkyl ring which may be fused to an aryl ring, regardless of the attachment to the remainder of the molecule. Further, cycloalkyl also includes “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0056] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”, such as (C3-C6cycloalkyl)-C1-C3alkyl. As used herein, “(C3-C6cycloalkyl)-C1-C3alkyl” refers to a oneto three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to six carbon atoms, in particular, one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having three to six carbon atoms.

[0057] “Cycloalkyl-alkoxy” refers to the group “-alkoxy-cycloalkyl” (e.g., C3-C7cycloalkyl-C1-C6 alkoxy- or C3-C7 cycloalkyl-C1-C3 alkoxy-), such as -OCH2- cyclopropyl. As used herein, “C3-C7 cycloalkyl-C1-C6 alkoxy” refers to an alkoxy group having a one to six carbon alkyl chain, wherein one of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to seven carbon atoms, in particular, one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having three to seven carbon atoms. As used herein, “C3-C7cycloalkyl-C1-C3alkoxy” refers to an alkoxy group having a one to three carbon alkyl chain, wherein one of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to seven carbon atoms, in particular, one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having three to seven carbon atoms.“Guanidino” refers to -NRyC(=NRz)(NRyRz), wherein each Ryand Rzare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0058] “Cyano-alkyl” refers to the group, “-alkyl-cyano”. As used herein, “cyano- (C1-C6 alkyl)” refers to a one to six carbon alkyl chain wherein one of the hydrogen atoms on any carbon is replaced by a cyano group.

[0059] “Hydrazino” refers to -NHNH2.

[0060] “Imino” refers to a group -C(NRy)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0061] “Imido” refers to a group -C(O)NRyC(O)Rz, wherein Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0062] “Halogen” or “halo” refers to atoms occupying group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0063] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by ahalogen. For example, halo-C1-C3alkyl refers to an alkyl group of 1 to 3 carbons wherein at least one hydrogen atom is replaced by a halogen. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl and the like.

[0064] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a halogen. Non-limiting examples of haloalkoxy are -OCH2CF3, -OCF2H, and -OCF3.

[0065] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced by a hydroxy group (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term “hydroxy-C1-C3alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term “hydroxy-C1-C6alkyl” refers to a one to six carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0066] “Hydroxyalkoxy” refers to the group “-alkoxy-hydroxy,” (e.g., hydroxy-C1-C3 alkoxy, hydroxy-C1-C6 alkoxy). The term “hydroxy-C1-C3 alkoxy” refers to an alkoxy group containing a one to three carbon alkyl chain wherein one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term “hydroxy-C1-C6 alkoxy” refers to an alkoxy group containing a one to six carbon alkyl chain wherein one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkoxy include -OCH2CH2OH and -OCH2C(CH3)2OH.

[0067] “Heteroalkyl” refers to an alkyl group in which one or more of the carbonatoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molecule is through a carbon atom. In certain embodiments, the heteroalkyl can have 1 to 3 carbon atoms (e.g., C1-C3heteroalkyl) or 1 to 6 carbon atoms (e.g., C1-C6heteroalkyl), and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatomic groups. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms of the alkyl group in the “heteroalkyl” may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NRy-, -O-, -S-, -S(O)-, - S(O)2-, and the like, wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfones (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2O CH3, etc.) and amines (e.g., -CH2NRyCH3, -CH(CH3)NRyCH3, -CH2CH2NRyCH3, -CH2CH2NRyCH2CH2NRyC H3, etc., where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted, as defined herein). In certain embodiments, heteroalkyl can have 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0068] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C1-C20heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C12heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-C8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 9-10 membered ring systems (i.e., 9-10 membered heteroaryl), 5-10 memberedring systems (i.e., 5-10 membered heteroaryl), 5-7 membered ring systems (i.e., 5-7 membered heteroaryl), 5-6 membered ring systems (i.e., 5-6 membered heteroaryl), or 4- 6 membered ring systems (i.e., 4-6 membered heteroaryl), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1- oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridinyl and imidazo[1,5-a]pyridinyl, where the heteroaryl can be bound via either ring of the fused system. Any aromatic ring or ring system, having a single or multiple fused rings, containing at least one heteroatom, is considered a heteroaryl regardless of the attachment to the remainder of the molecule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above.

[0069] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”, such as (5- to 10- membered heteroaryl)-C1-C3 alkyl. As used, herein, “(5- to 10-membered heteroaryl)-C1- C3alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a heteroaryl group having 5- to 10- members, in particular, one hydrogen on one carbon of the chain is replaced by a (5- to 10-membered heteroaryl group.

[0070] “Hydroxy-alkoxy-alkyl” refers to the group “-alkyl-alkoxy-hydroxy”. The term “hydroxy-C1-C3-alkoxy-C1-C3 alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having a one to three carbon alkyl chain, wherein one hydrogen on one carbon of the alkoxy carbon chain isreplaced by a hydroxy group.

[0071] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or spiro, and may comprise one or more (e.g., 1 to 3) N-oxide (-O-) or oxide (=O) moieties. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless of the attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass a ring or ring system comprising any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remainder of the molecule. The term heterocyclyl is also intended to encompass a ring system comprising a cycloalkyl ring which is fused to a heteroaryl ring, regardless of the attachment to the remainder of the molecule. Additionally, the term heterocyclyl is intended to encompass a ring system comprising a cycloalkyl ring which is fused to a heterocyclyl ring, regardless of the attachment to the remainder of the molecule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (i.e., C2-C20 heterocyclyl), 2 to 12 ring carbon atoms (i.e., C2-C12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10heterocyclyl), 2 to 8 ring carbon atoms (i.e., C2-C8heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-C12heterocyclyl), 3 to 8 ring carbon atoms (i.e., C3-C8 heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen. When the heterocyclyl ring contains 4- to 6- ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclyl. Also disclosed herein are 5- or 6-membered heterocyclyls, having 5 or 6 ring atoms, respectively, 4- to 10- membered heterocyclyls, having 4 to 10 ring atoms, 4- to 12- membered heterocyclyls, having 4 to 12 ring atoms, 4- to 7-membered heterocyclyls, having 4 to 7 ring atoms, 5- to 9- membered heterocyclyls, having 5 to 9 ring atoms, and 5- to 10-membered heterocyclyls, having 5 to 10 ring atoms. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyl,benzodioxolyl, benzo[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxinyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thienyl[1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl (i.e., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In certain embodiments, the term “heterocyclyl” can include “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples of the spiro-heterocyclyl rings include, e.g., bicyclic and tricyclic ring systems, such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6- azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of the fused- heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7- tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, where the heterocyclyl can be bound via either ring of the fused system.

[0072] “Heterocyclylalkyl” refers to the group “heterocyclyl-alkyl-,” such as (5- to 10-membered heterocyclyl)-C1-C3 alkyl. As used, herein, “(5- to 10-membered heterocyclyl)-C1-C3alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a heterocyclyl group having 5- to 10- members, in particular, one hydrogen on one carbon of the chain is replaced by a (5- to 10- membered heterocyclyl group.

[0073] “Nitro” refers to the group -N(O)2.

[0074] “Oxime” refers to the group -CRy(=NOH) wherein Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0075] “Sulfonyl” refers to the group -S(O)2Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0076] “Sulfinyl” refers to the group -S(O)Ry, where Ryis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulfinyl and toluenesulfinyl.

[0077] “Sulfonamido” refers to the groups -SO2NRyRzand -NRySO2Rz, where Ryand Rzare each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0078] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the term “optionally substituted” refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0079] The term “substituted” used herein means any of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) wherein at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclyl, heterocyclylalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide or -Si(Ry)3, wherein each Ryis independently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0080] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NRgRh, -NRgC(=O)Rh, -NRgC(=O)NRgRh, -NRgC(=O)ORh, -certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)Rg, - C(=O)ORg, -C(=O)NRgRh, -CH2SO2Rg, or -CH2SO2NRgRh. In the foregoing, Rgand Rhare the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl, or two of Rgand Rhand Riare taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0081] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is itself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above definitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a chemical group, the term “substituted” may describe other chemical groups defined herein.

[0082] In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to four. In certain embodiments, as used herein, the phrase “one or more” refers to one tothree.

[0083] Any compound or structure given herein, is intended to represent unlabeled forms as well as isotopically labeled forms (isotopologues) of the compounds. These forms of compounds may also be referred to as and include “isotopically enriched analogs.” Isotopically labeled compounds have structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as2H,3H,11C,13C,14C,13N,15N,15O,17O,18O,31P,32P,35S,18F,36Cl,123I, and125I, respectively. Various isotopically labeled compounds of the present disclosure, for example those into which radioactive isotopes such as3H,13C and14C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, detection or imaging techniques, such as positron emission tomography (PET) or single-photon emission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0084] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is / are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens have been replaced by deuterium.

[0085] Deuterium labelled or substituted therapeutic compounds of the disclosure may have improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excretion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and / or an improvement in therapeutic index. An18F,3H,11C labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds ofthis disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and preparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0086] The concentration of such a heavier isotope, specifically deuterium, may be defined by an isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “hydrogen”, the position is understood to have hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) is meant to represent deuterium. Further, in some embodiments, the corresponding deuterated analog is provided.

[0087] In many cases, the compounds of this disclosure are capable of forming acid and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0088] Provided also are a pharmaceutically acceptable salt, isotopically enriched analog, deuterated analog, isomer (such as a stereoisomer), mixture of isomers (such as a mixture of stereoisomers), prodrug, and metabolite of the compounds described herein.

[0089] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0090] The term “pharmaceutically acceptable salt” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitableorganic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methodologies that may be used to prepare nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-toluene- sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NH2(alkyl)), dialkyl amines (i.e., HN(alkyl)2), trialkyl amines (i.e., N(alkyl)3), substituted alkyl amines (i.e., NH2(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)2), tri(substituted alkyl) amines (i.e., N(substituted alkyl)3), alkenyl amines (i.e., NH2(alkenyl)), dialkenyl amines (i.e., HN(alkenyl)2), trialkenyl amines (i.e., N(alkenyl)3), substituted alkenyl amines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)2), tri(substituted alkenyl) amines (i.e., N(substituted alkenyl)3, mono-, di- or tri- cycloalkyl amines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-, di- or tri- arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3) or mixed amines, etc. Specific examples of suitable amines include, by way of example only, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine and the like.

[0091] The term “hydrate” refers to the complex formed by the combining of a compound described herein and water.

[0092] A “solvate” refers to an association or complex of one or more solvent molecules and a compound of the disclosure. Examples of solvents that form solvatesinclude, but are not limited to, water, isopropanol, ethanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine.

[0093] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of the equilibrium among tautomers, the compounds are understood by one of ordinary skill in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0094] The compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (S)- or, as (D)- or (L)- for amino acids. The present invention is meant to include all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the preparation / isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain olefinic double bonds or other centres of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers.

[0095] A “stereoisomer” refers to a compound made up of the same atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molecules are nonsuperimposeable mirror images of one another.

[0096] “Diastereomers” are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0097] Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0098] “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate derivatives), amides, guanidines, carbamates (e.g., N,N- dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Preparation, selection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol.14 of the A.C.S. Symposium Series; “Design of Prodrugs,” ed. H. Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0099] The term, “metabolite,” as used herein refers to a resulting product formed when a compound disclosed herein is metabolized. As used herein, the term “metabolized” refers to the sum of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance, such as a compound disclosed herein, is changed by an organism. For example, an aldehyde moiety (-C(O)H) may be reduced in vivo to a -CH2OH moiety.

[0100] Use of the word “inhibitor,” “inhibit” or “inhibition,” herein refers to activity of a compound of Formula I or a pharmaceutically acceptable salt on ferroportin, unless specified otherwise. By “inhibit” herein is meant to decrease the activity of ferroportin, as compared to the activity of ferroportin in the absence of the compound. In someembodiments, the term “inhibit” means a decrease in ferroportin activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibit means a decrease in ferroportin activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibit means a decrease in ferroportin activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of techniques that would be recognizable by one of skill in the art, including in vitro assays.

[0101] As used herein, the term “ferroportin inhibitor” and the like refers to a compound that reduces, inhibits, or otherwise diminishes one or more of the biological activities of ferroportin, for instance by inducing internalization of ferroportin. The activity could decrease by a statistically significant amount including, for example, a decrease of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of ferroportin compared to an appropriate control.

[0102] “Treatment” or “treating” is an approach for obtaining beneficial or desired results including clinical results. Beneficial or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or condition, and / or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and / or c) relieving the disease, that is, causing the regression of clinical symptoms (e.g., ameliorating the disease state, providing partial or total remission of the disease or condition, enhancing effect of another medication, delaying the progression of the disease, increasing the quality of life, and / or prolonging survival.

[0103] “Prevention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is atrisk or has a family history of the disease or condition.

[0104] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0105] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable salt, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a sickle cell disease. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and age of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0106] When any variable or substituent occurs more than one time in any structure or formulae, its definition in each occurrence is independent of its definition at every other occurrence. Combinations of substituents and / or variables are permissible only if such combinations result in chemically stable compounds. It is understood that substituents and substitution patterns on the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

[0107] Additional definitions may also be provided below as appropriate. II. Methods of Inhibiting Ferroportin and Treating Disease

[0108] In certain embodiments, the subject matter described herein is directed to a method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C3-alkyl, cyano, -NRGRH, halo-C1-C3alkoxy, -O-(CH2)u-Rbb, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 6; Rbbis 4- to 7- membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or NRGRH; Rccand Rddare each independently C1-C3alkyl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3alkoxy, and C1-C3alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or C1-C3alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3alkyl, C3-C7cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, cyclopropyl, and phenyl;R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1-C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10 aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl, hydroxy, amino, cyano, and halogen; and, wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy-(C1-C6alkyl), C1-C3alkoxy-C1-C6alkyl, C3-C10cycloalkyl, 5- to 10- membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (C6-C10 aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 10-membered heterocyclyl,C6-C10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halo-C1-C3 alkyl, halogen, C1-C3 alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the groupconsisting of C1-C6alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3alkyl, C1-C3alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10- membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl.

[0109] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I’.

[0110] In certain embodiments, the disease is related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload.

[0111] In certain embodiments, the disease is related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin.

[0112] In certain embodiments, the disease is hemochromatosis.

[0113] In certain embodiments, the disease is related to or caused by a hemoglobinopathy.

[0114] In certain embodiments, the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease.

[0115] In certain embodiments, the disease is sickle cell disease.

[0116] In certain embodiments, the sickle cell disease is sickle cell anemia.

[0117] Useful compounds for the methods described herein include those where the compound is of Formula I:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1- C3-alkyl, cyano, C3-C7cycloalkyl-C1-C3alkoxy, NRGRH, halo-C1-C3alkoxy, and C3-C6cycloalkyl; wherein RGand RHare each independently hydrogen or C1-C3 alkyl; or two R6groups, taken together with the atom to which each is attached, form a 5 or 6-membered heterocyclyl, C3-C7cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, and C-R6, wherein, 1 or 2 of Y1, Y2, Y3, and Y4can be N, NH, O, or S;f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3 alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6 cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3 alkoxy-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, 4- to 10-membered heterocyclyl, C1-C3 alkyl-sulfonyl-C1-C3 alkyl, COOH-(C1-C6 alkyl), cyano-(C1-C6alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3alkyl, and hydroxy-(C1-C6alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, said C3- C10cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of hydroxy, phenyl, amino, cyano, and halogen; andwherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of C1-C6 alkyl, hydroxy-(C1-C6 alkyl), C1-C3 alkoxy-C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 7-membered heterocyclyl, C6-C10aryl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (C6-C10aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C3 alkyl, and C3-C10 cycloalkyl; wherein said C3-C10cycloalkyl, 5- to 7-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10aryl)-C1-C3alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl of R4ais optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C6alkyl, halogen, halo-C1-C3alkyl, C3-C7cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halogen, and hydroxy; R4cand R4dare each independently selected from the group consisting ofhydrogen, C1-C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6 alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, C1-C3alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1-C3alkyl, C3-C7cycloalkyl, and C6-C10aryl.

[0118] Useful compounds for the methods described herein include those where R1and R2are each independently selected from the group consisting of hydrogen, -CF3, methyl, and ethyl.

[0119] Useful compounds for the methods described herein include those where R1and R2taken together with the atom to which each is attached form ring A.

[0120] Useful compounds for the methods described herein include those where the compound is of Formula IA:wherein, ring A is a 5- or 6-membered cycloalkyl, or 5- or 6-membered heteroaryl, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, phenyl, halogen, alkoxy, cyano, and 5- or 6- membered heteroaryl.

[0121] Useful compounds for the methods described herein include those where the compound is of Formula IB:wherein, Rx, independently in each instance, is halogen, C1-C6 alkyl, C1-C6 alkoxy, or cyano; p is 1 or 2; and m is 0, 1, or 2.

[0122] Useful compounds for the methods described herein include those where p is 1.

[0123] Useful compounds for the methods described herein include those where m is 0.

[0124] Useful compounds for the methods described herein include those where the compound is of Formula IC or IC’:wherein, RA1and RA2are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, phenyl, halogen, and 5- or 6-membered heteroaryl.

[0125] Useful compounds for the methods described herein include those where RA1and RA2are each independently C1-C3 alkyl, hydrogen, or phenyl.

[0126] Useful compounds for the methods described herein include those where RA1and RA2are each methyl.

[0127] Useful compounds for the methods described herein include those where RA1is phenyl and RA2is methyl or hydrogen.

[0128] Useful compounds for the methods described herein include those where Z is N.

[0129] Useful compounds for the methods described herein include those where f is 1.

[0130] The integer n will decrease by one each time a compound of Formula I’, IA, IB, IC, or IC’ contains a variable C-R6, N-R6, or S-R6, and the total number of n (the total number of C-R6, N-R6, or S-R6cannot exceed 3).

[0131] Useful compounds for the methods described herein include those where 0 to 3 of Y1, Y2, Y3, and Y4are each C-R6and the other(s) of Y1, Y2, Y3, and Y4is / are CH.

[0132] Useful compounds for the methods described herein include those where Y1is CH, Y2is C-R6, Y3is CH, and Y4is CH.

[0133] Useful compounds for the methods described herein include those where Y3is N and Y1, Y2, and Y4are each CH or C-R6.

[0134] Useful compounds for the methods described herein include those where Y2isN and Y1, Y3, Y4are each CH or C-R6.

[0135] Useful compounds for the methods described herein include those where Y1is N and Y2, Y3, and Y4are each CH or C-R6.

[0136] Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C3 alkoxy, hydroxy-C1-C3-alkyl, and NRGRH; wherein RGand RHare each independently hydrogen or C1-C3alkyl.

[0137] Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of methoxy, methyl, fluoro, chloro, ethyl, N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, and -CH2CH2OH.

[0138] Useful compounds for the methods described herein include those where R6, in each instance, is methoxy or methyl.

[0139] Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a 5 or 6- membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl.

[0140] Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, or phenyl ring.

[0141] Useful compounds for the methods described herein include those where n is 1.

[0142] Useful compounds for the methods described herein include those where n is 0.

[0143] Useful compounds for the methods described herein include those where R3is hydrogen or C1-C3alkyl.

[0144] Useful compounds for the methods described herein include those where R3is methyl.

[0145] Useful compounds for the methods described herein include those where R4is selected from the group consisting of optionally substituted cyclopropyl, (5- to 10- membered heteroaryl)-C1-C3 alkyl, and 4- to 10-membered heterocyclyl.

[0146] Useful compounds for the methods described herein include those where R4is an optionally substituted (5- to 10-membered heteroaryl)-C1-C3alkyl, wherein at leastone of the ring atoms ortho to the attachment point is a nitrogen or oxygen.

[0147] Useful compounds for the methods described herein include those where R4is selected from the group consisting of optionally substituted pyridinyl-methyl, pyridinyl- ethyl, pyrimidinyl-methyl, pyrazolyl-propyl, and benzoxazole-methyl.

[0148] Useful compounds for the methods described herein include those where R4is selected from the group consisting of -CH2CH2CH2OH, -CH2CH2OH, and -CH3C(H)(CH3)(OH).

[0149] Useful compounds for the methods described herein include those where R4is Ia:.

[0150] Useful compounds for the methods described herein include those where where R4is Ia and R4cand R4dare each independently hydrogen or methyl.

[0151] Useful compounds for the methods described herein include those where R4is Ia and R4cand R4dare each hydrogen.

[0152] Useful compounds for the methods described herein include those where R4is Ia and R4bis hydrogen.

[0153] Useful compounds for the methods described herein include those where R4is Ia and R4ais C1-C6alkyl.

[0154] Useful compounds for the methods described herein include those where R4is Ia and R4ais tert-butyl.

[0155] Useful compounds for the methods described herein include those where R4is Ia and R4ais C6-C10aryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, and C1-C3 alkoxy.

[0156] Useful compounds for the methods described herein include those where R4is Ia and R4ais phenyl optionally substituted with fluoro, methyl, or methoxy.

[0157] Useful compounds for the methods described herein include those where R4isIa and R4ais 5- to 10-membered monocyclic or bicyclic fused heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, and C1-C3 alkoxy.

[0158] Useful compounds for the methods described herein include those where R4is Ia and R4ais pyridinyl, isoxazolyl, or quinolinyl, optionally substituted with fluoro, methoxy, or methyl.

[0159] Useful compounds for the methods described herein include those where R4is Ia and R4ais C3-C7 cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, and C1-C3alkoxy.

[0160] Useful compounds for the methods described herein include those where R4is Ia and R4ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with methyl, trifluoromethyl, fluoro, or hydroxy.

[0161] Useful compounds for the methods described herein include those where R4is Ia and R4ais a 5- or 6-membered heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, and C1-C3alkoxy.

[0162] Useful compounds for the methods described herein include those where R4is Ia and R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, and tetrahydropyranyl, optionally substituted one or two times with methyl.

[0163] Useful compounds for the methods described herein include those where R4is Ia and R4ais (C6-C10 aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic heteroaryl)-C1- C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, haloalkyl, hydroxy, and C1-C3alkoxy.

[0164] Useful compounds for the methods described herein include those where R4is Ia and R4ais benzyl or pyridinyl-methyl.

[0165] Useful compounds for the methods described herein include those where R4is Ia and R4aand R4btaken together with the atom to which each is attached form a 5- to 7- membered heterocyclyl.

[0166] Useful compounds for the methods described herein include those where R4is Ia and R4aand R4btaken together with the nitrogen to which each is attached form apiperidinyl, morpholinyl, azepanyl, or piperazinyl.

[0167] Useful compounds for the methods described herein include those where R4is Ia and R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted one or two times with C1-C3alkyl.

[0168] Useful compounds for the methods described herein include those where R4is Ia and R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one, azetidin-2-one, or pyrrolidine-2-one, optionally substituted one or two times with C1-C3 alkyl.

[0169] Useful compounds for the methods described herein include those where R4is Ia and g is 0.

[0170] Useful compounds for the methods described herein include those where R4is Ia and g is 1.

[0171] Useful compounds for the methods described herein include those where R4is I

[0172] Useful compounds for the methods described herein include those where R4is Ib and R4cis hydrogen or methyl.

[0173] Useful compounds for the methods described herein include those where R4is Ib and R4ais methyl or phenyl.

[0174] Useful compounds for the methods described herein include those where R4is I.

[0175] Useful compounds for the methods described herein include those where R4is Ic and R4eis hydrogen or hydroxy.

[0176] Useful compounds for the methods described herein include those where R4is Ic and R4ais selected from the group consisting of ethyl, -C(O)NH2, and pyridine.

[0177] Useful compounds for the methods described herein include those where R4is Ic and R4bis hydrogen or ethyl.

[0178] Useful compounds for the methods described herein include those where R4is Ic and R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl.

[0179] Useful compounds for the methods described herein include those where R4is Ic and R4aand R4btaken together with the nitrogen to which each is attached form a piperidinyl, piperazinyl, pyrrolidonyl, or imidazolyl, optionally substituted with C1-C3alkyl.

[0180] Useful compounds for the methods described herein include those where R4is Ic and g is 0.

[0181] Useful compounds for the methods described herein include those where R4is Ic and g is 1.

[0182] Useful compounds for the methods described herein include those where R4is Ic and g is 2.

[0183] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 4-, 5-, 6-, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms atoms, wherein said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, phenyl, hydroxy-C1-C3 alkyl, -NHC(O)-(5- or 6-membered heteroaryl), -C(O)-CH3, and (5- or 6-membered heteroaryl)-C1-C3alkyl.

[0184] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form an optionally substituted piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, or piperidinyl.

[0185] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 7- membered monocyclic heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl.

[0186] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 7- membered monocyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted once with methyl or phenyl, and wherein said phenyl is optionally substituted with methoxy.

[0187] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11- membered bicyclic fused heterocyclyl containing one or two heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of methoxy and methyl.

[0188] Useful compounds for the methods described herein include those where p is 1 and Z is N. Useful compounds for the methods described herein include those where Y1, Y2, Y3, and Y4are each CH or C-R6. Useful compounds for the methods described herein include those where Y1is CH Y2is C-R6, and Y3, and Y4are each CH. Useful compounds of Formula I’ or I include those where Y3is N and Y1, Y2, and Y4are each CH or C-R6. Useful compounds for the methods described herein include those where Y2is N and Y1, Y3, Y4are each CH or C-R6. Useful compounds for the methods described herein include those where Y1is N and Y2, Y3, and Y4are each CH or C-R6.

[0189] Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C3- alkyl, -O-(CH2)u-Rbb, halo-C1-C3 alkoxy, -O-Rcc-O-Rdd, halo-C1-C3 alkyl, and -NRGRH; wherein, Rbbis -NRGRH; u is an integer from 1 to 3; RGand RHare each independently hydrogen or C1-C3alkyl; and Rccand Rddare each independently C1-C3alkyl. Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, - N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -O CH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3)2CH2OH, and -CH2CH2OH. Useful compounds for the methods described herein include those where R6, in each instance, is methoxy, -OCH2CH2OH, or -OCH2C(CH3)2OH.Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of -O-(CH2)u-Rbb, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 3; Rbbis 4- to 7-membered monocyclic heterocyclyl or C3-C7cycloalkyl; and wherein said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl. Useful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of cyclopropyl and -O-(CH2)u-Rbb; wherein, u is 0, 1, or 2; and Rbbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl. Useful compounds for the methods described herein include those where R6, in each instance, is selected from t ,indicates the point of attachment to Ring B. Useful compounds for the methods described herein include those

[0190] Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a 5- or 6- membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl. Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl. Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a ring selected from the group consisting of, , , ,fused with ring B, wherein the pair ofrepresent the attachment of the ring with Ring B Useful compounds for the methods described herein include those where two R6groups, taken together with the atom to which each is attached, form a form a ring selected from the group consistingfused with Ring B. Useful compounds for the methods described herein include those where two R6groups taken together with the atom to which each is attached form a ring fused with Ring B, where the bicyclic ring formed by Ring B and the two R6groups is selected from the group consisting, , , ,.

[0191] Useful compounds for the methods described herein include those where f is 1. Useful compounds for the methods described herein include those where f is 0, and. Useful compounds for the methods described herein include those where Ringwherein, n is 0 or 1; and Y2and Y3are each independently selected from the group consisting of CH, N, NH, NR6, S, O, and CR6, provided that only one of Y2and Y3can be N, NH, NR6, S, or O. Useful compounds for the methods described herein include those where Ring B is selected from the group consistingUseful compounds for the methods described herein include those where R6, in each instance, is selected from the group consisting of C1-C3alkyl and hydroxy-C1-C3alkyl. Useful compounds for the methods described herein include those where R6, in eachinstance, is selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH.

[0192] Useful compounds for the methods described herein include those where n is 2, wherein one R6is selected from the group consisting of methyl and methoxy and the other R6is selected from the group consisting of methyl, methoxy, halogen, and - OCH2CH2OH.

[0193] Useful compounds for the methods described herein include those where R3is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH. Useful compounds for the methods described herein include those where R3is methyl.

[0194] Useful compounds for the methods described herein include those where R4is a (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7 cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and wherein said phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy. Useful compounds for the methods described herein include those where R4is a (6-membered heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6-membered heteroaryl is a nitrogen. Useful compounds for the methods described herein include those where R4is selected from the group consisting of pyridinyl-methyl, pyrimidinyl- methyl, benzoxazole-methyl, and triazolyl-methyl, each optionally substituted with phenyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro. Useful compounds for the methods described herein include those where R4is selected from the group consisting of

[0195] Useful compounds for the methods described herein include those where R4is. Useful compounds for the methods described herein include those where R4cis selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, - CH2OC(CH3)3, and -CH2CH2SCH3; and R4dis selected from the group consisting of hydrogen and methyl; or, R4cand R4dtaken together with the atom to which each is attached form a cyclopropyl ring. Useful compounds for the methods described herein include those where R4cand R4dare each hydrogen. Useful compounds for the methods described herein include those where R4bis hydrogen. Useful compounds for the methods described herein include those where R4ais C1-C6 alkyl. Useful compounds for the methods described herein include those where R4atert-butyl. Useful compounds for the methods described herein include those where R4ais phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds for the methods described herein include those where R4ais phenyl optionally substituted withone substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy. Useful compounds for the methods described herein include those where R4ais selected from the group consisting. Useful compounds for the methods described herein include those where R4ais 5- to 10- membered monocyclic or fused bicyclic heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl. Useful compounds for the methods described herein include those where R4ais pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl. Useful compounds for the methods describedherein include those where R4ais selected from the group consisting, , , , ,a. Useful compounds for the methods described herein include those where R4ais C3-C7 cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds for the methods described herein include those where R4ais selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan-1-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy. Useful compounds for the methods described herein include thosewhere R4ais selected from the group consisting. Useful compounds for the methods described herein include those where R4ais a 5- to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, oxo, C3-C7cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds for the methods described herein include those where R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, methoxy, and oxo. Useful compounds for the methods described herein include those where R4ais selected from the group consisting. Useful compounds for the methods described herein include those where R4ais (C6-C10 monocyclic or fused bicyclic aryl)-C1-C3alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl. Useful compounds for the methods described herein include those where R4ais selected from the group consisting of phenyl-methyl, 1-cyclobutyl-2- ethyl-5-methyl-1H-imidazolyl, and pyridinyl-methyl. Useful compounds for the methods described herein include those where R4ais selected from the group consisting of. Useful compounds for the methods described herein include those where R4ais selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3. Useful compounds for the methods described herein include those where R4aand R4btaken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3alkoxy. Useful compounds for the methods described herein include those where R4aand R4btaken together with the atom to which each is attachedform a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, and methoxy. Useful compounds for the methods described herein include those where R4aand R4btaken together with the atom to which each is attached form a. Useful compounds for the methods described herein include those where R4band R4ctaken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3alkyl. Useful compounds for the methods described herein include those e where R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one or a pyrrolidine- 2-one, optionally substituted one or two times with methyl.

[0196] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 7- membered monocyclic or bridged bicyclic heterocyclyl containing one or twoheteroatoms; wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3alkyl, cyano, oxo, halogen, halo-C1-C3alkyl, and C6- C10 monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3alkyl. Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl or oxo; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein said phenyl is optionally substituted with methoxy. Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form

[0197] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11- membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, C1-C3alkoxy, hydroxy, and halogen. Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form

[0198] Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a 4- or 6- membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4- membered monocyclic heterocyclyl is optionally substituted with -(CH2)sC(=O)NRkRl; wherein, s is 0, 1, or 2; Rkis hydrogen or C1-C3alkyl; and Rlis selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and, said 6- membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, oxo, halogen, cyano, and -NRqRw; wherein, Rqis hydrogen or C1-C3alkyl; Rwis C6-C10monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy Useful compounds for the methods described herein include those where R3and R4taken together with the nitrogen atom to which each is attached form a.

[0199] Useful compounds for the methods described herein include those where Rx, in each instance, is methyl. Useful compounds for the methods described herein includethose where m is 0. Useful compounds for the methods described herein include those where m is 2.

[0200] In certain embodiments, the subject matter described herein is directed to a method of preventing and treating kidney injuries in a subject, comprising administering to the subject an effective amount of a compound of Formula I or Formula I’ or a pharmaceutically acceptable salt thereof. In certain aspects of these embodiments, the compound of Formula I or Formula I’ can be co-administered with another pharmaceutically active compound. In certain aspects of these embodiments, the kidney injuries are those induced by catalytic free iron. In certain aspects of these embodiments, the kidney injuries are selected from renal ischemia-reperfusion injury (IRI), ischemic injury and acute kidney injuries. In a further aspect, kidney injuries are selected from acute kidney injury (AKI), renal ischemia-reperfusion injury (IRI), ischemic injury and AKI caused by ischemic injury, AKI following surgery or surgical intervention, such as in particular following cardiac surgery most often with procedures involving cardiopulmonary bypass, other major chest or abdominal surgery, and kidney injury associated with RBC transfusion.

[0201] The term “preventing” and the like includes the protection from ischemic renal injury, avoidance of occurrence of AKI or at least reducing the severity of AKI following ischemic injury, RBC transfusion or a surgery intervention e.g. by administering the compounds prior to or accompanying or shortly after an ischemic event, RBC transfusion or the surgery intervention to prevent or at least attenuate occurrence of kidney injuries induced by catalytic free iron.

[0202] Free catalytic iron or labile iron or NTBI is considered as a main cause of kidney injury, such as in particular AKI triggered by ischemia. The administration of the ferroportin inhibitor compounds of Formula I or Formula I’ as described herein can protect against the damaging effects of catalytic free iron. Without being bound to theory, the ferroportin inhibitors described herein can reduce or prevent the formation of catalytic free iron or NTBI by sequestering iron in macrophages of liver and spleen, therewith reducing its levels in plasma and reducing the risk of ROS formation. The compounds of Formula I or Formula I’ described herein act as ferroportin inhibitors, and have the potential to sequester iron in macrophages, thereby interrupting the cycle of self-sustaining release of catalytic free iron. The compounds of the Formula I or Formula I’ are suitable for the prevention and treatment of the kidney injuries described herein by limiting reactive oxygen species (ROS) to avoid kidney tissue injury. Further to catalytic free iron, NTBI and LPI (Labile Plasma Iron) can cause kidney injuries. NTBI encompasses all forms of serum iron that are not tightly associated with transferrin and is chemically and functionally heterogeneous. LPI represents a component of NTBI that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload.

[0203] The following parameters can be determined to evaluate the efficacy of the compounds for treating kidney injuries: plasma creatinine, glomerular filtration rate (including estimated glomerular filtration rate eGFR), urine albumin excretion, urine neutrophil gelatinase-associated lipocaiin (NGAL), NTBI, LPI, RBC hemolysis, blood urea nitrogen (BUN), plasma hemoglobin (Hb), total plasma iron, plasma hepcidin, renal neutrophil infiltration, serum IL-6, spleen, kidney and / or liver iron content, renal ferroportin, KIM-1 (Kidney Injury Mo!ecule- 1) as an acute marker for kidney injury in blood and urine, and H-ferritin. Additionally or alternatively, the efficacy of the compounds of the present invention can be determined via the kidney tubular injury score, such as e.g. the CSA-NGAL score (Cardiac Surgery Associated NGAL Score) for detecting acute tubular damage as described in more detail below, the KDIGO score described in more detail below or the EGTI score comprising Endothelial, Glomerular, Tubular and Interstitial (EGTI) components to evaluate histology (described e.g, by: Khalid et al. Kidney ischaemia reperfusion injury in the rat the EGTI scoring system as a valid and reliable tool for histological assessment" Journal of Histology & Histopatholoy, Vol.3, 2016).

[0204] The methods of treating or preventing kidney injury can result in a decrease of serum creatinine (sCr) in the subject. The methods of treating or preventing kidney injury can result in a corrected (decreased) urine albumin excretion in the subject. The methods of treating or preventing kidney injury can result in a decrease of blood urea nitrogen (BUN) in the subject. The methods of treating or preventing kidney injury can result in a decrease of total plasma iron in the subject. The methods of treating or preventing kidney injury can result in a decrease of interleukin-6 (!L-6) levels in thesubject. The methods of treating or preventing kidney injury can result in a decrease of KIM-1 levels in the subject. The methods of treating or preventing kidney injury can result in an increase in spleen and / or liver iron concentration in the subject. The methods of treating or preventing kidney injury can result in a decrease in kidney iron concentration in the subject. The methods of treating or preventing kidney injury can result in reduced NTBI levels. The methods of treating or preventing kidney injury can result in reduced LPI levels in the subject. The methods of treating or preventing kidney injury can result in an inhibition of tubular injury, such as tubular necrosis. The methods of treating or preventing kidney injury can result in an inhibition of apoptosis. The methods of treating or preventing kidney injury can result in a reduced IRI-induced renal neutrophil infiltration. The methods of treating or preventing kidney injury can result in reduced ROS levels in kidney tissue of the subject. The methods of treating or preventing kidney injury can result in corrected (increased) kidney H- ferritin levels in the subject. In particular, the methods of treating or preventing kidney injury can reduce the occurrence of AKI, renal ischemia- reperfusion injury and AKI caused by ischemic injury, AKI following surgery or surgical intervention, such as in particular following cardiac surgery most often with procedures involving cardiopulmonary bypass, other major chest or abdominal surgery, and kidney injury associated with RBC transfusion. The methods of treating or preventing kidney injury can comprise a) decrease, accelerated decrease or prevention of increase of serum creatinine; and / or b) increase or prevention of decrease of estimated glomerular filtration rate (eGFR); and / or c) decrease or prevention of increase of renal ferroportin; and / or d) increase or prevention of decrease of H-ferritin levels; and / or e) decrease or prevention of increase of renal neutrophil infiltration; and / or f) decrease or prevention of increase of serum IL-6 levels.

[0205] The following compounds of Table 1, or pharmaceutically acceptable salts thereof, are useful in the methods described herein:

[0206] Table 1 The masses for compounds in Table 1 that are not located in the table can be found in the synthetic examples.

[0207] The methods described herein may be applied to cell populations in vivo or ex vivo. “In vivo” means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo” means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to determine theoptimal schedule and / or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled in the art. The selected compounds may be further characterized to examine the safety or tolerance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0208] The ferroportin inhibition activity of the compounds of Formula I and pharmaceutically acceptable salts thereof provide methods particularly suitable for the use in the inhibition of iron transport mediated by ferroportin. As such, the compounds of Formula I and pharmaceutically acceptable salts thereof are useful in the prophylaxis and / or treatment of a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis.

[0209] Further, the compounds of Formula I are suitable for the use in an adjunctive therapy by limiting the amount of iron available to pathogenic microorganisms, e.g. the siderophilic bacteria Vibrio vulnificus and Yersinia enterocolitica, and common pathogens (e.g. Escherichia coli), thereby preventing or treating infections, inflammation, sepsis, and septic shock caused by said pathogenic microorganisms.

[0210] In certain embodiments, the subject matter described herein is directed to a method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0211] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, increased iron levels, increased iron absorption, iron overload (e.g. due to blood transfusions), increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amountof a compound of Formula I or a pharmaceutically acceptable salt thereof. In aspects of these embodiemnts, the treating comprises inhibiting iron transport mediated by ferroportin in the subject.

[0212] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload.

[0213] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin. In a certain aspect of this embodiment, the disease is hemochromatosis.

[0214] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by a hemoglobinopathy. In a certain aspects of this embodiment, the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease. In certain aspects of this embodiment, the disease is sickle cell disease. In certain aspect of this embodiment, the disease is sickle cell anemia.

[0215] In certain embodiments, the diseases being associated with, being related to, being caused by or leading to increased iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) or ineffective erythropoiesis comprise thalassemia, hemoglobinopathy, such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), haemochromatosis, hemolytic anemia, such as sickle cell anemia and congenital dyserythropoietic anemia. Additional diseases being associated with, being related to, being caused by or leading to increased iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) include neurodegenerative diseases, such as for example Alzheimer's disease, Parkinson's disease, Huntington’s disease, multiple sclerosis, Wilsonʼs disease, amyotrophic lateral sclerosis (ALS), and Friedreich’s Ataxia, wherein the compounds and methods are considered to be effective by limiting the deposition or increase of iron in tissue or cells; conditions associated with the formation of radicals, reactive oxygen species (ROS) and oxidative stress caused by excess iron or iron overload; cardiac, liver and endocrine damage caused by excess iron or ironoverload; inflammation triggered by excess iron or iron overload; diseases associated with ineffective erythropoiesis, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera, and congenital dyserythropoietic anemia; diseases, disorders and / or disease conditions that comprise iron overload caused by mutations in genes involved in sensing the systemic iron stores, such as hepcidin / hepcidin antimicrobial peptide (HAMP), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as in particular diseases related to HFE and HJV gene mutations; diseases related to ferroportin mutations; chronic hemolysis associated diseases, sickle cell diseases (including sickle cell anemia (HbSS) as well as hemoglobin SC disease (HbSC), hemoglobin S beta-plus-thalassemia (HbS / β+), and hemoglobin S beta-zero-thalassemia (HbS / β0)), red cell membrane disorders, Glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythropoietic porphyria, Friedreich's Ataxia, as well as subgroups of iron overload such as transfusional iron overload, iron intoxication, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron overload, Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis and red blood cell disorders comprising thalassemia, including alpha thalassemia, beta thalassemia and delta thalassemia, thalassemia intermedia, sickle cell disease and myelodyplastic syndrome; liver diseases (e.g. hepatitis B virus infection, hepatitis C virus infection, alcoholic liver disease, autoimmune hepatitis), other conditions including ataxia, Friedreich's ataxia, age-related macular degeneration, age- related cataract, age-related retinal diseases and neurodegenerative disease, such as pantothenate kinase-associated neurodegeneration, restless leg syndrome and Huntington's disease. In certain embodiments, the disease is sickle cell anemia. The ferroportin inhibition activity, for instance by inducing internalization of ferroportin, of the compounds of Formula I and pharmaceutically acceptable salts thereof can be determined by the assays described herein as well as those described in WO2018 / 192973, incorporated herein by reference in its entirety.

[0216] The activity of the compounds of Formula I in the treatment of sickle cell anemia (sickle cell disease) can be determined by using a mouse model, such as e.g. described by Yulin Zhao et al. in "MEK1 / 2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease"; The FASEB Journal Vol.30, No.3, pp 1171-1186,2016. Said mouse model can be suitably adapted to determine the activity of the compounds of Formula I in the treatment of sickle cell anemia. In certain embodiments, the disease is caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload states, such as thalassemia, sickle cell disease and hemochromatosis. In certain embodiments, the disease is related to or caused by reduced hepcidin levels, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis. In certain embodiments, the disease is selected from the group consisting of thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, and hemolytic anemia.

[0217] In certain embodiments, the methods of administering and treating described herein further comprise co-administration of one or more additional pharmaceutically active compounds or in combination with a blood transfusion.

[0218] In a combination therapy, the pharmaceutically active compounds can be administered at the same time, in the same formulation, or at different times. Such combination therapy comprises co-administration of a compound of Formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound. Combination therapy in a fixed dose combination therapy comprises co-administration of a compound of Formula I or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in a free dose combination therapy comprises co- administration of a compound of Formula I or a pharmaceutically acceptable salt thereof and at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequential use of the individual compounds over a period of time.

[0219] The additional pharmaceutically active compound includes in particular drugs for reducing iron overload (e.g., Tmprss6-ASO or siRNA) or iron chelators, in particular curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine and / or deferiprone, or antioxidants such as n-acetyl cysteine, anti-diabetics such as GLP-1 receptor agonists, antibiotics such as penicillin, vancomycin (Van) or tobramycin, antifungal drugs, anti- viral drugs such as interferon-a or ribavirin, drugs for the treatment of malaria, anticancer agents, drugs for the treatment of neurodegenerative diseases such as Alzheimer's diseaseand Parkinson's disease (e.g., dopamine agonists such as Levodopa), or immunosuppressants (cyclosporine A or cyclosporine A derivatives), iron supplements, vitamin supplements, red cell production stimulators (e.g., erythropoietin, Epo), anti- inflammatory agents, anti-thrombolytics, statins, vasopressors and inotropic compounds. A further object of the present invention relates to the use of the above combinations for the prophylaxis and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload states such as in particular thalassemia, sickle cell disease and hemochromatosis and other disorders as described in the present application. III. Pharmaceutical Compositions and Modes of Administration

[0220] Compounds provided herein are usually administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of the compounds described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, including sterile aqueous solution and various organic solvents, permeation enhancers, solubilizers and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington’s Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa.17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc.3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0221] The pharmaceutical compositions may be administered in either single or multiple doses. The pharmaceutical composition may be administered by various methods including, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra- arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

[0222] One mode for administration is parenteral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or emulsions, with sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs,mannitol, dextrose, or a sterile aqueous solution, and similar pharmaceutical vehicles.

[0223] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi- solid, or liquid material, which acts as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as a solid or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions, and sterile packaged powders.

[0224] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methyl cellulose. The formulations can additionally include lubricating agents such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propylhydroxy- benzoates; sweetening agents; and flavoring agents.

[0225] The compositions that include at least one compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof can be formulated so as to provide quick, sustained or delayed release of the active ingredient after administration to the subject by employing procedures known in the art. Controlled release drug delivery systems for oral administration include osmotic pump systems and dissolutional systems containing polymer-coated reservoirs or drug-polymer matrix formulations. Examples of controlled release systems are given in U.S. Patent Nos.3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion of thecompounds described herein in controlled amounts. The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos.5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0226] For preparing solid compositions such as tablets, the principal active ingredient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable salt, a stereoisomer, or a mixture of stereoisomers thereof. When referring to these preformulation compositions as homogeneous, the active ingredient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equally effective unit dosage forms such as tablets, pills and capsules.

[0227] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodenum or to be delayed in release. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cetyl alcohol, and cellulose acetate.

[0228] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be inhaled directly from the nebulizing device or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powdercompositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0229] The specific dose level of a compound of the present application for any particular subject will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease in the subject undergoing therapy. For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg / kg). Dosages of between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 and 100 mg / kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg / kg may be appropriate. Normalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. A dose may be administered once a day (QID), twice per day (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism, and excretion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regimen may be repeated for a number of cycles of therapy. IV. Methods of Preparing Compounds of Formula I and Pharmaceutically Acceptable Salts Thereof

[0230] Compounds can be synthesized by synthetic routes that include processes analogous to those well-known in the chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry II, Editors Katritzky and Rees, Elsevier, 1997, e.g., Volume 3; Liebigs Annalen der Chemie, (9):1910-16, (1985); Helvetica Chimica Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-31, (1990), each of which are expressly incorporated by reference. Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared usingmethods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents for Organic Synthesis, v.1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database). DTT refers to dithiothreitol. DHAA refers to dehydroascorbic acid.

[0231] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful in synthesizing compounds and necessary reagents and intermediates are known in the art and include, for example, those described in R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G .M. Wuts, Protective Groups in Organic Synthesis, 3rdEd., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subsequent editions thereof.

[0232] Compounds may be prepared singly or as compound libraries comprising at least 2, for example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel syntheses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus, according to a further aspect, there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.

[0233] The subject matter described herein is directed to the following embodiments: 1B. A method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C3-alkyl, cyano, -NRGRH, halo-C1-C3alkoxy, -O-(CH2)u-Rbb, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 6; Rbbis 4- to 7- membered monocyclic heterocyclyl, C3-C7cycloalkyl, or NRGRH; Rccand Rddare each independently C1-C3 alkyl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or C1-C3alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3alkyl, C3-C7cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, cyclopropyl, and phenyl;R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1-C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10 aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl, hydroxy, amino, cyano, and halogen; and, wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy-(C1-C6alkyl), C1-C3alkoxy-C1-C6alkyl, C3-C10cycloalkyl, 5- to 10- membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (C6-C10 aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 10-membered heterocyclyl,C6-C10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halo-C1-C3 alkyl, halogen, C1-C3 alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the groupconsisting of C1-C6alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3alkyl, C1-C3alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10- membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl. 2B. A method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C3-alkyl, cyano, -NRGRH, halo-C1-C3alkoxy, -O-(CH2)u-Rbb, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 6; Rbbis 4- to 7- membered monocyclic heterocyclyl, C3-C7cycloalkyl, or NRGRH; Rccand Rddare each independently C1-C3 alkyl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or C1-C3alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3alkyl, C3-C7cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, cyclopropyl, and phenyl;R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1-C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10 aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, 5- to 7-membered heterocyclyl, hydroxy, amino, cyano, and halogen; and, wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of hydrogen, C1-C6alkyl, hydroxy-(C1-C6alkyl), C1-C3alkoxy-C1-C6alkyl, C3-C10cycloalkyl, 5- to 10- membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (C6-C10 aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 10-membered heterocyclyl,C6-C10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halo-C1-C3 alkyl, halogen, C1-C3 alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the groupconsisting of C1-C6alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3alkyl, C1-C3alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10- membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl. 1A. A method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein,Z is N or CR5; R5is hydrogen, halogen, or C1-C3 alkyl; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1- C3-alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NRGRH, halo-C1-C3 alkoxy, and C3-C6 cycloalkyl; wherein RGand RHare each independently hydrogen or C1-C3alkyl; or two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered heterocyclyl, C3-C7 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, and C (when R6is attached thereto), wherein, 1 or 2 of Y1, Y2, Y3, and Y4can be N, NH, O, or S; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, haloalkyl, C1- C3alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, haloalkyl, C1- C3 alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6 cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, carboxylic acid-(C1- C6alkyl), cyano-(C1-C6alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3alkyl, and hydroxy-(C1-C6alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of hydroxy, phenyl, amino, cyano, and halogen; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of C1-C6 alkyl, hydroxy-(C1-C6 alkyl), C1-C3alkoxy-C1-C6alkyl, C3-C10cycloalkyl, 5- to 9-membered heterocyclyl, C6-C10aryl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (C6-C10aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3 alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10cycloalkyl, 5- to 9-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroarylin said (5- to 10-membered heteroaryl)-C1-C3alkyl, C6-C10aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl of R4ais optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, haloalkyl, C3-C7 cycloalkyl, hydroxy, C1-C6 alkoxy, cyano, nitro, phenyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6alkyl; or, R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6alkyl, halogen, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3 alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein the heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-memberedheterocyclyl)-C1-C3alkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3alkyl, and Rwis C6-C10aryl or C3-C7cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl. 2A. A method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3 alkyl; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1- C3-alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NRGRH, halo-C1-C3 alkoxy, and C3-C6 cycloalkyl; wherein RGand RHare each independently hydrogen or C1-C3alkyl; or two R6groups, taken together with the atom to which each is attached, form a 5 or 6-membered heterocyclyl, C3-C7cycloalkyl, C6-C10aryl, or 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, and C (when R6is attached thereto), wherein, 1 or 2 of Y1, Y2, Y3, and Y4can be N, O, or S; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6alkyl, haloalkyl, C1- C3alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, haloalkyl, C1- C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A;wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3 alkoxy-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3 alkyl-sulfonyl-C1-C3 alkyl, carboxylic acid-(C1- C6alkyl), cyano-(C1-C6alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3alkyl, and hydroxy-(C1-C6alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of hydroxy, phenyl, amino, cyano, and halogen; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of C1-C6alkyl, hydroxy-(C1-C6alkyl), C1-C3 alkoxy-C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 7-memberedheterocyclyl, C6-C10aryl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (C6-C10aryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3 alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 7-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, C6-C10aryl in said (C6-C10aryl)-C1-C3alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl of R4ais optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C6alkyl, halogen, haloalkyl, C3-C7cycloalkyl, hydroxy, C1-C6 alkoxy, cyano, nitro, phenyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy; R4bis hydrogen or C1-C6alkyl; or, R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halogen, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6alkoxy-C1-C3alkyl, C3-C7cycloalkyl, and C1-C6alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkoxy, and C1-C3alkyl;or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein the heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6 alkyl), (4- to 10-membered heterocyclyl)-C1-C3alkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, phenyl, −C(=O)−C1-C6alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl. 3A. The method of embodiment 2B or 2A, wherein the disease is related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload. 4A. The method of embodiment 2B or 2A, wherein the disease is related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin.5A. The method of embodiment 4A, wherein the disease is hemochromatosis. 6A. The method of embodiment 3A, wherein the disease is related to or caused by a hemoglobinopathy. 7A. The method of embodiment 6A, wherein the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease. 8A. The method of embodiment 7A, wherein the disease is sickle cell disease. 9A. The method of embodiment 8A, wherein the sickle cell disease is sickle cell anemia. 10A. The method of embodiment 2B, 2A, 3A, 4A, 5A, 6A, 7A, 8A, or 9A, wherein the treating comprises inhibiting iron transport mediated by ferroportin in the subject. 11A. The method of any one of embodiments 1B, 2B, or 1A-10A, wherein R1and R2are each independently selected from the group consisting of hydrogen, -CF3, methyl, and ethyl. 12A. The method of any one of embodiments 1B, 2B, or 1A-10A, wherein R1and R2taken together with the atom to which each is attached form ring A. 13A. The method of embodiment 12A, wherein the compound is of Formula IA:wherein, ring A is a 5- or 6-membered cycloalkyl, or 5- or 6-membered heteroaryl, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, phenyl, halogen, alkoxy, cyano, and 5- or 6- membered heteroaryl. 14A. The method of embodiment 13A, wherein the compound is of Formula IB:wherein, Rx, independently in each instance, is halogen, C1-C6 alkyl, C1-C6 alkoxy, or cyano; p is 1 or 2; and m is 0, 1, or 2. 15A. The method of embodiment 14A, wherein p is 1. 16A. The method of embodiment 14A, wherein m is 0. 17A. The method of embodiment 13A, wherein the compound is of Formula IC or IC’:wherein, RA1and RA2are each independently selected from the group consisting of hydrogen, C1-C3 alkyl, phenyl, halogen, and 5- or 6-membered heteroaryl. 18A. The method of embodiment 17A, wherein RA1and RA2are each independently C1-C3 alkyl, hydrogen, or phenyl. 19A. The method of embodiment 18A, wherein RA1and RA2are each methyl. 20A. The method of embodiment 18A, wherein RA1is phenyl and RA2is methyl or hydrogen. 21A. The method of any one of embodiments 1B, 2B, or 1A-20A, wherein Z is N. 22A. The method of any one of embodiments 1B, 2B, or 1A-21A, wherein f is 1. 23A. The method of any one of embodiments 1B, 2B, or 1A-22A, wherein 0 to 3 of Y1, Y2, Y3, and Y4are each C (to which R6is bound) and the other(s) of Y1, Y2, Y3, and Y4is / are CH. 24A. The method of any one of embodiments 1B, 2B, or 1A-22A, wherein Y3is N and Y1, Y2, and Y4are each CH or C (to which R6is bound). 25A. The method of any one of embodiments 1B, 2B, or 1A-22A, wherein Y2is N and Y1, Y3, Y4are each CH or C (to which R6is bound). 26A. The method of any one of embodiments 1B, 2B, or 1A-22A, wherein Y1is N and Y2, Y3, and Y4are each CH or C (to which R6is bound). 27A. The method of any one of embodiments 1B, 2B, or 1A-26A, wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C3 alkoxy, hydroxy-C1-C3-alkyl, and NRGRH; wherein RGand RHare each independently hydrogen or C1-C3alkyl. 28A. The method of embodiment 27A, wherein R6, in each instance, is selected from the group consisting of methoxy, methyl, fluoro, chloro, ethyl, N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, and -CH2CH2OH. 29A. The method of embodiment 28A, wherein R6, in each instance, is methoxy or methyl. 30A. The method of any one of embodiments 1B, 2B, or 1A-26A, wherein two R6groups, taken together with the atom to which each is attached, form a 5 or 6-memberedheterocyclyl, C6-C10aryl, or 5- to 10- membered heteroaryl. 31A. The method of embodiment 30A, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, or phenyl ring. 32A. The method of any one of embodiments 1B, 2B, or 1A-31A, wherein n is 1. 33A. The method of any one of embodiments 1B, 2B, or 1A-31A, wherein n is 0. 34A. The method of any one of embodiments 1B, 2B, or 1A-33A, wherein R3is hydrogen or C1-C3alkyl. 35A. The method of any one of embodiments 1B, 2B, or 1A-34A, wherein R3is methyl. 36A. The method of any one of embodiments 1B, 2B, or 1A-35A, wherein R4is selected from the group consisting of optionally substituted cyclopropyl, (5- to 10- membered heteroaryl)-C1-C3 alkyl, and 4- to 10-membered heterocyclyl. 37A. The method of embodiment 36A, wherein R4is an optionally substituted (5- to 10-membered heteroaryl)-C1-C3alkyl, wherein at least one of the ring atoms ortho to the attachment point is a nitrogen or oxygen. 38A. The method of embodiment 37A, wherein R4is selected from the group consisting of optionally substituted pyridinyl-methyl, pyridinyl-ethyl, pyrimidinyl-methyl, pyrazolyl-propyl, and benzoxazole-methyl. 39A. The method of any one of embodiments 1B, 2B, or 1A-35A, wherein R4is selected from the group consisting of -CH2CH2CH2OH, -CH2CH2OH, and -CH3C(H)(CH3)(OH). 40A. The method of any one of embodiments 1B, 2B, or 1A-35A, wherein R4is. 41A. The method of embodiment 40A, wherein R4cand R4dare each independently hydrogen or methyl. 42A. The method of embodiment 41A, wherein R4cand R4dare each hydrogen.43A. The method of any one of embodiments 40A-42A, wherein R4bis hydrogen. 44A. The method of any one of embodiments 40A-43A, wherein R4ais C1-C6 alkyl. 45A. The method of embodiment 44A, wherein R4ais tert-butyl. 46A. The method of any one of embodiments 40A-43A, wherein R4ais C6-C10aryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, and C1-C3 alkoxy. 47A. The method of embodiment 46A, wherein R4ais phenyl optionally substituted with fluoro, methyl, or methoxy. 48A. The method of any one of embodiments 40A-43A, wherein R4ais 5- to 10- membered monocyclic or bicyclic fused heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, haloalkyl, hydroxy, and C1-C3 alkoxy. 49A. The method of embodiment 48A, wherein R4ais pyridinyl, isoxazolyl, or quinolinyl, optionally substituted with fluoro, methoxy, or methyl. 50A. The method of any one of embodiments 40A-43A, wherein R4ais C3-C7 cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, haloalkyl, hydroxy, and C1-C3alkoxy. 51A. The method of embodiment 50A, wherein R4ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with methyl, trifluoromethyl, fluoro, or hydroxy. 52A. The method of any one of embodiments 40A-43A, wherein R4ais a 5- or 6- membered heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, haloalkyl, hydroxy, and C1-C3 alkoxy. 53A. The method of embodiment 52A, wherein R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, and tetrahydropyranyl, optionally substituted one or two times with methyl. 54A. The method of any one of embodiments 40A-43A, wherein R4ais (C6-C10 aryl)- C1-C3alkyl or (5- to 10-membered monocyclic heteroaryl)-C1-C3alkyl, optionally substituted with one or two substituents, each independently selected from the groupconsisting of halogen, C1-C6alkyl, haloalkyl, hydroxy, and C1-C3alkoxy. 55A. The method of embodiment 54A, wherein R4ais benzyl or pyridinyl-methyl. 56A. The method of any one of embodiments 40A-42A, wherein R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl. 57A. The method of embodiment 56A, wherein R4aand R4btaken together with the atom to which each is attached form a piperidinyl, morpholinyl, azepanyl, or piperazinyl. 58A. The method of any one of embodiments 40A or 44A-55A, wherein R4band R4ctaken together with the atom to which each is attached form a 4- to 7-membered heterocyclyl optionally substituted one or two times with C1-C3 alkyl. 59A. The method of embodiment 58A, wherein R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one, azetidin-2-one, or pyrrolidine-2- one, optionally substituted one or two times with C1-C3 alkyl. 60A. The method of any one of embodiments 40A-59A, wherein g is 0. 61A. The method of any one of embodiments 40A-59A, wherein g is 1. 62A. The method of any one of embodiments 1B, 2B, or 1A-35A, wherein R4is. 63A. The method of embodiment 62A, wherein R4cis hydrogen or methyl. 64A. The method of embodiment 62A or 63A, wherein R4ais methyl or phenyl. 65A. The method of any one of embodiments 1B, 2B, or 1A-35A, wherein R4is. 66A. The method of embodiment 65A, wherein R4eis hydrogen or hydroxy.67A. The method of embodiment 65A or 66A, wherein R4ais selected from the group consisting of ethyl, -C(O)NH2, and pyridine. 68A. The method of any one of embodiments 65A-67A, wherein R4bis hydrogen or ethyl. 69A. The method of embodiment 65A or 66A, wherein R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10- membered heteroaryl. 70A. The method of embodiment 69A, wherein R4aand R4btaken together with the atom to which each is attached form a piperidinyl, piperazinyl, pyrrolidonyl, or imidazolyl, optionally substituted with C1-C3alkyl. 71A. The method of any one of embodiments 65A-70A, wherein g is 0. 72A. The method of any one of embodiments 65A-70A, wherein g is 1. 73A. The method of any one of embodiments 65A-70A, wherein g is 2. 74A. The method of any one of embodiments 1B, 2B, or 1A-33A, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 4-, 5-, 6-, or 7- membered monocyclic heterocyclyl containing one or two heteroatoms atoms, wherein said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, phenyl, hydroxy-C1-C3 alkyl, -NHC(O)-(5- or 6-membered heteroaryl), -C(O)-CH3, and (5- or 6-membered heteroaryl)-C1-C3alkyl. 75A. The method of embodiment 74A, wherein R3and R4taken together with the nitrogen atom to which each is attached form an optionally substituted piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, or piperidinyl. 76A. The method of embodiment 74A, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl. 77A. The method of embodiment 74A, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted once with methyl or phenyl, and wherein said phenyl isoptionally substituted with methoxy. 78A. The method of any one of embodiments 1B, 2B, or 1A-33A, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11- membered bicyclic fused heterocyclyl containing one or two heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of methoxy and methyl. 79A. The method of embodiment 1A or 2A, wherein the compound of Formula I is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 80B. The method of embodiment 15A, wherein p is 1. 81B. The method of embodiment 80B, wherein Z is N. 82B. The method of embodiment 80B or 81B, wherein Y1, Y2, Y3, and Y4are each CH or C-R6. 82bb. The method of embodiment 80B or 81B, wherein Y1in CH, Y2is C-R6, and Y3, and Y4are each CH. 83B. The method of embodiment 80B or 81B, wherein Y3is N and Y1, Y2, and Y4are each CH or C-R6. 84B. The method of embodiment 80B or 81B, wherein Y2is N and Y1, Y3, Y4are each CH or C-R6. 85B. The method of embodiment 80B or 81B, wherein Y1is N and Y2, Y3, and Y4are each CH or C-R6. 86B. The method of any one of embodiments 80B-85B, wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, -O-(CH2)u-Rbb, halo-C1- C3alkoxy, -O-Rcc-O-Rdd, halo-C1-C3alkyl, and NRGRH; wherein, Rbbis NRGRH; u is an integer from 1 to 3; RGand RHare each independently hydrogen or C1-C3alkyl; and Rccand Rddare each independently C1-C3 alkyl. 87B. The method of embodiment 86B, wherein R6, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3) 2CH2OH, and -CH2CH2OH. 88B. The method of embodiment 87B, wherein R6, in each instance, is methoxy, -OCH2CH2OH, or -OCH2C(CH3)2OH. 89B. The method of any one of embodiments 80B-85B, wherein R6, in each instance, is selected from the group consisting of -O-(CH2)u-Rbb, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 3; Rbbis 4-to 7-membered heterocyclyl or C3-C7 cycloalkyl; and wherein said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3alkoxy, and C1-C3alkyl. 90B. The method of embodiment 89B, wherein R6, in each instance, is selected from the group consisting of cyclopropyl and -O-(CH2)u-Rbb; wherein, u is 0, 1, or 2; and Rbbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl. 91B. The method of embodiment 90B, wherein R6, in each instance, is selected from92B. The method of embodiment 91B, wherein93B. The method of any one of embodiments 80B-85B, wherein two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl. 94B. The method of embodiment 93B, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl. 95B. The method of embodiment 93B or 94B, wherein two R6groups, taken together with the atom to which each is attached, form a ring selected from the group consisting ofring B, wherein the pair ofrepresent the attachment of the ring with Ring B. 96B. The method of embodiment 95B, wherein two R6groups, taken together with the atom to which each is attached, form a form a ring selected from the group consisting offused with Ring B. 97B. The method of any one of embodiments 80B-96B, wherein f is 1. 98B. The method of embodiment 80B or 81B, wherein f is 0, and Ring B is. 99B. The method of embodiment 98B, wherein Ringwherein, n is 0 or 1; and Y2and Y3are each independently selected from the group consisting of CH, N, NH, NR6, S, O, and CR6, provided that only one of Y2and Y3can be N, NH, NR6, S, or O. 100B. The method of embodiment 98B or 99B, wherein Ring B is selected from the group consisting, and. 101B. The method of any one of embodiments 98B-100B, wherein R6, in each instance, is selected from the group consisting of C1-C3alkyl and hydroxy-C1-C3alkyl. 102B. The method of embodiment 101B, wherein R6, in each instance, is selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH. 103B. The method of any one of embodiments 80B-102B, wherein n is 1. 104B. The method of any one of embodiments 80B-102B, wherein n is 0.105B. The method of any one of embodiments 80B-92B, wherein n is 2. 106B. The method of embodiment 105B, wherein one R6is selected from the group consisting of methyl and methoxy and the other R6is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH. 107B. The method of any one of embodiments 80B-106B, wherein R3is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH. 108B. The method of embodiment 107B, wherein R3is methyl. 109B. The method of any one of embodiments 80B-108B, wherein R4is a (5- to 10- membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and wherein said phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkyl, halogen, and hydroxy. 110B. The method of embodiment 109B, wherein R4is a (6-membered heteroaryl)- methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6- membered heteroaryl is a nitrogen. 111B. The method of embodiment 109B or 110B, wherein R4is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, and triazolyl- methyl, each optionally substituted with phenyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro. 112B. The method of claim 111, wherein R4is selected from the group consisting of113B. The method of any one of embodiments 80B-108B, wherein, wherein R4is, wherein g is 0. 114B. The method of embodiment 113B, wherein R4cis selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3; and R4dis selected from the group consisting of hydrogen and methyl; or, R4cand R4dtaken together with the atom to which each is attached form a cyclopropyl ring. 115B. The method of embodiment 114B, wherein R4cand R4dare each hydrogen. 116B. The method of embodiment 113B, wherein R4bis hydrogen. 117B. The method of any one of embodiments 113B-116B, wherein R4ais C1-C6alkyl. 118B. The method of embodiment 117B, wherein R4ais tert-butyl. 119B. The method of any one of embodiments 113B-116B, wherein R4ais phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. 120B. The method of embodiment 119B, wherein R4ais phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy. 121B. The method of embodiment 120B, wherein R4ais selected from the group consisting122B. The method of any one of embodiments 113B-116B, wherein R4ais 5- to 10- membered monocyclic or fused bicyclic heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl. 123B. The method of embodiment 122B, wherein R4ais pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl. 124B. The method of embodiment 123B, wherein R4ais selected from the group125B. The method of any one of embodiments 113B-116B, wherein R4ais C3-C7cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. 126B. The method of embodiment 125B, wherein R4ais selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan- 1-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy. 127B. The method of embodiment 126B, wherein R4ais selected from the group128B. The method of any one of embodiments 113B-116B, wherein R4ais a 5- to 10- membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1- C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10- membered monocyclic or fused bicyclic heterocyclyl. 129B. The method of embodiment 128B, wherein R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, and methoxy. 130B. The method of embodiment 129B, wherein R4ais selected from the group. 131B. The method of any one of embodiments 113B-116B, or a pharmaceutically acceptable salt thereof, wherein R4ais (C6-C10 monocyclic or fused bicyclic aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl,optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl. 132B. The method of embodiment 131B, wherein R4ais selected from the group consisting of phenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, and pyridinyl-methyl. 133B. The method of embodiment 132B, wherein R4ais selected from the group134B. The method of any one of embodiments 113B-116B, wherein R4ais selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3. 135B. The method of any one of embodiments 113B-116B, wherein R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy. 136B. The method of embodiment 135B, wherein R4aand R4btaken together with the nitrogen to which each is attached form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, and methoxy. 137B. The method of embodiment 136B, wherein R4aand R4btaken together with the nitrogen to which each is attached form138B. The method of any one of embodiments 113B or 117B-134B, wherein R4band R4ctaken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3alkyl. 139B. The method of embodiment 138B, wherein R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one or a pyrrolidine-2-one, optionally substituted one or two times with methyl. 140B. The method of any one of embodiments 80B-106B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing one or two heteroatoms; wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3alkyl, cyano, halogen, halo-C1-C3alkyl, and C6-C10monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkoxy, hydroxy, halogen, and C1-C3alkyl. 141B. The method of embodiment 140B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, and methyl, and wherein said phenyl is optionally substituted with methoxy. 142B. The method of embodiment 141B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a143B. The method of any one of embodiments 80B-106B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused, bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3alkyl, C1-C3alkoxy, hydroxy, and halogen.144B. The method of embodiment 143B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a. 145B. The method of any one of embodiments 80B-106B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH2)sC(=O)NRkRl; wherein, s is 0, 1, or 2; Rkis hydrogen or C1-C3 alkyl; andRlis selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, halogen, cyano, and NRqRw; wherein, Rqis hydrogen or C1-C3alkyl; Rwis C6-C10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy. 146B. The method of embodiment 145B, wherein R3and R4taken together with the nitrogen atom to which each is attached form a. 147B. The method of any one of embodiments 80B-146B, wherein Rx, in each instance, is methyl. 148B. The method of any one of embodiments 80B-147B, wherein m is 0. 149B. The method of any one of embodiments 80B-147B, wherein m is 2. 150B. The method of embodiment 1B or 2B, wherein the compound of Formula I’ is a compound selected from Table 1, or a pharmaceutically acceptable salt thereof. 1D. A method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, halo-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C10 alkoxy, hydroxy-C1-C10-alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6alkyl)-alkyl)- NRGIRHI, -S-C1-C3alkyl, -S-C1-C3alkyl-NRG1RH1, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10 alkoxy or -O-(C1-C6 alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1- C3alkoxy; Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3alkyl, - S-C1-C3alkyl, -C(O)NRG1RH1, or -NRGRH; Rccis C1-C3 alkyl; and Rddis C1-C3alkyl or a 6-membered heteroaryl;wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3alkyl, C1-C3alkoxy, and C1-C3alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3alkyl, C3-C7cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl;wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, halo-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1-C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3alkyl)-T, 5- to 7- membered heterocyclyl, hydroxy, amino, cyano, and halogen; T is selected from the group consisting of C6-C10 monocyclic or fused bicyclic aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5;R4ais selected from the group consisting of hydrogen, C1-C10alkyl, hydroxy-(C1-C6 alkyl), C1-C3 alkoxy-C1-C6 alkyl, halo-C1-C3 alkyl, -C1-C6 alkyl- NRJ1RJ2, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (5- to 10- membered heterocyclyl)-C1-C3 alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, RJ1and RJ2are independently hydrogen or C1-C3alkyl; r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3 alkyl, C6-C10aryl, C6-C10aryl-C1-C3alkyl, and C3-C10cycloalkyl; wherein said C3-C10cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10aryl)-C1-C3alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, halogen, halo-C1-C6alkyl, halo-C1-C3alkoxy, C3-C7 cycloalkyl, hydroxy, C1-C6 alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6alkyl, halo-C1-C3alkyl, halogen, C1-C3alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6alkoxy-C1-C3alkyl, C3-C7cycloalkyl, and C1-C6alkyl; or, R4band R4ctaken together with the atom to which each is attachedform a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6 alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10- membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3alkyl, and Rwis C6-C10aryl or C3-C7cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl.2D. A method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3 alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C10alkoxy, hydroxy-C1-C10-alkyl, cyano, -NRGRH, halo-C1-C3alkoxy, -O-(C1-C6alkyl)-alkyl)- NRGIRHI, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NRG1RH1, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10alkoxy or -O-(C1-C6alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1- C3alkoxy;Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, - S-C1-C3 alkyl, -C(O)NRG1RH1, or -NRGRH; Rccis C1-C3alkyl; and Rddis C1-C3 alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3 alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1-C3alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6-membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1- C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, halo-C1-C3alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1-C6alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3alkyl, and hydroxy-(C1-C6alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3 alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, said C3- C10cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10 aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3 alkyl)-T, 5- to 7- membered heterocyclyl, hydroxy, amino, cyano, and halogen; T is selected from the group consisting of C6-C10monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5-to 7-membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of hydrogen, C1-C10 alkyl, hydroxy-(C1-C6alkyl), C1-C3alkoxy-C1-C6alkyl, halo-C1-C3alkyl, -C1-C6alkyl- NRJ1RJ2, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (C6-C10 aryl)-C1-C3 alkyl, (5- to 10- membered heterocyclyl)-C1-C3alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, RJ1and RJ2are independently hydrogen or C1-C3 alkyl; r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10 aryl, C6-C10 aryl-C1-C3 alkyl, and C3-C10 cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7 cycloalkyl, hydroxy, C1-C6 alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selectedfrom C1-C6alkyl, halo-C1-C3alkyl, halogen, C1-C3alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6alkoxy-C1-C3alkyl, C3-C7cycloalkyl, and C1-C6alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1-C3 alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3alkyl, C1-C3alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10- membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, C1-C3alkoxy, and hydroxy; Rqis hydrogen or C1-C3 alkyl, and Rwis C6-C10 aryl or C3-C7 cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3;Rkis hydrogen or C1-C3alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1- C3 alkyl, C3-C7 cycloalkyl, and C6-C10 aryl. 3D. The method of embodiment 2, wherein the disease is related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload. 4D. The method of embodiment 2, wherein the disease is related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin. 5D. The method of embodiment 4, wherein the disease is hemochromatosis. 6D. The method of embodiment 3, wherein the disease is related to or caused by a hemoglobinopathy. 7D. The method of embodiment 6, wherein the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease. 8D. The method of embodiment 7, wherein the disease is sickle cell disease. 9D. The method of embodiment 8, wherein the sickle cell disease is sickle cell anemia. 10D. The method of embodiment 2, 3, 4, 5, 6, 7, 8, or 9, wherein the treating comprises inhibiting iron transport mediated by ferroportin in the subject. 1. The method of any one of embodiments 1-10D, wherein the compound is of Formula (I’):or a pharmaceutically acceptable salt thereof; wherein, Z is N or CH;Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C10alkoxy, hydroxy-C1-C10- alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-Rbb, -O-Rbb, -(C1-C6 alkyl)- NRGIRHI, -S-C1-C3alkyl, -S-C1-C3alkyl-NRG1RH1, halo-C1-C3alkyl, -O-Rcc-O-Rdd, 5- to 7-membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10 alkoxy or -O-(C1-C6 alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7cycloalkyl, 5- or 6- membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NRG1RH1, or -NRGRH; Rccis C1-C3alkyl; and Rddis C1-C3alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3alkyl, C1-C3alkoxy, and C1-C3alkyl; RG1and RH1are each independently hydrogen or C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6- membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionallysubstituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; p is 1 or 2; Rx, in each instance, is halogen, C1-C6alkyl, C1-C3alkoxy, hydroxy, or cyano; m is 0, 1, or 2; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3 alkyl, halo-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting of: i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-C1-C3 alkyl; wherein, said heteroaryl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C6-C10 monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3 alkyl)-T, and 5- to 7-membered monocyclic heterocyclyl; T is selected from the group consisting of C6-C10monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl substituent of R4is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and when p is 1, C1-C3alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is linear; and,i. wherein, R4aand R4gare each independently selected from the group consisting of hydrogen, C1- C10alkyl, hydroxy-C1-C6alkyl, halo-C1-C3alkyl, C1-C3alkoxy-C1-C6alkyl, -C1-C6alkyl- NRJ1RJ2, C3-C7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, C6-C10monocyclic or fused bicyclic aryl, 5- to 10- membered monocyclic or fused bicyclic heteroaryl, (C6-C10monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1- C3 alkyl; RJ1and RJ2are independently hydrogen or C1-C3alkyl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl of R4aor R4gis optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, halo-C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10- membered monocyclic, fused bicyclic, or spiro heterocyclyl; R4bis hydrogen or C1-C6alkyl; or R4aand R4btaken together with the atom to which each is attached form a 5- to 10- membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, and C1-C3alkoxy; or R4band R4ctaken together with the atom to which each is attached form a 5- to 7- membered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3alkyl; or R4cand R4dare each independently selected from the group consisting of hydrogen, C1- C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1-C6alkoxy-C1- C3alkyl, C3-C7cycloalkyl, and C1-C3alkyl; or R4cand R4dtaken together with the atom to which each is attached form a C3-C7cycloalkyl; or, when p is 1, R3and R4taken together with the nitrogen atom to which each is attached can form a: i. 7-membered fused bicyclic heterocyclyl, 7-membered bridged bicyclic heterocyclyl, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms; wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3alkyl, cyano, halogen, halo-C1-C3alkyl, and C6-C10monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1- C3 alkoxy, and -(CH2)sC(=O)NRkRl; wherein, s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C10 monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, halogen, cyano, and -NRqRw; wherein, Rqis hydrogen or C1-C3alkyl; and Rwis C6-C10monocyclic or fused bicyclic aryl or C3-C7cycloalkyl, wherein said aryl orcycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or, iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl, or 12-membered bicyclic bridged and fused heterocyclyl, wherein said 8-, 9-, or 11-membered heterocyclyl contains one heteroatom and said 10- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said 10-, 11-, or 12-membered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy; or, when p is 2, R3and R4taken together with the nitrogen atom to which each is attached can form a: i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6alkyl), hydroxy, and C1-C3alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, cyano, C1-C3 alkyl, hydroxy, -NRGRH, and -(CH2)sC(=O)NRkRl. 2. The method of any one of embodiments 1D-10D or 1, wherein p is 1. 3. The method of any one of embodiments 1D-10D, 1, or 2,wherein Z is N. 4. The method of any one of embodiments 1D-10D, or 1-3, wherein Y1, Y2, Y3, and Y4are each CH or C-R6. 5. The method of any one of embodiments 1D-10D, or 1-4, wherein Y1is CH, Y2is C-R6, Y3is CH, and Y4is CH. 6. The method of any one of embodiments 1D-10D, or 1-5, wherein Y3is N and Y1, Y2, and Y4are each CH or C-R6. 7. The method of any one of embodiments 1D-10D, or 1-6, wherein Y2is N and Y1, Y3, Y4are each CH or C-R6. 8. The method of any one of embodiments 1D-10D, or 1-7, wherein Y1is N and Y2, Y3, and Y4are each CH or C-R6.9. The method of any one of embodiments 1D-10D, or 1-8, wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C10 alkoxy, hydroxy-C1-C10-alkyl, -O-(C1- C6alkyl)-Rbb, halo-C1-C3alkoxy, -O-Rcc-O-Rdd, halo-C1-C3alkyl, -(C1-C6alkyl)- NRGIRHI, -S-CH3, -S(CH2)2N(CH3)2, and -NRGRH; wherein, Rbbis -NRGRH, -C(O)N(CH3)2, -S(O)2CH3, or -SCH3; RGand RHare each independently hydrogen, optionally deuterated C1-C3alkyl, or -C(O)RGa, wherein RGais C1-C3 alkyl; RGIand RHIare each independently hydrogen or C1-C3 alkyl; Rccand Rddare each independently C1-C3alkyl; and, wherein the alkyl moiety in hydroxy-C1-C10alkoxy is optionally substituted with hydroxy, halogen, or C1-C3 alkoxy. 10. The method of any one of embodiments 1D-10D, or 1-9, wherein R6, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, - CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3)2CH2OH, -OCH2CH(CH3)OH, -OCH2CH2NHC(O)CH3, -OC(CH3)2CH2N(CH3)2, -OCH(CH3)CH2OH, -OCH2CH(CH(CH3)2)O H, -OCH2CH(CH2CH3)OH, -OCH2C(CH2CH3)2OH, -OCH2CH2N(CH2CH3)2, -OCH(CH3)CH2N(CH3)2, -OCH2C(O)N(CH3)2, -OCH2C(CH3)2N(CH3)2, -OCH2CH(CH2OH)OH, -O CH2CH2NH(CH3), -OCH2CH(CF3)OH, -OCH2C(CH3)(CH2CH3)OH, -OCH2CH(CH2OC H3)OH, -OCH2CH(CH2F)OH, -(CH2)3N(CH3)2, -(CH2)3N(CH3)H, -O(CH2)2S(O)2CH3, - O(CH2)2SCH3, -(CH2)2C(CH3)2OH, -OCH2CH2N(CD3)2, and -CH2CH2OH. 11. The method of any one of embodiments 1D-10D, or 1-10, wherein R6, in each instance, is methoxy, -OCH2CH2N(CH3)2, -OCH2CH2OH, or -OCH2C(CH3)2OH. 12. The method of any one of embodiments 1D-10D, or 1-11, wherein R6, in each instance, is -OCH2CH2N(CH3)2 or -OCH2C(CH3)2OH. 13. The method of any one of embodiments 1D-10D, or 1-12, wherein R6, in each instance, is selected from the group consisting of -O-(C1-C6alkyl)-Rbb, -O-Rbb, -O-Rcc-O-Rdd, 5- to 7-membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, Rccis C1-C3 alkyl and Rddis 6-membered heteroaryl; Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, 5- or 6-membered monocyclic heteroaryl, or C3-C7 cycloalkyl; and wherein said cycloalkyl, heteroaryl, or heterocyclyl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, C1-C3 alkoxy, halo-C1-C3 alkyl, and C1-C3 alkyl. 14. The method of any one of embodiments 1D-10D, or 1-13, wherein R6, in each instance, is selected from the group consisting of cyclopropyl, -O--O-(CH2)2-O-pyridazinyl, and optionally C1-C3 alkyl-substituted imidazolyl; wherein, Rbbis selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranol, oxetanyl, dioxolanyl, azetidinyl, morpholinyl, piperazinyl, 2-oxa-5-azabicyclo[2.2.1]heptane, imidazolyl, tetrazolyl, pyridazinyl, piperidinyl, thiomorpholinyl, and pyrrolidinyl, each optionally substituted with hydroxy, fluoro, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, methoxy, ethyl, or methyl. 15. The method of any one of embodiments 1D-10D, or 1-14, wherein R6, in each instance, is selected from the group consisting,,16. The method of any one of embodiments 1D-10D, or 1-15, wherein R6is17. The method of any one of embodiments 1D-10D, or 1-16, wherein two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl. 18. The method of any one of embodiments 1D-10D, or 1-17, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl. 19. The method of any one of embodiments 1D-10D, or 1-18, wherein two R6groups, taken together with the atom to which each is attached, form a ring selected from the,ring with Ring B. 20. The method of any one of embodiments 1D-10D, or 1-19, wherein two R6groups, taken together with the atom to which each is attached, form a form a ring selected fromthe group consistingfused with Ring B. 21. The method of any one of embodiments 1D-10D, or 1-20, wherein f is 1. 22. The method of any one of embodiments 1D-10D, or 1-21, wherein f is 0, andn is 0 or 1; and Y2and Y3are each independently selected from the group consisting of CH, N, NH, NR6, S, O, and CR6, provided that only one of Y2and Y3can be N, NH, NR6, S, or O. 24. The method of any one of embodiments 1D-10D, or 1-23, wherein Ring B is selected from the group consisting25. The method of any one of embodiments 1D-10D, or 1-24, wherein R6, in each instance, is selected from the group consisting of C1-C3 alkyl and hydroxy-C1-C3 alkyl.26. The method of any one of embodiments 1D-10D, or 1-25, wherein R6, in each instance, is selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH. 27. The method of any one of embodiments 1D-10D, or 1-26, wherein n is 1. 28. The method of any one of embodiments 1D-10D, or 1-27, wherein n is 0. 29. The method of any one of embodiments 1D-10D, or 1-28, wherein n is 2. 30. The method of any one of embodiments 1D-10D, or 1-29, wherein one R6is selected from the group consisting of methyl and methoxy and the other R6is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH. 31. The method of any one of embodiments 1D-10D, or 1-30, wherein R3is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, phenyl, -CH2CF3, and -CH2CH2OH. 32. The method of any one of embodiments 1D-10D, or 1-31, wherein R3is methyl. 33. The method of any one of embodiments 1D-10D, or 1-32, wherein R4is a (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7cycloalkyl, -(C1-C3alkyl)-phenyl, and 5- to 7- membered monocyclic heterocyclyl, and wherein said phenyl either alone or in -(C1-C3 alkyl)-phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkyl, halogen, and hydroxy. 34. The method of any one of embodiments 1D-10D, or 1-33, wherein R4is a (6- membered heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6-membered heteroaryl is a nitrogen. 35. The method of any one of embodiments 1D-10D, or 1-34, wherein R4is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, oxazolyl-methyl, and triazolyl-methyl, each optionally substituted with phenyl or benzyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro. 36. The method of any one of embodiments 1D-10D, or 1-35, wherein R4is selectedfrom the group consisting. 37. The method of any one of embodiments 1D-10D, or 1-36, wherein R4is. 38. The method of any one of embodiments 1D-10D, or 1-37, wherein R4cis selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3,and -CH2CH2SCH3; and R4dis selected from the group consisting of hydrogen and methyl; or, R4cand R4dtaken together with the atom to which each is attached form a cyclopropyl ring. 39. The method of any one of embodiments 1D-10D, or 1-38, wherein R4cand R4dare each hydrogen. 40. The method of any one of embodiments 1D-10D, or 1-39, wherein R4bis hydrogen. 41. The method of any one of embodiments 1D-10D, or 1-40, wherein R4ais C1-C6 alkyl. 42. The method of any one of embodiments 1D-10D, or 1-41, wherein R4ais methyl, ethyl, isopropyl, tert-butyl, or 3-methylpentan-3-yl. 43. The method of any one of embodiments 1D-10D, or 1-42, wherein R4ais tert- butyl or isopropyl. 44. The method of any one of embodiments 1D-10D, or 1-43, wherein R4ais phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. 45. The method of any one of embodiments 1D-10D, or 1-44, wherein R4ais phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy. 46. The method of any one of embodiments 1D-10D, or 1-45, wherein R4ais selected from the group consisting47. The method of any one of embodiments 1D-10D, or 1-46, wherein R4ais 5- to 10- membered monocyclic or fused bicyclic heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl. 48. The method of any one of embodiments 1D-10D, or 1-47, wherein R4ais pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl. 49. The method of any one of embodiments 1D-10D, or 1-48, wherein R4ais selected. 50. The method of any one of embodiments 1D-10D, or 1-49, or a pharmaceutically acceptable salt thereof, wherein R4ais C3-C7cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10- membered monocyclic or fused bicyclic heterocyclyl. 51. The method of any one of embodiments 1D-10D, or 1-50, wherein R4ais selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan-1-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy.52. The method of any one of embodiments 1D-10D, or 1-51, wherein R4ais selected f, an . 53. The method of any one of embodiments 1D-10D, or 1-52, wherein R4ais a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10- membered monocyclic or fused bicyclic heterocyclyl. 54. The method of any one of embodiments 1D-10D, or 1-53, wherein R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, oxetanyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, and methoxy. 55. The method of any one of embodiments 1D-10D, or 1-54, wherein R4ais selectedf56. The method of any one of embodiments 1D-10D, or 1-55, wherein R4ais (C6-C10 monocyclic or fused bicyclic aryl)-C1-C3alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl. 57. The method of any one of embodiments 1D-10D, or 1-56, wherein R4ais selected from the group consisting of benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl-methyl. 58. The method of any one of embodiments 1D-10D, or 1-57, wherein R4ais selected f. 59. The method of any one of embodiments 1D-10D, or 1-58, wherein R4ais selected from the group consisting of hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, and -C1-C6alkyl-NRJ1RJ2, wherein RJ1and RJ2are each independently hydrogen or C1-C3alkyl. 60. The method of any one of embodiments 1D-10D, or 1-59, wherein R4ais selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, -C(CH3)2CH2OCH3, -CH(CH3)CH2OH, -CH2CH2N(C H3)2, and -CH2CF3. 61. The method of any one of embodiments 1D-10D, or 1-60, wherein R4ais -C(CH3)2CH2OH. 62. The method of any one of embodiments 1D-10D, or 1-61, wherein R4aand R4btaken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy. 63. The method of any one of embodiments 1D-10D, or 1-62, wherein R4aand R4btaken together with the atom to which each is attached form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, 2,3-dihydro-1H-pyrrolo[2,3- c]pyridine, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, methyl, fluoro, and methoxy. 64. The method of any one of embodiments 1D-10D, or 1-63, wherein R4aand R4btaken together with the atom to which each is attached form a. 65. The method of any one of embodiments 1D-10D, or 1-64, wherein R4band R4ctaken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3 alkyl. 66. The method of any one of embodiments 1D-10D, or 1-65, wherein R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one or a pyrrolidine-2-one, optionally substituted one or two times with methyl. 67. The method of any one of embodiments 1D-10D, or 1-66, wherein R4is, wherein R4gis selected from the group consisting of C6-C10 monocyclic or fused bicyclic aryl and C1-C3 alkyl. 68. The method of any one of embodiments 1D-10D, or 1-67, wherein R4gis selected from the group consisting of phenyl and methyl. 69. The method of any one of embodiments 1D-10D, or 1-68, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing one or two heteroatoms; wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, cyano, and C1-C3alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3alkyl, cyano, halogen, halo-C1-C3 alkyl, and C6-C10 monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkoxy, hydroxy, halogen, and C1-C3 alkyl. 70. The method of any one of embodiments 1D-10D, or 1-69, wherein R3and R4taken together with the nitrogen atom to which each is attached form a monocyclic 7- membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, and methyl, and wherein said phenyl is optionally substituted with methoxy. 71. The method of any one of embodiments 1D-10D, or 1-70, wherein R3and R4taken together with the nitrogen atom to which each is attached form a. 72. The method of any one of embodiments 1D-10D, or 1-71, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11- membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy, and halogen. 73. The method of any one of embodiments 1D-10D, or 1-72, wherein R3and R4taken together with the nitrogen atom to which each is attached form74. The method of any one of embodiments 1D-10D, or 1-73, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH2)sC(=O)NRkRl; wherein, s is 0, 1, or 2; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, halogen, cyano, and -NRqRw; wherein,Rqis hydrogen or C1-C3alkyl; Rwis C6-C10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl; and, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3 alkoxy. 75. The method of any one of embodiments 1D-10D, or 1-74, wherein R3and R4taken together with the nitrogen atom to which each is attached form a76. The method of any one of embodiments 1D-10D, or 1-75, wherein Rx, in each instance, is methyl. 77. The method of any one of embodiments 1D-10D, or 1-76, wherein m is 0. 78. The method of any one of embodiments 1D-10D, or 1-77, wherein m is 2. 79. The method of any one of embodiments 1D-10D, or 1-78, or a pharmaceutically acceptable salt thereof, wherein, Z is N; p is 1; f is 1; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C10alkoxy, hydroxy-C1-C10- alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-Rbb, -O-Rbb, -(C1-C6 alkyl)- NRGIRHI, halo-C1-C3 alkyl, -O-Rcc-O-Rdd, 5- to 7-membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10 alkoxy or -O-(C1-C6 alkyl)-Rbbis optionallysubstituted with hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3alkoxy; Rbbis 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NRGRH; Rccand Rddare each independently C1-C3 alkyl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6or Rbbis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; and, RG1and RH1are each independently hydrogen or C1-C3 alkyl; RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3 alkyl; wherein, RGais C1-C3alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6- membered monocyclic heterocyclyl fused with Ring B, a C4-C7cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, or 2; R3is selected from the group consisting of hydrogen, phenyl, -CH2CH2OH, and optionally deuterated methyl or ethyl;wherein, R4cis selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, - CH2OC(CH3)3, and -CH2CH2SCH3; R4dis selected from the group consisting of hydrogen and methyl; or,R4cand R4dtaken together with the atom to which each is attached form a cyclopropyl ring; R4bis hydrogen or methyl; R4ais selected from the group consisting of hydrogen, C1-C10alkyl, hydroxy-C1- C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, -C1-C6 alkyl-NRJ1RJ2, C3-C7 cycloalkyl, 5- to 10- membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, C6-C10 monocyclic or fused bicyclic aryl, 4- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C10 monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10- membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, halo-C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl; RJ1and RJ2are independently hydrogen or C1-C3 alkyl; or, R4aand R4btaken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, and C1-C3alkoxy; Rx, in each instance, is C1-C3alkyl; and m is 0, 1, or 2. 80. The method of any one of embodiments 1D-10D, or 1-79, or a pharmaceutically acceptable salt thereof, wherein m is 0. 81. The method of any one of embodiments 1D-10D, or 1-80, or a pharmaceutically acceptable salt thereof, wherein m is 2 and Rx, in each instance, is methyl. 82. The method of any one of embodiments 1D-10D, or 1-81, or a pharmaceutically acceptable salt thereof, wherein, Y1, Y2, Y3, and Y4are each CH or C-R6; Y3is N and Y1, Y2, and Y4are each CH or C-R6; Y2is N and Y1, Y3, Y4are each CH or C-R6; orY1is N and Y2, Y3, and Y4are each CH or C-R6. 83. The method of any one of embodiments 1D-10D, or 1-82, or a pharmaceutically acceptable salt thereof, wherein Y1is CH, Y2is C-R6, Y3is CH, and Y4is CH. 84. The method of any one of embodiments 1D-10D, or 1-83, or a pharmaceutically acceptable salt thereof; wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C10-alkyl, -O-Rbb, -O-(C1-C6alkyl)-Rbb, halo-C1-C3alkoxy, -O-Rcc-O-Rdd, halo-C1-C3 alkyl, C3-C6 cycloalkyl, and -NRGRH; wherein, Rbbis -NRGRH, 4- to 6-membered monocyclic heterocyclyl, or C3-C7 cycloalkyl; RGand RHare each independently hydrogen or C1-C3alkyl; Rccand Rddare each independently C1-C3alkyl; and, wherein, said cycloalkyl or heterocyclyl of R6or Rbbis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3alkyl. 85. The method of any one of embodiments 1D-10D, or 1-84, or a pharmaceutically acceptable salt thereof, wherein Rbbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, morpholinyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl; or, Rbbis -N(CH3)2. 86. The method of any one of embodiments 1D-10D, or 1-85, or a pharmaceutically acceptable salt thereof, wherein R6, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH3)2, hydroxy, -OCH2CH(CH3)OH, -OCH2CH2N(CH2CH3)2, -OCH2C(CH3)(CH2CH3)OH, -O CH2CH(CH2OCH3)OH, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2C H2N(CH3)2, -OCH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CRing B. 87. The method of any one of embodiments 1D-10D, or 1-86, or a pharmaceutically acceptable salt thereof, wherein R6, in each instance, is88. The method of any one of embodiments 1D-10D, or 1-87, or a pharmaceutically acceptable salt thereof, wherein R6, in each instance, is. 89. The method of any one of embodiments 1D-10D, or 1-88, or a pharmaceutically acceptable salt thereof, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl. 90. The method of any one of embodiments 1D-10D, or 1-89, or a pharmaceutically acceptable salt thereof, wherein R3is methyl. 91. The method of any one of embodiments 1D-10D, or 1-90, or a pharmaceutically acceptable salt thereof, wherein n is 1. 92. The method of any one of embodiments 1D-10D, or 1-91, or a pharmaceutically acceptable salt thereof, wherein R4bis hydrogen. 93. The method of any one of embodiments 1D-10D, or 1-92, or a pharmaceutically acceptable salt thereof, wherein R4ais selected from the group consisting of: i. tert-butyl or isopropyl; ii. phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy; iii. pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, and methyl; iv. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan-1-yl, optionally substituted with one or two substituents, eachindependently selected from the group consisting of methyl, -CF3, fluoro, and hydroxy; v. tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl and methoxy; vi. benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl- methyl; and vii. -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3. 94. The method of any one of embodiments 1D-10D, or 1-93, wherein the compound is selected from Table 1, or a pharmaceutically acceptable salt thereof.

[0234] The General Procedures and Examples provide exemplary methods for preparing compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the Schemes, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of derivatives and / or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art. General Synthetic Schemes

[0235] General synthetic approaches to FPN1 compounds 1a and 1b. In certain embodiments, compound 1a can be synthesized as shown in Scheme 1, the core intermediate 2a could be displaced by various substituted amine 3a via method A to give intermediate 4a, which was then coupled with various organometallic reagent 5a to provide final compound 1a. Alternatively, final compound 1a could be synthesized as shown in Scheme 2. Intermediate 2a could be displaced by primary amine 6a to give intermediate 7a, after coupling with organometallic reagent 5a, the resulting intermediate 8a could then alkylated by a halide to give compound 1a. Final compound 1b could be synthesized according to scheme 3. Intermediate 2a was displaced by glycinate 9a to provide intermediate 10a, after coupling with organometallic reagent 5a, the resultingintermediate 11a was saponified. The corresponding carboxylic acid intermediate 12a was coupled with various amine to form compound 1b.

[0236] Modifications and variations to schemes 1-3 can be made based on the availability of starting materials and synthetic compatibility of reagents, starting materials, or intermediates. This should be obvious to those who are familiar with the art. For example, R1 and R2 could be hydrogen, halogen, simple alkyl or could join to form a ring; R3could be hydrogen or alkyl; R4could be alkyl substituted by aminocarbonyl, alkoxy; or R3 and R4 could join together to form a cyclic amine. For method B, another available heteroaromatic Suzuki or Stille reagent could be used to provide the final compound 1a.

[0237] Scheme 1a depicts a method for preparing exemplary compounds using Method A and Method B.Scheme 1a

[0238] Scheme 1b depicts a method for preparing exemplary compounds using Method A, Method B, and Method C.Scheme 1b

[0239] Scheme 1c depicts a method for preparing exemplary compounds using Method A, Method B, Method D, and Method E.Scheme 1c

[0240] General synthetic approaches to compounds 1a’ and 1b’.

[0241] In certain embodiments, compounds 1a’ and 1b’ can be synthesized as shown in Scheme 2 and Scheme 3. According to Scheme 2, the core thiophenepyrimidine intermediate 2a’ was displaced by various substituted amine 3a’ via method F to give intermediate 4a’, which was then reacted with various organometallic reagent 5a’ to provide final compound 1a’. According to Scheme 3, The intermediate 6a’ was saponified to provide carboxylic intermediate 7a’ which was subsequently coupled with amine to provide final compound 1b’.

[0242] Scheme 2 depicts a method for preparing exemplary compounds using Method F and Method G.Scheme 2

[0243] Scheme 3 depicts a method for preparing exemplary compounds using Method F, Method G, Method H, and Method I.Scheme 3

[0244] Modifications and variations to Scheme 2 and Scheme 3 can be made based on the availability of starting materials and synthetic compatibility of reagents and starting materials or intermediates. For example, R1and R2could be hydrogen, halogen, simple alkyl or join to form a ring; R3 could be hydrogen or alkyl; R4 could be alkyl substituted by aminocarbonyl or alkoxy; or, R3and R4could be joined together to form a cyclic amine. For method G, another available heteroaromatic Suzuki or Stille reagent could be used to provide final compound 1a’. For Method I, various substituted aniline, fused hetereoaromatic amine, alkylamine, or cycloalkyl amine could be used for the amide coupling reaction to provide final compound 1b’.

[0245] The conditions and reagesnts for Methods A-I are provided in the below Examples. The following examples are offered by way of illustration and not by way of limitation. 1. SYNTHETIC EXAMPLES Example 1.01 Method A: General synthetic method for nucleophilic coupling of amine to intermediate 4

[0246] Into a 100-mL round-bottom flask, was placed dichloropyrimidine intermediate 2 (1.00 equiv), CH3CN, amine 3 (1.10 equiv), and triethylamine (2.00 equiv). The resulting solution was stirred for 3 hr at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether to give intermediate 4. Example 1.02Method B: General synthetic method for metal mediated cross coupling

[0247] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed intermediate 4 (1.00 equiv), dioxane, organometallic reagent 5a (2.0 equiv) and Pd(dppf)Cl2(, 0.05 equiv). The resulting solution was stirred overnight at 100°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1) or subjected to preparative HPLC purification to give compound 1a, 8a, or 11a. Example 1.03 Method C: General synthetic method for alkylation with halide to give compound 1a

[0248] Intermediate 8a (1.00 eq.) was dissolved in DMF and cooled in an ice bath. Sodium hydride (2.00 eq.) (60%) was added in two portions and the reaction was stirred for 45 min. Halide (2.00 eq.) was added slowly and the mixture was stirred for 1.5 h more. Water (20 ml) and ethyl acetate (100 ml) were added, the phases were separated, and the aqueous phase was extracted with more ethyl acetate The combined organic phases were washed with some water and dried over sodium sulfate. After evaporation of solvent, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile / 0.1 % aqueous formic acid gradient). The purified fractions were treated with 1 M HCl and freeze-dried to give compound 1a. Example 1.04 Method D: General synthetic method for saponification to give 12a

[0249] Intermediate 11a (1.00 eq.) was dissolved in THF and methanol. Lithium hydroxide (5.00 eq.) was dissolved in water and was added dropwise to the solution. After 7 h, the mixture was acidified carefully with 6 M HCl to pH 3 and evaporated to dryness. The residue was co-evaporated with toluene and dried under high vacuum to give 12a. Example 1.05 Method E: General synthetic method for amide formation to give 1b

[0250] Intermediate 12a (1.00 eq.) was suspended in N,N-dimethylformamide, N,N- Diisopropylethylamine (2.50 eq.), amine (1.35 eq.) and then 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.35 eq.) were added. After 40 h, ethyl acetate (50 ml) andsodium bicarbonate solution (20 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvents, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile / 0.1 % aqueous formic acid gradient) to give compound 1b. Example 1.06 Experimental Procedures for Common Intermediates

[0251] Scheme 4 depicts a method for preparing Intermediate I [

[0253] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.00 g; 10.58 mmol; 1.00 eq.) was dissolved in acetonitrile (36 ml). (2-Ethoxy-2-oxoethyl)(methyl)azanium chloride (2.11 g; 13.75 mmol; 1.30 eq., sarcosine ethyl ester HCl) was added, followed by N,N-diisopropylethylamine (4.6 mL; 26.45 mmol; 2.50 eq.) slowly. The reaction was stirred at 25oC for 22 h and then at 50oC for 20 h. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate / hexanes gradient) to give ethyl 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetate (2.18 g, 76%) as a solid.1H NMR (400 MHz, Chloroform-d) δ 4.30 – 4.19 (m, 4H), 3.31 (s, 3H), 3.11 (t, J = 7.4 Hz, 2H), 2.88 (t, J = 7.9 Hz, 2H), 2.12 – 2.02 (m, 2H), 1.30 (t, J = 7.2 Hz, 3H).

[0254] Step 2

[0255] Ethyl 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetate (900.00 mg; 3.34 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (9 ml) and purged with argon.2-(Tributylstannyl)pyridine (2.34 mL; 6.67 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (385.58 mg; 0.33 mmol; 0.10 eq.) were added, the reaction vessel was sealed, and then stirred in a heat bath at 105oC. After 16 h, the solvent was evaporated and the residue was purified by silica gel chromatography (methanol / dichloromethane) to give ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetate (0.72 g, 62%)1H NMR (400 MHz, Chloroform-d) δ 8.83 (d, J = 4.8 Hz, 1H), 8.39 – 8.28 (m, 1H), 7.86 – 7.77 (m, 1H), 7.41 – 7.32 (m, 1H), 4.37 (s, 2H), 4.20 (q, J = 7.2, 1.5 Hz, 2H), 3.42 (s, 3H), 3.23 – 3.12 (m, 4H), 2.15 – 2.07 (m, 2H), 1.27 – 1.23 (m, 3H). MS (ES+): (M+H)+= 269.9.

[0256] Step 3

[0257] Ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetate (0.72 g; 2.30 mmol; 1.00 eq.) was dissolved in THF (20 ml) and methanol (5 ml). Lithium hydroxide (0.28 g; 11.52 mmol; 5.00 eq.) dissolved in water (8 ml) was added dropwise to the solution. After 7 h, the mixture was acidified carefully with 6 M HCl to pH 3 and evaporated to dryness. The residue was co-evaporated with toluene and dried under high vacuum to give 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetic acid hydrochloride (Intermediate I) as an off- white solid.1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.7 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.21 – 8.12 (m, 1H), 7.75 (dd, J = 7.8, 4.8 Hz, 1H), 3.28 – 3.27 (m, 2H), 3.07 – 3.01 (m, 2H), 2.15 – 2.05 (m, 2H). MS (ES+): (M+H)+= 284.9. Example 1.07

[0258] Scheme 5 depicts a method for preparing Intermediate II O eOH,

[0260] Into a 1-L 3-necked round-bottom flask was placed 2- (benzyloxycarbonylamino)acetic acid (20.0 g, 95.6 mmol, 1.00 equiv), DCM (500 mL), HOBt (15.5 g, 114.7 mmol, 1.20 equiv), EDCI (22.0 g, 114.7 mmol, 1.20 equiv), and tert-butylamine (21.0 g, 286.8 mmol, 3.00 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with PE / EA ether (0-50%). This resulted in 25.1 g (99%) of benzyl N-[(tert-butylcarbamoyl)methyl]-carbamate as a white solid. LCMS: (ES, m / z) : [M+H] + 265.

[0261] Into a 250-mL round-bottom flask, was placed benzyl N-[(tert-butylcarbamoyl)methyl]carbamate (7.0 g, 26.48 mmol, 1.00 equiv), MeOH (50 mL), and Pd / C(10%) (0.70 g, 10%). The resulting solution was stirred overnight at room temperature under H2 (1 atm). The solids were filtered out. The resulting mixture was concentrated. This resulted in 3.3 g (95%) of 2-amino-N-tert-butylacetamide as a colorless oil. LCMS: (ES, m / z): [M+H]+: 131.

[0262] Into a 50-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7H- cyclopenta[d]pyrimidine (0.80 g, 4.23 mmol, 1.00 equiv), THF (20 mL), TEA (0.51g, 5.04 mmol, 1.19 equiv), and 2-amino-N-tert-butylacetamide (0.58 g, 4.44 mmol, 1.05 equiv). The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate / hexane (0-50%). This resulted in 0.688 g (57%) of N-tert-butyl-2-([2-chloro- 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)acetamide as a white solid. LCMS (ES, m / z): [M+H]+: 283.1. Example 1.08

[0263] Synthesis of 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]azepane (Compound 92).

[0264] Scheme 6 depicts a synthetic route for preparing an exemplary compound.[

[0266] Into a 100-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7H- cyclopenta[d]pyrimidine (500.00 mg, 2.645 mmol, 1.00 equiv), acetonitrile (20.00 mL, 0.487 mmol, 0.18 equiv), azepane (314.78 mg, 3.174 mmol, 1.20 equiv), and TEA (321.17 mg, 3.174 mmol, 1.20 equiv). The resulting solution was stirred for 2 hr at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:3) to give 600 mg (90.10%) of 1- [2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane as a solid.

[0267] Step 2

[0268] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphere of nitrogen, was placed 1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]azepane (300.00 mg, 1.192 mmol, 1.00 equiv), dioxane (20.00 mL), 2- (tributylstannyl)pyridine (877.39 mg, 2.383 mmol, 2.0 equiv), and Pd(dppf)Cl2 (43.60 mg, 0.060 mmol, 0.05 equiv). The resulting solution was stirred overnight at 100 degreesC in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). The crude product was purified by re-crystallization from EA (ethyl acetate). This resulted in 79 mg (24.16%) of 1-[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane as a white solid.1H NMR (300 MHz, DMSO-d6): δ 8.66 (d, J=4.5Hz, 1H), 8.25 (d, J=7.8Hz, 1H), 7.882 (t, J=7.8Hz, 1H), 7.42 (dd, J=5.1Hz, 6.0 Hz ,1H), 3.78-3.64 (m, 4H), 3.11-3.00 (m, 2H), 2.83-2.78 (m, 2H), 2.08-1.97 (m, 2H), 1.76 (s, 4H), 1.49 (s, 2H). LCMS:(ES) [M+1]+m / z 295.2. Example 1.09

[0269] Synthesis of 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- oxazepane (Compound 93).

[0270] Scheme 7 depicts a synthetic route for preparing an exemplary compound. [

[0272] Into a 100-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7H- cyclopenta[d]pyrimidine (500.00 mg, 1.00 equiv), CH3CN (10.00 mL), 1,4-oxazepane hydrochloride (402.00 mg, 1.10 equiv), and TEA (534.00 mg, 2.00 equiv). The resulting solution was stirred for 3 hr at 80 degrees C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:2). This resulted in 600 mg (89.28%) of 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as a brown solid.

[0273] Step 2

[0274] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphere of nitrogen, was placed 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]- 1,4-oxazepane (0.30 g, 1.18 mmol, 1.00 equiv), dioxane (20 mL), 2- (tributylstannyl)pyridine (0.87 g, 2.36 mmol, 2.0 equiv), Pd(dppf)Cl2(0.04 g, 0.035 mmol, 0.05 equiv). The resulting solution was stirred overnight at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate / petroleum ether (1:1). The crude product was purified by re-crystallization from EA. This resulted in 358.1 mg (90%) of 4-[2-(pyridin-2-yl)- 5H,6H,7H-1-λ-4-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as a light brown solid.1H NMR (300 MHz, DMSO-d6): δ 8.66 (dd, J=0.9, 0.9Hz, 1H), 8.25 (d, J=7.8Hz, 1H), 7.91- 7.86 (m, 1H), 7.45-7.41 (m ,1H), 3.97-3.87 (m, 4H), 3.85-3.75 (m, 2H), 3.66-3.62 (m, 2H), 3.08 (t, J=7.5Hz, 2H), 2.85-2.80 (m, 2H), 2.06-1.96 (m, 4H). LCMS (ES) [M+1]+ m / z 297.2. Example 1.010

[0275] Synthesis of 1-[2-(3-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]azepane (Compound 71).

[0276] Compound 71 was synthesized similar to compound 92 replacing 2- (tributylstannyl)pyridine with 4-fluoro-2-(tributylstannyl)pyridine.1H NMR (400 MHz, Methanol-d4) δ 8.46 (d, J = 4.8 Hz, 1H), 7.77 – 7.68 (m, 1H), 7.54 (dt, J = 8.5, 4.3 Hz, 1H), 3.82 (t, J = 6.1 Hz, 4H), 3.19 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.9 Hz, 2H), 2.11 (p, J = 7.7 Hz, 2H), 1.80 (s, 4H), 1.59 (p, J = 2.8 Hz, 4H). LCMS (ES) [M+1]+m / z 312.4. Example 1.011

[0277] Synthesis of 5-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2- oxa-5-azabicyclo[2.2.1]heptane (Compound 72).

[0278] Compound 72 was synthesized similar to compound 92 replacing azepane with 2-oxa-5-azabicyclo[2.2.1]heptane. LCMS (ES+): (M+H)+= 295.0.1H NMR (400 MHz, Chloroform-d) δ 8.85 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 7.89 – 7.79 (m, 1H), 7.39 (dd, J = 7.5, 4.9 Hz, 1H), 5.33 (s, 1H), 4.71 (s, 1H), 4.00 – 3.94 (m, 2H), 3.83 – 3.76 (m, 2H), 3.20 – 2.96 (m, 4H), 2.19 – 1.94 (m, 4H). Example 1.012

[0279] Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine (Compound 73)

[0280] Scheme 8 depicts a synthetic route for preparing an exemplary compound. [

[0282] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (204.00 mg; 1.08 mmol; 1.00 eq.) was dissolved in acetonitrile (4 ml).2-pyridinylmethanamine (0.15 mL; 1.40 mmol; 1.30 eq.) was added followed by N, N-diisopropylethylamine (0.28 mL; 1.62 mmol; 1.50 eq.) slowly. The reaction was stirred at 25oC for 18 h, then at 50oC for 6 h. The solvent was evaporated, and the residue was purified by silica gel chromatography (methanol / dichloromethane gradient) to give 2-chloro-N-(pyridin-2-ylmethyl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (277 mg, 98%) as a white solid..1H NMR (400 MHz, Chloroform-d) δ 8.58 (d, J = 5.2 Hz, 1H), 7.97 – 7.88 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.45 – 7.38 (m, 1H), 6.63 (s, 1H), 4.86 (d, J = 5.3 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.19 – 2.09 (m, 2H).

[0283] Step 2

[0284] 2-Chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (274.00 mg; 1.05 mmol; 1.00 eq.) was suspended in 1,4-dioxane (5 ml) and mixture was purged with argon.2-(Tributylstannyl)pyridine (0.74 mL; 2.10 mmol; 2.00 eq.) and then tetrakis(triphenylphosphane) palladium (121.44 mg; 0.11 mmol; 0.10 eq.) were added. The reaction vessel was sealed, and the contents stirred in a heat bath at 105oC for 16 h. Solvent was evaporated and the residue was purified by silica gel chromatography (methanol / dichloromethane gradient) to give 2-(pyridin-2-yl)-N-(pyridin-2-ylmethyl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (161 mg, 50%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 8.87 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.94 – 7.88 (m, 1H), 7.80 – 7.73 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.4, 4.9 Hz, 1H), 7.30 – 7.26 (m, 1H), 7.13 (s, 1H), 5.07 (d, J = 5.1 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.24 – 2.16 (m, 2H). MS (ES+): (M+H)+= 304.0.

[0285] Step 3

[0286] 2-(Pyridin-2-yl)-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- amine (0.16 g; 0.53 mmol; 1.00 eq.) was dissolved in DMF (10 ml) and cooled in an ice bath. Sodium hydride (42 mg; 1.05 mmol; 2.00 eq.) (60%) was added in two portions and the reaction was stirred for 45 m. Iodomethane (66 µL; 1.05 mmol; 2.00 eq.) was added slowly and the mixture was stirred for 1.5 h more. Water (20 ml) and ethyl acetate (100ml) were added, the phases were separated, and the aqueous phase was extracted with more ethyl acetate (3 x 75 ml) and 3:1 chloroform:isopropanol (50 ml). The combined organic phases were washed with some water (5 ml) and dried over sodium sulfate. After evaporation of solvent, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile / 0.1 % aqueous formic acid gradient). The purified fractions were treated with 1 M HCl and freeze-dried to give N- methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- amine hydrochloride (90 mg, 48%) as a white solid.1H NMR (400 MHz, Chloroform-d) δ 9.08 (d, J = 5.3 Hz, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.29 – 7.98 (m, 3H), 7.75 – 7.68 (m, 1H), 7.55 – 7.47 (m, 1H), 5.68 (s, 2H), 3.67 (s, 3H), 3.52 – 3.37 (m, 2H), 3.26 – 3.14 (m, 2H), 2.23 – 2.12 (m, 2H). MS (ES+): (M+H)+= 317.9. Example 1.013

[0287] Synthesis of N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)pyrimidin-4- yl]amino}acetamide (Compound 75).

[0288] Scheme 9 depicts a synthetic route for preparing an exemplary compound.Scheme 9

[0289] 2-{4-[(Carboxymethyl)(methyl)amino]-5H,6H,7H-cyclopenta[d]pyrimidin-2- yl}pyridin-1-ium chloride (Intermediate I) (150.00 mg; 0.35 mmol; 1.00 eq.) wassuspended in N,N-dimethylformamide (3.5 ml). N,N-Diisopropylethylamine (0.15 mL; 0.87 mmol; 2.50 eq.), 4-methoxyaniline (57.5 mg; 0.47 mmol; 1.35 eq.) and then 1- [bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 177.6 mg; 0.47 mmol; 1.35 eq.) were added. After 40 h, ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After evaporation of the solvents, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile / 0.1 % aqueous formic acid gradient) to give N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (formate salt, 46 mg, 34%) as a solid.1H NMR (400 MHz, Chloroform-d) δ 10.18 (s, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.04 – 7.93 (m, 1H), 7.56 – 7.46 (m, 3H), 6.76 (d, J = 8.6 Hz, 2H), 4.56 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 3.24 (t, J = 7.4 Hz, 2H), 2.99 (t, J = 7.9 Hz, 2H), 2.12 (p, J = 7.7 Hz, 2H). MS (ES+): (M+H)+= 390.1. Example 1.014

[0290] Synthesis of N-(3-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 74).

[0291] Compound 74 was synthesized similar to Compound 75 replacing 4- methoxyaniline with 3-fluoroaniline. LCMS (ES+): (M+H)+= 379.0.1H NMR (400 MHz, Chloroform-d) δ 10.80 (s, 1H), 9.10 – 8.96 (m, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.21 – 8.09 (m, 1H), 7.72 – 7.58 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.21 – 7.11 (m, 1H), 6.75 – 6.65 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J = 7.4 Hz, 2H), 2.97 (t, J = 7.9 Hz, 2H), 2.14 (p, J = 7.7 Hz, 2H). Example 1.015

[0292] Synthesis of 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]- 1,2,3,4-tetrahydroquinoline (Compound 76)

[0293] Scheme 10 depicts a synthetic route for preparing an exemplary compound. [

[0295] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100.00 mg; 0.53 mmol; 1.00 eq.) in AcCN (2 mL) was added 1,2,3,4- tetrahydroquinoline (73.98 mg; 0.56 mmol; 1.05 eq.) followed by Hunig's base (0.19 mL; 1.06 mmol; 2.00 eq.). The mixture was heated at 75 °C for 2 h, the mixture was cooled and concentrated, the residue was diluted with water, the resulting precipitate was collected by filtration, and dried under vacuum to give 1-{2-chloro-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}-1,2,3,4-tetrahydroquinoline (25 mg). LCMS (ES+): (M+H)+= 286.2, 288.2.

[0296] Step 2

[0297] To a solution of 1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-1,2,3,4- tetrahydroquinoline (25.00 mg; 0.09 mmol; 1.00 eq.) in toluene (1.5 mL) was added 2- (tributylstannyl)pyridine (48.31 mg; 0.13 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (10.11 mg; 0.01 mmol; 0.10 eq.). The mixture was degassed and heated at 110 °C for 15 h. The mixture was cooled and concentrated, diluted with AcCN and water, and subjected to purification by preparative HPLC to give 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline (36 mg).1H NMR (400 MHz, Methanol-d4) δ 8.73 – 8.67 (m, 1H), 8.42 (dt, J = 8.0, 1.2 Hz, 1H), 7.96 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 7.17 (q, J = 7.5 Hz, 2H), 7.03 (td, J = 7.5, 1.3 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.10 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H), 2.02 (dp, J = 36.1, 7.5, 7.0 Hz, 4H). LCMS (ES+): (M+H)+= 329.1. Example 1.016

[0298] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-phenylacetamide (Compound 77)

[0299] Compound 77 was synthesized similar to Compound 75 replacing 4- methoxyaniline with aniline. LC MS (ES+): (M+H)+= 360.0.1H NMR (400 MHz, Chloroform-d) δ 10.39 (s, 1H), 8.98 – 8.87 (m, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.08 – 7.96 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.59 – 7.51 (m, 1H), 7.25 – 7.17 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 4.61 (s, 2H), 3.52 (s, 3H), 3.26 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.9 Hz, 2H), 2.18 – 2.07 (m, 2H). Example 1.017

[0300] Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 78)

[0301] Compound 78 was synthesized similar to Compound 75 replacing 4- methoxyaniline with cyclohexanamine.1H NMR (400 MHz, Chloroform-d) δ 9.07 – 8.93 (m, 1H), 8.59 (d, J = 8.0 Hz, 1H), 8.12 – 8.01 (m, 1H), 7.83 – 7.64 (m, 1H), 7.59 (d, J = 6.7 Hz, 1H), 4.47 (s, 2H), 3.78 – 3.68 (m, 1H), 3.47 (s, 3H), 3.24 (t, J = 7.4 Hz, 2H), 3.00 (t, J = 7.9 Hz, 2H), 2.17 – 2.07 (m, 2H), 1.75 (d, J = 12.0 Hz, 2H), 1.65 – 1.58 (m, 2H), 1.56 – 1.49 (m, 1H), 1.28 – 1.06 (m, 5H). LCMS (ES+): (M+H)+= 366.0. Example 1.018

[0302] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-(oxan-4-yl)acetamide (Compound 79)

[0303] Compound 79 was synthesized similar to Compound 75 by replacing 4- methoxyaniline with 4-aminotetrahydropyran. LCMS (ES+): (M+H)+= 368.1.1H NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1H), 8.87 (d, J = 8.0 Hz, 1H), 8.81 – 8.73 (m, 1H), 8.45 – 8.35 (m, 1H), 7.92 – 7.84 (m, 1H), 4.76 (s, 2H), 3.93 – 3.84 (m, 3H), 3.58 (s, 3H), 3.40 – 3.30 (m, 4H), 2.96 (t, J = 7.9 Hz, 2H), 2.16 – 2.11 (m, 2H), 1.75 – 1.56 (m, 4H). Example 1.019

[0304] Synthesis of N-ethyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine (Compound 80)

[0305] Compound 80 was synthesized similar to Compound 73 by replacing 2- pyridinylmethanamine with 2-pyrimidinylmethylamine and replacing iodomethane with ethyl iodide. LCMS (ES+): (M+H)+= 333.0.1H NMR (400 MHz, Chloroform-d) δ 8.96 – 8.82 (m, 3H), 8.52 (d, J = 7.7 Hz, 1H), 8.18 – 8.09 (m, 1H), 7.75 – 7.68 (m, 1H), 7.55 (s, 1H), 5.43 (s, 2H), 4.01 (q, J = 7.1 Hz, 2H), 3.32 – 3.13 (m, 4H), 2.28 – 2.17 (m, 2H), 1.37 (t, J = 6.9 Hz, 3H). Example 1.020

[0306] Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 81)

[0307] Compound 81 was synthesized similar to Compound 73 by replacing 2- pyridinylmethanamine with 2-pyrimidinylmethylamine. LCMS (ES+): (M+H)+= 319.1.1H NMR (400 MHz, Chloroform-d) δ 8.78 – 8.69 (m, 3H), 8.33 (s, 1H), 8.18 (d, J = 8.0 Hz, 1H), 7.79 – 7.72 (m, 1H), 7.38 – 7.31 (m, 1H), 7.22 – 7.17 (m, 1H), 5.14 (s, 2H), 3.53 (s, 3H), 3.21 (t, J = 7.4 Hz, 2H), 3.15 – 3.10 (m, 2H), 2.13 – 2.07 (m, 2H). Example 1.021

[0308] Synthesis of N-[(1,3-benzoxazol-2-yl)methyl]-N-methyl-2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 82)

[0309] Compound 82 was synthesized similar to Compound 73 by replacing 2- pyridinylmethanamine with 1,3-benzoxazol-2-ylmethanamine. LCMS (ES+): (M+H)+= 358.0.1H NMR (400 MHz, Chloroform-d) δ 8.82 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 7.86 – 7.77 (m, 1H), 7.74 – 7.67 (m, 1H), 7.54 – 7.47 (m, 1H), 7.41 – 7.35 (m, 1H), 7.35 – 7.29 (m, 2H), 5.25 (s, 2H), 3.54 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 3.18 – 3.11 (m, 2H), 2.16 – 2.12 (m, 2H). Example 1.022

[0310] Synthesis of 3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]- 2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 83)

[0311] Compound 83 was synthesized similar to compound 92 by replacing azepane with 2,3,4,5-tetrahydro-1H-benzo[d]azepine. LCMS (ES+): (M+H)+= 343.0.1H NMR (400 MHz, Chloroform-d) δ 8.81 (d, J = 4.8 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 – 7.80 (m, 1H), 7.39 (dd, J = 7.5, 4.9 Hz, 1H), 7.15 (s, 4H), 6.10 (s, 2H), 4.08 – 3.99 (m, 4H), 3.15 – 3.02 (m, 8H), 2.19 – 2.08 (m, 2H). Example 1.023

[0312] Synthesis of N-(2-methoxyethyl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine (Compound 84)

[0313] Compound 84 was synthesized similar to compound 92 by replacing azepane with N-(2-methoxyethyl)-N-methylamine. LCMS (ES+): (M+H)+= 285.0.1H NMR (400 MHz, Chloroform-d) δ 8.81 (dd, J = 4.7, 2.0 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.34 (dd, J = 8.2, 1.5 Hz, 1H), 7.89 – 7.80 (m, 1H), 7.50 – 7.27 (m, 3H), 3.97 – 3.90 (m, 2H), 3.70 – 3.63 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 3.23 – 3.14 (m, 4H), 2.16 – 2.07 (m, 2H). Example 1.024

[0314] Synthesis of 1-methyl-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin- 4-yl]-1,4-diazepane (Compound 85)

[0315] Compound 85 was synthesized similar to compound 92 by replacing azepane with 1-methyl-1,4-diazepane. LCMS (ES+): (M+H)+= 310.1.1H NMR (400 MHz, Chloroform-d) δ 8.79 (d, J = 4.8 Hz, 1H), 8.29 – 8.21 (m, 1H), 7.86 – 7.76 (m, 1H), 7.40 – 7.34 (m, 1H), 4.36 – 4.22 (m, 2H), 3.98 (t, J = 6.7 Hz, 2H), 3.50 – 3.40 (m, 2H), 3.28 – 3.18 (m, 2H), 3.11 (t, J = 7.3 Hz, 2H), 3.03 (t, J = 7.8 Hz, 2H), 2.82 (s, 3H), 2.56 (s, 2H), 2.15 – 2.04 (m, 2H). Example 1.025

[0316] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-1-(morpholin-4-yl)ethan-1-one (Compound 86)

[0317] Compound 86 was synthesized similar to Compound 75 by replacing 4- methoxyaniline with morpholine. LCMS (ES+): (M+H)+= 354.0.1H NMR (400 MHz, Chloroform-d) δ 8.96 – 8.86 (m, 1H), 8.50 – 8.37 (m, 1H), 8.21 – 8.15 (m, 1H), 8.07 – 7.93 (m, 1H), 7.60 – 7.48 (m, 1H), 4.86 – 4.75 (m, 2H), 3.81 – 3.74 (m, 2H), 3.71 – 3.66 (m, 4H), 3.62 – 3.58 (m, 2H), 3.41 (s, 3H), 3.29 – 3.25 (m, 2H), 3.06 – 3.00 (m, 2H), 2.17 – 2.05 (m, 2H). Example 1.026

[0318] Synthesis of N-methyl-N-(2-phenoxyethyl)-2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine (Compound 87)

[0319] Compound 87 was synthesized similar to compound 92 by replacing azepane with N-methyl-N-(2-phenoxyethyl)amine. LCMS (ES+): (M+H)+= 285.0.1H NMR (400 MHz, Chloroform-d) δ 9.09 (d, J = 4.9 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.16 – 8.00 (m, 1H), 7.69 – 7.63 (m, 1H), 7.29 – 7.25 (m, 2H), 6.98 – 6.91 (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), 4.36 (s, 4H), 3.61 (s, 3H), 3.45 (t, J = 7.8 Hz, 2H), 3.29 (t, J = 7.3 Hz, 2H), 2.24 – 2.13 (m, 2H). Example 1.027

[0320] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-1-(piperidin-1-yl)ethan-1-one (Compound 88)

[0321] Compound 88 was synthesized similar to Compound 75 replacing 4- methoxyaniline with piperidine. LCMS (ES+): (M+H)+= 352.1.1H NMR (400 MHz, Chloroform-d) δ 9.03 (d, J = 5.1 Hz, 1H), 8.69 – 8.55 (m, 1H), 8.23 – 8.07 (m, 1H), 7.74 – 7.64 (m, 1H), 5.17 – 4.78 (m, 2H), 3.64 – 3.56 (m, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.44 (s, 3H), 3.33 – 3.20 (m, 4H), 2.20 – 2.10 (m, 2H), 1.73 – 1.62 (m, 4H), 1.57 – 1.49 (m, 2H). Example 1.028

[0322] Synthesis of N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 89).

[0323] Compound 89 was synthesized similar to Compound 75 by replacing 4- methoxyaniline with tert-butylamine.1H NMR (400 MHz, Chloroform-d) δ 9.33 – 9.18 (m, 1H), 8.87 (d, J = 7.7 Hz, 1H), 8.43 – 8.33 (m, 1H), 8.28 (s, 1H), 7.91 – 7.79 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 3.00 (t, J = 7.9 Hz, 2H), 2.17 – 2.07 (m, 2H), 1.27 (s, 9H). MS (ES+): (M+H)+= 340.0. Example 1.029

[0324] Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 91)[

[0326] 2-{[(Tert-butoxy)carbonyl](methyl)amino}propanoic acid (500 mg; 2.5 mmol; 1 eq.) was dissolved in DMF (6 ml). N, N-diisopropylethylamine (1.1 mL; 6.15 mmol; 2.5 eq.) and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxid hexafluorophosphate (HATU, 1262 mg; 3.3 mmol; 1.35 eq.) were added. Cyclohexanamine (0.38 mL; 3.3 mmol; 1.35 eq.) was added and the reaction mixture was stirred at 25oC. After 14 h, the reaction was diluted with ethyl acetate (50 ml), water (15 ml) and sodium bicarbonate solution (30 ml). The phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). the combined organics were washed with sodium chloride solution (50 ml) and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexanes gradient) to give tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g, 68%) as white crystals. LCMS (ES+): (M+H)+= 285.0.

[0327] Step 2

[0328] Tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g; 1.7 mmol; 1 eq.) was dissolved in dichloromethane (12 ml) and cooled in an ice bath. Trifluoroacetic acid (6 mL) was added slowly and the reaction was stirred at 20 °C. After 1.6 h, the reaction was evaporated to a residue and then co-evaporated from toluene (40 ml). The crude product of N-cyclohexyl-2-(methylamino)propanamide; trifluoroacetic acid salt was used directly in the next step.

[0329] Step 3

[0330] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg; 0.79 mmol; 1 eq.) was dissolved in acetonitrile (3 ml) containing N-cyclohexyl-2- (methylamino)propenamide trifluoroacetic acid salt (355 mg; 1.19 mmol; 1.5 eq.). N,N- diisopropylethylamine (0.55 mL; 3.2 mmol; 4 eq.) was added and the reaction was stirred at 50oC for 14 h, then at 60oC for 6 h, and to 30oC over 18 h. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexanes gradient) to give 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N- cyclohexylpropanamide (174 mg, 65%) as a film. LCMS (ES+): (M+H)+= 337.2.

[0331] Step 4

[0332] 2-({2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N- cyclohexylpropanamide (174 mg; 0.52 mmol; 1 eq.) was dissolved in 1,4-dioxane (4 ml). and the solution was purged with Ar gas.2-(Tributylstannyl)pyridine (0.39 mL; 1.03 mmol; 2 eq.) was added followed by tetrakis(triphenylphosphane) palladium (60 mg; 0.05 mmol; 0.1 eq.) The reaction vessel was sealed and stirred in a heat bath at 110oC for 15 h. After evaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile / 0.1 % aqueous formic acid gradient) to give N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}propenamide (86 mg, 43%) as an off-white solid. LCMS (ES+): (M+H)+= 380.0.1H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.96 – 7.84 (m, 1H), 7.53 – 7.42 (m, 1H), 5.16 (q, J = 7.0 Hz, 1H), 3.63 – 3.49 (m, 1H), 3.25 – 3.16 (m, 1H), 3.14 – 3.06 (m, 4H), 2.93 – 2.76 (m, 2H), 1.74 (s, 1H), 1.65 (s, 1H), 1.59 – 1.44 (m, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.25 – 1.12 (m, 3H), 1.07 – 0.93 (m, 2H). Example 1.030

[0333] Synthesis of N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 90)

[0334] Compound 90 was synthesized similar to Compound 91 by replacing cyclohexanamine with tert-butylamine. LCMS (ES+): (M+H)+= 354.4.1H NMR (400 MHz, DMSO-d6) δ 8.80 – 8.74 (m, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.09 – 8.01 (m, 1H),7.81 (s, 1H), 7.66 – 7.59 (m, 1H), 5.14 (q, J = 7.0 Hz, 1H), 3.26 (s, 3H), 3.24 – 3.10 (m, 2H), 3.05 – 2.88 (m, 2H), 2.15 – 1.97 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.21 (s, 9H). Example 1.031

[0335] Synthesis of 10-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-10- azatricyclo[6.3.1.0^{2,7}]dodeca-2,4,6-triene (Compound 1)

[0336] Compound 1 was synthesized similar to compound 92 by replacing azepane with 10-azatricyclo[6.3.1.0²,7]dodeca-2(7),3,5-triene. LCMS (ES+): (M+H)+= 355.0.1H NMR (400 MHz, Chloroform-d) δ 8.66 (s, 1H), 8.45 – 8.12 (m, 1H), 7.71 (s, 1H), 7.26 – 6.87 (m, 5H), 4.46 – 4.19 (m, 2H), 3.52 – 3.10 (m, 4H), 2.99 – 2.74 (m, 4H), 2.34 (s, 1H), 2.01 – 1.76 (m, 3H). Example 1.032

[0337] Synthesis of 7-methoxy-3-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 2)

[0338] Compound 2 was synthesized similar to compound 92 by replacing azepane with 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. LCMS (ES+): (M+H)+= 373.11H NMR (400 MHz, Chloroform-d) δ 8.90 – 8.70 (m, 1H), 8.40 (d, J = 7.1 Hz, 2H), 7.90 – 7.76 (m, 1H), 7.43 – 7.31 (m, 1H), 7.07 (d, J = 8.2 Hz, 1H), 6.77 – 6.60 (m, 2H), 4.10 –3.91 (m, 4H), 3.79 (s, 3H), 3.15 – 2.91 (m, 8H), 2.19 – 2.07 (m, 2H). Example 1.033

[0339] Synthesis of 6-methoxy-3-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydro-1H-3-benzazepine (Compound 3)

[0340] Compound 3 was synthesized similar to compound 92 by replacing azepane with 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine. LCMS (ES+): (M+H)+= 373.0.1H NMR (400 MHz, Chloroform-d) δ 8.81 (dd, J = 4.8, 1.8 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.86 – 7.77 (m, 1H), 7.39 – 7.31 (m, 1H), 7.14 – 7.07 (m, 1H), 6.79 – 6.74 (m, 2H), 4.00 (dt, J = 25.4, 4.9 Hz, 4H), 3.81 (s, 3H), 3.17 – 3.03 (m, 8H), 2.15 – 2.06 (m, 2H). Example 1.0030

[0341] Synthesis of 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (Compound 4)

[0342] Scheme 11 depicts a synthetic route for preparing an exemplary compound.[

[0344] Tert-butyl 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4- diazepane-1-carboxylate (200 mg; 0.51 mmol; 1 eq.) was dissolved in dichloromethane (5 ml). Trifluoroacetic acid (2.5 mL) was added slowly and the reaction was stirred at 25oC. After 1 h, the reaction was evaporated to dryness and the residue was co-evaporated with toluene. LCMS (ES+): (M+H)+= 296.

[0345] Step 2

[0346] 1-[2-(Pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (108 mg; 0.37 mmol; 1.15 eq.) and 1-iodo-3-methoxybenzene (75 mg; 0.32 mmol; 1 eq.) were mixed with 1,4-dioxane (1 ml) and tert-butanol (0.5 ml). The mixture was purged with Ar gas.2-[2-(Dicyclohexylphosphanyl)phenyl]-N,N-dimethylaniline (25 mg; 0.06mmol; 0.20 eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg; 0.02 mmol; 0.05 eq.) and sodium tert-butoxide (46 mg; 0.48 mmol; 1.50 eq.) were added and the reaction vessel was sealed and stirred at 100oC. After 19 h, additional portions of reagents (iodide, ligand, palladium catalyst and base) were added to drive product formation. The reaction mixture was then filtered, concentrated and purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-50% acetonitrile / 0.1 % aqueous formic acid gradient) to give 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (19 mg, 15%) as a yellow solid.

[0347] MS (ES+): (M+H)+= 402.1.1H NMR (400 MHz, Chloroform-d) δ 8.94 – 8.87 (m, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.02 – 7.92 (m, 1H), 7.62 – 7.53 (m, 1H), 7.19 – 7.10 (m, 1H), 6.41 (d, J = 8.3 Hz, 1H), 6.35 – 6.28 (m, 2H), 4.30 – 4.22 (m, 2H), 3.92 – 3.86 (m, 2H), 3.81 – 3.76 (m, 5H), 3.64 (t, J = 6.2 Hz, 2H), 3.36 (t, J = 8.0 Hz, 2H), 3.18 (t, J = 7.4 Hz, 2H), 2.27 – 2.15 (m, 4H). Example 1.034

[0348] Synthesis of N-(pyridin-2-yl)-2-{[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 5)

[0349] Scheme 12 depicts a synthetic route for preparing an exemplary compound.[

[0351] Into a 50-mL 3-necked round-bottom flask, was placed [(tert- butoxycarbonyl)amino]acetic acid (2.0 g, 11.42 mmol, 1.0 equiv), DMF (20.0 mL), 2- aminopyridine (1.29 g, 13.71 mmol, 1.2 equiv) and DIPEA (3.69 g, 28.54 mmol, 2.5 equiv). This was followed by the addition of HATU (5.21 g, 13.70 mmol, 1.2 equiv) in several batches at 0oC. The reaction solution was stirred for 2 h at room temperature. The reaction was then quenched by the addition of 50 mL of H2O, filtered and the collected solid was dried under infrared lamp.2.4 g (84% yield) of tert-butyl N-[[(pyridin-2- yl)carbamoyl]methyl]carbamate was obtained as white solid. LCMS (ES) [M+1]+m / z: 252.

[0352] Step 2

[0353] Into a 50-mL round-bottom flask, was placed tert-butyl N-[[(pyridin-2- yl)carbamoyl]methyl]carbamate (2.40 g, 9.55 mmol, 1.0 equiv) and DCM (20.0 mL). Tothe above mixture was added HCl (g) (2 M in EA) (19.0 mL) at 0oC. The mixture was stirred for 2 h at room temperature. The mixture was concentrated to remove the solvent, 1.4 g (78% yield) of 2-amino-N-(pyridin-2-yl)acetamide hydrochloride was obtained as white solid. LCMS (ES) [M-HCl+1]+m / z: 152.

[0354] Step 3

[0355] Into a 100-mL round-bottom flask, was placed 2-amino-N-(pyridin-2- yl)acetamide hydrochloride (1.40 g, 7.46 mmol, 1.0 equiv), NMP (30.0 mL), 2,4- dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (1.30 g, 6.88 mmol, 0.9 equiv), DIEA (2.70 g, 20.89 mmol, 2.80 equiv). The mixture was stirred for 12 h at 60oC in an oil bath. After being cooled to room temperature, the reaction was diluted with H2O (50 mL) and extracted with 3x40 mL of ethyl acetate. The combined organic phase was washed with 3 x40 ml of brine, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate / petroleum ether (1:2).320 mg (14% yield) of 2-([2-chloro-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide was obtained as a white solid. LCMS (ES) [M+1]+m / z: 304.

[0356] Step 4

[0357] Into a 50-mL round-bottom flask, was placed 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide (320 mg, 1.05 mmol, 1.0 equiv), dioxane (20.0 mL), 2-(tributylstannyl)pyridine (465 mg, 1.26 mmol, 1.2 equiv), and Pd(dppf)Cl2 (86 mg, 0.11 mmol, 0.1 equiv). The mixture was stirred for 12 h at 110oC in an oil bath under N2atmosphere. The reaction mixture was cooled to room temperature and concentrated to remove the solvent. The residue was purified by silica gel column with ethyl acetate / petroleum ether (3:1). The crude product was further purified by Flash-Prep-HPLC with the following conditions: Column: HPH C18, 50*3.0 mm, 2.6 um, Mobile Phase A: Water / 0.05% NH3.H2O, Mobile Phase B: CH3CN, Flow rate: 1.2 mL / min, Gradient: 5% B to 100% B within 1.1 min, hold 0.7 min.78.9 mg (22% yield) of N-(pyridin-2-yl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino]acetamide was obtained as off-white solid.1H-NMR (300 MHz, DMSO-d6, ppm): δ 10.60 (s, 1H), 8.61 (d, J = 4.6 Hz, 1H), 8.33 (dd, J = 4.9, 1.1 Hz, 1H) 8.23 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78-7.69 (m, 2H), 7.40-7.35 (m, 2H), 7.09 (ddd, J = 7.3, 4.8, 1.0 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.09 (p, J = 7.5 Hz, 2H). LCMS: (ES, m / z): [M+H]+: 347.1. Example 1.035

[0358] Synthesis of N-(2-fluorophenyl)-2-{[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 6)

[0359] Scheme 13 depicts a synthetic route for preparing an exemplary compound.Scheme 13

[0360] Into a 50-mL round-bottom flask, was placed [[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), 2-fluoroaniline (98 mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU (337 mg, 0.88 mmol, 1.5 equiv). The resulting solution was stirred for 2 h at room temperature. The reaction solution was diluted with 5 mL of CH3CN and filtered. The filtrate was purified by Prep-HPLC with the following conditions (SHIMADZU (HPLC-01)): Column, Welch Xtimate C18, 21.2*250 mm, 5um, mobile phase, Water (10 mmol / L NH4HCO3) and MeOH: CH3CN=1:1 (25% Phase B up to 65% in 15 min), Detector, UV, 254 nm. This provided 117.3 mg of N-(2-fluorophenyl)-2-[[2- (pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as light yellow solid.1H NMR (300 MHz, DMSO-d6) δ 10.03 (br, 1H), 8.63-8.61 (m, 1H), 8.31-8.28 (m, 1H), 7.88-7.75 (m, 2H), 7.50-7.37 (m, 2H), 7.29-7.18 (m, 1H), 7.18-7.08 (m, 2H), 4.28 (d, J = 5.4 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.14-2.04 (m, 2H). LCMS (ES)[M+1]+m / z: 364.1. Example 1.036

[0361] Synthesis of 2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}-N-(quinolin-7-yl)acetamide (Compound 7)

[0362] Scheme 14 depicts a synthetic route for preparing an exemplary compound.Scheme 14

[0363] Into a 50-mL round-bottom flask at 0oC was placed [[2-(pyridin-2-yl)- 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), quinolin-7-amine (128 mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU (337 mg, 0.88 mmol, 1.5 equiv). After addition, the mixture was stirred for 2 h at room temperature. The reaction solution was diluted with 5 mL of CH3CN and filtered. The filtrate was purified by Prep-HPLC with the following conditions: Column, Welch Xtimate C18, 21.2*250 mm, 5 um, mobile phase, Water (10 mmol / L NH4HCO3) and MeOH: CH3CN=1:1 (25% Phase B up to 70% in 15 min); Detector, UV 254 nm. This provided 118.0 mg (50%) of 2-((2-(pyridin-2-yl)-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)-N-(quinolin-7-yl)acetamide was obtained as grey solid.1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.82 (dd, J = 4.2, 1.8 Hz, 1H), 8.64-8.61 (m, 1H), 8.43 (d, J = 1.8 Hz, 1H), 8.29-8.25 (m, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.81-7.69 (m, 2H), 7.54-7.50 (m, 1H), 7.43-7.36 (m, 2H), 4.30 (d, J = 5.7 Hz, 2H), 2.90-2.76 (m, 4H), 2.15-2.05 (m, 2H). LCMS: (ES, m / z): [M+1]+m / z: 397.1. Example 1.037

[0364] Synthesis of N-tert-butyl-2-{[2-(pyrimidin-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 8)

[0365] Scheme 15 depicts a synthetic route for preparing an exemplary compound.Scheme 15

[0366] Into a 10-mL sealed tube purged and maintained in an inert atmosphere of nitrogen, was placed N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino)acetamide (0.30 g, 1.06 mmol, 1.00 equiv), dioxane (10 mL), 4- (tributylstannyl)pyrimidine (0.47 g, 1.27 mmol, 1.20 equiv), and Pd(dppf)Cl2.CH2Cl2 (0.17 g, 0.20 equiv). The resulting solution was stirred overnight at 130 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with MeOH / EA (1:9). The crude product was purified by Prep-HPLC with the following conditions: Column, welch X-timate C18,21.2*250mm, 5um; mobile phase; phase A water(10mmol / L NH4HCO3), phase B CH3CN / MeOH(1:1) (15% B up to 60% in 15min); Detector, 220nm. This resulted in 57.7 mg (16.7%) of N-tert-butyl-2-[[2-(pyrimidin-4- yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as a white solid.1H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.28 (s, 1H), 8.93 (d, J=5.1 Hz), 8.32 (d, J=5.1 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J = 6.0 Hz, 1H), 3.97 (d, J = 5.7 Hz, 2H), 2.87 (q, J=7.8 Hz, 2H), 2.76 (q, J=7.2 Hz, 2H), 2.13-2.06 (m, 2H),1.24 (s, 9H). LCMS: (ES, m / z): [M+H]+: 327.2. Example 1.038

[0367] Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide (Compound 9)

[0368] Scheme 16 depicts a synthetic route for preparing an exemplary compound. [

[0370] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (1272.53 mg, 3.46 mmol, 1.30 equiv), dioxane (10.00 mL), and Pd(PPh3)4 (307.25 mg, 0.26 mmol, 0.10 equiv). The resulting solution was stirred overnight at 110oC. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH3.H2O) and CAN (50% Phase B up to 80% in 11 min); Detector, 254. This resulted in 350 mg (57.06%) of 2-[4-chloro-5H,6H,7H- cyclopenta[b]pyridin-2-yl]pyridine as white solid. LCMS (ES) [M+H]+ m / z: 231.

[0371] Step 2

[0372] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen was placed 2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (160.00 mg, 0.69 mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (99.32 mg, 0.76 mmol, 1.10 equiv), Pd(OAc)2 (15.57 mg, 0.069 mmol, 0.10 equiv), Cs2CO3 (451.94 mg, 1.38 mmol, 2.00 equiv), BINAP (86.37 mg, 0.14 mmol, 0.20 equiv), dioxane (10.00 mL). The resulting solution was stirred for overnight at 100oC. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (300 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 167.7 mg (74.53%) of N-tert-butyl-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamide as off-white solid.1HNMR (300 MHz, DMSO-d6) δ 8.59 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.30 (dt, J = 8.0, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.66 (s, 1H), 7.41-7.30 (m, 2H), 6.00 (t, J = 5.7 Hz, 1H), 3.77 (d, J = 5.7 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.12-2.02 (m, 2H), 1.27 (s, 9H). LCMS (ES, m / z): [M+H] +: 325.1. Example 1.039

[0373] Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4- yl]amino}acetamide (Compound 10)

[0374] Scheme 17 depicts a synthetic route for preparing an exemplary compound.

[0376] Into a 40-mL vial, was placed 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.00 g, 4.92 mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (0.71 g, 5.47 mmol, 1.11 equiv), DIEA (1.27 g, 9.85 mmol, 2.00 equiv), and CH3CN (10.00 mL). The resulting solution was stirred overnight at 80oC. The reaction mixture was cooled to room temperature. The crude product (2 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH3.H2O) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. This resulted in 1.1 g (75.26%) of N-tert-butyl-2-[(2-chloro-5,6,7,8- tetrahydroquinazolin-4-yl)amino]acetamide as a white solid. LCMS (ES) [M+H]+ m / z:297.

[0377] Step 2

[0378] Into a 40-mL vial purged and maintained with an inert atmosphere of nitrogen, was placed N-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4- yl)amino]acetamide (500.00 mg, 1.68 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (806.26 mg, 2.19 mmol, 1.30 equiv), dioxane (10.00 mL) and Pd(dppf)Cl2 (123.26 mg, 0.17 mmol, 0.10 equiv). The resulting solution was stirred for overnight at 110oC. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (800 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 139.2 mg (24.34%) of N-tert-butyl-2-[[2-(pyridin-2-yl)-5,6,7,8- tetrahydroquinazolin-4-yl]amino]acetamide as white solid.1H-NMR (300 MHz, DMSO- d6) δ8.65 (ddd, J = 4.8, 1.8, 0.9 Hz, 1H), 8.33 (dt, J = 8.0, 1.1 Hz, 1H), 7.87 (td, J = 7.7, 1.8 Hz, 1H), 7.71 (s, 1H), 7.45-7.40 (m, 1H), 6.88 (t, J = 5.6 Hz, 1H), 3.95 (d, J = 5.6 Hz, 2H), 2.73-2.63 (m, 2H), 2.46-2.38 (m, 2H), 1.81-1.78 (m, 4H), 1.24 (s, 9H). LCMS (ES, m / z): [M+H]+: 340.1 Example 1.040

[0379] Synthesis of N-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]piperidin-3-amine (Compound 11)

[0381] 1-Bromo-4-methoxybenzene (0.25 g; 1.34 mmol; 1 eq.) and tert-butyl 3- amino-1-piperidinecarboxylate (0.32 g; 1.6 mmol; 1.2 eq.) were dissolved in 1,4-dioxane (5 ml) and tert-butanol (2.5 ml). The solution was purged with Ar gas, and sodium tert- butoxide (0.26 g; 2.67 mmol; 2 eq.), 2-[2-(dicyclohexylphosphanyl)phenyl]-N,N- dimethylaniline (52.6 mg; 0.13 mmol; 0.1 eq.) and tris(dibenzylideneacetone)dipalladium(0) (61.2 mg; 0.07 mmol; 0.05 eq.) were added. The sealed reaction vessel was stirred...

Claims

THAT WHICH IS CLAIMED:

1. A method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3 alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C10 alkoxy, hydroxy-C1-C10-alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-alkyl)- NRGIRHI, -S-C1-C3alkyl, -S-C1-C3alkyl-NRG1RH1, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10alkoxy or -O-(C1-C6alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3alkoxy;Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NRG1RH1, or -NRGRH; Rccis C1-C3alkyl; and Rddis C1-C3 alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3 alkyl; wherein, RGais C1-C3 alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6- membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1- C3alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1-C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6- membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, halo-C1-C3alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1- C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10 aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3alkyl)-T, 5- to 7-membered heterocyclyl, hydroxy, amino, cyano, and halogen; T is selected from the group consisting of C6-C10 monocyclic or fused bicyclic aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7- membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl isoptionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of hydrogen, C1-C10alkyl, hydroxy-(C1- C6 alkyl), C1-C3 alkoxy-C1-C6 alkyl, halo-C1-C3 alkyl, -C1-C6 alkyl-NRJ1RJ2, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)- C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, RJ1and RJ2are independently hydrogen or C1-C3 alkyl; r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10aryl, C6-C10 aryl-C1-C3 alkyl, and C3-C10 cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7 cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, and hydroxy; R4bis hydrogen or C1-C6alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6alkyl, halo-C1-C3alkyl, halogen, C1-C3 alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1- C6alkoxy-C1-C3alkyl, C3-C7cycloalkyl, and C1-C6alkyl;or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, and C1-C3alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1- C3 alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6 alkyl), (4- to 10-membered heterocyclyl)-C1-C3 alkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, phenyl, −C(=O)−C1-C6alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3alkyl, and Rwis C6-C10aryl or C3-C7cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7cycloalkyl, and C6-C10aryl.

2. A method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin,increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I’:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; Ring, whereinindicates the point of attachment to the remainder of the molecule; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, halo-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C10alkoxy, hydroxy-C1-C10-alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-alkyl)- NRGIRHI, -S-C1-C3alkyl, -S-C1-C3alkyl-NRG1RH1, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10 alkoxy or -O-(C1-C6 alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3alkoxy; Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NRG1RH1, or -NRGRH;Rccis C1-C3alkyl; and Rddis C1-C3 alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkyl; and, RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3 alkyl; wherein, RGais C1-C3alkyl or hydrogen; or, two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6- membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R6, N-R6, and C-R6, provided that 1 or 2 of Y1, Y2, Y3, and Y4can be N, N-R6, NH, O, SH or S-R6; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1- C3alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1- C3 alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A;wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6- membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl; wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, halo-C1-C3alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, 4- to 10-membered heterocyclyl, C1-C3alkyl-sulfonyl-C1-C3alkyl, COOH-(C1-C6alkyl), cyano-(C1- C6 alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3 alkyl, and hydroxy-(C1-C6 alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3alkyl, said C3-C10cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of C6-C10aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3alkyl)-T, 5- to 7-membered heterocyclyl, hydroxy, amino, cyano, and halogen; T is selected from the group consisting of C6-C10 monocyclic or fused bicyclic aryl, C3-C7cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7- membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5;R4ais selected from the group consisting of hydrogen, C1-C10alkyl, hydroxy-(C1- C6 alkyl), C1-C3 alkoxy-C1-C6 alkyl, halo-C1-C3 alkyl, -C1-C6 alkyl-NRJ1RJ2, C3-C10 cycloalkyl, 4- to 10-membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)- C1-C3alkyl, (C6-C10aryl)-C1-C3alkyl, (5- to 10-membered heterocyclyl)-C1-C3alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10-membered heteroaryl; wherein, RJ1and RJ2are independently hydrogen or C1-C3 alkyl; r is 0, 1, 2, 3, 4, or 5; Rjis selected from the group consisting of hydrogen, C1-C3 alkyl, C6-C10 aryl, C6-C10 aryl-C1-C3 alkyl, and C3-C10 cycloalkyl; wherein said C3-C10cycloalkyl, 5- to 10-membered heterocyclyl, C6-C10aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C6 alkyl, halo-C1-C3 alkoxy, C3-C7 cycloalkyl, hydroxy, C1-C6alkoxy, cyano, nitro, phenyl, and 5- to 10-membered heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6alkyl; or, R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 10-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6alkyl, halo-C1-C3alkyl, halogen, C1-C3 alkoxy, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1- C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, andC1-C3alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1- C3 alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to 12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3alkyl, (5- to 10-membered heteroaryl)-C1-C3alkyl, phenyl, −C(=O)−C1-C6alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3 alkoxy, and hydroxy; Rqis hydrogen or C1-C3alkyl, and Rwis C6-C10aryl or C3-C7cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7cycloalkyl, and C6-C10aryl.

3. The method of claim 2, wherein the disease is related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload.

4. The method of claim 2, wherein the disease is related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin.

5. The method of claim 4, wherein the disease is hemochromatosis.

6. The method of claim 3, wherein the disease is related to or caused by a hemoglobinopathy.

7. The method of claim 6, wherein the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease.

8. The method of claim 7, wherein the disease is sickle cell disease.

9. The method of claim 8, wherein the sickle cell disease is sickle cell anemia.

10. The method of claim 2, 3, 4, 5, 6, 7, 8, or 9, wherein the treating comprises inhibiting iron transport mediated by ferroportin in the subject.

11. The method of any one of the preceding claims, wherein the compound is a compound of Formula I:or a pharmaceutically acceptable salt thereof; wherein, Z is N or CR5; R5is hydrogen, halogen, or C1-C3alkyl; R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C10alkoxy, hydroxy-C1-C10-alkyl, cyano, -NRGRH, halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-Rbb, -O-Rbb, -(C1-C6 alkyl)- NRGIRHI, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NRG1RH1, halo-C1-C3 alkyl, -O-Rcc-O-Rdd, 5- to 7- membered monocyclic heteroaryl, and C3-C6cycloalkyl; wherein, the alkyl moiety in hydroxy-C1-C10 alkoxy or -O-(C1-C6 alkyl)-Rbbis optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; Rbbis 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7cycloalkyl, 5- or 6- membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NRG1RH1, or -NRGRH; Rccis C1-C3 alkyl; and Rddis C1-C3alkyl or a 6-membered heteroaryl; wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R6, Rbb, or Rddis optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, C1-C3 alkoxy, and C1-C3 alkyl; RG1and RH1are each independently hydrogen or C1-C3alkyl; and RGand RHare each independently hydrogen, -C(O)RGa, or optionally deuterated C1-C3 alkyl; wherein, RGais C1-C3alkyl or hydrogen; or two R6groups, taken together with the atom to which each is attached, form a 5 or 6- membered heterocyclyl, C3-C7 cycloalkyl, C6-C10 aryl, or 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y1, Y2, Y3, and Y4are each independently selected from the group consisting of CH, N, NH, O, S, and C-R6, wherein, 1 or 2 of Y1, Y2, Y3, and Y4can be N, NH, O, or S; f is 0 or 1; R1is selected from the group consisting of hydrogen, C1-C6alkyl, halo-C1-C6alkyl, C1- C3 alkoxy, and hydroxy; R2is selected from the group consisting of hydrogen, C1-C6 alkyl, halo-C1-C6 alkyl, C1- C3alkoxy, and hydroxy; or, R1and R2taken together with the atom to which each is attached form ring A; wherein ring A is selected from the group consisting of C5-C6cycloalkyl, 5- or 6- membered heterocyclyl, phenyl, and 5- or 6-membered heteroaryl;wherein ring A is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, phenyl, halogen, C1-C3 alkoxy, cyano, and 5- or 6-membered heteroaryl; R3is selected from the group consisting of hydrogen, optionally deuterated C1-C3alkyl, hydroxy-C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, cyclopropyl, and phenyl; R4is selected from the group consisting ofcycloalkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (5- to 10-membered heterocyclyl)-C1-C3 alkyl, 4- to 10-membered heterocyclyl, C1-C3 alkyl-sulfonyl-C1-C3 alkyl, COOH-(C1-C6 alkyl), cyano-(C1- C6alkyl), hydroxy-(C1-C3-alkoxy)-C1-C3alkyl, and hydroxy-(C1-C6alkyl); wherein said heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl, said heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, said C3-C10 cycloalkyl, or said 4- to 10-membered heterocyclyl is optionally with one or two substituents, each independently selected from the group consisting of hydroxy, phenyl, amino, cyano, and halogen; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, and hydroxy; g is 0, 1, 2, 3, 4, or 5; R4ais selected from the group consisting of C1-C6alkyl, hydroxy-(C1-C6alkyl), C1-C3 alkoxy-C1-C6 alkyl, C3-C10 cycloalkyl, 5- to 7-membered heterocyclyl, C6-C10 aryl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, (C6-C10 aryl)-C1-C3 alkyl, (5- to 10- membered heterocyclyl)-C1-C3alkyl, -(CH2)rC(=O)Rj, -(CH2)rC(=O)NHRj, and 5- to 10- membered heteroaryl; wherein, r is 0, 1, 2, 3, 4, or 5;Rjis selected from the group consisting of hydrogen, C1-C3alkyl, C6-C10aryl, C6-C10 aryl-C1-C3 alkyl, and C3-C10 cycloalkyl; wherein said C3-C10 cycloalkyl, 5- to 7-membered heterocyclyl, C6-C10 aryl, 5- to 10-membered heteroaryl, 5- to 10-membered heteroaryl in said (5- to 10-membered heteroaryl)-C1-C3 alkyl, C6-C10 aryl in said (C6-C10 aryl)-C1-C3 alkyl, or 5- to 10-membered heterocyclyl in said (5- to 10-membered heterocyclyl)-C1-C3alkyl of R4ais optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C6 alkyl, halogen, halo-C1-C3 alkyl, C3-C7 cycloalkyl, hydroxy, C1-C6 alkoxy, cyano, nitro, phenyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclyl; and wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, and hydroxy; R4bis hydrogen or C1-C6 alkyl; or, R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl optionally substituted with one or two substituents each independently selected from C1-C6 alkyl, halogen, and hydroxy; R4cand R4dare each independently selected from the group consisting of hydrogen, C1-C3alkoxy, hydroxy, C1-C3alkyl-thio-C1-C3alkyl, hydroxy-C1-C6alkyl, C1- C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl, and C1-C6 alkyl; or, R4band R4ctaken together with the atom to which each is attached form a 4- to 7- membered heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, and C1-C3 alkyl; or, R4cand R4dtaken together with the atom to which each is attached form a C3-C5 cycloalkyl; R4eis selected from the group consisting of hydrogen, hydroxy, halogen, and C1- C3alkyl; or R3and R4taken together with the nitrogen atom to which each is attached form a 4- to12-membered heterocyclyl; wherein said heterocyclyl (formed by NR3R4) is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6 alkyl, hydroxy, hydroxy-(C1-C6alkyl), (4- to 10-membered heterocyclyl)-C1-C3alkyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, phenyl, −C(=O)−C1-C6 alkyl, -NHC(=O)-(5- to 10-membered heteroaryl), cyano, halogen, C1-C3 alkoxy, NRqRw, -(CH2)sC(=O)NRkRl, and 5- to 10-membered heteroaryl; wherein said phenyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, C1-C3alkoxy, and hydroxy; Rqis hydrogen or C1-C3alkyl, and Rwis C6-C10aryl or C3-C7cycloalkyl; wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3alkyl, hydroxy, and C1-C3alkoxy; s is 0, 1, 2, or 3; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, hydroxy, C1-C3alkyl, C3-C7 cycloalkyl, and C6-C10 aryl.

12. The method of any one of the preceding claims, wherein R1and R2are each independently selected from the group consisting of hydrogen, -CF3, methyl, and ethyl.

13. The method of any one of claims 1-11, wherein R1and R2taken together with the atom to which each is attached form ring A.

14. The method of claim 13, wherein the compound is of Formula IA:wherein, ring A is a 5- or 6-membered cycloalkyl, or 5- or 6-membered heteroaryl, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C6alkyl, phenyl, halogen, alkoxy, cyano, and 5- or 6-membered heteroaryl.

15. The method of claim 14, wherein the compound is of Formula IB:wherein, Rx, independently in each instance, is halogen, C1-C6 alkyl, C1-C6 alkoxy, or cyano; p is 1 or 2; and m is 0, 1, or 2.

16. The method of claim 15, wherein p is 1.

17. The method of claim 15, wherein m is 0.

18. The method of claim 14, wherein the compound is of Formula IC or IC’:wherein, RA1and RA2are each independently selected from the group consisting of hydrogen, C1-C3alkyl, phenyl, halogen, and 5- or 6-membered heteroaryl.

19. The method of claim 18, wherein RA1and RA2are each independently C1-C3 alkyl, hydrogen, or phenyl.

20. The method of claim 19, wherein RA1and RA2are each methyl.

21. The method of claim 19, wherein RA1is phenyl and RA2is methyl or hydrogen.

22. The method of any one of the preceding claims, wherein Z is N.

23. The method of any one of the preceding claims, wherein f is 1.

24. The method of any one of the preceding claims, wherein 0 to 3 of Y1, Y2, Y3, and Y4are each C-R6and the other(s) of Y1, Y2, Y3, and Y4is / are CH.

25. The method of any one of claims 1-22, wherein Y3is N and Y1, Y2, and Y4are each CH or C-R6.

26. The method of any one of claims 1-22, wherein Y2is N and Y1, Y3, Y4are each CH or C- R6.

27. The method of any one of claims 1-22, wherein Y1is N and Y2, Y3, and Y4are each CH or C-R6.

28. The method of any one of the preceding claims, wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3alkoxy, C1-C3alkyl, C1-C3alkoxy-C1-C3alkyl, hydroxy-C1-C3 alkoxy, hydroxy-C1-C3-alkyl, and NRGRH; wherein RGand RHare each independently hydrogen or C1-C3 alkyl.

29. The method of claim 28, wherein R6, in each instance, is selected from the group consisting of methoxy, methyl, fluoro, chloro, ethyl, N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, and -CH2CH2OH.

30. The method of claim 29, wherein R6, in each instance, is methoxy or methyl.

31. The method of any one of claims 1-27, wherein two R6groups, taken together with the atom to which each is attached, form a 5 or 6-membered heterocyclyl, C6-C10 aryl, or 5- to 10- membered heteroaryl.

32. The method of claim 31, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, or phenyl ring.

33. The method of any one of claims 1-32, wherein n is 1.

34. The method of any one of claims 1-32, wherein n is 0.

35. The method of any one of the preceding claims, wherein R3is hydrogen or C1-C3alkyl.

36. The method of any one of the preceding claims, wherein R3is methyl.

37. The method of any one of the preceding claims, wherein R4is selected from the group consisting of optionally substituted cyclopropyl, (5- to 10-membered heteroaryl)-C1-C3 alkyl, and 4- to 10-membered heterocyclyl.

38. The method of claim 37, wherein R4is an optionally substituted (5- to 10-membered heteroaryl)-C1-C3 alkyl.

39. The method of claim 38, wherein R4is selected from the group consisting of optionally substituted pyridinyl-methyl, pyridinyl-ethyl, pyrimidinyl-methyl, pyrazolyl-propyl, and benzoxazole-methyl.

40. The method of any one of claims 1-36, wherein R4is selected from the group consisting of -CH2CH2CH2OH, -CH2CH2OH, and -CH3C(H)(CH3)(OH).

41. The method of any one of claims 1-36, wherein42. The method of claim 41, wherein R4cand R4dare each independently hydrogen or methyl.

43. The method of 42, wherein R4cand R4dare each hydrogen.

44. The method of any one of claims 41-43, wherein R4bis hydrogen.

45. The method of any one of claims 41-44, wherein R4ais C1-C6 alkyl.

46. The method of claim 45, wherein R4ais tert-butyl or isopropyl.

47. The method of any one of claims 41-44, wherein R4ais C6-C10 aryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, and C1-C3alkoxy.

48. The method of claim 47, wherein R4ais phenyl optionally substituted with fluoro, methyl, or methoxy.

49. The method of any one of claims 41-42, wherein R4ais 5- to 10-membered monocyclic or bicyclic fused heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

50. The method of claim 49, wherein R4ais pyridinyl, isoxazolyl, or quinolinyl, optionally substituted with fluoro, methoxy, or methyl.

51. The method of any one of claims 41-44, wherein R4ais C3-C7cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

52. The method of claim 51, wherein R4ais cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with methyl, trifluoromethyl, fluoro, or hydroxy.

53. The method of any one of claims 41-44, wherein R4ais a 5- or 6-membered heterocyclyl,optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

54. The method of claim 53, wherein R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, and tetrahydropyranyl, optionally substituted one or two times with methyl.

55. The method of any one of claims 41-44, wherein R4ais (C6-C10 aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, and C1-C3alkoxy.

56. The method of claim 55, wherein R4ais benzyl or pyridinyl-methyl.

57. The method of any one of claims 41-43, wherein R4aand R4btaken together with the nitrogen to which each is attached form a 5- to 7-membered heterocyclyl.

58. The method of claim 57, wherein R4aand R4btaken together with the nitrogen to which each is attached form a piperidinyl, morpholinyl, azepanyl, or piperazinyl.

59. The method of any one of claims 41 or 45-56, wherein R4band R4ctaken together with the atom to which each is attached form a 4- to 7-membered heterocyclyl optionally substituted one or two times with C1-C3 alkyl.

60. The method of claim 59, wherein R4band R4ctaken together with the atom to which each is attached form a piperidin-2-one, azetidin-2-one, or pyrrolidine-2-one, optionally substituted one or two times with C1-C3alkyl.

61. The method of any one of claims 41-60, wherein g is 0.

62. The method of any one of claims 41-60, wherein g is 1.

63. The method of any one of claims 1-36, wherein.

64. The method of claim 63, wherein R4cis hydrogen or methyl.

65. The method of claim 63 or 64, wherein R4ais methyl or phenyl.

66. The method of any one of claims 1-36, wherein R4is.

67. The method of claim 66, wherein R4eis hydrogen or hydroxy.

68. The method of claim 66 or 67, wherein R4ais selected from the group consisting of ethyl, -C(O)NH2, and pyridine.

69. The method of any one of claims 66-68, wherein R4bis hydrogen or ethyl.

70. The method of claim 66 or 67, wherein R4aand R4btaken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl or 5- to 10-membered heteroaryl.

71. The method of claim 70, wherein R4aand R4btaken together with the atom to which each is attached form a piperidinyl, piperazinyl, pyrrolidonyl, or imidazolyl, optionally substitutedwith C1-C3alkyl.

72. The method of any one of claims 66-71, wherein g is 0.

73. The method of any one of claims 66-71, wherein g is 1.

74. The method of any one of claims 66-71, wherein g is 2.

75. The method of any one of claims 1-34, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 4-, 5-, 6-, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms atoms, wherein said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, ethyl, hydroxy, methoxy, phenyl, hydroxy-C1-C3 alkyl, -NHC(O)-(5- or 6-membered heteroaryl), -C(O)-CH3, and (5- or 6-membered heteroaryl)-C1-C3alkyl.

76. The method of claim 75, wherein R3and R4taken together with the nitrogen atom to which each is attached form an optionally substituted piperazinyl, morpholinyl, azetidinyl, pyrrolidinyl, or piperidinyl.

77. The method of claim 75, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl.

78. The method of claim 75, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted once with methyl or phenyl, and wherein said phenyl is optionally substituted with methoxy.

79. The method of any one of claims 1-34, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11-membered bicyclic fused heterocyclyl containing one or two heteroatoms, optionally substituted with one or two substituents, eachindependently selected from the group consisting of methoxy and methyl.

80. The method of claim 15, wherein p is 1.

81. The method of claim 80, wherein Z is N.

82. The method of claim 80 or 81, wherein Y1, Y2, Y3, and Y4are each CH or C-R6.

83. The method of claim 80 or 81, wherein Y3is N and Y1, Y2, and Y4are each CH or C-R6.

84. The method of claim 80 or 81, wherein Y2is N and Y1, Y3, Y4are each CH or C-R6.

85. The method of claim 80 or 81, wherein Y1is N and Y2, Y3, and Y4are each CH or C-R6.

86. The method of any one of claims 80-85, wherein R6, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6alkoxy, hydroxy-C1-C3-alkyl, -O-(C1-C6alkyl)-Rbb, -O-Rbb, halo-C1-C3alkoxy, -O-Rcc-O-Rdd, halo-C1-C3 alkyl, and NRGRH; wherein, Rbbis NRGRH; RGand RHare each independently hydrogen or C1-C3alkyl; and Rccand Rddare each independently C1-C3alkyl.

87. The method of claim 86, wherein R6, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -OCH2C(C H3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3)2CH2OH, and -CH2CH2OH.

88. The method of claim 87, wherein R6, in each instance, is methoxy, -OCH2CH2OH, or -OCH2C(CH3)2OH.

89. The method of any one of claims 80-85, wherein R6, in each instance, is selected from the group consisting of -O-(C1-C6 alkyl)-Rbb, -O-Rbb, and C3-C6 cycloalkyl; wherein, Rbbis 4-to 7-membered heterocyclyl or C3-C7cycloalkyl; and wherein said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3alkyl.

90. The method of claim 89, wherein R6, in each instance, is selected from the group consisting of cyclopropyl and -O-Rbb, -O-CH2-Rbb, and -O-(CH2)2-Rbb; wherein, Rbbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl.

91. The method of claim 90, wherein R6, in each instance, is selected from the groupattachment to Ring B.

92. The method of claim 91, wherein.

93. The method of any one of claims 80-85, wherein two R6groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl.

94. The method of claim 93, wherein two R6groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl.

95. The method of claim 93 or 94, wherein two R6groups, taken together with the atom to which each is attached, form a ring selected from the group consisting, , , , ,fused with ring B, wherein the pair ofrepresent the attachment of the ring with Ring B.

96. The method of claim 95, wherein two R6groups, taken together with the atom to which each is attached, form a form a ring selected from the group consistingfused with Ring B.

97. The method of any one of claims 80-96, wherein f is 1.

98. The method of claim 80 or 81, wherein f is 0, and Ring.

99. The method of claim 98, wherein Ringwherein, n is 0 or 1; and Y2and Y3are each independently selected from the group consisting of CH, N, NH, NR6, S, O, and CR6, provided that only one of Y2and Y3can be N, NH, NR6, S, or O.

100. The method of claim 98 or 99, wherein Ring B is selected from the group consisting of101. The method of any one of claims 98-100, wherein R6, in each instance, is selected from the group consisting of C1-C3alkyl and hydroxy-C1-C3alkyl.

102. The method of claim 101, wherein R6, in each instance, is selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH.

103. The method of any one of claims 80-102, wherein n is 1.

104. The method of any one of claims 80-102, wherein n is 0.

105. The method of any one of claims 80-92, wherein n is 2.

106. The method of claim 105, wherein one R6is selected from the group consisting of methyl and methoxy and the other R6is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH.

107. The method of any one of claims 80-106, wherein R3is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH.

108. The method of claim 107, wherein R3is methyl.

109. The method of any one of claims 80-108, wherein R4is a (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7 cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and wherein said phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy.

110. The method of claim 109, wherein R4is a (6-membered heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6-membered heteroaryl is a nitrogen.

111. The method of claim 109 or 110, wherein R4is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, and triazolyl-methyl, each optionally substituted with phenyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro.

112. The method of claim 111, wherein R4is selected from the group consisting of.

113. The method of any one of claims 80-108, wherein, wherein, wherein g is 0.

114. The method of claim 113, wherein R4cis selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3; and R4dis selected from the group consisting of hydrogen and methyl; or, R4cand R4dtaken together with the atom to which each is attached form a cyclopropyl ring.

115. The method of claim 114, wherein R4cand R4dare each hydrogen.

116. The method of claim 113, wherein R4bis hydrogen.

117. The method of any one of claims 113-116, wherein R4ais C1-C6alkyl.

118. The method of claim 117, wherein R4ais tert-butyl.

119. The method of any one of claims 113-116, wherein R4ais phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl.

120. The method of claim 119, wherein R4ais phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy.

121. The method of claim 120, wherein R4ais selected from the group consisting of122. The method of any one of claims 113-116, wherein R4ais 5- to 10-membered monocyclic or fused bicyclic heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl,hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl.

123. The method of claim 122, wherein R4ais pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl.

124. The method of claim 123, wherein R4ais selected from the group consisting of, , , , , , ,125. The method of any one of claims 113-116, wherein R4ais C3-C7cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10- membered monocyclic or fused bicyclic heterocyclyl.

126. The method of claim 125, wherein R4ais selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[1.1.1]pentan-1-yl, optionally substituted with one or two substituents, each independently selected from the group consistingof methyl, -CF3, fluoro, or hydroxy.

127. The method of claim 126, wherein R4ais selected from the group consisting of128. The method of any one of claims 113-116, wherein R4ais a 5- to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl.

129. The method of claim 128, wherein R4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, and methoxy.

130. The method of claim 129, wherein R4ais selected from the group consisting of131. The method of any one of claims 113-116, or a pharmaceutically acceptable salt thereof, wherein R4ais (C6-C10monocyclic or fused bicyclic aryl)-C1-C3alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3alkyl, hydroxy, C1-C3alkoxy, C3-C7cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl.

132. The method of claim 131, wherein R4ais selected from the group consisting of phenyl- methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, and pyridinyl-methyl. 1134. The method of any one of claims 113-116, wherein R4ais selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3.

135. The method of any one of claims 113-116, wherein R4aand R4btaken together with thenitrogen to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3alkoxy.

136. The method of claim 135, wherein R4aand R4btaken together with the nitrogen to which each is attached form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, and methoxy.

137. The method of claim 136, wherein R4aand R4btaken together with the nitrogen to which138. The method of any one of claims 113 or 117-134, wherein R4band R4ctaken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3alkyl.

139. The method of claim 138, wherein R4band R4ctaken together with the atom to whicheach is attached form a piperidin-2-one or a pyrrolidine-2-one, optionally substituted one or two times with methyl.

140. The method of any one of claims 80-106, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing one or two heteroatoms; wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, halogen, halo-C1-C3alkyl, and C6-C10monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3alkoxy, hydroxy, halogen, and C1-C3 alkyl.

141. The method of claim 140, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, and methyl, and wherein said phenyl is optionally substituted with methoxy.

142. The method of claim 141, wherein R3and R4taken together with the nitrogen atom to143. The method of any one of claims 80-106, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused, bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from thegroup consisting of C1-C3alkyl, C1-C3alkoxy, hydroxy, and halogen.

144. The method of claim 143, wherein R3and R4taken together with the nitrogen atom to145. The method of any one of claims 80-106, wherein R3and R4taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH2)sC(=O)NRkRl; wherein, s is 0, 1, or 2; Rkis hydrogen or C1-C3 alkyl; and Rlis selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl;and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, halogen, cyano, and NRqRw; wherein, Rqis hydrogen or C1-C3 alkyl; Rwis C6-C10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

146. The method of claim 145, wherein R3and R4taken together with the nitrogen atom to which each is attached form a.

147. The method of any one of claims 80-146, wherein Rx, in each instance, is methyl.

148. The method of any one of claims 80-147, wherein m is 0.

149. The method of any one of claims 80-147, wherein m is 2.

150. The method of claim 1 or 2, wherein the compound of Formula I’ is a compound selectedfrom Table 1, or a pharmaceutically acceptable salt thereof.