Cycloalkylpyrimidines as ferroportin inhibitors

Abstract

The subject matter described herein is directed to ferroportin inhibitors that are compounds of Formula I or Formula I', and pharmaceutically acceptable salts thereof, methods for making the compounds, pharmaceutical compositions containing the compounds, and methods for administering the compounds for the prevention and / or treatment of diseases caused by a deficiency of hepcidin or iron metabolism disorders, particularly iron overload conditions such as thalassemia, sickle cell disease, and iron overload, and also kidney damage.

Description

[Technical Field]

[0001] (CROSS-REFERENCE TO RELATED APPLICATIONS) This application claims the benefit of and priority to U.S. Provisional Patent Application No. 63 / 016,891, filed April 28, 2020, and U.S. Provisional Patent Application No. 63 / 127,774, filed December 18, 2020, the entire contents of each of which are incorporated herein by reference.

[0002] FIELD OF THE INVENTION The subject matter described herein is directed to ferroportin inhibitor compounds, methods for making the compounds, pharmaceutical compositions thereof, and their use in the prevention and / or treatment of diseases caused by a deficiency of hepcidin or iron metabolism disorders, particularly iron overload conditions such as thalassemia, sickle cell disease, and iron overload, and also renal damage. [Background technology]

[0003] Iron is an essential trace element in nearly all living organisms. In humans, iron is a key factor for cellular functions such as oxygen transport, oxygen uptake, mitochondrial electron transport, cognitive function, and energy metabolism. Iron is present in enzymes, hemoglobin, and myoglobin, as well as in depots in the form of ferritin and hemosiderin. In hemoglobin, approximately half of the total iron is present as heme iron bound to hemoglobin in red blood cells. The average human body contains approximately 4 to 5 grams of iron. Adults require 0.5 to 1.5 mg of iron per day, whereas infants and pregnant women require 2 to 5 mg of iron per day.

[0004] In healthy adults, the normal loss of iron of about 1 mg per day is usually compensated for through dietary intake. Iron balance is regulated primarily by iron recovery from hemoglobin in recycled and senescent red blood cells and by duodenal absorption of dietary iron in the form of ferrous and trivalent ferrous ions.

[0005] Absorption is regulated by the organism depending on iron needs and the size of the iron depot. Generally, Fe(III) compounds dissolve in the stomach, which has a sufficiently acidic pH, making them available for absorption. Iron absorption occurs in the upper small intestine via mucosal cells. Trivalent non-heme iron is first reduced to Fe(II) at the intestinal cell membrane for absorption, for example, by ferric reductase (membrane-bound duodenal cytochrome b), which can then transport the material into intestinal cells via the transport protein DMT1 (divalent metal transporter 1). In contrast, heme iron crosses the cell membrane and enters intestinal cells unchanged. In intestinal cells, iron is either stored in ferritin as depot iron or released into the bloodstream by the transport protein ferroportin. The divalent iron transported into the bloodstream by ferroportin is converted to trivalent iron by oxidases (ceruloplasmin, heffertin). The trivalent iron is then transported to its destination in the body by transferrin. ("Balancing acts: molecular control of mammalian iron metabolism," MW Hentze, Cell, 1:17, 2004, 285-297) Hepcidin plays a central role in this process because it is an essential regulator of iron absorption. The hepcidin-ferroportin system directly controls iron metabolism.

[0006] Iron uptake and storage are regulated by hepcidin. Hepcidin antimicrobial peptide (HAMP; also known as LEAP-1; also referred to as hepcidin) is a 25-amino acid peptide (Krause et al., FEBS Lett. 480, 147-150, 2000). Hepcidin has a hairpin structure in which eight cysteines form four disulfide bonds (Jordan et al., J Biol Chem. 284, 24155-24167, 2009). Deletion of the first five amino acids completely abolishes biological activity, suggesting that the N-terminus is important for iron regulatory function (Nemeth et al., Blood, 107, 328-333, 2006). Hepcidin is produced in the liver and functions as a master iron regulatory hormone, regulating intestinal iron uptake and iron storage in other organs (Ganz, Hematol. Am. Soc. Hematol. Educ. Program, 29-35, 507 2006; 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 and causing degradation of the iron transport molecule ferroportin (Sebastiani et al., Front. Pharmacol. 7, 160, 2016).

[0007] Hepcidin formation is regulated in direct correlation with the iron level in the body: if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed; if iron and oxygen levels are low or erythropoiesis is increased, hepcidin formation is suppressed. In small intestinal mucosal cells and macrophages, hepcidin binds to the transport protein ferroportin, which traditionally transports recycled iron from the phagocyte interior into the blood.

[0008] Ferroportin is an iron transporter that controls the uptake and distribution of iron in the body, thus playing an important role in regulating blood iron levels. The transport protein ferroportin is a 571-amino acid transmembrane protein found in the liver, spleen, kidney, heart, intestine, and placenta. Ferroportin is specifically localized in the basement membrane of intestinal epithelial cells. Thus, bound ferroportin acts to transport iron into the blood. In this case, ferroportin most likely transports iron as Fe2+. When hepcidin binds to ferroportin, it is transported to the interior of the cell, where it is degraded, resulting in an almost complete blockage of cellular release of recycled iron from phagocytes. If ferroportin is inactivated, for example, by hepcidin, and is therefore unable to excrete iron stored in mucosal cells, the stored iron is lost through the natural excretion of the cells via feces. Thus, when ferroportin is inactivated or inhibited, for example by hepcidin, intestinal iron absorption is reduced.

[0009] A decrease in hepcidin leads to an increase in ferroportin, thus enhancing the release of stored iron, for example, promoting iron absorption from food, resulting in elevated serum iron levels, i.e., iron overload. Iron overload causes many diseases and undesirable conditions. Iron overload can be treated by removing iron from the body. This treatment involves regularly scheduled phlebotomy (bloodletting). For patients who cannot tolerate conventional blood draws, chelating agents are available for use. The drawback of treating iron overload with chelation therapy is that it removes chelated iron from the body when iron overload has already occurred, rather than preventing the development of damage.

[0010] Thus, there remains a need in the art that has not been effectively addressed for compounds that act as ferroportin inhibitors with desirable efficacy and therapeutic potential. This problem, as well as other problems resulting from iron imbalance, are addressed by the subject matter described herein. Summary of the Invention

[0011] In certain embodiments, the subject matter described herein is directed to a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof:

[0012] In certain embodiments, the subject matter described herein is directed to a pharmaceutical composition comprising a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the subject matter described herein is directed to a method of inhibiting ferroportin-mediated iron transport in a subject, comprising administering to the subject an effective amount of a compound of Formula I or Formula I', a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising a compound of Formula I or Formula I'.

[0014] In certain embodiments, the subject matter described herein is directed to a method of making a compound of formula I or formula I'.

[0015] Other embodiments are also described. DETAILED DESCRIPTION OF THE INVENTION

[0016] Described herein are ferroportin inhibitors, which are compounds of Formula I and Formula I', methods for preparing the compounds, pharmaceutical compositions containing the compounds, and their use in the prevention and / or treatment of diseases caused by a deficiency of hepcidin or iron metabolism disorders, particularly iron overload conditions such as thalassemia, sickle cell disease, and iron overload. Ferroportin is an iron transport protein involved in the uptake of released iron via the intestine, its transfer into the blood circulation, and ultimately its delivery to the appropriate tissues and organs. Inactivation or inhibition of ferroportin reduces or prevents iron transport, thereby reducing intestinal iron absorption and ultimately the amount of iron in the body. These compounds, compositions, and methods can be used as effective therapies for the prevention and treatment of iron metabolism disorders associated with elevated iron levels. It would be desirable to provide compounds, compositions, and methods that exhibit few side effects, minimal toxicity, and good bioavailability and compatibility.

[0017] Iron overload is associated with a variety of diseases (Blanchette et al., Expert Rev. Hematol. 9, 169-186, 2016). Hereditary iron overload, the most common genetic disorder in Europe, is caused by a lack of hepcidin or insensitivity to hepcidin (Powell et al., The Lancet 388, 706-716, 2016). Clinical manifestations of iron overload include liver cirrhosis, diabetes, and skin hyperpigmentation (Powell et al., The Lancet 388, 706-716, 2016). While the disease can be managed with phlebotomy, this solution can be cumbersome and does not treat the cause of the disease.

[0018] Iron-loading anemias, such as beta-thalassemia, are also associated with reduced hepcidin levels (Origa et al., Haematologica 92, 583-588, 2007). Treating this disease with hepcidin mimetics has been shown to not only address iron overload but also improve the ineffective erythropoiesis that occurs in this disease (Casura et al., Blood 128, 265-276, 2016). This could be of great benefit to these patients, who may be less dependent on blood transfusions, which can contribute to iron overload in thalassemia patients.

[0019] Myelofibrosis, myelodysplastic syndrome, and sickle cell disease are diseases characterized by ineffective erythropoiesis, which can 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). Decreased hepcidin levels have been reported 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.

[0020] Polycythemia vera is a disease characterized by increased erythropoiesis. Animal studies have shown that high doses of hepcidin mimetics can ameliorate this disease by reducing erythropoiesis (Casu et al., Blood 128, 265-276, 2016).

[0021] Reducing iron uptake, and therefore serum iron levels, may be effective even in diseases where iron loading is normal, such as renal disease (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).

[0022] Hepcidin itself has a complex structure, which requires complicated manufacturing and has a limited duration of action in vivo, limiting its use as a pharmaceutical. Continuous efforts have been made to search for hepcidin mimetics and compounds that can be used to increase hepcidin levels.

[0023] A general solution relates to small hepcidin-derived or hepcidin-like peptides that can be produced inexpensively and used to treat hepcidin-associated diseases and disorders, such as those described herein. These so-called mini-hepcidins are rationally designed small peptides that mimic hepcidin activity and may also be useful in treating iron overload and iron-overload-related disease conditions.

[0024] Such mini-hepcidin peptides are described, for example, in WO 2010 / 065815A2 and WO 2013 / 086143A1. WO 2015 / 157283A1 and its counterpart US9,315,545B2 describe hepcidin mimetic peptides and their use in hepcidin-related disorders such as iron overload, β-thalassemia, iron overload, etc., and cover Merganser Biotech's developmental compound M012, which is being evaluated in a Phase 1 clinical program as a potential transformational therapy for a number of blood disorders, including β-thalassemia, low-risk myelodysplasia, and polycythemia vera.

[0025] WO 2014 / 145561A2 and WO 2015 / 200916A2 describe other small hepcidin peptide analogs and their use in the treatment or prevention of iron overload disease and iron-loaded anemia, and further related disorders.Furthermore, WO 2015 / 042515A1 relates to hepcidin and its peptide fragments, particularly for treating renal ischemia-reperfusion injury or acute kidney injury.Furthermore, minihepcidin analogs are described, for example, in Preza et al., J. Clin. Invest., 121(12), 4880-4888, 2011, or in CN 104 011 066 and WO 2016 / 109363A1.

[0026] Ferroportin inhibitors, as well as compounds with hepcidin-like activity, are also sought after to have additional utilities, such as improved solubility, stability, and / or efficacy. An advantage of the ferroportin inhibitors of Formula I described herein is that they are produced in sufficient yields by the synthetic routes disclosed herein.

[0027] The presently disclosed subject matter will now be described in more detail below. However, many modifications and other embodiments of the presently disclosed subject matter described herein will be apparent to those skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings set forth in the foregoing description. Accordingly, it should be understood that the presently disclosed subject matter is not limited to the particular embodiments disclosed, and that modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein extends to all alternatives, modifications, and equivalents. Unless otherwise specified, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art. All publications, patent applications, patents, and other references cited herein are incorporated in their entirety by reference. In the event that one or more of the incorporated references, patents, and similar materials differs from or conflicts with this application (including, but not limited to, defined terms, usage, described techniques, etc.), this application controls.

[0028] I. Definition As used herein, the following words, phrases, and symbols generally have the same meanings as indicated below, except to the extent that the context in which they are used indicates other words, phrases, and symbols.

[0029] A dash ("-") that is not between two letters or symbols is used to indicate a point of attachment of a substituent. For example, -C(O)NH2 is attached through the carbon atom. Dashes preceding or at the end of a chemical group are for convenience, and the chemical group may be drawn with or without one or more dashes without losing its ordinary meaning. A wavy or dashed line drawn through the end of or perpendicular to a line in a structural formula indicates a particular point of attachment of the group. No directionality or stereochemistry is indicated or implied by the convention of depicting or naming chemical groups unless chemically or structurally required.

[0030] Prefix “C” u -C v" indicates that the following group has u to v carbon atoms. For example, "C1-C6 alkyl" indicates that the alkyl group has 1 to 6 carbon atoms.

[0031] With reference to the term "about," a value or parameter herein encompasses (and describes) embodiments directed to the value or parameter itself. In certain embodiments, the term "about" encompasses the stated value ±50%. In certain other embodiments, the term "about" encompasses the stated value ±20%. In certain other embodiments, the term "about" encompasses the stated value ±10%. In other embodiments, the term "about" encompasses the stated value ±5%. In certain other embodiments, the term "about" encompasses the stated value ±1%. In certain other embodiments, the term "about" encompasses the stated value ±0.5%, and in certain other embodiments, 0.1%. Such variations are appropriate for practicing the disclosed methods or utilizing the disclosed compositions. Also, the term "about x" includes the description of "x." Additionally, the singular forms "a" and "the" include plural references unless the context clearly dictates otherwise. Thus, for example, reference to "a compound" includes a plurality of such compounds, and reference to "an assay" includes reference to one or more assays and equivalents thereof known to those skilled in the art.

[0032] "Alkyl" refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl refers to a group having 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 12 carbon atoms (i.e., C1-C 12alkyl), 1 to 8 carbon atoms (i.e., C1-C8 alkyl), 1 to 6 carbon atoms (i.e., C1-C6 alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl), or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl, 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 a chemical name or identified by a molecular formula, all positional isomers having that number of carbons may be included; 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); "propyl" includes n-propyl (i.e., (CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0033] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl" groups, divalent "aryl" groups, etc. may also be referred to as "alkylene" or "alkylenyl" groups, "arylene" or "arylenyl" groups, respectively. Also, unless explicitly stated otherwise, when a combination of groups is referred to herein as a moiety, e.g., arylalkyl or aralkyl, the last-listed group contains the atom that attaches that moiety to the rest of the molecule.

[0034] "Alkenyl" refers to an alkyl group containing at least one carbon-carbon double bond and having 2 to 20 carbon atoms (i.e., C2-C 20alkenyl), alkyl groups having 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), alkyl groups having 2 to 6 carbon atoms (i.e., C2-C6 alkenyl), or alkyl groups having 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of alkenyl groups include, for example, ethenyl, propenyl, and butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0035] "Alkynyl" refers to an alkyl group containing at least one carbon-carbon triple bond and having 2 to 20 carbon atoms (i.e., C2-C 20 "C-C alkynyl" refers to an alkyl group having 2 to 8 carbon atoms (i.e., C-C alkynyl), an alkyl group having 2 to 6 carbon atoms (i.e., C-C alkynyl), or an alkyl group having 2 to 4 carbon atoms (i.e., C-C alkynyl). The term "alkynyl" also includes groups having one triple bond and one double bond.

[0036] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, such as methylene (-CH-), ethylene (-CHCH-), etc. As an example, "hydroxy-methylene" refers to HO-CH-*, where * is the point of attachment to the molecule.

[0037] "Alkoxy" refers to the group "alkyl-O-" (e.g., C1-C3 alkoxy or C1-C6 alkoxy). Examples of alkoxy groups include, for example, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, tert-butoxy, sec-butoxy, n-pentoxy, n-hexoxy, and 1,2-dimethylbutoxy.

[0038] "Alkoxy-alkyl" refers to the group "-alkyl-alkoxy." The term "C1-C3 alkoxy-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one hydrogen on any carbon is replaced by an alkoxy group having 1 to 3 carbons, particularly one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having 1 to 3 carbons. The term "C1-C6 alkoxy-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one hydrogen on any carbon is replaced by an alkoxy group having 1 to 6 carbons, particularly one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having 1 to 6 carbons. Non-limiting examples of alkoxy-alkyl include -CHOCH3, -CH2OC(CH3)3, and -C(CH3)2CH2OCH3.

[0039] "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.

[0040] "Acyl" is the group -C(O)R y where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyls include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl-carbonyl, and benzoyl.

[0041] An "amide" is the group -C(O)NR y R z and the group -NR y C(O)R zand "N-amido" groups, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which is optionally substituted as defined herein, or R y and R z and together form a cycloalkyl or heterocyclyl, each of which may be optionally substituted as defined herein.

[0042] "Amino" is the group -NR y R z where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0043] "Amidino" is -C(NR y )(NR z 2), where R y and R z refers independently to hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0044] "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 refers to a ring of 6 to 20 carbon ring atoms (i.e., C6-C6). 20 aryl), 6 to 12 carbon ring atoms (i.e., C6-C 12 aryl), or 6 to 10 carbon ring atoms (i.e., C6-C 10aryl). Examples of aryl groups include, for example, phenyl, naphthyl, fluorenyl, and anthryl. However, aryl does not encompass or overlap with heteroaryl, as defined below. When one or more aryl groups are fused to a heteroaryl, the resulting ring system is a heteroaryl, regardless of the point of attachment. When one or more aryl groups are fused to a heterocyclyl, the resulting ring system is a heterocyclyl, regardless of the point of attachment.

[0045] "Arylalkyl" or "aralkyl" refers to an alkyl group (C6-C 10 As used herein, the term "aryl-alkyl-" refers to the group "(C6-C3 alkyl)-C1-C3 alkyl. 10 "(Aryl)-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one hydrogen on any carbon is replaced by an aryl group having 6 to 10 carbon atoms, specifically, one hydrogen on one carbon of the alkyl chain is replaced by an aryl group having 6 to 10 carbon atoms. A non-limiting example of an arylalkyl is benzyl.

[0046] "Carbamoyl" is the group -OC(O)NR y R z and the group -NR y C(O)OR z and "N-carbamoyl" groups, where R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0047] "Carboxyl ester" or "ester" is -OC(O)R x and -C(O)OR x where R xis alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0048] "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., cyclic groups having at least one double bond) and carbocyclic fused ring systems (i.e., at least one non-aromatic ring) having at least one sp carbon atom. As used herein, cycloalkyl refers to a cyclic group having 3 to 20 carbon ring atoms (i.e., C3-C 20 cycloalkyl), 3 to 12 carbon ring atoms (i.e., C3-C 12 cycloalkyl), 3 to 10 carbon ring atoms (i.e., C3-C 10 Cycloalkyl groups include cycloalkyls having 3 to 8 carbon ring atoms (i.e., C-C cycloalkyl), 3 to 7 carbon ring atoms (i.e., C-C cycloalkyl), or 3 to 6 carbon ring atoms (i.e., C-C cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. Polycyclic groups include bridged and / or fused rings, such as, for example, bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[1.1.1]pentan-1-yl, adamantyl, norbornyl, decalinyl, 7,7-dimethylbicyclo[2.2.1]heptanyl, and the like. Furthermore, the term cycloalkyl is intended to encompass any ring or ring system, including a non-aromatic alkyl ring, optionally fused to an aryl ring, regardless of its attachment to the rest of the molecule. Furthermore, cycloalkyl also includes "spirocycloalkyl" when there are two substitution positions on the same carbon atom, for example, spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0049] "Cycloalkylalkyl" refers to the group "cycloalkyl-alkyl-," such as (C3-C6 cycloalkyl)-C1-C3 alkyl. As used herein, "(C3-C6 cycloalkyl)-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one hydrogen atom on any carbon is replaced by a cycloalkyl group having 3 to 6 carbon atoms, specifically one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having 3 to 6 carbon atoms.

[0050] "Cycloalkyl-alkoxy" refers to the group "-alkoxy-cycloalkyl" (e.g., C3-C7 cycloalkyl-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 an alkyl chain of 1 to 6 carbons in which one hydrogen atom on any carbon is replaced by a cycloalkyl group having 3 to 7 carbon atoms, particularly one hydrogen on one carbon in the chain is replaced by a cycloalkyl group having 3 to 7 carbon atoms. As used herein, "C3-C7 cycloalkyl-C1-C3 alkoxy" refers to an alkoxy group having an alkyl chain of 1 to 3 carbons in which one hydrogen atom on any carbon is replaced by a cycloalkyl group having 3 to 7 carbon atoms, particularly one hydrogen on one carbon in the chain is replaced by a cycloalkyl group having 3 to 7 carbon atoms.

[0051] "Guanidino" is -NR y C(=NR z )(NR y R z ), where each R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0052] "Hydrazino" refers to -NHNH2.

[0053] "Imino" is the group -C(NR y )R z where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0054] "Imide" is the group -C(O)NR y C(O)R z where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0055] "Halogen" or "halo" refers to atoms occupying Group VIIA of the periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0056] "Haloalkyl" refers to an unbranched or branched alkyl group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms are replaced with halogen. For example, halo-C1-C3 alkyl refers to an alkyl group of 1 to 3 carbons in which at least one hydrogen atom is replaced with halogen. If a residue is substituted with multiple halogens, 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, but need not, be the same halogens. Examples of haloalkyl include, for example, trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, 1,2-difluoroethyl, 3-bromo-2-fluoropropyl, 1,2-dibromoethyl, and the like.

[0057] "Haloalkoxy" refers to an alkoxy group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms have been replaced with halogen. Non-limiting examples of haloalkoxy are -OCHCF, -OCFH, and -OCF.

[0058] "Hydroxyalkyl" refers to an alkyl group, as defined above, in which one or more (e.g., 1 to 6, or 1 to 3) hydrogen atoms have been replaced with hydroxy groups (e.g., hydroxy-C1-C3-alkyl, hydroxy-C1-C6-alkyl). The term "hydroxy-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one or more hydrogens on any carbon have been replaced with hydroxy groups, particularly one hydrogen on one carbon of the chain has been replaced with a hydroxy group. The term "hydroxy-C1-C6 alkyl" refers to an alkyl chain of 1 to 6 carbons in which one or more hydrogens on any carbon have been replaced with hydroxy groups, particularly one hydrogen on one carbon of the chain has been replaced with a hydroxy group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0059] "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 an alkyl chain of 1 to 3 carbons where one or more hydrogens on any carbon are replaced with hydroxy groups, particularly one hydrogen on one carbon in the chain is replaced with a hydroxy group. The term "hydroxy-C1-C6 alkoxy" refers to an alkoxy group containing an alkyl chain of 1 to 6 carbons where one or more hydrogens on any carbon are replaced with hydroxy groups, particularly one hydrogen on one carbon in the chain is replaced with a hydroxy group. Non-limiting examples of hydroxyalkoxy include -OCH2CH2OH and -OCH2C(CH3)2OH.

[0060] "Heteroalkyl" refers to an alkyl group in which one or more carbon atoms (and any associated hydrogen atoms) are each independently replaced with the same or different heteroatomic groups, provided that the point of attachment to the remainder of the molecule is through a carbon atom. In certain embodiments, a heteroalkyl can have 1 to 3 carbon atoms (e.g., C1-C3 heteroalkyl) or 1 to 6 carbon atoms (e.g., C1-C6 heteroalkyl) and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatomic groups. The term "heteroalkyl" includes unbranched or branched saturated chains containing carbon and heteroatoms. As an example, one, two, or three carbon atoms of the alkyl group in a "heteroalkyl" can be independently replaced with the same or different heteroatomic groups. Heteroatomic groups include, but are not limited to, -NR y -, -O-, -S-, -S(O)-, -S(O)2-, etc., where R y is 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, for example, ethers (e.g., -CHOCH, -CH(CH)OCH, -CHCHOCH, -CHCHOCH, -CHCHOCHCHOCH, etc.), thioethers (e.g., -CHSCH, -CH(CH)SCH, -CHCHSCH, -CHCHSCHCHSCH, etc.), sulfones (e.g., -CHS(O)CH, -CH(CH)S(O)CH, -CHCHS(O)CH, -CHCHS(O)CHCHOCH, etc.), and amines (e.g., -CHNR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3 etc., where R yis 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.

[0061] "Heteroaryl" refers to a monocyclic, polycyclic, or multi-fused ring aromatic group having one or more hetero ring atoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl refers to a heterocyclic group having 1 to 20 carbon ring atoms (i.e., C1-C6) independently selected from nitrogen, oxygen, and sulfur. 20 heteroaryl), 3 to 12 carbon ring atoms (i.e., C3-C 12Heteroaryl), or 3 to 8 carbon ring atoms (i.e., C3-C8 heteroaryl), and 1 to 5 hetero ring atoms, 1 to 4 hetero ring atoms, 1 to 3 hetero ring atoms, 1 to 2 hetero ring atoms, or 1 hetero ring atom. In certain cases, heteroaryl includes 9-10 membered ring systems (i.e., 9-10 membered heteroaryl), 5-10 membered ring 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 having 1 to 4 hetero ring atoms, 1 to 3 hetero ring atoms, 1 to 2 hetero ring atoms, or 1 hetero ring atom independently selected from nitrogen, oxygen, and sulfur. Examples of heteroaryl groups include, for example, 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, and isoindo. Examples of aryl include aryl, 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 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 attached via either ring of the fused system.Any aromatic ring or ring system having single or multiple fused rings and containing at least one heteroatom is considered to be heteroaryl, regardless of attachment to the rest of the molecule (i.e., through any one fused ring). Heteroaryl does not encompass or overlap with heteroaryl as defined above.

[0062] "Heteroarylalkyl" refers to the group "heteroaryl-alkyl-", such as (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl. As used herein, "(5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl" refers to an alkyl chain of 1 to 3 carbons in which one or more hydrogens on any carbon are replaced by a 5- to 10-membered monocyclic heteroaryl group, specifically one hydrogen on one carbon of the chain is replaced by a (5- to 10-membered monocyclic heteroaryl) group.

[0063] "Heterocyclyl" refers to a saturated or partially unsaturated cyclic alkyl group having one or more heterocyclic atoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclyl" includes heterocycloalkenyl groups (i.e., heterocyclyl groups having at least one double bond), bridged heterocyclyl groups, fused heterocyclyl groups, and spiroheterocyclyl groups. A heterocyclyl may be monocyclic or polycyclic, where the polycyclic ring may be fused, bridged, or spirocyclic. Any non-aromatic ring containing at least one heteroatom is considered to be a heterocyclyl, regardless of connectivity (i.e., it may be attached via a carbon atom or a heteroatom). Furthermore, the term heterocyclyl is intended to include rings or ring systems containing any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of connectivity to the rest of the molecule. The term heterocyclyl is also intended to include ring systems containing a cycloalkyl ring fused to a heteroaryl ring, regardless of connectivity to the rest of the molecule. Additionally, the term heterocyclyl is intended to encompass ring systems containing a cycloalkyl ring fused to a heterocyclyl ring, regardless of attachment to the rest of the molecule. As used herein, heterocyclyl refers to a ring system having 2 to 20 carbon ring atoms (i.e., C-C 20 heterocyclyl), 2 to 12 carbon ring atoms (i.e., C2-C 12 heterocyclyl), 2 to 10 carbon ring atoms (i.e., C2-C 10 heterocyclyl), 2 to 8 carbon ring atoms (i.e., C2-C8 heterocyclyl), 3 to 12 carbon ring atoms (i.e., C3-C 12heterocyclyl), 3 to 8 carbon ring atoms (i.e., C3-C8 heterocyclyl), or 3 to 6 carbon ring atoms (i.e., C3-C6 heterocyclyl); and 1 to 5 hetero ring atoms, 1 to 4 hetero ring atoms, 1 to 3 hetero ring atoms, 1 to 2 hetero ring atoms, or 1 hetero ring atom 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, and 5- to 10-membered heterocyclyls having 5 to 10 ring atoms, respectively. Examples of heterocyclyl groups include, for example, 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, and the like.

[0023] Heterocyclyl includes 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperizonyl, 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 encompass "spiroheterocyclyl" when there are two positions for substitution on the same carbon atom.Examples of spiroheterocyclyl rings include bicyclic and tricyclic ring systems such as, for example, 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl, and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of 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 may be attached via either ring of the fused system.

[0064] "Heterocyclylalkyl" refers to the group "heterocyclyl-alkyl-".

[0065] "Oxime" is a group -CR y (=NOH), where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0066] "Oxo" refers to the group (=O).

[0067] "Sulfonyl" is the group -S(O)R y where R y is 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.

[0068] "Sulfinyl" is the group -S(O)R y where R yis 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.

[0069] "Sulfonamide" is the group -SO2NR y R z and -NR y SO2R z where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl; each of which may be optionally substituted as defined herein.

[0070] The term "desired" or "optionally" means that the subsequently described event or circumstance may or may not occur, and the description includes cases where the event or circumstance occurs and cases where it does not. Also, the term "optionally substituted" means that any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on the specified atom or group may or may not be replaced with a group other than hydrogen.

[0071] As used herein, the term "substituted" refers to any of the groups described above (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and / or heteroalkyl) in which at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom has been replaced by a bond to any of the following: 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, sulfonamide, thiol, thioxo, N-oxide or -Si(R y )3 (where each R y means that an atom other than hydrogen is replaced by an atom such as, independently, hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl, or heterocyclyl.

[0072] In certain embodiments, "substituted" refers to any of the alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, or heteroaryl groups described above, where 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, -NR g R h , -NR g C(=O)R h , -NR g C(=O)NR g R h, -NR g C(=O)OR h , -NR g S(=O) 1-2 R h , -C(=O)R g , -C(=O)OR g , -OC(=O)OR g , -OC(=O)R g , -C(=O)NR g R h , -OC(=O)NR g R h , -OR g , -SR g , -S(=O)R g , -S(=O)2R g , -OS(=O) 1-2 R g , -S(=O) 1-2 OR g , -NR g S(=O) 1-2 NR g R h , =NSO2R g , =NOR g , -S(=O) 1-2 NR g R h , -SF5, -SCF3, or -OCF3. In certain embodiments, "substituted" also refers to any of the groups described above in which one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms are replaced with -C(=O)R g , -C(=O)OR g , -C(=O)NR g R h , -CH2SO2R g , or -CH2SO2NR g R h In the above, R g and R hare the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and / or heteroarylalkyl. In certain embodiments, "substituted" also refers to 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 with 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 R g and R h and R i taken together with their bonding atoms form a heterocyclyl ring, optionally substituted with oxo, halo, or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy.

[0073] This specification does not include polymers or similar amorphous structures obtained by defining a substituent group with an infinite number of additional substituents (e.g., a substituted aryl group with a substituted alkyl group, which is itself substituted with a substituted aryl group, which is further substituted with a substituted heteroalkyl group). Unless otherwise specified, the maximum number of consecutive substitutions in the compounds described herein is three. For example, consecutive substitution of a substituted aryl group with two other substituted aryl groups is limited to ((substituted aryl)substituted aryl)substituted aryl. Similarly, the above definition does not include impermissible substitution patterns (e.g., a methyl substituted with five fluorines, or a heteroaryl group with two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to those skilled in the art. When used to modify a chemical group, the term "substituted" may describe other chemical groups defined herein.

[0074] In certain embodiments, as used herein, the term "one or more" refers to 1 to 5. In certain embodiments, as used herein, the term "one or more" refers to 1 to 4. In certain embodiments, as used herein, the term "one or more" refers to 1 to 3.

[0075] Any compound or structure provided herein is intended to represent unlabeled forms of the compound as well as isotopically labeled forms (isotopologues). These forms of the compound may also be referred to as and include "isotopically enriched analogs." Isotopically labeled compounds have the structures depicted herein except that one or more atoms are replaced with atoms having selected atomic masses or mass numbers. Examples of isotopes that can be incorporated into the disclosed compounds include: 2 H, 3 H, 11 C. 13 C. 14 C. 13 N, 15 N, 15 O. 17 O. 18 O. 31P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 Isotopically labeled compounds of the present disclosure include, for example, isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, respectively. 3 H, 13 C and 14 Compounds into which a radioactive isotope such as C has been incorporated. Such isotopically labeled 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 radiation treatment of patients.

[0076] The term "isotopically enriched analog" includes "deuterated analogs" of the compounds described herein in which one or more hydrogens, such as hydrogens on carbon atoms, have been replaced with deuterium. Such compounds exhibit increased resistance to metabolism and are thus useful for increasing the half-life of any compound when administered to mammals, particularly humans. 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 utilizing starting materials in which one or more hydrogens have been replaced with deuterium.

[0077] Deuterium-labeled or substituted therapeutic compounds of the present disclosure may have improved DMPK (drug metabolism and pharmacokinetic) properties related to distribution, metabolism, and excretion (ADME). Substitution with heavy isotopes such as deuterium may confer certain therapeutic advantages resulting from greater metabolic stability, e.g., increased in vivo half-life, reduced required dosage, and / or improved therapeutic index. 18 F,3 H, 11 C-labeled compounds may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of the present disclosure and their prodrugs can generally be prepared by substituting readily available isotopically labeled reagents for non-isotopically labeled reagents, as described in the schemes below or by carrying out the procedures disclosed in the Examples and Preparations. It is understood that deuterium in this context is considered a substituent of the compounds described herein.

[0078] The concentration of such heavier isotopes, specifically the concentration of deuterium, may be defined by the isotopic enrichment factor. In the compounds of the present disclosure, any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen," it is understood that the position has hydrogen in its naturally occurring isotopic composition. Thus, in the compounds of the present disclosure, any atom specifically designated as deuterium (D) is intended to represent deuterium. Furthermore, in some embodiments, the corresponding deuterated analogs are provided.

[0079] In many cases, the compounds of the present 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.

[0080] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (including stereoisomers), mixtures of isomers (including mixtures of stereoisomers), prodrugs, and metabolites of the compounds described herein.

[0081] "Pharmaceutically acceptable" or "physiologically acceptable" refers to compounds, salts, compositions, dosage forms and other materials that are useful in preparing pharmaceutical compositions suitable for veterinary or human medical use.

[0082] The term "pharmaceutically acceptable salt" of a given compound refers to a salt that retains the biological effectiveness and properties of the given compound and is not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts with inorganic acids and salts with organic acids. In addition, if a compound described herein is 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, can be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, according to conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognize various synthetic methods that can be used to prepare non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic and organic acids. Salts derived from inorganic acids include, for example, salts with hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, etc. Salts derived from organic acids include, for example, salts with 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-toluenesulfonic acid, salicylic acid, and the like. Similarly, 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, primary, secondary, and tertiary amines, such as alkylamines (i.e., NH2(alkyl)), dialkylamines (i.e., HN(alkyl)2), trialkylamines (i.e., N(alkyl)3), substituted alkylamines (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), alkenylamines (i.e., NH2(alkenyl)), dialkenylamines (i.e., HN(alkenyl)2), trialkenylamines (i.e., N(alkenyl)3), substituted alkenylamines (i.e., NH2(substituted alkenyl)), di(substituted alkenyl)amines

[0033] Suitable amines include, by way of example only, isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0083] The term "hydrate" refers to a complex formed by combining a compound described herein with water.

[0084] "Solvate" refers to an association or complex of one or more solvent molecules with a compound of the present disclosure. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0085] Some compounds exist as tautomers. Tautomers are in equilibrium with one another. For example, an amide-containing compound may exist in equilibrium with an imidic acid tautomer. Regardless of which tautomer is shown and the nature of the equilibrium between the tautomers, one skilled in the art will understand that the compound includes both the amide and imidic acid tautomers. Thus, a compound containing an amide is understood to include its imidic acid tautomer. Similarly, a compound containing an imidic acid is understood to include its amide tautomer.

[0086] The compounds of the present invention, or pharmaceutically acceptable salts thereof, contain asymmetric centers and can thus give rise to enantiomers, diastereomers, and other stereoisomeric forms, which can be defined in terms of absolute stereochemistry as (R) or (S), or, for amino acids, as (D) or (L). The present invention is intended to encompass all such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R) and (S), or (D) and (L) isomers can be prepared using chiral synthetic equivalents or chiral reagents or resolved using conventional techniques, such as chromatography and fractional crystallization. Conventional techniques for preparing / isolating individual enantiomers include chiral synthesis from appropriate optically pure precursors or resolution of the racemate (or racemate of a salt or derivative) using, for example, chiral high-performance liquid chromatography (HPLC). Where the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless otherwise specified, the compounds are intended to encompass both E and Z geometric isomers.

[0087] "Stereoisomers" refer to compounds composed of the same atoms joined by the same bonds but with different three-dimensional structures and are not interchangeable. The present invention contemplates various stereoisomers and mixtures thereof, and includes "enantiomers," which refer to two stereoisomers whose molecules are non-superimposable mirror images of one another.

[0088] "Diastereomers" are stereoisomers that have at least two asymmetric atoms, but which are not mirror-images of each other.

[0089] Relative centers of compounds described herein are shown diagrammatically using a "bold bond" style (bold or parallel lines), and absolute stereochemistry is shown using a wedge bond (bold or parallel lines).

[0090] "Prodrug" refers to any compound that releases an active parent drug in vivo according to the structures described herein when such prodrug is administered to a mammalian subject. Prodrugs of the compounds described herein are prepared by modifying functional groups present in the compounds described herein so that they are cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds described herein so that they are cleaved, either in routine manipulation or in vivo, to the parent compound. Prodrugs include compounds described herein in which a hydroxy, amino, carboxyl, or sulfhydryl group present in the compounds described herein can be cleaved in vivo to any group 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), and the like, of hydroxy functional groups present in the compounds described herein. The preparation, selection, and use of prodrugs are described in T. Higuchi and V. Stella, "Prodrugs as Novel Delivery Systems," ACS Symposium Series, Vol. 14; "Design of Prodrugs," H. Bundgaard, ed., Elsevier, 1985; and Bioreversible Carriers in Drug Design, Edward B. Roche, ed., American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference.

[0091] The term "metabolite," as used herein, refers to a product formed as a result of metabolizing a compound disclosed herein. As used herein, the term "metabolized" refers to the sum of the processes by which a particular substance, such as a compound disclosed herein, is transformed in an organism, including, but not limited to, hydrolysis and enzyme-catalyzed reactions. For example, an aldehyde moiety (-C(O)H) can be reduced to a -CHOH moiety in vivo.

[0092] The terms "inhibitor," "inhibit," or "inhibition," as used herein, unless otherwise specified, refer to the activity of a compound of Formula I or a pharmaceutically acceptable salt thereof against ferroportin. As used herein, "inhibit" refers to a decrease in ferroportin activity compared to the activity of ferroportin in the absence of the compound. In some embodiments, the term "inhibit" refers to 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 refers to 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, inhibiting refers to about a 95% to 100% decrease in ferroportin activity, e.g., a 95%, 96%, 97%, 98%, 99%, or 100% decrease in activity. Such a decrease can be measured using a variety of techniques, including in vitro assays, as will be recognized by those of skill in the art.

[0093] As used herein, the term "ferroportin inhibitor" or the like refers to a compound that reduces, inhibits, or otherwise decreases one or more biological activities of ferroportin, for example, by inducing internalization of ferroportin. The activity can be reduced a statistically significant amount, including, for example, a reduction in ferroportin activity of at least about 5%, 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95%, or 100%, as compared to a suitable control.

[0094] "Treatment" or "treating" refers to an approach to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results may include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms resulting from a disease or condition and / or reducing the severity of the disease or condition); b) delaying or halting the onset of one or more clinical symptoms associated with a disease or condition (e.g., stabilizing the disease or condition, preventing or slowing the worsening or progression of the disease or condition, and / or preventing or slowing the spread (e.g., metastasis) of the disease or condition); and / or c) palliating the disease, i.e., causing regression of clinical signs (e.g., ameliorating the pathology, providing partial or total remission of a disease or condition, enhancing the effect of another drug, slowing disease progression, improving quality of life, and / or extending survival).

[0095] "Prevention" or "preventing" refers to any treatment of a disease or condition that keeps the clinical signs of the disease or condition from developing. In some embodiments, the compounds may be administered to subjects (including humans) at risk for or with a family history of the disease or condition.

[0096] "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.

[0097] 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, refers to an amount sufficient to effect treatment to provide a therapeutic benefit, such as ameliorating symptoms or slowing progression of a disease, when administered to a subject. For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of sickle cell disease. A therapeutically effective amount will vary depending on the subject and disease or condition being treated, the subject's weight and age, the severity of the disease or condition, and the method of administration, and can be readily determined by one of ordinary skill in the art.

[0098] When any variable or substituent appears more than once in any structure or formula, its definition at 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 the substituents and substitution patterns in the compounds described herein can be selected by those skilled in the art to provide compounds that are chemically stable and can be easily synthesized by techniques known in the art and those methods described herein.

[0099] Further definitions may also be provided below where appropriate.

[0100] II. Compounds In certain embodiments, the subject matter described herein has formula I': [ka] [In the formula, Z is N or CH; Ring B is [ka] where [ka] indicates the point of attachment to the rest of the molecule; R 6 In each case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C 10 Alkoxy, Hydroxy-C1-C 10 -Alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-R bb , -OR bb , (C1-C6 alkyl)-NR GI R HI , -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 , halo-C1-C3 alkyl, -OR cc -OR dd , 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; Hydroxy-C1-C 10 Alkoxy or -O-(C1-C6 alkyl)-R bb wherein the alkyl moiety may be optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; R bb is a 4- to 7-membered monocyclic or bridged heterocyclyl, C-C cycloalkyl, 5- or 6-membered monocyclic heteroaryl, —SO—C-C alkyl, —S—C-C alkyl, —C(O)NR G1 R H1 , or -NR G R H and; R ccis C1-C3 alkyl; and R dd is C1-C3 alkyl or 6-membered heteroaryl; where R 6 , R bb , or R dd wherein said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, oxo, C1-C3 alkoxy, and C1-C3 alkyl; R G1 and R H1 are each independently hydrogen or C1-C3 alkyl; and R G and R H are each independently hydrogen, -C(O)R Ga or optionally deuterated C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or, 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; The heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, NH, O, S, SH, and SR, respectively. 6 , N.R.6 , and C.R. 6 where Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 One or two of these are N, NR 6 , NH, O, SH or SR 6 and can be; f is 0 or 1; p is 1 or 2; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, oxo, or cyano; m is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3 alkyl, halo-C1-C3 alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-C1-C3 alkyl; The heteroaryl or heterocyclyl may have one or two substituents, each of which is C-C 10 optionally substituted with a monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, (C-C alkyl)-T, and 5- to 7-membered monocyclic heterocyclyl; T is C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl; and where R 4wherein T or the aryl, cycloalkyl, heteroaryl, or heterocyclyl substituent is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is linear; and, ii. [ka] where: R 4a and R 4g Each of 10 Alkyl, hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 alkyl-NR J1 R J2 , C3-C7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiroheterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10 independently selected from the group consisting of (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; R J1 and R J2 are independently hydrogen or C1-C3 alkyl; where R 4a and R 4gthe cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or R 4b and R 4c and together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3 alkyl; or R 4c and R 4d are 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-C3 alkyl; or R 4c and R 4d and together with the atom to which each is attached form a C3-C7 cycloalkyl; Or, if p is 1, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. forming a 7-membered fused bicyclic heterocyclyl, a 7-membered bridged bicyclic heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the 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-C3 alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and wherein said aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forms a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l wherein s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w wherein R q is hydrogen or C1-C3 alkyl; and R w is C6-C 10 monocyclic or fused bicyclic aryl, or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. can form an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclyl, or a 12-membered bicyclic bridged and fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents (each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy); Or, if p is 2, R 3 and R 4 together with the nitrogen atom to which each is attached, i. forming a 6-membered monocyclic heterocyclyl containing one heteroatom and optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. one or two substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR G R H , and -(CH2) s C(=O)NRk R l and optionally substituted with a 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bridged, fused, or spiroheterocyclyl containing 1, 2, or 3 heteroatoms, selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If *teeth [ka] and ** is [ka] or *teeth [ka] and ** is [ka] and; wherein the compound of formula (I) is: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0101] In certain embodiments, the subject matter described herein has formula I': [ka] [In the formula, Z is N or CH; Ring B is [ka] where [ka] indicates the point of attachment to the rest of the molecule; R 6 is in each case halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(CH2) u R bb , halo-C1-C3 alkyl, -OR cc -OR dd , 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; u is an integer from 0 to 6; R bb is a 4- to 7-membered monocyclic heterocyclyl, C-C cycloalkyl, or -NR G R H and; R cc and R dd are 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 R G and R H are each independently hydrogen, -C(O)R Ga or C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; The heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 are each independently CH, N, NH, O, S, SH, or SR 6 , N.R. 6 , and C.R. 6 wherein Y is selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 One or two of them are N, NR 6 , NH, O, SH or SR 6 and can be; f is 0 or 1; p is 1 or 2; Rx is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, or cyano; m is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-branched or straight-chain C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-branched or straight-chain C1-C3 alkyl; The heteroaryl or heterocyclyl may have one or two substituents, each of which is C-C 10 independently selected from the group consisting of monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl, wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkyl, halogen, and hydroxy; and When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is linear; and ii. [ka] where: R 4a and R 4g are each hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiroheterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10independently selected from the group consisting of (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; where R 4a and R 4g the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or R 4b and R 4c each of which, together with the atom to which it is attached, forms a 5- to 7-membered monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3 alkyl; or R 4c and R 4d are 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-C3 alkyl; or R 4c and R 4deach together with the atom to which it is attached forms a C3-C7 cycloalkyl; Or, if p is 1, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. forming a 7-membered fused bicyclic heterocyclyl, a 7-membered bridged bicyclic heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and wherein said aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forming a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l and optionally substituted with an alkyl group independently selected from the group consisting of: s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R lis hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w and optionally substituted with an alkyl group independently selected from the group consisting of: R q is hydrogen or C1-C3 alkyl; and R w is C6-C 10 monocyclic or fused bicyclic aryl, or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclyl, or a 12-membered bicyclic bridged and fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy; Or, if p is 2, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. forming a 6-membered monocyclic heterocyclyl containing one heteroatom and optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. one or two substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR G R H , and -(CH2) s C(=O)NR k R l and optionally substituted with a 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bridged, fused, or spiroheterocyclyl containing 1, 2, or 3 heteroatoms, selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If * is [ka] and ** is [ka] Is; or * is [ka] and ** is [ka] and; wherein the compound of formula (I) is: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0102] In certain embodiments, the subject matter described herein has Formula I: [ka] [In the formula, Z is N or CH; R 6 is in each case halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NR G R H halo-C1-C3 alkoxy, and C3-C6 cycloalkyl; where R G and R H are each independently hydrogen or C1-C3 alkyl; Or, two R 6 The group, together with the atom to which each is attached, is a 5- or 6-membered heterocyclyl, C3-C7 cycloalkyl, C6-C 10 forming an aryl, or a 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, NH, O, S, and C(R 6 is attached thereto); provided that Y 1 , Y 2 , Y 3 , and Y4 one or two of may be N, NH, O, or S; f is 0 or 1; p is 1 or 2; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, or cyano; m is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3-alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-(branched or straight-chain) C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-(branched or straight-chain) C1-C3 alkyl; where: When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is linear; and ii. [ka] where: R 4a and R 4g are each hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl, C6-C 10 aryl, 5- to 10-membered monocyclic or bicyclic fused heteroaryl, (C6-C 10 independently selected from the group consisting of (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl; where R 4a and R 4gthe cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 7-membered heterocyclyl; or R 4b and R 4c each of which, together with the atom to which it is attached, forms a 5- to 7-membered heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, and C1-C3 alkyl; R 4c and R 4d are 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-C3 alkyl; or R 4c and R 4d and together with the atom to which each is attached form a C3-C7 cycloalkyl; Alternatively, if p is 1, then R 3 and R 4 and together with the nitrogen atom to which each is attached, i. forming a 7-membered bicyclic fused heterocyclyl, a 7-membered bridged heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, haloalkyl, and C-C alkyl. 10 aryl), wherein said aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forming a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l and optionally substituted with (independently selected from the group consisting of: where s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w and optionally substituted with (independently selected from the group consisting of: where R q is hydrogen or C1-C3 alkyl, and R wis C6-C 10 aryl or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; iii. forming an 8-, 9-, 10-, or 11-membered bicyclic fused heterocyclyl, or a 12-membered bicyclic bridged, fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy; Or, if p is 2, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. a 6-membered monocyclic heterocyclyl containing one heteroatom and optionally having one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. one or two substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, NR G R H , and -(CH2) s C(=O)NR k R l and optionally substituted with a 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bicyclic bridged, fused, or spiroheterocyclyl containing 1, 2, or 3 heteroatoms, selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If * is [ka] and ** is [ka] Is; or * is [ka] and ** is [ka] and; wherein the compound of formula (I) is: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0103] Useful compounds of formula I' or I include those where p is 1.

[0104] Useful compounds of Formula I' or I include those in which Z is N.

[0105] The integer n decreases by 1 each time, and the compound of formula I' or I has the variable group CR 6 , N.R. 6 , or SR 6 and the total number of n(CR 6 , N.R. 6 , or SR 6 The total number of which does not exceed 3)

[0106] Useful compounds of formula I' or I include compounds in which Y 1 , Y 2 , Y 3 , and Y 4 are CH or CR 6 In certain embodiments, useful compounds of formula I' or I include compounds where Y 1 is CH and Y 2 is CR 6 And Y 3 and Y 4 Useful compounds of formula I' or I include compounds where Y 3 is N and Y 1 , Y 2 , and Y 4 are CH or CR, respectively. 6 Useful compounds of formula I' or I include compounds in which Y 2 is N and Y 1 , Y 3 , Y 4 are CH or CR, respectively. 6 Useful compounds of formula I' or I include compounds in which Y 1 is N and Y 2 , Y 3 , and Y 4 are CH or CR, respectively. 6 Useful compounds of formula I' or I include compounds in which Y 1 is CH and Y 2 is CR 6 and Y 3 is CH and Y 4 is CH.

[0107] Useful compounds of formula I' or I include R 6 In any case, 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 R bb , halo-C1-C3 alkoxy, -OR cc -OR dd , halo-C1-C3 alkyl, hydroxy-C1-C 10 -Alkyl, -O-(C1-C6 alkyl)-R bb , -OR bb , -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 , and -NR G R H wherein hydroxy-C1-C 10 Alkoxy or -O-(C1-C6 alkyl)-R bb wherein the alkyl moiety may be optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; R bb Ga-NR G R H u is an integer from 1 to 3; R G and R H are each independently hydrogen or C1-C3 alkyl; and R cc and R dd is each independently C1-C3 alkyl. Useful compounds of formula I' or I include compounds where R 6In all cases, 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)OH, -OCH2CH(CH2CH3)OH, -OCH2C(CH2C H3)2OH, -OCH2CH2N(CH2CH3)2, -OCH(CH3)CH2N(CH3)2, -OCH2C(O)N(CH3)2, -OCH2C(CH3)2N(CH3)2, -OCH2CH(CH2OH)OH, -OCH2CH2NH(CH3), -OCH2CH(CF3)OH, -OCH2C(CH3)(CH2CH3)OH, -OCH2CH(CHOCH3)OH, -OCH2CH(CH2F)OH, (CH2)3N(CH3)2, (CH2)3N(CH3)H, -O-(CH2)2S(O)2CH3, -O-(CH2)2SCH3, (CH2)2C(CH3)2OH, and -CH2CH2OH. Additionally, useful compounds of Formula I' or I include compounds selected from the group consisting of R 6 is, in each case, methoxy, —OCHCHN(CH), —OCHCHOH, or —OCHC(CH)OH. Useful compounds of Formula I′ or I include compounds where R 6 In any case, -O-(CH2) u R bb and C3-C6 cycloalkyl; where u is an integer from 0 to 3; R bb is a 4- to 7-membered monocyclic heterocyclyl or C-C cycloalkyl; wherein the cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C-C alkoxy, and C-C alkyl. Useful compounds of Formula I' or I include compounds where R6 But in all cases, cyclopropyl and -O-(CH2) u R bb wherein u is 0, 1, or 2; R bb Useful compounds of formula I' or I include compounds where R is selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each of which is optionally substituted with hydroxy or methyl. 6 But in any case, [ka] [ka] selected from the group consisting of [ka] indicates the point of attachment to ring B. Useful compounds of formula I' or I include compounds where R 6 but [ka] Compounds are included in which:

[0108] Useful compounds of formula I' or I include two R 6 Useful compounds of Formula I' or I include compounds in which the groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C-C cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- or 6-membered monocyclic heteroaryl fused to Ring B, each of which is optionally substituted with one or two substituents (each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl). 6Useful compounds of Formula I' or I include compounds in which the groups, together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused to Ring B, which ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CHOH, and methyl. 6 groups, together with the atoms to which they are each attached, are fused to ring B; [ka] wherein the pair of rings is selected from the group consisting of [ka] indicates the bond between the ring and ring B. Useful compounds of formula I' or I include compounds where two adjacent R 6 groups, together with the atoms to which they are each attached, are fused to ring B; [ka] Useful compounds of formula I' or I include compounds in which two adjacent R 6 groups, together with the atoms to which they are each attached, form a ring fused to ring B, where ring B and two adjacent R 6 The bicyclic ring formed by the group [ka] The compounds include compounds selected from the group consisting of:

[0109] Useful compounds of Formula I' or Formula I include compounds where f is 1. Useful compounds of Formula I' or Formula I include compounds where f is 0 and ring B is [ka] Useful compounds of Formula I' or Formula I include compounds in which Ring B is [ka] where n is 0 or 1; Y 2 and Y 3 are CH, N, NH, and NR, respectively. 6 , S, O, and CR 6 and wherein Y is independently selected from the group consisting of: 2 and Y 3 Only one of N, NH, NR 6 , S, or O. Useful compounds of Formula I' or Formula I include those in which Ring B is [ka] Useful compounds of Formula I' or Formula I include compounds selected from the group consisting of: 6 In each case, the compound is selected from the group consisting of C1-C3 alkyl and hydroxy-C1-C3 alkyl. Useful compounds of Formula I' or Formula I include compounds in which R 6 In each case, the compounds are selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH.

[0110] Useful compounds of Formula I' or Formula I include compounds where n is 1. Useful compounds of Formula I' or Formula I include compounds where n is 0. Useful compounds of Formula I' or Formula I include compounds where n is 2, where one R 6 is selected from the group consisting of methyl and methoxy, and the other R 6 is selected from the group consisting of methyl, methoxy, halogen, and —OCH2CH2OH.

[0111] Useful compounds of Formula I' or Formula I include R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and —CHCHOH. Useful compounds of Formula I′ or Formula I include compounds where R 3is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, phenyl, -CH2CF3, and -CH2CH2OH. Useful compounds of Formula I' or Formula I include compounds where R 3 is methyl.

[0112] Useful compounds of Formula I' or Formula I include R 4 is (5-10 membered monocyclic or fused bicyclic heteroaryl)-methyl, where the heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C-C cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and the phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkyl, halogen, and hydroxy. Useful compounds of Formula I' or Formula I include compounds where R 4 is (6-membered heteroaryl)-methyl, and at least one ring atom ortho to the point of attachment of the 6-membered heteroaryl is nitrogen. Useful compounds of Formula I' or Formula I include compounds where R 4 is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, oxazolyl-methyl, and triazolyl-methyl, each optionally substituted with phenyl or benzyl, wherein the phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro. Useful compounds of Formula I' or Formula I include compounds where R 4 but [ka] The compounds include compounds selected from the group consisting of:

[0113] Useful compounds of Formula I' or Formula I include R 4 but [ka] Useful compounds of Formula I' or Formula I include compounds in which R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, —CHOH, —CHOC(CH) and —CHCHSCH; R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d and, together with the atom to which each is attached, form a cyclopropyl ring. Useful compounds of Formula I' or Formula I include compounds where R 4c and R 4d Useful compounds of Formula I' or Formula I include compounds where R 4b Useful compounds of Formula I' or Formula I include compounds where R 4a Useful compounds of Formula I' or Formula I include compounds where R 4a Useful compounds of Formula I' or Formula I include compounds where R is tert-butyl or isopropyl. 4a is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds of Formula I' or Formula I include compounds where R 4a is phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy. Useful compounds of Formula I' or Formula I include compounds where R 4a but [ka] Useful compounds of Formula I' or Formula I include compounds selected from the group consisting of: 4ais a 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, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl. Useful compounds of Formula I' or Formula I include compounds in which R 4a is pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyrazidinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl. Useful compounds of Formula I' or Formula I include compounds where R 4a but [ka] Useful compounds of Formula I' or Formula I include compounds independently selected from the group consisting of R 4a is C-C cycloalkyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds of Formula I' or Formula I include compounds in which R 4a is 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 of Formula I' or Formula I include compounds in which: [ka] Useful compounds of Formula I' or Formula I include compounds selected from the group consisting of: 4ais 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, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds of Formula I' or Formula I include compounds in which R 4a is 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, methoxy, and oxo. Useful compounds of Formula I' or Formula I include compounds in which R 4a but [ka] Useful compounds of Formula I' or Formula I include compounds selected from the group consisting of: 4a is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl; (C-C 10 Useful compounds of Formula I' or Formula I include (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl. 4a is selected from the group consisting of benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl-methyl. Useful compounds of Formula I' or Formula I include compounds where R 4a but [ka] Useful compounds of Formula I' or Formula I include compounds selected from the group consisting of: 4ais selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3. Useful compounds of Formula I' or Formula I include compounds where R 4a and R 4b and, taken 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, C-C alkyl, halo-C-C alkyl, hydroxy, and C-C alkoxy. Useful compounds of Formula I' or Formula I include compounds in which R 4a and R 4b and together with the atom to which each is attached form 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, hydroxy, and methoxy. Useful compounds of Formula I' or Formula I include compounds in which R 4a and R 4b and, together with the atoms to which they are bonded, [ka] Useful compounds of Formula I' or Formula I include compounds that form R 4b and R 4c and, taken together with the atom to which each is attached, form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with 1 or 2 substituents, each independently selected from C1-C3 alkyl. Useful compounds of Formula I' or Formula I include compounds where R 4b and R 4c and taken together with the atom to which each is attached form a piperidin-2-one or pyrrolidin-2-one optionally substituted one or two times with methyl.

[0114] Useful compounds of Formula I' or Formula I include R 4 but [ka] where R 4g But C6-C 10 Useful compounds of Formula I' or Formula I include compounds in which R is selected from the group consisting of monocyclic or fused bicyclic aryl, and C1-C3 alkyl. 4g is selected from the group consisting of phenyl and methyl.

[0115] Useful compounds of Formula I' or Formula I include R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms; where if the 7-membered heterocyclyl contains 1 heteroatom, the heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; where if the 7-membered heterocyclyl contains 2 heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 Useful compounds of Formula I' or Formula I include compounds where R is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, halogen, and C-C alkyl. 3 and R 4and, together with the nitrogen atom to which each is attached, form a 7-membered heterocyclyl containing one heteroatom, wherein the heterocyclyl is optionally substituted once with methyl or oxo; or form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein the heteroatoms are N or O and the heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, methyl, and oxo, wherein the phenyl is optionally substituted with methoxy. Useful compounds of Formula I' or Formula I include compounds in which R 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] Compounds that form:

[0116] Useful compounds of Formula I' or Formula I include R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 10- or 11-membered fused bicyclic heterocyclyl or a 12-membered bicyclic fused and bridged heterocyclyl containing one heteroatom, each of which is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of C-C alkyl, C-C alkoxy, hydroxy, and halogen. Useful compounds of Formula I' or Formula I include compounds in which R 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] Compounds that form:

[0117] Useful compounds of Formula I' or Formula I include R 3 and R 4and each together with the nitrogen atom to which it is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is -(CH) s C(=O)NR k R l s is 0, 1 or 2; R k is hydrogen or C1-C3 alkyl; R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; said 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w wherein R q is hydrogen or C1-C3 alkyl; R w C6-C 10 Useful compounds of Formula I' or Formula I include compounds that are monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, where the 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. 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] Compounds that form:

[0118] Useful compounds of Formula I' or Formula I include R x is, in each case, methyl. Useful compounds of Formula I' or Formula I include compounds where m is 0. Useful compounds of Formula I' or Formula I include compounds where m is 2.

[0119] The subject matter described herein includes the following compounds listed in Table 1, or pharmaceutically acceptable salts thereof:

[0120] Table 1. If the mass of a compound is not provided in Table 1, the mass of that compound can be found in the Synthesis Examples. [Table 1] [Table 2] [Table 3] [Table 4] [Table 5]

[0121] [Table 6] [Table 7] [Table 8] [Table 9] [Table 10]

[0122] [Table 11] [Table 12] [Table 13] [Table 14] [Table 15]

[0123] Table 16

Table 17

Table 18

Table 19

[0124] Table 21 Table 22 Table 23 Table 24 Table 25

[0125] Table 26 Table 27 Table 28 Table 29 Table 30

[0126] Table 31 Table 32

Table 33

[0127] Table 36 Table 37 Table 38 Table 39 Table 40

[0128] Table 41 Table 42 Table 43 Table 44 Table 45

[0129] Table 46 Table 47 Table 48 Table 49

Table 50

[0130] Table 51 Table 52 Table 53 Table 54 Table 55

[0131] Table 56 Table 57 Table 58 Table 59 Table 60

[0132] Table 61 Table 62 Table 63 Table 64 Table 65

[0133] Table 66 Table 67 Table 68 Table 69 Table 70

[0134] Table 71 Table 72 Table 73 Table 74 Table 75

[0135] Table 76 Table 77 Table 78 Table 79 Table 80

[0136] Table 81 Table 82 Table 83 Table 84 Table 85

[0137] Table 86 Table 87 Table 88 Table 89 Table 90

[0138]

Table 91

Table 93

Table 95

[0139] Table 96 Table 97 Table 98

Table 99

Table 100

[0140] Table 101 Table 102 Table 103 Table 104 Table 105

[0141] Table 106 Table 107 [Table 108] [Table 109] [Table 110]

[0142] III. Pharmaceutical Compositions and Methods of Administration The compounds provided herein are typically administered in the form of pharmaceutical compositions. Thus, pharmaceutical compositions are also provided that include one or more of the compounds described herein, or pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers thereof, and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants, and excipients. Suitable pharmaceutically acceptable vehicles may include, for example, diluents, penetration enhancers, solubilizers, and adjuvants, including inert solid diluents and fillers, sterile aqueous solutions, and various organic solvents. Such compositions are prepared by methods well known in the pharmaceutical arts. See, for example, Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th Ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd Ed. (Edited by G.S. Banker & C.T. Rhodes).

[0143] Pharmaceutical compositions can be administered in single dose or multiple doses.Pharmaceutical compositions can be administered by various methods, including, for example, rectal, buccal, intranasal or transdermal route.In certain embodiments, pharmaceutical compositions can be administered by intraarterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically or as an inhalant.

[0144] One method of administration is parenteral administration, for example, by injection. Forms in which the pharmaceutical compositions described herein can be formulated for administration by injection include, for example, aqueous or oily suspensions or emulsions containing sesame oil, corn oil, cottonseed oil, or peanut oil, as well as elixirs, mannitol, dextrose, or sterile aqueous solutions and similar pharmaceutical vehicles.

[0145] Oral administration is another route for administering the compounds described herein. Administration can be, for example, via capsules or enteric-coated tablets. In preparing pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof, the active ingredient is usually diluted with an excipient and / or enclosed in such a carrier, which can be in the form of a capsule, sachet, paper, or other container. When an excipient serves as a diluent, it can be in the form of a solid, semi-solid, or liquid material that acts as a vehicle, carrier, or medium for the active ingredient. Thus, the composition can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (as solids or in liquid media), for example, ointments containing up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injection solutions, and sterile packaged powders.

[0146] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, acacia gum, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup, and methylcellulose. The formulation may further include lubricants such as talc, magnesium stearate, and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl and propyl hydroxybenzoates; sweeteners; and flavoring agents.

[0147] Pharmaceutical compositions containing at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer, or mixture of stereoisomers thereof can be formulated to provide rapid, sustained, or delayed release of the active ingredient after administration to a subject by utilizing procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems (containing polymer-coated reservoirs or drug-polymer matrix formulations). Examples of controlled-release systems are described 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 utilizes transdermal delivery devices ("patches"). Such transdermal patches may be used to provide continuous or discontinuous infusion of the compounds described herein in controlled amounts. The construction and use of transdermal patches to deliver pharmaceutical agents is well known in the art. See, for example, US 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.

[0148] When preparing solid compositions such as tablets, the primary 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, stereoisomer, or mixture of stereoisomers. These preformulation compositions are said to be homogeneous because the active ingredient is dispersed evenly throughout the composition so that the composition can be readily subdivided into equally effective unit dosage forms such as tablets, pills, and capsules.

[0149] The tablets or pills of the compounds described herein may be coated or otherwise treated to provide a dosage form that provides the benefit of long-lasting action or to protect the compounds from the acidic conditions of the stomach. For example, the tablets or pills may comprise an inner dosage component and an outer dosage component, the latter being in the form of an envelope surrounding the former. The two components may be separated by an enteric layer that serves to resist disintegration in the stomach and allows the inner component to pass intact into the duodenum or be delayed in release. A variety of materials can be used for such enteric layers or coatings, including a number of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0150] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof, and powders. Liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by oral or nasal respiratory route for local or systemic effect. In another embodiment, compositions in pharmaceutically acceptable solvents may be nebulized by use of an inert gas. Nebulized solutions may be inhaled directly from the nebulizing device, or the nebulizing device may be attached to a face mask tent or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered from a device that delivers the formulation in an appropriate manner, preferably orally or nasally.

[0151] The specific dose level of the compounds of the present application for any particular subject will depend on various factors, including the activity of the specific compound used, age, body weight, health, sex, diet, administration time, administration route and excretion rate, drug combination, and the severity of the specific disease in the subject being treated. For example, the dosage can be expressed as milligrams of the compounds described herein per kg of subject body weight (mg / kg). A dosage between about 0.1 mg / kg and 150 mg / kg may be appropriate. In some embodiments, a dosage between about 0.1 mg / kg and 100 mg / kg may be appropriate. In other embodiments, a dosage between 0.5 mg / kg and 60 mg / kg may be appropriate. Normalizing according to subject body weight is particularly useful when adjusting dosages between subjects of widely different sizes, such as when using drugs in both children and adults, or when converting effective doses in non-human subjects, such as dogs, to dosages suitable for human subjects. Doses may be administered once daily (QID), twice daily (BID), or more frequently, depending on the pharmacokinetic and pharmacodynamic properties of a particular compound, including absorption, distribution, metabolism, and excretion. Additionally, toxicity factors may influence the dosage and administration schedule. When administered orally, pills, capsules, or tablets may be taken daily or less frequently for a specific period of time. The schedule may be repeated for many treatment cycles.

[0152] IV. Treatment method In certain embodiments, the subject matter described herein is directed to a method for inhibiting ferroportin-mediated iron transport 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.

[0153] In certain embodiments, the subject matter described herein is directed to a method of treating a subject suffering from a disease associated with or caused by decreased hepcidin levels, increased ferroportin levels, decreased sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or wasted erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I or Formula I'.

[0154] In certain embodiments, the disease is associated with or caused by decreased hepcidin levels, decreased sensitivity of ferroportin to hepcidin, a hemoglobin disorder, or iron overload.

[0155] In certain embodiments, the disease is associated with or caused by decreased hepcidin levels or decreased sensitivity of ferroportin to hepcidin.

[0156] In certain embodiments, the disease is iron overload.

[0157] In certain embodiments, the disease is associated with or caused by a hemoglobin disorder.

[0158] In certain embodiments, the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease.

[0159] In certain embodiments, the disease is sickle cell disease.

[0160] In certain embodiments, the sickle cell disease is sickle cell anemia.

[0161] The methods described herein may be applied to in vivo or in vitro cell populations. "In vivo" means within a living individual, such as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. "Ex vivo" means outside a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including fluid or tissue samples obtained from an individual. 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 optimal schedules and / or doses of administering the disclosed compounds for a given indication, cell type, individual, and other parameters. Information obtained from such use may be used to design protocols for in vivo treatment, either experimentally or in the clinic. Other ex vivo uses to which the compounds and compositions described herein may be applied are described below or will become apparent to those skilled in the art. Selected compounds may be further characterized to determine safety or tolerated dosages in human or non-human subjects. Such properties can be determined using methods commonly known to those skilled in the art.

[0162] The ferroportin inhibitory activity of the compounds of Formula I or Formula I', and their pharmaceutically acceptable salts, makes them particularly suitable for use in inhibiting ferroportin-mediated iron transport. Thus, the compounds of Formula I or Formula I', and their pharmaceutically acceptable salts, are useful in reducing hepcidin levels, increasing ferroportin levels, reducing the sensitivity of ferroportin to hepcidin, increasing iron levels, increasing iron absorption, and preventing and / or treating diseases associated with or caused by iron overload, increased erythropoiesis, stress erythropoiesis, or wasteful erythropoiesis.

[0163] Furthermore, the compounds of Formula I or Formula I' are suitable for use in adjunctive therapy by limiting the amount of iron available to pathogenic microorganisms, such as 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.

[0164] In certain embodiments, the subject matter described herein is directed to a method of inhibiting ferroportin-mediated iron transport 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.

[0165] In certain embodiments, the subject matter described herein is directed to a method of treating a subject suffering from a disease associated with or caused by decreased hepcidin levels, increased ferroportin levels, decreased sensitivity of ferroportin to hepcidin, a hemoglobin disorder, increased iron levels, increased iron absorption, iron overload (e.g., due to blood transfusions), increased erythropoiesis, stress erythropoiesis, or wasted erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof. In aspects of these embodiments, the treatment comprises inhibiting ferroportin-mediated iron transport in the subject.

[0166] In certain embodiments, the subject matter described herein is directed to methods of treating a subject suffering from a disease associated with or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobin disorder, or iron overload.

[0167] In certain embodiments, the subject matter described herein is directed to a method of treating a subject suffering from a disease associated with or caused by decreased hepcidin levels or decreased sensitivity of ferroportin to hepcidin. In certain aspects of this embodiment, the disease is iron overload.

[0168] In certain embodiments, the subject matter described herein is directed to a method for treating a subject suffering from a disease associated with or caused by hemoglobin disorder.In 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 aspects of this embodiment, the disease is sickle cell anemia.

[0169] In certain embodiments, diseases associated with, associated with, caused by, or leading to improved iron levels, increased iron absorption, iron overload (e.g., tissue iron overload), or wasteful erythropoiesis include thalassemia, hemoglobin disorders such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), hemochromatosis, and hemolytic anemia (e.g., sickle cell anemia and congenital dyserythropoiesis). Additional diseases associated with, associated with, caused by, or resulting from improved iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) include, for example, neurodegenerative diseases such as Alzheimer's disease, Parkinson's disease, Huntington's disease, multiple sclerosis, Wilson's disease, amyotrophic lateral sclerosis (ALS), and Friedreich's ataxia, in which the compounds and methods limit tissue or cellular iron deposition or accumulation, thereby limiting symptoms associated with the formation of radicals, reactive oxygen species (ROS), and oxidative stress caused by excess iron or iron overload; cardiac, hepatic, and endocrine damage caused by excess iron or inflammation resulting from iron overload; diseases associated with wasted erythropoiesis, such as myelodysplastic syndromes (MDS), polycythemia vera, and congenital dyserythropoietic anemia; diseases, disorders, and / or conditions involving iron overload caused by mutations in genes involved in sensing systemic iron stores, such as hepcidin / hepcidin antimicrobial peptide (HAMP), iron overload protein (HFE), hemojuvelin (HJV), and transferrin receptor 2 (TFR2), particularly diseases associated with HFE and HJV gene mutations; diseases associated with mutations in ferroportin;Chronic hemolysis-related disorders, sickle cell disease (including sickle cell anemia (HbSS) and hemoglobin S-C disease (HbSC), hemoglobin S beta-plus thalassemia (HbS / beta+), and hemoglobin S beta-zero thalassemia (HbS / beta0)), red blood cell membrane disorders, glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythroblastic porphyria, Friedreich's ataxia, and subgroups of iron overload disorders such as transfusional iron overload, iron poisoning, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron overload syndrome, Hall-Bodin-Spatz disease, and hyperferritinemia It is believed to be effective for treating red blood cell disorders, including thalassemia, ceruloplastin deficiency, neonatal hemacromatosis, and thalassemias including alpha thalassemia, beta thalassemia, and delta thalassemia, clonogenic thalassemia, sickle cell disease, and myelogenous syndrome; liver disorders (e.g., hepatitis B virus infection, hepatitis C virus infection, alcoholic liver disease, autoimmune hepatitis), ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataracts, age-related retinal disease, pantothenate kinase-associated neurodegeneration, restless leg syndrome, and Huntington's disease, among others. In certain embodiments, the disease is sickle cell anemia. For example, the ferroportin inhibitory activity of the compound of Formula I and its pharmaceutically acceptable salts by inducing ferroportin internalization can be determined by the assays described herein and the assays described in WO2018 / 192973 (incorporated herein by reference in its entirety).

[0170] The activity of the compound of Formula I or Formula I' in treating sickle cell anemia (sickle cell disease) can be measured by using a mouse experiment, for example, as described in Yulin Zhao et al., "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. The mouse experiment is appropriately adapted to the treatment of sickle cell anemia, and the activity of the compound of Formula I or Formula I' can be measured. In certain embodiments, the disease is caused by a lack of hepcidin or an iron metabolism disorder, particularly an iron overload condition such as thalassemia, sickle cell disease, and iron overload. In certain embodiments, the disease is associated with or caused by the following: reduced hepcidin level, increased iron level, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis or wasteful erythropoiesis.In certain embodiments, the disease is selected from the group consisting of thalassemia, hemoglobin disorder, hemoglobin E disease, hemoglobin H disease, hemochromatosis and hemolytic anemia.

[0171] In certain embodiments, the methods of administration and treatment described herein further comprise co-administration with one or more additional pharmaceutically active compounds or in combination with blood transfusions.

[0172] In combination therapy, pharmaceutically active compounds can be administered simultaneously, in the same formulation, or at different times. Such combination therapy includes co-administration of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof, with at least one additional pharmaceutically active compound. Combination therapy in fixed-dose combination therapy includes co-administration of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof, with at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in flexible-dose combination therapy includes co-administration of a compound of Formula I or Formula I', or a pharmaceutically acceptable salt thereof, with at least one additional pharmaceutically active compound, with each compound at a flexible dose, either by administering the individual compounds simultaneously or by using the individual compounds sequentially over a period of time.

[0173] Further pharmaceutically active compounds include drugs (e.g., Tmprss6-ASO or siRNA) or iron chelators, in particular for reducing iron overload, antioxidants such as curcumin, SSP-004184, deferithrin, deferasirox, deferoxamine and / or deferiprone, or n-acetylcysteine, antidiabetic agents such as GLP-1 receptor agonists, antibiotics such as penicillin, vancomycin (Van) or tobramycin, antifungal agents, interferon, antifungal agents ... These include antiviral drugs such as estrogen-a or ribavirin, drugs for treating malaria, anticancer drugs, drugs for treating neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (e.g., dopamine agonists such as levodopa), or immunosuppressants (cyclosporin A or cyclosporin A derivatives), iron supplements, vitamin supplements, erythropoiesis-stimulating agents (e.g., erythropoietin, Epo), anti-inflammatory agents, antithrombotic agents, statins, vasodilators, and cardiotonic compounds. A further object of the present invention relates to the use of the above-mentioned combination therapy for the prevention and / or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, for example, particularly iron overload conditions such as thalassemia, sickle cell disease, and iron overload, as well as other disorders described herein.

[0174] In certain embodiments, the subject matter described herein is directed to a method for treating beta-thalassemia (β-thalassemia) in a subject, comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. The compounds of Formula I described herein act as ferroportin inhibitors and can be used to treat severe forms of β-thalassemia, such as transfusion-dependent β-thalassemia, including β-thalassemia major and hemoglobin E β-thalassemia, and associated symptoms and conditions, such as impaired erythropoiesis in the bone marrow, wasted erythropoiesis, low hemoglobin levels / anemia, multiple organ failure, iron overload, liver iron overload and cardiac iron overload, pallor, fatigue, jaundice, and splenic enlargement, among others.

[0175] In particular, the severe forms of b-thalassemia are transfusion-dependent b-thalassemia (TDT), particularly including b-thalassemia major, and severe forms of hemoglobin E b-thalassemia. Severe forms of b-thalassemia and hemoglobin E 13-thalassemia require patients suffering from them to receive regular blood transfusions / red blood cell transfusions (RBC transfusions). Thus, such severe forms of b-thalassemia are also summarized as transfusion-dependent b-thalassemia (TDT). Therefore, the method for treating severe forms of b-thalassemia, particularly transfusion-dependent b-thalassemia (TDT), includes the method for treating severe forms of b-thalassemia, particularly b-thalassemia major and hemoglobin E b-thalassemia, by administering one or more compounds of Formula I described herein to a subject in need thereof.

[0176] The subject may be a patient suffering from b-thalassemia or hemoglobin E b-thalassemia and requiring regular blood transfusions; suffering from b-thalassemia major and / or severe hemoglobin E b-thalassemia, more particularly suffering from b-thalassemia major.

[0177] Methods for treating beta-thalassemia may result in the improvement of at least one parameter of red blood cell response, including reducing the transfusion burden in a subject; reducing the transfusion burden in a subject compared to the transfusion burden before treatment with the method; achieving no longer the need for transfusions in a transfusion-dependent b-thalassemia subject; reducing serum ferritin levels in a subject; and reducing symptoms associated with one or more clinical complications of transfusion-dependent b-thalassemia. Examples of transfusion-dependent b-thalassemia symptoms include, but are not limited to, growth retardation, pallor, jaundice, muscle weakness, genu valgum, hepatosplenomegaly, leg ulcers, the development of masses resulting from extramedullary hematopoiesis, skeletal changes due to bone marrow expansion, and clinical complications of chronic red blood cell transfusions, such as hepatitis B virus infection, hepatitis C virus infection, and human immunodeficiency virus infection, alloimmunization, and organ damage due to iron overload, such as liver damage, heart damage, and endocrine gland damage. Although the compounds of formula (I) are not believed to directly affect growth differentiation factor 11 (GDF11), reduced skeletal deformities may also occur due to reduced extramedullary erythropoiesis.

[0178] The following parameters can be measured to evaluate the effectiveness of the compound of the present invention in new medical applications: serum iron, NTBI level, LPI (labile serum iron) level, erythropoietin, TSAT (transferrin saturation), Hb (hemoglobin), Hct (hematocrit), MCV (mean cell volume), MCH (mean cell hemoglobin), RDW (red blood cell distribution width) and reticulocyte count, total blood count, spleen and liver weight, erythrocyte production in spleen and bone marrow, iron content in spleen and liver, and alpha-globin aggregates in RBC membrane.These measurements can be carried out by conventional methods in the art, particularly by the following method in more detail.Compound (I) of the present invention is suitable for improving at least one of these parameters.

[0179] The method may be administered prior to or concomitantly with transfusion to prevent or at least attenuate the occurrence of transfusion-related morbidity.

[0180] In certain embodiments, the subject matter described herein is directed to a method for preventing and treating kidney injury in a subject, comprising administering to the subject an effective amount of a compound of Formula I, or a pharmaceutically acceptable salt thereof. In certain aspects of these embodiments, the compound of Formula I can be co-administered with another pharmaceutically active compound. In certain aspects of these embodiments, the kidney injury is an injury induced by catalytic free iron. In certain aspects of these embodiments, the kidney injury is selected from renal ischemia-reperfusion injury (IRI), ischemic injury, and acute kidney injury. In further aspects, the kidney injury is selected from acute kidney injury (AKI), renal ischemia-reperfusion injury (IRI), ischemic injury, and AKI caused by ischemic injury, particularly AKI after surgery or surgical intervention, such as after cardiac surgery, most often involving cardiopulmonary bypass, other major thoracic or abdominal surgery, and kidney injury associated with RBC transfusion.

[0181] Terms such as "prevent" include, for example, protecting against ischemic renal injury, avoiding the development of AKI, or at least reducing the severity of AKI following ischemic injury, RBC transfusion, or surgical intervention, by administering a compound prior to, concomitant with, or immediately after an ischemic event, RBC transfusion, or surgical intervention, thereby preventing or at least attenuating the occurrence of catalytic free iron-induced renal injury.

[0182] Catalytic free iron, or labile iron, or NTBI is believed to be a major cause of ischemia-induced renal injury, particularly AKI. Administration of the ferroportin inhibitor compounds of Formula (I) described herein can antagonize and protect against the damaging effects of catalytic free iron. Without being bound by theory, the ferroportin inhibitors described herein can reduce or prevent the formation of catalytic free iron or NTBI by sequestering iron in macrophages in the liver and spleen, thereby lowering its levels in plasma and reducing the risk of ROS formation. The compounds of Formula I described herein may act as ferroportin inhibitors, sequestering iron in macrophages and thereby interrupting the cycle of self-sustained release of catalytic free iron. The compounds of Formula I avoid renal tissue damage by limiting reactive oxygen species (ROS), making them suitable for preventing and treating renal injury as described herein. In addition to catalytic free iron, NTBI and LPI (labile plasma iron) can also cause renal injury. NTBI encompasses all forms of serum iron that are not tightly bound to transferrin and are chemically and functionally heterogeneous. LPI represents a component of NTBI that has both redox-active and chelating properties, the ability to penetrate into organs, and induce tissue iron overload.

[0183] The following parameters may be measured to assess the efficacy of a compound for treating kidney injury: plasma creatinine, glomerular filtration rate (including estimated glomerular filtration rate eGFR), urinary albumin excretion, urinary neutrophil gelatinase-associated lipokine (NGAL), NTBI, LPI, RBC hemolysis, serum urea nitrogen (BUN), plasma hemoglobin (Hb), plasma total iron, plasma hepcidin, renal neutrophil infiltration, serum IL-6, spleen, kidney and / or liver iron content, renal ferroportin, KIM-1 (kidney injury molecule-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 invention may be determined via assessing histology (e.g., as described in Khalid et al., "Kidney ischemia reperfusion injury in the rat the EGTI scoring system as a valid and reliable tool for histological assessment," Journal of Histology & Histopathology, Vol. 3, 2016), for example, via renal ureteral injury scores such as the CSA-NGAL score (Cardiac Surgery Associated NGAL Score) to detect acute tubular injury, as described in more detail below, the KDIGO score, as described in more detail below, or the EGTI score (including endothelial, glomerular, tubular, and interstitial (EGTI) components).

[0184] A method for treating or preventing kidney injury may result in a decrease in serum creatinine (sCr) in a subject. A method for treating or preventing kidney injury may result in a correction (reduction) of urinary albumin excretion in a subject. A method for treating or preventing kidney injury may result in a decrease in serum urea nitrogen (BUN) in a subject. A method for treating or preventing kidney injury may result in a decrease in plasma total iron in a subject. A method for treating or preventing kidney injury may result in a decrease in interleukin-6 (IL-6) levels in a subject. A method for treating or preventing kidney injury may result in a decrease in KIM-1 levels in a subject. A method for treating or preventing kidney injury may result in a decrease in splenic and / or liver iron concentrations in a subject. A method for treating or preventing kidney injury may result in a decrease in kidney iron concentrations in a subject. A method for treating or preventing kidney injury may result in a decrease in NTBI levels. A method for treating or preventing kidney injury may result in a decrease in LP1 levels in a subject. A method for treating or preventing kidney injury may result in an inhibition of tubular injury, such as tubular necrosis. The method for treating or preventing kidney injury may result in the inhibition of apoptosis. The method for treating or preventing kidney injury may result in a reduction in IRI-induced renal neutrophil infiltration. The method for treating or preventing kidney injury may result in a reduction in ROS levels in the kidney tissue of a subject. The method for treating or preventing kidney injury may result in a correction (increase) in renal H-ferritin levels in a subject. In particular, the method for treating or preventing kidney injury may reduce the incidence of AKI, renal ischemia-reperfusion injury, and AKI caused by ischemic injury, especially AKI after postoperative or surgical interventions such as cardiac surgery, the majority of which involve cardiopulmonary bypass, other major thoracic or abdominal surgery, and kidney injury associated with RBC transfusion.Methods of treating or preventing kidney damage may include a) reducing, promoting a reduction, or preventing an increase in serum creatinine; and / or b) increasing or preventing a reduction in estimated glomerular filtration rate (eGFR); and / or c) reducing or preventing an increase in renal ferroportin; and / or d) improving or preventing a decrease in H-ferritin levels; and / or e) reducing or preventing an increase in renal neutrophil infiltration; and / or f) reducing or preventing an increase in serum IL-6 levels. V. Methods for Making Compounds of Formula I and Pharmaceutically Acceptable Salts Thereof

[0185] The compounds can be synthesized by synthetic routes, including methods well known in the art of chemistry, particularly in light of the description contained herein, and methods similar to 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 is incorporated herein by reference. Starting materials, including supplements, are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those of skill 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, NY (1967-2006 ed.) or by methods described in Beilstein's Handbuch der organischen Chemie, 4, Aufl. ed. Springer-Verlag, Berlin (also available through the Beilstein online database). DTT refers to dithiothreitol. DHAA refers to dehydroascorbic acid.

[0186] Synthetic chemistry transformations and protecting group methodologies (protection and deprotection) useful for synthesizing the compounds and the necessary reagents and intermediates are known in the art and include those described, for example, in R. Larock, Comprehensive-Organic Transformations, VCH Publishers (1989); T.W. Greene and P.G.M. Wuts, Protective Groups in-Organic Synthesis, 3rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for-Organic Synthesis, John Wiley and Sons (1995) and subsequent editions.

[0187] Compounds can be prepared singly or as libraries of compounds containing at least two, e.g., 5 to 1000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I may be prepared by combinatorial "split-and-mix" methods or by multiple parallel syntheses using either solution-phase or solid-phase chemistry, by procedures known to those of skill in the art. Thus, according to a further embodiment, there is provided a library of compounds containing at least two compounds, or pharmaceutically acceptable salts thereof.

[0188] The subject matter described herein relates to the following embodiments: 1A. Formula (I): [ka] [In the formula, Z is N or CH; R 6 is in each case halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NR G RH halo-C1-C3 alkoxy, and C3-C6 cycloalkyl; where R G and R H are each independently hydrogen or C1-C3 alkyl; or 2 R's 6 The group, together with the atom to which each is attached, is a 5- or 6-membered heterocyclyl, C3-C7 cycloalkyl, C6-C 10 forming an aryl, or a 5- to 10-membered heteroaryl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, NH, O, S, and C(R 6 is attached thereto); provided that Y 1 , Y 2 , Y 3 , and Y 4 one or two of may be N, NH, O, or S; f is 0 or 1; p is 1 or 2; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, or cyano; m is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3-alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-(branched or straight-chain) C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-(branched or straight-chain) C1-C3 alkyl; where: When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is linear; and ii. [ka] where: R 4a and R 4g are each hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl, C6-C 10 aryl, 5- to 10-membered monocyclic or bicyclic fused heteroaryl, (C6-C 10 independently selected from the group consisting of (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl; where R 4a and R 4g the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 7-membered heterocyclyl; or R 4b and R 4c each of which, together with the atom to which it is attached, forms a 5- to 7-membered heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halo, and C1-C3 alkyl; or R 4c and R 4dare 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-C3 alkyl; or R 4c and R 4d and together with the atom to which each is attached form a C3-C7 cycloalkyl; Alternatively, if p is 1, then R 3 and R 4 and together with the nitrogen atom to which each is attached, i. forming a 7-membered bicyclic fused heterocyclyl, a 7-membered bridged heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, haloalkyl, and C-C alkyl. 10 aryl); wherein the aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forming a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R land optionally substituted with (independently selected from the group consisting of: where s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w and optionally substituted with (independently selected from the group consisting of: where R q is hydrogen or C1-C3 alkyl, and R w is C6-C 10 aryl or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. forming an 8-, 9-, 10-, or 11-membered bicyclic fused heterocyclyl, or a 12-membered bicyclic bridged, fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy; Or, if p is 2, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. a 6-membered monocyclic heterocyclyl containing one heteroatom and optionally having one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. one or two substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, NR G R H , and -(CH2) s C(=O)NR k R l and optionally substituted with a 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bicyclic bridged, fused, or spiroheterocyclyl containing 1, 2, or 3 heteroatoms, selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If * is [ka] and ** is [ka] Is; or * is [ka] and ** is [ka] and; wherein the compound of formula (I) is: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof. 2A. The compound of embodiment 1A, where: Z is N; R 6 In each case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, and NR G R H selected from the group consisting of: where R G and R H are each independently hydrogen or C1-C3 alkyl; or 2 R's 6 When the group, together with the atom to which it is attached, is a 5- or 6-membered heterocyclyl, C-C 10 forming an aryl, or a 5- to 10-membered heteroaryl; n is 0, 1 or 2; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, NH, and C(R 6 is attached thereto); provided that Y 1 , Y 2 , Y 3 , and Y 4 one or two of which may be N or NH; f is 0 or 1; p is 1 or 2; m is 0; R 3 is selected from the group consisting of hydrogen, C1-C3 alkyl, and hydroxy-C1-C3-alkyl; R 4 is the following group: i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-(branched or straight-chain) C1-C3 alkyl; where: When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is linear; and ii. [ka] where: R 4a is C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic heterocyclyl, C6-C 10 aryl, 5- to 10-membered monocyclic or bicyclic fused heteroaryl, (C6-C 10 (aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl; where R 4a wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl; R 4g But C6-C 10 selected from the group consisting of aryl and C1-C3 alkyl; R 4bis hydrogen or C1-C6 alkyl; Or, R 4a and R 4b and each together with the atom to which it is attached form a 5- to 7-membered heterocyclyl; Or, R 4b and R 4c and together with the atom to which each is attached form a 5- to 7-membered heterocyclyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of C1-C3 alkyl; R 4c and R 4d are each independently hydrogen or C1-C3 alkyl; Or, R 4c and R 4d and together with the atom to which each is attached form a C3-C5 cycloalkyl; selected from the group consisting of: or, R 3 and R 4 and together with the nitrogen atom to which each is bonded, i. forming a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, haloalkyl, and C-C alkyl. 10 aryl); and wherein the aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forming a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is -(CH2) s C(=O)NR k R l optionally substituted with; where s is 0, 1, or 2; R k is hydrogen or C1-C3 alkyl; and R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w and optionally substituted with (independently selected from the group consisting of: where R q is hydrogen or C1-C3 alkyl, and R w C6-C 10 aryl or C3-C7 cycloalkyl, wherein the 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; or iii. Compounds containing one heteroatom forming a 10- or 11-membered bicyclic fused heterocyclyl, optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C-C alkyl, C-C alkoxy, hydroxy, and halogen. 3A. The compound of embodiment 1A or 2A, wherein Y 1 , Y 2 , Y 3 , and Y 4are CH or C (where R 6 A compound in which: 4A. The compound of embodiment 1A or 2A, wherein Y 3 is N and Y 1 , Y 2 , and Y 4 are CH or C (where R 6 A compound in which: 5A. The compound of embodiment 1A or 2A, wherein Y 2 is N and Y 1 , Y 3 , Y 4 are CH or C (where R 6 A compound in which: 6A. The compound of embodiment 1A or 2A, wherein Y 1 is N and Y 2 , Y 3 , and Y 4 are CH or C (where R 6 A compound in which: 7A. The compound of any one of embodiments 1A-6A, wherein R 6 In each case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C3 alkoxy, hydroxy-C1-C3-alkyl, and NR G R H selected from the group consisting of: where R G and R H are each independently hydrogen or C1-C3 alkyl. 8A. The compound of embodiment 7A, wherein R 6 in each case selected from the group consisting of methoxy, methyl, fluoro, chloro, ethyl, N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, and -CH2CH2OH. 9A. The compound of embodiment 8A, wherein R 6is in each case methoxy or methyl. 10A. The compound of any one of embodiments 1A-6A, wherein two R 6 When the group, together with the atom to which it is attached, is a 5- or 6-membered heterocyclyl, C-C 10 Compounds that form an aryl or a 5- to 10-membered heteroaryl. 11A. The compound of embodiment 10A, wherein two R 6 A compound in which groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, or phenyl ring. 12A. The compound of any one of embodiments 1A-11A, wherein n is 1. 13A. The compound of any one of embodiments 1A-11A, wherein n is 0. 14A. The compound of any one of embodiments 1A-13A, wherein f is 1. 15A. The compound of any one of embodiments 1A-13A, wherein f is 0. 16A. The compound of any one of embodiments 1A-15A, wherein R 3 is selected from the group consisting of hydrogen, methyl, and —CH2CH2OH. 17A. The compound of embodiment 16A, wherein R 3 is methyl. 18A. The compound of any one of embodiments 1A-17A, wherein R 4 is (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl. 19A. The compound of embodiment 18A, wherein R 4 is (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl, wherein at least one ring atom ortho to the point of attachment is nitrogen or oxygen. 20A. The compound of embodiment 18A or 19A, wherein R 4is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, and benzoxazole-methyl. 21A. The compound of any one of embodiments 1A-17A, wherein R 4 but [ka] A compound. 22A. The compound of embodiment 21A, wherein R 4c and R 4d is each independently hydrogen or methyl. 23A. The compound of embodiment 22A, wherein R 4c and R 4d A compound where each is hydrogen. 24A. The compound of any one of embodiments 21A-23A, wherein R 4b is hydrogen. 25A. The compound of any one of embodiments 21A-24A, wherein R 4a is C1-C6 alkyl. 26A. The compound of embodiment 25A, wherein R 4a is tert-butyl. 27A. The compound of any one of embodiments 21A-24A, wherein R 4a is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl; 10 A compound which is aryl. 28A. The compound of embodiment 27A, wherein R 4a is phenyl optionally substituted with fluoro or methoxy. 29A. The compound of any one of embodiments 21A-24A, wherein R 4ais a 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, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl. 30A. The compound of embodiment 29A, wherein R 4a is pyridinyl or quinolinyl optionally substituted with fluoro, methoxy, or methyl. 31A. The compound of any one of embodiments 21A-24A, wherein R 4a is a C3-C7 cycloalkyl optionally substituted with one or two substituents (each independently selected from the group consisting of halogen, C1-C6 alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl). 32A. The compound of embodiment 31A, wherein R 4a is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl optionally substituted with methyl, trifluoromethyl, fluoro, or hydroxy. 33A. The compound of any one of embodiments 21A-24A, wherein R 4a is a 5- or 6-membered heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl. 34A. The compound of embodiment 33A, wherein R 4ais selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl and oxo. 35A. The compound of any one of embodiments 21A-24A, wherein R 4a is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, haloalkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiroheterocyclyl; 10 (aryl)-C1-C3 alkyl, or (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl. 36A. The compound of embodiment 35A, wherein R 4a is phenyl-methyl or pyridinyl-methyl. 37A. The compound of any one of embodiments 21A-23A, wherein R 4a and R 4b and, together with the atom to which each is attached, form a 5- to 7-membered heterocyclyl. 38A. The compound of embodiment 37A, wherein R 4a and R 4b and each together with the atom to which it is attached is a 6-membered heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl. 39A. The compound of any one of embodiments 21A or 25A-36A, wherein R 4b and R 4c and taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl optionally substituted once or twice with C1-C3 alkyl. 40A. The compound of embodiment 39A, wherein R 4b and R 4cand together with the atom to which each is attached form piperidin-2-one or pyrrolidin-2-one, optionally substituted once or twice with C1-C3 alkyl. 41A. A compound of any one of embodiments 1A-17A, wherein R 4 but [ka] A compound. 42A. The compound of embodiment 41A, wherein R 4g is phenyl or methyl. 43A. A compound of any one of embodiments 1A-15A, wherein R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms. 44A. The compound of embodiment 43A, wherein R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 7-membered monocyclic heterocyclyl containing one heteroatom, which heterocyclyl is optionally substituted with methyl or oxo. 45A. The compound of embodiment 43A, wherein R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 7-membered monocyclic heterocyclyl containing two heteroatoms, where the heteroatoms are N or O, said heterocyclyl being optionally substituted once with phenyl, methyl, or oxo, and said phenyl being optionally substituted with methoxy. 46A. A compound of any one of embodiments 1A-15A, wherein R 3 and R 4 and taken together with the nitrogen atom to which each is attached form an 11-membered bicyclic fused heterocyclyl containing one heteroatom and optionally substituted with methoxy. 47A. The compound of any one of embodiments 1A-46A, wherein p is 1. 1B. Formula (I'): [ka] [In the formula, Z is N or CH; Ring B is [ka] where [ka] indicates the point of attachment to the rest of the molecule; R 6 is in each case halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3-alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(CH2) u R bb , halo-C1-C3 alkyl, -OR cc -OR dd , 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; u is an integer from 0 to 6; R bb is a 4- to 7-membered monocyclic heterocyclyl, C-C cycloalkyl, or -NR G R H and; R cc and R dd are 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 R Gand R H are each independently hydrogen, -C(O)R Ga or C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; The heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, NH, O, S, SH, and SR, respectively. 6 , N.R. 6 , and C.R. 6 wherein Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 One or two of these are N, NR 6 , NH, O, SH or SR 6 and can be; f is 0 or 1; p is 1 or 2; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, or cyano; m is 0, 1, or 2; R 3is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-(branched or straight-chain) C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-(branched or straight-chain) C1-C3 alkyl; The heteroaryl or heterocyclyl may have one or two substituents, each of which is C-C 10 independently selected from the group consisting of monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl, wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkyl, halogen, and hydroxy; and When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is linear; and ii. [ka] where R 4a and R 4g are each hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiroheterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10 independently selected from the group consisting of (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; where R 4a and R4g the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or R 4b and R 4c each of which, together with the atom to which it is attached, forms a 5- to 7-membered monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3 alkyl; or R 4c and R 4d are 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-C3 alkyl; or R 4c and R 4d each of which, together with the atom to which it is attached, forms a C3-C7 cycloalkyl; Or, if p is 1, R 3 and R 4 means, together with the nitrogen atom to which each is attached, the following group: i. can form a 7-membered fused bicyclic heterocyclyl, a 7-membered bridged bicyclic heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and wherein the aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. can form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l and optionally substituted with an alkyl group independently selected from the group consisting of: s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w and optionally substituted with an alkyl group independently selected from the group consisting of: R q is hydrogen or C1-C3 alkyl; and R w is C6-C 10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. can form an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclyl, or a 12-membered bicyclic bridged and fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents (each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy); Or, if p is 2, R 3 and R 4 and together with the nitrogen atom to which each is attached, i. containing one heteroatom and capable of forming a 6-membered monocyclic heterocyclyl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or 1, 2, or 3 heteroatoms and 1 or 2 substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NRG R H , and -(CH2) s C(=O)NR k R l which can form a 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiroheterocyclyl optionally substituted with selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If * is [ka] and ** is [ka] or *but [ka] and ** is [ka] and; and, The compounds of formula (I) are: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof Excluding compounds. 1C. Formula (I'): [ka] [In the formula, Z is N or CH; Ring B is [ka] where [ka] indicates the point of attachment to the rest of the molecule; R 6 In each case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C 10 Alkoxy, Hydroxy-C1-C 10 -Alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-R bb , -OR bb , (C1-C6 alkyl)-NR GI R H I, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 , halo-C1-C3 alkyl, -OR cc -OR dd , 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; Hydroxy-C1-C 10 Alkoxy or -O-(C1-C6 alkyl)-R bb wherein the alkyl moiety may be optionally substituted with cyano, hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; R bbis a 4- to 7-membered monocyclic or bridged heterocyclyl, C-C cycloalkyl, 5- or 6-membered monocyclic heteroaryl, —SO—C-C alkyl, —S—C-C alkyl, —C(O)NR G1 R H1 , or -NR G R H and; R cc is C1-C3 alkyl; and R dd is C1-C3 alkyl or 6-membered heteroaryl; where R 6 , R bb , or R dd wherein said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-C1-C3 alkyl, oxo, C1-C3 alkoxy, and C1-C3 alkyl; R G1 and R H1 are each independently hydrogen or C1-C3 alkyl; and R G and R H are each independently hydrogen, -C(O)R Ga or optionally deuterated C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or, 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; The heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, 2, or 3; Y 1 , Y 2 , Y 3 , and Y 4 Each of these is CH, N, NH, O, S, SH, SR 6 , N.R. 6 , and C.R. 6 where Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 One or two of these are N, NR 6 , NH, O, SH or SR 6 and can be; f is 0 or 1; p is 1 or 2; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, oxo, or cyano; m is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxy-C1-C3 alkyl, halo-C1-C3 alkyl, cyclopropyl, and phenyl; R 4 is the following group: i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or (6- or 7-membered monocyclic heterocyclyl)-C1-C3 alkyl; The heteroaryl or heterocyclyl may have one or two substituents, each of which is C-C 10optionally substituted with a monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, (C-C alkyl)-T, and 5- to 7-membered monocyclic heterocyclyl; T is C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl, C-C cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl; and where R 4 wherein T or the aryl, cycloalkyl, heteroaryl, or heterocyclyl substituent is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and When p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is linear; and, ii. [ka] where: R 4a and R 4g Each of 10 Alkyl, hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 alkyl-NR J1 R J2 , C3-C7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiroheterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10 independently selected from the group consisting of (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; R J1 and R J2 are independently hydrogen or C1-C3 alkyl; where R 4a and R 4g the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiroheterocyclyl; R 4b is hydrogen or C1-C6 alkyl; or R 4a and R 4b each of which, together with the atom to which it is attached, forms a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or R 4b and R 4c each of which, together with the atom to which it is attached, forms a 5- to 7-membered monocyclic heterocyclyl optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3 alkyl; or R 4c and R 4d are 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-C3 alkyl; or R 4c and R 4d each of which, together with the atom to which it is attached, forms a C3-C7 cycloalkyl; Or, if p is 1, R 3 and R 4and together with the nitrogen atom to which each is attached, i. forming a 7-membered fused bicyclic heterocyclyl, a 7-membered bridged bicyclic heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the 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-C3 alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and wherein said aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forms a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l wherein s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w wherein R q is hydrogen or C1-C3 alkyl; and R w is C6-C 10 monocyclic or fused bicyclic aryl, or C3-C7 cycloalkyl, wherein the aryl or cycloalkyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. can form an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclyl, or a 12-membered bicyclic bridged and fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents (each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy); Or, if p is 2, R 3 and R 4 together with the nitrogen atom to which each is attached, i. forming a 6-membered monocyclic heterocyclyl containing one heteroatom and optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. one or two substituents, each of which is selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR G R H , and -(CH2) s C(=O)NRk R l and optionally substituted with a 4- or 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bridged, fused, or spiroheterocyclyl containing 1, 2, or 3 heteroatoms, selected from the group consisting of or a pharmaceutically acceptable salt thereof; However, the structure of formula (I) [ka] If * is [ka] and ** is [ka] or *teeth [ka] and ** is [ka] and; and The compounds of formula (I) are: N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine; 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or salts thereof Compounds other than. 2B. The compound of embodiment 1B or 1C, or a pharmaceutically acceptable salt thereof, wherein p is 1. 3B. The compound of embodiment 1B, 2B, or 1C, or a pharmaceutically acceptable salt thereof, wherein Z is N. 4B. A compound of any one of embodiments 1B-3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , and Y 4 are CH or CR, respectively. 6 or a pharmaceutically acceptable salt thereof. 5C. A compound of embodiment 4B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH and Y 2 is CR 6 and Y 3 is CH and Y 4 is CH, or a pharmaceutically acceptable salt thereof. 5B. A compound of any one of embodiments 1B-3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 , and Y 4 are CH or CR, respectively. 6 or a pharmaceutically acceptable salt thereof. 6B. A compound of any one of embodiments 1B-3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 , Y 4 are CH or CR, respectively. 6 or a pharmaceutically acceptable salt thereof. 7B. A compound of any one of embodiments 1B-3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y2 , Y 3 , and Y 4 are CH or CR, respectively. 6 or a pharmaceutically acceptable salt thereof. 8B. A compound of any one of embodiments 1B-7B or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, 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 R bb , halo-C1-C3 alkoxy, -OR cc -OR dd , halo-C1-C3 alkyl, and -NR G R H wherein: R bb Ga-NR G R H and; u is an integer from 1 to 3; R G and R H are each independently hydrogen or C1-C3 alkyl; R cc and R dd are each independently C1-C3 alkyl; The compound or a pharmaceutically acceptable salt thereof. 9C. The compound of any one of embodiments 1C, 2B-8B, or 5C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C 10 Alkoxy, Hydroxy-C1-C 10 -Alkyl, -O-(C1-C6 alkyl)-R bb , halo-C1-C3 alkoxy, -OR cc -OR dd , halo-C1-C3 alkyl, (C1-C6 alkyl)-NR GI R HI, -S-CH3, -S(CH2)2N(CH3)2, and -NR G R H wherein: R bb But, -NR G R H , -C(O)N(CH3)2, -S(O)2CH3, or -SCH3; R G and R H are each independently hydrogen, optionally deuterated C1-C3 alkyl, or —C(O)R Ga where R Ga is C1-C3 alkyl; R GI and R HI are each independently hydrogen or C1-C3 alkyl; R cc and R dd are each independently C1-C3 alkyl; where hydroxy-C1-C 10 the alkyl portion of the alkoxy may be optionally substituted with hydroxy, halogen, or C1-C3 alkoxy; The compound or a pharmaceutically acceptable salt thereof. 9B. A compound of any one of embodiments 1B-8B, 5C, or 9C, or a pharmaceutically acceptable salt thereof, wherein R 6 wherein, in each case, 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, or a pharmaceutically acceptable salt thereof. 10C. The compound of embodiment 9C, or a pharmaceutically acceptable salt thereof, wherein R 6In all cases, 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)OH, -OCH2CH(CH2CH3)OH, -OCH2C(CH2CH3)2OH, -OCH2C A compound selected from the group consisting of HN(CHCH), -OCH(CH)CHN(CH), -OCHC(O)N(CH), -OCHC(CH)N(CH), -OCHCH(CHOH)OH, -OCHCHNH(CH), -OCHCH(CF)OH, -OCHC(CH)(CHCH)OH, -OCHCH(CHOCH)OH, -OCHCH(CHF)OH, (CH)N(CH), (CH)N(CH)H, -O-(CH)S(O)CH, -O-(CH)SCH, (CH)C(CH)OH, -OCHCHN(CD), and -CHCHOH. 10B. A compound of embodiment 9B, 9C, or 10C, or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case methoxy, —OCH2CH2OH, or —OCH2C(CH3)2OH, or a pharmaceutically acceptable salt thereof. 11C. The compound of embodiment 10C, or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case methoxy, —OCH2CH2N(CH3)2, —OCH2CH2OH, or —OCH2C(CH3)2OH, or a pharmaceutically acceptable salt thereof. 12C. The compound of embodiment 11C or a pharmaceutically acceptable salt thereof, wherein R 6is, in each case, —OCH2CH2N(CH3)2 or —OCH2C(CH3)2OH, or a pharmaceutically acceptable salt thereof. 11B. A compound of any one of embodiments 1B-7B, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, -O-(CH2) u R bb and C3-C6 cycloalkyl; u is an integer from 0 to 3; R bb is a 4- to 7-membered monocyclic heterocyclyl or C3-C7 cycloalkyl; wherein the 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; The compound or a pharmaceutically acceptable salt thereof. 12B. The compound of embodiment 11B, or a pharmaceutically acceptable salt thereof, wherein R 6 But in all cases, cyclopropyl and -O-(CH2) u R bb wherein: u is 0, 1, or 2; and R bb is selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each of which is optionally substituted with hydroxy or methyl; The compound or a pharmaceutically acceptable salt thereof. 13C. The compound of any one of embodiments 1C, 2B-8B, or 5C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, -O-(C1-C6 alkyl)-R bb , -OR bb , -OR cc -OR dd , 5-7 membered monocyclic heteroaryl, and C3-C6 cycloalkyl; Rcc is C1-C3 alkyl, and R dd is a 6-membered heteroaryl; R bb is a 4- to 7-membered monocyclic or bridged heterocyclyl, a 5- or 6-membered monocyclic heteroaryl, or a C3-C7 cycloalkyl; and R 6 , R bb , or R dd wherein said cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, C-C alkoxy, oxo, halo-C-C alkyl, and C-C alkyl; The compound or a pharmaceutically acceptable salt thereof. 14C. The compound of embodiment 13C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, cyclopropyl, -OR bb , -O-(CH2)-R bb , -O-(CH2)2-R bb , —O—(CH2)2—O-pyridazinyl, optionally C1-C3 alkyl substituted imidazolyl; R bb is 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 of which is optionally substituted with hydroxy, oxo, fluoro, —CF, —CHCF, —CHCHF, —CHCHF, methoxy, ethyl, or methyl; The compound or a pharmaceutically acceptable salt thereof. 15C. The compound of embodiment 14C, or a pharmaceutically acceptable salt thereof, wherein R 6 But in any case, [ka] [ka] selected from the group consisting of [ka] indicates the point of attachment to ring B, The compound or a pharmaceutically acceptable salt thereof. 13B. A compound of embodiment 12B, 14C, or 15C, or a pharmaceutically acceptable salt thereof, wherein R 6 But in any case, [ka] selected from the group consisting of [ka] indicates the point of attachment to ring B, The compound or a pharmaceutically acceptable salt thereof. 16C. The compound of embodiment 15C, or a pharmaceutically acceptable salt thereof, wherein R 6 but, [ka] 14B. A compound of any one of embodiments 13B or 13-16C, or a pharmaceutically acceptable salt thereof, wherein R 6 but [ka] 15B. A compound of any one of embodiments 1B-7B or 1C, or a pharmaceutically acceptable salt thereof, wherein two R 6groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to ring B, a C-C cycloalkyl fused to ring B, a phenyl fused to ring B, or a 5- or 6-membered monocyclic heteroaryl fused to ring B, each of which is optionally substituted with 1 or 2 substituents (each independently selected from C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl); The compound or a pharmaceutically acceptable salt thereof. 16B. A compound of any one of embodiments 1B-7B or 1C, or a pharmaceutically acceptable salt thereof, wherein two R 6 groups, together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused to Ring B, wherein the ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, —CHOH, and methyl; The compound or a pharmaceutically acceptable salt thereof. 17B. The compound of embodiment 16B, or a pharmaceutically acceptable salt thereof, wherein two R 6 groups, together with the atoms to which they are each attached, are fused to ring B; [ka] wherein the ring is selected from the group consisting of [ka] represents a bond between the ring and ring B. The compound or a pharmaceutically acceptable salt thereof. 18B. The compound of embodiment 17B, or a pharmaceutically acceptable salt thereof, wherein two R 6 groups, together with the atoms to which they are each attached, are fused to ring B; [ka] forming a ring selected from the group consisting of The compound or a pharmaceutically acceptable salt thereof. 18bb. A compound of any one of embodiments 15B-18B, or a pharmaceutically acceptable salt thereof, wherein Ring B is [ka] or a pharmaceutically acceptable salt thereof. 19B. The compound of any one of embodiments 1B-19B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein f is 1. 20B. The compound of embodiment 1B, 2B, 3B, or 1C, or a pharmaceutically acceptable salt thereof, wherein f is 0 and ring B is [ka] or a pharmaceutically acceptable salt thereof. 21B. The compound of embodiment 20B, or a pharmaceutically acceptable salt thereof, wherein Ring B is [ka] where: n is 0 or 1; Y 2 and Y 3 are each independently CH, N, NH, or NR 6 , S, O, and CR 6 wherein Y is selected from the group consisting of 2 and Y 3 Only one of N, NH, NR 6 , S, or O, The compound or a pharmaceutically acceptable salt thereof. 22B. The compound of embodiment 20B or 21B, or a pharmaceutically acceptable salt thereof, wherein Ring B is [ka] or a pharmaceutically acceptable salt thereof. 23B. The compound of any one of embodiments 20B-22B, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case selected from the group consisting of C1-C3 alkyl and hydroxy-C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. 24B. The compound of embodiment 23B, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH, and -CH2CH2CH2OH, or a pharmaceutically acceptable salt thereof. 25B. The compound of any one of embodiments 1B-24B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 1. 26B. The compound of any one of embodiments 1B-24B1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 0. 27B. The compound of any one of embodiments 1B-14B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 2. 28B. The compound of embodiment 27B, or a pharmaceutically acceptable salt thereof, wherein one R 6 is selected from the group consisting of methyl and methoxy, and the other R 6 is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH, or a pharmaceutically acceptable salt thereof. 31C. A compound of any one of embodiments 1-28B, or 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, -CD3, -CH2CF3, and -CH2CH2OH, or a pharmaceutically acceptable salt thereof. 29B. A compound of any one of embodiments 1B-28B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH, or a pharmaceutically acceptable salt thereof. 30B. The compound of embodiment 29B or 31C, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, or a pharmaceutically acceptable salt thereof. 33C. A compound of any one of embodiments 1B-30B, or 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 4 is (5-10 membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein the heteroaryl is optionally substituted with one or two substituents (each independently selected from the group consisting of phenyl, C-C cycloalkyl, (C-C alkyl)-phenyl, and 5- to 7-membered monocyclic heterocyclyl), and wherein the phenyl, cycloalkyl, or heterocyclyl in the sole phenyl, or (C-C alkyl)-phenyl is optionally substituted with one or two substituents (each independently selected from the group consisting of C-C alkyl, halogen, and hydroxy), or a pharmaceutically acceptable salt thereof. 31B. A compound of any one of embodiments 1B-30B, or 33C, or a pharmaceutically acceptable salt thereof, wherein R 4is (5-10 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 independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy, or a pharmaceutically acceptable salt thereof. 32B. A compound of embodiment 31B or 33C, or a pharmaceutically acceptable salt thereof, wherein R 4 is (6-membered heteroaryl)-methyl and at least one of the ring atoms ortho to the point of attachment on said 6-membered heteroaryl is nitrogen, or a pharmaceutically acceptable salt thereof. 35C. A compound of embodiment 33C or 32B, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, oxazolyl-methyl, and triazolyl-methyl, each of which is optionally substituted with phenyl or benzyl, wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro, or a pharmaceutically acceptable salt thereof. 33B. A compound of embodiment 31B, 32B, or 35C, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazole-methyl, and triazolyl-methyl, each of which is optionally substituted with phenyl, wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro, or a pharmaceutically acceptable salt thereof. 36C. The compound of embodiment 35C, or a pharmaceutically acceptable salt thereof, wherein R 4 but [ka] or a pharmaceutically acceptable salt thereof. 34B. The compound of embodiment 33B or 36C, or a pharmaceutically acceptable salt thereof, wherein R 4 but [ka] or a pharmaceutically acceptable salt thereof. 35B. The compound of any one of embodiments 1B-30B, or 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, or 36C, or a pharmaceutically acceptable salt thereof, wherein R 4 but [ka] or a pharmaceutically acceptable salt thereof. 36B. The compound of embodiment 35B, or a pharmaceutically acceptable salt thereof, wherein R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, —CHOH, —CHOC(CH) and —CHCHSCH; R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d and together with the atom to which each is attached form a cyclopropyl ring, or a pharmaceutically acceptable salt thereof. 37B. The compound of embodiment 36B, or a pharmaceutically acceptable salt thereof, wherein R 4c and R 4d and each are hydrogen, or a pharmaceutically acceptable salt thereof. 37bb. The compound of embodiment 36B, or a pharmaceutically acceptable salt thereof, wherein R 4c is hydrogen or methyl; R 4d is hydrogen, or a pharmaceutically acceptable salt thereof. 37bbb. A compound of embodiment 36B or 37bb, or a pharmaceutically acceptable salt thereof, wherein R 4c is methyl; R 4d is hydrogen, or a pharmaceutically acceptable salt thereof. 38B. The compound of any one of embodiments 35B-37B, or a pharmaceutically acceptable salt thereof, wherein R 4b is hydrogen, or a pharmaceutically acceptable salt thereof. 39B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is C1-C6 alkyl, or a pharmaceutically acceptable salt thereof. 42C. The compound of embodiment 39B, or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, ethyl, isopropyl, tert-butyl, or 3-methylpentan-3-yl, or a pharmaceutically acceptable salt thereof. 43C. A compound of embodiment 39B or 42C, or a pharmaceutically acceptable salt thereof, wherein R 4a is tert-butyl or isopropyl, or a pharmaceutically acceptable salt thereof. 40B. The compound of embodiment 39B or 42C, or a pharmaceutically acceptable salt thereof, wherein R 4a is tert-butyl, or a pharmaceutically acceptable salt thereof. 41B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is phenyl optionally substituted with 1 or 2 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), or a pharmaceutically acceptable salt thereof. 42B. The compound of embodiment 41B, or a pharmaceutically acceptable salt thereof, wherein R 4ais phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy, or a pharmaceutically acceptable salt thereof. 43B. The compound of embodiment 42B, wherein R 4a but, [ka] or a pharmaceutically acceptable salt thereof. 44B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is a 5- to 10-membered monocyclic or fused bicyclic heteroaryl optionally substituted with 1 or 2 substituents (each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl), or a pharmaceutically acceptable salt thereof. 45B. The compound of embodiment 44B, or a pharmaceutically acceptable salt thereof, wherein R 4a is pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyrazidinyl, or quinolinyl selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl, or a pharmaceutically acceptable salt thereof. 46B. The compound of embodiment 45B, or a pharmaceutically acceptable salt thereof, wherein R 4a but, [ka] or a pharmaceutically acceptable salt thereof. 47B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4ais C3-C7 cycloalkyl optionally substituted with 1 or 2 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), or a pharmaceutically acceptable salt thereof. 48B. The compound of embodiment 47B, or a pharmaceutically acceptable salt thereof, wherein R 4a is 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, or a pharmaceutically acceptable salt thereof. 52C. The compound of embodiment 48B, wherein R 4a but, [ka] or a pharmaceutically acceptable salt thereof. 49B. The compound of embodiment 48B or 52C, wherein R 4a but [ka] or a pharmaceutically acceptable salt thereof. 53C. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl optionally substituted with 1 or 2 substituents (each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl), or a pharmaceutically acceptable salt thereof. 50B. A compound of any one of embodiments 35B-38B or 53C, or a pharmaceutically acceptable salt thereof, wherein R 4a is a 5- to 10-membered monocyclic or fused bicyclic heterocyclyl optionally substituted with 1 or 2 substituents (each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl), or a pharmaceutically acceptable salt thereof. 54C. The compound of embodiment 53C, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, oxetanyl, and tetrahydropyranyl, each optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, methoxy, and oxo, or a pharmaceutically acceptable salt thereof. 51B. The compound of embodiment 50B, or a pharmaceutically acceptable salt thereof, wherein R 4a is 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, or a pharmaceutically acceptable salt thereof. 55C. The compound of embodiment 54C, wherein R 4a but [ka] or a pharmaceutically acceptable salt thereof. 52B. A compound of embodiment 51B or 55C, or a pharmaceutically acceptable salt thereof, wherein R 4a but [ka] or a pharmaceutically acceptable salt thereof. 53B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, C-C cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl; (C-C 10 A compound which is (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. 54B. The compound of embodiment 53B, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of phenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, and pyridinyl-methyl, or a pharmaceutically acceptable salt thereof. 57C. The compound of embodiment 53B, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl-methyl, or a pharmaceutically acceptable salt thereof. 55B. The compound of embodiment 54B or 57C, or a pharmaceutically acceptable salt thereof, wherein R 4a but [ka] or a pharmaceutically acceptable salt thereof. 59C. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, and -C1-C6 alkyl-NR J1 RJ2 where R J1 and R J2 are each independently hydrogen or C1-C3 alkyl, or a pharmaceutically acceptable salt thereof. 60C. The compound of embodiment 59C, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, -C(CH3)2CH2OCH3, -CH(CH3)CH2OH, -CH2CH2N(CH3)2, -CH2CF3, or a pharmaceutically acceptable salt thereof. 56B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3, or a pharmaceutically acceptable salt thereof. 61C. A compound of embodiment 59C, 60C, or 56B, or a pharmaceutically acceptable salt thereof, wherein R 4a is —C(CH3)2CH2OH, or a pharmaceutically acceptable salt thereof. 57B. A compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b and taken 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 1 or 2 substituents (each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy), or a pharmaceutically acceptable salt thereof. 63C. The compound of embodiment 57B, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4bor a pharmaceutically acceptable salt thereof, each of which, taken together with the atom to which it is attached, forms 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. 58B. A compound of embodiment 57B or 63C, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b and taken together with the atom to which each is attached form 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, or a pharmaceutically acceptable salt thereof. 64C. A compound of embodiment 63C or 58B, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b and, together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof. 59B. The compound of embodiment 58B or 64C, or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b and, together with the atoms to which they are bonded, [ka] or a pharmaceutically acceptable salt thereof. 60B. The compound of any one of embodiments 35B, 39B-56B, 42C, 43C, 52C, 53C, 54C, 55C, 59C, 60C, or 61C, or a pharmaceutically acceptable salt thereof, wherein R 4b and R4c and taken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl optionally substituted with 1 or 2 substituents (each independently selected from C1-C3 alkyl), or a pharmaceutically acceptable salt thereof. 61B. The compound of embodiment 60B, or a pharmaceutically acceptable salt thereof, wherein R 4b and R 4c and together with the atom to which each is attached form piperidin-2-one or pyrrolidin-2-one optionally substituted one or two times with methyl, or a pharmaceutically acceptable salt thereof. 62B. A compound of any one of embodiments 1B-30B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 4 but [ka] where R 4g But C6-C 10 A compound or a pharmaceutically acceptable salt thereof, selected from the group consisting of monocyclic or fused bicyclic aryl and C1-C3 alkyl. 63B. The compound of embodiment 62B, or a pharmaceutically acceptable salt thereof, wherein R 4g is selected from the group consisting of phenyl and methyl, or a pharmaceutically acceptable salt thereof. 64B. A compound of any one of embodiments 1B-28B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and, together with the nitrogen atom to which each is attached, form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered heterocyclyl contains one heteroatom, the heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C-C alkoxy, cyano, and C-C alkyl; and When the 7-membered heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may contain one, two, or three substituents, each of which is selected from the group consisting of C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and The aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; The compound or a pharmaceutically acceptable salt thereof. 65B. The compound of embodiment 64B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein the heterocyclyl is optionally substituted once with methyl or oxo; or form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein the heteroatoms are N or O and the heterocyclyl is optionally substituted with one or two substituents (each independently selected from the group consisting of phenyl, methyl, and oxo), wherein the phenyl is optionally substituted with methoxy, or a pharmaceutically acceptable salt thereof. 66B. The compound of embodiment 65B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] or a pharmaceutically acceptable salt thereof. 67B. A compound of any one of embodiments 1B-28B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and each together with the nitrogen atom to which they are attached form a 10- or 11-membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents (each independently selected from the group consisting of C-C alkyl, C-C alkoxy, hydroxy, and halogen), or a pharmaceutically acceptable salt thereof. 68B. The compound of embodiment 67B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] or a pharmaceutically acceptable salt thereof. 69B. A compound of any one of embodiments 1B-28B, 1C, 8C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom, wherein The 4-membered monocyclic heterocyclyl is -(CH2) s C(=O)NR k R l optionally substituted with; where: s is 0, 1, or 2; R k is hydrogen or C1-C3 alkyl; and R lis selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and The 6-membered monocyclic heterocyclyl may have one or two substituents, each of which is selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w wherein R q is hydrogen or C1-C3 alkyl; R w C6-C 10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl; wherein the 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; The compound or a pharmaceutically acceptable salt thereof. 70B. The compound of embodiment 69B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is bonded, [ka] or a pharmaceutically acceptable salt thereof. 71B. The compound of any one of embodiments 1B-70B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof, wherein R x is, in each case, methyl, or a pharmaceutically acceptable salt thereof. 72B. The compound of any one of embodiments 1B-71B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof, wherein m is 0. 73B. The compound of any one of embodiments 1B-71B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, or 64C, or a pharmaceutically acceptable salt thereof, wherein m is 2. 79C. A compound of claim 1, or a pharmaceutically acceptable salt thereof, wherein Z is N; p is 1; f is 1; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, and CR, respectively. 6 wherein Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 one or two of may be N; R 6 In any case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C 10 Alkoxy, Hydroxy-C1-C 10 -Alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-R bb , -OR bb , (C1-C6 alkyl)-NR GI R HI , halo-C1-C3 alkyl, -OR cc -OR dd, 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; Hydroxy-C1-C 10 Alkoxy or -O-(C1-C6 alkyl)-R bb wherein the alkyl moiety may be optionally substituted with hydroxy, hydroxy-C1-C3-alkyl, halogen, or C1-C3 alkoxy; R bb is a 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR G R H and; R cc and R dd are each independently C1-C3 alkyl; where R 6 or R bb 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 R G1 and R H1 are each independently hydrogen or C1-C3 alkyl; R G and R H each independently represents hydrogen, -C(O)R Ga or optionally deuterated C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; the heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, phenyl, —CHCHOH, and optionally deuterated methyl or ethyl; R 4 but [ka] where: R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, —CHOH, —CHOC(CH) and —CHCHSCH; R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d and together with the atom to which each is attached form a cyclopropyl ring; R 4b is hydrogen or methyl; R 4a But hydrogen, C1-C 10 Alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C1-C6 alkyl-NR J1 R J2 , C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 4- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10 (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; wherein R4a the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, halo-C-C alkoxy, oxo, C-C cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl; R J1 and R J2 are independently hydrogen or C1-C3 alkyl; or R 4a and R 4b and 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 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; R x is in each case C1-C3 alkyl; m is 0, 1, or 2; The compound or a pharmaceutically acceptable salt thereof. 74B. A compound of embodiment 1B, or a pharmaceutically acceptable salt thereof, wherein Z is N; p is 1; f is 1; Y 1 , Y 2 , Y 3 , and Y 4 are CH, N, and CR, respectively. 6 wherein Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 one or two of may be N; R 6In any case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(CH2) u R bb , halo-C1-C3 alkyl, -OR cc -OR dd , 5-7 membered monocyclic heteroaryl, and C3-C6 cycloalkyl; u is an integer from 0 to 6; R bb is a 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR G R H and; R cc and R dd are 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 R G and R H are each independently hydrogen, -C(O)R Ga or C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; or 2 R's 6 groups, together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused to Ring B, a C4-C7 cycloalkyl fused to Ring B, a phenyl fused to Ring B, or a 5- to 6-membered monocyclic heteroaryl fused to Ring B; the heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused to Ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C-C alkoxy, hydroxy, hydroxy-C-C-alkyl, C-C alkyl, C-C cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl; n is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and —CHCHOH; R 4 but [ka] where: R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, —CHOH, —CHOC(CH) and —CHCHSCH; R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d and together with the atom to which each is attached form a cyclopropyl ring; R 4b is hydrogen or methyl; R 4a is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10 (monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; wherein R 4awherein said cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 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, halo-C1-C3 alkyl, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl; or R 4a and R 4b and 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 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; R x is in each case C1-C3 alkyl; m is 0, 1, or 2; The compound or a pharmaceutically acceptable salt thereof. 75B. The compound of embodiment 74B or 79C, or a pharmaceutically acceptable salt thereof, wherein m is 0. 76B. The compound of embodiment 74B or 79C, or a pharmaceutically acceptable salt thereof, wherein m is 2 and R x is, in each case, methyl, or a pharmaceutically acceptable salt thereof. 77B. A compound of any one of embodiments 74B-76B or 79C, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , and Y 4 are CH or CR, respectively. 6 and; Y 3 is N and Y 1 , Y 2 , and Y 4 are CH or CR, respectively.6 Is it; Y 2 is N and Y 1 , Y 3 , Y 4 are CH or CR, respectively. 6 Is it; or Y 1 is N and Y 2 , Y 3 , and Y 4 are CH or CR, respectively. 6 That is, The compound or a pharmaceutically acceptable salt thereof. 77bb. A compound of any one of embodiments 74B-77B or 79C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH and Y 2 is CR 6 and Y 3 is CH and Y 4 is CH, or a pharmaceutically acceptable salt thereof. 83C. A compound of any one of embodiments 79C or 75B-77bb, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C 10 -Alkyl, -OR bb , —O—(C1-C6 alkyl)-R bb , halo-C1-C3 alkoxy, -OR cc -OR dd , halo-C1-C3 alkyl, C3-C6 cycloalkyl, and -NR G R H wherein R bb Ga-NR G R H , 4- to 6-membered monocyclic heterocyclyl, or C3-C7 cycloalkyl; R G and R Hare each independently hydrogen or C1-C3 alkyl; R cc and R dd are each independently C1-C3 alkyl; R 6 or R bb 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. The compound or a pharmaceutically acceptable salt thereof. 84C. The compound of embodiment 83C, wherein R bb is selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, morpholinyl, and pyrrolidinyl, each of which is optionally substituted with hydroxy or methyl; or R bb is —N(CH3)2, or a pharmaceutically acceptable salt thereof. 78B. A compound of any one of embodiments 74B-77B, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, 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 R bb , halo-C1-C3 alkoxy, -OR cc -OR dd , halo-C1-C3 alkyl, C3-C6 cycloalkyl, and -NR G R H wherein R bb Ga-NR G R H , 4- or 5-membered monocyclic heterocyclyl, or C3-C7 cycloalkyl; u is an integer from 0 to 3; R G and R H are each independently hydrogen or C1-C3 alkyl; Rcc and R dd are each independently C1-C3 alkyl; The 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. The compound or a pharmaceutically acceptable salt thereof. 79B. The compound of embodiment 78B, wherein R bb is selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each of which is optionally substituted with hydroxy or methyl. 85C. A compound of any one of embodiments 79C, 75B-77B, or 84C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH3)2, hydroxy, -OCH2CH(CH3)OH, -OCH2CH2N(CH2CH3)2, -OCH2C(CH3)(CH2CH3)OH, -OCH2CH(CH2OCH3)OH, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3)2CH2OH, -CH2CH2OH, [ka] selected from the group consisting of [ka] indicates the point of attachment to ring B, or a pharmaceutically acceptable salt thereof. 80B. A compound of any one of embodiments 74B-79B, or a pharmaceutically acceptable salt thereof, wherein R 6However, in all cases, 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, -CH2CH2OH, [ka] selected from the group consisting of [ka] indicates the point of attachment to ring B, or a pharmaceutically acceptable salt thereof. 86C. The compound of embodiment 85C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, methoxy, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, [ka] or a pharmaceutically acceptable salt thereof. 87C. The compound of embodiment 86C, or a pharmaceutically acceptable salt thereof, wherein R 6 In any case, methoxy, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, [ka] or a pharmaceutically acceptable salt thereof. 81B. The compound of embodiment 80B or 86C, or a pharmaceutically acceptable salt thereof, wherein R 6 but in all cases methoxy, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, or [ka] or a pharmaceutically acceptable salt thereof. 82B. A compound of any one of embodiments 74B-77B, or a pharmaceutically acceptable salt thereof, wherein two R 6 A compound or a pharmaceutically acceptable salt thereof, wherein the groups, together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused to Ring B, wherein the ring is optionally substituted with one substituent independently selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, —CHOH, and methyl. 83B. A compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl, or a pharmaceutically acceptable salt thereof. 84B. The compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein n is 1. 85B. A compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R 4b is hydrogen, or a pharmaceutically acceptable salt thereof. 92C. The compound of any one of embodiments 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R 4a but 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, pyrazidinyl, 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, each independently 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, methoxy, and oxo; 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 or a pharmaceutically acceptable salt thereof. 86B. A compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R 4a but: i.tert-butyl; ii. phenyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy; iii. pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyrazidinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl; iv. 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; 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, methoxy, and oxo; vi. Phenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl, and pyridinyl-methyl; and vii.-C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3 or a pharmaceutically acceptable salt thereof, independently selected from the group consisting of: 87B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, wherein R 4a and R 4b and taken together with the atom to which each is attached form 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, or a pharmaceutically acceptable salt thereof. 88B. A compound of embodiment 1B or 1C, or a pharmaceutically acceptable salt thereof, wherein Z is N; f is 1; R 6 In any case, C1-C3 alkyl, -NR G R H , halogen, and C1-C3 alkoxy; p is 1; n is 0 or 1; R Gand R H are each independently hydrogen or C1-C3 alkyl; Y 1 , Y 2 , Y 3 , and Y 4 are each independently CH, N, and CR 6 wherein Y is independently selected from the group consisting of 1 , Y 2 , Y 3 , and Y 4 one or two of may be N; R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, or cyano; m is 0; and R 3 and R 4 and together with the nitrogen atom to which each is bonded, i. forming a 7-membered fused bicyclic heterocyclyl, a 7-membered bridged bicyclic heterocyclyl, or a 7-membered monocyclic heterocyclyl containing 1 or 2 heteroatoms; wherein if the 7-membered monocyclic heterocyclyl contains one heteroatom, the 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-C3 alkyl; and When the 7-membered monocyclic heterocyclyl contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclyl may have one, two, or three substituents, each of which is selected from C-C alkyl, cyano, oxo, halogen, halo-C-C alkyl, and C-C alkyl. 10 and The aryl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl; ii. forming a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein the 4-membered monocyclic heterocyclyl is selected from one or two substituents, each of which is selected from halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l wherein s is 0, 1, 2, or 3; R k is hydrogen or C1-C3 alkyl; and R l is hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 selected from the group consisting of monocyclic or fused bicyclic aryl; wherein the 6-membered monocyclic heterocyclyl is selected from the group consisting of one or two substituents, each of which is selected from C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w wherein R q is hydrogen or C1-C3 alkyl; and R w is C6-C 10 is a monocyclic or bicyclic aryl or C3-C7 cycloalkyl of 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; or iii. Form an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclyl, or a 12-membered bicyclic bridged, fused heterocyclyl, wherein the 8-, 9-, or 11-membered heterocyclyl contains 1 heteroatom and the 10- or 12-membered heterocyclyl contains 1 or 2 heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclyl is optionally substituted with 1, 2, or 3 substituents, each independently selected from the group consisting of halogen, C-C alkyl, C-C alkoxy, and hydroxy. The compound or a pharmaceutically acceptable salt thereof. 89B. The compound of embodiment 88B, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 , and Y 4 are CH or CR, respectively. 6 or a pharmaceutically acceptable salt thereof. 90B. The compound of embodiment 88B or 89B, or a pharmaceutically acceptable salt thereof, wherein R 6 if present is selected from the group consisting of -N(CH3)2, methyl, methoxy, fluoro, and chloro, or a pharmaceutically acceptable salt thereof. 91B. A compound of any one of embodiments 88B-90B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein the heterocyclyl is optionally substituted once with methyl or oxo; or form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein the heteroatoms are N or O and the heterocyclyl is optionally substituted with one or two substituents (each independently selected from the group consisting of phenyl, methyl, and oxo), wherein the phenyl is optionally substituted with methoxy, or a pharmaceutically acceptable salt thereof. 92B. A compound of any one of embodiments 88B-90B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclyl containing one heteroatom, or form a 12-membered bicyclic fused, bridged heterocyclyl, each of which is optionally substituted with 1, 2, or 3 substituents (each independently selected from the group consisting of C-C alkyl, C-C alkoxy, hydroxy, and halogen), or a pharmaceutically acceptable salt thereof. 93B. A compound of any one of embodiments 88B-90B, or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 and together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; The 4-membered monocyclic heterocyclyl is -(CH2) s C(=O)NR k R l wherein s is 0, 1, or 2; R k is hydrogen or C1-C3 alkyl; and R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and The 6-membered monocyclic heterocyclyl may have one or two substituents, each of which is selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w wherein R q is hydrogen or C1-C3 alkyl; R w C6-C 10monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein the 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; The compound or a pharmaceutically acceptable salt thereof. 94B. A compound of embodiment 1B, 74B, or 1C, or a pharmaceutically acceptable salt thereof, where Z is N; p is 1; f is 1; Y 1 , Y 2 , Y 3 , and Y 4 each independently represents CH or CR 6 and R 6 In any case, C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, -O-(CH2) u R bb , halo-C1-C3 alkyl, -OR cc -OR dd and C-C cycloalkyl; or R 6 But in any case, -OR bb or -O-(C1-C6 alkoxy)-R bb where u is an integer from 0 to 6; R bb is a 4- to 7-membered monocyclic heterocyclyl, C-C cycloalkyl, or -NR G R H and; R cc and R dd are each independently C1-C3 alkyl; wherein said cycloalkyl or heterocyclyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; and R G and R H each independently represents hydrogen, -C(O)R Ga or C1-C3 alkyl; R Ga is C1-C3 alkyl or hydrogen; n is 0, 1, or 2; R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and —CHCHOH; R 4 but [ka] where R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, —CHOH, and —CHOC(CH); R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d and together with the atom to which each is attached form a cyclopropyl ring; R 4b is hydrogen or methyl; R 4a is hydrogen, C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, C6-C 10 Monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C6-C 10(monocyclic or fused bicyclic aryl)-C1-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl; wherein R 4a wherein said cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl is optionally substituted with 1, 2, or 3 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, halo-C1-C3 alkyl, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl; or R 4a and R 4b and 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 1 or 2 substituents, each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; R x is in each case C1-C3 alkyl; and m is 0, 1, or 2 The compound or a pharmaceutically acceptable salt thereof. 95B. The compound of embodiment 94B, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH and Y 2 is CR 6 and Y 3 is CH and Y 4 is CH, or a pharmaceutically acceptable salt thereof. 96B. The compound of embodiment 94B or 95B, or a pharmaceutically acceptable salt thereof, wherein R 6 hydroxy-C1-C6 alkoxy, and -O-(CH2) u R bb wherein u is an integer from 0 to 6; Rbb is a 4- to 7-membered monocyclic heterocyclyl, C-C cycloalkyl, or -NR G R H and; wherein said cycloalkyl or heterocyclyl is optionally substituted with 1 or 2 substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and C1-C3 alkyl; and R G and R H are each independently hydrogen or C1-C3 alkyl; and n is 0, 1, or 2 The compound or a pharmaceutically acceptable salt thereof. 97B. The compound of embodiment 96B, or a pharmaceutically acceptable salt thereof, wherein R 6 -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, and [ka] or a pharmaceutically acceptable salt thereof. 98B. A compound of any one of embodiments 94B-97B, or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl; R 4c and R 4d are each hydrogen; R 4b is hydrogen; R 4a is optionally substituted with 1 or 2 substituents (each independently selected from the group consisting of halogen, C-C alkyl, halo-C-C alkyl, hydroxy, C-C alkoxy, and halo-C-C alkoxy); 10 selected from the group consisting of monocyclic or fused bicyclic aryl, and 5- to 10-membered monocyclic or fused bicyclic heteroaryl; The compound or a pharmaceutically acceptable salt thereof. 99B. The compound of embodiment 98B, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of C1-C6 alkyl, phenyl, and pyridinyl, wherein said phenyl or pyrimidinyl is optionally substituted with C1-C3 alkoxy, or a pharmaceutically acceptable salt thereof. 100B. The compound of embodiment 99B, or a pharmaceutically acceptable salt thereof, wherein R 4a tert-butyl, and [ka] or a pharmaceutically acceptable salt thereof. 101B. A compound selected from Table 1 of Embodiment 1A, 1B, or 1C, or a pharmaceutically acceptable salt thereof. 102B. A pharmaceutical composition comprising a compound according to any one of embodiments 1B-101B, 1A-47A, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, 64C, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient. 103B. A method for inhibiting ferroportin-mediated iron transport in a subject, comprising administering to the subject an effective amount of a compound of any one of embodiments 1B-101B, 1A-47A, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, 31C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, 64C, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutical composition of embodiment 102B.

[0189] The general procedures and examples provide exemplary methods for preparing the compounds. Those skilled in the art will understand that other synthetic routes may be used to synthesize the compounds. While specific starting materials and reagents are described and discussed in the schemes, general procedures, and examples, other starting materials and reagents can be readily 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.

[0190] General synthetic scheme General synthetic methodology leading to FPN1 compounds 1a and 1b. In certain embodiments, compound 1a can be synthesized as shown in Scheme 1, where its core intermediate 2a is substituted with various substituted amines 3a via Method A to give intermediate 4a, which can then be coupled with various organometallic reagents 5a to give final compound 1a. Alternatively, final compound 1a can be synthesized as shown in Scheme 2. Intermediate 2a can be substituted with primary amine 6a to give intermediate 7a, which can be coupled with organometallic reagent 5a, followed by alkylation of the resulting intermediate 8a with a halide to give compound 1a. Final compound 1b can be synthesized according to Scheme 3. Intermediate 2a can be substituted with glycinate 9a to give intermediate 10a, which can be coupled with organometallic reagent 5a, followed by saponification of the resulting intermediate 11a. The corresponding carboxylic acid intermediate 12a can be coupled with various amines to form compound 1b.

[0191] Modifications and variations of Schemes 1-3 can be made based on the availability of starting materials and the synthetic suitability of reagents, starting materials, or intermediates. This will be apparent to those skilled in the art. For example, R1 and R2 can be hydrogen, halogen, simple alkyl, or can be joined together to form a ring; R3 can be hydrogen or alkyl; R4 can be alkyl or alkoxy substituted with aminocarbonyl; or R3 and R4 can be joined to form a cyclic amine. In Method B, another available heteroaromatic Suzuki or Stille reagent can be used to obtain the final compound 1a.

[0192] Scheme 1 describes how to prepare exemplary compounds using Method A and Method B. [ka]

[0193] Scheme 2 describes how to prepare exemplary compounds using Method A, Method B, and Method C. [ka]

[0194] Scheme 3 describes how to prepare exemplary compounds using Method A, Method B, Method D, and Method E. [ka]

[0195] Conditions and reagents for Method AE are provided in the Examples below. The following Examples are offered by way of illustration and not by way of limitation.

[0196] 1. Synthesis Example Example 1.1 Method A: General synthetic method for the nucleophilic coupling of amines with intermediate 4a In a 100 mL round-bottom flask was placed dichloropyrimidine intermediate 2a (1.00 equiv.), CHCN, amine 3a (1.10 equiv.), and triethylamine (2.00 equiv.). The resulting solution was stirred at 80° C. for 3 h. The resulting mixture was concentrated in vacuo. The residue was subjected to silica gel column chromatography using ethyl acetate / petroleum ether to give intermediate 4a.

[0197] Example 1.2 Method B: General synthetic method for metal-mediated cross-coupling In a 100 mL round-bottom flask purged with nitrogen and maintained under an inert atmosphere, intermediate 4a (1.00 equiv.), dioxane, organometallic reagent 5 (2.0 equiv.), and Pd(dppf)Cl (0.05 equiv.) were placed. The resulting solution was stirred at 100 °C overnight. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:1) or subjected to preparative HPLC purification to give compounds 1a, 8a, or 11a.

[0198] Example 1.3 Method C: General synthetic method for alkylation with halides to give compound 1a Intermediate 8a (1.00 equiv.) was dissolved in DMF and cooled in an ice bath. Sodium hydride (2.00 equiv.) (60%) was added in two portions and the reaction was stirred for 45 minutes. Halide (2.00 equiv.) was added slowly and the mixture was stirred for 1.5 hours more. Water (20 ml) and ethyl acetate (100 ml) were added, the phases were separated, and the aqueous phase was extracted with additional ethyl acetate. The organic phases were combined, washed with some water, and dried over sodium sulfate. After evaporation of the 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 fraction was treated with 1 M HCl and lyophilized to give compound 1a.

[0199] Example 1.4 Method D: General synthetic method for saponification to give 12a Intermediate 11a (1.00 equivalents) was dissolved in THF and methanol. Lithium hydroxide (5.00 equivalents) was dissolved in water and added dropwise to the solution. After 7 hours, the mixture was carefully acidified to pH 3 with 6M HCl and evaporated to dryness. The residue was co-evaporated with toluene, dried under high vacuum, and dried under high vacuum to obtain 12a.

[0200] Example 1.5 Method E: General synthetic method for amide formation to give 1b Intermediate 12a (1.00 equiv.) was suspended in N,N-dimethylformamide, N,N-diisopropylethylamine (2.50 equiv.), and amine (1.35 equiv.), followed by the addition of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1.35 equiv.). 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 solvent, the residue was purified by reverse-phase chromatography (Waters X-Select CSH C18 column, 0-70% acetonitrile / 0.1% aqueous formic acid gradient) to give compound 1b.

[0201] Example 1.6 Experimental procedures for common intermediates Scheme 4 describes a method for preparing intermediate I. [ka]

[0202] Process 1 [ka]

[0203] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.00 g; 10.58 mmol; 1.00 equiv.) was dissolved in acetonitrile (36 mL). (2-Ethoxy-2-oxoethyl)(methyl)azanium chloride (2.11 g; 13.75 mmol; 1.30 equiv., sarcosine ethyl ester·HCl) was added, followed by the slow addition of N,N-diisopropylethylamine (4.6 mL; 26.45 mmol; 2.50 equiv.). The reaction was stirred at 25°C for 22 hours and then at 50°C for 20 hours. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate / hexane 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. 1 H 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)

[0204] Process 2 [ka]

[0205] Ethyl 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetate (900.00 mg; 3.34 mmol; 1.00 equiv.) was dissolved in 1,4-dioxane (9 mL) and purged with argon. 2-(tributylstannyl)pyridine (2.34 mL; 6.67 mmol; 2.00 equiv.) and tetrakis(triphenylphosphane)palladium (385.58 mg; 0.33 mmol; 0.10 equiv.) were added, the reaction vessel was sealed, and the mixture was stirred in a heating bath at 105°C. After 16 hours, 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%). 1 H NMR (400MHz, chloroform-d) δ 8.83(d,J=4.8Hz,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, 1.5Hz,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

[0206] Process 3 [ka]

[0207] 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 equiv.) was dissolved in THF (20 mL) and methanol (5 mL). Lithium hydroxide (0.28 g; 11.52 mmol; 5.00 equiv.) dissolved in water (8 mL) was added dropwise to the solution. After 7 h, the mixture was carefully acidified to pH 3 with 6 M HCl 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. 1 H NMR (400MHz, DMSO-d6) δ 8.84(d,J=4.7Hz,1H), 8.41(d,J=7.9Hz,1H), 8.21-8.12(m,1H), 7.75(dd,J=7.8,4 .8Hz,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 1.7

[0208] Scheme 5 describes a method for preparing intermediate II. [ka]

[0209] Process 1 [ka]

[0210] In a 1 L three-necked round-bottom flask were placed 2-(benzyloxyoxycarbonylamino)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 at room temperature overnight. The resulting mixture was concentrated. The residue was applied to a silica gel column with PE / EA ether (0-50%). This afforded 25.1 g (99%) of benzyl N-[(tert-butylcarbamoyl)methyl]carbamate as a white solid. LCMS: (ES, m / z): [M+H] + :265 [ka]

[0211] In a 250 mL round-bottom flask were 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 under H2 (1 atm) at room temperature overnight. The solids were filtered off. The resulting mixture was concentrated. This afforded 3.3 g (95%) of 2-amino-N-tert-butylacetamide as a colorless oil. LCMS: (ES, m / z): [M+H] + :131 [ka]

[0212] A 50 mL round-bottom flask was charged with 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (0.80 g, 4.23 mmol, 1.00 equiv.), THF (20 mL), TEA (0.51 g, 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 at room temperature overnight. The resulting mixture was concentrated. The residue was subjected to ethyl acetate / hexane (0-50%) on a silica gel column. This afforded 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 1.8

[0213] Synthesis of 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 92) [ka]

[0214] Scheme 6 describes a synthetic route for preparing exemplary compounds. [ka]

[0215] Process 1 [ka]

[0216] A 100 mL round-bottom flask was charged with 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 triethanolamine (321.17 mg, 3.174 mmol, 1.20 equiv.). The resulting solution was stirred at 80 °C for 2 h. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:3) to afford 600 mg (90.10%) of 1-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane as a solid.

[0217] Process 2 [ka]

[0218] In a 100 mL round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere, 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)Cl (43.60 mg, 0.060 mmol, 0.05 equiv.) were placed. The resulting solution was stirred overnight at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1). The crude product was purified by recrystallization from EA (ethyl acetate). This gave 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 (300MHz, 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, 6.0Hz,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

[0219] Example 1.9 Synthesis of 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane (Compound 93) [ka]

[0220] Scheme 7 describes a synthetic route for preparing exemplary compounds. [ka]

[0221] Process 1 [ka]

[0222] A 100 mL round-bottom flask was charged with 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 triethanolamine (534.00 mg, 2.00 equiv.). The resulting solution was stirred at 80 °C for 3 h. The reaction progress was monitored by LCMS. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column with ethyl acetate / petroleum ether (1:2). This afforded 600 mg (89.28%) of 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as a brown solid.

[0223] Process 2 [ka]

[0224] In a 100 mL round-bottom flask purged with nitrogen and maintained under an inert nitrogen atmosphere, 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.), and Pd(dppf)Cl (0.04 g, 0.035 mmol, 0.05 equiv.) were placed. The resulting solution was stirred overnight at 100 °C in an oil bath. The resulting mixture was concentrated in vacuo. The residue was loaded onto a silica gel column using ethyl acetate / petroleum ether (1:1). The crude product was purified by recrystallization from EA. This gave 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 (300MHz, 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

[0225] Example 1.10 Synthesis of 1-[2-(3-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 71) [ka]

[0226] Compound 71 was synthesized in a manner similar to compound 92, using 4-fluoro-2-(tributylstannyl)pyridine instead of 2-(tributylstannyl)pyridine. 1 H NMR (400MHz, methanol-d4) δ 8.46(d,J=4.8Hz,1H), 7.77-7.68(m,1H), 7.54(dt,J=8.5, 4.3Hz,1H), 3.82(t,J=6.1Hz,4H), 3.19(t,J LCMS(ES) [M+1] + m / z 312.4

[0227] Example 1.11 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) [ka]

[0228] Compound 72 was synthesized in a manner similar to that of compound 92, using 2-oxa-5-azabicyclo[2.2.1]heptane instead of azepane. LCMS (ES+): (M+H) + =295.0; 1 H NMR (400MHz, chloroform-d) δ 8.85(d,J=4.8Hz,1H), 8.40(d,J=7.9Hz,1H), 7.89-7.79(m,1H), 7.39(dd,J=7.5, 4.9Hz,1H), 5.3 3(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)

[0229] Example 1.12 Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 73) [ka]

[0230] Scheme 8 describes a synthetic route for preparing exemplary compounds. [ka]

[0231] Process 1 [ka]

[0232] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (204.00 mg; 1.08 mmol; 1.00 equiv.) was dissolved in acetonitrile (4 mL). 2-Pyridinylmethanamine (0.15 mL; 1.40 mmol; 1.30 equiv.) was slowly added, followed by N,N-diisopropylethylamine (0.28 mL; 1.62 mmol; 1.50 equiv.). The reaction was stirred at 25°C for 18 hours and then at 50°C for 6 hours. 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. 1 H NMR (400MHz, chloroform-d) δ 8.58(d,J=5.2Hz,1H), 7.97-7.88(m,1H), 7.59(d,J=7.8Hz,1H), 7.45-7.38(m,1H), 6.63(s ,1H), 4.86(d,J=5.3Hz,2H), 2.87(t,J=7.8Hz,2H), 2.79(t,J=7.5Hz,2H), 2.19-2.09(m,2H)

[0233] Process 2 [ka]

[0234] 2-Chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (274.00 mg; 1.05 mmol; 1.00 equiv.) was suspended in 1,4-dioxane (5 mL) and the mixture was purged with argon. 2-(Tributylstannyl)pyridine (0.74 mL; 2.10 mmol; 2.00 equiv.) was added, followed by tetrakis(triphenylphosphane)palladium (121.44 mg; 0.11 mmol; 0.10 equiv.). The reaction vessel was sealed, and the contents were stirred in a heating bath at 105°C for 16 hours. The 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. 1 H NMR (400 MHz, chloroform-d) δ 8.87(d,J=5.0Hz,1H), 8.57(d,J=5.0Hz,1H), 8.49(d,J=8.0Hz,1H), 7.94 -7.88(m,1H), 7.80-7.73(m,1H), 7.65(d,J=7.9Hz,1H), 7.45(dd,J=7.4, 4.9Hz,1H), 7.30-7.26(m,1H), 7.13(s,1H), 5.07(d,J=5.1Hz,2H), 3.11( t,J=7.8Hz,2H), 2.95(t,J=7.5Hz,2H), 2.24-2.16(m,2H);MS(ES+):(M+H) + =304.0

[0235] Process 3 [ka]

[0236] 2-(Pyridin-2-yl)-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (0.16 g; 0.53 mmol; 1.00 equiv.) was dissolved in DMF (10 ml) and cooled in an ice bath. Sodium hydride (42 mg; 1.05 mmol; 2.00 equiv.) (60%) was added in two portions and the reaction was stirred for 45 minutes. Iodomethane (66 μL; 1.05 mmol; 2.00 equiv.) was added slowly and the mixture was stirred for 1.5 hours or longer. Water (20 ml) and ethyl acetate (100 ml) were added, the phases were separated, and the aqueous phase was extracted with additional ethyl acetate (3×75 ml) and 3:1 chloroform:isopropanol (50 ml). The organic phases were combined, washed with some water (5 ml), and dried over sodium sulfate. After evaporation of the solvent, the residue was purified by reverse-phase chromatography (Waters X-Select CSH C18 column, 0-70% acetonitrile / 0.1% aqueous formic acid gradient). The purified fraction was treated with 1 M HCl and lyophilized 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. 1 H NMR (400MHz, chloroform-d) δ 9.08(d,J=5.3Hz,1H), 8.69(d,J=5.5Hz,1H), 8.62(d,J=8.0Hz,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

[0237] Example 1.13 Synthesis of N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)pyrimidin-4-yl]amino}acetamide (Compound 75) [ka]

[0238] Scheme 9 describes a synthetic route for preparing exemplary compounds. [ka]

[0239] 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 equiv.) was suspended in N,N-dimethylformamide (3.5 mL). N,N-Diisopropylethylamine (0.15 mL; 0.87 mmol; 2.50 equiv.), 4-methoxyaniline (57.5 mg; 0.47 mmol; 1.35 equiv.), and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 177.6 mg; 0.47 mmol; 1.35 equiv.) were added. After 40 hours, 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 solvent, the residue was purified by reverse-phase chromatography (Waters X-Select 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, 46 mg, 34%) as a solid. 1H NMR (400MHz, chloroform-d) δ 10.18(s,1H), 8.86(d,J=5.0Hz,1H), 8.53(d,J=8.0Hz,1H), 8.22(s,1H), 8.04-7.93(m,1H), 7.56-7.46(m,3H), 6.76(d,J=8.6Hz) ,2H), 4.56(s,2H), 3.74(s,3H), 3.50(s,3H), 3.24(t,J=7.4Hz,2H), 2.99(t,J=7.9Hz,2H), 2.12(p,J=7.7Hz,2H);MS(ES+):(M+H) + =390.1

[0240] Example 1.14 Synthesis of N-(3-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 74) [ka]

[0241] Compound 74 was synthesized in the same manner as compound 75, using 3-fluoroaniline instead of 4-methoxyaniline. LCMS (ES+): (M+H) + =379.0; 1 H NMR (400MHz, chloroform-d) δ 10.80(s,1H), 9.10-8.96(m,1H), 8.67(d,J=7.9Hz,1H), 8.21-8.09(m,1H), 7.72-7.58(m,2H), 7.40(d,J=8.2Hz,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=7.4Hz,2H), 2.97(t,J=7.9Hz,2H), 2.14(p,J=7.7Hz,2H)

[0242] Example 1.15 Synthesis of 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline (Compound 76) [ka]

[0243] Scheme 10 describes a synthetic route for preparing exemplary compounds. [ka]

[0244] Process 1 [ka]

[0245] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100.00 mg; 0.53 mmol; 1.00 equiv.) in AcCN (2 mL) was added 1,2,3,4-tetrahydroquinoline (73.98 mg; 0.56 mmol; 1.05 equiv.), followed by Hunig's base (0.19 mL; 1.06 mmol; 2.00 equiv.). The mixture was heated at 75° C. for 2 hours. The mixture was cooled and concentrated, the residue was diluted with water, and 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

[0246] Process 2 [ka]

[0247] 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 equivalents) in toluene (1.5 mL) was added 2-(tributylstannyl)pyridine (48.31 mg; 0.13 mmol; 1.50 equivalents) and tetrakis(triphenylphosphane)palladium (10.11 mg; 0.01 mmol; 0.10 equivalents). The mixture was degassed and heated at 110 ° C for 15 hours. The mixture was cooled, 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). 1 H NMR (400MHz, methanol-d4) δ 8.73-8.67(m,1H), 8.42(dt,J=8.0, 1.2Hz,1H), 7.96(td,J=7.8, 1.8Hz,1H), 7.50 (ddd,J=7.5, 4.9, 1.3Hz,1H), 7.17(q,J=7.5Hz,2H), 7.03(td,J=7.5, 1.3Hz,1H), 6 .77(d,J=7.9Hz,1H), 4.10(t,J=6.5Hz,2H), 2.97(t,J=7.7Hz,2H), 2.82(t,J=6.6H z,2H), 2.31(t,J=7.3Hz,2H), 2.02(dp,J=36.1, 7.5, 7.0Hz,4H);LCMS(ES+):(M+H) + =329.1

[0248] Example 1.16 Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-phenylacetamide (Compound 77) [ka]

[0249] Compound 77 was synthesized in the same manner as compound 75, using aniline instead of 4-methoxyaniline. LC MS (ES+): (M+H) +=360.0; 1 H NMR (400MHz, chloroform-d) δ 10.39(s,1H), 8.98-8.87(m,1H), 8.58(d,J=8.0Hz,1H), 8.08-7.96(m,1H), 7.62(d,J=8.0Hz,2H), 7.59-7.51(m,1H), 7.25-7 .17(m,2H), 7.01(t,J=7.4Hz,1H), 4.61(s,2H), 3.52(s,3H), 3.26(t,J=7.4Hz,2H), 2.98(t,J=7.9Hz,2H), 2.18-2.07(m,2H)

[0250] Example 1.17 Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 78) [ka]

[0251] Compound 78 was synthesized in a similar manner to compound 75, using cyclohexanamine instead of 4-methoxyaniline. 1 H 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=7.4Hz,2H), 3.00(t,J=7.9Hz,2H), 2.17-2.07(m,2H), 1.75(d,J=12.0Hz,2 H), 1.65-1.58(m,2H), 1.56-1.49(m,1H), 1.28-1.06(m,5H);LCMS(ES+):(M+H) + =366.0

[0252] Example 1.18 Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-4-yl)acetamide (Compound 79) [ka]

[0253] Compound 79 was synthesized in a similar manner to compound 75, using 4-aminotetrahydropyran instead of 4-methoxyaniline. LCMS (ES+): (M+H) + =368.1; 1 H NMR (400MHz, chloroform-d) δ 9.32(s,1H), 8.87(d,J=8.0Hz,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=7.9Hz,2H), 2.16-2.11(m,2H), 1.75-1.56(m,4H)

[0254] Example 1.19 Synthesis of N-ethyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 80) [ka]

[0255] Compound 80 was synthesized in a manner similar to compound 73 by using 2-pyrimidinylmethylamine instead of 2-pyridinylmethanamine and ethyl iodide instead of iodomethane. LCMS (ES+): (M+H) + =333.0; 1H NMR (400MHz, chloroform-d) δ 8.96-8.82(m,3H), 8.52(d,J=7.7Hz,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=7.1Hz,2H), 3.32-3.13(m,4H), 2.28-2.17(m,2H), 1.37(t,J=6.9Hz,3H)

[0256] Example 1.20 Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 81) [ka]

[0257] Compound 81 was synthesized in a manner similar to compound 73 by using 2-pyrimidinylmethylamine instead of 2-pyridinylmethanamine. LCMS (ES+): (M+H) + =319.1; 1 H 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).

[0258] Example 1.21 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) [ka]

[0259] Compound 82 was synthesized in a manner similar to compound 73 by using 1,3-benzoxazol-2-ylmethanamine instead of 2-pyridinylmethanamine. LCMS (ES+): (M+H) + =358.0; 1 H NMR (400MHz, chloroform-d) δ 8.82(d,J=5.4Hz,1H), 8.34(d,J=8.0Hz,1H), 8.14(s,1H), 7.86-7.77(m,1H), 7.74-7.67(m,1H), 7.54-7.47(m,1H), 7.4 1-7.35(m,1H), 7.35-7.29(m,2H), 5.25(s,2H), 3.54(s,3H), 3.29(t,J=7.3Hz,2H), 3.18-3.11(m,2H), 2.16-2.12(m,2H)

[0260] Example 1.22 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) [ka]

[0261] Compound 83 was synthesized in a manner similar to compound 92 by using 2,3,4,5-tetrahydro-1H-benzo[d]azepine instead of azepane. LCMS (ES+): (M+H) + =343.0; 1 H NMR (400MHz, chloroform-d) δ 8.81(d,J=4.8Hz,1H), 8.41(d,J=7.9Hz,1H), 7.89-7.80(m,1H), 7.39(dd,J=7.5, 4.9Hz ,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)

[0262] Example 1.23 Synthesis of N-(2-methoxyethyl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (compound 84) [ka]

[0263] Compound 84 was synthesized in a similar manner to compound 92 by using N-(2-methoxyethyl)-N-methylamine instead of azepane. LCMS (ES+): (M+H) + =285.0; 1 H NMR (400MHz, chloroform-d) δ 8.81(dd,J=4.7, 2.0Hz,1H), 8.45(d,J=1.5Hz,1H), 8.34(dd,J=8.2, 1.5Hz,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)

[0264] Example 1.24 Synthesis of 1-methyl-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (Compound 85) [ka]

[0265] Compound 85 was synthesized in a manner similar to compound 92 by using 1-methyl-1,4-diazepane instead of azepane. LCMS (ES+): (M+H) + =310.1; 1H NMR (400MHz, chloroform-d) δ 8.79(d,J=4.8Hz,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=6.7Hz,2H), 3. 50-3.40(m,2H), 3.28-3.18(m,2H), 3.11(t,J=7.3Hz,2H), 3.03(t,J=7.8Hz,2H), 2.82(s,3H), 2.56(s,2H), 2.15-2.04(m,2H)

[0266] Example 1.25 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) [ka]

[0267] Compound 86 was synthesized in a similar manner to compound 75 by using morpholine instead of 4-methoxyaniline. LCMS (ES+): (M+H) + =354.0; 1 H NMR (400MHz, 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)

[0268] Example 1.26 Synthesis of N-methyl-N-(2-phenoxyethyl)-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 87) [ka]

[0269] Compound 87 was synthesized in a manner similar to compound 92 by using N-methyl-N-(2-phenoxyethyl)amine instead of azepane. LCMS (ES+): (M+H) + =285.0; 1 H NMR (400MHz, chloroform-d) δ 9.09(d,J=4.9Hz,1H), 8.57(d,J=7.8Hz,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=8.0Hz,2H), 4.36(s,4H), 3.61(s,3H), 3.45(t,J=7.8Hz,2H), 3.29(t,J=7.3Hz,2H), 2.24-2.13(m,2H)

[0270] Example 1.27 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) [ka]

[0271] Compound 88 was synthesized in a similar manner to compound 75 by using piperidine instead of 4-methoxyaniline. LCMS (ES+): (M+H) + =352.1; 1 H NMR (400MHz, chloroform-d) δ 9.03(d,J=5.1Hz,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,2 H), 3.52(t,J=5.6Hz,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)

[0272] Example 1.28 Synthesis of N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 89) [ka]

[0273] Compound 89 was synthesized in a similar manner to compound 75 by using tert-butylamine instead of 4-methoxyaniline. 1 H NMR (400MHz, chloroform-d) δ 9.33-9.18(m,1H), 8.87(d,J=7.7Hz,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=7.3Hz,2H), 3.00(t,J=7.9Hz,2H), 2.17-2.07(m,2H), 1.27(s,9H);MS(ES+):(M+H) + =340.0

[0274] Example 1.29 Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 91) [ka]

[0275] Process 1 [ka]

[0276] 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (500 mg; 2.5 mmol; 1 equiv.) was dissolved in DMF (6 mL). N,N-Diisopropylethylamine (1.1 mL; 6.15 mmol; 2.5 equiv.) was added, followed by 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate (HATU, 1262 mg; 3.3 mmol; 1.35 equiv.). Cyclohexanamine (0.38 mL; 3.3 mmol; 1.35 equiv.) was added, and the reaction mixture was stirred at 25 °C. After 14 h, the reaction mixture was diluted with ethyl acetate (50 mL), water (15 mL), and sodium bicarbonate solution (30 mL). The phases were separated, the aqueous phase was extracted with ethyl acetate (50 ml), the organic phases were combined, washed with sodium chloride solution (50 ml), and dried over sodium sulfate. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexane gradient) to give tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g, 68%) as white crystals. LCMS (ES+): (M+H) + =285.0

[0277] Process 2 [ka]

[0278] tert-Butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g; 1.7 mmol; 1 equivalent) 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 hours, the reaction was evaporated to a residue and then coevaporated from toluene (40 ml). The crude N-cyclohexyl-2-(methylamino)propanamide trifluoroacetate was used directly in the next step.

[0279] Process 3 [ka]

[0280] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg; 0.79 mmol; 1 equiv.) was dissolved in acetonitrile (3 mL) containing N-cyclohexyl-2-(methylamino)propenamide trifluoroacetate (355 mg; 1.19 mmol; 1.5 equiv.). N,N-Diisopropylethylamine (0.55 mL; 3.2 mmol; 4 equiv.) was added, and the reaction was stirred at 50°C for 14 h, then at 60°C for 6 h and at 30°C for 18 h. After evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexane 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

[0281] Process 4 [ka]

[0282] 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide (174 mg; 0.52 mmol; 1 equiv.) 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 equiv.) was added, followed by tetrakis(triphenylphosphane)palladium (60 mg; 0.05 mmol; 0.1 equiv.). The reaction vessel was sealed and stirred in a heating bath at 110° C. for 15 hours. After evaporation, the residue was purified by reverse phase chromatography (Waters X-Select 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; 1 H NMR (400MHz, DMSO-d6) δ 8.69(d,J=4.8Hz,1H), 8.34(d,J=7.9Hz,1H), 8.19(d,J=8.3Hz,1H), 7.96-7.8 4(m,1H), 7.53-7.42(m,1H), 5.16(q,J=7.0Hz,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=7.0Hz,3H), 1.25-1.12(m,3H), 1.07-0.93(m,2H)

[0283] Example 1.30 Synthesis of N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 90) [ka]

[0284] Compound 90 was synthesized in a similar manner to compound 91 by using tert-butylamine instead of cyclohexanamine. LCMS (ES+): (M+H) + =354.4; 1 H NMR (400MHz, DMSO-d6) δ 8.80-8.74(m,1H), 8.50(d,J=7.9Hz,1H), 8.09-8.01(m,1H), 7.81(s,1H), 7.66-7.59(m,1H), 5.14(q,J=7.0Hz ,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=7.1Hz,3H), 1.21(s,9H)

[0285] Example 1.31 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) [ka]

[0286] Compound 1 is a 10-azatricyclo[6.3.1.0]-azepane-substituted azepane. 2 ,7]dodeca-2(7),3,5-triene was used in the same manner as compound 92. LCMS (ES+): (M+H) + =355.0; 1 H 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)

[0287] Example 1.32 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) [ka]

[0288] Compound 2 was synthesized in a similar manner to compound 92 by using 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine instead of azepane. LCMS(ES+):(M+H) + =373.1; 1 H 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).

[0289] Example 1.33 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) [ka]

[0290] Compound 3 was synthesized in a manner similar to compound 92 by using 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine instead of azepane. LCMS (ES+): (M+H) + =373.0; 1H NMR (400MHz, chloroform-d) δ 8.81(dd,J=4.8, 1.8Hz,1H), 8.42(d,J=7.9Hz,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, 4.9Hz,4H), 3.81(s,3H), 3.17-3.03(m,8H), 2.15-2.06(m,2H)

[0291] Example 1.34 Synthesis of 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (Compound 4) [ka]

[0292] Scheme 11 describes a synthetic route for preparing exemplary compounds. [ka]

[0293] Process 1 [ka]

[0294] 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 25° C. After 1 h, the reaction was evaporated to dryness and the residue was co-evaporated with toluene. LCMS (ES+): (M+H) + =296

[0295] Process 2 [ka]

[0296] 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (108 mg; 0.37 mmol; 1.15 equivalents) and 1-iodo-3-methoxybenzene (75 mg; 0.32 mmol; 1 equivalent) 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; 0.06 mmol; 0.20 equiv.), tris(dibenzylideneacetone)dipalladium(0) (15 mg; 0.02 mmol; 0.05 equiv.), and sodium tert-butoxide (46 mg; 0.48 mmol; 1.50 equiv.) were added, and the reaction vessel was sealed and stirred at 100° C. After 19 h, an additional portion of the reagents (iodide, ligand, palladium catalyst, and base) was added, resulting in product formation. The reaction mixture was then filtered, concentrated, and purified by reverse-phase chromatography (Waters X-Select CSH C18 column, 0-50% acetonitrile / 0.1% aqueous formic acid gradient) to afford 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.

[0297] MS(ES+):(M+H) + =402.1; 1 H NMR (400 MHz, chloroform-d) δ 8.94-8.87(m,1H), 8.34(d,J=7.9Hz,1H), 8.02-7.92(m,1H), 7.62-7.5 3(m,1H), 7.19-7.10(m,1H), 6.41(d,J=8.3Hz,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=8.0Hz,2H), 3.18(t,J=7.4Hz,2H), 2.27-2.15(m,4H)

[0298] Example 1.35 Synthesis of N-(pyridin-2-yl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 5) [ka]

[0299] Scheme 12 describes a synthetic route for preparing exemplary compounds. [ka]

[0300] Process 1 [ka]

[0301] A 50 mL three-necked round-bottom flask was charged with [(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.). Following this procedure, HATU (5.21 g, 13.70 mmol, 1.2 equiv.) was added portionwise at 0 °C. The reaction solution was stirred at room temperature for 2 h. The reaction was then quenched by adding 50 mL of HO, filtered, and the solid was collected and dried under an infrared lamp. 2.4 g (84% yield) of tert-butyl N-[[(pyridin-2-yl)carbamoyl]methyl]carbamate was obtained as a white solid. LCMS(ES) [M+1] + m / z:252

[0302] Process 2 [ka]

[0303] In a 50 mL round-bottom flask, tert-butyl N-[[(pyridin-2-yl)carbamoyl]methyl]carbamate (2.40 g, 9.55 mmol, 1.0 equiv) and DCM (20.0 mL) were placed. To the above mixture, HCl (g) (2 M in EA) (19.0 mL) was added at 0 °C. The mixture was stirred at room temperature for 2 h. The mixture was concentrated to remove the solvent, affording 1.4 g (78% yield) of 2-amino-N-(pyridin-2-yl)acetamide hydrochloride as a white solid. LCMS (ES) [M-HCl+1] + m / z:152

[0304] Process 3 [ka]

[0305] A 100 mL round-bottom flask was charged with 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.), and DIEA (2.70 g, 20.89 mmol, 2.80 equiv.). The mixture was stirred in an oil bath at 60 °C for 12 h. After cooling to room temperature, the reaction mixture was diluted with HO (50 mL) and extracted with 3 × 40 mL of ethyl acetate. The combined organic phases were washed with 3 × 40 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 chromatography using ethyl acetate / petroleum ether (1:2). Obtained 320 mg (14% yield) of 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide as a white solid. LCMS (ES) [M+1] + m / z:304

[0306] Process 4 [ka]

[0307] In a 50 mL round-bottom flask, 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide (320 mg, 1.05 mmol, 1.0 equivalent), dioxane (20.0 mL), 2-(tributylstannyl)pyridine (465 mg, 1.26 mmol, 1.2 equivalent), and Pd(dppf)Cl (86 mg, 0.11 mmol, 0.1 equivalent) were placed. The mixture was stirred in an oil bath under a nitrogen atmosphere at 110 °C for 12 hours. The reaction mixture was cooled to room temperature and concentrated to remove the solvent. The residue was purified by silica gel column chromatography using ethyl acetate / petroleum ether (3:1). The crude product was further purified by Flash-Prep-HPLC using the following conditions: column: HPH C18, 50*3.0 mm, 2.6 μm, mobile phase A: water / 0.05% NH3·H2O, mobile phase B: CH3CN, flow rate: 1.2 mL / min, gradient: 5% B to 100% B in 1.1 min, hold for 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 an off-white solid. 1 H NMR (300MHz, DMSO-d6, ppm): δ 10.60(s,1H), 8.61(d,J=4.6Hz,1H), 8.33(dd,J=4.9, 1.1Hz,1H)8.23(d,J =8.1Hz,1H), 8.03(d,J=8.4Hz,1H), 7.78-7.69(m,2H), 7.40-7.35(m,2H), 7.09(ddd,J=7.3, 4.8, 1.0Hz,1H), 4.31(d,J=5.8Hz,2H), 2.86(t,J=7.7Hz,2H), 2.79(t,J=7.4Hz,2H), 2.09(p,J=7.5Hz,2H);LCMS:(ES, m / z):[M+H] + :347.1

[0308] Example 1.36 Synthesis of N-(2-fluorophenyl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 6) [ka]

[0309] Scheme 13 describes a synthetic route for preparing exemplary compounds. [ka]

[0310] In a 50 mL round-bottom flask, [[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1.0 equivalent), DMF (3.0 mL), 2-fluoroaniline (98 mg, 0.88 mmol, 1.5 equivalent), DIEA (153 mg, 1.18 mmol, 2.0 equivalent), and HATU (337 mg, 0.88 mmol, 1.5 equivalent) were placed. The resulting solution was stirred at room temperature for 2 hours. The reaction solution was diluted with 5 mL of CH3CN and filtered. The filtrate was purified by preparative HPLC under the following conditions (SHIMADZU (HPLC-01)): column, Welch Xtimate C18, 21.2 × 250 mm, 5 μm, mobile phase, water (10 mmol / L NH4HCO3) and MeOH:CH3CN = 1:1 (phase B from 25% to 65% in 15 min), detector, UV 254 nm, to give 117.3 mg of N-(2-fluorophenyl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as a light yellow solid. 1H NMR (300MHz, 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=5.4Hz,2H), 2.86(t,J=7.8Hz,2H), 2.78(t,J=7.4Hz,2H), 2.14-2.04(m,2H);LCMS(ES)[M+1] + m / z:364.1

[0311] Example 1.37 Synthesis of 2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7-yl)acetamide (Compound 7) [ka]

[0312] Scheme 14 describes a synthetic route for preparing exemplary compounds. [ka]

[0313] In a 50 mL round-bottom flask at 0 ° C., [[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.) were placed. After addition, the mixture was stirred at room temperature for 2 hours. The reaction solution was diluted with 5 mL of CH 3 CN and filtered. The filtrate was purified by preparative HPLC under the following conditions: column, Welch Extimate C18, 21.2 x 250 mm, 5 μm; mobile phase, water (10 mmol / L NH4HCO3) and MeOH:CH3CN = 1:1 (phase B from 25% to 70% over 15 min); detector, UV 254 nm. This afforded 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 as a gray solid. 1 H NMR (300MHz, DMSO-d6) δ 10.64(s,1H), 8.82(dd,J=4.2, 1.8Hz,1H), 8.64-8.61(m,1H), 8.43(d,J=1.8Hz,1H), 8.29-8.25(m,2H), 7.92(d,J=8.7Hz,1H), 7.81-7 .69(m,2H), 7.54-7.50(m,1H), 7.43-7.36(m,2H), 4.30(d,J=5.7Hz,2H), 2.90-2.76(m,4H), 2.15-2.05(m,2H);LCMS:(ES, m / z):[M+1] + m / z:397.1

[0314] Example 1.38 Synthesis of N-tert-butyl-2-{[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 8) [ka]

[0315] Scheme 15 describes a synthetic route for preparing exemplary compounds. [ka]

[0316] A 10 mL sealed tube, purged with nitrogen and maintained under an inert nitrogen atmosphere, was charged with 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)Cl.CHCl (0.17 g, 0.20 equiv.). The resulting solution was stirred at 130 °C overnight. The resulting mixture was concentrated. The residue was loaded onto a silica gel column with MeOH / EA (1:9). The crude product was purified by preparative HPLC under the following conditions: column, Welch Extimate C18, 21.2 x 250 mm, 5 μm; mobile phase, Phase A: water (10 mmol / L NH4HCO3), Phase B: CH3CN / MeOH (1:1) (15% to 60% Phase B in 15 min); detector, 220 nm, to afford 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. 1 H NMR: (300MHz, DMSO-d6, ppm): δ 9.28(s,1H), 8.93(d,J=5.1Hz), 8.32(d,J=5.1Hz,1H), 7.67(s,1H), 7.29(t,J=6.0Hz,1H), 3.97(d,J=5.7H) z,2H), 2.87(q,J=7.8Hz,2H), 2.76(q,J=7.2Hz,2H), 2.13-2.06(m,2H),1.24(s,9H);LCMS:(ES,m / z):[M+H] + :327.2

[0317] Example 1.39 Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide (Compound 9) [ka]

[0318] Scheme 16 describes synthetic routes for preparing exemplary compounds. [ka]

[0319] Process 1 [ka]

[0320] A 40 mL vial purged with nitrogen and maintained under an inert atmosphere was charged with 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 at 110 °C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (1 g) was purified by preparative HPLC using the following conditions: column, XBridge Prep C18-OBD column, 19 cm, 150 mm, 5 μm; mobile phase, water (0.1% NH3·H2O) and CAN (50% to 80% phase B in 11 min); detector, 254. This gave 350 mg (57.06%) of 2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine as a white solid. LCMS (ES) [M+H] + :m / z:231

[0321] Process 2 [ka]

[0322] A 40 mL vial purged with nitrogen and maintained under an inert atmosphere was charged with 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) (15.57 mg, 0.069 mmol, 0.10 equiv.), CsCO (451.94 mg, 1.38 mmol, 2.00 equiv.), BINAP (86.37 mg, 0.14 mmol, 0.20 equiv.), and dioxane (10.00 mL). The resulting solution was stirred at 100 °C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (300 mg) was purified by preparative HPLC using the following conditions: column, Xbridge-Prep C18-OBD column, 19 cm, 150 mm, 5 μm; mobile phase, water (0.1% NH4HCO3) and CAN (20% to 50% phase B in 11 min); detector, 254 nm. This afforded 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 an off-white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.59(ddd,J=4.8, 1.9, 0.9Hz,1H), 8.30(dt,J=8.0, 1.1Hz,1H), 7.84(td,J=7.7, 1.8Hz,1H), 7.66(s,1H), 7.41-7.30(m,2H), 6.00(t,J =5.7Hz,1H), 3.77(d,J=5.7Hz,2H), 2.88(t,J=7.6Hz,2H), 2.75(t,J=7.3Hz,2H), 2.12-2.02(m,2H), 1.27(s,9H);LCMS(ES, m / z):[M+H] + :325.1

[0323] Example 1.40 Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide (Compound 10) [ka]

[0324] Scheme 17 describes synthetic routes for preparing exemplary compounds. [ka]

[0325] Process 1 [ka]

[0326] A 40 mL vial was charged with 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 at 80 °C overnight. The reaction mixture was cooled to room temperature. The crude product (2 g) was purified by preparative HPLC using the following conditions: column, Xbridge-Prep C18-OBD column, 19 cm, 150 mm, 5 μm; mobile phase, water (0.1% NH3·H2O) and CAN (phase B from 20% to 60% in 11 min); detector, 254 nm. This gave 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

[0327] Process 2 [ka]

[0328] A 40 mL vial purged with nitrogen and maintained under an inert atmosphere was charged with 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)Cl (123.26 mg, 0.17 mmol, 0.10 equiv.). The resulting solution was stirred at 110 °C overnight. The reaction mixture was cooled to room temperature. The resulting mixture was concentrated. The crude product (800 mg) was purified by preparative HPLC using the following conditions: column, Xbridge-Prep C18-OBD column, 19 cm, 150 mm, 5 μm; mobile phase, water (0.1% NH4HCO3) and CAN (20% to 50% Phase B in 11 min); detector, 254 nm, to afford 139.2 mg (24.34%) of N-tert-butyl-2-[[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino]acetamide as a white solid. 1 H NMR (300MHz, DMSO-d6) δ 8.65(ddd,J=4.8, 1.8, 0.9Hz,1H), 8.33(dt,J=8.0, 1.1Hz,1H), 7.87(td,J=7.7, 1.8Hz,1H), 7.71(s,1H), 7.45-7.40(m,1H), 6.88( t,J=5.6Hz,1H), 3.95(d,J=5.6Hz,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

[0329] Example 1.41 Synthesis of N-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]piperidin-3-amine (Compound 11) [ka]

[0330] Process 1 [ka]

[0331] 1-Bromo-4-methoxybenzene (0.25 g; 1.34 mmol; 1 equivalent) and tert-butyl 3-amino-1-piperidinecarboxylate (0.32 g; 1.6 mmol; 1.2 equivalents) were dissolved in 1,4-dioxane (5 ml) and tert-butanol (2.5 ml). The solution was purged with Ar, and sodium tert-butoxide (0.26 g; 2.67 mmol; 2 equivalents), 2-[2-(dicyclohexylphosphanyl)phenyl]-N,N-dimethylaniline (52.6 mg; 0.13 mmol; 0.1 equivalents), and tris(dibenzylideneacetone)dipalladium(0) (61.2 mg; 0.07 mmol; 0.05 equivalents) were added. The reaction vessel was sealed and stirred in a heating bath at 100 °C for 6 hours. After cooling and evaporation, the residue was purified by silica gel chromatography (ethyl acetate / hexane gradient) to give tert-butyl 3-[(4-methoxyphenyl)amino]piperidine-1-carboxylate (178 mg, 43%) as a solid. LCMS (ES+): (M+H) + =307.0; 1 H NMR (400 MHz, chloroform-d) δ 6.82-6.76 (m, 2H), 6.76-6.60 (m, 2H), 4.09-3.93 (m, 1H), 3.76-3.67 (m, 4H), 3.33-3.22 (m, 1H), 3.09-2.95 (m, 1H), 2.95-2.75 (m, 1H), 2.07-1.95 (m, 1H), 1.76-1.68 (m, 1H), 1.45 (s, 9H)

[0332] Process 2 [ka]

[0333] tert-Butyl 3-[(4-methoxyphenyl)amino]piperidine-1-carboxylate (178 mg; 0.58 mmol; 1 equiv.) was dissolved in DCM (5 mL) and cooled in an ice bath. Trifluoroacetic acid (2.55 mL) was added slowly, and the reaction was stirred at 20 °C for 1 h. The reaction was evaporated, and the residue was co-evaporated with toluene to give 3-[(4-methoxyphenyl)amino]piperidin-1-ium trifluoroacetate, which was used directly in the next step.

[0334] Process 3 [ka]

[0335] To a round-bottom flask was added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100.00 mg; 0.53 mmol; 1.00 equiv.), acetonitrile (3.5 mL), 3-[(4-methoxyphenyl)amino]piperidin-1-ium trifluoroacetate (186.38 mg; 0.58 mmol; 1.10 equiv.), and Hunig's base (0.38 mL; 2.17 mmol; 4.10 equiv.). The mixture was stirred at approximately 70 °C. After cooling and evaporation, the residue was purified by silica gel chromatography (0 to 50% ethyl acetate / hexane gradient) to give 1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-(4-methoxyphenyl)piperidin-3-amine (144 mg, 76%). LCMS(ES+):(M+H) + =402.4

[0336] Process 4 [ka]

[0337] In a round-bottom flask, 1-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N-(4-methoxyphenyl)piperidin-3-amine (144.00 mg; 0.40 mmol; 1.00 equiv.) in 1,4-dioxane (dry, ca. 3 ml) was added, and the solution was purged with Ar. To the mixture was added 2-(tributylstannyl)pyridine (0.26 mL; 0.80 mmol; 2.00 equiv.) and tetrakis(triphenylphosphane)palladium (46.37 mg; 0.04 mmol; 0.10 equiv.), and the mixture was stirred in a heat block at 105° C. for 15 hours. The mixture was then concentrated, and the residue was purified by preparative HPLC to give N-(4-methoxyphenyl)-1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]piperidin-3-amine (52 mg) as a yellow solid. LCMS (ES+): (M+H) + =402.4; 1 H NMR (400MHz, chloroform-d) δ 9.01-8.83(m,1H), 8.38(d,J=8.6Hz,1H), 8.00-7.86(m,1H), 7.55-7.43(m,1H), 7.08-6.87(m,2H), 6.87-6.69(m,2H), 4.79(s,1H) ), 4.16-4.00(m,1H), 3.74(s,3H), 3.62-3.44(m,3H), 3.17-2.87(m,4H), 2.17-1.99(m,3H), 1.99-1.75(m,2H), 1.70-1.52(m,1H)

[0338] Example 1.42 Synthesis of N-tert-butyl-2-{[2-(5-methoxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 12) [ka]

[0339] Scheme 18 describes synthetic routes for preparing exemplary compounds. [ka]

[0340] A 40 mL vial purged with nitrogen and maintained under an inert nitrogen atmosphere was charged with a mixture of N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (200 mg, 0.674 mmol, 1.00 equiv.), dioxane (10.0 mL), 2-methoxy-5-(trimethylstannyl)pyrazine (275 mg, 1.01 mmol, 1.50 equiv.), and Pd(PPh3)4 (155 mg, 0.135 mmol, 0.20 equiv.). The resulting solution was stirred at 110 °C for 16 h. The resulting mixture was concentrated. The crude reaction mixture was filtered and subjected to reverse-phase preparative MPLC (Prep C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution from 5% MeCN in water to 35% MeCN in water over 15 min, both solvents containing 0.1% formic acid), which gave 71.7 mg (28%) of N-(tert-butyl)-2-((2-(5-methoxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as an off-white solid. 1 H NMR (300MHz, DMSO-d6, ppm): δ 9.12(d,J=1.4Hz,1H), 8.36(d,J=1.3Hz,1H), 7.68(s,1H), 4.13(s,2H), 3.98(s,3H), 3.27(s,3H) ), 3.14(t,J=7.3Hz,2H), 2.81(t,J=7.8Hz,2H), 2.00-1.95(m,2H), 1.25-1.22(m,9H);LCMS(ES) [M+1] + m / z:371.2

[0341] Example 1.43A Synthesis of N-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 174) [ka]

[0342] Scheme 19A describes a synthetic route for preparing exemplary compounds. [ka]

[0343] Process 1 [ka]

[0344] In a 250 mL three-necke...

Claims

1. formula: 【Chemical 1】 or a pharmaceutically acceptable salt thereof.

2. formula: 【Chemistry 2】 or a pharmaceutically acceptable salt thereof.

3. formula: 【Chemistry 3】 A compound represented by the formula:

4. formula: 【Chemistry 4】 A compound represented by the formula:

5. 10. A pharmaceutical composition for inhibiting ferroportin-mediated iron transport in a subject, comprising a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

6. Use of an effective amount of a compound described in any one of claims 1 or 2, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition described in claim 5, in the manufacture of a medicament for inhibiting ferroportin-mediated iron transport in a subject.

7. 10. A pharmaceutical composition for inhibiting ferroportin-mediated iron transport in a subject, comprising a compound according to claim 3 or 4, and a pharmaceutically acceptable excipient.

8. 10. Use of an effective amount of a compound according to any one of claims 3 or 4, or a pharmaceutical composition according to claim 7, in the manufacture of a medicament for inhibiting ferroportin-mediated iron transport in a subject.

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