Cycloalkylpyrimidines as ferroportin inhibitors

Abstract

The subject matter described herein pertains to transferrin inhibitor compounds of formula I or I', their pharmaceutically acceptable salts, methods for preparing such compounds, pharmaceutical compositions comprising such compounds, and methods of administering such compounds for the prevention and / or treatment of diseases caused by hepcidin deficiency or iron metabolic disorders, particularly iron overload conditions, such as thalassemia, sickle cell disease, and hemochromatosis, as well as kidney injury.

Description

[0001] Cross - reference to related applications

[0002] This application claims the benefit and priority of U.S. Provisional Application No. 63 / 016,891, filed on April 28, 2020, and U.S. Provisional Application No. 63 / 127,774, filed on December 18, 2020, the content of each of which is incorporated herein by reference in its entirety. Technical field

[0003] The subject matter described herein relates to hepcidin inhibitor compounds, methods for preparing such compounds, pharmaceutical compositions thereof, and their use in the prevention and / or treatment of diseases caused by hepcidin deficiency or iron metabolism disorders, particularly iron overload conditions, such as thalassemia, sickle cell disease, and hemochromatosis, as well as kidney injury. Background art

[0004] In almost all organisms, iron is an essential trace element. In humans, iron is a key component of oxygen transport, oxygen uptake, cellular functions such as mitochondrial electron transport, cognitive function, and energy metabolism. Iron exists in enzymes, heme, and myoglobin in the form of ferritin and hemosiderin. In the case of heme, approximately half of all iron is bound to the heme of red blood cells and exists as heme iron. The human body contains an average of about 4 to 5 g of iron. The iron requirement for adults is between 0.5 and 1.5 mg per day, while infants and pregnant women require 2 to 5 mg of iron per day.

[0005] The normal daily iron loss of about 1 mg in healthy adults is usually compensated for by food intake. Iron balance is mainly regulated by recycling and iron recovery from the heme of senescent red blood cells, as well as duodenal absorption of dietary iron in the form of divalent and trivalent iron ions.

[0006] Absorption is regulated by the organism depending on iron requirements and iron stores. In general, Fe(III) compounds will dissolve in the stomach at a sufficiently acidic pH and are thus available for absorption. Iron absorption occurs in the upper part of the small intestine through mucosal cells. Trivalent non-heme iron is first reduced to Fe(II) in the intestinal cell membrane, e.g., by a ferric reductase (membrane-bound duodenal cytochrome b), for absorption, so that it can subsequently be transported into the intestinal cell by means of the transporter DMT1 (divalent metal transporter 1). In contrast, heme iron enters the intestinal epithelial cells through the cell membrane without any change. In the intestinal epithelial cells, iron is stored as stored iron in ferritin or released into the blood by the transporter transferrin. Divalent iron transported into the blood by transferrin is converted to trivalent iron by an oxidase (ceruloplasmin, hephaestin). Trivalent iron is then transported to its destination in the organism by transferrin. (“Balancing acts: molecular control of mammalian iron metabolism”, M.W. Hentze, Cell, 1:17, 2004, 285 - 297). Hepcidin plays a central role in this process, as it is an essential regulator of iron absorption. The hepcidin - transferrin system directly regulates iron metabolism.

[0007] Iron absorption and storage are regulated by hepcidin. The hepcidin antimicrobial peptide (HAMP; also known as LEAP - 1; also called hepcidin) is a 25 - amino acid peptide (Krause et al., FEBS Lett. 480, 147 - 150, 2000). Hepcidin has a hairpin structure that contains 8 cysteines forming 4 disulfide bridges (Jordan et al., J Biol Chem. 284, 24155 - 24167, 2009). The N - terminus is very important for the iron - regulatory function, as the deletion of the first 5 amino acids leads to a complete loss of biological activity (Nemeth et al., Blood, 107, 328 - 333, 2006). Hepcidin is produced in the liver and acts as the main iron - regulatory hormone controlling intestinal iron absorption and regulates 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 absorption by binding to the iron - transport molecule transferrin and degrading it (Sebastiani et al., Front. Pharmacol. 7, 160, 2016).

[0008] The regulation of hepcidin formation is directly related to the iron content of an organism. That is, if an organism is supplied with sufficient iron and oxygen, more hepcidin is formed; if the iron and oxygen content is low, or in the case of increased erythropoiesis, less hepcidin is formed. In intestinal mucosal cells and macrophages, hepcidin binds to the transporter transferrin, which routinely transports iron recycled by phagocytosis from inside the cell to the blood.

[0009] Transferrin is an iron transporter that plays a key role in regulating iron absorption and distribution in the body and thus controlling the iron content in the blood. The transporter transferrin is a transmembrane protein composed of 571 amino acids, which is formed in the liver, spleen, kidney, heart, intestine, and placenta. Specifically, transferrin is located in the basement membrane of intestinal epithelial cells. Thus, transferrin bound in this way is used to export iron into the blood. In this case, transferrin most likely transports iron in the form of Fe 2+ . If hepcidin binds to transferrin, it will transport transferrin into the cell, where it is degraded, resulting in almost complete blockade of the release of recycled iron from the cell by phagocytosis. If transferrin is inactivated, for example, by hepcidin, such that it cannot export the iron stored in mucosal cells, the stored iron is lost via the natural excretion of the cells in feces. When transferrin is inactivated or inhibited, for example, by hepcidin, iron absorption in the intestine is thus reduced.

[0010] Reduced hepcidin results in increased active transferrin, thus allowing enhanced release of stored iron and enhanced iron absorption, for example, from food, leading to an increase in serum iron content, i.e., iron overload. Iron overload causes many diseases and undesired medical conditions. Iron overload can be treated by removing iron from the body. This treatment includes regularly scheduled phlebotomy (bloodletting). For patients who cannot tolerate regular blood draws, chelating agents are available. The disadvantage of treating iron overload by chelation therapy is that chelated iron is removed from the body when iron overload has already occurred, rather than preventing the occurrence of the disease.

[0011] Accordingly, there is an unmet need in the art for compounds that act as transferrin inhibitors with the desired efficacy and therapeutic potential. This problem and other problems stemming from iron imbalance are solved by the subject matter described herein. Summary of the Invention

[0012] In certain embodiments, the subject matter described herein pertains to a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof.

[0013] In certain embodiments, the subject matter described herein pertains to a pharmaceutical composition comprising a compound of formula I or formula I' or a pharmaceutically acceptable salt thereof.

[0014] In certain embodiments, the subject matter described herein relates to methods for inhibiting transferrin-mediated iron transport in a subject, which comprise 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'.

[0015] In certain embodiments, the subject matter described herein relates to methods for preparing a compound of formula I or formula I'.

[0016] Other embodiments are also described. DETAILED DESCRIPTION

[0017] Described herein are transferrin inhibitor compounds of formula I and formula I', methods for preparing said compounds, pharmaceutical compositions comprising said compounds, and their use in the prevention and / or treatment of diseases caused by hepcidin deficiency or iron metabolism disorders, particularly iron overload conditions, such as thalassemia, sickle cell disease, and hemochromatosis. Transferrin is an iron transport protein responsible for the absorption of iron released via the intestine and its transfer into the blood circulation, where the iron is ultimately delivered to appropriate tissues and organs. Inactivation or inhibition of transferrin reduces or prevents iron export, thereby reducing iron absorption in the intestine and ultimately reducing the amount of iron in the body. These compounds, compositions, and methods can be useful as effective therapies for preventing and treating iron metabolism disorders associated with increased iron content. There is a desire to provide compounds, compositions, and methods that exhibit minimal side effects, have very low toxicity, and good bioavailability and compatibility.

[0018] Iron overload is associated with various diseases (Blanchette et al., Expert Rev. Hematol. 9, 169 - 186, 2016). Hereditary hemochromatosis is the most common genetic disease in Europe and is caused by hepcidin deficiency or insensitivity (Powell et al., The Lancet 388, 706 - 716, 2016). The clinical manifestations of hemochromatosis are cirrhosis, diabetes, and skin pigmentation (Powell et al., The Lancet 388, 706 - 716, 2016). Although this disease can be managed by phlebotomy, this method can be cumbersome and does not address the cause of the disease.

[0019] Iron - loaded anemias such as β - thalassemia are also associated with reduced hepcidin levels (Origa et al., Haematologica 92, 583 - 588, 2007). Treatment of this disease with hepcidin mimetics not only resolves iron overload but also shows improvement in ineffective erythropoiesis occurring in this disease (Casu et al., Blood 128, 265 - 276, 2016). Such hepcidin mimetics may be particularly beneficial for thalassemia patients who may be less dependent on transfusions, which can cause iron overload in these patients.

[0020] Diseases characterized by myelofibrosis, myelodysplastic syndromes, and sickle cell disease are also characterized by ineffective erythropoiesis and may require frequent blood transfusions (Carreau et al., Blood Rev. 30, 349 - 356, 2016; Temraz et al., Crit. Rev. Oncol. Hematol. 91, 64 - 73, 2014; Walter et al., Acta Haematol. 122, 174 - 183, 2009). A reduced hepcidin content has been described in some of these patients (Cui et al., Leuk. Res. 38, 545 - 550, 2014; Santini et al., PLoS ONE 6, e23109, 2011). Hepcidin mimetics may also be beneficial to these patients.

[0021] Polycythemia vera is a disease characterized by increased erythropoiesis. In animal models, it has been shown that high doses of hepcidin mimetics can alleviate this disease by reducing erythropoiesis (Casu et al., Blood 128, 265 - 276, 2016).

[0022] Reduced iron absorption and consequent reduction in serum iron levels may even be beneficial in diseases with normal iron loading, such as kidney disease (Walker and Agarwal, Nephrol. 36, 62 - 70, 2016), iron - dependent bacterial infections (Arezes et al., Cell Host Microbe 17, 47 - 57, 2015), and polymicrobial sepsis (Zeng et al., Anesthesiology, 122, 374 - 386, 2015).

[0023] The use of hepcidin itself as a drug is limited due to its complex structure that requires complex manufacturing and its limited in - vivo duration of action. There has been a continuing effort to search for hepcidin mimetics and compounds that can be used to increase hepcidin levels.

[0024] Common approaches involve small hepcidin sources or hepcidin - like peptides that can be produced inexpensively and used to treat hepcidin - related diseases and conditions, such as those described herein. These so - called micro - hepcidins are rationally designed small peptides that mimic hepcidin activity and can be applied to treat iron overload and iron - overload - related disease symptoms.

[0025] These microhepcidin peptides are described, for example, in WO 2010 / 065815 A2 and WO 2013 / 086143 A1. WO2015 / 157283 A1 and corresponding US 9,315,545 B2 describe hepcidin mimetic peptides and their use in hepcidin-related disorders such as iron overload, β-thalassemia, hemochromatosis, etc., and cover the development compound M012 of Merganser Biotech, which has been evaluated in a Phase 1 clinical program as a potential transformative therapy for a variety of blood disorders including β-thalassemia, low-risk myelodysplasia, and polycythemia vera.

[0026] WO 2014 / 145561 A2 and WO 2015 / 200916 A2 describe other small hepcidin peptide analogs and their use in the treatment or prevention of various hepcidin-related diseases including iron overload diseases and iron-loaded anemia, as well as other related disorders. In addition, WO 2015 / 042515 A1 relates to hepcidin and its peptide fragments, which are particularly intended for the treatment of renal ischemia-reperfusion injury or acute kidney injury. In addition, microhepcidin analogs are described, for example, in Preza et al., J. Clin. Invest., 121(12), 4880-4888, 2011 or CN 104 011 066 and WO 2016 / 109363 A1.

[0027] There is a need for transferrin inhibitors that also have additional beneficial properties such as improved solubility, stability, and / or potency, as well as compounds having hepcidin-like activity. The advantage of the transferrin inhibitor compounds of formula I described herein is that they can be prepared in sufficient yield by the synthetic routes disclosed herein.

[0028] The subject matter disclosed in the present invention will now be described more fully hereinafter. However, many modifications and other embodiments of the subject matter disclosed in the present invention will come to mind to those skilled in the art to which the present invention pertains, having the benefit of the teachings presented in the foregoing description. Accordingly, it is to be understood that the subject matter disclosed in the present invention is not limited to the particular embodiments disclosed and that those modifications and other embodiments are intended to be included within the scope of the appended claims. In other words, the subject matter described herein covers all alternatives, modifications, and equivalents. All technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art unless otherwise defined. All publications, patent applications, patents, and other references mentioned herein are incorporated herein by reference in their entirety. In the event of a difference or conflict between one or more of the incorporated documents, patents, and the like, including but not limited to the defined terms, term usage, the described techniques, etc., and this application, this application shall control.

[0029] I. Definitions

[0030] As used in this specification, the following words, phrases and symbols generally are intended to have the meanings set forth below, unless the context in which they are used indicates otherwise.

[0031] A dash (“-”) not between two letters or symbols is used to indicate the point of attachment of a substituent. For example, -C(O)NH2 is attached via the carbon atom. Dashes at the beginning or end of a chemical group are for convenience; a chemical group may be depicted with or without one or more dashes without loss of its ordinary meaning. A wavy or dashed line drawn through or perpendicular to the end of a line in a structure indicates the designated point of attachment of a group. Unless chemically or structurally required, the order in which chemical groups are written or presented does not indicate or imply directionality or stereochemistry.

[0032] The 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 has 1 to 6 carbon atoms.

[0033] References herein to “about” a value or parameter include (and describe) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes an indicated amount ±50%. In certain other embodiments, the term “about” includes an indicated amount ±20%. In certain other embodiments, the term “about” includes an indicated amount ±10%. In other embodiments, the term “about” includes an indicated amount ±5%. In certain other embodiments, the term “about” includes an indicated amount ±1%. In certain other embodiments, the term “about” includes an indicated amount ±0.5%, and in certain other embodiments includes an indicated amount ±0.1%. These variations are suitable for practicing the disclosed methods or employing the disclosed compositions. In addition, the term “about x” includes the description of “x”. In addition, unless the context clearly dictates otherwise, the singular forms “a” and “the” include plural referents. Thus, for example, a reference to “a compound” includes plural such compounds, and a reference to “an analysis” includes a reference to one or more analyses known to those of ordinary skill in the art and their equivalents.

[0034] “Alkyl” refers to a non-branched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 12 carbon atoms (i.e., C1-C 12alkyl), having from 1 to 8 carbon atoms (i.e., C1-C8 alkyl), having from 1 to 6 carbon atoms (i.e., C1-C6 alkyl), having from 1 to 4 carbon atoms (i.e., C1-C4 alkyl), or having from 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl 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 having a specific number of carbon atoms is named by a chemical name or identified by a molecular formula, all positional isomers having that number of carbon atoms may be encompassed; thus, for example, "butyl" includes n-butyl (i.e., -(CH2)3CH3), sec-butyl (i.e., -CH(CH3)CH2CH3), isobutyl (i.e., -CH2CH(CH3)2), and tert-butyl (i.e., -C(CH3)3); and "propyl" includes n-propyl (i.e., -(CH2)2CH3) and isopropyl (i.e., -CH(CH3)2).

[0035] Certain commonly used alternative chemical names may be used. For example, divalent groups such as divalent "alkyl", divalent "aryl", etc. may also be referred to as "alkylene (or alkylenyl)", "arylene (or arylenyl)", respectively. In addition, unless explicitly indicated, when a combination of groups is referred to herein as a moiety (e.g., arylalkyl or aralkyl), the last-mentioned group contains the atom by which the moiety is attached to the remainder of the molecule.

[0036] "Alkenyl" means an alkyl group having at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (i.e., C2-C 20 alkenyl), having from 2 to 8 carbon atoms (i.e., C2-C8 alkenyl), having from 2 to 6 carbon atoms (i.e., C2-C6 alkenyl), or having from 2 to 4 carbon atoms (i.e., C2-C4 alkenyl). Examples of alkenyl include, for example, vinyl, propenyl, butadienyl (including 1,2-butadienyl and 1,3-butadienyl).

[0037] "Alkynyl" means an alkyl group having at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (i.e., C 2- C 20 alkynyl), having from 2 to 8 carbon atoms (i.e., C 2- C8 alkynyl), having from 2 to 6 carbon atoms (i.e., C 2- C6 alkynyl), or having from 2 to 4 carbon atoms (i.e., C 2- C4 alkynyl). The term "alkynyl" also includes those groups having one triple bond and one double bond.

[0038] The term "alkylene" by itself or as part of another substituent means a divalent group derived from an alkane, such as methylene -CH2-, ethylene -CH2CH2- and the like. As an example, "hydroxy -methylene" refers to HO-CH2-*, where * is the point of attachment to the molecule.

[0039] "Alkoxy" refers to the group "alkyl -O-" (e.g., C1 - C3 alkoxy or C1 - C6 alkoxy). Examples of alkoxy include, for example, methoxy, ethoxy, n - propoxy, isopropoxy, n - butoxy, tert - butoxy, sec - butoxy, n - pentyloxy, n - hexyloxy and 1,2 - dimethylbutoxy.

[0040] "Alkoxy -alkyl" refers to the group "-alkyl -alkoxy". The term "C1 - C3 alkoxy -C1 - C3 alkyl" refers to an alkyl chain of one to three carbons, where a hydrogen on any one carbon is replaced by an alkoxy having one to three carbons; specifically, a hydrogen on one carbon of the alkyl chain is replaced by an alkoxy having one to three carbons. The term "C1 - C6 alkoxy -C1 - C3 alkyl" refers to an alkyl chain of one to three carbons, where a hydrogen on any one carbon is replaced by an alkoxy having one to six carbons; specifically, a hydrogen on one carbon of the alkyl chain is replaced by an alkoxy having one to six carbons. Non - limiting examples of alkoxy -alkyl are -CH2OCH3, -CH2OC(CH3)3 and -C(CH3)2CH2OCH3.

[0041] "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.

[0042] "Acyl" refers to the group -C(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of acyl include, for example, formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl -carbonyl and benzoyl.

[0043] "Amido" refers to both "C - amido" and "N - amido", "C - amido" refers to the group -C(O)NR y R z and "N - amido" refers to the group -NR y C(O)R z , where R y and Rz is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein, or R y and R z together form cycloalkyl or heterocycloalkyl; each of which may be optionally substituted as defined herein.

[0044] "Amino" refers to the group -NR y R z wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0045] "Amidino" refers to -C(NR y )(NR z 2), wherein R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0046] "Aryl" refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g., bicyclic or tricyclic) including a fused system. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C 6- C 20 aryl), 6 to 12 carbocyclic atoms (i.e., C 6- C 12 aryl) or 6 to 10 carbocyclic atoms (i.e., C 6- C 10 aryl). Examples of aryl include, for example, phenyl, naphthyl, fluorenyl and anthracenyl. However, aryl does not in any way encompass or overlap with heteroaryl as defined below. If one or more aryl groups are fused to a heteroaryl group, the resulting ring system is heteroaryl, regardless of the point of attachment. If one or more aryl groups are fused to a heterocycloalkyl group, the resulting ring system is heterocycloalkyl, regardless of the point of attachment.

[0047] "Arylalkyl" or "aralkyl" refers to the group "aryl-alkyl-", such as (C6-C 10 aryl)-C1-C3 alkyl. As used herein, "(C6-C 10 aryl)-C1-C3 alkyl" refers to an alkyl chain of one to three carbons, wherein one of the hydrogen atoms on any carbon is replaced by an aryl group having six to ten carbon atoms, specifically, one hydrogen on one carbon of the alkyl chain is replaced by an aryl group having six to ten carbon atoms. A non-limiting example of arylalkyl is benzyl.

[0048] "Carbamoyl" refers to "O-carbamoyl" and "N-carbamoyl", where "O-carbamoyl" refers to the group -O-C(O)NR y R z and "N-carbamoyl" refers to the group -NR y C(O)OR z , where R y and R z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0049] "Carboxylic acid ester" or "ester" refers to both -OC(O)R x and -C(O)OR x , where R x is alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0050] "Cycloalkyl" refers to a saturated or partially unsaturated cycloalkyl having a single ring or multiple rings including fused, bridged and spiro ring systems. The term "cycloalkyl" includes cycloalkenyl (i.e., a cyclic group having at least one double bond) and a carbocyclic fused ring system having at least one sp 3 carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has 3 to 20 ring carbon atoms (i.e., C3-C 20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C 12 cycloalkyl), 3 to 10 ring carbon atoms (i.e., C3-C 10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3-C8 cycloalkyl), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl) or 3 to 6 ring carbon atoms (i.e., C3-C6 cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bridged and / or fused rings such as bicyclo[2.2.1]heptyl, bicyclo[2.2.2]octyl, bicyclo[1.1.1]pent-1-yl, adamantyl, norbornyl, decahydronaphthyl, 7,7-dimethyl-bicyclo[2.2.1]heptyl and similar groups. In addition, the term cycloalkyl is intended to encompass any ring or ring system containing any non-aromatic alkyl ring that can be fused to an aromatic ring, regardless of the connection to the rest of the molecule. In addition, when there are two substituents on the same carbon atom, cycloalkyl also includes "spirocycloalkyl", such as spiro[2.5]octyl, spiro[4.5]decyl or spiro[5.5]undecyl.

[0051] "Cycloalkylalkyl" means the group "cycloalkyl-alkyl-", such as (C3-C6 cycloalkyl)-C1-C3 alkyl. As used herein, "(C3-C6 cycloalkyl)-C1-C3 alkyl" means an alkyl chain of one to three carbons, wherein one of the hydrogen atoms on any carbon is replaced by a cycloalkyl having three to six carbon atoms. Specifically, one hydrogen on one carbon of the chain is replaced by a cycloalkyl having three to six carbon atoms.

[0052] "Cycloalkyl-alkoxy" means 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" means an alkoxy of an alkyl chain having one to six carbons, wherein one of the hydrogen atoms on any carbon is replaced by a cycloalkyl having three to seven carbon atoms. Specifically, one hydrogen on one carbon of the chain is replaced by a cycloalkyl having three to seven carbon atoms. As used herein, "C3-C7 cycloalkyl-C1-C3 alkoxy" means an alkoxy of an alkyl chain having one to three carbons, wherein one of the hydrogen atoms on any carbon is replaced by a cycloalkyl having three to seven carbon atoms. Specifically, one hydrogen on one carbon of the chain is replaced by a cycloalkyl having three to seven carbon atoms.

[0053] "Guanidino" means -NR y C(=NR z )(NR y R z ), wherein each R y and R z is independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0054] "Hydrazino" means -NHNH2.

[0055] "Imino" means the group -C(NR y )R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0056] "Imido" means the group -C(O)NR y C(O)R z , wherein R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocycloalkyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0057] "Halogen" or "halogens" refers to atoms that occupy Group VIIA of the periodic table of elements, such as fluoro group (fluorine), chloro group (chlorine), bromo group (bromine), or iodo group (iodine).

[0058] "Haloalkyl" refers to a non-branched or branched alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. For example, halo-C1-C3 alkyl refers to an alkyl having 1 to 3 carbons, wherein at least one hydrogen atom is replaced by a halogen. In the case where the residue is substituted by more than one halogen, it can be referred to by using a prefix corresponding to the number of the attached halogen moieties. Dihaloalkyl and trihaloalkyl refer to an alkyl substituted by two ("di") or three ("tri") halogens, which may (but not necessarily) be the same halogen. 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.

[0059] "Haloalkoxy" refers to an alkoxy as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a halogen. Non-limiting examples of haloalkoxy are -OCH2CF3, -OCF2H, and -OCF3.

[0060] "Hydroxyalkyl" refers to an alkyl as defined above, wherein one or more (e.g., 1 to 6 or 1 to 3) hydrogen atoms are replaced by a hydroxy group (e.g., hydroxy-C1-C3 alkyl, hydroxy-C1-C6 alkyl). The term "hydroxy-C1-C3 alkyl" refers to an alkyl chain having one to three carbons, wherein one or more hydrogens on any carbon are replaced by a hydroxy group, specifically, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term "hydroxy-C1-C6 alkyl" refers to an alkyl chain having one to six carbons, wherein one or more hydrogens on any carbon are replaced by a hydroxy group, specifically, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH3)2CH2OH.

[0061] "Hydroxyalkoxy" means the group "-alkoxy-hydroxy" (e.g., hydroxy-C1-C3 alkoxy, hydroxy-C1-C6 alkoxy). The term "hydroxy-C1-C3 alkoxy" means an alkoxy having an alkyl chain of one to three carbons, wherein one or more hydrogens on any carbon are replaced by a hydroxy group. Specifically, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term "hydroxy-C1-C6 alkoxy" means an alkoxy having an alkyl chain of one to six carbons, wherein one or more hydrogens on any carbon are replaced by a hydroxy group. Specifically, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkoxy include -OCH2CH2OH and -OCH2C(CH3)2OH.

[0062] "Heteroalkyl" means an alkyl in which one or more of the carbon atoms (and any associated hydrogen atoms) are each independently replaced by the same or different heteroatom groups, provided that the point of attachment to the remainder of the molecule is via a carbon atom. In certain embodiments, the heteroalkyl may 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 heteroatom groups. The term "heteroalkyl" includes non-branched or branched saturated chains having carbon and heteroatoms. For example, 1, 2, or 3 carbon atoms of the alkyl in "heteroalkyl" may be independently replaced by the same or different heteroatom groups. Heteroatom groups include, but are not limited to: -NR y -, -O-, -S-, -S(O)-, -S(O)2- and similar groups, wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of heteroalkyl include, for example, ether groups (e.g., -CH2OCH3, -CH(CH3)OCH3, -CH2CH2OCH3, -CH2CH2OCH2CH2OCH3, etc.), thioether groups (e.g., -CH2SCH3, -CH(CH3)SCH3, -CH2CH2SCH3, -CH2CH2SCH2CH2SCH3, etc.), sulfone groups (e.g., -CH2S(O)2CH3, -CH(CH3)S(O)2CH3, -CH2CH2S(O)2CH3, -CH2CH2S(O)2CH2CH2OCH3, etc.) and amino groups (e.g., -CH2NR y CH3, -CH(CH3)NR y CH3, -CH2CH2NR y CH3, -CH2CH2NR y CH2CH2NR y CH3, etc., wherein R yis hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein). In certain embodiments, the heteroalkyl may 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.

[0063] "Heteroaryl" refers to an aromatic group having a single ring, multiple rings or multiple fused rings, wherein one or more ring heteroatoms are independently selected from nitrogen, oxygen and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., C 1- C 20 heteroaryl), 3 to 12 ring carbon atoms (i.e., C 3- C 12 heteroaryl) or 3 to 8 carbocyclic atoms (i.e., C 3-C8 heteroaryl), and 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, said ring heteroatoms independently selected from nitrogen, oxygen and sulfur. In some cases, heteroaryl includes a 9- to 10-membered ring system (i.e., 9- to 10-membered heteroaryl), a 5- to 10-membered ring system (i.e., 5- to 10-membered heteroaryl), a 5- to 7-membered ring system (i.e., 5- to 7-membered heteroaryl), a 5- to 6-membered ring system (i.e., 5- to 6-membered heteroaryl) or a 4- to 6-membered ring system (i.e., 4- to 6-membered heteroaryl), each independently having 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl include, for example, acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl (benzothienyl / benzothiophenyl), benzotriazolyl, benzo[4,6]imidazo[1,2-a]pyridyl, carbazolyl, cinnolinyl, dibenzofuranyl, dibenzothiophenyl, furanyl, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolinyl, isoxazolyl, naphthyridinyl, oxadiazolyl, oxazolyl, 1-oxo-pyridinyl, 1-oxo-pyrimidinyl, 1-oxo-pyrazinyl, 1-oxo-pyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridyl, 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]thienyl, indazolyl, benzo[d]imidazolyl, pyrazolo[1,5-a]pyridyl and imidazo[1,5-a]pyridyl, wherein the heteroaryl may be attached via any ring of the fused system. Any aromatic ring having a single or multiple fused rings and containing at least one heteroatom is considered heteroaryl, regardless of the connection to the rest of the molecule (i.e., via any of the fused rings). Heteroaryl does not cover or overlap with aryl as defined above.

[0064] "Heteroarylalkyl" means 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" means an alkyl chain of one to three carbons, wherein one or more hydrogens on any carbon are replaced by a 5- to 10-membered monocyclic heteroaryl, specifically, one hydrogen on one carbon of the chain is replaced by a 5- to 10-membered monocyclic heteroaryl.

[0065] "Heterocyclic group" means a saturated or partially unsaturated cycloalkyl group having one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. The term "heterocyclic group" includes heteroalkenyl (i.e., a heterocyclic group having at least one double bond), bridged heterocyclic group, fused heterocyclic group, and spiro heterocyclic group. The heterocyclic group can be a single ring or multiple rings, where the multiple rings can be fused, bridged, or spiro-fused. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclic group, regardless of the connection (i.e., it can be bonded via a carbon atom or a heteroatom). In addition, the term heterocyclic group is intended to cover a ring or ring system containing any non-aromatic ring having at least one heteroatom that can be fused to an aromatic ring or heteroaromatic ring, regardless of the connection to the rest of the molecule. The term heterocyclic group is also intended to cover a ring system containing a cycloalkyl ring fused to a heteroaromatic ring, regardless of the connection to the rest of the molecule. Additionally, the term heterocyclic group is intended to cover a ring system containing a cycloalkyl ring fused to a heterocyclic group ring, regardless of the connection to the rest of the molecule. As used herein, the heterocyclic group has 2 to 20 ring carbon atoms (i.e., C2-C 20 heterocyclic group), 2 to 12 ring carbon atoms (i.e., C2-C 12 heterocyclic group), 2 to 10 ring carbon atoms (i.e., C2-C 10 heterocyclic group), 2 to 8 ring carbon atoms (i.e., C2-C8 heterocyclic group), 3 to 12 ring carbon atoms (i.e., C3-C 12heterocyclic group), 3 to 8 ring carbon atoms (i.e., C3-C8 heterocyclic group) or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclic group); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms or 1 ring heteroatom, and the ring heteroatoms are independently selected from nitrogen, sulfur or oxygen. When the heterocyclic group ring contains 4 to 6 ring atoms, it is also referred to herein as a 4- to 6-membered heterocyclic group. Also disclosed herein are 5- or 6-membered heterocyclic groups having 5 or 6 ring atoms respectively and 5- to 10-membered heterocyclic groups having 5 to 10 ring atoms. Examples of heterocyclic groups include, for example, azetidinyl, azepinyl, benzodioxolyl, benz[b][1,4]dioxepinyl, 1,4-benzodioxanyl, benzopyranyl, benzodioxenyl, benzopyrone, benzofuranone, dioxolanyl, dihydropyranyl, hydropyranyl, thieno[1,3]dithianyl, decahydroisoquinolinyl, furanone, imidazolinyl, imidazolidinyl, indolinyl, indolizinyl, isoindolinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidinone, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidinyl, tetrahydrofuranyl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thiophenyl / thienyl, tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl and 1,1-dioxo-thiomorpholinyl. In certain embodiments, when two substituents are present on the same carbon atom, the term "heterocyclic group" may include "spiroheterocyclic group". Examples of spiroheterocyclic group rings include, for example, bicyclic and tricyclic systems such as 2-oxa-7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-1-azaspiro[3.3]heptanyl. Examples of fused heterocyclic group rings include, but are not limited to: 1,2,3,4-tetrahydroisoquinolinyl, 4,5,6,7-tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolinyl, wherein the heterocyclic group can be attached via any ring of the fused system.

[0066] "heterocyclic group alkyl" means the group "heterocyclic group-alkyl-".

[0067] "oxime" means the group -CR y (=NOH), wherein R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0068] "oxo" means the group (=O).

[0069] "Sulfonyl" refers to the group -S(O)2R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfonyl groups are mesyl, ethylsulfonyl, benzenesulfonyl and toluenesulfonyl.

[0070] "Sulfinyl" refers to the group -S(O)R y , where R y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein. Examples of sulfinyl groups are methylsulfinyl, ethylsulfinyl, benzenesulfinyl and toluenesulfinyl.

[0071] "Sulfonamido" refers to the groups -SO2NRyR z and -NR y SO2Rz, where R y and R z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic group, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted as defined herein.

[0072] The term "optionally present" or "optionally" means that the subsequent described event or circumstance may or may not occur, and the description includes the case where the event or circumstance occurs and the case where the event or circumstance does not occur. In addition, 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 a specified atom or group may or may not be replaced by a moiety other than hydrogen.

[0073] As used herein, the term "substituted" means that at least one (e.g., 1 to 5, 1 to 4 or 1 to 3) hydrogen atoms in any one of the above groups (i.e., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclic group, heteroaryl and / or heteroalkyl) are replaced by a bond to one of the non-hydrogen atoms, such as but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amidino, aryl, aralkyl, azide, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halogen, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyl, heterocyclic group, heterocyclic groupalkyl, -NHNH2, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate group, -S(O)OH, -S(O)2OH, sulfonamido, thiol group, thione group, N-oxide or -Si(R y )3, where each R yIndependently hydrogen, alkyl, alkenyl, alkynyl, heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclic group.

[0074] In certain embodiments, "substituted" includes one or more (e.g., 1 to 5, 1 to 4 or 1 to 3) hydrogen atoms in any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclic, aryl or heteroaryl groups are independently replaced by deuterium, halogen, cyano, nitro, azide, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclic, 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 means that one or more (e.g., 1 to 5, 1 to 4 or 1 to 3) hydrogen atoms in any of the above groups are replaced by -C(=O)R g 、-C(=O)OR g 、-C(=O)NR g R h, -CH2SO2R g or -CH2SO2NR g R h is replaced. In the foregoing, R g and R h are the same or different and are independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic group, heterocyclic group alkyl, heteroaryl and / or heteroarylalkyl. In certain embodiments, "substituted" also means that one or more (e.g., 1 to 5, 1 to 4 or 1 to 3) hydrogen atoms in any of the above groups are replaced by a bond attached to one of the following: amino, cyano, hydroxy, imino, nitro, oxo, thioketone group, halogen, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclic group, N - heterocyclic group, heterocyclic group alkyl, heteroaryl and / or heteroarylalkyl, or R g and R h and R i together with the atoms to which they are attached form a heterocyclic ring optionally substituted with oxo, halogen or alkyl, and the alkyl is optionally substituted with oxo, halogen, amino, hydroxy or alkoxy.

[0075] This document is not intended to include polymers or similar infinite structures obtained by defining substituents with infinitely additional other substituents (e.g., a substituted aryl with a substituted alkyl, the substituted alkyl itself being substituted by a substituted aryl, the substituted aryl being further substituted by a substituted heteroalkyl, etc.). Unless otherwise indicated, the maximum number of consecutive substitutions in the compounds described herein is three. For example, the consecutive substitution of a substituted aryl with two other substituted aryls is limited to an aryl substituted by (an aryl substituted by (a substituted aryl)). Similarly, the above definitions are not intended to include non - allowed substitution patterns (e.g., a methyl substituted with 5 fluorines or a heteroaryl having two adjacent oxygen ring atoms). Such non - allowed substitution patterns are well known to those skilled in the art. When used to modify chemical groups, the term "substituted" can describe other chemical groups defined herein.

[0076] In certain embodiments, as used herein, the phrase "one or more" means one to five. In certain embodiments, as used herein, the phrase "one or more" means one to four. In certain embodiments, as used herein, the phrase "one or more" means one to three.

[0077] Any compound or structure given herein is intended to represent both the unlabeled form and the isotopically labeled form (isotopologue) of the compound. These compound forms may also be referred to as and include "isotope-enriched analogs". Isotopically labeled compounds have the structures depicted herein, except that one or more atoms are replaced by atoms having a selected atomic mass or mass number. Examples of isotopes that may be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, fluorine, chlorine, and iodine, such as, respectively, 2 H, 3 H, 11 C, 13 C, 14 C, 13 N, 15 N, 15 O, 17 O, 18 O, 31 P, 32 P, 35 S, 18 F, 36 Cl, 123 I, and 125 I. The compounds of the invention labeled with various isotopes are, for example, those in which there are radioactive isotopes such as 3 H, 13 C, and 14 C. These isotopically labeled compounds are useful for metabolic studies; reaction kinetics studies; detection or imaging techniques such as positron emission tomography (PET) or single photon emission computed tomography (SPECT), including drug or substrate tissue distribution analysis; or for radioactive treatment of patients.

[0078] The term "isotope-enriched analog" includes "deuterated analogs" of the compounds described herein, in which one or more hydrogens, such as hydrogens on carbon atoms, are replaced by deuterium. Such compounds exhibit increased metabolic resistance and are therefore useful for increasing the half-life of any compound when administered to a mammal (especially a human). See, for example, Foster, "Deuterium Isotope Effects in Studies of Drug Metabolism", Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example, by using starting materials in which one or more hydrogens have been replaced by deuterium.

[0079] The deuterium-labeled or substituted therapeutic compounds of the present invention may have improved DMPK (drug metabolism and pharmacokinetics) properties related to distribution, metabolism, and excretion (ADME). Substitution with a heavier isotope such as deuterium can result in certain therapeutic advantages arising from greater metabolic stability, such as increased in vivo half-life, reduced dose requirements, and / or improvement of the therapeutic index. The 18 F, 3 H, 11 C-labeled compounds are suitable for PET or SPECT or other imaging studies. The isotopically labeled compounds and prodrugs of the present invention can generally be prepared by substituting non-isotopically labeled reagents with readily available isotopically labeled reagents by procedures disclosed in the examples and preparations described in the process or below. It should be understood that in this context, deuterium is considered a substituent of the compounds described herein.

[0080] The concentration of such heavier isotopes, especially deuterium, can be defined by the isotope enrichment factor. In the compounds of the present invention, any atom not specifically designated as a particular isotope is intended to represent any stable isotope of that atom. Unless otherwise specified, when a position is specifically designated as "H" or "hydrogen", it should be understood that the position has hydrogen in its natural abundance isotope composition. Thus, any atom specifically designated as deuterium (D) in the compounds of the present invention is intended to represent deuterium. In addition, in some embodiments, corresponding deuterated analogs are provided.

[0081] In many cases, the compounds of the present invention are capable of forming acid salts and / or base salts by virtue of the presence of amino and / or carboxyl groups or groups similar thereto.

[0082] Also provided are pharmaceutically acceptable salts, isotopically enriched analogs, deuterated analogs, isomers (such as stereoisomers), mixtures of isomers (such as mixtures of stereoisomers), prodrugs, and metabolites of the compounds described herein.

[0083] "Pharmaceutically acceptable" or "physiologically acceptable" means that a compound, salt, composition, dosage form, and other substances are suitable for preparing a pharmaceutical composition suitable for veterinary or human pharmaceutical use.

[0084] The term "pharmaceutically acceptable salt" of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and are not biologically or otherwise undesirable. "Pharmaceutically acceptable salts" or "physiologically acceptable salts" include, for example, salts formed with inorganic acids and salts formed with organic acids. Additionally, if the compounds described herein are obtained in the form of acid addition salts, the free base can be obtained by basifying the solution of the acid salt. Conversely, if the product is a free base, addition salts, particularly pharmaceutically acceptable addition salts, 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 basic compounds. Those skilled in the art will recognize the various synthetic methods available for preparing non-toxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts can be prepared from inorganic acids and organic acids. Salts derived from inorganic acids include, for example, salts of hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Salts derived from organic acids include, for example, salts of 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 bases and organic bases. By way of example only, salts derived from inorganic bases include sodium salts, potassium salts, lithium salts, aluminum salts, ammonium salts, calcium salts, and magnesium salts. Salts derived from organic bases include, but are not limited to, salts of primary amines, secondary amines, 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)), bis(substituted alkyl)amines (i.e., HN(substituted alkyl)2), tris(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)), bis(substituted alkenyl)amines (i.e., HN(substituted alkenyl)2), tris(substituted alkenyl)amines (i.e., N(substituted alkenyl)3), mono-cycloalkyl, di-cycloalkyl, or tri-cycloalkylamines (i.e., NH2(cycloalkyl), HN(cycloalkyl)2, N(cycloalkyl)3), mono-aryl, di-aryl, or tri-arylamines (i.e., NH2(aryl), HN(aryl)2, N(aryl)3), or mixed amines, etc. By way of example only, specific examples of suitable amines include isopropylamine, trimethylamine, diethylamine, tri(isopropyl)amine, tri(n-propyl)amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morpholine, N-ethylpiperidine, and the like.

[0085] The term "hydrate" refers to a complex formed by combining the compounds described herein with water.

[0086] The term "solvate" refers to an association or complex of one or more solvent molecules with a compound of the present invention. Examples of solvents that form solvates include, but are not limited to, water, isopropanol, ethanol, methanol, dimethyl sulfoxide, ethyl acetate, acetic acid, and ethanolamine.

[0087] Some compounds exist in the form of tautomers. Tautomers are in equilibrium with each other. For example, an amide-containing compound may exist in equilibrium with its imino tautomer. Regardless of which tautomer is shown and regardless of the nature of the equilibrium between tautomers, a person of ordinary skill in the art generally understands a compound to include both the amide and imino tautomers. Thus, an amide-containing compound should be understood to include its imino tautomer. Similarly, an imino-containing compound should be understood to include its amide tautomer.

[0088] The compounds of the present invention or their pharmaceutically acceptable salts include asymmetric centers and can therefore give rise to enantiomers, diastereomers, and other stereoisomeric forms, which, in terms of absolute stereochemistry, can be defined as (R)- or (S)- or (D)- or (L)- for amino acids. The present invention is intended to include all such possible isomers, as well as their racemic and optically pure forms. The optically active (+) and (-), (R)- and (S)- or (D)- and (L)- isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques (such as chromatography and fractional crystallization). Conventional techniques for the preparation / separation of individual enantiomers include chiral synthesis from suitable optically pure precursors or resolution of the racemate (or the racemate of a salt or derivative) using, for example, chiral high performance liquid chromatography (HPLC). When the compounds described herein contain an alkene double bond or other geometrically asymmetric center, and unless otherwise specified, the compounds are intended to include the E and Z geometric isomers.

[0089] "Stereoisomers" are compounds that are composed of the same atoms bonded by the same bonds but have different three-dimensional structures that are not interchangeable. The present invention encompasses various stereoisomers and their mixtures and includes "enantiomers", which are two stereoisomers whose molecules are non-superimposable mirror images of each other.

[0090] "Diastereomers" are stereoisomers that have at least two asymmetric atoms but are not mirror images of each other.

[0091] The relative configuration of the compounds depicted herein is indicated graphically using the "thick bond" style (bold or parallel lines), and the absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0092] "Prodrug" means any compound that, upon administration to a mammalian subject, releases the active parent drug in vivo according to the structures described herein. Prodrugs of the compounds described herein are prepared by modifying a functional group present in the compounds described herein in such a way that the modification can be cleaved in vivo to release the parent compound. Prodrugs can be prepared by modifying a functional group present in a compound in such a way that the modification is cleaved in conventional processing or in vivo to afford the parent compound. Prodrugs include the compounds described herein in which a hydroxyl, amino, carboxyl, or thiol group of the compounds described herein is bonded to any group that can be cleaved in vivo to regenerate the free hydroxyl, amino, or thiol 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 the hydroxyl functional group in the compounds described herein. The preparation, selection, and use of prodrugs are discussed in T. Higuchi and V. Stella, "Pro-drugs as Novel Delivery Systems", Vol. 14 of the A.C.S. Symposium Series; "Design of Prodrugs", edited by H. Bundgaard, Elsevier, 1985; and Bioreversible Carriers in Drug Design, edited by Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which is incorporated herein by reference in its entirety.

[0093] As used herein, the term "metabolite" refers to the resulting product formed when a compound disclosed herein is metabolized. As used herein, the term "metabolism" refers to the sum total of processes by which a particular substance, such as a compound disclosed herein, is altered by an organism (including, but not limited to, hydrolysis reactions and enzyme-catalyzed reactions). For example, an aldehyde moiety (-C(O)H) can be reduced in vivo to a -CH2OH moiety.

[0094] Unless otherwise specified, the term "inhibitor" or "inhibit" as used herein applies to the activity of a compound of Formula I or a pharmaceutically acceptable salt thereof against transferrin. "Inhibit" as used herein means reducing the activity of transferrin as compared to the activity of transferrin in the absence of the compound. In some embodiments, the term "inhibit" means reducing transferrin activity by at least about 5%, at least about 10%, at least about 20%, at least about 25%, at least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90% or at least about 95%. In other embodiments, inhibit means reducing transferrin activity by about 5% to about 25%, about 25% to about 50%, about 50% to about 75% or about 75% to 100%. In some embodiments, inhibit means reducing transferrin activity by about 95% to 100%, such as a 95%, 96%, 97%, 98%, 99% or 100% reduction in activity. These reductions can be measured using a variety of techniques recognizable to those of skill in the art, including in vitro assays.

[0095] As used herein, the term "transferrin inhibitor" and the like refers to a compound that reduces, inhibits or otherwise attenuates one or more biological activities of transferrin, for example, by inducing internalization of transferrin. The activity can be reduced by a statistically significant amount, including, for example, a reduction in the activity of transferrin by 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 an appropriate control.

[0096] "Treatment" is a course of action used to obtain a beneficial or desired result, including a clinical result. Beneficial or desired clinical results can include one or more of the following: a) inhibiting a disease or condition (e.g., reducing one or more symptoms produced by the disease or condition, and / or alleviating the degree of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and / or preventing or delaying the spread of the disease or condition (e.g., metastasis)); and / or c) alleviating the disease, i.e., causing the clinical symptoms to subside (e.g., improving the disease state, providing a partial or complete remission of the disease or condition, enhancing the effect of another drug, delaying disease progression, improving quality of life and / or extending survival).

[0097] "Prevention" means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. In some embodiments, the compound can be administered to a subject (including a human) at risk of the disease or condition or having a family history of the disease or condition.

[0098] "Subject" refers to an animal that has become or will become the subject of treatment, observation, or experiment, such as a mammal (including a human). The methods described herein are applicable to human therapy and / or veterinary applications. In some embodiments, the subject is a mammal. In one embodiment, the subject is a human.

[0099] The "therapeutically effective amount" or "effective amount" of a compound or a pharmaceutically acceptable salt, tautomer, stereoisomer, stereoisomer mixture, prodrug, or deuterated analogue thereof described herein means an amount sufficient to effect treatment when administered to a subject to provide a therapeutic benefit (such as alleviating symptoms or slowing disease progression). For example, a therapeutically effective amount may be an amount sufficient to reduce the symptoms of sickle cell disease. The therapeutically effective amount can vary depending on the subject to be treated and the disease or condition, the weight and age of the subject, the severity of the disease or condition, and the mode of administration, and can be readily determined by one of ordinary skill in the art.

[0100] When any variable or substituent occurs more than once in any structure or formula, its definition at each occurrence is independent of its definition at each other occurrence. Combinations of substituents and / or variables are permissible provided that these combinations result in a chemically stable compound. It is understood that the substituents and substitution patterns with respect to the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemically stable and can be readily synthesized by techniques known in the art as well as those described herein.

[0101] Additional definitions may also be provided as needed below.

[0102] II. Compounds

[0103] In certain embodiments, the subject matter described herein pertains to compounds of Formula I':

[0104]

[0105] or a pharmaceutically acceptable salt thereof; wherein

[0106] Z is N or CH;

[0107] Ring B is wherein indicates the point of attachment to the remainder of the molecule;

[0108] R 6 in each case is selected from the group consisting of 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 RH 、halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-R bb 、-O-R bb 、-(C1-C6 alkyl)-NR GI R HI 、-S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 、halo-C 1- C3 alkyl, -O-R cc -O-R dd 、a 5- to 7-membered monocyclic heteroaryl and a C3-C6 cycloalkyl; wherein

[0109] hydroxy-C1-C 10 alkoxy or -O-(C1-C6 alkyl)-R bb the alkyl moiety in is optionally substituted with cyano, hydroxy, hydroxy-C1-C3 alkyl, halogen or C1-C3 alkoxy;

[0110] R bb is a 4- to 7-membered monocyclic or bridged heterocyclic group, a C3-C7 cycloalkyl, a 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NR G1 R H1 or -NR G R H ;

[0111] R cc is a C1-C3 alkyl; and

[0112] R dd is a C1-C3 alkyl or a 6-membered heteroaryl;

[0113] wherein R 6 、R bb or R dd the cycloalkyl, heterocyclic group or heteroaryl of 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;

[0114] R G1 and R H1 are each independently hydrogen or C1-C3 alkyl;

[0115] and

[0116] R G and R H are each independently hydrogen, -C(O)R Ga or optionally deuterated C1-C3 alkyl; wherein

[0117] RGa is a C1-C3 alkyl or hydrogen;

[0118] or

[0119] two Rs 6 together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- to 6-membered monocyclic heteroaryl group fused to ring B; wherein

[0120] the heterocyclic group, phenyl group, cycloalkyl group or heteroaryl group fused to ring B is optionally substituted by one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5- or 6-membered monocyclic heterocyclic group;

[0121] n is 0, 1, 2 or 3;

[0122] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of: CH, N, NH, O, S, SH, S-R 6 、N-R 6 and C-R 6 , provided that one or two of Y 1 、Y 2 、Y 3 and Y 4 can be N, N-R 6 、NH, O, SH or S-R 6 ;

[0123] f is 0 or 1;

[0124] p is 1 or 2;

[0125] R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, oxo or cyano;

[0126] m is 0, 1 or 2;

[0127] 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;

[0128] R 4 is selected from the group consisting of:

[0129] i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl or (6- or 7-membered monocyclic heterocyclic)-C1-C3 alkyl; wherein

[0130] the heteroaryl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C6-C 10 monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(C1-C3 alkyl)-T, and 5- to 7-membered monocyclic heterocyclic;

[0131] T is selected from the group consisting of: C6-C 10 monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclic; and

[0132] wherein R 4 of T or the aryl, cycloalkyl, heteroaryl, or heterocyclic substituent is optionally substituted with one or two substituents each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and

[0133] when p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is straight-chain;

[0134] and

[0135] ii.

[0136] wherein

[0137] R 4a and R 4g are each independently selected from the group consisting of: hydrogen; C1-C 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 spiro heterocyclic; 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;

[0138] R J1 and R J2 are independently hydrogen or C1-C3 alkyl;

[0139] wherein R 4a or R 4gThe cycloalkyl, heterocyclic group, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiro heterocyclic group;

[0140] R 4b is hydrogen or C1-C6 alkyl; or

[0141] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or

[0142] R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or

[0143] R 4c and R 4d are each independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-sulfanyl-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl and C1-C3 alkyl; or

[0144] R 4c and R 4d together with the atoms to which they are attached form a C3-C7 cycloalkyl;

[0145] or when p is 1,

[0146] R 3 and R 4 together with the nitrogen atoms to which they are attached may form:

[0147] i. a 7-membered fused bicyclic heterocyclic group, 7-membered bridged bicyclic heterocyclic group or 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0148] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0149] When the 7-membered monocyclic heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 a monocyclic or fused bicyclic aryl group; and

[0150] wherein the aryl group 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;

[0151] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0152] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ; wherein

[0153] s is 0, 1, 2 or 3;

[0154] R k is hydrogen or C1-C3 alkyl; and

[0155] R l is selected from the group consisting of: hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl and C6-C 10 a monocyclic or fused bicyclic aryl group;

[0156] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, oxo, halogen, cyano and -NR q R w ; wherein

[0157] R q is hydrogen or C1-C3 alkyl; and

[0158] R w is C6-C 10 a monocyclic or fused bicyclic aryl group or C3-C7 cycloalkyl, wherein the aryl group 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;

[0159] or

[0160] iii. An 8-, 9-, 10- or 11-membered fused bicyclic heterocyclic group, or a 12-membered bicyclic bridged and fused heterocyclic group, wherein the 8-, 9- or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11- or 12-membered heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy and hydroxy;

[0161] or when p is 2,

[0162] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0163] i. A 6-membered monocyclic heterocyclic group containing one heteroatom, which is 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

[0164] ii. A 4- or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-, 8-, 9-, 10- or 11-membered bridged bicyclic, fused bicyclic or spiro heterocyclic group containing one, two or three heteroatoms, which is optionally substituted with one or two substituents each independently 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 ;

[0165] provided that when the structure of formula (I) is

[0166] then,

[0167] * is and ** is or

[0168] * is and ** is

[0169] and

[0170] wherein the compound of formula (I) is not:

[0171] N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0172] 4-(Piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0173] 4-(Azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0174] 1-Propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0175] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0176] In certain embodiments, the subject matter described herein pertains to compounds of formula I':

[0177]

[0178] or a pharmaceutically acceptable salt thereof; wherein

[0179] Z is N or CH;

[0180] Ring B is wherein indicates the point of attachment to the remainder of the molecule;

[0181] R 6 in each case is selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, -NR G R H 、halo-C1-C3 alkoxy, -O-(CH2) u -R bb 、halo-C 1- C3 alkyl, -O-R cc -O-R dd 、5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein

[0182] u is an integer from 0 to 6;

[0183] R bb is a 4- to 7-membered monocyclic heterocyclic group, C3-C7 cycloalkyl or -NR G R H ;

[0184] R cc and R dd are each independently C1-C3 alkyl;

[0185] wherein the cycloalkyl, heterocyclyl or heteroaryl group is optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl;

[0186] and

[0187] R G and R H Each independently is hydrogen, -C(O)R Ga or C1-C3 alkyl; wherein

[0188] R Ga is C1-C3 alkyl or hydrogen;

[0189] or

[0190] Two R's 6 The groups, together with the atoms to which they are 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; wherein

[0191] The heterocyclyl, phenyl, cycloalkyl or heteroaryl fused to ring B is optionally substituted by one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5-membered or 6-membered monocyclic heterocyclyl;

[0192] n is 0, 1, 2, or 3;

[0193] Y 1 、Y 2 、Y 3 and Y 4 Each independently selected from the group consisting of: CH, N, NH, O, S, SH, SR 6 NR 6 and CR 6 , the condition is Y 1 、Y 2 、Y 3 and Y 4 One or two of them can be N, NR 6 , NH, O, SH or SR 6 ;

[0194] f is 0 or 1;

[0195] p is 1 or 2;

[0196] R x in each case halogen, C1-C6-alkyl, C1-C3-alkoxy, hydroxy or cyano;

[0197] m is 0, 1, or 2;

[0198] R 3 is selected from the group consisting of: hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl and phenyl;

[0199] R 4 is selected from the group consisting of:

[0200] i. branched or straight-chain (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or branched or straight-chain (6- or 7-membered monocyclic heterocyclic)-C1-C3 alkyl; wherein

[0201] the heteroaryl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C6-C 10 monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl and 5- to 7-membered monocyclic heterocyclic group, and wherein the aryl, cycloalkyl, heteroaryl or heterocyclic group is optionally substituted with one or two substituents each individually selected from the group consisting of C1-C3 alkyl, halogen and hydroxy; and

[0202] when p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl is straight-chain;

[0203] and

[0204] ii.

[0205] wherein

[0206] R 4a and R 4g are each independently selected from the group consisting of: 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 spiro heterocyclic group; 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;

[0207] wherein R 4a or R 4gThe cycloalkyl, heterocyclic group, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl may be optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiro heterocyclic groups;

[0208] R 4b is hydrogen or C1-C6 alkyl; or

[0209] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or

[0210] R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or

[0211] 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

[0212] R 4c and R 4d together with the atoms to which they are attached form a C3-C7 cycloalkyl;

[0213] or when p is 1,

[0214] R 3 and R 4 together with the nitrogen atoms to which they are attached may form:

[0215] i. a 7-membered fused bicyclic heterocyclic group, 7-membered bridged bicyclic heterocyclic group or 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0216] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0217] When the 7-membered monocyclic heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 a monocyclic or fused bicyclic aryl group; and

[0218] wherein the aryl group 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;

[0219] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0220] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ; wherein

[0221] s is 0, 1, 2 or 3;

[0222] R k is hydrogen or C1-C3 alkyl; and

[0223] R l is selected from the group consisting of: hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl and C6-C 10 a monocyclic or fused bicyclic aryl group;

[0224] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, oxo, halogen, cyano and -NR q R w ; wherein

[0225] R q is hydrogen or C1-C3 alkyl; and

[0226] R w is C6-C 10 a monocyclic or fused bicyclic aryl group or C3-C7 cycloalkyl, wherein the aryl group 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;

[0227] or

[0228] iii. An 8-, 9-, 10- or 11-membered fused bicyclic heterocyclic group, or a 12-membered bicyclic bridged and fused heterocyclic group, wherein the 8-, 9- or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11- or 12-membered heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy and hydroxy;

[0229] or when p is 2,

[0230] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0231] i. A 6-membered monocyclic heterocyclic group containing one heteroatom, which is 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

[0232] ii. A 4- or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-, 8-, 9-, 10- or 11-membered bridged bicyclic, fused bicyclic or spiro heterocyclic group containing one, two or three heteroatoms, which is optionally substituted with one or two substituents each independently 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 ;

[0233] Provided that when the structure of formula (I) is

[0234] then,

[0235] * is and ** is or

[0236] * is and ** is

[0237] and

[0238] wherein the compound of formula (I) is not:

[0239] N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0240] 4-(Piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0241] 4-(Azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0242] 1-Propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0243] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0244] In certain embodiments, the subject matter described herein pertains to compounds of Formula I:

[0245]

[0246] Wherein

[0247] Z is N or CH;

[0248] R 6 In each case is selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NR G R H 、halo-C1-C3 alkoxy and C3-C6 cycloalkyl;

[0249] Wherein R G and R H Are each independently hydrogen or C1-C3 alkyl;

[0250] Or two of the R 6 Groups together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group, C3-C7 cycloalkyl, C6-C 10 Aryl or a 5- to 10-membered heteroaryl;

[0251] n is 0, 1, 2 or 3;

[0252] Y 1 、Y 2 、Y 3 And Y 4 Are each independently selected from the group consisting of: CH, N, NH, O, S, and C (when R 6 Is attached thereto), provided that Y 1 、Y 2 、Y3 and Y 4 in each case, one or both of them may be N, NH, O or S;

[0253] f is 0 or 1;

[0254] p is 1 or 2;

[0255] R x in each case is halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy or cyano;

[0256] m is 0, 1 or 2;

[0257] R 3 is selected from the group consisting of: hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl and phenyl;

[0258] R 4 is selected from the group consisting of:

[0259] i. branched or straight-chain (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl, or branched or straight-chain (6- or 7-membered monocyclic heterocyclic)-C1-C3 alkyl;

[0260] wherein

[0261] when p is 1, the C1-C3 alkyl in (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is straight-chain;

[0262] and

[0263] ii.

[0264] wherein

[0265] R 4a and R 4g each independently is selected from the group consisting of: 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 heterocyclic group, 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;

[0266] wherein R 4a or R 4gThe cycloalkyl, heterocyclic, aryl, heteroaryl, arylalkyl or heteroarylalkyl is optionally substituted with one, two or three 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 spiro heterocyclic groups;

[0267] R 4b is hydrogen or C1-C6 alkyl;

[0268] or R 4a and R 4b together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group;

[0269] or R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl;

[0270] R 4c and R 4d are each independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkylthio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl and C1-C3 alkyl;

[0271] or R 4c and R 4d together with the atoms to which they are attached form a C3-C7 cycloalkyl;

[0272] or when p is 1,

[0273] R 3 and R 4 together with the nitrogen atom to which they are attached may form:

[0274] i. a 7-membered bicyclic fused heterocyclic group, 7-membered bridged heterocyclic group or 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0275] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0276] when the 7-membered monocyclic heterocyclic group contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, haloalkyl and C6-C10 an aryl group; and wherein the aryl group 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;

[0277] ii. a 4- or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0278] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2) s C(=O)NR k R l ;

[0279] where s is 0, 1, 2, or 3;

[0280] R k is hydrogen or C1-C3 alkyl; and

[0281] R l is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 aryl;

[0282] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w ;

[0283] where R q is hydrogen or C1-C3 alkyl and R w is C6-C 10 aryl or C3-C7 cycloalkyl, and 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;

[0284] iii. an 8-, 9-, 10-, or 11-membered bicyclic fused heterocyclic group, or a 12-membered bicyclic bridged fused heterocyclic group, wherein the 8-, 9-, or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclic group is optionally substituted with one, two, or three substituents each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy;

[0285] or when p is 2,

[0286] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0287] i. A 6-membered monocyclic heterocyclic group containing one heteroatom, which optionally has one or two substituents each independently selected from the group consisting of: halogen, hydroxy-(C1-C6 alkyl), hydroxy, oxo and C1-C3 alkoxy; or

[0288] ii. A 4-membered or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-membered, 8-membered, 9-membered, 10-membered or 11-membered bicyclic bridged, fused or spiro heterocyclic group containing one, two or three heteroatoms, which is optionally substituted by one or two substituents each independently 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 ;

[0289] Provided that when the structure of formula (I) is

[0290] then

[0291] * is and ** is or * is and ** is

[0292] or a pharmaceutically acceptable salt thereof; and

[0293] wherein the compound of formula (I) is not:

[0294] N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0295] 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0296] 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0297] 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0298] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0299] Suitable compounds of formula I' or I include those in which p is 1.

[0300] Suitable compounds of formula I' or I include those in which Z is N.

[0301] Whenever a compound of formula I' or I contains a variable C-R 6 , N-R 6 or S-R 6 , the integer n is decreased by one, and the total number of n (C-R 6 , N-R 6 or S-R 6 ) cannot exceed 3).

[0302] Suitable compounds of formula I' or I include those in which Y 1 , Y 2 , Y 3 and Y 4 are each CH or C-R 6 . In certain embodiments, suitable compounds of formula I' or I include those in which Y 1 is CH, Y 2 is C-R6 and Y 3 and Y 4 are each CH. Suitable compounds of formula I' or I include those in which Y 3 is N and Y 1 , Y 2 and Y 4 are each CH or C-R 6 . Suitable compounds of formula I' or I include those in which Y 2 is N and Y 1 , Y 3 , Y 4 are each CH or C-R 6 . Suitable compounds of formula I' or I include those in which Y 1 is N and Y 2 , Y 3 and Y 4 are each CH or C-R 6 . Suitable compounds of formula I' or I include those in which Y 1 is CH, Y 2 is C-R 6 , Y 3 is CH and Y 4 is CH.

[0303] Suitable compounds of formula I' or I include those in which R 6In each case, selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, -O-(CH2) u -R bb 、halo-C1-C3 alkoxy, -O-R cc -O-R dd 、halo-C1-C3 alkyl, hydroxy-C1-C 10 alkyl, -O-(C1-C6 alkyl)-R bb 、-O-R bb 、-S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 and -NR G R H ; wherein the alkyl moiety in hydroxy-C 1- C 10 alkoxy or -O-(C1-C6 alkyl)-R bb is optionally substituted with cyano, hydroxy, hydroxy-C1-C3 alkyl, halogen or C1-C3 alkoxy; R bb is -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 are each independently C1-C3 alkylalkyl. Suitable compounds of formula I' or I include those compounds wherein R 6In each case, selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, 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, -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(CH2OCH3)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. In addition, applicable compounds of formula I' or I include those in which R 6 In each case is methoxy, -OCH2CH2N(CH3)2, -OCH2CH2OH or -OCH2C(CH3)2OH. Applicable compounds of formula I' or I include those compounds in which R 6 In each case selected from -O-(CH2) u -R bb and C3-C6; where u is an integer from 0 to 3; R bb Is a 4- to 7-membered monocyclic heterocyclic group or a C3-C7 cycloalkyl group; and wherein the cycloalkyl group or heterocyclic group is optionally substituted by one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl. Applicable compounds of formula I' or I include those compounds in which R 6 In each case selected from the group consisting of cyclopropyl and -O-(CH2) u -R bb ; where u is 0, 1 or 2; and R bbSelected from the group consisting of: cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl and pyrrolidinyl, each optionally substituted with a hydroxyl group or a methyl group. Suitable compounds of formula I' or I include those in which R 6 In each case, those compounds selected from the group consisting of:

[0304]

[0305]

[0306] Wherein Indicates the point of attachment to ring B. Suitable compounds of formula I' or I include those in which R 6 Is Those compounds.

[0307] Suitable compounds of formula I' or I include those compounds in which two R 6 Groups together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- or 6-membered monocyclic heteroaryl group fused to ring B, each of said groups being optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, hydroxyl, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5- or 6-membered monocyclic heterocyclic group. Suitable compounds of formula I' or I include those compounds in which two R 6 Groups together with the atoms to which they are attached form a pyrazolyl, dioxanyl, pyridyl, pyrimidinyl, thiazolyl, furyl, dioxolanyl or phenyl ring fused to ring B, wherein the ring is optionally substituted with a substituent selected from the group consisting of: hydroxyl, methoxy, tetrahydropyranyl, -CH2OH and methyl. Suitable compounds of formula I' or I include those compounds in which two adjacent R 6 Groups together with the atoms to which they are attached form a ring fused to ring B selected from the group consisting of:

[0308] Wherein the pair Represents the connection of the ring to ring B. Suitable compounds of formula I' or I include those compounds in which two adjacent R 6 Groups together with the atoms to which they are attached form a ring fused to ring B selected from the group consisting of: Suitable compounds of formula I' or formula I include those compounds in which two adjacent R 6 Groups together with the atoms to which they are attached form a ring fused to ring B, wherein ring B and two adjacent R 6The bicyclic rings formed by the groups are selected from the group consisting of:

[0309] Suitable compounds of formula I' or formula I include those compounds in which f is 1. Suitable compounds of formula I' or formula I include those compounds in which f is 0 and ring B is Those compounds. Suitable compounds of formula I' or formula I include those compounds in which ring B is where n is 0 or 1; and Y 2 and Y 3 each independently is selected from the group consisting of: CH, N, NH, NR 6 、S、O and CR 6 , provided that Y 2 and Y 3 only one of them can be N, NH, NR 6 、S or O. Suitable compounds of formula I' or formula I include those compounds in which ring B is selected from the group consisting of: Suitable compounds of formula I' or formula I include those compounds in which R 6 in each case is selected from the group consisting of C1-C3 alkyl and hydroxy-C1-C3 alkyl. Suitable compounds of formula I' or formula I include those compounds in which R 6 in each case is selected from the group consisting of methyl, ethyl, n-propyl, -CH2CH2OH and -CH2CH2CH2OH.

[0310] Suitable compounds of formula I' or formula I include those compounds in which n is 1. Suitable compounds of formula I' or formula I include those compounds in which n is 0. Suitable compounds of formula I' or formula I include those compounds in which 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.

[0311] Suitable compounds of formula I' or formula I include those compounds in which R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH2CH2OH. Suitable compounds of formula I' or formula I include those compounds in which R 3 is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, phenyl-CH2CF3 and -CH2CH2OH. Suitable compounds of formula I' or formula I include those compounds in which R 3 is methyl.

[0312] Suitable compounds of formula I' or formula I include those compounds in which R 4is (5 - to 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, C3 - C7 cycloalkyl, and 5 - to 7 - membered monocyclic heterocyclic group, and wherein the phenyl, cycloalkyl, or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1 - C3 alkyl, halogen, and hydroxy. Suitable compounds of formula I' or formula I include those compounds wherein R 4 is (6 - membered heteroaryl)-methyl, wherein at least one of the ring atoms adjacent to the point of attachment in the 6 - membered heteroaryl is nitrogen. Suitable compounds of formula I' or formula I include those compounds wherein R 4 is selected from the group consisting of: pyridinyl - methyl, pyrimidinyl - methyl, benzoxazol - methyl, oxazolyl - methyl, and triazolyl - methyl, each of which is optionally substituted with phenyl or benzyl, and wherein the phenyl is optionally substituted with a substituent selected from the group consisting of fluorine, methyl, and chlorine. Suitable compounds of formula I' or formula I include those wherein R 4 is selected from the group consisting of:

[0313] Suitable compounds of formula I' or formula I include those wherein R 4 is Those compounds. Suitable compounds of formula I' or formula I include those compounds wherein R 4c is selected from the group consisting of: hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3; and R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d together with the atoms to which they are respectively attached form a cyclopropyl ring. Suitable compounds of formula I' or formula I include those wherein R 4c and R 4d are each hydrogen. Suitable compounds of formula I' or formula I include those wherein R 4b is hydrogen. Suitable compounds of formula I' or formula I include those wherein R 4a is C1 - C6 alkyl. Suitable compounds of formula I' or formula I include those wherein R 4a is tert - butyl or isopropyl. Suitable compounds of formula I' or formula I include those compounds wherein R 4a is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1 - C6 alkyl, halo - C1 - C3 alkyl, hydroxy, C1 - C3 alkoxy, C3 - C7 cycloalkyl, and 5 - to 10 - membered monocyclic or fused bicyclic heterocyclic group. Suitable compounds of formula I' or formula I include those compounds wherein R4a is a phenyl group optionally substituted by a substituent selected from the group consisting of fluorine, chlorine, methyl and methoxy. Suitable compounds of formula I' or formula I include those in which R 4a are selected from the group consisting of:

[0314] Suitable compounds of formula I' or formula I include those compounds in which R 4a is a 5- to 10-membered monocyclic or fused bicyclic heteroaryl group optionally substituted by one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl and 5- to 10-membered monocyclic, fused bicyclic or spiroheterocyclic groups. Suitable compounds of formula I' or formula I include those compounds in which R 4a is pyridyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridazinyl or quinolinyl, optionally substituted by a substituent selected from the group consisting of: fluorine, chlorine, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3 or methyl. Suitable compounds of formula I' or formula I include those in which R 4a are selected from the group consisting of:

[0315]

[0316] Suitable compounds of formula I' or formula I include those compounds in which R 4a is a C3-C7 cycloalkyl group optionally substituted by one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups. Suitable compounds of formula I' or formula I include those compounds in which R 4a is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and bicyclo[1.1.1]pent-1-yl, optionally substituted by one or two substituents each independently selected from the group consisting of: methyl, -CF3, fluorine or hydroxy. Suitable compounds of formula I' or formula I include those in which R 4a are selected from the group consisting of: Suitable compounds of formula I' or formula I include those compounds in which R 4aA 4- to 10-membered monocyclic or fused bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups. Suitable compounds of formula I' or formula I include those compounds in which R 4a is selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl, oxetanyl, and tetrahydropyranyl, which is optionally substituted with one or two substituents each independently selected from the group consisting of methyl, methoxy, and oxo. Suitable compounds of formula I' or formula I include those in which R 4a is selected from the group consisting of: Suitable compounds of formula I' or formula I include those compounds in which R 4a is (C6-C 10 monocyclic or fused bicyclic aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, which is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclic groups. Suitable compounds of formula I' or formula I include those in which R 4a is selected from the group consisting of benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinyl-methyl. Suitable compounds of formula I' or formula I include those in which R 4a is selected from the group consisting of: Suitable compounds of formula I' or formula I include those in which R 4a is selected from the group consisting of -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3. Suitable compounds of formula I' or formula I include those compounds in which R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy. Suitable compounds of formula I' or formula I include those compounds in which R 4a and R 4bTogether with the atoms to which they are attached, form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl or piperazinyl group, which group is optionally substituted by one or two substituents each independently selected from the group consisting of methyl, fluoro, hydroxy and methoxy.

[0317] Suitable compounds of formula I' or formula I include those compounds in which R 4a and R 4b Together with the atoms to which they are attached, form

[0318] Suitable compounds of formula I' or formula I include those compounds in which R 4b and R 4c Together with the atoms to which they are attached, form a 5- to 7-membered monocyclic heterocyclic group optionally substituted by one or two substituents each independently selected from C1-C3 alkyl. Suitable compounds of formula I' or formula I include those compounds in which R 4b and R 4c Together with the atoms to which they are attached, form a piperidin-2-one or pyrrolidin-2-one optionally substituted one or two times by methyl.

[0319] Suitable compounds of formula I' or formula I include those compounds in which R 4 is wherein R 4g is selected from the group consisting of C6-C 10 monocyclic or fused bicyclic aryl and C1-C3 alkyl. Suitable compounds of formula I' or formula I include those compounds in which R 4a is selected from the group consisting of phenyl and methyl.

[0320] Suitable compounds of formula I' or formula I include those compounds in which R 3 and R 4 Together with the nitrogen atoms to which they are attached, form a 7-membered monocyclic or bridged bicyclic heterocyclic group containing one or two heteroatoms; wherein when the 7-membered heterocyclic group contains one heteroatom, the heterocyclic group is optionally substituted by 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 heterocyclic group contains two heteroatoms, said heteroatoms are each independently N or O, and the heterocyclic group is optionally substituted by one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10a monocyclic or fused bicyclic aryl; 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. Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form: a monocyclic 7-membered heterocyclic group containing one heteroatom, wherein said heterocyclic group is optionally substituted once with methyl or oxo; or a 7-membered monocyclic or bridged bicyclic heterocyclic group containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein said phenyl is optionally substituted with methoxy. Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0321]

[0322] Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclic group containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclic group, each of said groups being optionally substituted with one, two, or three substituents each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy, and halogen. Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0323]

[0324] Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclic group containing one heteroatom; wherein said 4-membered monocyclic heterocyclic group is optionally substituted with -(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 said 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR q Rw ; wherein R q is hydrogen or C1-C3 alkyl; R w is 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. Suitable compounds of formula I' or formula I include those compounds wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0325] Suitable compounds of formula I' or formula I include those compounds wherein R x is in each case methyl. Suitable compounds of formula I' or formula I include those compounds wherein m is 0. Suitable compounds of formula I' or formula I include those compounds wherein m is 2.

[0326] The subject matter described herein includes the compounds in Table 1 below or pharmaceutically acceptable salts thereof:

[0327] Table 1. In the case where the mass of the compound is not provided in Table 1, the mass of the compound can be found in the synthetic examples.

[0328]

[0329]

[0330]

[0331]

[0332]

[0333]

[0334]

[0335]

[0336]

[0337]

[0338]

[0339]

[0340]

[0341]

[0342]

[0343]

[0344]

[0345]

[0346]

[0347]

[0348]

[0349]

[0350]

[0351]

[0352]

[0353]

[0354]

[0355]

[0356]

[0357]

[0358]

[0359]

[0360]

[0361]

[0362]

[0363]

[0364]

[0365]

[0366]

[0367]

[0368]

[0369]

[0370]

[0371]

[0372]

[0373]

[0374]

[0375]

[0376]

[0377]

[0378]

[0379]

[0380]

[0381]

[0382]

[0383]

[0384]

[0385]

[0386]

[0387]

[0388]

[0389]

[0390]

[0391]

[0392]

[0393]

[0394]

[0395]

[0396]

[0397]

[0398]

[0399]

[0400]

[0401]

[0402]

[0403]

[0404]

[0405]

[0406]

[0407]

[0408]

[0409]

[0410]

[0411]

[0412]

[0413]

[0414]

[0415]

[0416]

[0417]

[0418]

[0419]

[0420]

[0421]

[0422]

[0423]

[0424] III. Pharmaceutical Compositions and Modes of Administration

[0425] The compounds provided herein are generally administered in the form of pharmaceutical compositions. Accordingly, the present invention also provides pharmaceutical compositions comprising 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 can include, for example, inert solid diluents and fillers, diluents (including sterile aqueous solutions and various organic solvents), penetration enhancers, solubilizers, and adjuvants. Such compositions are prepared in a manner well known in the pharmaceutical art. See, e.g., Remington's Pharmaceutical Sciences, Mace Publishing Co., Philadelphia, Pa., 17th ed. (1985); and Modern Pharmaceutics, Marcel Dekker, Inc., 3rd ed. (eds. G.S. Banker and C.T. Rhodes).

[0426] The pharmaceutical compositions can be administered in single or multiple dose forms. The pharmaceutical compositions can be administered by a variety of methods, including, for example, rectal, buccal, intranasal, and transdermal routes. In certain embodiments, the pharmaceutical compositions can be administered by intra-arterial injection, intravenous, intraperitoneal, parenteral, intramuscular, subcutaneous, oral, topical, or in the form of an inhalant.

[0427] One mode of administration is parenteral, such as by injection. Forms in which the pharmaceutical compositions described herein can be incorporated 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.

[0428] Oral administration can be another route for administering the compounds described herein. It can be administered, for example, via capsules or enteric-coated tablets. When preparing a pharmaceutical composition comprising at least one compound described herein or a pharmaceutically acceptable salt, stereoisomer or mixture of stereoisomers thereof, the active ingredient is usually diluted by an excipient and / or enclosed within such a carrier which can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semi-solid or liquid material which serves as a vehicle, carrier or medium for the active ingredient. Thus, the compositions can be in the form of tablets, pills, powders, lozenges, sachets, cachets, elixirs, suspensions, emulsions, solutions, syrups, aerosols (in solid form or in a liquid medium), ointments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, sterile injectable solutions and sterile packaged powders.

[0429] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starch, gum acacia, calcium phosphate, alginate, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, sterile water, syrup and methylcellulose. The formulations can additionally include: lubricants such as talc, magnesium stearate and mineral oil; wetting agents; emulsifying and suspending agents; preservatives such as methyl hydroxybenzoate and propyl hydroxybenzoate; sweetening agents; and flavoring agents.

[0430] Compositions comprising 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 procedures known in the art. Controlled-release drug delivery systems for oral administration include osmotic pump systems and dissolution systems containing reservoir capsules or drug-polymer matrix formulations with coated polymer coatings. Examples of controlled-release systems are given in U.S. Patent Nos. 3,845,770, 4,326,525, 4,902,514 and 5,616,345. Another formulation for use in the methods disclosed herein employs a transdermal delivery device ("patch"). Such transdermal patches can be used to provide a continuous or discontinuous infusion of the compounds described herein in a controlled amount. The construction and use of transdermal patches for delivering pharmaceutical agents are well known in the art. See, for example, U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches can be constructed to deliver the pharmaceutical agent continuously, pulsatilely or on demand.

[0431] For the preparation of solid compositions, such as tablets, the main active ingredient can be mixed with pharmaceutical excipients to form a solid pre-formulated composition that is a homogeneous mixture containing the compounds or their pharmaceutically acceptable salts, stereoisomers, or mixtures of stereoisomers described herein. When referring to these pre-formulated compositions as homogeneous, the active ingredient is uniformly dispersed throughout the composition such that the composition can be readily re-divided into equally effective unit dosage forms, such as tablets, pills, and capsules.

[0432] Tablets or pills of the compounds described herein can be coated or otherwise compounded to provide dosage forms that afford the advantage of extended action or protection from the acidic conditions of the stomach. For example, a tablet or pill can include an inner dosage and an outer dosage component, the latter in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to prevent disintegration in the stomach and permits the intact inner component to pass into the duodenum or to be released retarded. A variety of materials can be used for such enteric layers or coatings, including a variety of polymeric acids and mixtures of polymeric acids with materials such as shellac, cetyl alcohol, and cellulose acetate.

[0433] Compositions for inhalation or insufflation can include solutions and suspensions as well as powders in pharmaceutically acceptable aqueous or organic solvents or mixtures thereof. The liquid or solid compositions can contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route to achieve local or systemic effects. In other embodiments, the pharmaceutically acceptable solvent containing the composition is nebulized by use of an inert gas. The nebulized solution can be inhaled directly from the nebulizing device or the nebulizing device can be connected to a face mask or intermittent positive pressure breathing machine. Solutions, suspensions, or powder compositions are preferably administered by the oral or nasal route from a device that delivers the formulation in an appropriate manner.

[0434] The specific dosage level of the compounds of the present application for any particular subject will depend on a variety of factors, including the activity of the particular compound employed, the age, weight, general health, sex, diet, time of administration, route of administration and rate of excretion of the subject being treated, drug combination and the severity of the particular disease. For example, the dosage may be expressed as milligrams of the compound described herein per kilogram of the subject's body weight (mg / kg). Dosages between about 0.1 and 150 mg / kg may be appropriate. In some embodiments, about 0.1 to 100 mg / kg may be appropriate. In other embodiments, dosages between 0.5 and 60 mg / kg may be appropriate. Standardizing according to the body weight of the subject is particularly applicable when adjusting dosages among subjects of widely different sizes, such as when using a drug in both children and adults or when converting an effective dosage in a non-human subject such as a dog to a dosage suitable for a human subject. Depending on the pharmacokinetic and pharmacodynamic properties, including absorption, distribution, metabolism and secretion of the particular compound, the dosage may be administered once a day (QID), twice a day (BID) or more frequently. In addition, toxicity factors may affect the dosage and administration regimen. When administered orally, the pills, capsules or tablets may be taken daily or at a lower frequency for a specified period of time. The regimen may be repeated for multiple treatment cycles.

[0435] IV. Methods of Treatment

[0436] In certain embodiments, the subject matter described herein is directed to a method of inhibiting transferrin-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.

[0437] 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 content, increased transferrin content, decreased sensitivity of transferrin to hepcidin, increased iron content, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis or ineffective erythropoiesis, the method comprising administering to the subject an effective amount of a compound of Formula I or Formula I'.

[0438] In certain embodiments, the disease is associated with or caused by decreased hepcidin content, decreased sensitivity of transferrin to hepcidin, abnormal heme or iron overload.

[0439] In certain embodiments, the disease is associated with or caused by decreased hepcidin content or decreased sensitivity of transferrin to hepcidin.

[0440] In certain embodiments, the disease is hemochromatosis.

[0441] In certain embodiments, the disease is associated with or caused by abnormal heme.

[0442] In certain embodiments, the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease.

[0443] In certain embodiments, the disease is sickle cell disease.

[0444] In certain embodiments, the sickle cell disease is sickle cell anemia.

[0445] The methods described herein can be applied to in vivo or ex vivo cell populations. "In vivo" means within a living individual, such as within an animal or a human. In this context, the methods described herein can be used therapeutically in an individual. "Ex vivo" means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples, including body fluid or tissue samples obtained from an individual. These samples can be obtained by methods well known in the art. Exemplary body fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein can be used for various purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein can be used ex vivo to determine the optimal administration schedule and / or dose of the compounds of the invention for a given indication, cell type, individual, and other parameters. Information gathered from such use can be used for experimental purposes or in the clinic to establish an in vivo treatment regimen. Other ex vivo uses for which the compounds and compositions described herein may be suitable are described below or will be apparent to those skilled in the art. The selected compounds can be further characterized to test for safety or tolerable dose in human or non-human subjects. These properties can be tested using methods generally known to those skilled in the art.

[0446] The transferrin inhibitory activity of the compounds of formula I or formula I' and their pharmaceutically acceptable salts provides methods particularly suitable for inhibiting transferrin-mediated iron transport. Thus, the compounds of formula I or formula I' and their pharmaceutically acceptable salts are suitable for the prevention and / or treatment of diseases associated with or caused by: decreased hepcidin levels, increased transferrin levels, decreased sensitivity of transferrin to hepcidin, increased iron content, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis.

[0447] In addition, 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 Vibrio vulnificus and Yersinia enterocolitica) and common pathogens (such as Escherichia coli), thereby preventing or treating infections, inflammations, sepsis, and septic shock caused by the pathogenic microorganisms.

[0448] In certain embodiments, the subject matter described herein is directed to a method of inhibiting transferrin-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.

[0449] 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 transferrin levels, decreased sensitivity of transferrin to hepcidin, abnormal heme, increased iron content, increased iron absorption, iron overload (e.g., attributable to transfusions), increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, the method 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, treatment comprises inhibiting transferrin-mediated iron transport in the subject.

[0450] 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, decreased sensitivity of transferrin to hepcidin, abnormal heme, or iron overload.

[0451] 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 transferrin to hepcidin. In certain aspects of this embodiment, the disease is hemochromatosis.

[0452] 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 abnormal heme. 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.

[0453] In certain embodiments, diseases associated with, related to, caused by, or resulting from increased iron content, increased iron uptake, iron overload (such as tissue iron overload), or ineffective erythropoiesis include thalassemia, hemoglobinopathies (such as hemoglobin E disease (HbE), hemoglobin H disease (HbH)), hemochromatosis, hemolytic anemia (such as sickle cell anemia), and congenital dyserythropoietic anemia.Additional diseases associated with, related to, caused by, or resulting from increased iron content, increased iron absorption, and iron overload (e.g., tissue iron overload) include 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 are considered effective in limiting or increasing iron deposition in tissues or cells; conditions associated with the formation of free radicals, reactive oxygen species (ROS), and oxidative stress caused by excess iron or iron overload; heart, liver, and endocrine damage caused by excess iron or iron overload; inflammation triggered by excess iron or iron overload; diseases associated with ineffective erythropoiesis such as myelodysplastic syndrome (MDS, myelodysplasia), polycythemia vera, and congenital dyserythropoietic anemia; diseases, disorders, and / or disease conditions of iron overload caused by mutations in genes involved in systemic iron storage sensing such as hepcidin / hepcilin antimicrobial peptide (HAMP), hemochromatosis protein (HFE), hemojuvelin (HJV), and transferrin receptor 2 (TFR2), such as diseases particularly related to HFE and HJV gene mutations; diseases related to transferrin mutations; chronic hemolysis-related diseases; sickle cell diseases (including sickle cell anemia (HbSS) and hemoglobin SC disease (HbSC), hemoglobin Sβ+ thalassemia (HbS / β+), and hemoglobin Sβ0 thalassemia (HbS / β0)); erythrocyte membrane disorders; glucose-6-phosphate dehydrogenase deficiency (G6PD deficiency); erythropoietic porphyria; Friedreich's Ataxia; and subsets of iron overload such as transfusional iron overload, iron poisoning, pulmonary hemosiderosis, osteopenia, insulin resistance, African iron overload, Hallervorden-Spatz disease, hyperferritinemia, ceruloplasmin deficiency, neonatal hemochromatosis, and erythrocyte abnormalities, including thalassemia, including alpha thalassemia, beta thalassemia, and delta thalassemia, intermediate thalassemia, sickle cell diseases, and myelodysplastic syndromes; liver diseases (e.g., hepatitis B virus infection, hepatitis C virus infection, alcoholic liver disease, autoimmune hepatitis); other conditions, including ataxia, Friedreich's Ataxia, age-related macular degeneration, age-related cataract, age-related retinal diseases, and neurodegenerative diseases such as pantothenate kinase-associated neurodegeneration, restless legs syndrome, and Huntington's disease.In certain embodiments, the disease is sickle cell anemia. The transferrin inhibitory activity of the compounds of Formula I and their pharmaceutically acceptable salts, e.g., achieved by inducing transferrin internalization, can be determined by the assays described herein and those described in WO2018 / 192973, which is incorporated herein by reference in its entirety.

[0454] The activity of the compounds of Formula I or Formula I' in the treatment of sickle cell anemia (sickle cell disease) can be determined using a mouse model, such as the mouse model described by Yulin Zhao et al. in “MEK1 / 2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease”; The FASEB Journal, Volume 30, Number 3, pages 1171 - 1186, 2016. This mouse model can be suitable for determining the activity of the compounds of Formula I or Formula I' in the treatment of sickle cell anemia. In certain embodiments, the disease is caused by hepcidin deficiency or iron metabolism disorders, especially iron overload conditions, such as thalassemia, sickle cell disease, and hemochromatosis. In certain embodiments, the disease is associated with or caused by decreased hepcidin levels, increased iron content, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis. In certain embodiments, the disease is selected from the group consisting of: thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, hemochromatosis, and hemolytic anemia.

[0455] In certain embodiments, the administration and treatment methods described herein further comprise co - administering or administering in combination with a transfusion one or more additional pharmaceutically active compounds.

[0456] In combination therapies, the pharmaceutically active compounds can be administered simultaneously in the same formulation or at different times. These combination therapies comprise co - administering a compound of Formula I or Formula I' or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound. The combination therapy in a fixed - dose combination therapy comprises co - administering 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. The combination therapy in a free - dose combination therapy comprises co - administering a compound of Formula I or Formula I' or a pharmaceutically acceptable salt thereof with at least one additional pharmaceutically active compound at free doses of the individual compounds by administering the individual compounds simultaneously or by sequential use of the individual compounds over a period of time.

[0457] Specifically, the additional pharmaceutically active compounds include drugs for reducing iron overload (such as Tmprss6-ASO or siRNA) or iron chelators, specifically curcumin, SSP-004184, Deferitrin, deferasirox, deferoxamine, and / or deferiprone; or antioxidants such as N-acetylcysteine; anti-diabetic agents such as GLP-1 receptor agonists; antibiotics such as penicillin, Vancomycin (Van), or tobramycin; antifungal drugs; antiviral drugs such as interferon-a or ribavirin; drugs for treating malaria; anti-cancer agents; drugs for treating neurodegenerative diseases (such as Alzheimer's disease and Parkinson's disease) (such as dopamine agonists such as Levodopa); or immunosuppressants (cyclosporine A or derivatives of cyclosporine A); iron supplements; vitamin supplements; erythropoiesis-stimulating agents (such as erythropoietin, Epo); anti-inflammatory agents; anti-thrombolytic agents; statins; vasopressors; and inotropic compounds. Another object of the present invention relates to the use of the above combinations for preventing and / or treating diseases (specifically, such as thalassemia, sickle cell disease, and hemochromatosis) caused by hepcidin deficiency or iron metabolic disorders (especially such as iron overload states) and other conditions described in the present application.

[0458] In certain embodiments, the subject matter described herein is directed to a method of treating beta-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 compound of Formula I as defined herein acts as a transferrin inhibitor and can be used to treat severe beta-thalassemia, such as transfusion-dependent beta-thalassemia, specifically including severe beta-thalassemia, hemoglobin E beta-thalassemia, and related symptomatic pathological conditions, specifically, such as defective bone marrow erythropoiesis, ineffective erythropoiesis, low hemoglobin content / anemia, multi-organ dysfunction, iron overload, liver iron load, and heart iron overload, pallor, fatigue, jaundice, and splenomegaly.

[0459] Specifically, severe β-thalassemia is transfusion-dependent β-thalassemia (TDT), specifically including severe β-thalassemia and hemoglobin E β-thalassemia. Severe β-thalassemia and hemoglobin E β-thalassemia require patients suffering from the disease to receive regular blood transfusions / red blood cell transfusions (RBC transfusions). Therefore, these severe β-thalassemias are also classified as transfusion-dependent β-thalassemia (TDT). Therefore, methods for treating severe β-thalassemia (specifically, such as transfusion-dependent β-thalassemia (TDT)) particularly include treating severe β-thalassemia and severe hemoglobin E β-thalassemia by administering to a subject in need one or more of the compounds of formula I as described herein.

[0460] A subject may: have β-thalassemia or hemoglobin E β-thalassemia and require regular blood transfusions; have severe β-thalassemia and / or hemoglobin E β-thalassemia, more particularly the patient has severe β-thalassemia.

[0461] The method for treating β-thalassemia will result in: a decrease in the NTBI content of the subject; a decrease in the LPI content of the subject, a decrease in the α-globin aggregate content of the subject; a decrease in the ROS content in the RBCs of the subject; a decrease in the liver iron concentration of the subject; a decrease in the myocardial iron concentration of the subject; an increase in at least one of the parameters Hct, MCV, MCH, ROW, and reticulocyte count of the subject; a response of red blood cells including a decrease in the transfusion load of the subject; a decrease in the transfusion load of the subject compared to the transfusion load before treatment with the method; achieving that transfusion-dependent β-thalassemia subjects no longer need transfusions; a decrease in the serum ferritin content of the subject; a reduction in symptoms associated with one or more transfusion-dependent β-thalassemia clinical complications. Non-limiting examples of transfusion-dependent β-thalassemia symptoms include growth retardation, pallor, jaundice, poor muscle tissue, genu valgum, hepatosplenomegaly, leg ulcers, extramedullary hematopoiesis mass formation, bone changes due to bone marrow expansion, and clinical complications of long-term 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 it is expected that the compound of formula (I) will not directly affect growth differentiation factor 11 (GDF11), a decrease in extramedullary erythropoiesis may also result in a reduction in bone deformities.

[0462] The following parameters can be measured to evaluate the efficacy of the compounds of the present invention in new medical uses: serum iron, NTBI content, LPI (labile plasma iron) content, erythropoietin, TSAT (transferrin saturation), Hb (hemoglobin), Hct (hematocrit), MCV (mean corpuscular volume), MCH (mean cell hemoglobin), RDW (red blood cell distribution width) and reticulocyte count, complete blood count, spleen and liver weights, erythropoiesis in the spleen and bone marrow, iron content in the spleen and liver, and α-globin aggregates in the RBC membrane. Conventional methods of this technique can be used, specifically determined by those methods described in more detail below. The compounds (I) of the present invention are suitable for improving at least one of these parameters.

[0463] The method can be carried out before or concomitant with a blood transfusion to prevent or at least slow the onset of a transfusion-induced pathological condition.

[0464] In certain embodiments, the subject matter described herein is directed to a method of 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 those induced by catalytically labile 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 another aspect, the kidney injury is selected from acute kidney injury (AKI), renal ischemia-reperfusion injury (IRI), ischemic injury, and AKI caused by ischemic injury, AKI after surgery or surgical intervention (specifically, such as after cardiac surgery most commonly using a procedure involving cardiopulmonary bypass, other major thoracic or abdominal surgeries), and kidney injury associated with RBC transfusion.

[0465] The terms "prevent" and the like include, for example, preventing ischemic kidney injury, avoiding the occurrence of AKI, or at least reducing the severity of ischemic injury, AKI after RBC transfusion or surgical intervention by administering a compound before, simultaneously, or shortly after an ischemic event, RBC transfusion, or surgical intervention, to prevent or at least slow the onset of kidney injury induced by catalytically labile iron.

[0466] Free catalytic iron or labile iron or NTBI is considered a major inducer of kidney injury, such as AKI triggered especially by ischemia. Administration of a transferrin inhibitor compound of formula (I) as described herein can prevent the damaging effects of catalytic free iron. Without being bound by theory, the transferrin inhibitors described herein can reduce or prevent the formation of catalytic free iron or NTBI by chelating iron in macrophages of the liver and spleen, thereby reducing its content in plasma and reducing the risk of ROS formation. The compounds of formula I described herein act as transferrin inhibitors and have the potential to chelate iron in macrophages, thereby interrupting the self-sustaining release cycle of catalytic free iron. The compounds of formula I are suitable for preventing and treating the kidney injuries described herein by limiting reactive oxygen species (ROS) to avoid kidney tissue damage. In addition to catalytic free iron, NTBI and LPI (labile plasma iron) can cause kidney injury. NTBI encompasses all forms of serum iron that are not tightly associated with transferrin and are chemically and functionally heterogeneous. LPI represents the redox-active and chelatable NTBI component that can penetrate into organs and induce tissue iron overload.

[0467] The following parameters can be measured to evaluate the efficacy of a compound in treating kidney injury: plasma creatinine, glomerular filtration rate (including estimated glomerular filtration rate eGFR), urinary albumin excretion rate, urinary neutrophil gelatinase-associated lipocalin (NGAL), NTBI, LPI, RBC hemolysis, blood urea nitrogen (BUN), plasma heme (Hb), total plasma iron, plasma hepcidin, renal neutrophil infiltration, serum IL-6, spleen, kidney and / or liver iron content, renal transferrin, KIM-1 (kidney injury molecule-1) as an acute marker of kidney injury in blood and urine, and H-ferritin. Additionally or alternatively, the efficacy of the compounds of the present invention can be determined via a tubular injury score, such as the CSA-NGAL score (cardiac surgery-related NGAL score) for detecting acute tubular injury described in more detail below, the KDIGO score described in more detail below, or the EGTI score (e.g., described by Khalid et al., "Kidney ischaemia reperfusion injury in the rat the EGTI scoring system as a valid and reliable tool for histological assessment", Journal of Histology & Histopatholoy, Vol. 3, 2016) for assessing histology that includes endothelial cell, glomerular, tubular, and interstitial (EGTI) components.

[0468] A method for treating or preventing kidney injury can reduce serum creatinine (sCr) in a subject. A method for treating or preventing kidney injury can correct (reduce) the urinary albumin excretion rate in a subject. A method for treating or preventing kidney injury can reduce blood urea nitrogen (BUN) in a subject. A method for treating or preventing kidney injury can reduce total plasma iron in a subject. A method for treating or preventing kidney injury can reduce the content of interleukin-6 (IL-6) in a subject. A method for treating or preventing kidney injury can reduce the content of KIM-1 in a subject. A method for treating or preventing kidney injury can increase the iron concentration in the spleen and / or liver of a subject. A method for treating or preventing kidney injury can reduce the iron concentration in the kidney of a subject. A method for treating or preventing kidney injury can reduce the content of NTBI. A method for treating or preventing kidney injury can reduce the content of LPI in a subject. A method for treating or preventing kidney injury can inhibit tubular injury, such as tubular necrosis. A method for treating or preventing kidney injury can inhibit apoptosis. A method for treating or preventing kidney injury can reduce IRI-induced renal neutrophil infiltration. A method for treating or preventing kidney injury can reduce the content of ROS in the renal tissue of a subject. A method for treating or preventing kidney injury can correct (increase) the content of renal H-ferritin in a subject. Specifically, a method for treating or preventing kidney injury can reduce the occurrence of AKI, renal ischemia-reperfusion injury, and AKI caused by ischemic injury, AKI after surgery or surgical intervention (specifically, such as after cardiac surgery where a procedure involving cardiopulmonary bypass is most commonly used, other major thoracic or abdominal surgeries), and kidney injury associated with RBC transfusion. A method for treating or preventing kidney injury can include a) reducing serum creatinine, accelerating the reduction of serum creatinine, or preventing the increase of serum creatinine; and / or b) increasing the estimated glomerular filtration rate (eGFR) or preventing its decrease; and / or c) reducing renal transferrin or preventing its increase; and / or d) increasing the content of H-ferritin or preventing its decrease; and / or e) reducing renal neutrophil infiltration or preventing its increase; and / or f) reducing the serum IL-6 content or preventing its increase.

[0469] V. Method for Preparing Compounds of Formula I and Their Pharmaceutically Acceptable Salts

[0470] The compounds can be synthesized by the following synthetic routes, which include methods similar to those well-known in chemical techniques, especially according to the descriptions contained herein and the methods for other heterocycles described in the following references: Comprehensive Heterocyclic Chemistry II, edited by Katritzky and Rees, Elsevier, 1997, for example, 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 expressly incorporated by reference. The starting materials are generally purchased from commercial sources such as Aldrich Chemicals (Milwaukee, WI), or are readily prepared using methods well-known to those skilled in the art (e.g., prepared by the methods generally described in the following references: Louis F. Fieser and Mary F. Fieser Reagents for Organic Synthesis, Volumes 1 - 23, Wiley, N.Y. (1967 - 2006 editions), or Beilsteins Handbuch der organischen Chemie, 4, Aufl., ed., Springer-Verlag, Berlin, including supplements (also available via the Beilstein online database)). DTT refers to dithiothreitol. DHAA refers to dehydroascorbic acid.

[0471] The synthetic chemical transformations and protecting group methods (addition and removal of protecting groups) applicable to the synthesis of the compounds and the required reagents and intermediates are known in the art and include, for example, the methods described in the following references: R. Larock, Comprehensive Organic Transformations, VCH Publishers (1989); T. W. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 3rd Edition, John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and its subsequent editions.

[0472] The compounds can be prepared individually or in the form of a library of compounds comprising at least 2, such as from 5 to 1,000 compounds or from 10 to 100 compounds. Libraries of compounds of formula I can be prepared by combinatorial'split and mix' methods or by multiple parallel syntheses using solution-phase or solid-phase chemistry, by procedures known to those skilled in the art. Accordingly, in another aspect, there is provided a library of compounds comprising at least 2 compounds or pharmaceutically acceptable salts thereof.

[0473] The subject matter described herein is directed to the following embodiments.

[0474] 1A. A compound of formula (I):

[0475]

[0476] or a pharmaceutically acceptable salt thereof; wherein

[0477] Z is N or CH;

[0478] R 6 in each case is selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, C3-C7 cycloalkyl-C1-C3 alkoxy, NR G R H 、halo-C1-C3 alkoxy and C3-C6 cycloalkyl;

[0479] wherein R G and R H are each independently hydrogen or C1-C3 alkyl; or

[0480] two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group, C3-C7 cycloalkyl, C6-C 10 aryl or 5- to 10-membered heteroaryl;

[0481] n is 0, 1, 2 or 3;

[0482] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of: CH, N, NH, O, S, and C (when R 6 is attached thereto), provided that 1 or 2 of Y 1 、Y 2 、Y 3 0]and Y 4 can be N, NH, O or S;

[0483] f is 0 or 1;

[0484] p is 1 or 2;

[0485] R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy or cyano;

[0486] m is 0, 1 or 2;

[0487] R 3 is selected from the group consisting of: hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl and phenyl;

[0488] R 4 is selected from the group consisting of:

[0489] i. branched or straight-chain (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl, or branched or straight-chain (6- or 7-membered monocyclic heterocyclic)-C1-C3 alkyl;

[0490] wherein

[0491] when p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is straight-chain;

[0492] and

[0493] ii.

[0494] wherein

[0495] R 4a and R 4g each independently is selected from the group consisting of: 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 heterocyclic group, 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;

[0496] wherein R 4a or R 4g the cycloalkyl, heterocyclic group, aryl, heteroaryl, arylalkyl or heteroaryl-alkyl of which is optionally substituted by one, two or three 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 spiro heterocyclic group;

[0497] R 4b is hydrogen or C1-C6 alkyl; or

[0498] R 4a and R 4b together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group; or

[0499] R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group substituted by one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or

[0500] R 4c and R 4d each independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkylthio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl and C1-C3 alkyl; or

[0501] R 4c and R 4d together with the atoms to which they are attached form a C3-C7 cycloalkyl;

[0502] or when p is 1,

[0503] R 3 and R 4 together with the nitrogen atoms to which they are attached may form:

[0504] i. a 7-membered bicyclic fused heterocyclic group, a 7-membered bridged heterocyclic group or a 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0505] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group is optionally substituted by 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

[0506] when the 7-membered monocyclic heterocyclic group contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclic group is optionally substituted by one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, haloalkyl and C6-C 10 aryl; and

[0507] wherein the aryl is optionally substituted by one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, hydroxy, halogen and C1-C3 alkyl;

[0508] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0509] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ;

[0510] wherein s is 0, 1, 2 or 3;

[0511] R k is hydrogen or C1-C3 alkyl; and

[0512] R l is selected from the group consisting of: hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl and C6-C 10 aryl;

[0513] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, oxo, halogen, cyano and NR q R w ;

[0514] wherein 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 one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, hydroxy and C1-C3 alkoxy;

[0515] or

[0516] iii. an 8-, 9-, 10- or 11-membered bicyclic fused heterocyclic group, or a 12-membered bicyclic bridged fused heterocyclic group, wherein the 8-, 9- or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11- or 12-membered heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy and hydroxy;

[0517] or when p is 2,

[0518] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0519] i. a 6-membered monocyclic heterocyclic group containing one heteroatom, which is 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

[0520] ii. A 4- or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-, 8-, 9-, 10- or 11-membered bicyclic bridged, fused or spiro heterocyclic group containing one, two or three heteroatoms, optionally substituted by one or two substituents each independently 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 ;

[0521] Provided that when the structure of formula (I) is

[0522] then

[0523] * is and ** is or

[0524] * is and ** is

[0525] and

[0526] wherein the compound of formula (I) is not:

[0527] N-((1,4-Dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0528] 4-(Piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0529] 4-(Azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0530] 1-Propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0531] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0532] 2A. A compound according to embodiment 1A,

[0533] wherein

[0534] Z is N;

[0535] R 6In each case, selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, and NR G R H ;

[0536] wherein R G and R H are each independently hydrogen or C1-C3 alkyl; or

[0537] wherein two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group, a C6-C 10 aryl, or a 5- to 10-membered heteroaryl;

[0538] n is 0, 1, or 2;

[0539] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of: CH, N, NH, and C (when R 6 is attached thereto), provided that 1 or 2 of Y 1 、Y 2 、Y 3 and Y 4 may be N or NH;

[0540] f is 0 or 1;

[0541] p is 1 or 2;

[0542] m is 0;

[0543] R 3 is selected from the group consisting of: hydrogen, C1-C3 alkyl, and hydroxy-C1-C3 alkyl;

[0544] R 4 is selected from the group consisting of:

[0545] i. branched or straight-chain (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl;

[0546] wherein

[0547] when p is 1, the C1-C3 alkyl in the (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-C1-C3 alkyl is straight-chain;

[0548] and

[0549] ii.

[0550] wherein

[0551] R 4a is selected from the group consisting of: C1-C6 alkyl, hydroxy-C1-C6 alkyl, C1-C3 alkoxy-C1-C6 alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic heterocyclic group, 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;

[0552] wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, arylalkyl or heteroaryl-alkyl of R 4a is optionally substituted by 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 spiro heterocyclic group;

[0553] R 4g is selected from the group consisting of: C6-C 10 aryl and C1-C3 alkyl;

[0554] R 4b is hydrogen or C1-C6 alkyl;

[0555] or R 4a and R 4b together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group;

[0556] or R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group optionally substituted by one or two substituents each independently selected from C1-C3 alkyl;

[0557] R 4c and R 4d are each independently hydrogen or C1-C3 alkyl;

[0558] or R 4c and R 4d together with the atoms to which they are attached form a C3-C5 cycloalkyl;

[0559] or

[0560] R 3 and R 4 together with the nitrogen atom to which they are attached form:

[0561] i. a 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0562] When the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0563] When the 7-membered monocyclic heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, haloalkyl and C6-C 10 aryl; and

[0564] 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;

[0565] ii. A 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0566] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with -(CH2) s C(=O)NR k R l substituted;

[0567] where s is 0, 1 or 2;

[0568] R k is hydrogen or C1-C3 alkyl; and

[0569] R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl and cyclohexyl;

[0570] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano and NR q R w ;

[0571] 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 one or two substituents each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or

[0572] iii. A 10-membered or 11-membered bicyclic fused heterocyclic group containing one heteroatom, which is optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy and halogen.

[0573] 3A. A compound according to embodiment 1A or 2A, wherein Y 1 , Y 2 , Y 3 and Y 4 are each CH or C(R 6 bonded thereto).

[0574] 4A. A compound according to embodiment 1A or 2A, wherein Y 3 is N and Y 1 , Y 2 and Y 4 are each CH or C(R 6 bonded thereto).

[0575] 5A. A compound according to embodiment 1A or 2A, wherein Y 2 is N and Y 1 , Y 3 , Y 4 are each CH or C(R 6 bonded thereto).

[0576] 6A. A compound according to embodiment 1A or 2A, wherein Y 1 is N and Y 2 , Y 3 and Y 4 are each CH or C(R 6 bonded thereto).

[0577] 7A. A compound according to any one of embodiments 1A to 6A, wherein R 6 is in each case selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C3 alkoxy, hydroxy-C1-C3 alkyl and NR G R H ;

[0578] wherein R G and R H are each independently hydrogen or C1-C3 alkyl.

[0579] 8A. A compound according to embodiment 7A, wherein R 6 is in each case selected from the group consisting of: methoxy, methyl, fluorine, chlorine, ethyl, N(CH3)2, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3 and -CH2CH2OH.

[0580] 9A. A compound according to embodiment 8A, wherein R 6 is in each case methoxy or methyl.

[0581] 10A. A compound according to any one of embodiments 1A to 6A, wherein the two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered heterocyclic group, a C6-C 10 aryl or a 5- to 10-membered heteroaryl.

[0582] 11A. A compound according to embodiment 10A, wherein the two R 6 groups together with the atoms to which they are attached form a pyrazolyl, dioxolanyl, pyridyl or phenyl ring.

[0583] 12A. A compound according to any one of embodiments 1A to 11A, wherein n is 1.

[0584] 13A. A compound according to any one of embodiments 1A to 11A, wherein n is 0.

[0585] 14A. A compound according to any one of embodiments 1A to 13A, wherein f is 1.

[0586] 15A. A compound according to any one of embodiments 1A to 13A, wherein f is 0.

[0587] 16A. A compound according to any one of embodiments 1A to 15A, wherein R 3 is selected from the group consisting of hydrogen, methyl and -CH2CH2OH.

[0588] 17A. A compound according to embodiment 16A, wherein R 3 is methyl.

[0589] 18A. A compound according to any one of embodiments 1A to 17A, wherein R 4 is (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl.

[0590] 19A. A compound according to embodiment 18A, wherein R 4 is (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl, wherein at least one of the ring atoms adjacent to the point of attachment is nitrogen or oxygen.

[0591] 20A. A compound according to embodiment 18A or 19A, wherein R 4 is selected from the group consisting of pyridyl-methyl, pyrimidinyl-methyl and benzoxazolyl-methyl.

[0592] 21A. A compound according to any one of embodiments 1A to 17A, wherein R 4 is

[0593] 22A. A compound according to embodiment 21A, wherein R 4c and R4d Each is independently hydrogen or methyl.

[0594] 23A. A compound according to embodiment 22A, wherein R 4c and R 4d are each hydrogen.

[0595] 24A. A compound according to any one of embodiments 21A to 23A, wherein R 4b is hydrogen.

[0596] 25A. A compound according to any one of embodiments 21A to 24A, wherein R 4a is a C1-C6 alkyl group.

[0597] 26A. A compound according to embodiment 25A, wherein R 4a is tert-butyl.

[0598] 27A. A compound according to any one of embodiments 21A to 24A, wherein R 4a is a C6-C 10 aryl 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 spiro heterocyclic groups.

[0599] 28A. A compound according to embodiment 27A, wherein R 4a is a phenyl optionally substituted with fluoro or methoxy.

[0600] 29A. A compound according to any one of embodiments 21A to 24A, wherein R 4a is 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, C1-C6 alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclic groups.

[0601] 30A. A compound according to embodiment 29A, wherein R 4a is a pyridyl or quinolinyl optionally substituted with fluoro, methoxy or methyl.

[0602] 31A. A compound according to any one of embodiments 21A to 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 spiro heterocyclic groups.

[0603] 32A. A compound according to embodiment 31A, wherein R 4a is cyclopropyl, cyclobutyl, cyclopentyl or cyclohexyl, optionally substituted with methyl, trifluoromethyl, fluorine or hydroxy.

[0604] 33A. A compound according to any one of embodiments 21A to 24A, wherein R 4a is a 5- or 6-membered heterocyclic group 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 spiro heterocyclic groups.

[0605] 34A. A compound according to embodiment 33A, wherein R 4a is 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.

[0606] 35A. A compound according to any one of embodiments 21A to 24A, wherein R 4a is (C6-C 10 aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic heteroaryl)-C1-C3 alkyl, optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halogen, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused or spiro heterocyclic groups.

[0607] 36A. A compound according to embodiment 35A, wherein R 4a is phenyl-methyl or pyridinyl-methyl.

[0608] 37A. A compound according to any one of embodiments 21A to 23A, wherein R 4a and R 4b together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group.

[0609] 38A. A compound according to embodiment 37A, wherein R 4a and R 4b together with the atoms to which they are attached form a 6-membered heterocyclic group selected from the group consisting of piperidinyl, morpholinyl and piperazinyl.

[0610] 39A. A compound according to any one of embodiments 21A or 25A to 36A, wherein R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered heterocyclic group optionally substituted one or two times with C1-C3 alkyl.

[0611] 40A. A compound as in embodiment 39A, wherein R 4b and R 4c together with the atoms to which they are attached form a piperidin-2-one or pyrrolidin-2-one optionally substituted one or two times with C1-C3 alkyl.

[0612] 41A. A compound as in any one of embodiments 1A to 17A, wherein R 4 is

[0613] 42A. A compound as in embodiment 41A, wherein R 4g is phenyl or methyl.

[0614] 43A. A compound as in any one of embodiments 1A to 15A, wherein R 3 and R 4 together with the nitrogen atoms to which they are attached form a 7-membered monocyclic heterocyclic group containing one or two heteroatoms.

[0615] 44A. A compound as in embodiment 43A, wherein R 3 and R 4 together with the nitrogen atoms to which they are attached form a 7-membered monocyclic heterocyclic group containing one heteroatom, wherein the heterocyclic group is optionally substituted once with methyl or oxo.

[0616] 45A. A compound as in embodiment 43A, wherein R 3 and R 4 together with the nitrogen atoms to which they are attached form a 7-membered monocyclic heterocyclic group containing two heteroatoms, wherein the heteroatoms are N or O, and the heterocyclic group is optionally substituted once with phenyl, methyl or oxo, and wherein the phenyl is optionally substituted with methoxy.

[0617] 46A. A compound as in any one of embodiments 1A to 15A, wherein R 3 and R 4 together with the nitrogen atoms to which they are attached form an optionally methoxy-substituted 11-membered bicyclic fused heterocyclic group containing one heteroatom.

[0618] 47A. A compound as in any one of embodiments 1A to 46A, wherein p is 1.

[0619] 1B. A compound of formula (I'):

[0620]

[0621] or a pharmaceutically acceptable salt thereof; wherein

[0622] Z is N or CH;

[0623] Ring B is wherein indicates the point of attachment to the remainder of the molecule;

[0624] R 6 is in each case selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(CH2) u -R bb , halo-C 1- C3 alkyl, -O-R cc -O-R dd , a 5- to 7-membered monocyclic heteroaryl and a C3-C6 cycloalkyl; wherein

[0625] u is an integer from 0 to 6;

[0626] R bb is a 4- to 7-membered monocyclic heterocyclic group, a C3-C7 cycloalkyl or -NR G R H ;

[0627] R cc and R dd are each independently C1-C3 alkyl;

[0628] wherein the cycloalkyl, heterocyclic group or heteroaryl is optionally substituted by one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl;

[0629] and

[0630] R G and R H are each independently hydrogen, -C(O)R Ga or C1-C3 alkyl; wherein

[0631] R Ga is C1-C3 alkyl or hydrogen;

[0632] or

[0633] two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group 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; wherein

[0634] The heterocyclyl, phenyl, cycloalkyl or heteroaryl fused to ring B is optionally substituted by one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5-membered or 6-membered monocyclic heterocyclyl;

[0635] n is 0, 1, 2, or 3;

[0636] Y 1 , Y 2 , Y 3 and Y 4 Each independently selected from the group consisting of: CH, N, NH, O, S, SH, SR 6 NR 6 and CR 6 , the condition is Y 1 , Y 2 , Y 3 and Y 4 One or two of them can be N, NR 6 , NH, O, SH or SR 6 ;

[0637] f is 0 or 1;

[0638] p is 1 or 2;

[0639] R x in each case halogen, C1-C6-alkyl, C1-C3-alkoxy, hydroxy or cyano;

[0640] m is 0, 1 or 2;

[0641] R 3 Selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-C1-C3 alkyl, cyclopropyl and phenyl;

[0642] R 4 Selected from the group consisting of:

[0643] i. branched or straight chain (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, or branched or straight chain (6- or 7-membered monocyclic heterocyclyl)-C1-C3 alkyl; wherein

[0644] The heteroaryl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C6-C 10 Monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5-membered or 6-membered heteroaryl, and 5- to 7-membered monocyclic heterocyclyl, wherein the aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and

[0645] When p is 1, the C1-C3 alkyl group in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl group is a straight-chain one;

[0646] and

[0647] ii.

[0648] wherein

[0649] R 4a and R 4g each independently selected from the group consisting of: 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 spiroheterocyclic group; 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;

[0650] wherein the cycloalkyl, heterocyclic group, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl of R 4a or R 4g is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiroheterocyclic group;

[0651] R 4b is hydrogen or C1-C6 alkyl; or

[0652] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or

[0653] R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or

[0654] R 4c and R 4deach independently selected from the group consisting of: hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkylthio-C1-C3 alkyl, hydroxy-C1-C6 alkyl, C1-C6 alkoxy-C1-C3 alkyl, C3-C7 cycloalkyl and C1-C3 alkyl; or

[0655] R 4c and R 4d together with the atoms to which they are respectively attached form a C3-C7 cycloalkyl;

[0656] or when p is 1,

[0657] R 3 and R 4 together with the nitrogen atoms to which they are respectively attached may form:

[0658] i. a 7-membered fused bicyclic heterocyclic group, a 7-membered bridged bicyclic heterocyclic group or a 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0659] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0660] when the 7-membered monocyclic heterocyclic group contains two heteroatoms, the heteroatoms are each independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 a monocyclic or fused bicyclic aryl; and

[0661] 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;

[0662] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0663] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ; wherein

[0664] s is 0, 1, 2 or 3;

[0665] R k is hydrogen or C1-C3 alkyl; and

[0666] R lSelected from the group consisting of: hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and C6-C 10 a monocyclic or fused bicyclic aryl;

[0667] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, oxo, halogen, cyano, and -NR q R w ; wherein

[0668] R q is hydrogen or C1-C3 alkyl; and

[0669] R w is C6-C 10 a 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;

[0670] or

[0671] iii. an 8-, 9-, 10-, or 11-membered fused bicyclic heterocyclic group, or a 12-membered bicyclic bridged and fused heterocyclic group, wherein the 8-, 9-, or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11-, or 12-membered heterocyclic group is optionally substituted with one, two, or three substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy;

[0672] or when p is 2,

[0673] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0674] i. a 6-membered monocyclic heterocyclic group containing one heteroatom, which is 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

[0675] ii. a 4- or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiro heterocyclic group containing one, two, or three heteroatoms, which is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR G R H and -(CH2) s C(=O)NR k Rl ;

[0676] The condition is that when the structure of formula (I) is

[0677] when,

[0678] * is and ** is or

[0679] * is and ** is

[0680] and

[0681] wherein the compound of formula (I) is not:

[0682] N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0683] 4-(piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0684] 4-(azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0685] 1-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0686] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0687] 1C. A compound of formula (I'):

[0688]

[0689] or a pharmaceutically acceptable salt thereof; wherein

[0690] Z is N or CH;

[0691] Ring B is wherein indicates the point of attachment to the rest of the molecule;

[0692] R 6 in each case is selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C 10 alkoxy, hydroxy-C1-C10 Alkyl, cyano, -NR G R H , halo-C1-C3 alkoxy, -O-(C1-C6 alkyl)-R bb , -O-R bb , -(C1-C6 alkyl)-NR GI R HI , -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 , halo-C 1- C3 alkyl, -O-R cc -O-R dd , 5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein

[0693] Hydroxy-C1-C 10 alkoxy or -O-(C1-C6 alkyl)-R bb the alkyl moiety in is optionally substituted with cyano, hydroxy, hydroxy-C1-C3 alkyl, halogen or C1-C3 alkoxy;

[0694] R bb is a 4- to 7-membered monocyclic or bridged heterocyclic group, C3-C7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NR G1 R H1 or -NR G R H ;

[0695] R cc is C1-C3 alkyl; and

[0696] R dd is C1-C3 alkyl or 6-membered heteroaryl;

[0697] wherein R 6 , R bb or R dd the cycloalkyl, heterocyclic or heteroaryl moiety of 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;

[0698] R G1 and R H1 are each independently hydrogen or C1-C3 alkyl;

[0699] and

[0700] R G and R H are each independently hydrogen, -C(O)R Gaor an optionally deuterated C1-C3 alkyl group; wherein

[0701] R Ga is a C1-C3 alkyl group or hydrogen;

[0702] or

[0703] two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- to 6-membered monocyclic heteroaryl group fused to ring B; wherein

[0704] the heterocyclic group, phenyl group, cycloalkyl group or heteroaryl group fused to ring B is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5- or 6-membered monocyclic heterocyclic group;

[0705] n is 0, 1, 2 or 3;

[0706] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of: CH, N, NH, O, S, SH, S-R 6 、N-R 6 and C-R 6 , provided that one or two of Y 1 、Y 2 、Y 3 and Y 4 can be N, N-R 6 、NH, O, SH or S-R 6 ;

[0707] f is 0 or 1;

[0708] p is 1 or 2;

[0709] R x is in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, oxo or cyano;

[0710] m is 0, 1 or 2;

[0711] 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;

[0712] R 4 is selected from the group consisting of:

[0713] i. (5 - to 10 - membered monocyclic or fused bicyclic heteroaryl)-C1 - C3 alkyl or (6 - or 7 - membered monocyclic heterocyclic)-C1 - C3 alkyl; wherein

[0714] the heteroaryl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C6 - C 10 monocyclic or fused bicyclic aryl, C3 - C7 cycloalkyl, 5 - or 6 - membered heteroaryl, -(C1 - C3 alkyl)-T, and 5 - to 7 - membered monocyclic heterocyclic;

[0715] T is selected from the group consisting of: C6 - C 10 monocyclic or fused bicyclic aryl, C3 - C7 cycloalkyl, 5 - or 6 - membered heteroaryl, and 5 - to 7 - membered monocyclic heterocyclic; and

[0716] wherein R 4 of T or the aryl, cycloalkyl, heteroaryl, or heterocyclic substituent is optionally substituted with one or two substituents each individually selected from the group consisting of C1 - C3 alkyl, halogen, and hydroxy; and

[0717] when p is 1, the C1 - C3 alkyl in the (5 - to 10 - membered monocyclic or fused bicyclic heteroaryl)-C1 - C3 alkyl is straight - chain;

[0718] and

[0719] ii.

[0720] wherein

[0721] R 4a and R 4g are each independently selected from the group consisting of: hydrogen; C1 - C 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 spiro heterocyclic; 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;

[0722] R J1 and R J2 are independently hydrogen or C1 - C3 alkyl;

[0723] wherein R 4a or R 4gThe cycloalkyl, heterocyclic, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiro heterocyclic groups;

[0724] R 4b is hydrogen or C1-C6 alkyl; or

[0725] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or

[0726] R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or

[0727] 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

[0728] R 4c and R 4d together with the atoms to which they are attached form a C3-C7 cycloalkyl;

[0729] or when p is 1,

[0730] R 3 and R 4 together with the nitrogen atoms to which they are attached may form:

[0731] i. a 7-membered fused bicyclic heterocyclic group, 7-membered bridged bicyclic heterocyclic group or 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[0732] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[0733] When the 7-membered monocyclic heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 monocyclic or fused bicyclic aryl; and

[0734] 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;

[0735] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[0736] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ; wherein

[0737] s is 0, 1, 2 or 3;

[0738] R k is hydrogen or C1-C3 alkyl; and

[0739] R l is selected from the group consisting of: hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl and C6-C 10 monocyclic or fused bicyclic aryl;

[0740] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: C1-C3 alkoxy, oxo, halogen, cyano and -NR q R w ; wherein

[0741] R q is hydrogen or C1-C3 alkyl; and

[0742] R w is 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;

[0743] or

[0744] iii. An 8-, 9-, 10- or 11-membered fused bicyclic heterocyclic group, or a 12-membered bicyclic bridged and fused heterocyclic group, wherein the 8-, 9- or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11- or 12-membered heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen, C1-C3 alkyl, C1-C3 alkoxy and hydroxy;

[0745] or when p is 2,

[0746] R 3 and R 4 together with the nitrogen atom to which each is attached may form:

[0747] i. A 6-membered monocyclic heterocyclic group containing one heteroatom, which is 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

[0748] ii. A 4- or 7-membered monocyclic heterocyclic group containing one or two heteroatoms, or a 7-, 8-, 9-, 10- or 11-membered bridged bicyclic, fused bicyclic or spiro heterocyclic group containing one, two or three heteroatoms, which is optionally substituted with one or two substituents each independently 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 ;

[0749] provided that when the structure of formula (I) is

[0750] then,

[0751] * is and ** is or

[0752] * is and ** is

[0753] and

[0754] wherein the compound of formula (I) is not:

[0755] N-((1,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine;

[0756] 4-(Piperidin-1-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0757] 4-(Azepan-1-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

[0758] 1-Propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,4-diazepan-2-one; or

[0759] 2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-1,2-oxazepane; or a salt thereof.

[0760] 2B. A compound according to embodiment 1B or 1C, or a pharmaceutically acceptable salt thereof, wherein p is 1.

[0761] 3B. A compound according to embodiment 1B, 2B or 1C, or a pharmaceutically acceptable salt thereof, wherein Z is N.

[0762] 4B. A compound according to any one of embodiments 1B to 3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 are each CH or C-R 6 .

[0763] 5C. A compound according to embodiment 4B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH, Y 2 is C-R 6 , Y 3 is CH, and Y 4 is CH.

[0764] 5B. A compound according to any one of embodiments 1B to 3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 and Y 4 are each CH or C-R 6 .

[0765] 6B. A compound according to any one of embodiments 1B to 3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 , Y 4 are each CH or C-R 6 .

[0766] 7B. A compound according to any one of embodiments 1B to 3B or 1C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 , Y 3 and Y 4 are each CH or C-R 6 .

[0767] 8B. A compound according to any one of embodiments 1B to 7B, or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, -O-(CH2) u -R bb , halo-C 1- C3 alkoxy, -O-R cc -O-R dd , halo-C1-C3 alkyl and -NR G R H ; wherein

[0768] R bb is -NR G R H ;

[0769] u is an integer from 1 to 3;

[0770] R G and R H are each independently hydrogen or C1-C3 alkyl; and

[0771] R cc and R dd are each independently C1-C3 alkyl.

[0772] 9C. A compound according to any one of embodiments 1C, 2B to 8B or 5C, or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: 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, -O-R cc -O-R dd , halo-C1-C3 alkyl, -(C1-C6 alkyl)-NR GI R HI , -S-CH3, -S(CH2)2N(CH3)2 and -NRG R H ; wherein

[0773] R bb is -NR G R H , -C(O)N(CH3)2, -S(O)2CH3 or -SCH3;

[0774] R G and R H are each independently hydrogen, optionally deuterated C1-C3 alkyl or -C(O)R Ga ; wherein R Ga is C1-C3 alkyl;

[0775] R GI and R HI are each independently hydrogen or C1-C3 alkyl;

[0776] R cc and R dd are each independently C1-C3 alkyl; and

[0777] wherein the alkyl moiety in hydroxy-C 1- C 10 alkoxy is optionally substituted with hydroxy, halogen or C1-C3 alkoxy.

[0778] 9B. A compound according to any one of embodiments 1B to 8B, 5C or 9C or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, 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.

[0779] 10C. A compound according to embodiment 9C or a pharmaceutically acceptable salt thereof, wherein R 6In each case, selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, 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, -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(CH2OCH3)OH, -OCH2CH(CH2F)OH, -(CH2)3N(CH3)2, -(CH2)3N(CH3)H, -O(CH2)2S(O)2CH3, -O(CH2)2SCH3, -(CH2)2C(CH3)2OH, -OCH2CH2N(CD3)2 and -CH2CH2OH.

[0780] 10B. A compound according to embodiment 9B, 9C or 10C or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case methoxy, -OCH2CH2OH or -OCH2C(CH3)2OH.

[0781] 11C. A compound according to embodiment 10C or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case methoxy, -OCH2CH2N(CH3)2, -OCH2CH2OH or -OCH2C(CH3)2OH.

[0782] 12C. A compound according to embodiment 11C or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case -OCH2CH2N(CH3)2 or -OCH2C(CH3)2OH.

[0783] 11B. A compound according to any one of embodiments 1B to 7B or a pharmaceutically acceptable salt thereof, wherein R 6In each case, selected from the group consisting of: -O-(CH2) u -R bb and C3-C6; wherein

[0784] u is an integer from 0 to 3;

[0785] R bb is a 4- to 7-membered monocyclic heterocyclic group or a C3-C7 cycloalkyl group; and

[0786] wherein the cycloalkyl group or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of a hydroxyl group, a C1-C3 alkoxy group, and a C1-C3 alkyl group.

[0787] 12B. A compound according to embodiment 11B or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of cyclopropyl and -O-(CH2) u -R bb ; wherein

[0788] u is 0, 1 or 2; and

[0789] R bb is selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl and pyrrolidinyl, each optionally substituted with a hydroxyl group or a methyl group.

[0790] 13C. A compound according to any one of embodiments 1C, 2B to 8B or 5C or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of -O-(C1-C6 alkyl)-R bb , -O-R bb , -O-R cc -O-R dd , a 5- to 7-membered monocyclic heteroaryl group and a C3-C6 cycloalkyl group; wherein

[0791] R cc is a C1-C3 alkyl group and R dd is a 6-membered heteroaryl group;

[0792] R bb is a 4- to 7-membered monocyclic or bridged heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or a C3-C7 cycloalkyl group; and

[0793] wherein the cycloalkyl group, heteroaryl group or heterocyclic group of R 6 , R bb or R dd is optionally substituted with one or two substituents each independently selected from the group consisting of a hydroxyl group, a halogen, a C1-C3 alkoxy group, an oxo group, a halo-C1-C3 alkyl group and a C1-C3 alkyl group.

[0794] 14C. A compound according to embodiment 13C or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: cyclopropyl, -O-R bb , -O-(CH2)-R bb and -O-(CH2)2-R bb , -O-(CH2)2-O-pyridazinyl, imidazolyl optionally substituted with C1-C3 alkyl; wherein

[0795] R bb is selected from the group consisting of: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyran-ol, 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, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, methoxy, ethyl or methyl.

[0796] 15C. A compound according to embodiment 14C or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of:

[0797]

[0798] wherein indicates the point of attachment to ring B.

[0799] 13B. A compound according to embodiment 12B, 14C or 15C or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of:

[0800] , wherein indicates the point of attachment to ring B.

[0801] 16C. A compound according to embodiment 15C or a pharmaceutically acceptable salt thereof, wherein R 6 is

[0802] 14B. A compound according to embodiment 13B or 13 to 16C or a pharmaceutically acceptable salt thereof, wherein R 6 is

[0803]

[0804] 15B. A compound according to any one of embodiments 1B to 7B or 1C, or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups, together with the atoms to which they are attached, form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- or 6-membered monocyclic heteroaryl group fused to ring B, and each of said groups is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclic group.

[0805] 16B. A compound according to any one of embodiments 1B to 7B or 1C, or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups, together with the atoms to which they are attached, form a pyrazolyl, dioxanyl, pyridyl, pyrimidinyl, thiazolyl, furyl, dioxolanyl, or phenyl ring fused to ring B, and the ring is optionally substituted with a substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl.

[0806] 17B. A compound according to embodiment 16B, or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups, together with the atoms to which they are attached, form a ring selected from the group consisting of a ring fused to ring B

[0807] wherein the pair represents the connection of the ring to ring B.

[0808] 18B. A compound according to embodiment 17B, or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups, together with the atoms to which they are attached, form a ring selected from the group consisting of a ring fused to ring B

[0809]

[0810] 18.bb A compound according to any one of embodiments 15B to 18B, wherein ring B is selected from the group consisting of

[0811]

[0812] 19B. A compound according to any one of embodiments 1B to 19B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable salt thereof, wherein f is 1.

[0813] 20B. A compound according to embodiment 1B, 2B, 3B or 1C, or a pharmaceutically acceptable salt thereof, wherein f is 0 and ring B is

[0814] 21B. A compound according to embodiment 20B, or a pharmaceutically acceptable salt thereof, wherein ring B is wherein

[0815] n is 0 or 1; and

[0816] Y 2 and Y 3 each independently is selected from the group consisting of: CH, N, NH, NR 6 、S, O and CR 6 , provided that Y 2 and Y 3 only one of them can be N, NH, NR 6 , S or O.

[0817] 22B. A compound according to embodiment 20B or 21B, or a pharmaceutically acceptable salt thereof, wherein ring B is selected from the group consisting of:

[0818] 23B. A compound according to any one of embodiments 20B to 22B, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of C1-C3 alkyl and hydroxy-C1-C3 alkyl.

[0819] 24B. A compound according to embodiment 23B, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: methyl, ethyl, n-propyl, -CH2CH2OH and -CH2CH2CH2OH.

[0820] 25B. A compound according to any one of embodiments 1B to 24B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0821] 26B. A compound according to any one of embodiments 1B to 24B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 0.

[0822] 27B. A compound according to any one of embodiments 1B to 14B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C or 16C, or a pharmaceutically acceptable salt thereof, wherein n is 2.

[0823] 28B. A compound as in embodiment 27B, 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.

[0824] 31C. A compound or a pharmaceutically acceptable salt thereof as in any one of embodiments 1 to 28B or 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, or 16C, wherein R 3 is selected from the group consisting of: hydrogen, methyl, ethyl, phenyl, -CD3, -CH2CF3, and -CH2CH2OH.

[0825] 29B. A compound or a pharmaceutically acceptable salt thereof as in any one of embodiments 1B to 28B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, wherein R 3 is selected from the group consisting of: hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH.

[0826] 30B. A compound or a pharmaceutically acceptable salt thereof as in embodiment 29B or 31C, wherein R 3 is methyl.

[0827] 33C. A compound or a pharmaceutically acceptable salt thereof as in any one of embodiments 1B to 30B or 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C, or 31C, wherein R 4 is (5- to 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, C3-C7 cycloalkyl, -(C1-C3 alkyl)-phenyl, and 5- to 7-membered monocyclic heterocyclic group, and wherein the phenyl, cycloalkyl, or heterocyclic group in the phenyl, -(C1-C3 alkyl)-phenyl, or alone is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxyl.

[0828] 31B. A compound or a pharmaceutically acceptable salt thereof as in any one of embodiments 1B to 30B or 33C, wherein R 4 is (5- to 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, C3-C7 cycloalkyl, and 5- to 7-membered monocyclic heterocyclic group, and wherein the phenyl, cycloalkyl, or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkyl, halogen, and hydroxyl.

[0829] 32B. A compound according to embodiment 31B or 33C, or a pharmaceutically acceptable salt thereof, wherein R 4 is (6 - membered heteroaryl)-methyl, wherein at least one of the ring atoms adjacent to the point of attachment in the 6 - membered heteroaryl is nitrogen.

[0830] 35C. A compound according to embodiment 33C or 32B, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyridyl - methyl, pyrimidinyl - methyl, benzoxazol - methyl, oxazolyl - methyl, and triazolyl - methyl, each optionally substituted by phenyl or benzyl, and wherein the phenyl is optionally substituted by a substituent selected from the group consisting of fluorine, methyl, and chlorine.

[0831] 33B. A compound according to embodiment 31B, 32B or 35C, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of pyridyl - methyl, pyrimidinyl - methyl, benzoxazol - methyl, and triazolyl - methyl, each optionally substituted by phenyl, and wherein the phenyl is optionally substituted by a substituent selected from the group consisting of fluorine, methyl, and chlorine.

[0832] 36C. A compound according to embodiment 35C, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

[0833] 34B. A compound according to embodiment 33B or 36C, or a pharmaceutically acceptable salt thereof, wherein R 4 is selected from the group consisting of:

[0834] 35B. A compound according to any one of embodiments 1B to 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 is

[0835] 36B. A compound according to embodiment 35B, or a pharmaceutically acceptable salt thereof, wherein R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3; and R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d together with the atoms to which they are respectively attached form a cyclopropyl ring.

[0836] 37B. A compound according to embodiment 36B or a pharmaceutically acceptable salt thereof, wherein R 4c and R 4d are each hydrogen.

[0837] 37bb. A compound according to embodiment 36B or a pharmaceutically acceptable salt thereof, wherein R 4c is hydrogen or methyl; and R 4d is hydrogen.

[0838] 37bbb. A compound according to embodiment 36B or 37bb or a pharmaceutically acceptable salt thereof, wherein R 4c is methyl; and R 4d is hydrogen.

[0839] 38B. A compound according to any one of embodiments 35B to 37B or a pharmaceutically acceptable salt thereof, wherein R 4b is hydrogen.

[0840] 39B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is C1-C6 alkyl.

[0841] 42C. A compound according to embodiment 39B or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, ethyl, isopropyl, tert-butyl or 3-methylpentan-3-yl.

[0842] 43C. A compound according to embodiment 39B or 42C or a pharmaceutically acceptable salt thereof, wherein R 4a is tert-butyl or isopropyl.

[0843] 40B. A compound according to embodiment 39B or 42C or a pharmaceutically acceptable salt thereof, wherein R 4a is tert-butyl.

[0844] 41B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group.

[0845] 42B. A compound according to embodiment 41B or a pharmaceutically acceptable salt thereof, wherein R 4a is phenyl optionally substituted with a substituent selected from the group consisting of fluorine, chlorine, methyl and methoxy.

[0846] 43B. A compound according to embodiment 42B, wherein R4a Selected from the group consisting of:

[0847]

[0848] 44B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is 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, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic or spiroheterocyclic groups.

[0849] 45B. A compound according to embodiment 44B or a pharmaceutically acceptable salt thereof, wherein R 4a is pyridyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridazinyl or quinolinyl, optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3 or methyl.

[0850] 46B. A compound according to embodiment 45B or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

[0851]

[0852] 47B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, 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, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups.

[0853] 48B. A compound according to 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, fluorine or hydroxy.

[0854] 52C. A compound according to embodiment 48B, wherein R 4a is selected from the group consisting of:

[0855]

[0856]

[0857] 49B. A compound as in embodiment 48B or 52C, wherein R 4a is selected from the group consisting of:

[0858]

[0859] 53C. A compound as in any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is a 4- to 10-membered monocyclic or fused bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups.

[0860] 50B. A compound as in any one of embodiments 35B to 38B or 53C or a pharmaceutically acceptable salt thereof, wherein R 4a is a 5- to 10-membered monocyclic or fused bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups.

[0861] 54C. A compound as in 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, which are optionally substituted with one or two substituents each independently selected from the group consisting of methyl, methoxy, and oxo.

[0862] 51B. A compound as in 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, which are optionally substituted with one or two substituents each independently selected from the group consisting of methyl, methoxy, and oxo.

[0863] 55C. A compound as in embodiment 54C, wherein R 4a is selected from the group consisting of:

[0864]

[0865] 52B. A compound as in embodiment 51B or 55C, wherein R 4a is selected from the group consisting of:

[0866]

[0867] 53B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is (C6-C 10 monocyclic or fused bicyclic aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, which is optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclic group.

[0868] 54B. A compound according to 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.

[0869] 57C. A compound according to 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.

[0870] 55B. A compound according to embodiment 54B or 57C or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

[0871] 59C. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of: hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl, and -C1-C6 alkyl-NR J1 R J2 wherein R J1 and R J2 are each independently hydrogen or C1-C3 alkyl.

[0872] 60C. A compound according to 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, and -CH2CF3.

[0873] 56B. A compound according to any one of embodiments 35B to 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.

[0874] 61C. A compound according to embodiment 59C, 60C or 56B or a pharmaceutically acceptable salt thereof, wherein R 4a is -C(CH3)2CH2OH.

[0875] 57B. A compound according to any one of embodiments 35B to 38B or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group, which is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

[0876] 63C. A compound according to embodiment 57B or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are attached form piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, 2,3-dihydro-1H-pyrrolo[2,3-c]pyridinyl, or piperazinyl, said groups being optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, methyl, fluoro, and methoxy.

[0877] 58B. A compound according to embodiment 57B or 63C or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are attached form piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl, or piperazinyl, said groups being optionally substituted with one or two substituents each independently selected from the group consisting of methyl, fluoro, and methoxy.

[0878] 64C. A compound according to embodiment 63C or 58B or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are attached form

[0879] 59B. A compound according to embodiment 58B or 64C or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4bTogether with the atoms to which they are attached, form

[0880]

[0881] 60B. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 35B, 39B to 56B, 42C, 43C, 52C, 53C, 54C, 55C, 59C, 60C or 61C, wherein R 4b and R 4c Together with the atoms to which they are attached, form a 5- to 7-membered monocyclic heterocyclic group optionally substituted one or twice with substituents each independently selected from C1-C3 alkyl groups.

[0882] 61B. A compound or a pharmaceutically acceptable salt thereof according to embodiment 60B, wherein R 4b and R 4c Together with the atoms to which they are attached, form piperidin-2-one or pyrrolidin-2-one optionally substituted one or twice with methyl groups.

[0883] 62B. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1B to 30B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C or 31C, wherein R 4 is wherein R 4g is selected from the group consisting of C6-C 10 monocyclic or fused bicyclic aryl groups and C1-C3 alkyl groups.

[0884] 63B. A compound or a pharmaceutically acceptable salt thereof according to embodiment 62B, wherein R 4g is selected from the group consisting of phenyl and methyl.

[0885] 64B. A compound or a pharmaceutically acceptable salt thereof according to any one of embodiments 1B to 28B, 1C, 5C, 9C, 10C, 11C, 12C, 13C, 14C, 15C, 16C or 31C, wherein R 3 and R 4 Together with the nitrogen atoms to which they are attached, form a 7-membered monocyclic or bridged bicyclic heterocyclic group containing one or two heteroatoms;

[0886] wherein when the 7-membered heterocyclic group contains one heteroatom, the heterocyclic group is optionally substituted one, two or three times with substituents each independently selected from the group consisting of: oxo, halogen, hydroxy, C1-C3 alkoxy, cyano and C1-C3 alkyl; and

[0887] When the 7-membered heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 a monocyclic or fused bicyclic aryl; and

[0888] 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.

[0889] 65B. A compound according to embodiment 64B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form: a 7-membered heterocyclic group containing one heteroatom, wherein the heterocyclic group is optionally substituted once with methyl or oxo; or a 7-membered monocyclic or bridged bicyclic heterocyclic group containing two heteroatoms, wherein the heteroatoms are N or O, and the heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of phenyl, methyl and oxo, and wherein the phenyl is optionally substituted with methoxy.

[0890] 66B. A compound according to embodiment 65B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0891] 67B. A compound according to any one of embodiments 1B to 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 together with the nitrogen atom to which each is attached form a 10-membered or 11-membered fused bicyclic heterocyclic group containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclic group, each of said groups being optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy and halogen.

[0892] 68B. A compound according to embodiment 67B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0893] 69B. A compound according to any one of embodiments 1B to 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 together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclic group containing one heteroatom; wherein

[0894] the 4-membered monocyclic heterocyclic group is optionally substituted with -(CH2) s C(=O)NR k R l ; wherein

[0895] s is 0, 1 or 2;

[0896] R k is hydrogen or C1-C3 alkyl; and

[0897] R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl and cyclohexyl;

[0898] and

[0899] the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano and -NR q R w ; wherein

[0900] R q is hydrogen or C1-C3 alkyl;

[0901] R w is C6-C 10 monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl,

[0902] 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.

[0903] 70B. A compound according to embodiment 69B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form

[0904]

[0905] 71B. A compound according to any one of embodiments 1B to 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 In each case it is methyl.

[0906] 72B. A compound according to any one of Embodiments 1B to 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.

[0907] 73B. A compound according to any one of Embodiments 1B to 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.

[0908] 79C. A compound according to embodiment 1 or a pharmaceutically acceptable salt thereof, wherein

[0909] Z is N;

[0910] p is 1;

[0911] f is 1;

[0912] Y 1 , Y 2 , Y 3 and Y 4 Each independently selected from CH, N and CR 6 The group is composed of 1 , Y 2 , Y 3 and Y 4 One or two of them may be N;

[0913] R 6 In each case, selected from the group consisting of: 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 、-ORbb 、 -(C1-C6 alkyl)-NR GI R HI 、 halo-C 1- C3 alkyl, -O-R cc -O-R dd 、 5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein

[0914] hydroxy-C1-C 10 alkoxy or -O-(C1-C6 alkyl)-R bb the alkyl moiety in is optionally substituted with hydroxy, hydroxy-C1-C3 alkyl, halogen or C1-C3 alkoxy;

[0915] R bb is a 4- to 7-membered monocyclic heterocyclic group, C3-C7 cycloalkyl or -NR G R H ;

[0916] R cc and R dd are each independently C1-C3 alkyl;

[0917] wherein R 6 or R bb the cycloalkyl, heterocyclic group or heteroaryl of is optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl;

[0918] and

[0919] R G1 and R H1 are each independently hydrogen or C1-C3 alkyl;

[0920] R G and R H are each independently hydrogen, -C(O)R Ga or optionally deuterated C1-C3 alkyl; wherein

[0921] R Ga is C1-C3 alkyl or hydrogen;

[0922] or

[0923] two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group 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; wherein

[0924] The heterocyclic group, phenyl, cycloalkyl or heteroaryl fused to ring B is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5- or 6-membered monocyclic heterocyclic group;

[0925] n is 0, 1 or 2;

[0926] R 3 is selected from the group consisting of hydrogen, phenyl, -CH2CH2OH and optionally deuterated methyl or ethyl;

[0927] R 4 is wherein

[0928] R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3 and -CH2CH2SCH3;

[0929] R 4d is selected from the group consisting of hydrogen and methyl;

[0930] or

[0931] R 4c and R 4d together with the atoms to which they are respectively attached form a cyclopropyl ring;

[0932] R 4b is hydrogen or methyl;

[0933] R 4a is selected from the group consisting of 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 heterocyclic group; 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 the cycloalkyl, heterocyclic group, aryl, heteroaryl, arylalkyl or heteroaryl-alkyl of R 4a is optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, halo-C1-C3 alkoxy, oxo, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group;

[0934] R J1 and R J2 are each independently hydrogen or C1-C3 alkyl;

[0935] or

[0936] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy;

[0937] R x is in each case C1-C3 alkyl; and

[0938] m is 0, 1 or 2.

[0939] 74B. A compound according to embodiment 1B or a pharmaceutically acceptable salt thereof, wherein

[0940] Z is N;

[0941] p is 1;

[0942] f is 1;

[0943] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of CH, N and C-R 6 provided that one or two of Y 1 、Y 2 、Y 3 and Y 4 may be N;

[0944] R 6 is in each case selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C3 alkyl, cyano, -NR G R H 、halo-C1-C3 alkoxy, -O-(CH2) u -R bb 、halo-C 1- C3 alkyl, -O-R cc -O-R dd 、5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein

[0945] u is an integer from 0 to 6;

[0946] Rbb a 4- to 7-membered monocyclic heterocyclic group, a C3-C7 cycloalkyl group, or -NR G R H ;

[0947] R cc and R dd each independently is a C1-C3 alkyl group;

[0948] wherein the cycloalkyl group, heterocyclic group, or heteroaryl group is optionally substituted with one or two substituents each independently selected from the group consisting of a hydroxyl group, a C1-C3 alkoxy group, and a C1-C3 alkyl group;

[0949] and

[0950] R G and R H each independently is hydrogen, -C(O)R Ga or a C1-C3 alkyl group; wherein

[0951] R Ga is a C1-C3 alkyl group or hydrogen;

[0952] or

[0953] two R 6 groups together with the atoms to which they are attached form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- to 6-membered monocyclic heteroaryl group fused to ring B; wherein

[0954] the heterocyclic group, phenyl group, cycloalkyl group, or heteroaryl group fused to ring B is optionally substituted with one or two substituents each independently selected from the group consisting of: a C1-C3 alkoxy group, a hydroxyl group, a hydroxy-C1-C3 alkyl group, a C1-C3 alkyl group, a C3-C7 cycloalkyl group, and a 5- or 6-membered monocyclic heterocyclic group;

[0955] n is 0, 1, or 2;

[0956] R 3 is selected from the group consisting of: hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH;

[0957] R 4 is wherein

[0958] R 4c is selected from the group consisting of: hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3;

[0959] R 4d is selected from the group consisting of hydrogen and methyl;

[0960] or

[0961] R 4c and R 4d together with the atoms to which they are attached form a cyclopropyl ring;

[0962] R 4b is hydrogen or methyl;

[0963] R 4a is selected from the group consisting of: 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 heterocyclic group; 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 of the cycloalkyl, heterocyclic group, aryl, heteroaryl, arylalkyl or heteroaryl-alkyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, oxo, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group;

[0964] or

[0965] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy;

[0966] R x is in each case C1-C3 alkyl; and

[0967] m is 0, 1 or 2.

[0968] 75B. A compound according to embodiment 74B or 79C or a pharmaceutically acceptable salt thereof, wherein m is 0.

[0969] 76B. A compound according to embodiment 74B or 79C or a pharmaceutically acceptable salt thereof, wherein m is 2 and R x is in each case methyl.

[0970] 77B. A compound according to any one of embodiments 74B to 76B or 79C or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y2 and Y 3 and Y 4 each is CH or C-R 6 ;

[0971] Y 3 is N and Y 1 and Y 2 and Y 4 each is CH or C-R 6 ;

[0972] Y 2 is N and Y 1 and Y 3 and Y 4 each is CH or C-R 6 ;

[0973] or

[0974] Y 1 is N and Y 2 and Y 3 and Y 4 each is CH or C-R 6 .

[0975] 77bb. A compound according to any one of embodiments 74B to 77B or 79C, or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH, Y 2 is C-R 6 , Y 3 is CH, and Y 4 is CH.

[0976] 83C. A compound according to any one of embodiments 79C or 75B to 77bb, or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C3 alkyl, hydroxy-C1-C6 alkoxy, hydroxy-C1-C 10 alkyl, -O-R bb , -O-(C1-C6 alkyl)-R bb , halo-C1-C3 alkoxy, -O-R cc -O-R dd , halo-C1-C3 alkyl, C3-C6 cycloalkyl and -NR G R H ; wherein

[0977] R bb is -NR G R H , a 4- to 6-membered monocyclic heterocyclic group or a C3-C7 cycloalkyl;

[0978] R G and R H each independently is hydrogen or a C1-C3 alkyl group;

[0979] R cc and R dd each independently is a C1-C3 alkyl group; and wherein

[0980] R 6 or R bb the cycloalkyl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of a hydroxyl group, a C1-C3 alkoxy group, and a C1-C3 alkyl group.

[0981] 84C. A compound according to embodiment 83C, wherein R bb is selected from the group consisting of: cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, morpholinyl, and pyrrolidinyl, each optionally substituted with a hydroxyl group or a methyl group; or R bb is -N(CH3)2.

[0982] 78B. A compound according to any one of embodiments 74B to 77B or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: a halogen, a hydroxyl group, a C1-C3 alkoxy group, a C1-C3 alkyl group, a C1-C3 alkoxy-C1-C3 alkyl group, a hydroxy-C1-C6 alkoxy group, a hydroxy-C1-C3 alkyl group, -O-(CH2) u -R bb , a halo-C 1- C3 alkoxy group, -O-R cc -O-R dd , a halo-C 1- C3 alkyl group, a C3-C6 cycloalkyl group, and -NR G R H ; wherein

[0983] R bb is -NR G R H , a 4- or 5-membered monocyclic heterocyclic group, or a C3-C7 cycloalkyl group;

[0984] u is an integer from 0 to 3;

[0985] R G and R H each independently is hydrogen or a C1-C3 alkyl group;

[0986] R cc and R dd each independently is a C1-C3 alkyl group; and wherein

[0987] The cycloalkyl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of a hydroxyl group, a C1-C3 alkoxy group, and a C1-C3 alkyl group.

[0988] 79B. A compound according to 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 a hydroxyl group or a methyl group.

[0989] 85C. A compound according to any one of embodiments 79C, 75B to 77B, or 84C, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, ethyl, -N(CH3)2, hydroxyl, -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, wherein indicates the point of attachment to ring B.

[0990] 80B. A compound according to any one of embodiments 74B to 79B, or a pharmaceutically acceptable salt thereof, wherein R 6 in each case is selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, ethyl, -N(CH3)2, hydroxyl, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH, -OCH2CF3, -OCHF2, -OCF3, -OCH2CH2OCH3, -OCH2CH2F, -OC(CH3)2CH2OH, -CH2CH2OH,

[0991] wherein indicates the point of attachment to ring B.

[0992] 86C. A compound according to embodiment 85C, or a pharmaceutically acceptable salt thereof, wherein R 6In each case, it is methoxy, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH,

[0993] 87C. A compound according to embodiment 86C or a pharmaceutically acceptable salt thereof, wherein R 6 In each case, it is methoxy, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH,

[0994] 81B. A compound according to embodiment 80B or 86C or a pharmaceutically acceptable salt thereof, wherein R 6 In each case, it is methoxy, -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH or

[0995]

[0996] 82B. A compound according to any one of embodiments 74B to 77B or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups together with the atoms to which they are attached form a pyrazolyl, dioxanyl, pyridyl, pyrimidinyl, thiazolyl, furyl, dioxolanyl or phenyl ring fused to ring B, wherein the ring is optionally substituted with a substituent selected from the group consisting of: hydroxy, methoxy, tetrahydropyranyl, -CH2OH and methyl.

[0997] 83B. A compound according to any one of embodiments 74B to 82B, 79C, 83C, 84C, 85C, 86C or 87C or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

[0998] 84B. A compound according to any one of embodiments 74B to 82B, 79C, 83C, 84C, 85C, 86C or 87C or a pharmaceutically acceptable salt thereof, wherein n is 1.

[0999] 85B. A compound according to any one of embodiments 74B to 84B, 79C, 83C, 84C, 85C, 86C or 87C or a pharmaceutically acceptable salt thereof, wherein R 4b is hydrogen.

[1000] 92C. A compound according to any one of embodiments 79C, 83C, 84C, 85C, 86C or 87C or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

[1001] i. tert-butyl or isopropyl;

[1002] ii. phenyl, optionally substituted with a substituent selected from the group consisting of fluorine, chlorine, methyl, and methoxy;

[1003] iii. pyridyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridazinyl, or quinolinyl, optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, and methyl;

[1004] 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, fluorine, and hydroxy;

[1005] 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;

[1006] vi. benzyl, 2-(1-cyclobutyl-5-methyl-1H-imidazol-2-yl)ethyl, and pyridinylmethyl;

[1007] and

[1008] vii. -C(CH3)2CH2OH, -CH2CH2OH, and -C(CH3)2CH2OCH3.

[1009] 86B. A compound according to any one of embodiments 74B to 84B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

[1010] i. tert-butyl;

[1011] ii. phenyl, optionally substituted with a substituent selected from the group consisting of fluorine, chlorine, methyl, and methoxy;

[1012] iii. pyridyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyridazinyl, or quinolinyl, optionally substituted with a substituent selected from the group consisting of: fluorine, chlorine, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl;

[1013] 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, fluorine, or hydroxy;

[1014] v. tetrahydrofuranyl, pyrrolidinyl, benzo[d][1,3]dioxolyl and tetrahydropyranyl, which are optionally substituted by one or two substituents each independently selected from the group consisting of methyl, methoxy and oxo;

[1015] vi. phenyl-methyl, 1-cyclobutyl-2-ethyl-5-methyl-1H-imidazolyl and pyridinyl-methyl;

[1016] and

[1017] vii. -C(CH3)2CH2OH, -CH2CH2OH and -C(CH3)2CH2OCH3.

[1018] 87B. A compound according to any one of embodiments 74B to 84B, 79C, 83C, 84C, 85C, 86C or 87C, wherein R 4a and R 4b together with the atoms to which they are attached form piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1]heptanyl or piperazinyl, and the group is optionally substituted by one or two substituents each independently selected from the group consisting of methyl, fluorine and methoxy.

[1019] 88B. A compound according to embodiment 1B or 1C or a pharmaceutically acceptable salt thereof, wherein

[1020] Z is N;

[1021] f is 1;

[1022] R 6 in each case is selected from the group consisting of C1-C3 alkyl, -NR G R H , halogen and C1-C3 alkoxy;

[1023] p is 1

[1024] n is 0 or 1

[1025] R G and R H are each independently hydrogen or C1-C3 alkyl;

[1026] Y 1 、Y 2 、Y 3 and Y 4 are each independently selected from the group consisting of CH, N and C-R 6 provided that one or two of Y 1 、Y 2 、Y 3 and Y 4 can be N;

[1027] R x In each case, it is halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy or cyano;

[1028] m is 0; and

[1029] R 3 and R 4 together with the nitrogen atom to which each is attached form:

[1030] i. a 7-membered fused bicyclic heterocyclic group, a 7-membered bridged bicyclic heterocyclic group or a 7-membered monocyclic heterocyclic group containing one or two heteroatoms;

[1031] wherein when the 7-membered monocyclic heterocyclic group contains one heteroatom, the heterocyclic group 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

[1032] when the 7-membered monocyclic heterocyclic group contains two heteroatoms, each of the heteroatoms is independently N or O, and the heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-C1-C3 alkyl and C6-C 10 a monocyclic or fused bicyclic aryl; and

[1033] 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;

[1034] ii. a 4-membered or 6-membered monocyclic heterocyclic group containing one heteroatom;

[1035] wherein the 4-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo and -(CH2) s C(=O)NR k R l ; wherein

[1036] s is 0, 1, 2 or 3;

[1037] R k is hydrogen or C1-C3 alkyl; and

[1038] R l is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl and C6-C 10 a monocyclic or fused bicyclic aryl;

[1039] wherein the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and NR q R w ; wherein

[1040] R q is hydrogen or C1-C3 alkyl; and

[1041] R w is C6-C 10 monocyclic or 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;

[1042] or

[1043] iii. an 8-, 9-, 10- or 11-membered fused bicyclic heterocyclic group, or a 12-membered bicyclic bridged fused heterocyclic group, wherein the 8-, 9- or 11-membered heterocyclic group contains one heteroatom and the 10- or 12-membered heterocyclic group contains one or two heteroatoms; and wherein the 10-, 11- or 12-membered heterocyclic group is optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy.

[1044] 89B. A compound according to embodiment 88B or a pharmaceutically acceptable salt thereof, wherein Y 1 , Y 2 , Y 3 and Y 4 are each CH or C-R 6 .

[1045] 90B. A compound according to 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.

[1046] 91B. A compound according to any one of embodiments 88B to 90B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 , together with the nitrogen atom to which they are attached, form: a 7-membered heterocyclic group containing one heteroatom, wherein the heterocyclic group is optionally substituted once with methyl or oxo; or a 7-membered monocyclic or bridged bicyclic heterocyclic group containing two heteroatoms, wherein the heteroatoms are N or O, and the heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein the phenyl is optionally substituted with methoxy.

[1047] 92B. A compound according to any one of embodiments 88B to 90B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclic group containing one heteroatom, or a 12-membered bicyclic fused bridged heterocyclic group, each of said groups being optionally substituted with one, two or three substituents each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy and halogen.

[1048] 93B. A compound according to any one of embodiments 88B to 90B or a pharmaceutically acceptable salt thereof, wherein R 3 and R 4 together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclic group containing one heteroatom; wherein

[1049] the 4-membered monocyclic heterocyclic group is optionally substituted with -(CH2) s C(=O)NR k R l ; wherein

[1050] s is 0, 1 or 2;

[1051] R k is hydrogen or C1-C3 alkyl; and

[1052] R l is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl and cyclohexyl;

[1053] and

[1054] the 6-membered monocyclic heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano and NR q R w ; wherein

[1055] R q is hydrogen or C1-C3 alkyl;

[1056] R w is a 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.

[1057] 94B. A compound according to embodiment 1B, 74B or 1C or a pharmaceutically acceptable salt thereof, wherein

[1058] Z is N;

[1059] p is 1;

[1060] f is 1;

[1061] Y1, Y2, Y3 and Y4 are each independently CH or C-R 6 .

[1062] R 6 in each case selected from the group consisting of: 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-C 1- C3 alkyl, -O-R cc -O-R dd and C3-C6 cycloalkyl;; or R 6 in each case is -O-R bb or -O-(C1-C6 alkoxy)-R bb , wherein

[1063] u is an integer from 0 to 6;

[1064] R bb is a 4- to 7-membered monocyclic heterocyclic group, C3-C7 cycloalkyl or -NR G R H ;

[1065] R cc and R dd are each independently C1-C3 alkyl;

[1066] wherein the cycloalkyl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl;

[1067] and

[1068] R G and R H are each independently hydrogen, -C(O)R Ga or C1-C3 alkyl; wherein

[1069] R Ga is C1-C3 alkyl or hydrogen;

[1070] n is 0, 1 or 2;

[1071] R 3 is selected from the group consisting of hydrogen, methyl, ethyl, phenyl and -CH2CH2OH;

[1072] R 4 is wherein

[1073] R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH and -CH2OC(CH3)3;

[1074] R 4d is selected from the group consisting of hydrogen and methyl;

[1075] or

[1076] R 4c and R 4d together with the atoms to which they are attached form a cyclopropyl ring;

[1077] R 4b is hydrogen or methyl;

[1078] R 4a is selected from the group consisting of 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 heterocyclic group; 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 of the cycloalkyl, heterocyclic group, aryl, heteroaryl, arylalkyl or heteroaryl-alkyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, halo-C1-C3 alkoxy, halo-C1-C3 alkyl, oxo, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group;

[1079] or

[1080] R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy;

[1081] R x is in each case C1-C3 alkyl; and

[1082] m is 0, 1 or 2.

[1083] 95B. A compound according to embodiment 94B or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH, Y2 is C-R 6 and Y 3 is CH, and Y 4 is CH.

[1084] 96B. A compound according to embodiment 94B or 95B, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of hydroxy-C1-C6 alkoxy and -O-(CH2) u -R bb ; wherein

[1085] u is an integer from 0 to 6;

[1086] R bb is a 4- to 7-membered monocyclic heterocyclic group, C3-C7 cycloalkyl or -NR G R H ;

[1087] wherein the cycloalkyl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of hydroxy, C1-C3 alkoxy and C1-C3 alkyl;

[1088] and

[1089] R G and R H are each independently hydrogen or C1-C3 alkyl; and

[1090] n is 0, 1 or 2.

[1091] 97B. A compound according to embodiment 96B, or a pharmaceutically acceptable salt thereof, wherein R 6 is selected from the group consisting of: -OCH2CH2OH, -OCH2CH2N(CH3)2, -OCH2C(CH3)2OH and

[1092] 98B. A compound according to any one of embodiments 94B to 97B, or a pharmaceutically acceptable salt thereof, wherein:

[1093] R 3 is methyl;

[1094] R 4c and R 4d are each hydrogen;

[1095] R 4b is hydrogen; and

[1096] R 4a is selected from the group consisting of C1-C6 alkyl, C6-C 10A monocyclic or fused bicyclic aryl group and a 5- to 10-membered monocyclic or fused bicyclic heteroaryl group, which are optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, and halo-C1-C3 alkoxy.

[1097] 99B. A compound according to embodiment 98B or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of: C1-C6 alkyl, phenyl, and pyridyl, wherein the phenyl or pyrimidinyl is optionally substituted with C1-C3 alkoxy.

[1098] 100B. A compound according to embodiment 99B or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of: tert-butyl and

[1099] 101B. A compound according to embodiment 1A, 1B, or 1C or a pharmaceutically acceptable salt thereof, the compound being selected from Table 1.

[1100] 102B. A pharmaceutical composition comprising a compound according to any one of embodiments 1B to 101B, 1A to 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.

[1101] 103B. A method of inhibiting transferrin-mediated iron transport in a subject, comprising administering to the subject an effective amount of a compound according to any one of embodiments 1B to 101B, 1A to 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 according to embodiment 102B.

[1102] General procedures and examples provide illustrative methods for preparing compounds. Those skilled in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although specific starting materials and reagents are depicted and discussed in the schemes, general procedures, and examples, other starting materials and reagents may be readily substituted to provide various derivatives and / or reaction conditions. Additionally, the various illustrative compounds prepared by the described methods may be further modified according to the invention using conventional chemical methods well known to those skilled in the art.

[1103] General synthetic procedure

[1104] General synthetic methods for compounds 1a and 1b of FPN1. In certain embodiments, compound 1a can be synthesized as shown in Scheme 1. The core intermediate 2a can be displaced by various substituted amines 3a via Method A to obtain intermediate 4a, which is then coupled with various organometallic reagents 5a to obtain the final compound 1a. Alternatively, the final compound 1a can be synthesized as shown in Scheme 2. Intermediate 2a can be displaced by a primary amine 6a to obtain intermediate 7a, and after coupling with the organometallic reagent 5a, the resulting intermediate 8a can be alkylated by a halide to obtain compound 1a. The final compound 1b can be synthesized according to Scheme 3. Intermediate 2a is displaced by a glycine ester 9a to obtain intermediate 10a, and after coupling with the organometallic reagent 5a, the resulting intermediate 11a is saponified. The corresponding formic acid intermediate 12a is coupled with various amines to form compound 1b.

[1105] Modifications and variations of Schemes 1 to 3 can be made based on the availability of starting materials and the synthetic compatibility of the 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 linked to the ring; R3 can be hydrogen or alkyl; R4 can be alkyl substituted with an aminocarbonyl or an alkoxy group; or R3 and R4 can be linked together to form a cyclic amine. For Method B, another available heteroaromatic Suzuki or Stille reagent can be used to obtain the final compound 1a.

[1106] Scheme 1 depicts a method for preparing exemplary compounds using Method A and Method B.

[1107]

[1108] Scheme 1

[1109] Scheme 2 depicts a method for preparing exemplary compounds using Method A, Method B, and Method C.

[1110]

[1111] Scheme 2

[1112] Scheme 3 depicts a method for preparing exemplary compounds using Method A, Method B, Method D, and Method E.

[1113]

[1114] Scheme 3

[1115] The conditions and reagents for Methods A to E are provided in the following examples. The following examples are provided by way of illustration and not limitation.

[1116] 1. Synthetic Examples

[1117] Example 1.1

[1118] Method A: General synthetic method for amine nucleophilic coupling to obtain intermediate 4a

[1119] Put dichloropyrimidine intermediate 2a (1.00 equivalent), CH3CN, amine 3a (1.10 equivalents) and triethylamine (2.00 equivalents) into a 100 mL round-bottom flask. Stir the resulting solution at 80 °C for 3 hr. Concentrate the resulting mixture in vacuo. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether to obtain intermediate 4a.

[1120] Example 1.2

[1121] Method B: General synthetic method for metal-mediated cross-coupling

[1122] Put intermediate 4a (1.00 equivalent), dioxane, organometallic reagent 5 (2.0 equivalents) and Pd(dppf)Cl2 (0.05 equivalent) into a 100 mL round-bottom flask purged and maintained with an inert nitrogen atmosphere. Stir the resulting solution at 100 °C overnight. Concentrate the resulting mixture in vacuo. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (1:1) or purify it by preparative HPLC to obtain compound 1a, 8a or 11a.

[1123] Example 1.3

[1124] Method C: General synthetic method for alkylation using halide to obtain compound 1a

[1125] Dissolve intermediate 8a (1.00 equivalent) in DMF and cool in an ice bath. Add sodium hydride (2.00 equivalents) (60%) in two portions and stir the reactants for 45 min. Slowly add halide (2.00 equivalents) and stir the mixture for another 1.5 h. Add water (20 mL) and ethyl acetate (100 mL), separate the phases, and extract the aqueous phase with more ethyl acetate. Wash the combined organic phases with some water and dry over sodium sulfate. After evaporating the solvent, purify the residue by reverse-phase chromatography (Waters XSelect CSH C18 column, 0 - 70% acetonitrile / 0.1% aqueous formic acid gradient). Treat the purified eluate with 1M HCl and lyophilize to obtain compound 1a.

[1126] Example 1.4

[1127] Method D: General synthetic method for saponification to obtain compound 12a

[1128] Dissolve intermediate 11a (1.00 equivalent) in THF and methanol. Dissolve lithium hydroxide (5.00 equivalents) in water and add dropwise to the solution. After 7 h, carefully acidify the mixture to pH 3 with 6 M HCl and evaporate to dryness. Co-evaporate the residue with toluene and dry under high vacuum to obtain 12a.

[1129] Example 1.5

[1130] Method E: General synthetic method for amide formation to obtain compound 1b

[1131] Suspend intermediate 12a (1.00 equivalent) in N,N-dimethylformamide, and then add N,N-diisopropylethylamine (2.50 equivalents), amine (1.35 equivalents), and 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU, 1.35 equivalents). After 40 h, add ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml), separate the phases, and extract the aqueous phase with ethyl acetate (50 ml). Wash the combined organic phases with sodium chloride solution and dry over sodium sulfate. After evaporating the solvent, purify the residue by reverse-phase chromatography (Waters XSelect CSH C18 column, 0 - 70% acetonitrile / 0.1% aqueous formic acid gradient) to obtain compound 1b.

[1132] Example 1.6

[1133] Experimental procedures for common intermediates

[1134] Scheme 4 depicts a method for preparing intermediate I

[1135]

[1136] Scheme 4

[1137] Step 1

[1138]

[1139] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.00 g; 10.58 mmol; 1.00 eq) was dissolved in acetonitrile (36 mL). (2-Ethoxy-2-oxoethyl)(methyl)ammonium chloride (2.11 g; 13.75 mmol; 1.30 eq, sarcosine ethyl ester HCl) was added slowly, followed by N,N-diisopropylethylamine (4.6 mL; 26.45 mmol; 2.50 eq). The reaction mixture was stirred at 25 °C for 22 h and then at 50 °C for 20 h. 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).

[1140] Step 2

[1141]

[1142] Ethyl 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetate (900.00 mg; 3.34 mmol; 1.00 eq) was dissolved in 1,4-dioxane (9 mL) and purged with argon. 2-(Tributylstannyl)pyridine (2.34 mL; 6.67 mmol; 2.00 eq) and tetrakis(triphenylphosphine)palladium (385.58 mg; 0.33 mmol; 0.10 eq) were added, the reaction vessel was sealed, and then stirred in a thermal bath at 105 °C. After 16 h, the solvent was evaporated and the residue was purified by silica gel chromatography (methanol / dichloromethane) to give ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetate (0.72 g, 62%). 1 H NMR (400 MHz, chloroform-d) δ 8.83 (d, J = 4.8 Hz, 1H), 8.39 - 8.28 (m, 1H), 7.86 - 7.77 (m, 1H), 7.41 - 7.32 (m, 1H), 4.37 (s, 2H), 4.20 (q, J = 7.2, 1.5 Hz, 2H), 3.42 (s, 3H), 3.23 - 3.12 (m, 4H), 2.15 - 2.07 (m, 2H), 1.27 - 1.23 (m, 3H). MS (ES+): (M+H) += 269.9。

[1143] Step 3

[1144]

[1145] Dissolve ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetate (0.72 g; 2.30 mmol; 1.00 eq) in THF (20 ml) and methanol (5 ml). Add lithium hydroxide (0.28 g; 11.52 mmol; 5.00 eq) dissolved in water (8 ml) dropwise to the solution. After 7 h, carefully acidify the mixture to pH 3 with 6M HCl and evaporate to dryness. Co-evaporate the residue with toluene and dry under high vacuum to give ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetate hydrochloride (Intermediate I) as an off-white solid. 1 1H NMR (400 MHz, DMSO-d6) δ 8.84 (d, J = 4.7 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 8.21 - 8.12 (m, 1H), 7.75 (dd, J = 7.8, 4.8 Hz, 1H), 3.28 - 3.27 (m, 2H), 3.07 - 3.01 (m, 2H), 2.15 - 2.05 (m, 2H). MS (ES+): (M+H) + = 284.9。

[1146] Example 1.7

[1147] Scheme 5 depicts a method for preparing Intermediate II

[1148]

[1149] Scheme 5

[1150] Step 1

[1151]

[1152] 2-(Benzyloxycarbonylamino)acetic acid (20.0 g, 95.6 mmol, 1.00 eq), DCM (500 mL), HOBt (15.5 g, 114.7 mmol, 1.20 eq), EDCI (22.0 g, 114.7 mmol, 1.20 eq) and tert-butylamine (21.0 g, 286.8 mmol, 3.00 eq) were placed into a 1 L three-necked round-bottom flask. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column containing PE / EA ether (0 - 50%). Thereby, 25.1 g (99%) of benzyl N-[(tert-butylcarbamoyl)methyl]carbamate as a white solid was produced. LCMS: (ES, m / z): [M+H]+ 265.

[1153]

[1154] Benzyl N-[(tert-butylcarbamoyl)methyl]carbamate (7.0 g, 26.48 mmol, 1.00 eq), MeOH (50 mL) and Pd / C (10%) (0.70 g, 10%) were placed into a 250 mL round-bottom flask. The resulting solution was stirred overnight at room temperature under H2 (1 atm). The solid was filtered out. The resulting mixture was concentrated. Thereby, 3.3 g (95%) of 2-amino-N-tert-butylacetamide as a colorless oil was produced. LCMS: (ES, m / z): [M+H]+: 131.

[1155]

[1156] 2,4-Dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (0.80 g, 4.23 mmol, 1.00 eq), THF (20 mL), TEA (0.51 g, 5.04 mmol, 1.19 eq) and 2-amino-N-tert-butylacetamide (0.58 g, 4.44 mmol, 1.05 eq) were placed into a 50 mL round-bottom flask. The resulting solution was stirred overnight at room temperature. The resulting mixture was concentrated. The residue was applied to a silica gel column containing ethyl acetate / hexane (0 - 50%). Thereby, 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 was produced. LCMS (ES, m / z): [M+H] + : 283.1.

[1157] Example 1.8

[1158] Synthesis of 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 92).

[1159]

[1160] Procedure 6 depicts the synthetic route for preparing the exemplary compound.

[1161]

[1162] Procedure 6

[1163] Step 1

[1164]

[1165] Place 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (500.00 mg, 2.645 mmol, 1.00 equiv), acetonitrile (20.00 mL, 0.487 mmol, 0.18 equiv), azepane (314.78 mg, 3.174 mmol, 1.20 equiv), and TEA (321.17 mg, 3.174 mmol, 1.20 equiv) into a 100 mL round-bottom flask. Stir the resulting solution at 80 °C for 2 h. Concentrate the resulting mixture in vacuo. Apply the residue onto a silica gel column containing ethyl acetate / petroleum ether (1:3) to give 600 mg (90.10%) of 1-[2-chloro-\\(5H\\),\\(6H\\),\\(7H\\)-cyclopenta[d]pyrimidin-4-yl]azepane as a solid.

[1166] Step 2

[1167]

[1168] Place 1-[2-chloro-\\(5H\\),\\(6H\\),\\(7H\\)-cyclopenta[d]pyrimidin-4-yl]azepane (300.00 mg, 1.192 mmol, 1.00 equiv), dioxane (20.00 mL), 2-(tributylstannyl)pyridine (877.39 mg, 2.383 mmol, 2.0 equiv), and Pd(dppf)Cl2 (43.60 mg, 0.060 mmol, 0.05 equiv) into a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. Stir the resulting solution in an oil bath at 100 °C overnight. Concentrate the resulting mixture. Apply the residue onto a silica gel column containing ethyl acetate / petroleum ether (1:1). Purify the crude product by recrystallization from EA (ethyl acetate). This gives 79 mg (24.16%) of 1-[2-(pyridin-2-yl)-\\(5H\\),\\(6H\\),\\(7H\\)-cyclopenta[d]pyrimidin-4-yl]azepane as a white solid. 11H NMR (300 MHz, DMSO-d6): δ 8.66 (d, J = 4.5 Hz, 1H), 8.25 (d, J = 7.8 Hz, 1H), 7.882 (t, J = 7.8 Hz, 1H), 7.42 (dd, J = 5.1 Hz, 6.0 Hz, 1H), 3.78 - 3.64 (m, 4H), 3.11 - 3.00 (m, 2H), 2.83 - 2.78 (m, 2H), 2.08 - 1.97 (m, 2H), 1.76 (s, 4H), 1.49 (s, 2H). LCMS: (ES) [M+1] + m / z 295.2

[1169] Example 1.9

[1170] Synthesis of 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane (Compound 93).

[1171]

[1172] Scheme 7 depicts the synthetic route for preparing the exemplary compound.

[1173]

[1174] Scheme 7

[1175] Step 1

[1176]

[1177] Place 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (500.00 mg, 1.00 eq), CH3CN (10.00 mL), 1,4-oxazepane hydrochloride (402.00 mg, 1.10 eq) and TEA (534.00 mg, 2.00 eq) into a 100 mL round-bottom flask. Stir the resulting solution at 80 °C for 3 h. Monitor the reaction progress by LCMS. Concentrate the resulting mixture in vacuo. Apply the residue to a silica gel column containing ethyl acetate / petroleum ether (1:2). Thereby, 600 mg (89.28%) of 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as a brown solid is produced.

[1178] Step 2

[1179]

[1180] 4-[2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane (0.30 g, 1.18 mmol, 1.00 eq), dioxane (20 mL), 2-(tributylstannyl)pyridine (0.87 g, 2.36 mmol, 2.0 eq), and Pd(dppf)Cl2 (0.04 g, 0.035 mmol, 0.05 eq) were placed in a 100 mL round-bottom flask purged and maintained under an inert nitrogen atmosphere. The resulting solution was stirred overnight at 100 °C in an oil bath. The resulting mixture was concentrated in vacuo. The residue was applied to a silica gel column containing ethyl acetate / petroleum ether (1:1). The crude product was purified by recrystallization from EA. There was thus produced 358.1 mg (90%) of 4-[2-(pyridin-2-yl)-5H,6H,7H-1-λ4-cyclopenta[d]pyrimidin-4-yl]-1,4-oxazepane as a light brown solid. 1H NMR (300 MHz, DMSO-d6): δ 8.66 (dd, J = 0.9, 0.9 Hz, 1H), 8.25 (d, J = 7.8 Hz, 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 = 7.5 Hz, 2H), 2.85 - 2.80 (m, 2H), 2.06 - 1.96 (m, 4H). LCMS (ES) [M+1]+ m / z 297.2.

[1181] Example 1.10

[1182] Synthesis of 1-[2-(3-Fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 71).

[1183]

[1184] Compound 71 was synthesized in a similar manner to Compound 92, replacing 2-(tributylstannyl)pyridine with 4-fluoro-2-(tributylstannyl)pyridine. 1 H NMR (400 MHz, methanol-d4) δ 8.46 (d, J = 4.8 Hz, 1H), 7.77 - 7.68 (m, 1H), 7.54 (dt, J = 8.5, 4.3 Hz, 1H), 3.82 (t, J = 6.1 Hz, 4H), 3.19 (t, J = 7.4 Hz, 2H), 2.89 (t, J = 7.9 Hz, 2H), 2.11 (p, J = 7.7 Hz, 2H), 1.80 (s, 4H), 1.59 (p, J = 2.8 Hz, 4H). LCMS (ES) [M+1] + m / z 312.4.

[1185] Example 1.11

[1186] Synthesize 5-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2-oxa-5-azabicyclo[2.2.1]heptane (Compound 72).

[1187]

[1188] Replace azepane with 2-oxa-5-azabicyclo[2.2.1]heptane and synthesize Compound 72 similarly to Compound 92. LCMS (ES+): (M+H) + = 295.0 1 H NMR (400 MHz, chloroform-d) δ 8.85 (d, J = 4.8 Hz, 1H), 8.40 (d, J = 7.9 Hz, 1H), 7.89 - 7.79 (m, 1H), 7.39 (dd, J = 7.5, 4.9 Hz, 1H), 5.33 (s, 1H), 4.71 (s, 1H), 4.00 - 3.94 (m, 2H), 3.83 - 3.76 (m, 2H), 3.20 - 2.96 (m, 4H), 2.19 - 1.94 (m, 4H).

[1189] Example 1.12

[1190] Synthesize N-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 73)

[1191]

[1192] Scheme 8 depicts the synthetic route for preparing the exemplary compound.

[1193]

[1194] Scheme 8

[1195] Step 1

[1196]

[1197] 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-Pyridylmethanamine (0.15 mL; 1.40 mmol; 1.30 equiv) was added slowly, followed by N,N-diisopropylethylamine (0.28 mL; 1.62 mmol; 1.50 equiv). The reaction mixture was stirred at 25 °C for 18 h and then at 50 °C for 6 h. The solvent was evaporated and the residue was purified by silica gel chromatography (methanol / dichloromethane gradient) to give 2-chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine as a white solid (277 mg, 98%). 1 H NMR (400 MHz, chloroform-d) δ 8.58 (d, J = 5.2 Hz, 1H), 7.97 - 7.88 (m, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.45 - 7.38 (m, 1H), 6.63 (s, 1H), 4.86 (d, J = 5.3 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.19 - 2.09 (m, 2H).

[1198] Step 2

[1199]

[1200] 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) and then tetrakis(triphenylphosphine)palladium (121.44 mg; 0.11 mmol; 0.10 equiv) were added. The reaction vessel was sealed and the contents were stirred in a thermal bath at 105 °C for 16 h. 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 as a white solid (161 mg, 50%). 11H NMR (400 MHz, chloroform-d) δ 8.87 (d, J = 5.0 Hz, 1H), 8.57 (d, J = 5.0 Hz, 1H), 8.49 (d, J = 8.0 Hz, 1H), 7.94 - 7.88 (m, 1H), 7.80 - 7.73 (m, 1H), 7.65 (d, J = 7.9 Hz, 1H), 7.45 (dd, J = 7.4, 4.9 Hz, 1H), 7.30 - 7.26 (m, 1H), 7.13 (s, 1H), 5.07 (d, J = 5.1 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 2.95 (t, J = 7.5 Hz, 2H), 2.24 - 2.16 (m, 2H). MS (ES+): (M+H) + = 304.0。

[1201] Step 3

[1202]

[1203] Dissolve 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) in DMF (10 ml) and cool in an ice bath. Add sodium hydride (42 mg; 1.05 mmol; 2.00 equiv) (60%) in two portions and stir the reaction mixture for 45 min. Slowly add methyl iodide (66 μL; 1.05 mmol; 2.00 equiv) and stir the mixture for an additional 1.5 h. Add water (20 ml) and ethyl acetate (100 ml), separate the phases, and extract the aqueous phase with more ethyl acetate (3 × 75 ml) and chloroform:isopropanol 3:1 (50 ml). Wash the combined organic phases with some water (5 ml) and dry over sodium sulfate. After evaporation of the solvent, purify the residue by reverse-phase chromatography (Waters XSelect CSH C18 column, 0 - 70% acetonitrile / water solution of 0.1% formic acid gradient). Treat the purified eluate with 1M HCl and lyophilize to give N-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine hydrochloride as a white solid (90 mg, 48%). 11H NMR (400 MHz, chloroform-d) δ 9.08 (d, J = 5.3 Hz, 1H), 8.69 (d, J = 5.5 Hz, 1H), 8.62 (d, J = 8.0 Hz, 1H), 8.29 - 7.98 (m, 3H), 7.75 - 7.68 (m, 1H), 7.55 - 7.47 (m, 1H), 5.68 (s, 2H), 3.67 (s, 3H), 3.52 - 3.37 (m, 2H), 3.26 - 3.14 (m, 2H), 2.23 - 2.12 (m, 2H). MS (ES+): (M+H) + = 317.9

[1204] Example 1.13

[1205] Synthesize N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)pyrimidin-4-yl]amino}acetamide (Compound 75).

[1206]

[1207] Scheme 9 depicts the synthetic route for preparing the exemplary compound.

[1208]

[1209] Scheme 9

[1210] Suspend 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) in N,N-dimethylformamide (3.5 ml). Add 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). After 40 h, add ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml), separate the phases, and extract the aqueous phase with ethyl acetate (50 ml). Wash the combined organic phases with sodium chloride solution and dry over sodium sulfate. After evaporation of the solvent, purify the residue by reverse-phase chromatography (Waters XSelect CSH C18 column, 0 - 70% acetonitrile / 0.1% aqueous formic acid gradient) to give N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (formate, 46 mg, 34%). 11H NMR (400 MHz, chloroform-d) δ 10.18 (s, 1H), 8.86 (d, J = 5.0 Hz, 1H), 8.53 (d, J = 8.0 Hz, 1H), 8.22 (s, 1H), 8.04 - 7.93 (m, 1H), 7.56 - 7.46 (m, 3H), 6.76 (d, J = 8.6 Hz, 2H), 4.56 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 3.24 (t, J = 7.4 Hz, 2H), 2.99 (t, J = 7.9 Hz, 2H), 2.12 (p, J = 7.7 Hz, 2H). MS (ES+): (M+H) + = 390.1

[1211] Example 1.14

[1212] Synthesize N-(3-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 74).

[1213]

[1214] Replace 4-methoxyaniline with 3-fluoroaniline and synthesize Compound 74 similarly to Compound 75. LCMS (ES+): (M+H) + = 379.0 1 1H NMR (400 MHz, chloroform-d) δ 10.80 (s, 1H), 9.10 - 8.96 (m, 1H), 8.67 (d, J = 7.9 Hz, 1H), 8.21 - 8.09 (m, 1H), 7.72 - 7.58 (m, 2H), 7.40 (d, J = 8.2 Hz, 1H), 7.21 - 7.11 (m, 1H), 6.75 - 6.65 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J = 7.4 Hz, 2H), 2.97 (t, J = 7.9 Hz, 2H), 2.14 (p, J = 7.7 Hz, 2H).

[1215] Example 1.15

[1216] Synthesize 1-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,2,3,4-tetrahydroquinoline (Compound 76)

[1217]

[1218] Scheme 10 depicts the synthetic route for preparing the exemplary compounds.

[1219]

[1220] Process 10

[1221] Step 1

[1222]

[1223] 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 h, the mixture was cooled and concentrated, the residue was diluted with water, the resulting precipitate was collected by filtration, and dried in vacuo 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.

[1224] Step 2

[1225]

[1226] 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 equiv) in toluene (1.5 mL) was added 2-(tributylstannyl)pyridine (48.31 mg; 0.13 mmol; 1.50 equiv) and tetrakis(triphenylphosphine)palladium (10.11 mg; 0.01 mmol; 0.10 equiv). The mixture was degassed and heated at 110 °C for 15 h. The mixture was cooled and concentrated, diluted with AcCN and water, and purified 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). 11H NMR (400 MHz, methanol-d4) δ 8.73 - 8.67 (m, 1H), 8.42 (dt, J = 8.0, 1.2 Hz, 1H), 7.96 (td, J = 7.8, 1.8 Hz, 1H), 7.50 (ddd, J = 7.5, 4.9, 1.3 Hz, 1H), 7.17 (q, J = 7.5 Hz, 2H), 7.03 (td, J = 7.5, 1.3 Hz, 1H), 6.77 (d, J = 7.9 Hz, 1H), 4.10 (t, J = 6.5 Hz, 2H), 2.97 (t, J = 7.7 Hz, 2H), 2.82 (t, J = 6.6 Hz, 2H), 2.31 (t, J = 7.3 Hz, 2H), 2.02 (dp, J = 36.1, 7.5, 7.0 Hz, 4H). LCMS (ES+): (M+H) + = 329.1

[1227] Example 1.16

[1228] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-phenylacetamide (Compound 77)

[1229]

[1230] Replace 4-methoxyaniline with aniline, and synthesize Compound 77 in a similar manner to Compound 75. LC MS (ES+): (M+H) + = 360.0 1 1H NMR (400 MHz, chloroform-d) δ 10.39 (s, 1H), 8.98 - 8.87 (m, 1H), 8.58 (d, J = 8.0 Hz, 1H), 8.08 - 7.96 (m, 1H), 7.62 (d, J = 8.0 Hz, 2H), 7.59 - 7.51 (m, 1H), 7.25 - 7.17 (m, 2H), 7.01 (t, J = 7.4 Hz, 1H), 4.61 (s, 2H), 3.52 (s, 3H), 3.26 (t, J = 7.4 Hz, 2H), 2.98 (t, J = 7.9 Hz, 2H), 2.18 - 2.07 (m, 2H).

[1231] Example 1.17

[1232] Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 78)

[1233]

[1234] Replace 4-methoxyaniline with cyclohexylamine and synthesize compound 78 analogously to compound 75. 1 H NMR(400MHz, chloroform-d) δ 9.07 - 8.93(m, 1H), 8.59(d, J = 8.0Hz, 1H), 8.12 - 8.01(m, 1H), 7.83 - 7.64(m, 1H), 7.59(d, J = 6.7Hz, 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, 2H), 1.65 - 1.58(m, 2H), 1.56 - 1.49(m, 1H), 1.28 - 1.06(m, 5H). LCMS(ES+): (M+H) + = 366.0.

[1235] Example 1.18

[1236] Synthesize 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(oxan-4-yl)acetamide (Compound 79)

[1237]

[1238] Replace 4-methoxyaniline with 4-aminotetrahydropyran and synthesize compound 79 analogously to compound 75. 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).

[1239] Example 1.19

[1240] Synthesize N-ethyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 80)

[1241]

[1242] Replace 2-pyridylmethylamine with 2-pyrimidinylmethylamine and replace iodomethane with iodoethane, and synthesize compound 80 similarly to compound 73. LCMS(ES+):(M+H) + = 333.0 1 H NMR(400MHz, chloroform-d) δ8.96 - 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).

[1243] Example 1.20

[1244] Synthesize N-methyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (compound 81)

[1245]

[1246] Replace 2-pyridylmethylamine with 2-pyrimidinylmethylamine, and synthesize compound 81 similarly to compound 73. LCMS(ES+):(M+H) + = 319.1 1 H NMR(400MHz, chloroform-d) δ8.78 - 8.69(m, 3H), 8.33(s, 1H), 8.18(d, J = 8.0Hz, 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 = 7.4Hz, 2H), 3.15 - 3.10(m, 2H), 2.13 - 2.07(m, 2H).

[1247] Example 1.21

[1248] Synthesize N-[(1,3-benzoxazol-2-yl)methyl]-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (compound 82)

[1249]

[1250] Replace 2-pyridylmethylamine with 1,3-benzoxazol-2-ylmethylamine, and synthesize compound 82 similarly to compound 73. LCMS(ES+):(M+H) += 358.0。 1 H NMR (400 MHz, chloroform-d) δ 8.82 (d, J = 5.4 Hz, 1H), 8.34 (d, J = 8.0 Hz, 1H), 8.14 (s, 1H), 7.86 - 7.77 (m, 1H), 7.74 - 7.67 (m, 1H), 7.54 - 7.47 (m, 1H), 7.41 - 7.35 (m, 1H), 7.35 - 7.29 (m, 2H), 5.25 (s, 2H), 3.54 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 3.18 - 3.11 (m, 2H), 2.16 - 2.12 (m, 2H)。

[1251] Example 1.22

[1252] 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)

[1253]

[1254] Replace azepane with 2,3,4,5-tetrahydro-1H-benzo[d]azepine, and synthesize Compound 83 similarly to Compound 92. LCMS (ES+): (M+H) + = 343.0。 1 H NMR (400 MHz, chloroform-d) δ 8.81 (d, J = 4.8 Hz, 1H), 8.41 (d, J = 7.9 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.39 (dd, J = 7.5, 4.9 Hz, 1H), 7.15 (s, 4H), 6.10 (s, 2H), 4.08 - 3.99 (m, 4H), 3.15 - 3.02 (m, 8H), 2.19 - 2.08 (m, 2H)。

[1255] Example 1.23

[1256] Synthesis of N-(2-methoxyethyl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 84)

[1257]

[1258] Replace azepane with N-(2-methoxyethyl)-N-methylamine, and synthesize Compound 84 similarly to Compound 92. LCMS (ES+): (M+H) + = 285.0。 11H NMR (400 MHz, chloroform-d) δ 8.81 (dd, J = 4.7, 2.0 Hz, 1H), 8.45 (d, J = 1.5 Hz, 1H), 8.34 (dd, J = 8.2, 1.5 Hz, 1H), 7.89 - 7.80 (m, 1H), 7.50 - 7.27 (m, 3H), 3.97 - 3.90 (m, 2H), 3.70 - 3.63 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 3.23 - 3.14 (m, 4H), 2.16 - 2.07 (m, 2H).

[1259] Example 1.24

[1260] Synthesis of 1-methyl-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (Compound 85)

[1261]

[1262] Compound 85 was synthesized in a similar manner to Compound 92 by replacing azepane with 1-methyl-1,4-diazepane. LCMS (ES+): (M+H) + = 310.1. 1 1H NMR (400 MHz, chloroform-d) δ 8.79 (d, J = 4.8 Hz, 1H), 8.29 - 8.21 (m, 1H), 7.86 - 7.76 (m, 1H), 7.40 - 7.34 (m, 1H), 4.36 - 4.22 (m, 2H), 3.98 (t, J = 6.7 Hz, 2H), 3.50 - 3.40 (m, 2H), 3.28 - 3.18 (m, 2H), 3.11 (t, J = 7.3 Hz, 2H), 3.03 (t, J = 7.8 Hz, 2H), 2.82 (s, 3H), 2.56 (s, 2H), 2.15 - 2.04 (m, 2H).

[1263] Example 1.25

[1264] 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)

[1265]

[1266] Compound 86 was synthesized in a similar manner to Compound 75 by replacing 4-methoxyaniline with morpholine. LCMS (ES+): (M+H) + = 354.0. 11H NMR (400 MHz, chloroform-d) δ 8.96 - 8.86 (m, 1H), 8.50 - 8.37 (m, 1H), 8.21 - 8.15 (m, 1H), 8.07 - 7.93 (m, 1H), 7.60 - 7.48 (m, 1H), 4.86 - 4.75 (m, 2H), 3.81 - 3.74 (m, 2H), 3.71 - 3.66 (m, 4H), 3.62 - 3.58 (m, 2H), 3.41 (s, 3H), 3.29 - 3.25 (m, 2H), 3.06 - 3.00 (m, 2H), 2.17 - 2.05 (m, 2H).

[1267] Example 1.26

[1268] Synthesis of N-methyl-N-(2-phenoxyethyl)-2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 87)

[1269]

[1270] Replace azepane with N-methyl-N-(2-phenoxyethyl)amine, and synthesize Compound 87 similarly to Compound 92. LCMS (ES+): (M+H) + = 285.0. 1 1H NMR (400 MHz, chloroform-d) δ 9.09 (d, J = 4.9 Hz, 1H), 8.57 (d, J = 7.8 Hz, 1H), 8.16 - 8.00 (m, 1H), 7.69 - 7.63 (m, 1H), 7.29 - 7.25 (m, 2H), 6.98 - 6.91 (m, 1H), 6.86 (d, J = 8.0 Hz, 2H), 4.36 (s, 4H), 3.61 (s, 3H), 3.45 (t, J = 7.8 Hz, 2H), 3.29 (t, J = 7.3 Hz, 2H), 2.24 - 2.13 (m, 2H).

[1271] Example 1.27

[1272] 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)

[1273]

[1274] Replace 4-methoxyaniline with piperidine, and synthesize Compound 88 similarly to Compound 75. LCMS (ES+): (M+H) + = 352.1. 11H NMR (400 MHz, chloroform-d) δ 9.03 (d, J = 5.1 Hz, 1H), 8.69 - 8.55 (m, 1H), 8.23 - 8.07 (m, 1H), 7.74 - 7.64 (m, 1H), 5.17 - 4.78 (m, 2H), 3.64 - 3.56 (m, 2H), 3.52 (t, J = 5.6 Hz, 2H), 3.44 (s, 3H), 3.33 - 3.20 (m, 4H), 2.20 - 2.10 (m, 2H), 1.73 - 1.62 (m, 4H), 1.57 - 1.49 (m, 2H).

[1275] Example 1.28

[1276] Synthesize N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 89).

[1277]

[1278] Replace 4-methoxyaniline with tert-butylamine and synthesize Compound 89 similarly to Compound 75. 1 1H NMR (400 MHz, chloroform-d) δ 9.33 - 9.18 (m, 1H), 8.87 (d, J = 7.7 Hz, 1H), 8.43 - 8.33 (m, 1H), 8.28 (s, 1H), 7.91 - 7.79 (m, 1H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J = 7.3 Hz, 2H), 3.00 (t, J = 7.9 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.27 (s, 9H). MS (ES+): (M+H) + = 340.0.

[1279] Example 1.29

[1280] Synthesize N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}lactam (Compound 91)

[1281]

[1282] Step 1

[1283]

[1284] Dissolve 2-{[(tert-butoxy)carbonyl](methyl)amino}propanoic acid (500 mg; 2.5 mmol; 1 equiv) in DMF (6 mL). Add N,N-diisopropylethylamine (1.1 mL; 6.15 mmol; 2.5 equiv) and then 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium hexafluorophosphate 3-oxide (HATU, 1262 mg; 3.3 mmol; 1.35 equiv). Add cyclohexylamine (0.38 mL; 3.3 mmol; 1.35 equiv) and stir the reaction mixture at 25 °C. After 14 h, dilute the reaction with ethyl acetate (50 mL), water (15 mL), and sodium bicarbonate solution (30 mL). Separate the phases and extract the aqueous phase with ethyl acetate (50 mL). Wash the combined organics with sodium chloride solution (50 mL) and dry over sodium sulfate. After evaporation, purify the residue by silica gel chromatography (ethyl acetate / hexane gradient) to give tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate as white crystals (0.48 g, 68%). LCMS (ES+): (M+H) + = 285.0.

[1285] Step 2

[1286]

[1287] Dissolve tert-butyl N-[1-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g; 1.7 mmol; 1 equiv) in dichloromethane (12 mL) and cool in an ice bath. Slowly add trifluoroacetic acid (6 mL) and stir the reaction at 20 °C. After 1.6 h, evaporate the reaction to a residue and then co-evaporate from toluene (40 mL). The crude product N-cyclohexyl-2-(methylamino)propanamide trifluoroacetate is used directly in the next step.

[1288] Step 3

[1289]

[1290] 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)acrylamide 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 mixture was stirred at 50 °C for 14 h, then at 60 °C for 6 h and allowed to reach 30 °C over 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.

[1291] Step 4

[1292]

[1293] 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(triphenylphosphine)palladium (60 mg; 0.05 mmol; 0.1 equiv). The reaction vessel was sealed and stirred in a hot bath at 110 °C for 15 h. After evaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0 - 70% acetonitrile / 0.1% aqueous formic acid gradient) to give N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acrylamide (86 mg, 43%) as an off-white solid. LCMS (ES+): (M+H) + = 380.0. 11H NMR (400 MHz, DMSO-d6) δ 8.69 (d, J = 4.8 Hz, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.19 (d, J = 8.3 Hz, 1H), 7.96 - 7.84 (m, 1H), 7.53 - 7.42 (m, 1H), 5.16 (q, J = 7.0 Hz, 1H), 3.63 - 3.49 (m, 1H), 3.25 - 3.16 (m, 1H), 3.14 - 3.06 (m, 4H), 2.93 - 2.76 (m, 2H), 1.74 (s, 1H), 1.65 (s, 1H), 1.59 - 1.44 (m, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.25 - 1.12 (m, 3H), 1.07 - 0.93 (m, 2H).

[1294] Example 1.30

[1295] Synthesis of N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}lactam (Compound 90)

[1296]

[1297] Compound 90 was synthesized in a similar manner to Compound 91 by replacing cyclohexylamine with tert-butylamine. LCMS (ES+): (M+H) + = 354.4. 1 1H NMR (400 MHz, DMSO-d6) δ 8.80 - 8.74 (m, 1H), 8.50 (d, J = 7.9 Hz, 1H), 8.09 - 8.01 (m, 1H), 7.81 (s, 1H), 7.66 - 7.59 (m, 1H), 5.14 (q, J = 7.0 Hz, 1H), 3.26 (s, 3H), 3.24 - 3.10 (m, 2H), 3.05 - 2.88 (m, 2H), 2.15 - 1.97 (m, 3H), 1.40 (d, J = 7.1 Hz, 3H), 1.21 (s, 9H).

[1298] Example 1.31

[1299] Synthesis of 10-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-10-azatricyclo[6.3.1.02,7]dodeca-2,4,6-triene (Compound 1)

[1300]

[1301] Using 10-azatricyclo[6.3.1.0 2,7]Dodeca-2(7),3,5-triene substituted azepane, compound 1 was synthesized similarly to compound 92. LCMS(ES+):(M+H) + = 355.0 1 H NMR(400MHz, chloroform-d)δ8.66(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).

[1302] Example 1.32

[1303] Synthesize 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)

[1304]

[1305] Replace azepane with 7-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, and compound 2 was synthesized similarly to compound 92. LCMS(ES+):(M+H) + = 373.1 1 H NMR(400MHz, chloroform-d)δ8.90 - 8.70(m, 1H), 8.40(d, J = 7.1Hz, 2H), 7.90 - 7.76(m, 1H), 7.43 - 7.31(m, 1H), 7.07(d, J = 8.2Hz, 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).

[1306] Example 1.33

[1307] Synthesize 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)

[1308]

[1309] Replace azepane with 6-methoxy-2,3,4,5-tetrahydro-1H-3-benzazepine, and compound 3 was synthesized similarly to compound 92. LCMS(ES+):(M+H) + = 373.01 1H NMR (400 MHz, chloroform-d) δ 8.81 (dd, J = 4.8, 1.8 Hz, 1H), 8.42 (d, J = 7.9 Hz, 1H), 7.86 - 7.77 (m, 1H), 7.39 - 7.31 (m, 1H), 7.14 - 7.07 (m, 1H), 6.79 - 6.74 (m, 2H), 4.00 (dt, J = 25.4, 4.9 Hz, 4H), 3.81 (s, 3H), 3.17 - 3.03 (m, 8H), 2.15 - 2.06 (m, 2H).

[1310] Example 1.34

[1311] Synthesis of 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (Compound 4)

[1312]

[1313] Scheme 11 depicts the synthetic route for preparing the exemplary compound.

[1314]

[1315] Scheme 11

[1316] Step 1

[1317]

[1318] Dissolve 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 equiv) in dichloromethane (5 ml). Slowly add trifluoroacetic acid (2.5 mL) and stir the reaction mixture at 25 °C. After 1 h, evaporate the reaction mixture to dryness and co-evaporate the residue with toluene. LCMS (ES+): (M + H) + = 296.

[1319] Step 2

[1320]

[1321] 1-[2-(Pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane (108 mg; 0.37 mmol; 1.15 equiv) and 1-iodo-3-methoxybenzene (75 mg; 0.32 mmol; 1 equiv) were combined 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, additional portions of the reagents (iodide, ligand, palladium catalyst, and base) were added to drive product formation. The reaction mixture was then filtered, concentrated, and purified by reverse-phase chromatography (Waters XSelect CSH C18 column, 0-50% acetonitrile / 0.1% aqueous formic acid gradient) to afford 1-(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-1,4-diazepane as a yellow solid (19 mg, 15%).

[1322] MS(ES+):(M+H) + = 402.1. 1 H NMR (400 MHz, chloroform-d) δ 8.94 - 8.87 (m, 1H), 8.34 (d, J = 7.9 Hz, 1H), 8.02 - 7.92 (m, 1H), 7.62 - 7.53 (m, 1H), 7.19 - 7.10 (m, 1H), 6.41 (d, J = 8.3 Hz, 1H), 6.35 - 6.28 (m, 2H), 4.30 - 4.22 (m, 2H), 3.92 - 3.86 (m, 2H), 3.81 - 3.76 (m, 5H), 3.64 (t, J = 6.2 Hz, 2H), 3.36 (t, J = 8.0 Hz, 2H), 3.18 (t, J = 7.4 Hz, 2H), 2.27 - 2.15 (m, 4H).

[1323] Example 1.35

[1324] Synthesis of N-(pyridin-2-yl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 5)

[1325]

[1326] Scheme 12 depicts the synthetic route for the preparation of the exemplary compound.

[1327]

[1328] Process 12

[1329] Step 1

[1330]

[1331] Put [(tert-butoxycarbonyl)amino]acetic acid (2.0 g, 11.42 mmol, 1.0 equivalent), DMF (20.0 mL), 2-aminopyridine (1.29 g, 13.71 mmol, 1.2 equivalents), and DIPEA (3.69 g, 28.54 mmol, 2.5 equivalents) into a 50 mL three-necked round-bottom flask. Then add HATU (5.21 g, 13.70 mmol, 1.2 equivalents) in several portions at 0 °C. Stir the reaction solution at room temperature for 2 h. Subsequently, quench the reactants by adding 50 mL of H2O, filter, and dry the collected solid under an infrared lamp. 2.4 g (yield 84%) of tert-butyl N-[[(pyridin-2-yl)carbamoyl]methyl]carbamate as a white solid was obtained. LCMS (ES) [M+1] + m / z: 252.

[1332] Step 2

[1333]

[1334] Put tert-butyl N-[[(pyridin-2-yl)carbamoyl]methyl]carbamate (2.40 g, 9.55 mmol, 1.0 equivalent) and DCM (20.0 mL) into a 50 mL round-bottom flask. Add HCl(g) (2 M in EA) (19.0 mL) to the above mixture at 0 °C. Stir the mixture at room temperature for 2 h. Concentrate the mixture to remove the solvent to obtain 1.4 g (yield 78%) of 2-amino-N-(pyridin-2-yl)acetamide hydrochloride as a white solid. LCMS (ES) [M-HCl+1] + m / z: 152.

[1335] Step 3

[1336]

[1337] Place 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) into a 100 mL round-bottom flask. Stir the mixture at 60 °C in an oil bath for 12 h. After cooling to room temperature, dilute the reaction mixture with H2O (50 mL) and extract with 3 × 40 mL of ethyl acetate. Wash the combined organic phases with 3 × 40 mL of brine, dry over anhydrous sodium sulfate, filter, and concentrate the filtrate under reduced pressure. Purify the residue by silica gel column chromatography with ethyl acetate / petroleum ether (1:2). Obtain 320 mg (yield 14%) 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.

[1338] Step 4

[1339]

[1340] Place 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-N-(pyridin-2-yl)acetamide (320 mg, 1.05 mmol, 1.0 equiv), dioxane (20.0 mL), 2-(tributylstannyl)pyridine (465 mg, 1.26 mmol, 1.2 equiv), and Pd(dppf)Cl2 (86 mg, 0.11 mmol, 0.1 equiv) into a 50 mL round-bottom flask. Stir the mixture at 110 °C in an oil bath under a N2 atmosphere for 12 h. Cool the reaction mixture to room temperature and concentrate to remove the solvent. Purify the residue by silica gel column chromatography with ethyl acetate / petroleum ether (3:1). Further purify the crude product by preparative HPLC using the following conditions: column: HPH C18, 50*3.0 mm, 2.6 um, mobile phase A: water / 0.05% NH3·H2O, mobile phase B: CH3CN, flow rate: 1.2 mL / min, gradient: from 5% B to 100% B in 1.1 min, hold for 0.7 min. Obtain 78.9 mg (yield 22%) of N-(pyridin-2-yl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 10.60 (s, 1H), 8.61 (d, J = 4.6 Hz, 1H), 8.33 (dd, J = 4.9, 1.1 Hz, 1H), 8.23 (d, J = 8.1 Hz, 1H), 8.03 (d, J = 8.4 Hz, 1H), 7.78 - 7.69 (m, 2H), 7.40 - 7.35 (m, 2H), 7.09 (ddd, J = 7.3, 4.8, 1.0 Hz, 1H), 4.31 (d, J = 5.8 Hz, 2H), 2.86 (t, J = 7.7 Hz, 2H), 2.79 (t, J = 7.4 Hz, 2H), 2.09 (p, J = 7.5 Hz, 2H). LCMS: (ES, m / z): [M + H] + : 347.1。

[1341] Example 1.36

[1342] Synthesis of N-(2-Fluorophenyl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 6)

[1343]

[1344] Scheme 13 depicts the synthetic route for preparing the exemplary compound.

[1345]

[1346] Scheme 13

[1347] Place [[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), 2-fluoroaniline (98 mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU (337 mg, 0.88 mmol, 1.5 equiv) into a 50 mL round-bottom flask. Stir the resulting solution at room temperature for 2 h. Dilute the reaction solution with 5 mL of CH3CN and filter. Purify the filtrate by preparative HPLC (SHIMADZU (HPLC-01)) using the following conditions: column, Welch Xtimate C18, 21.2*250 mm, 5 um, mobile phase: water (10 mmol / L NH4HCO3) and MeOH:CH3CN = 1:1 (from 25% phase B to 65% in 15 min), detector, UV, 254 nm. This gives 117.3 mg of N-(2-fluorophenyl)-2-[[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as a pale yellow solid. 1 1H NMR (300 MHz, DMSO-d6) δ 10.03 (br, 1H), 8.63 - 8.61 (m, 1H), 8.31 - 8.28 (m, 1H), 7.88 - 7.75 (m, 2H), 7.50 - 7.37 (m, 2H), 7.29 - 7.18 (m, 1H), 7.18 - 7.08 (m, 2H), 4.28 (d, J = 5.4 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 2.78 (t, J = 7.4 Hz, 2H), 2.14 - 2.04 (m, 2H). LCMS (ES) [[M+1]] + m / z: 364.1.

[1348] Example 1.37

[1349] Synthesis of 2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(quinolin-7-yl)acetamide (Compound 7)

[1350]

[1351] Scheme 14 depicts the synthetic route for preparing the exemplary compounds.

[1352]

[1353] Scheme 14

[1354] 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 in a 50 mL round-bottom flask. After addition, the mixture was stirred at room temperature for 2 h. The reaction solution was diluted with 5 mL of CH3CN and filtered. The filtrate was purified by preparative HPLC using the following conditions: column, Welch Xtimate C18, 21.2*250 mm, 5 um, mobile phase: water (10 mmol / L NH4HCO3) and MeOH:CH3CN = 1:1 (from 25% phase B to 70% in 15 min); detector, UV 254 nm. 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 was thus obtained. 1 1H NMR (300 MHz, DMSO-d6) δ 10.64 (s, 1H), 8.82 (dd, J = 4.2, 1.8 Hz, 1H), 8.64 - 8.61 (m, 1H), 8.43 (d, J = 1.8 Hz, 1H), 8.29 - 8.25 (m, 2H), 7.92 (d, J = 8.7 Hz, 1H), 7.81 - 7.69 (m, 2H), 7.54 - 7.50 (m, 1H), 7.43 - 7.36 (m, 2H), 4.30 (d, J = 5.7 Hz, 2H), 2.90 - 2.76 (m, 4H), 2.15 - 2.05 (m, 2H). LCMS: (ES, m / z): [M+1] + m / z: 397.1.

[1355] Example 1.38

[1356] Synthesis of N-tert-butyl-2-{[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 8)

[1357]

[1358] Scheme 15 depicts the synthetic route for preparing the exemplary compounds.

[1359]

[1360] Scheme 15

[1361] Into a 10 mL sealed tube purged and maintained in an inert nitrogen atmosphere, N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)acetamide (0.30 g, 1.06 mmol, 1.00 equiv), dioxane (10 mL), 4-(tributylstannyl)pyrimidine (0.47 g, 1.27 mmol, 1.20 equiv) and Pd(dppf)Cl2·CH2Cl2 (0.17 g, 0.20 equiv) were placed. The resulting solution was stirred overnight at 130 °C. The resulting mixture was concentrated. The residue was applied to a silica gel column containing MeOH / EA (1:9). The crude product was purified by preparative HPLC using the following conditions: column, welch X-timate C18, 21.2 * 250 mm, 5 μm; mobile phase; phase A water (10 mmol / L NH4HCO3), phase B CH3CN / MeOH (1:1) (from 15% B to 60% in 15 min); detector, 220 nm. There was thus produced 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 1H-NMR: (300 MHz, DMSO-d6, ppm): δ 9.28 (s, 1H), 8.93 (d, J = 5.1 Hz), 8.32 (d, J = 5.1 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J = 6.0 Hz, 1H), 3.97 (d, J = 5.7 Hz, 2H), 2.87 (q, J = 7.8 Hz, 2H), 2.76 (q, J = 7.2 Hz, 2H), 2.13 - 2.06 (m, 2H), 1.24 (s, 9H). LCMS: (ES, m / z): [M + H] + : 327.2.

[1362] Example 1.39

[1363] Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino}acetamide (Compound 9)

[1364]

[1365] Scheme 16 depicts the synthetic route for preparing the exemplary compound.

[1366]

[1367] Scheme 16

[1368] Step 1

[1369]

[1370] Into a 40 mL vial purged and maintained with an inert nitrogen atmosphere were placed 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (1272.53 mg, 3.46 mmol, 1.30 equiv), dioxane (10.00 mL), and Pd(PPh3)4 (307.25 mg, 0.26 mmol, 0.10 equiv). The resulting solution was stirred overnight at 110 °C. 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 (from 50% phase B to 80% in 11 min); detector, 254. There was thus produced 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.

[1371] Step 2

[1372]

[1373] 2-[4-Chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (160.00 mg, 0.69 mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (99.32 mg, 0.76 mmol, 1.10 equiv), Pd(OAc)2 (15.57 mg, 0.069 mmol, 0.10 equiv), Cs2CO3 (451.94 mg, 1.38 mmol, 2.00 equiv), BINAP (86.37 mg, 0.14 mmol, 0.20 equiv), and dioxane (10.00 mL) were placed into a 40 mL vial purged and maintained with an inert nitrogen atmosphere. The resulting solution was stirred overnight at 100 °C. 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 (from 20% phase B to 50% in 11 min); detector, 254 nm. There was thus produced 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. 1H NMR (300 MHz, DMSO-d6) δ 8.59 (ddd, J = 4.8, 1.9, 0.9 Hz, 1H), 8.30 (dt, J = 8.0, 1.1 Hz, 1H), 7.84 (td, J = 7.7, 1.8 Hz, 1H), 7.66 (s, 1H), 7.41 - 7.30 (m, 2H), 6.00 (t, J = 5.7 Hz, 1H), 3.77 (d, J = 5.7 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.12 - 2.02 (m, 2H), 1.27 (s, 9H). LCMS (ES, m / z): [M + H]+: 325.1.

[1374] Example 1.40

[1375] Synthesis of N-tert-butyl-2-{[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl]amino}acetamide (Compound 10)

[1376]

[1377] Scheme 17 depicts the synthetic route for preparing the exemplary compound.

[1378]

[1379] Scheme 17

[1380] Step 1

[1381]

[1382] Place 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) into a 40 mL vial. Stir the resulting solution at 80 °C overnight. Cool the reaction mixture to room temperature. Purify the crude product (2 g) 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 (from 20% phase B to 60% in 11 min); detector, 254. This gives 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.

[1383] Step 2

[1384]

[1385] Place N-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino]acetamide (500.00 mg, 1.68 mmol, 1.00 equiv), 2-(tributylstannyl)pyridine (806.26 mg, 2.19 mmol, 1.30 equiv), dioxane (10.00 mL) and Pd(dppf)Cl2 (123.26 mg, 0.17 mmol, 0.10 equiv) into a 40 mL vial purged and maintained with an inert nitrogen atmo...

Claims

1. A compound of formula (I'): or a pharmaceutically acceptable salt thereof; wherein Z is N; Ring B is wherein indicates the point of attachment to the remainder of the molecule; R 6 In each case, selected from the group consisting of: 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 , -O-R bb , -(C1-C6 alkyl)-NR GI R HI , -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR G1 R H1 , halo-C 1- C3 alkyl, -O-R cc -O-R dd , 5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein hydroxy-C1-C 10 alkoxy or -O-(C1-C6 alkyl)-R bb wherein the alkyl moiety is 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 heterocyclic group, C3-C7 cycloalkyl, 5- or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NR G1 R H1 or -NR G R H ; R cc is a C1-C3 alkylene; and R dd is a C1-C3 alkyl or a 6-membered heteroaryl; wherein R 6 , R bb or R dd of the cycloalkyl, heterocyclic or heteroaryl group is optionally substituted by 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 each independently is hydrogen or a C1-C3 alkyl group; and R G and R H each independently is hydrogen, -C(O)R Ga or an optionally deuterated C1-C3 alkyl; wherein R Ga is a C1-C3 alkyl or hydrogen; or Two Rs 6 group, together with the atom(s) to which it is attached, forms a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B or a 5- to 6-membered monocyclic heteroaryl group fused to ring B; wherein the heterocyclic group, phenyl, cycloalkyl or heteroaryl fused to ring B is optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3 alkyl, C1-C3 alkyl, C3-C7 cycloalkyl and 5- or 6-membered monocyclic heterocyclic group; n is 0, 1, 2 or 3; Y 1 , Y 2 , Y 3 and Y 4 Each independently selected from the group consisting of: CH, N, NH, O, S, NR 6 and CR 6 , the condition is Y 1 , Y 2 , Y 3 and Y 4 No more than one of them is N or NR 6 , NH, O or S; f is 0 or 1; p is 1 or 2; R x in each case halogen, C1-C6 alkyl, C1-C3 alkoxy, hydroxy, oxo or cyano; m is 0, 1 or 2; R 3 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 For wherein R 4g selected from the group consisting of: hydrogen; C1-C 10 alkyl; hydroxy-C1-C6 alkyl; and C6-C 10 monocyclic or fused bicyclic aryl; wherein R 4g the aryl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiro heterocyclic groups; R 4a selected from the group consisting of: hydrogen; C1-C 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 spiro heterocyclic group; 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; R J1 and R J2 are each independently hydrogen or a C1-C3 alkyl group; wherein R 4a the cycloalkyl, heterocyclic group, aryl, heteroaryl, aryl-alkyl or heteroaryl-alkyl is optionally substituted with one, two or three substituents each independently selected from the group consisting of: halogen; C1-C6 alkyl; halo-C1-C3 alkyl; hydroxy; C1-C3 alkoxy; halo-C1-C3 alkoxy; oxo; C3-C7 cycloalkyl; and 5- to 10-membered monocyclic, fused bicyclic or spiro heterocyclic group; R 4b is hydrogen or a C1-C6 alkyl group; or R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of: halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy; or R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one, two or three substituents each independently selected from the group consisting of: hydroxy, halogen and C1-C3 alkyl; or R 4c and R 4d each independently is 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 together with the atoms to which they are attached form a C3-C7 cycloalkyl group; and the heterocyclic group, heteroaryl and spiroheterocyclic group contain 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur; provided that when n is 0, the compound is not:

2. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein p is 1.

3. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein Y 1 and Y 2 and Y 3 and Y 4 each is CH or C-R 6 .

4. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein Y 1 is CH, Y 2 is C-R 6 ; Y 3 is CH, and Y 4 is CH.

5. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein Y 3 is N and Y 1 , Y 2 and Y 4 are each CH or C-R 6 .

6. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein Y 2 is N and Y 1 , Y 3 , Y 4 each is CH or C-R 6 .

7. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein Y 1 is N and Y 2 , Y 3 and Y 4 are each CH or C-R 6 .

8. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-C1-C 10 alkoxy, hydroxy-C1-C 10 alkyl, -O-(C1-C6 alkyl)-R bb , halo-C 1- C3 alkoxy, -O-R cc -O-R dd , halo-C 1- C3 alkyl, -(C1-C6 alkyl)-NR GI R HI , -S-CH3, -S(CH2)2N(CH3)2 and -NR G R H ; wherein R bb is -NR G R H , -C(O)N(CH3)2, -S(O)2CH3 or -SCH3; R G and R H each independently is hydrogen, optionally deuterated C1-C3 alkyl or -C(O)R Ga ; wherein R Ga is C1-C3 alkyl; R GI and R HI each independently is hydrogen or a C1-C3 alkyl group; R cc is a C1-C3 alkylene group; R dd is a C1-C3 alkyl group; and wherein the hydroxy-C 1- C 10 alkyl moiety in the alkoxy group is optionally substituted with hydroxy, halogen or C1-C3 alkoxy.

9. The compound according to claim 8 or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: methoxy, ethoxy, methyl, fluorine, chlorine, 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, -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(CH2OCH3)OH, -OCH2CH(CH2F)OH, -(CH2)3N(CH3)2, -(CH2)3N(CH3)H, -O(CH2)2S(O)2CH3, -O(CH2)2SCH3, -(CH2)2C(CH3)2OH, -OCH2CH2N(CD3)2 and -CH2CH2OH.

10. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: -O-(C1-C6 alkyl)-R bb , -O-R bb , -O-R cc -O-R dd , 5- to 7-membered monocyclic heteroaryl and C3-C6 cycloalkyl; wherein R cc is a C1-C3 alkylene group and R dd is a 6-membered heteroaryl group; R bb is a 4- to 7-membered monocyclic or bridged heterocyclic group, a 5- or 6-membered monocyclic heteroaryl group or a C3-C7 cycloalkyl group; and wherein R 6 , R bb or R dd of the cycloalkyl, heteroaryl or heterocyclic group is optionally substituted with one or two substituents each independently selected from the group consisting of: hydroxy, halogen, C1-C3 alkoxy, oxo, halo-C1-C3 alkyl and C1-C3 alkyl, wherein the heterocyclic group and heteroaryl contain 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

11. The compound according to claim 10 or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: cyclopropyl, -O-R bb , -O-(CH2)-R bb , -O-(CH2)2-R bb , -O-(CH2)2-O-pyridazinyl and an optionally present imidazolyl substituted with a C1-C3 alkyl group; wherein R bb selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranyl, 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, -CF3, -CH2CF3, -CH2CHF2, -CH2CH2F, methoxy, ethyl or methyl.

12. The compound according to claim 11 or a pharmaceutically acceptable salt thereof, wherein R 6 is in each case selected from the group consisting of: wherein indicates the connection point with ring B.

13. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups, together with the atoms to which they are attached, form a 5- or 6-membered monocyclic heterocyclic group fused to ring B, a C4-C7 cycloalkyl group fused to ring B, a phenyl group fused to ring B, or a 5- or 6-membered monocyclic heteroaryl group fused to ring B, each optionally substituted with one or two substituents each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C1-C3-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclic groups, wherein the heterocyclic groups and heteroaryl groups contain 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

14. The compound according to claim 13 or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups together with the atoms to which they are attached form a pyrazolyl, dioxanyl, pyridyl, pyrimidinyl, thiazolyl, furyl, dioxolanyl or phenyl ring fused to ring B, wherein the ring is optionally substituted with a substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH and methyl.

15. The compound according to claim 14 or a pharmaceutically acceptable salt thereof, wherein the two R 6 groups together with the atoms to which they are attached form a ring selected from the group consisting of: fused to ring B wherein the pair represents the connection of the ring to ring B.

16. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein f is 1.

17. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein f is 0 and ring B is wherein n is 0 or 1; and Y 2 and Y 3 each independently selected from the group consisting of: CH, N, NH, NR 6 , S, O and CR 6 , provided that Y 2 and Y 3 only one of which may be N, NH, NR 6 , S or O.

18. The compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 2, wherein n is 1.

19. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 3 is selected from the group consisting of hydrogen, methyl, -CD3, ethyl, phenyl, -CH2CF3 and -CH2CH2OH.

20. The compound according to claim 19 or a pharmaceutically acceptable salt thereof, wherein R 3 is methyl.

21. The compound according to claim 1 or a pharmaceutically acceptable salt thereof, wherein R 4 is 22. The compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein R 4c is selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2OC(CH3)3, and -CH2CH2SCH3; and R 4d is selected from the group consisting of hydrogen and methyl; or R 4c and R 4d together with the atoms to which they are respectively attached form a cyclopropyl ring.

23. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein R 4c and R 4d are each hydrogen.

24. A compound according to any one of claims 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4b is hydrogen.

25. A compound according to any one of claims 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4a is C1-C6 alkyl.

26. The compound according to claim 22 or a pharmaceutically acceptable salt thereof, wherein R 4a is methyl, ethyl, isopropyl, tert-butyl or 3-methylpentan-3-yl.

27. A compound according to any one of claims 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4a is phenyl optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclic groups, wherein said heterocyclic groups contain 1 to 5 heteroatoms independently selected from nitrogen, oxygen, and sulfur.

28. The compound according to claim 27 or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

29. A compound according to any one of claims 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4a is: 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, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl and 5- to 10-membered monocyclic, fused bicyclic or spiroheterocyclic group; A C3-C7 cycloalkyl optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group; A 4- to 10-membered monocyclic or fused bicyclic heterocyclic group optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl and 5- to 10-membered monocyclic or fused bicyclic heterocyclic group; (C6-C 10 monocyclic or fused bicyclic aryl)-C1-C3 alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C1-C3 alkyl, which is optionally substituted with one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclic group, or hydroxy-C1-C6 alkyl, halo-C1-C3 alkyl, C1-C3 alkoxy-C1-C6 alkyl and -C1-C6 alkyl-NR J1 R J2 , wherein R J1 and R J2 are each independently hydrogen or C1-C3 alkyl, wherein the heterocyclic group, heteroaryl and spiroheterocyclic group contain 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

30. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

31. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

32. The compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

33. A compound according to claim 29 or a pharmaceutically acceptable salt thereof, wherein R 4a is selected from the group consisting of:

34. The compound according to claim 29 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, and -CH2CF3.

35. A compound according to any one of claims 21 to 23 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are attached form a 5- to 10-membered monocyclic, fused bicyclic or bridged bicyclic heterocyclic group, said group being optionally substituted by one or two substituents each independently selected from the group consisting of halogen, C1-C6 alkyl, halo-C1-C3 alkyl, hydroxy and C1-C3 alkoxy, wherein the heterocyclic group contains 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

36. The compound according to claim 35 or a pharmaceutically acceptable salt thereof, wherein R 4a and R 4b together with the atoms to which they are respectively attached form 37. A compound according to claim 21 or a pharmaceutically acceptable salt thereof, wherein R 4b and R 4c together with the atoms to which they are attached form a 5- to 7-membered monocyclic heterocyclic group optionally substituted with one or two substituents each independently selected from C1-C3 alkyl, wherein the heterocyclic group contains 1 to 5 heteroatoms independently selected from nitrogen, oxygen and sulfur.

38. A compound according to any one of claims 1 to 2 or a pharmaceutically acceptable salt thereof, wherein R 4 is wherein R 4g is selected from the group consisting of C6-C 10 monocyclic or fused bicyclic aryl and C1-C3 alkyl.

39. The compound according to claim 38 or a pharmaceutically acceptable salt thereof, wherein R 4g is selected from the group consisting of phenyl and methyl.

40. The compound or a pharmaceutically acceptable salt thereof according to claim 1, wherein the compound is selected from the group consisting of the following compounds:

41. A pharmaceutical composition comprising the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40, and a pharmaceutically acceptable excipient.

42. Use of the compound or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 40 in the preparation of a pharmaceutical composition for inhibiting transferrin-mediated iron transport in a subject.

43. A compound having the following formula:

44. A compound having the following formula: or a pharmaceutically acceptable salt thereof.

45. A pharmaceutical composition comprising the compound of claim 43 or the compound of claim 44 or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

46. Use of a compound according to claim 43 or a compound according to claim 44 or a pharmaceutically acceptable salt thereof in the preparation of a pharmaceutical composition for inhibiting transferrin-mediated iron transport in a subject.

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