OA21052A

OA21052A - Cycloalkyl pyrimidines as ferroportin inhibitors.

Info

Publication number: OA21052A
Application number: OA1202200442
Authority: OA
Inventors: Zhe Li; Qing Xu; Carsten ALT; Shahul Nilar; Peter Michael RADEMACHER; Calvin Wesley Yee
Original assignee: Global Blood Therapeutics, Inc.
Priority date: 2020-04-28
Filing date: 2021-04-28
Publication date: 2023-10-09

Abstract

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

Description

CYCLOALKYL PYRIMIDINES AS FERROPORTIN INHIBITORS

CROSS REFERENCE TO RELATED APPLICATIONS

[0001] This application claims the benefît of and priority to U.S. Provisional Application No.

S 63/016,891, filed on April 28, 2020, and U.S. Provisional Application No. 63/127,774, filed on December 18, 2020, the contents of each of which are hereby incorporated by reference in their entirety.

FIELD

[0002] The subject matter described herein is directed to ferroportin inhibitor compounds, methods 10 of making the compounds, their pharmaceutical compositions, and their use in the prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overioad States, such as thaiassemia, sickle cell disease and hemochromatosis, and also kidney injuries.

BACKGROUND

[0003] In nearly ail organisms, iron is an essential trace element. In humans, iron is a critical component for oxygen transport, oxygen uptake, cell fonctions such as mitochondrial électron transport, cognitive functions, and energy metabolism. Iron is présent in enzymes, hemoglobin and myoglobin, as well as in depots in the form of ferritin and hemosiderin. With respect to hemoglobin, approximately halfof ail iron is présent as heme iron, bound in the hemoglobin ofthe érythrocytes. The human body contains on average approximately 4 to 5 g iron. The iron requirement of a human adult is between 0.5 to 1.5 mg per day, whereas infants and women during pregnancy require 2 to 5 mg of iron per day. [0004] In a healthy human adult, the normal daily loss of iron of about I mg is usually replaced via food intake. Iron balance is primarily regulated by recycling and iron recovery from hemoglobin of aging érythrocytes and the duodenal absorption of dietary iron in the form of divalent as well as trivalent 25 iron ions.

[0005] Absorption is regulated by the organism depending on the iron requirement and the size of the iron depot. Usually, Fe(lII) compounds are dissolved in the stomach at a sufficiently acidic pFI value and thus made available for absorption. The absorption of the iron is carried out in the upper small intestine by mucosal cells. Trivalent non-heme iron is first reduced in the intestinal cell membrane to

Fe(ll) for absorption, for example by ferrie reductase (membrane-bound duodenal cytochrome b), so that

it can then be transported into the intestinal cells by means ofthe transport protein DMTl (divalent métal transporter l). In contrast, heme iron enters the enterocytes through the cell membrane without any change. In the enterocytes, iron is either stored in ferritin as depot iron, or released into the blood by the transport protein ferroportin. The divalent iron transported into the blood by ferroportin is converted 5 into trivalent iron by oxidases (ceruloplasmin, hephaestin). The trivalent iron is then transported to its destination in the organism by transferrin. (“Balancing acts: molecular control of mammalian iron metabolism, M.W. Hentze, Cell, l :17, 2004, 285-297). Hepcidin plays a central rôle in this process because it is the essential regulating factor of iron absorption. The hepcidin-ferroportin System directly régulâtes iron metabolism.

[0006] Iron uptake and storage is regulated by hepcidin. Hepcidin Antimicrobial Peptide (HAMP;

also known as LEAP-1 ; further referred to as Hepcidin) is a 25 amino acid peptide (Krause et al., FEBS Lett. 480, 147-150, 2000). Hepcidin has a hairpin structure with 8 cysteines that form 4 disulfide bridges (Jordan et al., J Biol Chem. 284, 24155-24167, 2009). The N-terminus appears to be important for the iron-regulatory fonction since délétion of the First 5 amino acids resulted in complété loss of bioactivity (Nemeth et al., Blood, 107,328-333, 2006). Hepcidin is produced in the liver and fonctions as the master iron regulatory hormone controlling intestinal iron uptake, and also régulâtes iron storage in other organs (Ganz, Hematol. Am.

Soc. Hematol. Educ. Program, 29-35, 507 2006; Hunier et al., J. Biol. Chem. 277, 37597-37603, 2002; Park et al., J. Biol. Chem. 276, 7806-7810, 2001). Hepcidin limits iron-uptake by binding to 20 the iron transport molécule ferroportin and causing its dégradation (Sebastiani et al., Front.

Pharmacol. 7, 160, 2016).

[0007] The formation of hepcidin is regulated în direct corrélation to the organism’s iron level, Le., if the organism is supplied with sufficient iron and oxygen, more hepcidin is formed; if iron and oxygen levels are low, or in case of increased erythropoiesis, less hepcidin is formed. In the small intestinal 25 mucosal cells and in the macrophages hepcidin binds with the transport protein ferroportin, which conventionally transports the phagocytotically recycled iron from the interior of the cell into the blood. [0008] Ferroportin is an iron transporter that plays a key rôle in regulating iron uptake and distribution in the body and thus in controlling iron levels in the blood. The transport protein ferroportin is a transmembrane protein consisting of 571 amino acids which is formed in the liver, spleen, kidneys, 30 heart, intestine and placenta. In particular, ferroportin is localized in the basolateral membrane of intestinal épithélial cells. Ferroportin bound in this way thus acts to export the iron into the blood. In this

case, it is most probable that ferroportin transports iron as Fe²⁺. If hepcidin binds to ferroportin, ferroportin is transported into the interior of the cell, where its breakdown takes place so that the release ofthe phagocytotically recycled iron from the cells is then almost completely blocked. Ifthe ferroportin is inactivated, for example by hepcidin, so that it is unable to export the iron which is stored in the mucosal cells, the stored iron is lost with the naturel shedding of cells via the stools. The absorption of iron in the intestine is therefore reduced, when ferroportin is inactivated or inhibited, for example by hepcidin.

[0009] A decrease of hepcidin results in an increase of active ferroportin, thus allowing an enhanced release of stored iron and an enhanced iron uptake, e.g., from the food, resulting in an increase in sérum iron levels, i.e., iron overload. Iron overload causes many diseases and undesired medical conditions. Iron overload can be treated by removal of the iron from the body. This treatment includes regularly scheduled phlébotomies (bloodletting). For patients unable to tolerate routine blood draws, there are chelating agents available for use. A disadvantage in the treatment of iron overload by chélation therapy is the removal ofthe chelated iron from the body when the iron overload has already occurred instead of preventing the occurrence ofthe disorder.

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

BRIEF SUMMARY

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

[0012] In certain embodiments, the subject matter described herein is directed to a pharmaceutical composition comprisîng a compound of Formula I or Formula I’ or a pharmaceutically acceptable sait 25 thereof.

[0013] In certain embodiments, the subject matter described herein is directed to methods of inhibiting iron transport mediated by ferroportin in a subject, comprisîng administering to the subject an effective amount of a compound of Formula I or Formula Γ, a pharmaceutically acceptable sait thereof, or a pharmaceutical composition comprisîng a compound of Formula I or Formula Γ.

[0014] In certain embodiments, the subject matter described herein is directed to methods of

preparing compounds of Formula I or Formula Γ.

[0015] Other embodiments are also described.

DETAILED DESCRIPTION

[0016] Described herein are ferroportin inhibitor compounds of Formula I and Formula F, methods of making the compounds, pharmaceutical compositions comprising the compounds and their use in the prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload States, such as thalassemia, sickle cell disease and hemochroinatosis. Ferroportin is the iron transport protein responsible for the uptake of the released iron via the intestine and its transfer into the blood circulation, where ultimately the iron is delivered to the appropriate tissues and organs. Inactivation or inhibition of the ferroportin reduces or prevents the export of the iron, thereby reducing the absorption of iron in the intestine and ultimately the amount of iron in the body. These compounds, compositions and methods can be used for an effective therapy for the prophylaxis and treatment of iron metabolism disorders which are associated with increased iron levels. It is désirable to provide compounds, compositions and methods that exhibit few side effects, hâve very low toxicity and good bioavailability and compatibility.

[0017] Iron overload has been associated with a variety of diseases (Blanchette étal., Expert Rev. Hematol. 9, 169-186, 2016). Hereditary hemochroinatosis is the most common inherited disease in Europe and is caused by lack of, or insensitivity to, hepcidin (Powell et al., The Lancet

388, 706-716, 2016). The clinical manifestation of hemochromatosis are hepatic cirrhosis, diabètes, and skin pigmentation (Powell et al., The Lancet 388, 706-716, 2016). While this disease can be managed by phlebotomy, this approach may be cumbersome and does not treat the cause of the disease.

[0018] Iron-loading anémias such as beta-thalassemia are also associated with reduced hepcidin 25 levels (Origa et al., Haematoiogica 92, 583-588, 2007). Treatment of this disease with hepcidin mimetics may not only address the iron overload, but has also been shown to improve the ineffective erythropoiesis that occurs in this disease (Casu et al., Blood 128, 265-276, 2016). This may be of major beneflt for thalassemia patients who may be less dépendent on blood transfusions, which can contribute to the iron overload in these patients.

[0019] Myelofibrosis, myelodysplastic syndrome, and sickle cell disease are diseases that are

also characterized by ineffective erythropoiesis and that may require frequent blood transfusions (Carreau et al., Blood Rev. 30, 349-356, 2016; Temraz et al., Crit. Rev. Oncol. Hematol. 91,64-73, 2014; Walter étal., Acta Haematol. 122, 174-183, 2009). Reduced hepcidin levels hâve 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 bénéficiai in these patients.

[0020] Polycythemia vera is a disease characterized by increased erythropoiesis. It has been shown in animal models that high doses of hepcidin mimetics can ameliorate this disease by diminishing erythropoiesis (Casu et al., Blood 128, 265-276, 2016).

[0021] Réduction of iron uptake and thereby sérum iron levels may even be bénéficiai in diseases where iron load is normal, such as kidney diseases (Walker and Agarwal, NephroL 36, 6270, 2016), infections with iron-dependent bacteria (Arezes et al., Cell Host Microbe 17, 47-57, 2015), and polymicrobial sepsis (Zeng et al., Anesthesiology, 122, 374-386, 2015).

[0022] Hepcidin itself is limited in its use as a drug because of its complex structure which requires acomplicated manufacturang, and also its limited in vivo duration of action. Continuous 15 efforts hâve been made to search for hepcidin mimetics and Chemical compounds that could be used to increase hepcidin levels.

[0023] A common approach relates to small hepcidin-derived or hepcidin-like peptides, which can be produced affordably, and can be used to treat hepcidin-related diseases and disorders such as those described herein. Such so-called mini-hepcidins are rationally designed small peptides that 20 mimic hepcidin activity and may be useful for the treatment of iron overload, and also iron overload related disease symptoms.

[0024] Such mini-hepcidin peptides are described for example in WO 2010/065815 A2 and WO 2013/086143 Al. WO 2015/157283 Al and the corresponding US 9,315,545 B2 describe hepcidin mimetic peptides and the use thereof in hepcidin-related disorders, such as iron overload, beta25 thalassemia, hemochromatosis etc. and cover a development compound MO 12 ofthe company Merganser Biotech, having been under évaluation in a Phase 1 clinical program as a potentially transformative therapy for a number of hematoiogical diseases including beta-thalassemia, low risk myelodysplasia and polycythemia vera.

[0025] WO 2014/145561 A2 and WO 2015/200916 A2 describe further small hepcidin peptide 30 analogues and the use thereof in the treatment or prévention of a variety of hepcidin-related diseases, including iron overload diseases and iron-loading anémias, and further related disorders.

Further, WO2015/042515 Al relates to hepcidin and its peptide fragments, which are particularly intended for treating rénal ischemia reperfusion injury or acute kidney injury. Further, minihepcidin analogs are described for example by Preza et ai, S. Clin. Invest., I2l (12), 4880-4888, 2011 or in CN 104 Oi l 066 and in WO 2016/109363 Al.

[0026] Ferroportin inhibitors as well as compounds that hâve hepcidin-like activity are needed that also possess additional bénéficiai properties such as improved solubility, stability, and/or potency. An advantage of the ferroportin inhibitor compounds of Formula I described herein is their préparation in sufficient yields by the synthetic routes disclosed herein.

[0027] The presently disclosed subject matter will now be described more fully hereinafter.

However, many modifications and other embodiments of the presently disclosed subject matter set forth herein will corne to mind to one skilled in the art to which the presently disclosed subject matter pertains having the benefit of the teachings presented in the foregoing descriptions. Therefore, it is to be understood that the presently disclosed subject matter is not to be limited to the spécifie embodiments disclosed and tbat 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 ail alternatives, modifications, and équivalents. Unless otherwise defined, ail technical and scientific tenus used herein hâve the same meaning as commonly understood by one of ordinary skill in this field. Ail publications, patent applications, patents, and other references mentioned herein are incorporated by reference in their entirety. In the event that one or more of the incorporated literature, patents, and similar materials differs from or contradicts this application, includîng but not limited to defined terms, term usage, described techniques, or the iike, this application Controls.

I . Définitions

[0028] As used in the présent spécification, the following words, phrases and symbols are generally 25 intended to hâve the meanings as set forth below, except to the extent that the context in which they are used indicates otherwise.

[0029] A dash that is not between two letters or symbols is used to indicate a point of attachment for a substituent. For example, -C(O)NFh is attached through the carbon atom. A dash at the front or end of a Chemical group is a matter of convenience; Chemical groups may be depîcted with or without one or more dashes without losing their ordinary meaning. A wavy line or a dashed line drawn through or perpendicular across the end of a line in a structure indicates a specîfied point of attachment of a group. Unless chemically or structurally required, no directionality or stereochemistry is indicated or implîed by the order in which a Chemical group is written or named.

[0030] The prefix “C_u-C_v” indicates that the following group has from u to v carbon atoms. For example, “Ci-Ce alkyl” indicates that the alkyl group has from l to 6 carbon atoms.

[0031 ] Reference to “about” a value or parameter herein includes (and describes) embodiments that are directed to that value or parameter per se. In certain embodiments, the term “about” includes the indicated amount ± 50%. In certain other embodiments, the term “about” includes the indicated amount ± 20%. In certain other embodiments, the term “about” includes the indicated amount ± 10%. In other embodiments, the term “about” includes the indicated amount ± 5%. In certain other embodiments, the 10 term “about” includes the indicated amount ±1%. In certain other embodiments, the term “about” includes the indicated amount ±0.5% and in certain other embodiments, 0.1%. Such variations are appropriate to perform the disclosed methods or employ the disclosed compositions. Also, to the term “about x” includes description of “x”. Also, the singular forms “a” and “the” include plural référencés unless the context clearly dictâtes otherwise. Thus, e.g., reference to “the compound” includes a plurality 15 of such compounds and reference to “the assay” includes reference to one or more assays and équivalents thereof known to those ski lied in the art.

[0032] “Alkyl” refers to an unbranched or branched saturated hydrocarbon chain. As used herein, alkyl has 1 to 20 carbon atoms (i.e., C1-C20 alkyl), 1 to 12 carbon atoms (i.e., C1-C12 alkyl), 1 to 8 carbon atoms (i.e., Ci-Cs alkyl), 1 to 6 carbon atoms (i.e., Ci-Cê alkyl), 1 to 4 carbon atoms (i.e., C1-C4 alkyl), 20 or 1 to 3 carbon atoms (i.e., C1-C3 alkyl). Examples of alkyl groups include, e.g., methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl and 3-methylpentyl. When an alkyl residue having a spécifie number of carbons is named by Chemical name or identified by molecular formula, ail positional isomers having that number of carbons may be encompassed; thus, for example, “butyl” includes n-butyl (i.e., -(CH₂)3CH₃), sec-butyl (i.e., 25 CH(CH₃)CH₂CH₃), isobutyl (i.e., -CHzCHiCHj)?) and tert-butyl (i.e., -C(CH₃)3); and “propyl” includes n-propyl (i.e., -(CHzhCFb) and isopropyl (i.e., -CHfofhû).

[0033] Certain commonly used alternative Chemical names may be used. For example, a divalent group such as a divalent “alkyl” group, a divalent “aryl” group, etc., may also be referred to as an “alkylene” group or an “alkylenyl” group, an “arylene” group or an “arylenyl” group, respectively. 30 Also, unless indicated explicitly otherwise, where combinations of groups are referred to herein as one moiety, e.g., aryialkyl or aralkyl, the last mentioned group contains the atom by which the moiety is

attached to the rest of the molécule.

[0034] “Alkenyl” refers to an alkyl group containing at least one carbon-carbon double bond and having from 2 to 20 carbon atoms (Le., C2-C20 alkenyl), 2 to 8 carbon atoms (Le., Cz-Cs alkenyl), 2 to 6 carbon atoms (Le., C₂-Cé alkenyl) or 2 to 4 carbon atoms (Le., C2-C4 alkenyl). Examples of alkenyl groups include, e.g., ethenyl, propenyl, butadienyl (including l,2-butadienyl and 1,3-butadienyl). [0035] “Alkynyl” refers to an alkyl group containing at least one carbon-carbon triple bond and having from 2 to 20 carbon atoms (Le., C2-C20 alkynyl), 2 to 8 carbon atoms (Le., Cz-Cs alkynyl), 2 to 6 carbon atoms (Le., C2-C6 alkynyl) or 2 to 4 carbon atoms (Le., C2-C4 alkynyl). The tenu “alkynyl” also includes those groups having one triple bond and one double bond.

[0036] The term “aikylene” by itself or as part of another substituent means a divalent radical derived from an alkane, such as, methylene —CH?—, ethylene —CH2CH2—, and the like. As an example, a “hydroxy-methylene” refers to HO—-CH2—*, where * is the attachment point to the molécule.

[0037] “Alkoxy” refers to the group “alkyl-O-” (e.g., C1-C3 alkoxy or Ci-Ce alkoxy). Examples of alkoxy groups include, e.g., methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, tert-butoxy, secbutoxy, n-pentoxy, n-hexoxy and 1,2-dimethylbutoxy.

[0038] “Alkoxy-alkyl” refers to the group “-alkyl-alkoxy” The term “C1-C3 alkoxy-Ci-Cj alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to three carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to three carbons. The term, “Ci-Cs alkoxy-Ci-Cs alkyl” refers to a one to three carbon alkyl chain where one hydrogen on any carbon is replaced by an alkoxy group having one to six carbons, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an alkoxy group having one to six carbons. Non-limiting examples of alkoxy-alkyl are -CH2OCH3, CH₂OC(CH3)3, and -C(CH₃)2CH2OCH₃.

[0039] “Alkylthio” refers to the group “alkyl-S-”. “Alkylthioalkyl” refers to the group -alkyl-Salkyl, such as -Ci-Cs-alkyl-S-Ci-Cj alkyl. A non-limiting example of alkylthioalkyl is -CH2CH2SCH3. “Alkylsulfinyl” refers to the group “alkyl-S(O)-”. “Alkylsulfonyl” refers to the group “aIkyl-S(O)₂-”. “Alkylsulfonylalkyl” refers to -alkyl-S(O)2-alkyî.

[0040] “Acyl” refers to a group -C(O)R^y, wherein R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of acyl include, e.g., formyl, acetyl, cyclohexylcarbonyl, cyclohexylmethyl21052

carbonyl and benzoyl.

[004i ] “Amido” refers to both a “C-amido” group which refers to the group -C(O)NR^yR^z and an “Namido” group which refers to the group -NR^yC(O)R^z, wherein R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein, or R^y and R^z are taken together to form a cycloalkyl or heterocyclyl; each of which may be optionally substituted, as defined herein.

[0042] “Amino” refers to the group -NR^yR^z wherein R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0043] “Amidino” refers to -C(NR^y)(NR^z2), wherein R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0044] “Aryl” refers to an aromatic carbocyclic group having a single ring (e.g., monocyclic) or multiple rings (e.g, bicyclic or tricyclic) including fused Systems. As used herein, aryl has 6 to 20 ring carbon atoms (i.e., C6-C20 aryl), 6 to 12 carbon ring atoms (i.e., Cé-Ci2 aryl), or 6 to 10 carbon ring atoms (le., Cs-Cio aryl). Examples of aryl groups include, e.g., phenyl, naphthyl, fluorenyl and anthryl. Aryl, however, does not encompass or overlap in any way with heteroaryl defined below. If one or more aryl groups are fused with a heteroaryl, the resulting ring system is heteroaryl regardless ofthe point of attachment. If one or more aryl groups are fused with a heterocyclyl, the resulting ring system is heterocyclyl regardless of the point of attachment.

[0045] “Arylalkyl” or “Aralkyl” refers to the group “aryl-alkyl-”, such as (Cô-Cio aryl)-Ci-Cs alkyl. As used herein, “(Cô-Cio aryl)-Ci-Cj alkyl” refers to a one to three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by an aryl group having six to ten carbon atoms, in particular, one hydrogen on one carbon of the alkyl chain is replaced by an aryl group having six to ten carbon atoms. A non-limiting example of arylalkyl is benzyl.

[0046] “Carbamoyl” refers to both an “O-carbamoyl” group which refers to the group -OC(O)NR^yR^z and an “N-carbamoyl” group which refers to the group -NR^yC(O)OR^z, wherein R^y and R^zare independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

3Û [0047] “Carboxyl ester” or “ester” refer to both -OC(O)R^X and -C(O)OR\ wherein R* is alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be

ΙΟ optionally substituted, as defined herein.

[0048] “Cycloalkyl” refers to a saturated or partially unsaturated cyclic alkyl group having a single ring or multiple rings including fused, bridged and spiro ring Systems. The term “cycloalkyl” includes cycloalkenyl groups (i.e., the cyclic group having at least one double bond) and carbocyclic fused ring systems having at least one sp³ carbon atom (i.e., at least one non-aromatic ring). As used herein, cycloalkyl has from 3 to 20 ring carbon atoms (i.e., C3-C20 cycloalkyl), 3 to 12 ring carbon atoms (i.e., C3-C12 cycloalkyl), 3 to IO ring carbon atoms (i.e., C3-C10 cycloalkyl), 3 to 8 ring carbon atoms (i.e., C3Cs cycloalkyl), 3 to 7 ring carbon atoms (i.e., C3-C7 cycloalkyl), or 3 to 6 ring carbon atoms (i.e., C3-C₆cycloalkyl). Monocyclic groups include, for example, cyclopropyl, cyclobutyi, cyclopentyl, cyclohexyl, 10 cycloheptyl and cyclooctyl. Polycyclic groups include, for example, bridged and/or fused rings, such as bicyclo[2.2.1]heptanyl, bicyclo[2.2.2]octanyl, bicyclo[l.l.l]pentan-l-yl, adamantyl, norbornyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl and the like. Further, the term cycloalkyl is intended to encompass any ring or ring system comprising a non-aromatic alkyl ring which may be fused to an aryl ring, regardless ofthe attachment to the remainder of the molécule. Further, cycloalkyl also includes 15 “spirocycloalkyl” when there are two positions for substitution on the same carbon atom, for example spiro[2.5]octanyl, spiro[4.5]decanyl, or spiro[5.5]undecanyl.

[0049] “Cycloalkylalkyl” refers to the group “cycloalkyl-alkyl-”, such as (C3-C6 cycloalkyl)-Ci-C3 alkyl. As used herein, “(C3-C6 cycloalkyl)-Ci-C3 alkyl” refers to a one to three carbon alkyl chain where one of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to six carbon 20 atoms, in particular, one hydrogen on one carbon of the chain is replaced by a cycloalkyl group having three to six carbon atoms.

[0050] “Cycloalkyl-alkoxy” refers to the group “-alkoxy-cycloalkyl” (e.g., C3-C7 cycloalkyl-Ci-Cô alkoxy- or C3-C7 cycloalkyl-Ci-Ca alkoxy-), such as -OCHz-cycIopropyl. As used herein, “C3-C7 cycloalkyl-Ci-Cs alkoxy” refers to an alkoxy group having a one to six carbon alkyl chain, wherein one 25 of the hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to seven carbon atoms, in particular, one hydrogen on one carbon ofthe chain is replaced by a cycloalkyl group having three to seven carbon atoms. As used herein, “C3-C7 cycloalkyl-Ci-C3 alkoxy” refers to an alkoxy group having a one to three carbon alkyl chain, wherein one ofthe hydrogen atoms on any carbon is replaced by a cycloalkyl group having three to seven carbon atoms, in particular, one hydrogen on one carbon of 30 the chain is replaced by a cycloalkyl group having three to seven carbon atoms.

[0051] “Guanidino” refers to -NR^yC(=NR^z)(NR^yR^z), wherein each R^y and R^z are independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0052] “Hydrazino” refers to -NHNHi[0053] “Imino” refers to a group -C(NR^y)R^z, wherein R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0054] “Imido” refers to a group -C(O)NR^yC(O)R^z, wherein R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0055] “Halogen” or “halo” refers to atoms occupying group VIIA ofthe periodic table, such as fluoro (fluorine), chloro (chlorine), bromo (bromine) or iodo (iodine).

[0056] “Haloalkyl” refers to an unbranched or branched alkyl group as defined above, wherein one or more (e.g., I to 6, or l to 3) hydrogen atoms are replaced by a halogen. For example, halo-Ci-C₃ alkyl refers to an alkyl group of I to 3 carbons wherein at least one hydrogen atom is replaced by a halogen. Where a residue is substituted with more than one halogen, it may be referred to by using a prefix corresponding to the number of halogen moieties attached. Dihaloalkyl and trihaloalkyl refer to alkyl substituted with two (“di”) or three (“tri”) halo groups, which may be, but are not necessarily, the same halogen. Examples of haloalkyl include, e.g., trifluoromethyl, difluoromethyl, fluoromethyl, trichloromethyl, 2,2,2-trifluoroethyl, l,2-difluoroethyl, 3-bromo-2-fluoropropyl, l,2-dibromoethyl and the like.

[0057] “Haloalkoxy” refers to an alkoxy group as defined above, wherein one or more (e.g., I to 6, or l to 3) hydrogen atoms are replaced by a halogen. Non-limiting examples of haloalkoxy are -OCH2CF3, -OCF₂H, and -OCF₃.

[0058] “Hydroxyalkyl” refers to an alkyl group as defined above, wherein one or more (e.g., I to 6, or l to 3) hydrogen atoms are replaced by a hydroxy group (e.g., hydroxy-Ci-C₃-alkyl, hydroxy-Ci-Céalkyl). The term “hydroxy-Ci-Cj alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term “hydroxy-Ci-Cg alkyl” refers to a one to six carbon alkyl chain where one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkyl include -CH2OH, -CH2CH2OH, and -C(CH₃)₂CH₂OH.

[0059] “Hydroxyalkoxy” refers to the group “-alkoxy-hydroxy,” (e.g., hydroxy-Ci-C₃ alkoxy, hydroxy-Ci-C₆ alkoxy), The term “hydroxy-Ci-C₃ alkoxy” refers to an alkoxy group containing a one to three carbon alkyl chain wherein one or more hydrogens on any carbon is replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. The term “hydroxy-Ci-Cô alkoxy” refers to an alkoxy group containing a one to six carbon alkyl chain wherein one or more hydrogens on any carbon îs replaced by a hydroxy group, in particular, one hydrogen on one carbon of the chain is replaced by a hydroxy group. Non-limiting examples of hydroxyalkoxy include -OCH2CH2OH and -OCH₂C(CH₃)2OH.

[0060] “Heteroalkyl” refers to an alkyl group in which one or more of the carbon atoms (and any 10 associated hydrogen atoms) are each independently replaced with the same or different heteroatomic group, provided the point of attachment to the remainder of the molécule is through a carbon atom. In certain embodiments, the heteroalkyl can hâve 1 to 3 carbon atoms (e.g., C1-C3 heteroalkyl) or 1 to 6 carbon atoms (e.g., Ci-Ce heteroalkyl), and one or more (e.g., 1, 2, or 3) heteroatoms or heteroatomic groups. The term “heteroalkyl” includes unbranched or branched saturated chain having carbon and heteroatoms. By way of example, 1, 2 or 3 carbon atoms of the alkyl group in the “heteroalkyl” may be independently replaced with the same or different heteroatomic group. Heteroatomic groups include, but are not limited to, -NR^y-, -O-, -S-, -S(O)-, -S(O)₂-, and the like, wherein R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of heteroalkyl groups include, e.g., ethers (e.g, -CH2OCH3, -CH(CH₃)OCH₃, -CH₂CH₂OCH₃, -CH2CH2OCH2CH2OCH3, etc.), thioethers (e.g., -CH2SCH₃, -CH(CH₃)SCH₃, -CH₂CH2SCH₃, -CH₂CH2SCH2CH₂SCH₃, etc.), sulfones (e.g., -CH₂S(O)2CH₃, -CH(CH₃)S(O)₂CH₃, -CH2CH₂S(O)2CH₃, -CH₂CH2S(O)2CH2CH2OCH₃, etc.) and amines (e.g., -CH₂NR^yCH3, -CH(CH3)NR^yCH3, -CH₂CH2NR^yCH3, -CH2CH2NR^yCH2CH2NR^yCH₃, etc., where R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl, or heteroaryl;

each of which may be optionally substituted, as defined herein). In certain embodiments, heteroalkyl can hâve 1 to 20 carbon atoms, 1 to 15 carbon atoms, 1 to 12 carbon atoms, 1 to 10 carbon atoms, 1 to 8 carbon atoms, or 1 to 4 carbon atoms; and 1 to 3 heteroatoms, 1 to 2 heteroatoms, or 1 heteroatom.

[0061] “Heteroaryl” refers to an aromatic group having a single ring, multiple rings or multiple fused rings, with one or more ring heteroatoms independently selected from nitrogen, oxygen, and sulfur. As used herein, heteroaryl includes 1 to 20 ring carbon atoms (i.e., Cj-C₂o heteroaryl), 3 to 12 ring carbon atoms (i.e., C3-C12 heteroaryl), or 3 to 8 carbon ring atoms (i.e., C₃-Cs heteroaryl), and 1 to 5

ring heteroatoms, i to 4 ring heteroatoms, l to 3 ring heteroatoms, l to 2 ring heteroatoms, or i ring heteroatom independently selected from nitrogen, oxygen and sulfur. In certain instances, heteroaryl includes 9-10 membered ring Systems (i.e., 9-I0 membered heteroaryl), 5-l0 membered ring Systems (Le., 5-10 membered heteroaryl), 5-7 membered ring Systems (Le., 5-7 membered heteroaryl), 5-6 membered ring Systems (Le., 5-6 membered heteroaryl), or 4-6 membered ring Systems (Le., 4-6 membered heteroaryl), each independently having i to 4 ring heteroatoms, l to 3 ring heteroatoms, l to 2 ring heteroatoms, or l ring heteroatom independently selected from nitrogen, oxygen and sulfur. Examples of heteroaryl groups include, e.g., acridinyl, benzimidazolyl, benzothiazolyl, benzindolyl, benzofuranyl, benzothiazolyl, benzothiadiazolyl, benzonaphthofuranyl, benzoxazolyl, benzothienyl 10 (benzothiophenyl), benzotriazolyi, benzo[4,6]imidazo[l,2-a]pyridyl, carbazolyl, cinnolinyi, dibenzofuranyl, dibenzothiophenyl, furanyi, isothiazolyl, imidazolyl, indazolyl, indolyl, indazolyl, isoindolyl, isoquinolyl, isoxazolyl, naphthyridinyl, oxadiazotyl, oxazolyl, 1-oxidopyridinyl, 1-oxidopyrimidinyl, 1-oxidopyrazinyl, 1-oxidopyridazinyl, phenazinyl, phthalazinyl, pteridinyl, purinyl, pyrrolyl, pyrazolyl, pyridinyl, pyrazinyl, pyrimidinyl, pyridazinyl, quinazolinyl, quinoxalinyl, quinolinyl, quinuclidinyl, isoquinolinyl, thiazolyl, thiadiazolyl, triazolyl, tetrazolyl and triazinyl. Examples of the fused-heteroaryl rings include, but are not limited to, benzo[d]thiazolyl, quinolinyl, isoquinolinyl, benzo[b]thiophenyl, indazolyl, benzo[d] imidazolyl, pyrazolo[l,5-a]pyridinyl and imidazo[l,5-a]pyridinyl, where the heteroaryl can be bound via either ring ofthe fused System. Any aromatic ring or ring system, having a single or multiple fused rings, containing at least one heteroatom, 20 is considered a heteroaryl regardless of the attachment to the remainder of the molécule (i.e., through any one of the fused rings). Heteroaryl does not encompass or overlap with aryl as defined above. [0062] “Heteroarylalkyl” refers to the group “heteroaryl-alkyl-”, such as (5- to 10-membered monocyclic heteroaryl)-Ci-C3 alkyl. As used, herein, “(5- to 10-membered monocyclic heteroaryl)-CiC3 alkyl” refers to a one to three carbon alkyl chain where one or more hydrogens on any carbon is replaced by a monocyclic heteroaryl group having 5- to 10- members, in particular, one hydrogen on one carbon of the chain is replaced by a (5- to 10-membered monocyclic heteroaryl group.

[0063] “Heterocyclyl” refers to a saturated or partially unsaturated cyclic alkyl group, with one or more ring heteroatoms independently selected from nitrogen, oxygen and sulfur. The term “heterocyclyl” includes heterocycloalkenyl groups (i.e., the heterocyclyl group having at least one double bond), bridged-heterocyclyl groups, fused-heterocyclyl groups and spiro-heterocyclyl groups. A heterocyclyl may be a single ring or multiple rings wherein the multiple rings may be fused, bridged or

spiro. Any non-aromatic ring containing at least one heteroatom is considered a heterocyclyl, regardless ofthe attachment (i.e., can be bound through a carbon atom or a heteroatom). Further, the term heterocyclyl is intended to encompass a ring or ring System comprising any non-aromatic ring containing at least one heteroatom, which ring may be fused to an aryl or heteroaryl ring, regardless of the attachment to the remaînder of the molécule. The tenn heterocyclyl is also intended to encompass a ring System comprising a cycloalkyl ring which is fused to a heteroaryl ring, regardless of the attachment to the remaînder ofthe molécule. Additionally, the term heterocyclyl is intended to encompass a ring System comprising a cycloalkyl ring which is fused to a heterocyclyl ring, regardless of the attachment to the remaînder of the molécule. As used herein, heterocyclyl has 2 to 20 ring carbon atoms (Le., C2-C20 heterocyclyl), 2 to 12 ring carbon atoms (Le., C2-C12 heterocyclyl), 2 to 10 ring carbon atoms (i.e., C2-C10 heterocyclyl), 2 to 8 ring carbon atoms (Le., C:-Cs heterocyclyl), 3 to 12 ring carbon atoms (i.e., C3-C12 heterocyclyl), 3 to 8 ring carbon atoms (Le., Cj-Cs heterocyclyl), or 3 to 6 ring carbon atoms (i.e., C3-C6 heterocyclyl); having 1 to 5 ring heteroatoms, 1 to 4 ring heteroatoms, 1 to 3 ring heteroatoms, 1 to 2 ring heteroatoms, or 1 ring heteroatom independently selected from nitrogen, sulfur or oxygen.

When the heterocyclyl ring contains 4- to 6- ring atoms, it is also referred to herein as a 4- to 6membered heterocyclyl. Also disclosed herein are 5- or 6-membered heterocyclyls, having 5 or 6 ring atoms, respectively, and 5- to 10-membered heterocyclyls, having 5 to 10 ring atoms. Examples of heterocyclyl groups include, e.g., azetidinyl, azepinyi, benzodioxolyl, benzo[b][l,4]dioxepinyl, 1,4benzodioxanyl, benzopyranyl, benzodioxînyl, benzopyranonyl, benzofuranonyl, dioxolanyl, dihydropyranyl, hydropyranyl, thieny 1[ 1,3]dithianyl, decahydroisoquinolyl, furanonyl, imidazolinyl, imidazolidinyl, indolinyl, indolîzinyl, isoindolînyl, îsothiazolidinyl, isoxazolidinyl, morpholinyl, octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl, 2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, oxiranyl, oxetanyl, phenothiazinyl, phenoxazinyl, piperidinyl, piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl, thiazolidiny 1, tetrahydrofuryl, tetrahydropyranyl, trithianyl, tetrahydroquinolinyl, thîophenyl (Le., thienyl), tetrahydropyranyl, thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholînyl and 1,1 -dioxo-thiomorpholinyl. In certain embodiments, the term “heterocyclyl” can include “spiroheterocyclyl” when there are two positions for substitution on the same carbon atom. Examples ofthe spiro-heterocyclyl rings include, e.g., bîcyclic and tricyclic ring Systems, such as 2-oxa7-azaspiro[3.5]nonanyl, 2-oxa-6-azaspiro[3.4]octanyl and 6-oxa-l-azaspiro[3.3]heptanyl. Examples of the fused-heterocyclyl rings include, but are not limited to, 1,2,3,4-tetrahydroisoquînolinyl, 4,5,6,7tetrahydrothieno[2,3-c]pyridinyl, indolinyl and isoindolînyl, where the heterocyclyl can be bound via

either ring of the fused system.

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

[0065] “Oxime” refers to the group -CR^y(=NOH) wherein R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as 5 defined herein.

[0066] “Oxo” refers to the group (=0).

[0067] “Sulfonyl” refers to the group -S(O)2R^y, where R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfonyl are methylsulfonyl, ethylsulfonyl, phenylsulfonyl and toluenesulfonyl.

[0068] “Sulfinyl” refers to the group -S(O)R\ where R^y is hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein. Examples of sulfinyl are methylsulfinyl, ethylsulfinyl, phenylsulflnyl and toluenesulfinyl.

[0069] “Sulfonamido” refers to the groups -SO₂NR^yR^z and -NR^ySO₂R^z, where R^y and R^z are each independently hydrogen, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroalkyl or heteroaryl; each of which may be optionally substituted, as defined herein.

[0070] The terms “optional” or “optionally” means that the subsequently described event or circumstance may or may not occur and that the description includes instances where said event or circumstance occurs and instances in which it does not. Also, the tenu “optionally substituted” refers to any one or more (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atoms on the designated atom or group may or may not be replaced by a moiety other than hydrogen.

[0071] The term “substituted” used herein means any ofthe above groups (Le., alkyl, alkenyl, alkynyl, alkylene, alkoxy, haloalkyl, haloalkoxy, cycloalkyl, aryl, heterocyclyl, heteroaryl, and/or heteroalkyl) wherein at least one (e.g., 1 to 5, 1 to 4, or 1 to 3) hydrogen atom is replaced by a bond to a non-hydrogen atom such as, but not limited to alkyl, alkenyl, alkynyl, alkoxy, alkylthio, acyl, amido, amino, amîdino, aryl, aralkyl, azido, carbamoyl, carboxyl, carboxyl ester, cyano, cycloalkyl, cycloalkylalkyl, guanidino, halo, haloalkyl, haloalkoxy, hydroxyalkyl, heteroalkyl, heteroaryl, heteroarylalkyï, heterocyclyl, heterocyclylalkyl, -NHNI-h, =NNH2, imino, imido, hydroxy, oxo, oxime, nitro, sulfonyl, sulfinyl, alkylsulfonyl, alkylsulfinyl, thiocyanate, -S(O)OH, -S(O)2OH, sulfonamido, thiol, thioxo, N-oxide or -Si(R^y)3, wherein each R^y is independently hydrogen, alkyl, alkenyl, alkynyl,

I6 heteroalkyl, cycloalkyl, aryl, heteroaryl or heterocyclyl.

[0072] In certain embodiments, “substituted” includes any of the above alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl or heteroaryl groups in which one or more (e.g., I to 5, l to 4, or l to 3) hydrogen atoms are independently replaced with deuterium, halo, cyano, nitro, azido, oxo, alkyl, alkenyl, alkynyl, haloalkyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, -NR^gR^h, -NR^sC(=O)R^h, NR^gC(=O)NR^gR^h, -NRKZteO jOR^ -NR^gS(=O)i-2R^h, -C(=O)R^g, -C(=O)OR^S, -OC(=O)OR^g, -OC(=O)R^g, -C(=O)NR^gR^h, -OC(=O)NR^ÊR^h, -OR^g, -SR^Ê, -S(=O)R^g, -S(=O)2R^g, -OS(=O)i-2R^s, -S(=O)i-2OR^s, NR^gS(=O)u2NR^gR^h, =NSO2R^g, =N0R^g, -S(=0)i-2NR^gR^h, -SF5, -SCF3 or -OCF3. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., I to 5, l to 4, or l to 3) hydrogen atoms are replaced with -C(=O)R^S, -C(—O)OR^g, -C(=O)NR^gR^h, -CH2SO₂R^g, or CH₂SO₂NR^gR^h. In the foregoing, R^Ê and R^h are the same or different and independently hydrogen, alkyl, alkenyl, alkynyl, alkoxy, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl. In certain embodiments, “substituted” also means any of the above groups in which one or more (e.g., I to 5, l to 4, or l to 3) hydrogen atoms are replaced by a bond to an amino, cyano, hydroxyl, imino, nitro, oxo, thioxo, halo, alkyl, alkoxy, alkylamino, thioalkyl, aryl, aralkyl, cycloalkyl, cycloalkylalkyl, haloalkyl, heterocyclyl, N-heterocyclyl, heterocyclylalkyl, heteroaryl, and/or heteroarylalkyl, or two of R^g and R^h and R' are taken together with the atoms to which they are attached to form a heterocyclyl ring optionally substituted with oxo, halo or alkyl optionally substituted with oxo, halo, amino, hydroxyl, or alkoxy. [0073] Polymers or similar indefinite structures arrived at by defining substituents with further substituents appended ad infinitum (e.g., a substituted aryl having a substituted alkyl which is îtself substituted with a substituted aryl group, which is further substituted by a substituted heteroalkyl group, etc.) are not intended for inclusion herein. Unless otherwise noted, the maximum number of serial substitutions in compounds described herein is three. For example, serial substitutions of substituted aryl groups with two other substituted aryl groups are limited to ((substituted aryl)substituted aryl) substituted aryl. Similarly, the above définitions are not intended to include impermissible substitution patterns (e.g., methyl substituted with 5 fluorines or heteroaryl groups having two adjacent oxygen ring atoms). Such impermissible substitution patterns are well known to the skilled artisan. When used to modify a Chemical group, the term “substituted” may describe other Chemical groups defined herein. [0074] In certain embodiments, as used herein, the phrase “one or more” refers to one to five. In certain embodiments, as used herein, the phrase “one or more” refers to one to four. In certain

embodiments, as used herein, the phrase “one or more” refers to one to three.

[0075] Any compound or structure given herein, is întended to represent unlabeled forms as well as isotopically labeled forms (isotopologues) ofthe compounds. These forms of compounds may also be referred to as and include “isotopically enriched analogs.” Isotopically labeled compounds hâve structures depicted herein, except that one or more atoms are replaced by an atom having a selected atomic mass or mass number. Examples of isotopes that can be incorporated into the disclosed compounds include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorous, fluorine, chlorine and iodine, such as ²H, ³H, ⁿC, ^,3C, ^l4C, ^,3N, ^!5N, ^,5O, ^l7O, ^iSO,³¹ P, ³²P, ³⁵S, ^,8F, ³⁶CI, ^,23I, and ¹²⁵I, respectively. Various isotopically labeled compounds of the présent disclosure, for example those into which radioactive isotopes such as ³H, ¹³C and ¹⁴C are incorporated. Such isotopically labelled compounds may be useful in metabolic studies, reaction kinetic studies, détection or imaging techniques, such as positron émission tomography (PET) or single-photon émission computed tomography (SPECT) including drug or substrate tissue distribution assays or in radioactive treatment of patients.

[0076] The term “isotopically enriched analogs” includes “deuterated analogs” of compounds described herein in which one or more hydrogens is/are replaced by deuterium, such as a hydrogen on a carbon atom. Such compounds exhibit increased résistance to metabolism and are thus useful for increasing the half-life of any compound when administered to a mammal, particularly a human. See, for example, Foster, “Deuterium Isotope Effects in Studies of Drug Metabolism,” Trends Pharmacol. Sci. 5(12):524-527 (1984). Such compounds are synthesized by means well known in the art, for example by employing starting materials in which one or more hydrogens hâve been replaced by deuterium. [0077] Deuterium labelled or substituted therapeutic compounds of the disclosure may hâve improved DMPK (drug metabolism and pharmacokinetics) properties, relating to distribution, metabolism and excrétion (ADME). Substitution with heavier isotopes such as deuterium may afford certain therapeutic advantages resulting from greater metabolic stability, for example increased in vivo half-life, reduced dosage requirements and/or an improvement in therapeutic index. An ^l8F, ³H, ^HC labeled compound may be useful for PET or SPECT or other imaging studies. Isotopically labeled compounds of this disclosure and prodrugs thereof can generally be prepared by carrying out the procedures disclosed in the schemes or in the examples and préparations described below by substituting a readily available isotopically labeled reagent for a non-isotopically labeled reagent. It is understood that deuterium in this context is regarded as a substituent in a compound described herein.

[0078] The concentration of such a heavier isotope, specifically deuterium, may be defined by an

isotopic enrichment factor. In the compounds of this disclosure any atom not specifically designated as a particular isotope is meant to represent any stable isotope of that atom. Unless otherwise stated, when a position is designated specifically as “H” or “'hydrogen”, the position is understood to hâve hydrogen at its natural abundance isotopic composition. Accordingly, in the compounds of this disclosure any atom specifically designated as a deuterium (D) îs meant to represent deuterium. Further, in some embodiments, the corresponding deuterated analog is provided.

[0079] In many cases, the compounds of this disclosure are capable of forming acid and/or base salts by virtue ofthe presence ofamino and/or carboxyl groups or groups similar thereto.

[0080] Provided also are a pharmaceutically acceptable sait, isotopically enriched analog, deuterated 10 analog, isomer (such as a stereoisomer), mixture of isomers (such as a mixture of stéréo isomers), prodrug, and métabolite ofthe compounds described herein.

[0081] “Pharmaceutically acceptable” or “physiologically acceptable” refer to compounds, salts, compositions, dosage forms and other materials which are useful in preparing a pharmaceutical composition that is suitable for veterinary or human pharmaceutical use.

[0082] The term “pharmaceutically acceptable sait” of a given compound refers to salts that retain the biological effectiveness and properties of the given compound and which are not biologically or otherwise undesirable. “Pharmaceutically acceptable salts” or “physiologically acceptable salts” include, for example, salts with inorganic acids and salts with an organic acid. In addition, if the compounds described herein are obtained as an acid addition sait, the free base can be obtained by basifying a solution of the acid sait. Conversely, if the product is a free base, an addition sait, particularly a pharmaceutically acceptable addition sait, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds. Those skilled in the art will recognîze various synthetic méthodologies that may be used to préparé nontoxic pharmaceutically acceptable addition salts. Pharmaceutically acceptable acid addition salts may be prepared from inorganic and organic acids. Salts derived from inorganic acids include, e.g., hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid and the like. Salts derived from organic acids include, e.g., acetic acid, propionic acid, gluconic acid, glycolic acid, pyruvic acid, oxalic acid, malic acid, malonic acid, succinic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, p-to!uene-sulfonic acid, salicylic acid and the like. Likewise, pharmaceutically acceptable base addition salts can be prepared from inorganic and organic bases. Salts

derived from inorganic bases include, by way of example only, sodium, potassium, lithium, aluminum, ammonium, calcium and magnésium salts. Salts derived from organic bases include, but are not limited to, salts of primary, secondary and tertiary amines, such as alkyl amines (i.e., NHifalkyl)), dialkyI amines (i.e., HN(aIkyl)2), trialkyl amines (i.e., N(alkyl)s), substituted alkyl amines (i.e., NH₂(substituted alkyl)), di(substituted alkyl) amines (i.e., HN(substituted alkyl)₂), tri(substituted alkyl) amines (i.e., N(substituted alkyl)₃), alkenyl amines (i.e., NH₂(alkenyl)), dialkenyl amines (i.e., HN(alkenyI)2), trialkenyl amines (i.e., N(alkenyl)î), substituted alkenyl amines (i.e., NH₂(substîtuted alkenyl)), di(substituted alkenyl) amines (i.e., HN(substituted alkenyl)₂), tri(substituted alkenyl) amines (Le., N(substituted alkenyl)₃, mono-, di- or tri- cycloalkyl amines (i.e., Nbhfcycloalkyl), HN(cycloalkyl)2, 10 M(cycloalkyl)₃), mono-, di- or tri- arylamines (i.e., NH₂(aryl), HN(aryl)₂, N(aryl)₃) or mixed amines, etc.

Spécifie examples of suitable amines include, by way of example only, isopropylamine, trimethy] amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine, ethanolamine, 2-dimethylaminoethanol, piperazine, piperidine, morphoiine, N-ethylpiperidine and the like.

[0083] The term “hydrate” refers to the complex formed by the combining of a compound described 15 herein and water.

[0084] A “solvaté” refers to an association or complex of one or more solvent molécules and a compound of the disclosure. Examples of solvents that form solvatés include, but are not limited to, water, isopropanol, éthanol, methanol, dimethylsulfoxide, ethylacetate, acetic acid and ethanolamine. [0085] Some of the compounds exist as tautomers. Tautomers are in equilibrium with one another.

For example, amide containing compounds may exist in equilibrium with imidic acid tautomers. Regardless of which tautomer is shown and regardless of the nature of’the equilibrium among tautomers, the compounds are understood by one of ordinary ski 11 in the art to comprise both amide and imidic acid tautomers. Thus, the amide containing compounds are understood to include their imidic acid tautomers. Likewise, the imidic acid containing compounds are understood to include their amide tautomers.

[0086] The compounds of the invention, or their pharmaceutically acceptable salts include an asymmetric center and may thus give rise to enantiomers, diastereomers, and other stéréoisomeric forms that may be defined, in terms of absoiute stereochemistry, as (R)- or (5)- or, as (D)- or (L)- for amino acids. The present invention is meant to include ail such possible isomers, as well as their racemic and optically pure forms. Optically active (+) and (-), (R)- and (S)-, or (D)- and (L)- isotners may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques, for example, chromatography and fractional crystallization. Conventional techniques for the

preparation/isolation of individual enantiomers include chiral synthesis from a suitable optically pure precursor or resolution of the racemate (or the racemate of a sait or dérivative) using, for example, chiral high performance liquid chromatography (HPLC), When the compounds described herein contain olefinic double bonds or other centres of géométrie asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z géométrie isomers,

[0087] A “stereoisomer” refers to a compound made up of the saine atoms bonded by the same bonds but having different three-dimensional structures, which are not interchangeable. The present invention contemplâtes various stereoisomers and mixtures thereof and includes “enantiomers,” which refers to two stereoisomers whose molécules are nonsuperimposeable mirror images of one another.

[0088] “Diastereomers” are stereoisomers that hâve at least two asymmetric atoms, but which are not mirror-îmages of each other.

[0089] Relative centers of the compounds as depicted herein are indicated graphically using the “thick bond” style (bold or parallel lines) and absolute stereochemistry is depicted using wedge bonds (bold or parallel lines).

[0090] “Prodrugs” means any compound which releases an active parent drug according to a structure described herein in vivo when such prodrug is adminîstered to a mammalian subject. Prodrugs of a compound described herein are prepared by modifying functional groups present in the compound described herein in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs may be prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo, to the parent compounds. Prodrugs include compounds described herein wherein a hydroxy, amino, carboxyl, or sulfhydryl group in a compound described herein is bonded to any group that may be cleaved in vivo to regenerate the free hydroxy, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate and benzoate dérivatives), amides, guanidines, carbamates (e.g., Ν,Ν-dimethylaminocarbonyl) of hydroxy functional groups in compounds described herein and the like. Préparation, sélection and use of prodrugs is discussed in T. Higuchi and V. Stella, “Pro-drugs as Novel Delivery Systems,” Vol. 14 ofthe A.C.S. Symposium Sériés; “Design of Prodrugs,” ed. H.

Bundgaard, Elsevier, 1985; and in Bioreversible Carriers in Drug Design, ed. Edward B. Roche, American Pharmaceutical Association and Pergamon Press, 1987, each of which are hereby incorporated by reference in their entirety.

[0091 ] The term, “métabolite,” as used herein refers to a resulting product formed when a compound disclosed herein is metabolized. As used herein, the term “metabolized” refers to the sum of processes (including but not limited to hydrolysis reactions and reactions catalyzed by enzymes) by which a particular substance, such as a compound disclosed herein, is changed by an organism. For example, an aldéhyde moiety (-C(O)H) may be reduced in vivo to a -CH₂OH moiety.

[0092] Use of the word “inhibitor,” “inhibit” or “inhibition,” herein refers to activity of a compound of Formula I or a pharmaceutically acceptable sait on ferroportin, unless specified otherwise. By “inhibit” herein is meant to decrease the activity of ferroportin, as compared to the activity of ferroportin in the absence of the compound. In some embodiments, the term “inhibit” means a decrease in ferroportin activity of at least about 5%, at least about 10%, at least about 20%, at least about 25%, at 10 least about 50%, at least about 60%, at least about 70%, at least about 80%, at least about 90%, or at least about 95%. In other embodiments, inhibit means a decrease in ferroportin activity of about 5% to about 25%, about 25% to about 50%, about 50% to about 75%, or about 75% to 100%. In some embodiments, inhibit means a decrease in ferroportin activity of about 95% to 100%, e.g., a decrease in activity of 95%, 96%, 97%, 98%, 99%, or 100%. Such decreases can be measured using a variety of 15 techniques that would be recognizabie by one of skill in the art, including in vitro assays.

[0093] As used herein, the terni “ferroportin inhibitor” and the like refers to a compound that reduces, inhibits, or otherwise diminishes one or more of the biological activitîes of ferroportin, for instance by inducing internaiization of ferroportin. The activity could decrease by a statistically significant amount including, for example, a decrease ofat least about 5%, 10%, 15%, 20%, 25%, 30%, 20 35%, 40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 95% or 100% of the activity of ferroportin compared to an appropriate control.

[0094] “Treatment” or “treating” is an approach for obtaining bénéficiai or desired results including clinical results. Bénéficiai or desired clinical results may include one or more of the following: a) inhibiting the disease or condition (e.g., decreasing one or more symptoms resulting from the disease or 25 condition, and/or diminishing the extent of the disease or condition); b) slowing or arresting the development of one or more clinical symptoms associated with the disease or condition (e.g., stabilizing the disease or condition, preventing or delaying the worsening or progression of the disease or condition, and/or preventing or delaying the spread (e.g., metastasis) of the disease or condition); and/or c) relieving the disease, that is, causing the régression of clinical symptoms (e.g., ameliorating the disease 30 state, providing partial or total remission of the disease or condition, enhancing effect of another médication, delaying the progression of the disease, increasing the quality of life, and/or prolonging

survival.

[0095] “Prévention” or “preventing” means any treatment of a disease or condition that causes the clinical symptoms of the disease or condition not to develop. Compounds may, in some embodiments, be administered to a subject (including a human) who is at risk or has a family history of the disease or 5 condition.

[0096] “Subject” refers to an animal, such as a mammal (including a human), that has been or will be the object of treatment, observation or experiment. The methods described herein may be useful in human therapy and/or veterinary applications. In some embodiments, the subject is a mammal. Jn one embodiment, the subject is a human.

[0097] The term “therapeutically effective amount” or “effective amount” of a compound described herein or a pharmaceutically acceptable sait, tautomer, stereoisomer, mixture of stereoisomers, prodrug, or deuterated analog thereof means an amount sufficient to effect treatment when administered to a subject, to provide a therapeutic benefit such as amelioration of symptoms or slowing of disease progression. For example, a therapeutically effective amount may be an amount sufficient to decrease a symptom of a sickle cell disease. The therapeutically effective amount may vary depending on the subject, and disease or condition being treated, the weight and âge of the subject, the severity of the disease or condition, and the manner of administering, which can readily be determined by one of ordinary skill in the art.

[0098] When any variable or substituent occurs more than one time in any structure or formulae, its 20 définition in each occurrence is independent of its définition at every other occurrence. Combinations of substituents and/or variables are permissibie only if such combinations resuît in chemicalîy stable compounds. It is understood that substituents and substitution patterns on the compounds described herein can be selected by one of ordinary skill in the art to provide compounds that are chemicalîy stable and that can be readily synthesized by techniques known in the art as well as those methods set forth herein.

[0099] Additional définitions may also be provided below as appropriate.

II. Compounds

[0100] In certain embodiments, the subject matter described herein is directed to compounds of Formula I’:

or a pharmaceutically acceptable sait thereof; wherein, Z is N or CH;

wherein ’ indicates the point of attachment to the remainder of the molécule;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-Ci-Cs alkyl, hydroxy-Ci-Cio alkoxy, hydroxy-Ci-Cio-alkyl, cyano, -NR^GR^H, haIo-Ci-C3 alkoxy, -O-(Ci-C6alkyl)-R^bb, -O-R^bb, -(Ci-C6 alkyl)NR^GIR^HI, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR^GlR^Hl, halo-CiXhalkyl, -O-R^cc-O-R^dd, 5-to 7membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, the alkyl moiety in hydroxy-Ci-Cio alkoxy or -O-(Ci-Cs alkyl)-R^bb is optionally substituted with cyano, hydroxy, hydroxy-Ci-C₃-alkyl, halogen, orCi-Cs alkoxy;

R^bb is 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7 cycloalkyl, 5or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NR^GlR^Hi, or -NR^gR^h;

R^ce is C1-C3 alkyl; and

R^dd is Ci-Caalkyt or a 6-membered heteroaryl;

wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶, R^bb, or R^dd is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-Ci-Cs alkyl, oxo, Ci-C₃alkoxy, and Ci-Caalkyl;

R^Gl and R^H1 are each independently hydrogen or C1-C3 alkyl; and,

R^g and R^H are each independently hydrogen, -C(O)R^Ga, or optionally deuterated Ci-Csalkyl; wherein,

R^Ga is C1-C3 alkyl or hydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-Ci-Cj-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1,2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R⁶, N-R⁶, and C-R⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N-R⁶, NH, O, SH or S-R⁶;

f is 0 or 1 ;

p is 1 or 2;

R^x, in each instance, is halogen, Ci-Cé alkyl, C1-C3 alkoxy, hydroxy, oxo, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxyC1-C3 alkyl, halo-Ci-C3 alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl, or (6or 7-membered monocyclic heterocyclyl)-Ci-C3 alkyl; wherein, said heteroaryl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Ce-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(Ci-C₃ alkyl)-T, and 5- to 7-membered monocyclic heterocyclyl;

T is selected from the group consistîng of Cô-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl substituent of R⁴ is optionally substituted with one or two substituents, each individually selected from the group consistîng of C1-C3 alkyl, halogen, and hydroxy; and when p is l, C1-C3 alkyl in the (5- to ΊΟ-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl is linear;

and.

R^4a R i i

wherein,

R^4a and R^4g are each independently selected from the group consistîng of hydrogen, Ci-Cio alkyl, hydroxy-C ।-Cô alkyl, halo-Ci-Cs alkyl, C1-C3 alkoxy-Ci-Cô alkyl, -Ci-Cô alkyl-NR^JlR^J2, C3-C7 cycloalkyl, 4- to lO-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, Cô-Cio monocyclic or fused bicyclic aryl, 5- to 1 O-membered monocyclic or fused bicyclic heteroaryl, (Cê-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl;

R^J1 and R^J2 are independently hydrogen or Ci-Cjalkyl;

wherein the cycloalkyl, heterocyclyl, 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 consistîng of halogen, Ci-Cê alkyl, halo-Ci-Cj alkyl, hydroxy, C1-C3 alkoxy, halo-Ci-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;

R^4b is hydrogen or Ci-Cô alkyl; or

R^4a and R^4b taken together with the atom to which each îs attached form a 5- to

ΊΟ-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-C& alkyl, halo-Ci-Cs alkyl, hydroxy, and C1-C3 alkoxy; or

R^4b and R^4c taken together with the atom to which each is attached form a 5-to 7membered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and Ci-Csalkyl; or

R^4c and R^4d are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 aJkyl-thio-C!-C3 alkyl, hydroxy-Ci-C₆ alkyl, CiC& alkoxy-Ci-Cs alkyl, C3-C7 cycloalkyl, and C1-C3 alkyl; or

R^4c and R⁴*¹ taken together with the atom to which each is attached form a C3-C7 cycloalkyl;

or, when p is 1,

R³ and R⁴ taken together with the nitrogen atom to which each is attached can form a: i. 7-membered fused bicyclic heterocyclyl, 7-membered bridged bicyclic heterocyclyl, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-Cs alkyl, and Cg-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one of two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2)_sC(=O)NR^kR^l;

wherein, s is 0, l, 2, or 3;

R^k is hydrogen or C1-C3 alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, CjCî alkyl, C3-C7 cycloalkyl, and Cé-Cio monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein,

R^q is hydrogen or C1-C3 alkyl; and

R^wis Cé-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy;

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

or, when p is 2,

R³ and R⁴ taken together with the nitrogen atom to which each is attached can form a: i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(Ci-C& alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyi, hydroxy, -NR^ÜR^H, and -(CH2)_sC(-O)NR^kR'; provided that when the structure of Formula (I) is

\ H * is and ” is ; or

H \ % * is ' and ** is ;

and, wherein the compound of Formula (I) is not:

jV-((F4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pyrimidin-4amine;

4-(piperidin-l-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

4-(azepan-l-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoiine;

l-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[tZ]pynmidin-4-yl)-[,4-diazepan2-one; or

2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[rf]pyrimidin-4-yl)-l,2-oxazepane; or a sait thereof.

[0101] In certain embodiments, the subject matter described herein is directed to compounds of

Formula Γ:

(Γ) or a pharmaceutically acceptable sait thereof; wherein, Z is N or CH;

wherein 5 indicates the point of attachment to the remainder of the molécule;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, Ci-Ci alkoxy, Ci-Csalkyl, C1-C3 alkoxy-Ci-C3alkyl, hydroxy-Ci-Cô alkoxy, hydroxy-Cj-C3-alkyl, cyano, -NR^GR^H, halo-Ci-C3 alkoxy, -0-(CH2)u-R^bb, halo-Ci-C₃ alkyl, -O-R^cc-O-R^dd, 5- to 7membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 6;

R^bb is 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR^GR^H; R^cc and R^dd are each independently Ci-C₃ alkyl;

wherein, said cycloalkyl, heterocyclyl, or heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, Ci-C₃ alkoxy, and Ci-C₃alkyl;

and,

R^g and R^h are each independently hydrogen, -C(O)R^Ga, or C1-C3 alkyl; wherein, R^Ga is C1-C3 alkyl or hydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of Ci-C₃ alkoxy, hydroxy, hydroxy-Ci-Cs-alkyl, Ct-C₃ alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, l, 2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R⁶, N-R⁶, and C-R⁶, provided that I or 2 of Y¹, Y², Y³, and Y⁴ can be N, N-R⁶, NH, O, SH or S-R⁶;

f is 0 or 1;

p is 1 or 2;

R\ in each instance, is halogen, Ci-C₆ alkyl, C1-C3 alkoxy, hydroxy, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, Ci-C3 alkyl, hydroxy-Ci-C3 alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C₃ alkyl branched or linear, or (6- or 7-membered monocyclic heterocyclyl)-Ci-C3 alkyl branched or linear; wherein, said heteroaryl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Cô-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7membered monocyclic heterocyclyl, and wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and, when p is 1, C1-C3 alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C₃ alkyl is linear;

and,

R^4a R^4g

wherein,

R^4a and R^4ê are each independently selected from the group consisting of hydrogen, Ci-Cè alkyl, hydroxy-Ci-Cô alkyl, Ci-Cs alkoxy-Ci-Cô alkyl, C3-C7 cycloalkyl, 5 5- to l O-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl,

Co-Cio monocyclic or fused bicyclic aryl, 5- to lO-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cjo monocyclic or fused bicyclic aryl)-Ci-Cs alkyl, and (5- to 10membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or 10 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-Ct-C₃ alkyl, hydroxy, C1-C3 alkoxy, halo-Ci-Ca alkoxy, oxo, C3-C7 cycloalkyl, and 5- to I O-membered monocyclic, fused bicyclic, or spiro heterocyclyl;

R^4b is hydrogen or Ci-Ce alkyl; or

R^4a and R^4b taken together with the atom to which each is attached form a 5 - to 1 O-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, halo-Ci-C₃ alkyl, hydroxy, and C1-C3 alkoxy; or 20 R^4b and R^4c taken together with the atom to which each is attached form a 5- to 7metnbered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and Ci-C3alkyl; or

R^4e and R^4d are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-Ci-Cs alkyl, hydroxy-Ci-Cô alkyl, CjCô alkoxy-Ci-C3 alkyl, C3-C7 cycloalkyl, and C1-C3 alkyl; or

R^4c and R^4d taken together with the atom to which each is attached form a C3-C7 cycloalkyl;

or, when p is I,

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-Ca alkyl, and Cô-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii, 4. or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2)_sC(=0)NR^kR^l; wherein, s is 0, 1, 2, or 3;

R^k is hydrogen or C1-C3 alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, Cr C3 alkyl, C3-C7 cycloalkyl, and Cé-Cio monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein,

R^q is hydrogen or C1-C3 alkyl; and

R^wis Cé-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cîalkyl, hydroxy, and C1-C3alkoxy;

or, when p is 2,

R³ and R⁴ taken together with the nitrogen atom to which each is attached can form a:

i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(C 1-Cô alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR^GR^H, and -(CH2)sC(=O)NR^kR';

provided that when the structure of Formula (I) is

\ % \

* is and ** is; or

H, \ \ * is ' and ** is;

and, wherein the compound of Formula (1) is not:

_JV-((l,4-dioxan-2-yI)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[iZ]pyrimidin-4amine;

4-(piperidin-l-yl)-2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

4-(azepan-l -y l)-2-(6-propylpyridin-2-y 1)-5,6,7,8-tetrahydroquinazolîne;

1-propy 1-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i7|pyrimidin-4-yl)-l,4-diazepan2-one; or

2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[cZ]pyrimidin-4-yl)-l,2-oxazepane; or a sait thereof.

[0102] In certain embodiments, the subject matter described herein is dîrected to compounds of

Formula I:

wherein,

Z is N or CH;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, CiC3 alkyl, C1-C3 alkoxy-Ci-Cs alkyl, hydroxy-C i-Cè alkoxy, hydroxy-C]-C3-alkyl, cyano, C3-C7 cycloalkyl-Ci-Cs alkoxy, NR^GR^H, halo-Ci-C3 alkoxy, and C₃-C& cycloalkyl;

wherein R^G and R^H are each independently hydrogen or Cj-C₃ alkyl;

or, wherein two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered heterocyclyl, C3-C7 cycloalkyl, Ce-Cio aryl, or 5- to ΊΟ-membered heteroaryl;

n is 0, t, 2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, N H, O, S, and C (when R⁶ is attached thereto), provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, NH, O, or S;

f is 0 or 1 ;

p is 1 or 2;

R^x, in each instance, is halogen, Cj-Cô alkyl, C1-C3 alkoxy, hydroxy, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-Ci-C₃-alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-Ci-C3 alkyl branched or

linear, or (6- or 7-membered monocyclic heterocyclyl)-Ci-C3 alkyl branched or linear;

wherein, when p îs l, Cj-C₃ alkyl in (5- to 10-niembered monocyclic or bicyclic fused heteroaryl)C1-C3 alkyl is linear;

and,

R^4a R⁴9

wherein,

R^4a and R^4g are each independently selected from the group consisting of hydrogen, Ci-Ce alkyl, hydroxy-C ।-Cô alkyl, C1-C3 alkoxy-Ci-Cé alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, 10 bicyclic fused, or spiro heterocyclyl, C6-C10 aryl, 5- to 10-membered monocyclic or bicyclic fused heteroaryl, (Cs-Cio aryl)-Ci-C₃ alkyl, and (5- to 10-membered monocyclic heteroaryl)-Ci-C3 alkyl;

wherein tbe cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R^4aor R⁴® is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 15 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl;

R^4b is hydrogen orCi-Côalkyl;

or, R^4a and R^4b taken together with the atom to which each is attached form a 5- to 7membered heterocyclyl;

or, R^4b and R^4e taken together with the atom to which each is attached form a 5- to 720 membered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halo, and C1-C3 alkyl;

R^4c and R^4d are each independently selected from the group consisting of hydrogen, C]C₃ alkoxy, hydroxy, C1-C3 alkyl-thio-Ci-Cs alkyl, hydroxy-Ci-Ce alkyl, Ci-Cé alkoxy-Ci-C₃ alkyl, C3C7 cycloalkyl, and C1-C3 alkyl;

or, R^4c and R^4d taken together with the atom to which each is attached form a C3-C7 cycloalkyl;

or, when p is l,

i. 7-membered bicyclic fused heterocyclyl, 7-membered bridged heterocyclyl, or 7membered monocyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and Cï-Cs alkyl; and when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, haloalkyl, and Cé-Cw aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom;

wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH₂)_sC(=O)NR^kR^l;

wherein s is 0, 1, 2, or 3;

R^k is hydrogen or C1-C3 alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, C1-C3 alkyl, C3-C7 cycloalkyl, and Cô-Cioaryl;

wherein said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Ci-C3 alkoxy, oxo, halogen, cyano, and NR^qR^w;

wherein R^q is hydrogen or C1-C3 alkyl and R^wis Cô-Cio aryl or C3-C7 cycloalkyl, and wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C|-C₃ alkoxy;

iiî. 8-, 9-, ΙΟ- or l l-membered bicyclic fused heterocyclyl, or 12-membered bicyclic bridged, fused heterocyclyl, wherein said 8-, 9-, or l l-membered heterocyclyl contains one heteroatom and said 10- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said 10-, 11-, or 12membered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy;

or, when p is 2,

i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally with one or two substituents, each independently selected from the group consisting of halogen, hydroxy- (Ci-Ce alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9, 10-, or i l-membered bicyclic bridged, fused, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, NR^GR^H, and -(CH2)sC(=O)NR^kR';

provided that when the structure of Formula (I) is

or a pharmaceutically acceptable sait thereof; and wherein the compound of Formula (I) is not:

Æ-((l ,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pynmidin-4amine;

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

4-(azepan-l-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

l-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta|X]pynmidin-4-yl)-l,4-diazepan2-one; or

2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pyrimidin-4-yl)-l,2-oxazepane; or a sait thereof.

[0103] Useful compounds of Formula F or I include those where p is 1.

[0104] Useful compounds of Formula Γ or I include those where Z is N.

[0105] The integer n will decrease by one each time a compound of Formula 1’ or I contains a variable C-R⁶, N-R⁶, or S-R⁶, and the total number of n (the total number of C-R⁶, N-R⁶, or S-R⁶ cannot exceed 3).

[0106] Useful compounds of Formula I’ or I include those where Y¹, Y², Y³, and Y⁴ are each CH or C-R⁶. In certain embodiments, useful compounds of Formula Γ or I include those where Y¹ is CH Y² is C-Rô, and Y³, and Y⁴ are each CH. Useful compounds of Formula Γ or I include those where Y³ is N and Y¹, Y², and Y⁴ are each CH or C-R⁶. Useful compounds of Formula F or I include those where Y² is N and Y¹, Y³, Y⁴ are each CH or C-R⁶. Useful compounds of Formula Γ or I include those where Y¹ is N and Y², Y³, and Y⁴ are each CH or C-R⁶. Useful compounds of Formula Γ or I include those where Y¹is CH, Y² is C-R⁶, Y³ is CH, and Y⁴ is CH.

[0107] Useful compounds of Formula Γ or I include those where R⁶, in each instance, is selected from the group consistîng of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-Ci-Cj alkyl, hydroxy-Ci-Côalkoxy, hydroxy-Ci-Cs-alkyl, -O-(CH2)_U-R^bb, halo-Ci-C3 alkoxy, -O-R^cc-O-R^dd, halo-CiC3 alkyl, hydroxy-Ci-Cw-alkyl, -O-(Ci-Cs alkyl)-R^bb, -O-R^bb, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR^G1R^H1and -NR^GR^H; wherein, the alkyl moiety in hydroxy-Ci-Cio alkoxy or -O-(Ci-C6alkyl)-R^bb is optionally substituted with cyano, hydroxy, hydroxyCi-Ca-alkyl, halogen, or C1-C3 alkoxy; R^bb is -NR^GR^H; u is an integer from 1 to 3; R^G and R^H are each independently hydrogen or Ci-C₃ alkyl; and and R^dd are each independently C1-C3 alkyl. Usefiil compounds of Formula Γ or I include those where R⁶, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH₃)₂, hydroxy, -OCH2CH2OH, -CH2OH, -CH2OCH3, -OCH2CH2NH2, -OCH2CH₂N(CH₃)2, -OCH2C(CH₃)₂O

H, -OCH2CF3, -OCHF2, -OCF3, -OCH₂CH₂OCH₃, -OCH₂CH₂F, -OC(CH₃)2CH₂OH, -OCH₂CH(CH₃)O H, -OCH₂CH2NHC(O)CH₃, -OC(CH₃)2CH₂N(CH₃)2, -OCH(CH₃)CH₂OH, -OCH₂CH(CH(CH₃)₂)OH, -o CH₂CH(CH₂CH₃)OH, -OCH₂C(CH₂CH₃)₂OH, -OCH₂CH₂N(CH2CH₃)₂, -OCH(CH₃)CH₂N(CH₃)2, -oc H₂C(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. Further, useful compounds of Formula F or I include those where R⁶, în each instance, is methoxy, -OCH2CH2N(CH3)2, -OCH2CH2OH, or -OCH2C(CH3)2OH. Useful compounds of Formula I’ or l include those where R⁶, în each instance, is selected from the group consisting of -O-(CH2)u-R^bb, and C3-Cé cycloalkyl; wherein, u is an integer from 0 to 3; R^bb is 4- to 7-membered monocyclic heterocyclyl or C3-C7 cycloalkyl; and wherein said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C]-C3 alkoxy, and C1-C3 alkyl. Useful compounds of Formula Γ or I include those where R⁶, in each instance, is selected from the group consisting of cyclopropyl and -O-(CH2)u-R^bb; wherein, u is 0, l, or 2; and R^bbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl. Useful compounds of Formula Γ or l

point of attachment to Ring B.. Useful compounds of Formula Γ or I include those where R⁶ is

[0108] Useful compounds of Formula Γ or I include those where two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-Ci-Cs-alkyl, C1-C3 10 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl. Useful compounds of Formula

Γ or I include those where two R⁶ groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl. Useful compounds of

Formula Γ or 1 include those where two vicinal R⁶ groups, taken together with the atom to which each is

fused with ring B, wherein the pair of represent the attachment of the ring with Ring B. Useful compounds of Formula Γ or I include those where two vicinal R⁶ groups, taken together with the atom to which each is attached, form a form a ring selected from the group consisting of

fused with Ring B. Useful compounds of Formula Γ or

Formula I include those where two vicinal R⁶ groups taken together with the atom to which each îs

attached form a ring fused with Ring B, where the bicyclic ring formed by Ring B and the two vicinal R⁶

[0109] Useful compounds of Formula Γ or Formula 1 include those where fis 1. Useful compounds

or 1; and Y² and Y³ are each independently selected from the group consisting of CH, N, NH, NR⁶, S,

O, and CR⁶, provided that only one of Y² and Y³ can be N, NH, NR⁶, S, or O. Usefui compounds of Formula F or Formula I include those where Ring B is selected from the group consisting of

Formula F or Formula l include those where R⁶, in each instance, is selected from the group consisting of C1-C3 alkyl and hydroxy-Ci-C₃ alkyl. Usefui compounds of Formula F or Formula I include those where R⁶, in each instance, is selected from the group consisting of methyl, ethyl, n-propyl, CH2CH2OH, and -CH2CH2CH2OH.

[0110] Usefui compounds of Formula F or Formula I include those where n is l. Usefui compounds of Formula F or Formula I include those where n is 0. Usefui compounds of Formula F or Formula 1 include those where n is 2, wherein one R⁶ is selected from the group consisting of methyl and methoxy and the other R⁶ is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH. [011 l [ Usefui compounds of Formula J’ or Formula I include those where R³ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH. Usefui compounds of Formula Γ or Formula I include those where R³ is selected from the group consisting of hydrogen, methyl, -CD₃, ethyl, phenyl, -CH2CF₃, and -CH2CH2OH. Usefui compounds of Formula F or Formula I include those where R³ is methyl.

[0112] Usefui compounds of Formula F or Formula I include those where R⁴is a (5- to 10membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7 cycloalkyl, and 5- to 7-meinbered monocyclic heterocyclyl, and wherein said phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C|-C₃ alkyl, halogen, and hydroxy. Usefui compounds of Formula F or Formula 1 include those where R⁴ is a (6-membered heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6-membered heteroaryl is a nitrogen. Usefui compounds of Formula F or Formula i include those where R⁴ is selected from the group consisting of pyridinylmethyl, pyrimidinyl-methyl, benzoxazole-methyl, oxazolyl-methyl, and triazolyl-methyl, each optionally substituted with phenyl or benzyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro. Usefui compounds of

R^4a

[ΟΙ 13] Useful compounds of Formula Γ or Formula l include those where R⁴ is ³¹ R . Useful 5 compounds of Formula 1’ or Formula 1 include those where R^4c is selected from the group consisting of hydrogen, methyl, îsopropyl, -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 taken together with the atom to which each is attached form a cyclopropyl ring. Useful compounds of Formula Γ or Formula I include those where R^4c and R^4d are each hydrogen. Useful compounds of Formula Γ or Formula ί include those where R^4b is 10 hydrogen. Useful compounds of Formula Γ or Formula 1 include those where R^4a is Cj-Cô alkyl. Useful

compounds of Formula I’ or Formula I include those where R^4a tert-butyl or isopropyl. Useful compounds of Formula I’ or Formula I include those where R^4a is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cé alkyi, halo-Ci-C3 alkyi, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to ΊΟ-membered monocyclic or fused 5 bicyclic heterocyclyl. Useful compounds of Formula Γ or Formula I include those where R^4a is phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy. Useful compounds of Formula Γ or Formula I include those where R^4a is selected from the

Useful compounds of Formula Γ or Formula I include those where R^4a is 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, Ci-Cô alkyi, halo-Ci-C3 alkyi, hydroxy, C1-C3 alkoxy, C3C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl. Useful compounds of Formula Γ or Formula I include those where R^4a is pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyî, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl. Useful compounds of Formula Γ or Formula I include those where R^4a is selected from the group consisting of

N---N

. Useful compounds of Formula Γ or Formula I include those where R^4a is Ca-C? cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, halo-Cj-Ca alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl. Useful compounds of Formula I’ or Formula I include those where R^4a is selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclofi.i. 1 ]pentan-1-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy. Useful compounds of Formula Γ or Formula I include those where R^4a is selected from the group consisting of

. Useful compounds of Formula Γ or Formula I include those where R^4a is a 4- to 10membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, halo-Ci-C₃alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused

bicyclic heterocyclyl. Useful compounds of Formula Γ or Formula I include those where R^4a is selected from the group consisting of tetrahydrofuranyl, pyrrolidinyL benzo[d][l,3]dioxolyl, oxetanyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, methoxy, and oxo. Useful compounds of Formula F or Formula I

include those where R^4a is selected from the group consisting of

Γ or Formula I include those where R^4a is (Cô-Ciq monocyclic or fused bicyclic aryl)-Ci-C3 alkyl or (5to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, halo-

C1-C3 alkyl, hydroxy, Ci-Csalkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl. Useful compounds of Formula Γ or Formula 1 include those where R^4a is selected from the group consisting of benzyl, 2-(l-cyclobutyl-5-methyl-lH-imidazol·2-yl)ethyl, and pyridinylmethyl. Useful compounds of Formula Γ or Formula I include those where R^4a is selected from the

Formula Γ or Formula I include those where R^4a is selected from the group consisting of-C(CH3)2CH₂OH, -CH2CH2OH, and -QCHsjzCHjOCHh. Useful compounds of Formula I’ or Formula l include those where R^4a and R^4b taken together with the atom to which each is attached form a 5- to l O-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ct-Ce alkyl, halo-Ci-Ca alkyl, hydroxy, and C1-C3 alkoxy. Useful compounds of Formula Γ or Formula I include those where R^4a and R^4b taken together with the atom to which each is attached form a piperîdinyl, morpholinyl, pyrrolidinyl, azepanyl, indolînyl, azabicyclo[3.1.l]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, hydroxy, and methoxy. Useful compounds of Formula Γ or Formula I include those where R^4a and R^4b taken together with the atom to which each is attached form a

compounds of Formula Γ or Formula I include those where R^4b and R^4e taken together with the atom to 15 which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3 alkyl. Useful compounds of Formula Γ or Formula I include those where R^4b and R^4c taken together with the atom to which each is attached form a piperidin-2-one or a pyrrolidine-2-one, optionally substituted one or two times with methyl.

R⁴⁹I .0

[0114] Useful compounds of Formula J’ or Formula I include those where R⁴ is , wherein

R^4g is selected from the group consisting of Cô-Cio monocyclic or fused bicyclic aryl and C1-C3 alkyl. Useful compounds of Formula I’ or Formula I include those where R^4s is selected from the group consisting of phenyl and methyl.

[Ol 15] Useful compounds of Formula I’ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing one or two heteroatoms; wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting ofoxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and Cj-C3 alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-Ci alkyl, and Cô-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl. Useful compounds of Formula I’ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl or oxo; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein said phenyl is optionally substituted with methoxy. Useful compounds of Formula Γ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is

[Ol 16] Useful compounds of Formula Γ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is attached form a lO- or l l-membered fused bicyclic heterocyclyl 5 containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, C1-C3 alkoxy, hydroxy, and halogen. Useful compounds of Formula Γ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is attached form a

[0117] Useful compounds of Formula Γ or Formula I include those where R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH2)sC(=O)NR^kR^l; wherein, s is 0, l, or 2; R^k is hydrogen or C1-C3 alkyl; and R¹ is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl; and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein, R^q is hydrogen or C1-C3 alkyl; R^w is Cs-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy. Useful compounds of Formula Γ or Formula 1 include those where R³ and R⁴ taken together with the nitrogen atom to which

[ΟΙ 18] Useful compounds of Fonnula Γ or Formula I include those where R^x, in each instance, is methyl. Useful compounds of Formula Γ or Formula I include those where m is 0. Useful compounds of Fonnula Γ or Formula 1 include those where m is 2.

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

[0120] Table 1. Where the mass for a compound is not provîded in Table 1, the mass can be found for the compound in the synthetic examples.

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
1	p PM)	10-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]-10azatricyclo[6.3.1.0^A{2,7}]dodeca2,4,6-triene	355
2	/ o 8	7-methoxy-3-[2-(pyridin-2-yl)- 5H,6H,7H- cyclopentafd] pyrimidin-4-yl]- 2,3,4,5-tetrahydro-l H-3benzazepine	373.1
3	M3 ÇA X	6'methoxy-3-[2-(pyridin-2-yl)5Η,6Η,7Η- cyclopenta[d]pyrimidin-4-ylj2,3,4,5-tetrahydro-lH-3- benzazepine	373

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
4	\ /=\ /T^n VL A ^νΠ	l -(3-methoxy pbeny l)-4-[2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimî din-4-y !]-1,4diazepane	402.1
5	.A Ch O	N -(py ridin-2-y ] )-2- {[2-(pyridin-2yl)-5H,6H,7Hcyclopenta[d]pynmidin-4yl]amino}acetamide	347.1
6	Q. HN^O A VL A^ ^νΊπ ^νΆ	N-(2-fluorophenyl)-2-{[2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrîmidin-4y l ] am î no} acetam i de	364.1
7	Q JKp <v^ ° ^z=\ w	2-{[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}-N-(quinolm-7yl)acetamide	397.1

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
8	Vk N^lN	N-tert-butyi-2-{[2-(pyrimidin~4- yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- y J \|amino] acetamîde	327.2
9	Hr	CZ ⁷z y—z o \__/ X	N-tert-butyl-2-{[2-(pyridia-2-y!)5H,6H,7H-cyclopenta[b]pyridin4-yl]amino}acetamide	325.1
10	HP	W_ \=z ¹z=/	N-tert-butyl-2-{[2-(pyridin-2-yl)5,6,7,8-tetrahydroquinazolin-4y]]amino} acetamîde	340.1
11	\ O O o iz y=z M	N-(4-methoxyphenyl)- i-[2(pyridin-2-yi)-5H,6H,7Hcyclopenta[d]pyr!midin-4yl]piperidin-3-amine	402.4

Compound No.	Structure	KJPAC Name	Mass Found (M+l)
I2	HN^O tel	N-tert-butyl-2-{[2-(5- meth oxy py razi n - 2 -y 1 )-5 H, 6H, 7 Hcyc]openta[d]pyrimidin-4yl](methyl)amino}acetamide	371.2
13	jM ^z=\ Z— /	2-[4-(azepan-1 -yl)-5H,6H,7Hcy cl openta[d] pyrimidin-2-y 1 ]N,N-dimethylpyridîn-4-amine	338.1
14	0 < L if ^νΎΥ	1 -[2~(4-methylpyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl]azepane	309.2
15	Μ O Μ /M O Z—G Z	N-(2-methoxy phenyl )-2{methyl[2-(pyridin-2-yl)5Η,6Η,7Ηcyclopenta[d]pyriniidîn-4yl]amino}acetamide	390.3

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
16	HN	^0			N-tert-buty l-2-{ methyl [2-(pyndin2-yl)-5H,6H,7Hcyclopenta[b]pyridin-4-	339.2
	'Ν'			yl]amino}acetamide
	f	Ύ N,
17	NH			N -c y c l o hexy l -1 - {met hy l [2(pyridîn-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-	392.2
				yl]amîno}cyclopropane-l-
				carboxamide
	/''''Ύ'N < II
	\ As. A N	N.
I8	H o—			2-{4-[(5aS,8aS)-octahydro-2H- cyclopenta[b][l,4]oxazepîn-5-yl]-
	^aX-n	J		5H,6H,7H-
	H ï	N II		cyclopenta[d]pyrimidin-2yljpyridine
			Y η
19	H	A ..A			N-tert-butyl-2-methyl-2{methyl [2-(pyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4-	368.1
	/'N'	N II		yl]amîno}propanamide
			Yj

Compound No.	Structure	[UPAC Name	Mass Found (M+l)
20	Ai i h λΛ° ¹< 1 if ^NAf>	N-tert-buty 1-2-{phenyl [2-(pyridin- 2-yl)-5H,6H,7H- cycJopenta[d]pyrimidin-4yl]amino}propanamide	415.8
21	A	2-{methyl [2-(pyridin-2-y] )5H,6H,7H- cyclopenta[d]pynmidin-4~ yl]amino}-N-(quînolin-7yl)acetamide	411.2
22	Q Y > O^NH ”V Z^V^N VU A ^Nn	N-(2-fluorophenyl)-2-{methyl[2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	378.2
23	HN^O V /V'N W N V	N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5,6,7,8- tetrahy droquinazolin-4- yl]amino}acetamide	354.2

6l

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
24	HN^O \ k if	N-tert-butyl-2-{methyl[2-(4methy lpyridin-2-y l )-5 H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	354.2
25	0 —C \ /—\ z=< zÀ ; / \ I \ / W	2-{methyI[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}-N-(1- methylcyclohexyl)acetamide	380.3
26	PyJ o \=z ^xd ’O	2-{methyl [2-(pyridin-2-yl )- 5H,6H,7H- cyclopenta[d]pyrimidm-4yl]amino}-N-(oxan-3yl)acetamide	368.2
27	O cT	N-benzyl-2-{methyl[2-(pyridin-2yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]aniino}acetamide	374.2

Compound No.	Structure	1UPAC Na me	Mass Found (M+l)
28	T _o Z Z \\ //	N-tert-butyl-2-{[2-(5- hydroxypyrazin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4y l ] (m ethy l )am i no} acetami de	357.2
29	H <Ύ^ΝΥ° ^u <i> λ/ν N^J	N-cyclohexyl-l-[2-(pyridin-2-yl)5H,6H,7Hcyc!openta[d]pyrimidin-4yl]azetidine-3-carboxamide	378.3
30	I O z=\	N-cyclohexyl-1 -[2-(4methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyriniidin-4yl]azetidine-3-carboxamide	392.4

Compound No.	Structure	IUP AC Naine	Mass Found (M+l)
31	O^NH 'N' /An < I ï ^N n	N-(l-methyl-2-oxopyrrolidin-3yl)-2-{methyl[2-(pyridin-2-yl)5H,6H,7Hcyclopenta[d] pyrimidin-4yl]amino}acetamîde	381.3
32	_FJ / ⁰ C. ' O HN^O Vk A ^ΝΑίΊ N^ÿJ	N-(2,2-difluoro-2H-l,3benzodioxol-5-y l)-2-{ methyl [2(pyridin-2-yl)-5H,6H,7HcyclopenÎa[d]pyrimidin-4yl]amîno}acetamîde	440.3
	HN^-O Ah /An A)	N-tert-buty i-2- {[2-(pyrimidîn-2yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 ] am i no } acetam id e	327.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
34	/ O	N-tert-butyl-2-{[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrîniidin-4y l ] ( m ethy l )am i no} acetam i de	370.2
35	hnS.o Λκ n VU A x n ]iT °	N-tert-buty l-2-( {2- [4(methoxymethyl)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](metliyl)amino)acetamidc	384.2
36	O ,^ZA Va² v7 O	N-tert-buty l-2- {ethy l [2-(py ridin-2yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl] amino }acetamide	354.2
37	U 4+ \=z ) z=/ Ç } ° \_/ X	N-tert-buty1-2-[(2hydroxy ethy l)[2-(py ridin-2-y 1)5H,6H,7Hcyc!openta[d]pyrimidin-4yl]amîno]acetamide	370.2

Compound No.	Structure	ÏUPAC Na me	Mass Found (M+l)
3S	q/ d	2- {methyl [2-(py ridîn-2-y l)5H,6H,7H- cyclopenta[d]pyrünidin-4y l]amino} -N-[(pyridin-2yl)methy]]acetamide	375.2
39	I O O· Z—4 Z yft b	N-tert-butyl-2-({2-[6-(2- hydroxyethoxy)pyrîdin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	400.2
40	r-O I	N-tert-buty]-2-({2-[5-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimÎdîn-4y l} (methyl )amino)acet amide	400.3

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
41	HN^.O Ή'' Vk A N ^OH	N-tert-buty 1-2-( {2-[4(hydroxymethyl)pyridin-2-yi]5H,6H,7Hcyclopenîa[d]pyrimidin-4yl}(methyl)amino)acetamide	370.2
42	H O^N^Ά Ar n L L if ^N ikV^ ^νΆ	N-tert-buty 1-2- {methyi[2-(4methy lpyridîn-2-y 1)-5,6,7,8tetrahydroquinazolin-4yl]amino}acetamide	368.2
43	T O O \=:z O	N -tert-buty 1-2-( {2-[5-(2hydroxyethyl)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl} (methyl )amino)acetamide	384.2
44	T Q O	N-tert-butyl-2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cy c lop enta [ d] py rim i di n -4yl} (methyl )amino)acetami de	400.2

Compound No.	Structure	IUP AC Name	Mass Found (M+l)
45	—\ NT H 7 Zr' < Il	2-{4-[(5aS,8aS)-octahydro-2Hcyclopenta[b][ 1,4]oxazepin-5-yl]5H,6H,7H- cyclopenta[d]pyrimidin-2-yl}-4methylpyridine

46		l-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]azepan-2-one
	/V^N χ II

47	<-NH Cr N	442-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yi]-l,4diazepan-2-one	310
	zz^x n < i j]
	N-M
48	a? h T ZM^N < II	2-{4-[(5aS,8aR)-octahydro-2Hcyclopenta[b][ 1,4]oxazepin-5-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-2- yljpyridine
	^νΛζ

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
49	O H ï ^νΎΥ	2- {4-[(5aS,8aR)-octahydro-2Hcyclopenta[b][l,4]oxazepin-5-yl]- 5Η,6Η,7Η- cyclopeiita[d]pyrimidin-2-yl}-4m ethyl pyridine
50	O V-NH λΧν VA ^N tA	t-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]py rîmi din-4-yl ]-1,4diazepan-5-one	309.9
51	β, z 7-z o X H_z/ / \ I \	(2R)-N-tert-buty]-2-{methyl[2(pyndin-2-yi)-5H,6H,7Hcyciopenta[d]pyrimidin-4yl]amino} propanam ide	354.4
52	μ P M	(2S)-N-tert-buty!-2-{methyl[2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}propanamide	354.4

Compound No.	Structure	1UPAC Name	Mass Found (M+1)
53	—O °ç	l-[2-(4-inethoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl]azepane	325.1
54	a? h JL U ï ¹ ^νΎΥ N A	2-{4-[(5aS,8aR)-octahydro-2Hcyclopenta[b][l,4]oxazepin-5-yl]5I-I,6H,7H- cyclopenta[d]pyrimîdin-2-yl}-4methoxypyridine
55	H , CK,N / ΗνΆ^ 1 H VU Λ ^N n A	(3 R)-6,6-dimethyl-3-{ [2-(pyridin2-yl)-5H,6H,7H- cyclopenîa[d] pyrimi din-4- y l]ami no} pi péri dîn-2-one	338.2
56	A O —L^-*¹²=\ °	(3S)-6,6-dimethyl-3-{[2-(pyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl] amino} pi peridin-2-one	338.2

Compound No.	Structure	1UPAC Name	Mass Found (M+l)
57	hnÇ^o /^r'N _Λ vk A ^N Ύγ	N-tert-butyl-2-{[2-(4cy c l o propy 1 py rid i n-2 -y 1 ) 5H,6H,7Hcyciopenta[d]pyrimidin-4yl](methyl)amirio}acetamide	380.2
58	LL· θ / ^z \ /M O	N-tert-butyl-2-{[2-(4fluoropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîdin-4yl](methyl)amino}acetamide	358.1
59	Ht¹	c^o Λ 1 /X ^Ντίη	N-tert-buty 1-2- {methyl [2-(6- methylpyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- y 1 ] am ino }acetamide	354.3
60	Hr	< x.0 V L iï ^Νητγ	N-tert-butyl-2-{[2-(4,5dimethylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	368.2

7l

Compound No.	Structure	HJPAC Name	Mass Found (M+t)
61	id p	N IQ	x O 2 o iz )—z	N-( l -hydroxy-2-methylpropan-2y l)-2- {methyl [2-(pyrîdi π-2-y l)5H,6H,7Hcyclopenta[d]pyrimidin-4y l ] amino} acetamide	356.2
62	id o	N h	H HJ N,../Z	N-( l -hy droxy-2-methy l propan-2y l)-2- {inethy i [2-(4-methy Ipyridin2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino} acetamide	370.1
63	id p	N lj^	H N^J	N-(4-hydroxy-2-methylbutan-2yl)-2-{methyl[2-(pyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y]]amino}acetamide	370.3
64	/y/ o	N IQ	H '^N^\> ¥Ύ N^-¹	N-cy clopenty I-2- {methy l [2-(4methylpyridin-2-yl)-5H,6H,7Hcyc iopenta[d] py rimi di n-4yl]amino}acetamide	366.2

Compound			IUPAC Name	Mass Found
No.	Structure		(M+l)
65	0¾	H / T T ° N II	2- {methyl [2-(4-methy lpyrîdin-2yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amîno}-N-(3-methyloxolan-3yl)acetamide	382.3
		H ' \|
66	°A	H	N-(3-fluorophenyl)-2-{methyl[2(4-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrÎmidin-4yl]amino}acetamide	392.1
	< \| n
	^74	H Zf N
67		H .N.^	N-tert-buty l-2- {methy l [2(pyrimidin-2-yl)-5H,6H,7Hcy c l ope nta[ b ] py rid i n-4 y l] amino} acetamide	340.1
		\ il

68	CK	H	N-tert-butyl-2-{methyl[2-(4methylpyridni-2-yl)-5H,6H,7Hcyclopenta[b]pyridin-4yl]amino} acetamide	353.2
		4 // / ^Z

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
69	Q z z. V- z o Vz M Z=< ZI ^d J Ά>	N-[2-( l -cyclobutyl-5-methyl-1Hinnidazo]-2-yl)ethylJ-2-{methyi[2(pyridin-2-yl)-5H,6H,7Hcyclopenla[d]pyrimidin-4y l]amino} acetamide	446.2
70	H J T ) Ά ⁿ'N /'Ά'ν ÇA A ⁿAîA	N-[5-(azepan- l-yl)-l,3,4thiadiazol-2-y ] ]-2- {methyl[2(pyridin-2-y1)-5H,6H,7Hcyclopenta[d]pyrimidin-4yljaminojacetamide	465.3
71	0 f \ I. a À ^NAA ^νΆ	l-(2-(3-fluoropyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yljazepane	312.4
72	ft N /aA'n \ JL L ^N tA	5-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]-2oxa-5-azabicyclo[2.2.1 ]heptane	295

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
73	i			N-methyl-2-(pyridin-2-yl)-N- [(pyridin-2-yl)methy]]-5H,6H,7H- cyclopenta[d]pyrimidin-4-amine	317.9
	N^J	N
		N^ÿ
74		H		N-(3-fluorophenyl)-2-{methyl[2-	379
	CK	A	F	(pyridîn-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-
				yj] amino jacetamide
	ΛίΥ < \| h
	'''W	Y l
75		H		N-(4-methoxyphenyl)-2-	390.1
		T „		{methyl [2-(pyridin-2-yl )- 5H,6H,7H-
	'N''		o I	cyc!openta[d]pyrimidin-4-
	/A^N			y l ] am i no} acetam i de
	N	o
76		N II		l-[2-(pyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]1,2,3,4-tetrahydroquinoline	329.1
		rA

Compound No.	Structure	1UPAC Name	Mass Found (M+l)
77	H T IJ	2-{ methy l[2-(pyrî din-2-y 1 )5H,6H,7Hcyclopenta[d]pyriniidîn-4yl]amino}-N-phenylacetamide	360
	A'Z'N \ Il

78	H û.^ ,N.. 'Ν'	N-cyclohexy l-2-{ methy l [2(pyridin-2-yl)“5H,6H,7Hcyclopenta[d \| pyrimidin-4y 1] amino} acetamide	366
	ZZ^N x 1 L
	^N^J
79	H O. .N. J Z Z N ZZ^n < Il	2- {methy 1 [2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yi]amino}-N-(oxan-4yl)acetamide	368.1
	^νΛτΖ N^V
80	U Va ''—z z-	N-ethy l-2-(pyridin-2-y l )-N- [(pyrimidin-2-yl)methyl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4-amine	333
	Ζτ N < Il
	ⁿVz N^Z

Compound No.	Structure	ÏUPAC Naine	Mass Found (M+1)
SI	/ Z	N-methyl-2-(pyridin-2-yl)-N[(pyrimid in-2-y l)methy 1]5H,6H,7Hcyclopenta[d]pyrimidin-4-amine	319.1
	/^T^N < Il
	^νΛΓ7
82	kZo	N-[( 1,3 -benzoxazol-2-y l)methy 1] N-methyl-2-(pyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4-amine	358

	< ! \|i

83	\—ç	3-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîdin-4-yl]2,3,4,5-tetrahydro-l H-3benzazepine	343

	Λκ n \ Il
	N^¹

Compound No.	Structure	IUPAC Name	Mass Pound (M+l)
84		N	N \|\|	N-(2-methoxyethyl)-N-methyl-2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine	285
		N	Τι η
85	N — S	N		l-methyl-4-[2-(pyridin-2-yl)- 5H,6H,7H- cyclopentafd] pyrimidin-4-y l ] -1,4 diazepane	310.1

86	O. N	'N	ⁿ-V	2-{ methyl [2-(pyridin-2-y l)5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}-l-(morpholin-4yl)ethan-l-one	354
			TA N^A

Compound No.	Structure	IIJPAC Name	Mass Found (M+l)
87	Q o. A'·'	N f NJ ⁿ A	N-methyl-N-(2-phenoxyethyi)-2(pyridin-2-y])-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine	347
88	o. 'Ά < L h	NJ ^νΆ	2-{ methyl [2-(pyridin-2-y i )- 5H,6H,7H- cyclopenta[d]py rimi di n-4- yl]amîno}-1 -(piperidin-1 -yl)ethan1-one	352.1
89	R z A^z p \=Z \-d	H	N-tert-butyl-2-{methyl[2-(pyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}acetamide	340
90	nj	H A Ii η	N-tert-buty 1-2- {methyl[2-(pyridin2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}propanamide	354.4

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
9I	X	N-cyclohexy l-2- {methyl [2(pyridin-2-y!)-5H,6H,7Hcyclopenta[d]pyrimidin-4y l ] am i no} pro panami d e	380
	/A^xN < Il

92		l-[2-(pyridin-2-yl)-5H,6H,7Hcy c ! o penta [d] py ri m i d i n -4 yl]azepane	295.2
	Γτ n < II

93	-Q 0	4-[2-(pyrîdîn-2-yl)-5 H,6H,7Hcyclopenta[d]pyrimidm-4-yl]-1,4oxazepane	297.2
	Λγ n

94		l -[2-( i ,3-thiazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yljazepane	301.2
	/X^N \ Il
	N=/

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
95		3- {methy l[2-(py ridî n-2-y 1)5H,6H,7Hcyclopenta[d]pyrimidin-4y]]amino}-l -pheny]pyrrolidin-2one	386.3
96	0ό zv O ¹	l-[2-(4-chloropyridîn-2-y])“ 5H,6H,7H- cy c 1 openta[d] py rimi d i n - 4yl]azepane	329.3
97	Bo D Z	1 -[2-( 1 -methyl-1 H-imidazol-4-y 1)5H,6H,7H- cyclopenta[d]pyrimidin-4yl]azepane	298.2
98	U, UL Q IZ /^- —\ ^z^\ O z-Z. z. ' b	2- {methyl [2-(pyridin-2-y 1 )- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amîno}-N-[l- (trifluoromethyï)cyclopropyl]aceta mide	392

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
99	y? < 1 if		F 1 0	2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[l(tnfluoromethyl)cyclopropyl]aceta mide	421.7
100	H ° _γ Ύ Z'rN i VL A J ^νΎΥ	N-tert-butyl-2-{[2-(4-ethylpyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide	368.2
101	Q, Z y—Z o rT	o		(2R)-N-tert-buty 1-2- {[2-(4ιηεΐΚοχγργπάίη^-γΟ-ίΗ,όΗ,ΖΗcyclopenta[d] pyrim i din-4yl](meîhyl)amino}propanamide	3844
102	z*Y-z^Z p 2={ ZT O y	n.		N-tert-buty 1-2-( {2- [4(dimethylamino)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl((methyl)amino)acetamide	383.2

Compound No.	Structure	IUPAC Naine	Mass Found (M+I)
103	O 1	N-tert-butyl-2-{methyl[2-(3methylpyridin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4yl]amîno}acetamide	354.2
104	% H IZ 3=z —\ ^z=\ o zA z ' u	N-tert-buty 1-2-{methyl [2-(5methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîdîn-4yl]amino}acetamide	354.1
105	H i ^o<vⁿ>L AA /AA < L X ^ΝΑίΎ	2- {methy 1 [2-(4-methy 1 pyrîdin-2yi)-5H,6H,7H- cyclopenta[d]pyrimidin-4yi]amino}-N-(l- methylcyclopentyl)acetamide	380.2
106	oN H A' zA'n	N-tert-butyl-2-{methyl[2(pyrimidin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4yl]amino}acetamide	341.2

Compound No.	Structure	IUPAC Name	Mass Found (M+I)
107	I x O 4 \ χ V —4—Z 'd	N-tert-butyl-2-({2-[5-(2hydroxyethyl)-] ,3-thiazol-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	390.2
108	o A^z A ta w	(2R)-N-cyclohexyl-2-{methy![2- (pyridin-2-yl)-5H,6H_s7H- cyclopenta[d]pyrimidjn-4yl]amino}propanamide	380.4
i09	? O^NH Z^-A'N VU A ^NWi ^N A	(2R)-N-(3,3*difluorocyclobutyl)2-{ methy! [2-(pyridin-2-yl )5H,6H,7Hcyc1openta[d]pyrimidin-4yl]atnîno}propanamide	388.3
110	o V^z M / θ TZ A Z	N-tert-buty 1-2-[methy 1(2-{IHpyrazolo[3,4-c]pyridin-5-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	380.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
111	F O^NH VY Λ n Y	N—	2-{methyl[2-(1-methyHH- imîdazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}-N-[l- (trifluoromethyl)cyclopropyl]aceÎa mide	395.2
l !2	tx.i /Α^Ν \ JL ï	ilH ν' N— N==/	(2R.)-N-tert-butyl-2-{ methyl [2-( 1 methyl-1 H-imidazoî-4-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y l] amino} pro panam ide	357.4
H3	⁷	IH I Z	χ/χΖ^Η	N-tert-butyl-2-({2-[4-(2hydroxyethyl)pyridin-2-yi]5H.6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	384.2
H4	fl. Z y—Z O VA ?	fl F	JH HJ ^JxA	(2R)-N-tert-butyl-3-methyl-2{methy 1 [2-(pyrî din-2-y 1)5H,6H,7Hcyclopenta[d]pyrim i din-4y l]amino} butanamide	382

Compound No.	Structure	IÜPAC Name	Mass Found (M+l)
115	q z ri— z o /	NH N^J	(2S)-N-tert-butyl-3-methyl-2{methyl[2-(pyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}butanamide	382
116	ri' O z A z 0 ri w / / f —4--	IH 1	(2R)-N -tert-butyl-2- {methyl [2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}-4- (methylsulfanyl)butanamide	414
117	O^N ~Ά' /riA'l \A A ^{N r} N	H	(2S)-N-tert-buty 1-2- {methy 1[2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}-4- (methylsulfanyl)butanamide	414.1
118	riA /riA < 1 x ^N r%- N^/	(2R)-N -cyclohexy 1-2- {methy 1 [ 2( I -methyl-1 H-îmidazol-4-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amiiio}propanamîde	383.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
119	z^^-z⁷ o \=z —d ,—. Z=< * Z—( } / \ T \__/ /O	(2R)-N-cyclohexyl-2-{[2-(4methoxypyridin-2-yl)-5l·f,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}propanamide	410.1
120	R'. z y-z o _z R^z / -Æ— ~Λ V O y =	(2S)-3-(tert-butoxy)-N-tert-butyl- 2- {methy 1 [2-(pyridin-2-y 1 )- 5H,6H,7H- cyclopenta[d]pyrimidin-4y!]amino}propanamide	426.1
121	Cto, N H ΛΆ < I if ^νύα ⁿx	(2R)-3 -(tert-butoxy )-N-tert-butyl 2-{ methy I [2-(pyridin-2-y 1 )5H,6H,7H- cyclopenta[d] pyrimidi n-4yl]amino}propanamide	426.1
122	z^“\ o O O Pa /^z=\ ’ H	N-tert-butyl-2-[(2-{2H,3H- [l,4]dioxino[2,3-c]pyridin-7-yl]5H,6H.7H- cyclopenta[d]pyrimidin-4y l )(m et hy l )am i no] acetam i d e	398.2

Compound No.	Structure	IUPAC Name	Mass Fourni (M+l)
123	° z A	(2S)-N-tert-butyl-3-hydroxy-2- {inethyl[2-(pyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4y l ] ami nojpropanamide	369.9
124	A^OH ΛρΝ Vk A/\ ⁿaîA	(2R)-N-iert-butyl-3-hydroxy-2{methyl [2 -(pyridin-2-y l)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino] pro panam ide	370
125	oJih Ά /Άν vA A ^NYv N=y	N-tert-butyl-2-{ methyl [2-(l methyl-lH-imidazol-4-yl)- 5H,6H,7H- cy c l op enta [d ] py ri m i d i n-4yl]amino}acetamide	343.2
126	0 jiH AA A n r	N-tert-butyl-2-{ethyl[2-(4methoxypyridin-2-yl)-5H,6H,7HcycIopenta[d]pyrimidin-4y l]amîno} acetam ide	384.1

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
I27	H . J XI N N F /V'N VU A ^NV N	N-( 6-fl u oro py ri d i n- 3-y 1 )-2{methyl [2-(pyridin-2-yl)5H,6H,7Hcyc lopenta[d]pyrimi din-4yl]amino} acetamide	379.1
128	Jy/ o q y ' Π	N-(6-fluoropyridin-3-yl)-2-{[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	409.2
129	H j il ''N ^XN^F ZV^N XX ^Ννν N=/	N-(6-fluoropyridin-3-yl)-2{methyl[2-( 1 -methyl- 1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d] pyrimidin-4yl]amino} acetamide	382.2
130	y, Y /7° X w uy	(3 R)-3- {methy ! [2-(pyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}-l-phenylpyrrolidin-2- one	386
131	d Zj	(3 S)-3 - {methy 1 [2-(pyridîn-2-y 1)- 5H,6H,7H- cyclopenta[d]pyrîmidin-4yl]amîno}-l -phenylpynOlidin-2one	386

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
132	I / O	(3 R)-3- {[2-(4-methoxypyridin-2yl)-5H,6H,7Hcyclopenta[d]pyrimidîn-4yl](methy])amino}-l phenylpyrrolidin-2-one	415.9
133	I / O IZ \=z —\ O z—K Z ^zu	N-(2-hy droxyethyl )-2- {[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimid!n-4y 1 ]( methyl )am i η o} ac etam i de	358.2
134	z-o o Q b IZ / ^z A ÿ	2- ( [2-(4-methoxy pyridi ιι-2-y l)5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino} -N-(oxan-4yl)acetamide	398.2
135	H Ο. vX· ⁿmTY N-M	2-{ [2-(4-methoxypyridin-2-yl)5H,6H,7H- cyc!openta[d]pyrimidin-4yl](meÎhyl)amino}-N-(oxolari'3yl)acetamide	384.1

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
136	I z^z' 0 \ zA ZI 4 T o o / T	N-( I -hydroxy-2-methylpropan-2yl)-2-{[2-(4-methoxypyridin-2yl)-5H,6H,7Hcyclopenta[d] pyrimidin-4yl](methy])amino}acetamide	386.2
137	p, z ⁰ —ç zA ZI 4 ό _	N-cyclohexyl-2-{ [2-(4inethoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	396.2
138	Ο^.Ν^^,Ρ J LJ LL α^^,ο^ ^νΎΎ	N-(3 -fl uoropheny l )-2- {[2-(4methoxypyridin-2-yl)-5H,6H,7Hcycl opentafd] pyri midin-4y l](methyl)amino) acetam ide	408.2
139	Ce ^q/A ?=< O z—A z A	N-(l-methoxy-2-methylpropan-2yl)-2-{[2-(4-methoxypyridin-2yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}aceÎamide	400.2

Compound No.	Structure	ÏUPAC Naine	Mass Found (M+l)
140	H /Ά ÇA A o N ^A OH ⁿA	2-({2-[4-(2- hy droxyethoxy )py ri d in-2 -y 1 ] 5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxan-4yl)acetamide	428.2
141	Jy_z ^z o \=Z -4 zA ZI H 6^	N-[(lR,2R)-2- hydroxycyclohexyl]-2-{[2-(4methoxy pyridi n-2-y 1 )-5 H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	412.3
142	H A' AA aAn < 1 if ^N }7X	N-cyclohexy 1-2- {methy l[2-( 1 methyl-1 H-imidazol-4-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	369.2
143	H A A OH Ar n < 1 if ^NA%- NA	N-( 1 -hydroxy~2-methylpropan-2yl)-2-{ methy ! [2-( 1 -methy 1 -1 Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pynmidin-4yl]amino}acetamide	359.2

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
144	I I Ç P h )=z ° I	N-cyclohexyl-2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	426.2
145	</ \ % H IZ 3=z —\ ² A O Z—<Λ Z Tj	N-tert-butyl-2-{ [2-(4,5- dimethoxypyridin-2-yl)5H,6H,7H- cycïopenta[d]pyriinidin-4yl](methyl)amino}acet amide	400.2
146	H / (Χ,νΤ J L ⁰ V-Y ⁿ A	2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(3methyloxolan-3-yl)acetamide	398
147	R, Z y—Z O M O A¹	2-{methyl[2-( l -methyl-1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y l] amino} -N-(3~methyloxolan-3 yl)acetamide	371

Compound No.	Structure	ILJPAC Name	Mass Found (M+l)
148	H ^ογ^Νχ-οΗ /^r n vA n γ y oh	N-( 1 -hydroxy-2-methylpropan-2yl)-2-({2-[4-(2- hy d ro xy ethoxy )py ri d in-2 -y 1 ] - 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methy!)amino)acetamide	416.2
149	z O 0 b zz y=z	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyciopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxolan-3yl)acetamide	414.2
150	0 H¹ 1 \z	N-cyclopentyl-2-{methyl[2-( 1 methyl-1 H-imidazol-4-yl)5H,6H,7Hcyclopenta[d]pyrimidin~4yl]amino)acetamide	355.2
I5l	\ P ' 0 b iz yz oy	2-{[2-(4-methoxypyridin-2-yl)5H,6H,7H- cyclopenta[d]pynmidin-4yl](methyl)amino}-N-(6methoxypyridîn-3-yl)acetamide	421.2
152	H O^N N AA A^^^O. ^N zV	N-(5-methoxypyridin-2-y 1 )-2- {[2(4-methoxypyndin-2-y!)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	421.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
153	Z. z y-z p —\ z=Z M o %-z ^/ O \	2-{[2-(4-m ethoxy pyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](inethyl)aniino}-N-(2methoxypyrimidin-5-yl)acetamide	422.2
154	/ Z O 0 O IZ \=z I	2-{[2-(4-methoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(l-methyl1 H-pyrazol-4-yl)acetamide	394.2
155	' / aD IZ pz	2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(lmethyJcyclopentyl)acetamide	396.2
156	I °Ζ^Ν'γζ CfS ¹ ^ΝΎΥ Ν,^	N-tert-butyi-2-{[2-(4- methoxy pyridin-2-yl)-5 H,6H,7HcydopenÎa[d]pyrimidin-4- yl](methyl)amino}-Nmethylacetamide	384.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
157	Z z y— z o z=< z— O ^z o—	2-{[2-(4-methoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidîn-4yl](methyl)amino}-N,Nd i methy lacetam î de	342.2
158	—λ zA ZI q z o Z	N-tert-butyl-2-{[2-(4cyanopy ridi n-2-yl)-5H,6H,7Hcyc!openta[d]pyrimidin-4yl](methyl)amino}acetamide	365.2
159	o \=^ \—c / ZI <Q Ά o V	N-tert-butyl-2-({2-[4- (cyclopropylmethoxy)pyridin*2yl]-5H,6H,7Hcyc!openta[d]pyrimidin-4yl}(methyl)amino)acetamide	410.2
160	o Az \ zA ZI v- z	N-tert-buty l-2- {methy ! [2-( l methy l-l H-pyrazol-3-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amîno}acetamide	343.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
161	H / Ζτ 'N <L JT ^N N=V	2- {methy l[2-( 1 -methyl-1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}-N-(l- methy ley c l o p enty 1 jacetam i de	369.2
162	H °γ^ΝΧ Cr ï ¹ ΥΑ.,Α,Ν Y /> N-Z	N-tert-butyl-2-{ methyl [2-(lmethyl-1 H-imidazoi-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y i ] am i no} acetam i de	343.2
163	z= ° Z K	N-tert-buty 1-2-{methy 1[2-(1,3oxazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimid!n-4yl]amino}acetamide	330.2
164	H O^N^- zVn Χγ	N-tert-buty 1-2- {methy l[2-( 1,3 oxazol-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1] ami no] acetamide	330.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
165	z^/ o M Z=< 21 8	N-tert-buty 1-2- {[2-(isoqui nol in-3 - yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4y l](methyl )amino} acetam ide	390.2
166	M &	N-tert-butyl-2- [(2- {im tdazof 1,2a]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 )(m et hy 1 )am ino] acetam ide	379.2
167	H .F J IJ ^N’ ~ /'d'N N	N-(3-fluorophenyl )-2-( {2-(4-(2hydroxyethoxy)pyridin-2-yîj5H,6H,7Hcyclopenta[d]pyrimîdin-4y])(methy])amino)acetainide	438.2
168	/ T / \ R ° yy <H> TZ \=z ° A 1___	N-[(lR,2S)-2- hydroxycyclohexyl]-2-{[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4 yl](methyi)amino}acetamide	412.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
169	PA / Z A— z o A z Ap 4 a	N-[(lS,2R)-2- hydroxycyclohexyI]-2-{[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	412.2
170	LL ° Az ~Z.=(_ ZI o- o Z /	N-[(lR,2S)-2- hydroxycyclopentyl]-2-{[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidîn-4yl](methyl)amino}acetamide	398.2
I7l	PyL o \=H zV zi M A O ' X /	N-[(lS,2R)-2hydroxycyclopenty 1 ]-2- {[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 ]( methy 1 )am ί η o} acetamide	398.2
172	/ T O °-p K IZ Az p y	N-[(1R,2R>2- hydroxycy clopenty 1 ]-2- {[2-(4methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 ](methy 1 )am ino} acetami de	398.2

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
173	n OH ,Τό N AA nA	N-[(lS,2S)-2- hy d roxy cy c 1 openty 1 ] -2 - {[ 2- ( 4methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamLde	398.2
174	fl,. z )— z o /z z^Z zi w A o 0^' X	N-tert-buty 1-2-( {2-[4-(2-hydroxy2-methy 1 propoxy ) py ri di n-2-y 1] 5H,6H,7Hcyc!openta[d] pyrimidi n-4yl}(methyl)amino)acetamide	428.2
175	\=Z. S—f zA zœ r %	N-tert-butyl-2-{methyî[2(pyridazin-3-yl)-5H,6H,7Hcyc!openia[d]pyrimidin-4yl]amîno}acetamide	341.2
176	Ύ ZzAn < L II H ^N iYtA N AA	N4ert-butyl-2-[methyl(2-{ 1Hpy razolo[4,3 -c]py rîdi n-6-y l} 5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	380.2
177	JAo /z \ ZI M d o ? < ' o J1	2-[methyl({2-[4-(2,2,2- trifiuoroethoxy)pyrÎdin-2-yl]5H,6H,7H- cyclopenta[d] pyrimidi n-4yl})amino]-N-( 1 -methyl-lHpy razol-4-y !)acetam ide	462.1

ιοο

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
178	H OlZ	Q o—	2 - {[ 2 -( 4-m etho xy py r i d i π-2-y 1 )- 5H,6H,7H- cyclopenta[d]pyrimidin-4yi](methyl)amino}-N-(pyrimidin5-yl)acetamide	392.1
]79	ο” O O T	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin~4yl}(methyl)amino)-N-(lmeÎhylcyclopentyl)acetamide	426.3
180	o zZ' z	JH ii η	N-tert-buty 1-2- {[2-(3 methoxypyridin-2-yl)-5H,6H,7Hcy c1openta[d]pyrim idin-4yl](methyl)amino}acetamide	370.2
181	Q, Z />—Z O / * M /	JH OH ι Ί	N-tert-butyl-2-{[2-(3hydroxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acet amide	356.2

ιοί

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
182	OfS	IH V NH M=/	N-tert-butyl-2-{ [2-( 1 H-imidazol4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acet amide	329.2
183	riz h— z O A	JH H	(2R)-N-tert-butyl-2-[methyl(2- {1 H-pyrazolo[3,4-c]pyridin-5-yl}- 5H,6H,7H- cyclopenta[d] pyrîmî di n-4yl)amino]propanamide	394.2
184	<A A w 12 Z Z	2-[methyl(2-{ 1 H-pyrazolo[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrtmidin-4- yl)atnino]-N-(l- m ethy ley c lopenty l)acetamide	406.2

I02

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
1S5	z Z 'zi O οΆ x \ / L A^-^ z^z	2-[methyl(2-{ ] H-pyrazolo[3,4c]pyridin-5-yl}-5H,6H,7Hcyc]openta[d]pyrimidin-4- yl)amino]-N-(3-methyloxolan-3yl)acetamide	408.2
186	H °YⁿV^n A %Ao ï I COL ^NNA	N-(2-methoxypyrîmidin-5-y])-2{ methy l[2-( 1 -methyl-1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 ] am in o } acetam ide	395.2
187	Φ O^NH ctS VA A λ. N jV OH ^NxX	2-({2-[4-(2- hydroxyethoxy)pyridîn-2-ylJ5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyi)amino)-N-(6methoxypyridin-3-yl)acetamide	451.2

J 03

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
188	o— Cr N OlS Ά A	1 -(4-methoxyphenyl)-4-[2- (pyridin-2-yl)-5H,6H.7H- cyclopenÎa[d]pyrimidin-4-yl]-l,4diazepan-2-one	416.1
189	H j TJ Ά orS ^N ΎΎ ^N A	N-(4- fluorophenyl )-2- {[2-(4 methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d\|pyrimidin-4yl](methyl)amino}acetamîde	408.1
190	H O^N N J Tl 'N Α-Ά) cL ^N + N- N=/	N-(5-methoxypyridin-2-yl)-2{methy 1 [2-( 1 -methyl -1Himidazol-4-y])-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	394.2
191	V z λ—z o jvm /\ H H W / O 1 ( 1 \ 1 o I	N-tert-buty 1-2-( {2-[4-(2hydroxyethoxy)-5-methylpyridîn- 2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4yi}(methyl)amino)acetamide	414.2

104

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
192	- O / A	N-tert-butyl-2-{[2-(4-methoxy-5methylpyndin-2-yl)-5H,6H,7Hcyclopenta[d]pyrîmidin-4yl](meÎhyl)amino]aceÎamide	384.2
193	t X ' o	N-tert-butyi-2-{ [2-( l -ethyl-1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidîn-4y i](methy l)amino }acetam ide	357.2
194	H O^N^· ZV^'n < JL jf ^N r>	N-tert-buty l-2-{ [2-( l -ethyl-1Himidazol-5-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	357.2
195	H Z^tn \ L. jf ^N T^N-\ N=/ A-OH	N-tert-buty l-2-({2-[l -(2hydroxyethyl)-lH-imidazol-4-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	373.3

105

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
196	H n VU x HO	N-tert-buty]-2-({2-[l-(2- hy drox y ethy 1 )-1 H-i m i dazo 1 -5-y l]~ 5H,6H,7H- cyclopenta[d]pyrimidin-4- yj}(inethyl)amino)acetamide	373.3
197	H XX, X X-X /^X'N ÇA x^ N 7\| X^ OH ^NX	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(metbyl)amino)-N-(2methoxypyrimidin-5-yl)acetamide	452.2
198	H X X /X'N YA N η X OH nX	N-(4-fluorophenyl)-2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	438.2
199	H Y Y? 'n' Λτ n YY X^\ o N X^ X' OH ⁿA	2-({2-[4-(2- hydroxyethoxy)pyridîn-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4y]} (methy 1 )amino)-N-(6methylpyndin-3-yl)acetamide	435.2

106

Compound No,	Structure	IUPAC Name	Mass Found (M+I)
200	H T I A V-U ^NfY	2- {[2-(4-m ethoxypy ridi π-2-y I)5H,6H,7H- cyclopenta[d]pyrimidîn-4yl](methyl)amino}-N-(6“ methylpyridin-3-yl)acetamide	405.2
201	H °TV^N A AAk VU Λ ^NWiNî/	N-(6-methoxypyrîdin-3-yl)-2{methyl[2-( 1 -methyl-1Himidazol-4-yl)-5H.6H,7Hcyclopenta[d]pyrimidm-4y]]amino}acetamide	394.2
202	H J TA Ar n vl a ^N tV- Nî/	N-(4-f] uoropheny 1 )-2- {methy l [2( 1 -methyl-1 H-imidazol-4-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	381.2
203	Y A °K Vn A~r N A, if n ]A ^N V	4-(4-methoxy phenyl) -1 - [2(pyridi n-2-y 1 )-5 H,6H,7 Hcyclopenta[d]pyrimidin-4-yl]-1,4dîazepan-5-one	416.1

107

Compound No.	Structure	ÏUPAC Naine	Mass Found (M+l)
204	o A	(2R)-2-{methyi[2-(pyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4y!]amino}-N-(l- methy icy c 1 o propy 1 ) pro panam i de	352.1
205	Ho H A o	(3 S)-3- {[2-(4-methoxypyridin-2yl)-5H,6H,7H- cy c ! o penta [d] py r t m i d i n-4 - y l](methy 1 )am ino} -1 - phenylpyrrolidin-2-one	416.3
206	F 0 /Ά·_ΝVU Aoo ^νΆ	(3S)-l-(4-fluorophenyl)-3{methyl [2-(py ri di n-2-yl )5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}pyrrol!din-2-one	404.2
207	A N N' ΛύΑ ÇA A ^N n ^νΆ	(3 S)-3 -{methy l[2-(py ridin-2-y 1)5H,6H,7H- cyclopenta[d]pyrimîdîn-4yl]amino}-H1- m ethy 1 cy c i ope nty l )py rro 1 i d i n-2one	392.2

108

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
208	fri °γ-Ζ ZZ^N Vk Jk ⁿ A	(3 S)-3 -{methy l [2-(pyridin-2-y l)5H,6H,7Hcyclopenta[d]pyrimidîn-4yl]amino}-l-(pyridin-4yl)pyrroiidin-2-one	386.9
209	H O^N N J 11 ~N' '-'“A ΖΤ ^N Vk A O n hi η oh ^N V	2-({2-[4-(2- hydro xy ethoxy )pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyi)amino)-N-(5methoxypyridin-2-yl)acetamide	451.2
210	H CK „ Y YY Z' '''O'' Z^t~n . . AA n j\| oh n A	2-({2-[4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6methoxypyridin-3-yl)acetamide	479.3
211	O r^~ \=^ A 7 A Z’	N-tert-buty ]-2-[methy 1(2-{4[(oxetan-3-yl)meÎhoxy]pyridin-2- yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yl)amino]acet amide	426.2

109

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
212	R.-. ,Z^z	JH Il \| T J^R F	(2R)-N-tert-butyl-2-({2-[4- (difl uorom ethoxy )py r i di n-2-y 1 ] 5H,6H,7H- cy cl openta[d]pyrim idin-4- y[}(methyl)amino)-4(methylsulfanyl)butanamide	480.4
213	LL Z^Z'_Z Vx V O iz z /z A	2-({2-[4- ( d î fl uoromethoxy)py ri di n-2-y 1]- 5H,6H,7H- cyclopenta[d] pyrimidin-4yl}(methyl)amino)-N-(l-meÎhyl] H-pyrazol-4-yl)acetamîde	429.9
214	H O^N Z' Zf'N vA A ^N V N	H P ( O O X	2-({2-[4-(2-hydroxy-2* met hy l p ropo xy )py ridi n-2 -y 1 ] 5Η_;6Η,7Ηcyclopenta[d]pyrîmidin-4yl}(methyl)amino)-N-(5in eth oxy py ri d i n -2-y 1 )acetam i de	479.3
215	1Z )—z ^Z=\ ”Z	M zA 7 ¹	2-({2-[4- (cyclopropylmethoxy)pyridin-2yl]-5H,6H,7H- cyclopenta[d]pyrîmidin-4' yl}(methyl)amîno)'N-(l -methyllH-pyrazol-4-yl)acetamide	434.1

no

Compound No.	Structure	IÜPAC Name	Mass Found (M+l)
216	H °v^Np A^ Azq /''-AA ^'Vyv F	2-({2-[4- (difiuoromethoxy)pyridin-2-yl]- 5H,6H,7H- cy c 1 o penta [d ] py ri m i d i n-4 yl}(methyl)amîno)-N-(6fluoropy ridi n-3 -y l)acetainide	445.1
217	\ \ o Au. 0 h IZ Az \ z=( O Z-(\ Z 0	2-({2-[4- (difluoromethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4- yl }(methyl)amino)-N-(5- methoxypyridin-2-yl)acetaniide	456.9
218	ü, Z ^Z O Az A^¹Z A ZI M ri	2-{[2-(isoquînolin-3-y!)- 5H,6H,7H- cyc!openta[d]pyrimidin-4yl](methyl)amino} -N-( 1 - methy 1lH-pyrazol-4-yl)acetamide	414.0
219	1 1 ! \ O 2 0 f IZ \=z ^A f=\ U	N-(6-methoxypyridin-3-yl)-2[methyl(2-{ 1 H-pyrazolo[3,4c]pyridin-5-ylE5H,6H,7Hcyciopenta[d]pyrimidin-4y[)amino]acetamide	431.2

Compound No.	Structure	IUPAC Name	Mass Found (M+1)
220	H । y n— ZzV'N < I if ⁿX^n- N==/	N-( 1 -methyl-1 H-pyrazol-4-y!)-2{methyl[2-( 1 -methyl-1Himidazol-4-yl)-5H_i6H,7Hcyclopenta[d]pyrimidm-4y l]amî no] acetamide	367.2
221	O X² \ ZI 8 0 W 4	N-(6-fluoropyridin-3-yl)-2-{[2(isoquinolin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	429.1
222	H T Ix N' AkA. XX x^^ ^N τΤΥΥ n^W	2-{[2-(isoquinolin-3-yl)- 5H.6H,7H- cyclopenta[d]pyrimidîn-4yl](methy])annino}-N-(6methylpyridin-3-y])acetamide	425.2
223	P 0 h IZ / z —y Z y ” Z	2-{[2-(4-ethoxypyridin-2-y!)- 5H,6H,7H- cy clopenta[d]py rimidi n-4- yl](methyl)amino}-N-(6- methoxypyridin-3-yl)acetamide	435.2

112

Compound No.	Structure	IUPAC Name	Mass Found (M+i)
224	b, Z 9—Z o M zte ZI b 0 s. <	2-({2-[4- (cyclopropylmethoxy)pyridin-2yl]-5H,6H,7H- cy c 1 opentaf d ] py ri m ΐ d tn-4 yi}(methyl)amino)-N-(6methoxypyridin-3-yl)acetamide	461.3
225	H °_τ ^ν _Γν ν' ^N Y Y Y	2-({2-[4- (difluoromet hoxy )pyridin-2-y I]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N(6methoxypy ridin-3-y 1 )acetamide	457.2
226	cMo z Y IZ / ^z Y	N-tert-butyl-2-[(2- {2H[l,3]dioxolo[4,5-c]pyridln-6-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(meihyl)amino]acetamide	384.2
227	z^ Z o Y^z —c Z=< ZI 0 b XX cX	2-{[2-(isoquinoJ i n-3 -y 1 )5H,6H,7Hcyclopenta[d]pyriniidin-4yl](metbyl)amino}-N-(6melhoxypyridin-3-y])acetamide	441.3

113

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
228	Q Z b—Z O Ας \ zA ZI 0 c	2- {[2-( îsoquinolin-3 -y 1)5H,6H,7H- cyclopenta[d] pyrimidin-4- y 1 J(methy l)ami no} -N-(py ridin-3y])acetamide	411.3
229	LL LL _> A 0 1? IZ 2—Z	N-(6-methoxypyridin-3-yl)-2[methyl({2-[4-(2,2,2îrifluoroeÎhoxy)pyridin-2-yl]5H_;6H,7Hcyclopenta[d]pyrimidîn-4yl})amîno]acetamide	489.2
230	X. LL LL O All 0 b XZ >=z	N-(6-inethoxy py ridîn-3 -y l)-2[methyl({2-[4(trifluoromethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d] py rimidin-4yl})amino]acetamide	475.3
231	LL LL ! A A O xz Az ^z=\ O Z A Z À	2-[methyl({2-[4- (trifluoromethoxy)pyridin-2-yl]5H,6H,7H- cyck>penta[d] pyrimi din-4yl})amino]-N-( 1 -methyl-lHpy razo l - 4-y 1 ) acetam i d e	448.2

ll4

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
232	H CK^N N n' ΖΎ^ N Vk A nVn H	2-[methyl(2-{ lH-pyrazoiop,4c]pyridin-5-yl}-5H,6H,7Hcy c l op enta[d] py r im i d i n-4 y l)amîno]-N-( l -methyl-1Hpy razo! -3 -y l )acet amide	404.3
233	A A 0 H IZ Az V	2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cy c l op enta [d] py rimi d i n-4yl](methyl)amino}-N-(5methoxypyridin-2-yl)acetamide	441.3
234	H Wa a^f ''N' A^q-^f Zt^x n Vk A ⁿVAA ^νΆκ	2-{[2-(îsoquinolin-3-y!)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[6(trifluoromethoxy)pyridin-3yl]acetamide	495.2
235	H ZAZ \ JL A ^NxW	2- {[2-(îsoquinol in-3 -y l )5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methy])amino}-N-(5methylpyridin-3-yl)acetamide	425.2

115

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
236	X' Y ΧΖ Xz	2- {[2-(isoquinol in-3-yl)- 5H,6H,7H- cy c lopenta[ d] py ri m i di n - 4yl](methyl)amino}-N-(l-inethyllH-imidazol-4-yl)acetamide	414.3
237	üz y-z o Xz zX ZI M Y O *	2- {[2-(isoquinol in-3 -yl)- 5H,6H,7H- cyclopenta[d]pyrimidm-4yJ](methyl)amtno}-N-(l-methyll H-pyrazol-3-yl)acetamide	414.3
238	d i IZ / ^HX	2-({2-[4-(2- methoxyethoxy)pyridiii-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl} (methy l)amino)-N-(6methoxypyridin-3-yl)acetamide	465.3
239	\ o o K ô IZ z X f=\ o z4 z ' b	N-tert-butyl-2-({2-[4-(2- methoxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyciopenta[d \|pyrimidin-4yl}(methyl)amino)acetamide	414.3

116

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
240	H ογΝγΑ ^X N^x -Ά .A F Art N VU A ^NWrT ^N ΑΆ	N-(5-fluoropyridin-3-yl)-2-{[2(isoquinoiin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}aceÎamide	429.2
24]	zj/ o Az \—Ç Z=/ ZI p A o __	N-tert-butyl-2-({2-[4-(2fl uoro ethoxy ) pyridi n -2-y 1 ] 5H,6H,7HcyclopenÎa[d]pyrimidin-4y i} (methyl )amino)acetamide	402.3
242	LL d U IZ Az V /V • A	2-({2-[4-(2-fluoroethoxy)pyridîn- 2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(6- methoxypyridin-3-yl)acetamide	453.3
243	zj 0 A z zz M zd ? 1 Tl	2-( {2- [4-(2-fluoroethoxy)pyridin- 2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4- yl} (methyl)amino)-N-( 1 -methyl- l H-py razo 1 -4-y 1 lacetam i d e	426.3

117

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
244			H		N-( 6 -methoxy py ri di n-3 -y l )-2 -	442.2
	Cl·		-N J	'N	{methyl [2-( 1,7-naphthyridin-6- yl)-5H,6H,7H-
	^N'	'N			cy c lopentafd] py rim i diii -4y!]amino}acetamide
	\ ^A> N'	n	H Y	'N
245			H		N-tert-buty l-2-[methy l( {2- [4-	412
	0„				(oxetan-3 -y loxy)py ridin-2-y 1] 5H,6H,7H-
	A’	’N			cy c 1 ope nta[ d] py rim i d i n - 4yl} )amino]acetamide
	N'		T Y N^/	V-0
246			0^ An		(2R)-N-(6-methoxypyridin-3-yl)3-methy 1-2- {methyl [2-(py ridin-2-	433.2
					yl)-5H,6H,7HcyclopenÎa[d]pyrimidin-4yl]amîno}butanamide
	O;		NH
	A'	'N II
	\ Ax N'		YY

118

Compound No.	Structure	IUPAC Name	Mass Found (M+I)
247	\ /Ύ¹ Y- O VZyq *=< ^O X	(2 S )-N-(6-methoxy pyridin-3-yl)3-methyl-2-{methyl[2-(pyridin-2yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y l ] am ί η o} butanam ide	433.2
248	z \ \ / 1 ^x>—z /-- }=Z w z=<	(2R)-3-methyl-N-( 1 -methyl-1Hpy razol-4-yl)-2- {methyl [2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d] pyrimid in-4y l]amino} butanamide	406.2
249	A z y—z o X^z / Az z={ —\ z—G 1 / \ \ Z A-Z W	(2S)-3-methyl-N-( 1 -methyi-1 Hpyrazol-4-y l)-2- {methy l [2(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidiii-4yl]amino}butanamide	406.2

119

Compound No.	Structure	ÏUPAC Naine	Mass Found (M+l)
250	o A H Z=< * ZI Ά 0 \	(2R)-2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4- yl](methyl)amino} -N-(6- m ethoxy py ri di n-3 -y 1 ) propan am i d e	455.2
251	H />0'n vA. Jù o n oh ⁿ A	(2R)-N-(3-fluoropheny 1)-2-( {2-[4(2-hydroxy ethoxy )pyri din-2-y 1]5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amino)propanamide	452.3
252	H o^AA J V /^tAn ÇA x o - 'N γ Ί ^N > «A	N-(3-fluorophenyl)-2-[methyl(2{4-[2-(pyrrolidin-lyl)ethoxy]pyridin-2-yl} 5H,6H,7Hcyclopenta[d]pyrimîdin-4yl)amino]acetamide	491.3
253	H °γ^Νγ^ 'Ά /Xz ΑΧ M ^Vo	N-(6-methoxypyridin-3-y!)-2[methyi({2-[4-(oxetan-3yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]acetamide	463.3
254	0 A M z^ ZI M d 0 Z d ’	2-[methyl( {2-[4-(oxetan-3 yloxy)pyridin-2-yl]-5H,6H,7Hcyciopenta[d]pyrimidin-4yl} )amino]-N-( 1 -methyl-1Hpyrazol-4-yl)acetamide	436.2

120

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
255	AA Q J)	2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrÎmidin-4- y l] (methyl )ami no} -1 -(piperidin-1 yl)ethan-!-one	402.2
256	Tcf AA \ VJ	2-{[2-(isoquinolin-3-yl)5Η,6Η,7Ηcyclopenta[d]pyrimîdin-4yl](methyi)amino}-l -(4methylpîperazin-1 -yl)ethan-1 -one	417.3
257	H 0- /x. ] ]\| ^N N AA-qX /AA ^N ïi Ύ AA'xA	N-(6-methoxypyridin-3-yl)-2- { methy l [ 2 - ( l ,6-naphthyridin-7- y])-5H,6H,7H- cyclopenta[d]pyrimidin-4yl]amino}acetamide	442.2
258	dz Vz o J=* M Z=< ZI 0 0 ^Z O	N-(6-methoxypyrîdm-3-yl)-2{methyl[2-(2,6-naphthyridin-3yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl] amino }acetamide	442.2

121

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
259	8° ) T b ΙΖ Az V /^ZA A	2-{[2-(4-ethoxypyridîn-2-y!)- 5H,6H,7H- cyclopenta[d]pyrîmidin-4yl](methyl)amino}-N-(2m ethoxy py r i m i d i n - 5 - y i ) acetam ide	436.2
260	H LXa /A n s / A-U A ,-<., ^.0, N fA OH	2-({2-[4-(2-hydroxy-2methyipropoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl} (methyl)amino)-N-(2methoxy py rîm id in- 5 -y 1 ) acetam i de	480.2
261	ü. z Vz o Α^Λ A ^{1 z}=\ ^ZI M o	N-tert-butyl-2-{[2-(6- methoxyisoquinolin-3-yl)- 5H,6H,7H- cyclopenÎa[d]pyrimidin-4y l](methyl)amino} acetamide	420.2
262	L T—\ ^z \ o zA z fl	N-tert-butyl-2-{ [2-(7methoxyisoquinolin-3-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y 1 ]( methy 1 )am i no} acetam i de	420.2

122

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
263	Q p A Zz AJ	-θ^^ΌΗ	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-1 -(pîperidin-1 yl)ethan-i-one	412.3
264	H O^N J I 'N ZZ^N < 1 if ^N Ύ	TA 0	N-(6-fluoropyridin-3-yl)-2[methyl({2-[l-(oxan-2-yl)-lHpyrazolo[3,4-c]pyridin-5-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]acetamide	503.2
265	H 0^.N Z' ZZ^N < 1 if ^N T^	y ^z °\	N -( 5 -ni ethoxy py ri d i n-2 -y 1 )-2 [methyl(2-{ lH-pyrazolo[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	431.1
266	H N ZzA AA A ^Nr^:	TA H	N-(6-fl uoropy ridin-3-y !)-2[tnethyl(2-{ 1 H-pyrazolo[3,4c]pyridin-5-y]}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetainide	419.0

123

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
267	H T T A A AA^n VU A/^ nvV\ «Vn H	2-[methyl(2-{ lH-pyrazo!o[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]-N-(6-methylpyridin-3yl)acetamide	415.1
268	H °VAn Ά Ar n VU A ^NViVV ^N aVⁿ	N-(6-methoxypyridin-3-yl)-2{methy l [2-(2,7-naphthy ridin-3yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y!]amino}acetamide	442.3
269	zRh* O Az zA ZI M 0 ( O \ \ o I	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4- yi}(methyl)amino)-N-(4m eth oxy pheny l ) acet am i de	450.2
270	H Y’Vn 'n AA\ λΛ ^ho> AVVrv ^νάΑα	2-({2-[5- (hy droxymethy l)isoqui nolîn-3-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6methyipyridîn-3'yl)acetamide	455.2

124

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
271	H °._V ^N,_Z.,^F J ï J Ά AK n < I if ^Nr n- N=/	N-(3 -fluorophenyl)-2- {methy 1 [2( 1 -methyl-1 H-imidazol-4-y l)5H,6H,7Hcyclopenta[d]pyrimidin-4yl] amino }acetamide	381.2
272	.1/ O >^z M z—i ZI V 0 O /	N-(3-methoxypheny])-2{methy l{2-( 1 -methyl-1Himidazoi-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino} acetamide	393.2
273	ü. z ri—Z 0 z A A H V O ^z-z	(2R)-2-{[2-(isoquinolin-3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(pyridazin4-yl)propanamide	426.7
274	zl/ O >^z W Z=/ < ZI R ri w d^z -n	(2R)-2-{[2-(isoqutnolin-3-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[6(trifl uoromethy l)pyridin-3 yl]propanamide	493.7

125

Compound No.	Structure	IUPAC Name	Mass Found (M+i)
275	H Χ^ΝγΧο_Η /Xn vA X ^N Χν_λ OH	N-( 1 -hydroxy-2-methylpropan-2yl)-2-({2-[l-(3-hydroxypropyl)1 H-imidazoi-4-yl]-5H ,6H,7Hcyclopenta[d]pynmidin-4yl}(methyl)amino)acet amide	403.3
276	I o Y V p b IZ >=z X 7=\ Έ	2-[(2-{4-[(l-hydroxy-2- methylpropan-2-yl)oxy]pyridïn-2- yl}-5H,6H,7H- cy c 1 op enta[d] py ri m i di n -4 - y l )(methyî Jamino] -N-(2- methoxypyrimidin-5-yl)acetamide	480.3
277	LL 0 p ’ ‘R	(2R)-N-(3-fluorophenyl)-2{methy 1 [2 -( 1 -methyl- i Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}propanamide	395.2
278	H αν' 0A x_ X>	(2R)-N-(3-methoxy phenyl)-2{methyl[2-( 1 -methyl-1Himidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimîdin-4yl]amino} propanam ide	407.2

126

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
279	H T ï J ν' Λτ _N vA c ^N Vï ^N Y	''''OH	2-({2-[4-(2- hydroxyethoxy)pyrîdin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(3methoxyphenyl)acetamide	450.2
280	X/ o M z=Ç zi H Q 9 o I	N-(3-fluorophenyl)-2-({2-[4-(2hydroxy-2- methylpropoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	466.2
281	v n IZ Χλ /Y O Z—6 Z V	ν' Ύ ,o.	2-{[2-(4-methoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(l-methyl6-oxo-l,6-dibydropyridin-3yl)acetamide	421.2
282	O \ Z=< ZI Q Y	“1 0	2-[(2-{2H,3H-[l,4]dioxino[2,3c]py ridi n-7-yl} -5 H,6H,7Hcyclopenta[d]pynmidîn-4yl)(methyl)amino]-N-(3fluorophenyl)acetamide	436.2

I27

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
283	H T o A o N CF₃ ^ΧνΎΥ1	2-{[2-(isoquinolsn~3-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[5(trifluoromefhoxy)pyridin-3yl]acetamide	495.2
284	ζγ- Z o M Z A ZI M ô O '0Z o z	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4- y l} (methy l)ami no)-N-( 5methylpyrazin-2-yl) acetam ide	436.2
285	H CK,N. ,l< T U VU K/\ O Νγν 'OH ^NX	2-({2-[4-(2- hydroxyethoxy)py Hdin-2-y I ] - 5H,6H,7H- cyclopenta[d]pyrimidin-4- y l} (methyl )amino)-N-(6- methoxypyridazin-3-yi)acetamide	452.2
286	z o f U IZ \=z V	2-({2-[4-(2hydroxyethoxy )pyridin-2-yl ] 5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6methylpyridazin-3-yl)acetamide	436.2
287	zKz' 0 A M z=7 zz Μ K 7° 7^Z1	2- {[2-(4-methoxypyridin-2-yl)5H,6H,7H- cy c l o penta[d ]pyrimidin-4yl](methyl)amino}-N-(l-methyl2-oxo-1,2-dihydropyridin-4yl)acetamide	421.2

I28

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
288	H °γΟ^Ν /'γΑ ^dOC^NH	2-[methyl(2-{ lH-pyrazoîo[3,4c]pyridin-5-yl}-5H,6H.7Hcyclopenta[d]pyrimidin-4yl)amîno]-N-[6(trif]uoromethyi)pyridin-3yl]acetamide	469.1
289	LL P fl xz >=z \—\ z=( O^Z Z—ά Z À	N-(4-fiuorophenyl)-2-[methyl(2- {l H-pyrazolo[3,4-c]pyridin-5-yl}- 5H,6H,7H- cyclopeiita[d]pyrimidin-4- y ] ) am i η o ] acetami de	418.1
290	H °yOⁿ ^ΚΓ ^ΝάΥ₀^ /a<An a-U a~x n A ^oh ^νΎ	2-({2-(4-(2- hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4y l} (methy l)amino)-N-(5methoxypyrazin-2-yl)acetamÎde	452.3
29]	H YyV A' 'ν’ A-U YaAa n Yy oh	2-({2-[4-(2- hy droxy ethoxy )py ri d i n -2 -y l ] - 5H,6H,7H- cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2- methylpyrimidin-5-yl)acetamide	436.2

129

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
292	a z yz o Az \ zA ZI w /T A p s	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(3methylphenyilacetamide	434.2
293	bfl o V= z z=/ zz H d z X w	2-({2-[4-(2-aminoethoxy)pyridin- 2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amtno)-N-(3fluorophenyl)acetamide	437.2
294	p. Z Az o >^z M Z A ZI H Q s —z \	2-[(2-{4-[2- (dimethylamino)ethoxy]pyndin-2- yl}-5H,6H,7H- cy clopenta[d] pyriinidin-4~ yl)(methyl)amino]-N-(3fluorophenyl)acetamide	465.3
295	p. z y-z o Az \ zA zi Q <fl fl fl ( O \ \ o z	2-((2-(4-(2hydroxyethoxy)pyrîdin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(5methoxypyrimidin-2-yl)acetamide	452.3
296	T O z. ° A b zz Az V _jb fl	2-({2-[4-(2- hydroxy ethoxy ) py rid in-2-y l]- 5H,6H,7H- cyciopenia[d]pyrimidin-4yl}(methyl)amino)-N-(1-methyl1 H-pyrazol-4-yl)acetamide	424.2

130

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
297	H γπ 'Ν’ /Άν ÇA A ' N γγ/ ΟΗ	2-({2-[6- (hydroxymethyl)isoquinolin-3-yl]5H.6H.7Hcyclopenta[d]pyrimidin-4y l} (methy l)amino )-N-(6methylpyridin-3-yl)acetamide	455.2
298	P-4 o Çz \—Ç zÇ ZI -π γζ	2 - {[ 2 - (5 -fl uoropyridin-2-y l)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(6methylpyridin-3-yl)acetamide	393.1
299	R z V—z O Çz V—Ç Z=/ ZI γ A ΊΊ	N-tert-butyl-2-{[2-(5fiuoropyridin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4yl](methyl)amino}acetamide	358.1
300	Q. z Vz o r z Y zi V\ o	N-tert-buty l-2- {[2-(5 chl oropyridin-2-y l )-5 H,6H.7 Hcyciopenta[d]pyrimidin-4yl](methyl)amino}acetamîde	374.7, 376.7

I3l

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
30i	ω^ζ z M IZ V	N-tert-butyl-2-[methyi(2{[l,3]thiazolo[4,5-c]pyridin-6-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	397.2
302	H °TⁿTⁿ At m \ / N γ y OH J	2-({2*[4-(2-hydroxy-2methy Ipropoxy )py ridin-2-y l] 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6methylpyridin-3-yl)acetamide	463.3
303	H /Ά^Χ _Ν Vk A ^N ΎΥ ⁿ1_f	N-tert-bLityl-2-{[2-(5-fluoro-4methyIpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yî](methy!)ammo}acetamide	372.2
304	O AM zM zi 0 0 z_x ω A^z O \	N-( 6-m eth oxy py ri d i n-3 -y l)-2[methyl(2-{ [ l ,3]thiazolo\|4,5c]pyridin-6-yl}-5H,6H,7Hcycîopenta[d]pyrîmidin-4yl)amîno]acetamide	448.2

132

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
305	yy o A H 0 fl o d	(2 R)-N-tert-butyl-2-[methyl({2[4-(oxetan-3-yloxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl})amino]propanamide	426.3
306	H A' AaA AA^n ⁿ ύύ ^NAA	2-{[2-(5-fluoro-4’methoxypyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(6methylpyridin-3-y])acetamide	423.1
307	H ^O;AAz^f A’ A AA π A-U JJ N YV OH	N-(3-fluorophenyl)-2-[(2-{4-[(lhy droxycy clopropyljmethoxy] pyri din-2-yl}-5H,6H,7Hcyclopen1a[d]pyrïmidin-4yl)(methy!)amino]acetamîde	464.2
308	V O z A^z ° Az \ zA ZI O o Pz o I	N-(6-cyclopropylpyridin-3-yl)-2({2-[4-(2-hydroxyethoxy)pyridin- 2-y]]-5H,6H,7H- cyclopenta[d]pyrimidin-4y]}(methyl)amino)acet amide	461.2

133

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
309	d k IZ * )—z A ,A A	(2R)-2-({2-[4-(2- hydroxy ethoxy )pyridin-2-y l ] 5H,6H,7H- cyclopenta[d]pyrimidm-4yl}(methyl)amino)-N-(6tneth oxy py ri d i n-3 -y l ) p ro pan am i d e	465.3
310	Pyl 0 A H Z=/ * zi w H z, / ° i o I	(2R)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4y l} (methyl )amino)-N-( l -methy ll H-pyrazol-4-yl) propanam ide	438.2
311	H a < VL K n γ γ OH n J	(2R)-N-tert-butyl-2-({2-[4-(2hy d roxy etho xy ) py r i d in - 2-y l ] 5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)propanamide	414.3
312	H °vⁿY^n πΆ Aa^xzaAn AA ^N iY A ^V°	(2R)-N-(6-methoxypyridin-3-yl)2-[methy l( {2-[4-(oxetan-3yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimi di n-4y l} )amino]propanam ide	477.3

I34

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
313	o< ''N'	H _,N N	Ud	N-(4-fluoropheny!)-2-[methyl(2{l -methyl-1 H-pyrazolo[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl )amino]acetamide	432.1
	N'	II H Ν_χ.	ya \
314	0 n	H N 11	ii	N-(4-fluorophenyl)-2-[iTiethyl(2{2-methyl-2H-pyrazo!o[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	432.1
	N	II	Γ* N— X*N
315	^NyA 'bT \ I ï	F ^°·^-^·ΟΗ	2-({2-[4-({[l-(3-fluorophenyl)lH-l,2,4-tnazol-5- y l]methyl} (methy l)amino )- 5H,6H,7H- cyclopenta[d]pyrimidm-2yi]pyrîdin-4-yl}oxy)ethan-l-ol	462.2
316	O< 'N' N'	H I l N jf II	X O zd o O to.	(2R)-2-({2-[4-(2- hy droxy ethoxy )pyridin-2-y I]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6methylpyridin-3-yl)propanainide	449.3

135

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
317	o Y^z zY ZI -X P Q	N-tert-butyl-2-[methyl(2-(4-[(3S)oxolan-3 -y loxy]pyridin-2-yl }5H,6H,7HcyclopenÎa[d]pyrimidin-4yl)amino]acetamïde	426.2
318	H ''Ύ zvYn XX ^N^YYY γγ	N -tert-buty i-2-[methy l(2- {4[(3 R)-oxolan-3 -yloxy]pyridin-2- yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yl)amino]acetamide	426.3
319	IM _F γΌ Ύ /T n υΛ y o N YlY ^OH N-Y	2-( {2-[4-( {[4-(3-fluorophenyl)4H-l,2,4-triazol-3- y Ijmethy 1} (methy l)am ino)5H,6H,7H- cyclopenta[d]pyrimidin-2yl]pyridin-4-yl]oxy)ethan-]-ol	462.2
320	Y/y H v/AX νγ \ o o I	(3S)-l-(3-fluorophenyl)-3-({2-[4(2-hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimîdin-4yl}(methyl)amino)piperidin-2-otie	478.3

I36

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
321	I O O Z .p ’ff	(3R)-l-(3-fluorophenyl)-3-({2-[4(2-hy droxyethoxy )pyri di n-2-y l]5H,6H,7Hcyclopenta[d]pyrimidin-4- y 1} (methy ! )amino)piperi din-2-one	478.2
322	c o Z 0 —z >=z X _f=\ °	N-tert-buty !-N-methyl-2[methy 1( {2-[4-(oxetan-3yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yj})amino]acetamide	426.3
323	o q o o	2-[methy]({2-[4-(oxetan-3yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimid!n-4yl})amino]-l-(piperidin-1yl)ethan-1 -one	424.3
324	H y i je ζΎ^ν XX ^N ΤΐΊ VA N^J ^V°	2-[methyl({2-[4-(oxetan-3yloxy)pyridin-2-yl]-5H,6H,7HcyclopenÎa[d]pyrimidin-4yl})amino]-N-(6-methylpyridin-3yl)acetamîde	447.2

137

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
325	o H M zA ZI H 0 rX -	N-(4-chl orophenyl)-2-[methy l ( {2[4-(oxetan-3-yloxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]acetamide	466.2
326	d h IZ fz A	2-[methy l( {2- [4-(oxetan-3 yioxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]-N-(4methy l phenyl) acetam ide	446.2
327	r-° p 0 Ta tz Az V /^z=( O zA z / yp	N-(4-methoxyphenyl)-2[methy l( {2-[4-(oxetan-3 yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]acetamide	462.2
328	_zQ-z^Z o \=z \ ZA ZI M fl ω^ζ	N -te rt-buty l-2-[methyl(2{[],3]thiazolo[5,4-c]pyridin-6-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetainide	397.2

138

Compound No.	Structure	ÏUPAC Name	Mass Found (M+l)
329	zR^ ° \=z zZ ZI M 0 M .Z /-Z o \	N-(6-methoxypy ridî n-3 -y 1 )-2 [methy 1(2- {[ 1,3 ]thî azolo\|5,4clpyridin-6-yl}-5H,6H,7Hcyclopenta[d] pyrimidin-4yl)amino]aceÎamîde	448.2
330	a, z Vz o \=Z k— z=/ ZI Y P ç o T	2-[(2-{4-[(l- hydroxycyclopropy 1 )methoxy ] pyrî din-2-yl}-5H,6H,7H- cyciopenta[d]pyrîmidin-4- yl)(meÎhyl)amino]-N-(6- methylpyridin-3-y!)acetamide	461.2
331	H Y YY 'W /XX n VU X/^ 0 N J Y OH N A	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5- dimethyl-5H,6H,7H- cyclopenta[d]pyriniidin-4- yl}(methyl)amino)-N-(6- methylpyridin-3-yl)acetamide	463.3
332	O Az ZP ZI 0 H o *7^	N-tert-buty 1-2- {meth y 1 [ 2 - ( 4{[(2S_i3S)-2-methyloxetan-3yl]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y!]amino}acetamide	426.3

139

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
333	fLl o Az zA ZI o Ί,' cA	N-tert-buty 1-2- {methyl [2 -(4{[(2R,3 S)-2-methy loxetan-3 yl]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4y l ] am i no} acetam ide	426,3
334	4 0 ( O \ \ o	2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4y 1} (methy l)amino)-N-(4methoxypheny l)-N m ethy lacetam i de	464.2
335	X o ^xo $ \r TT V_z Az	2-({2-[4-(2- hydroxyethoxy)pyridin-2-y!]5H,6H,7Hcyclopenta[d]pyrimidin-4y ]} (methy l)amino)-1 -(5-methoxy2,3-dihydro-lH-indol-l-yl)ethan1-one	476.2
336	Z a y- o IZ HZ At A O ZT Z ' 8	N-tert-butyl-2-[methyl(2-{2methyl-2H-pyrazolo[3,4c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	394.1

140

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
337	H O,NCF₃T A AA A, „.crA N Ο H ⁿ A	2-( {2-[4-(2-hydroxy -2 methy!propoxy)pyridin-2-yl]- 5H,6H,7H- cycJopenta[d]pyrimidin-4yl}(methyl)amino)-N-[l(Îrifluoromethyl)cyclopropyl]aceta mi de	480.2
338	Ai / z Vz O Az υγ z/ ZI q a Ο ^ω d____	2- [methyl( {2-[4-(oxetan-3 y loxy)pyridin-2-y l ] -5H,6H,7Hcyclopenta[d]pyrimidin-4yl})amino]-N-[l- (trifluoromethyl)cyclopropyl]aceta mîde	464.2
339	H J IA 'Ύ ^'-''Άΐ /Y'n AA_N A^^o^^ n γ	N-(4-chiorophenyl)-2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimîdin-4y l} (methy l)amino)acetamide	454.2
340	z^C—z 0 Az zA ZI M À 0 O-^	N-{ bicyclo[ l. I. I ]pentan-1 -yl} -2[methyl({2-[4-(oxetan-3yioxylpyridin-Z-ylJ-SH^HTHcyclopenta[d]pyrimidin-4yl})amino]acetamide	422.2

I4l

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
341	0. A² y. b *	N-tert-buty l-2-[(2-{furo[3,2c]pyridin-6-yl}-5H,6H,7Hcy c lop enta[ d] py ri m i di n -4yl)(methyl)amino]acetamide	380.2
342	p o b Tz /^Zz °	2-[methyl(2-(4-[(3R)-oxolan-3yloxy]pyridin-2-yl} -5Η,6Η,7Ηcy c l op enta [d] py rimi d i n-4yl)amîno]-1 -(piperidin-1 -yl)ethanl-one	438.3
343	<ύ d o b '—Z pz	2-[methyl(2- {4-[( 3 S)-oxolan-3 yloxy]pyridin-2-yl}-5H,6H,7Hcyciopenia[d]pyrimidin-4yl)amîno]-l -(piperidin-1 -yl)etban1-one	438.3
344	\ z— \ (. o ) b b rz —\ ^z=\ Z	2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yl}-5H,6H,7Hcyc!openta[d]pyrimidin-4yl)(methyl)amino]-N-(6methoxy pyridi n-3 -y l)acetamîde	478.3

142

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
345	Z p 0 A ΞΖ Ya /L ° YCC	N-(3-fluorophenyl)-2-[methyl(2{4-[(ls,3s)-3hydroxycyclobutoxy]pyridin-2yl}-5H,6H,7Hcyc[openta[d]pyrimidin-4yl)amino]acet amide	464.2
346	H T La ZAz LL ^N ίΓΎ va ⁿxA A/	N-(6-methoxy pyridin-3 -y 1 )-2[methy](2-{4-[(3R)-oxolan-3yloxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidÎn-4yl)amino]acetamîde	477.2
347	O \ \ / o s—¹ 0 0 IZ >=z °L L	N-(6-methoxypyridin-3-yl)-2[methyl(2-{4-[(3S)-oxolan-3yloxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4y l)amino]acetam ide	477.3
348	Z— O ZZ^^- _(=z^ °	N-tert-buty 1-2- [(2-{4-[2(dimethylamino)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pynmidin-4yl)(methy])amino]acetamide	427.3
349	H °Α^Ν''^γ\_ι /An LL A^x^o^-x. N '/ Y OH N A	N-{bicyclo[l.Ll]pentan-l-yl}-2( {2-[4-(2-hy droxyethoxy)pyridin2-yl]-5H,6H,7Hcyclopenta[d]pyrimidiïi-4yl}(methyl)amino)acetamide	410.3

143

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
350	z^ z. o	A z ^λzA zz ri	Ά>η	2-({2-[4-(2- hy drox y ethoxy )py r i d i n - 2-y I ] 5H,6H,7Hcyclopenta[d]pynmidin-4y l} (methy l)ami no )-N-(3 -methy ll ,2-thiazol-5-yl)acetamide	441.2
351	J- O ή b r A A^z	'^'OH	2-({2-[4-( {[ l -(3-fluorophenyl)lH-l,2,4-triazol-3- y l]methyl} (methy i )amino)- 5H,6H,7H- cyclopenÎa[d]pyrimidin-2- yl]pyridin-4-yl}oxy)ethan-1-ol	462.3
352	zk/ O	H A r t [ T) ^νΆ	-N N—	N-tert-butyl-2-[methyl({2-[4-( 1methy 1* 1 H-py razol-4-y 1 )pyri din-2yI]-5H,6H,7Hcyclopenta[d]pyrim!din-4yi})amino]acetamide	420.3
353	0.; ~N	I / z o P A ^XZA zA	Koh	N-( 1 -cyclopropyl-1 H-pyrazol-4yi)-2-({2-[4-(2- hydroxyethoxy)pyridin-2-y]]- 5H,6H,7H- cyclopenta[d]pyrimidîn-4y]}(methyl)amino)acet amide	450.2

144

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
354	x O Ο ! V	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-l-(pyrro]idinl -yl)ethan-1 -one	398.2
355	F °y^NX Ά' λΑ'ν VU ο n γ η oh	l-(4,4-difluoropiperidm-l-yl)-2({2-[4-(2-hydroxyethoxy)pyridin2-yl]-5H,6H,7H- cy c l openta [d] py r i m i d i n-4yl}(methyl)amino)ethan-l-one	448.3
356	V z y— z o Vz zV zi A Q xz	2-({2-[4-(2- acetamîdoethoxy)pyridin-2-yl]5H,6H,7H- cyclopenÎa[d]pyrimidin-4yl}(methyl)amino)-N-(3fluorophenyl)acetamide	479.1
357	T o o V pA -d	l -(azepan-1 -y 1)-2-( {2- [4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7H- cycJopenta[d]pyrimidin-4yl}(methyl)amino)ethan-l-one	426.3

145

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
358	dyl o Vz Z toi Z—\ O o d	l -(azepan-1 -yl)-2-[methyl({2-[4(oxetan-3 -y l oxy ) py ri di n- 2 -y l] 5H,6H,7H- cyclopenta[d]pyrimidin-4- y i} )ami no]ethan-1 -one	438.3
359	zA o \=z zA z^ M Q O Tl O Z	l-(4-fluoropiperidin-l-yl)-2-({2[4-(2-hydroxyethoxy)pyridin-2y!]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl}( methyl )amino)eth an-1 -one	430.2
360	H °γ^Νη< /^X^N vA N Ti X OH	N-tert-buty l-2-[ethy l( {2-[4-(2hydroxyethoxy)pyridin-2-yl]5H,6H,7HcyclopenÎa[d]pyrimidin-4yl} )amino]acetamîde	414.3
361	H 'Ν' /Xn ΎΑ Λ x_wO_x/ ·.. N Y 'T OH nX	N-tert-butyi-2-({ 2-(4-(2hydroxyethoxy)pyridin-2-y!]-5,5dmiethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4yl} (methy !)amino)acetamide	428.3

146

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
362	m q D o d I	2-({2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5,5dimethyl-5H,61-I,7Hcyciopenta[d]pyrîmidîn-4yl}(methyl)amino)-l-(piperidin-lyl)eihan-1 -one	440.3
363	! VJ / „ z A^z ° ¹ ' zj ZI T rt : o Az ( o \ \ □ z	2-({2-[4-(2- hydroxyethoxy )py ridin-2-y 1 ]-5,5di methy 1-5 Η,6Η,7Ηcyc!openta[d]pyrimidin-4yl}(methyl)amîno)-N-(6metboxypyridin-3-yl)acetainide	479.3
364	I o o '—z Fz V ^z=\ fl	1 - {3 -azabicyclo[3.1.1] heptan-3yl}-2-({2-[4-(2- hydroxy ethoxy ) py ri d i n-2 -y 1]- 5H,6H,7H- cyclopenta[d]pyrimidÎEi-4yl}(methyl)amino)ethan-l-one	424.2
365	H °ύ^νκ Ά od “ CO	N-iert-buty l-2-[(2- {furo[2,3 c]pyrîdin-5-yl}-5H,6H,7Hcyclopenta[d] pyrimi di n-4yl)(methyl)amino]acetamide	380.3
366	H CÔL^oJL· U	N-tert-buty t-2-[(2- {4-[(2R)-2hydroxypropoxy]pyridin-2-yl}- 5H,6H,7H- cydopenta[d]pyrîmidin-4yl)(methyl)amino]acetamide	414.3

I47

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
367	J< b H	2-({2-[4-(2- hyd roxy ethoxy )py ri d in-2 - y l ] 5Η,6Η,7Η- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(2methylbutan-2-yl)acetamide	414.3
368	A N λΛ	l-(2,2-dimethylpyrrolidin-l-yl)-2({2-[4-(2-hydroxyethoxy)pyridin2-yl]-5H,6H,7H- cyclopenta[d]pyrimidïn-4yl} (methy l) ami no )ethan-1 - one	426.3
369	oùL” A '“'''N A M ^H	N-tert-butyl-2-({2-[4-(2acetamidoethoxy )pyridin-2-y I]5H,6H,7Hcyclopenta[d]pyrimidin-4yî}(methy])amino)acetamide	441.3
370	H CÔyyA	N-tert-butyl-2-[(2-{4-[(2S)-2hydroxypropoxy]pyridin-2-yl}5H,6H,7Hcyclopenta[d]pynmidîn-4yi)(methyl)amino]acetamide	414.3
371	^ογΑγ A <o^z AA	2-{[2-(4-metboxypyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[(3S)oxolan-3-yl]acetamide	384.2
372	°T^O orS ΑΑ'	2-{[2-(4-methoxypyridin-2-yl)5H,6H,7H- cyclopenta[d]pyrimidin-4ytJOnethyOaminol-N-EIjR)oxolan-3-yl]acetamide	384.2

148

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
373	°T^U Ur ^aM'	2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenta[d]pyrimidin-4- y l ] (methy l)ami no} -N - ( oxetan- 3 yl)acetamide	370,2
374	Vu /Ύ	2-({2-[4-(2- h y drox y ethoxy )py ri din-2 -y l ] - 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxetan-3yl)acetamide	400.2
375	οΎ nS	2-({2-[4-(2- hy droxy ethoxy ) py ri d in-2-y l ] 5H_S6H,7Hcyclopenta[d]pyrimîdin-4yl}(methyl)amino)-l-{5-methoxylH,2H,3H-pyrrolo[2,3-c]pyridinl-yi}ethan-l-one	477.2
376	N Ola _λ	2-({2-(4-(2- hydroxyethoxy )py ridin-2-y l]5H,6H,7Hcyclopenta[d]pyrimidin-4yl} (methyl)amino)-N-( l methylcyc[obutyl)acetamide	412.3
377	b Z b /Y O Z—V Z Y	2-[(2-{4-[(2R)-2- bydroxypropoxy ]py ridi n-2-y l} 5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(lmethylcyclo buty l) acetam ide	426.3
378	H oXu-oY	2-[(2-{4-[(2S)-2- hy droxypropoxyjpy rid i n-2-y l} 5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(1methylcyclobutyl)acetamide	426.3
379	2 Ύ N	N-[(4-benzyl-1,3-oxazol-2yl)methyl]-2-(4-methoxypyridin2-yl)-N-methyi-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine	428.2

149

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
380	O N N V	2-(4-methoxypyridin-2-yl)-Nmethyl-N-[(4-pheny l-1,3-oxazol2-y l )methy l] -5 H,6H,7H- cy c l openta [d] py rim i d i ti-4-am i ne	414.2
38l	H aVn Γ\ AM	N-tert-buty l-2-[(2-{4-[(lhydroxycycl openty l )m ethoxy ] py ri din-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4y l )( methy l ) atn ino ] acetam i de	454.3
382	O^fiO Ap N * , v-U 3c	2-({2-[4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-l-(piperidin-lyl)ethan-1 -one	440.3
383	<UV <yH v ^UnV_Y°Vh	N-{bicyclo[l .1.1 jpentan- !-yl}-2( {2- [4-(2-hy droxy-2methy]propoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimîdin-4yl}(methyl)amino)acetamide	438.2
384	Ά <1X,,,O υ K	N-tert-buty 1-2- {[2 -(4- {[(2 R)-1 hydroxypropan-2-y]]oxy}pyridin- 2-yl)-5H,6H,7H- cyciopenta[d]pyrimidin-4yl](methyl)amino}acetamide	414.3
385	Ol x λ	N-tert-butyl-2-{[2-(4-{[(2S)-ïhydroxypropan-2-yl]oxy}pyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	414.3

150

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
386	R' A H _xQ A o h Z	N-tert-buty ]-2-[(2-{4-[(2S )-2hydroxy-3-methylbutoxy]pyridin2-yî}-5H,6H,7Hcyclopenta[d]pyrimidîn-4yl)(methy])amtno]acetamide	442.3
387	H ^N' AT N Y M ™	N-tert-buty l-2-[(2-{4-[(2 R)-2hy droxy-3-methy Ibutoxy Jpyridin2-yl}-5H,6H,7Hcyclopenta[d]pyrîmidin-4yi)(methy!)amino]acetamide	442.3
388	H °γ^Νη< Υτ Ar n /X N >\|Y	N-tert-butyi-2-[(2-{4-[(1hydroxycyclobutyl)methoxy]pyrid in-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino] acetami de	440.3
389	oAh Ά Y V ^vJvvT'A„ N η ^*r Un M	2-({2-[4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]5H,6H_S7H- cyciopenta[d]pyrimidin-4yl}(methyl)amino)-N-(propan-2yljacetamÎde	414.3
390	kA X AiiS v τ.ΑγΛ«	N-ethyl-2-({2-[4-(2-hydroxy-2methy 1 pro poxy ) py ri d in- 2-y 1 ] 5H,6H,7Hcyclopenta[d]pyrimidîn-4yl}(methyl)amino)acet amide	400.2
391	F θγΟ* <Ax	l-(4,4-difluoropiperidin- J -yl)-2({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyi)amino)ethan-l-one	476.3

Î5l

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
392	H ΟγΜ,Λ / ZTi ^N	2-({2-[4-(2- hydroxyethoxy )pyrid in-2-y l ]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyi)amino)-N-(3methylpentan-3-yl)acetamide	428.3
393	H Xr Af N A	N-tert-buty1-2-[(2- {4-[(2R)-2hydroxybutoxy\|pyridin-2-yi}~ 5H,6H,7H“ cyclopenta[d]pyrimidin-4yl)(methyi)amino]acetamide	428.3
394	H J7 /Z^N A Vk A »,q	N-tert-buty l-2-[(2- {4-[(2S)-2hydroxybutoxy]pyridin-2-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	428.3
395	H °γ^Νγ; ZZ^N / \ \ L JL a Sz	N-tert-buty 1-2-( {2-[4-(2-ethy 1-2hydroxybutoxy)pyridin-2-y]]5H,6H,7Hcyclopenta[d]pyrimidÎn-4yl}(methyl)amtno)acetamide	456.3
396	U Ar A-Λ I I vk α_λ S< n liT	N-tert-butyl-2-[(2-{4-[(lhydroxycyclohexyl)naethoxy]pyrid in-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	468.3
397	n 9H °j y5 'Ά Aja.o^x ^N U ^0H	2-({2-[4-(2-hydroxy-2- m ethy l propo xy )py ri d i n-2 -y l]5H,6H,7H- cy dopent a[d\|pyrîmidin-4- yl}(methyl)amîno)-N-[(lR,2S)-2hydroxycydopentyl]acetamide	456.3

152

Compound No.	Structure	ÏUPAC Name	Mass Found (M+l)
398	Y ''N'’ rfS v 'A Ήί^γ·⁰ Άκ	N-cyclopropyl-2-({2-\|4-(2hydroxy-2methylpropoxy)pyridîn-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methy])amino)acetamide	412.3
399	-c Ύ Q Q O Œ	2-( {2- [4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-l-(morpholin4-yl)ethan-1-one	442.3
400	Λ <Υι ï M C	N-tert-butyl-2-[(2-{4-[2- (diethylamîno)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrîmidin-4yl)(methyl)amino]acetamide	455.4
401	o0h ''H''* /Ά	N-tert-buty!-2-[methyl(2-{4-[2(pyrrolîdin-l-yl)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	453.4
402	oyk 'Ά aîS A^sv⁰ v-·',j A ’ ¹	N-tert-buty'l-2-{[2-(4-{[(2S)-l- (dimethylamino)propan-2yl]oxy}pyridin-2-y])-5H,6H,7Hcyclopenta[d]pyriinidin-4y 1 ] ( met hy 1 )am ino} acet am i de	441.3
403	oA Hr /Ai ^{N 0} AA -X λ. JL ^N ΥΎA «A	2-{[2-(4-{[(tert- butylcarbainoyl)methyl](methyl)a mino}-5H,6H,7H- cyclopenta[d]pyrimidin-2yl)pyridin-4-y]]oxy}-N,Ndimethylacetamide	441.3

153

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
404	VCiY	N-tert-butyl-2-[(2-{4-[2(dimethyiamino)-2methylpropoxy]pyridin-2-yl}5H_t6H,7Hcyclopenta[d]pyrimÎdin-4yl)(methyl)ammo]acetamide	455.4
405	H Λ /ηΐ^Ν f J VqV	N-tert-butyl-2-[(2-{4-[(4hydroxyoxan-4yl)methoxy]pyridin-2-yl}5H,6H,7Hcyclopenta[d]pyrimidin-4yl )( methy l)amîno]acetamide	470.3
406	T °γ* -Z VJI „ n _ , T'^YVŸ^’ M ^{1 1}	N-tert-butyl-2-{[2-(4-{[(2R)-l(dimethylamino)propan-2yl]oxy}pyridîn-2-y()-5H,6H,7Hcyclopenta[d]pyrimidin-4y]](methyl)amino}acetamide	441.3
407	o,2hh 'fT (Ïj β Μ ^{Λ 1}	N-tert-butyl-2-{[2-(4-{[l- (dimethylamîno)-2-methyipropan2-yI]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîd!n-4y]](methyl)amîno}acetamide	455.4
408	Y O^NH ''iv yyS U ^r	(2R)-N-tert-butyl-2-[(2-{4-[2(dim ethyl amino)ethoxy] pyr i d î n-2 yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]propanamide	441.3
409	çt Hhr ηΛι v ŸA X ό X V1 hÎ^J	N-tert-butyl-2-({2-[4-(2-hydroxy2-meîhylpropoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimjdin-4yl} amino)acetamide	414.3
410	&Q Q jÿ $ λ —z	N-( 1 -cyclopropyl-1 H-pyrazol-4yl)-2-[(2-{4-[2- (d imethy ! am inojethoxy ] py ri d i n-2 yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	477.3

154

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
4ll	Y <Aii ΓΛ	N-tert-butyl-2-{ methyl [2-(4{[(2 R)-1 -methyl pyrrol idin-2yl]methoxy}pyridin-2-yi)- 5H,6H,7H- cyclopenta[d]pyrimidîn-4yl]amino}acetamide	453.4
412	H Y <Ίι ΐ ΓΛ M '	N-tert-buty 1-2- {methy l [2-(4{[(2S)-1 -methylpyrrolidin-2yl]methoxy}pyridin-2-y1)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]ammo}acetamide	453.4
413	H °τΎ <îS Y ¹	N-tert-butyl-2-[(2-{4-[2- (dimethyIamino)ethoxy]pyridin-2yi}-5,5-dimethy]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	455.3
414	°τΑ	N-tert-buty 1-2-{[2-(4-{ [(4R)-2,2dimethyl-1,3-dioxolan-4y!]methoxy}pyridîn-2-yl)5H,6H,7Hcyclopenta[d]pyrimidîn-4yl](methyl)amino}acetamide	470.2
415	H Yr _r°H 4ήγΛ	N-tert-buty 1-2-[(2-{4-[(2R)-2,3 dihydroxypropoxy]pyridin-2-yl}5H,6H,7Hcyclopenta[d]pyrim!din-4yl)(methyl)amino]acetamide	430.1
416	γγ ''hr <Ίι i X-JL _ ^N t/V A	N-tert-butyl-2-[methyl(2-{4-[(l methylazetidin-3-yl)oxy]pyridin2-yI}-5H,6H,7Hcyclopenta[d]pynmidm-4yl)amiuo]acetamide	425.3

155

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
417	θγΟ oS M ¹	2-[(2-{4-[2- (di methy lami no)ethoxy]pyridin-2yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amÎno]-l-(pyrrolidin1 -yljethan-1 -one	425.3
418	X Z — $ rf o Y ô Ά	2-[(2-{4-[2- ( d i m ethy 1 am i n ojeth o xy ] py ri di n -2 yl}-5H,6H,7H- cy clopenta[d]py rimi din-4yl)(methyl)amino]-N-[l(trifluoromethyl)cyclopropyl]aceta mi de	479.3
419	O^NH X 'bv⁰ ’^^λ'^ν X ^H	N-tert-butyl-2-[methyl(2-{4-[2( m ethyl am ΐ η o Jet hoxy ] py rid i n -2 yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	413.3
420	o b ⁰ A 1	2-( {2-(4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amîno)-l-(pyrrolidinl-yl)ethan-l-one	426.3
421	°0Ό A <~0i v Ι0Ύ	N-cy clopenty!-2-( {2-(4-(2hydroxy-2- methylpropoxy)pyridin-2-yI]5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	440.3
422	H O^JI^ <01 V ^H	2-({2-[4-(2-hydroxy-2methy[propoxy)pyridin-2-yl]- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-[(3R)oxolan-3-ylJacetamide	442.3

156

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
423	Z A— Z O An. Q % ο ~ \	2-[(2-{4-[2-(dimethylamîno)-2m eth y 1 propoxy ] py ri d i n-2 -y 1} 5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-[l(trifluoromethyl)cyclopropyl]aceîa mide	507.3
424	PU ° R d —Z X	2-[(2-{4-[2- (dÎmethylamino)ethoxy]pyridin-2yl}-5H,6H,7HcyclopenÎa[d]pyrimidin-4yl)(methyl)amino]-N-[(3R)oxolan-3-yl]acetamtde	441.2
425	Π Λ—Zî O Vz / _Z ^z=< Hr w O X T	N-tert-buty l-2-[(2- {4-[( 1 -hydroxy2~methy!propan-2-yi)oxy]pyridin2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin’4y l)(methy l)amino] acetamide	428.1
426	oC!h A At T cf, W -A zx a A ^N fl Y OU	N-tert-butyl-2-[methyl({2-[4- (3,3,3-trifluoro-2- hydroxypropoxy)pyridin-2-y1]- 5H,6H,7H- cyclopenta[d]pyrimidin-4y!} )amino]acetamide	468.1

157

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
427	V z Az Q A A / -O * ' o 'q x	N-tert-buty 1-2-( {2-(4-(2hydroxyethoxy)-6-methyîpyridin- 2-yl]-5H,6H,7H- cy c lopenta[d]pyrim idin-4yl}(methyl)amino)acet amide	414.3
428	V A Ad /d o —z \	2-((2-{4-(2- (dimethyiamino)ethoxyJpyridin-2yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4ylXmethyl)am!no]-N-(propan-2yl)acetamide	413.3
429	d~C”d fl H V / z={ zX / \ X \ w o	2-[methyl(2-{4-(2-(pyrrolidin-ly l)ethoxy ] py rîdin-2-y l} 5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]-N-(propan-2yl)acetamide	439.3
430	L/ X o j—z A	2-(methyl(2-{4-[2-(morpholin-4yl)ethoxy]pyrîdin-2-y1}- 5H,6H,7H- cyclopenta[d]pyrimidin-4yl)amino]-N-(propan-2yl)acetamide	455.3

158

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
431	z O O z 2 1 V _f=\ ° 1	2-[(2-{4-[(l- hy d ro xy cy c 1 o propy 1 )meth oxy ] py r i din-2-yl}-5H,6H,7H- cy c lop enîa[d] py r ΐ m i d in-4yl)(methyl)amino]-N-(propan-2yl)acetamide	412.3
432	M^-/.⁰A A p γ $ ^z Z— /	2-[methyl(2-{4-[2-(4methy!piperazin-1 yl)ethoxy]pyridîn-2-yl}5H,6H,7H- cyclopenta[d]pyrimidin-4yl)amino]-N-(propan-2yl)acetamide	468.3
433	K' Z Mz O jm H * ZT O —z \	(2R)-2-[(2-{4-[2- (dimethylamiuo)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amîno]-N-(propan-2y l)pro panam i de	427.3
434	y—2i ¹ w V O -i	(2S)-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(propan-2yl)propanamide	427.3
435	\ z— O Ρλ ,^ζΊ O Zp h / y=z	2-[(2~{4-[2- (dimethy!amiuo)ethoxy]pyridin-2y]}-5,5-dimethyl-5H,6H,7Hcyclopenta[d]pyrimîdin-4y])(methyl)amino]-N-(propan-2yl)acetamide	441.3

159

Compound No.	Structure	IUPAC Name	Mass Found (M+I)
436	/“A / V/RJ Q fl O /—z X ^=° o—J	2-[methyl(2-{ 4-(2-(3oxomorphohn-4·y l)ethoxy ]pyridin-2-y 1} - 5H,6H,7H- cyclopenta[d]pyrimidin-4yl)amîno]-N-(propan-2yl)acetaniide	469.3
437	v/ M	N-tert-butyI-2- {methy 1 [2-(4{[(3R)-1 -methylpynolidin~3yl]oxy}pyridin-2-yl)-5H,6H₅7Hcyclopenta[d]pyrimidin-4y 1 ] am i no} acetam ide	439.3
438	i 6 O Z.fl fl ^z σ	N-tert-butyl-2-{methyl[2-(4{[(3S)-l-methylpyrrolidin-3yi]oxy}pyridîn-2-yi)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl] amino }acetamide	439.4
440	b Z A z o fl M / fl/ ⁵T O x	N-tert-butyl-2-({2-[4-(2-hydroxy2-methylpropoxy)-6- methylpyridin-2-yl]-5H,6H,7H- cy c 1 openta[d]py rimi din-4y]}(methyl)amino)acetamide	442.3

I60

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
44]	I r o o ù b r z /³ ⁰	N-ethyl-2-[(2-{4-[(l- hydroxycyc]opropyl)methoxy]pyri din-2-yl}-5H_i6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amîno]acetamide	398.2
442	O z=/ zze q ( o T	N-ethyl-2-({2-[4-(2-ethyl-2h y dro xy butoxy )py ri d i n-2-y 1] 5H,6H,7Hcyclopenta[d]pyrimidin-4y]}(methy])amtno)acet amide	428.3
443	Jy/ o // M Z=< ZŒ O ^/ o zc	2-({2-[4-(2-ethyl-2hydroxybutoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidm-4y 1} (methy l)ami no)-Nmethy lacetam ide	414.3
444	O V/ vq zL Z2 q u o V o cU— □:	2-((2- {4- [(4-hy droxyoxan-4y llmethoxy ] py r i d i n-2-y l}5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(propan-2y])acetamide	456.3
445	H Hr Ar n / W Αχ-χΑ A< ^11^1 -<4i	N-tert-buty l-2-[(2- {4-[(2R)-2- hydroxy-2-methylbutoxy]pyridin2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yi)(methy])amino]acetamide	442.3

I6l

Compound No,	Structure	IUPAC Name	Mass Found (M+l)
446	x o x )=Z 'A3	N-tert-buty l-2-[(2-{4-[(2 S)-2hydroxy-2 -methy l butoxy ] py r id i n 2-yi]-5H,6H,7Hcyclopenta[d]pyriinidin-4y l )( m ethy l )am i no] acetam i de	442.3
447	x K o v	N-ethyl-2-[(2-{4-[(4hydroxyoxan-4y!)methoxy]pyridîn-2-yl}5H,6H,7Hcyclopetita[d]pyrimidin-4yl)(methyl)amino]acetamide	442.3
448	X o _oa j-P V	2- [(2-{4-[(2R)-2-hy droxy-3methoxypropoxy]pyridin-2-yl}5H,6H,7H- cyclopenta[d]pyrimidm-4yl)(methyl)amino]-N-(propan-2yl)acetamide	430.2
449	w X o	2-({2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]-6,6dimethyi-5H,6H,7H- cyclopenta[d]pyrimidin-4yl}(methy])amino)-N-(propan-2y] (acetamide	442.3
450	Oyt^ Ar ^^oh	2-( {2-[4-(2-hydroxy-2- methylpropoxy)pyridin-2-yl]-7,7dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4y1}(methy!)amino)-N-(propan-2yl (acetamide	442.3

162

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
451	o g o y A o z—^Xz ^z o	N-tert-buty 1-2-((2-{4-[(2S)-2,3dihy droxy propoxy ]pyridin-2-yl} - 5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methy l)amino] acetamide	430.2
452	s o A 0 to J~C °	N-tert-buty 1-2- [(2- {4-[(2S )-3 fluoro-2-hydroxypropoxy]pyridin2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamîde	432.1
453	' A ¹ A w z=< / zx Q X o	(2R)-2-({2-[4-(2-hydroxy-2- m ethy 1 pro poxy) py ri d i n - 2-y 1] - 5H,6H,7H- cy clopenta[d]pyrim idin-4yl}(methyl)amino)-N-(propan-2yljpropanamide	428.3
454	X _ O y- Λ A-€> 9	N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yl}-6,6-dimethyl-5H,6H.7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	455.3
455	A ÿ-Z '—( z=Z zz V# Y o —Z \	2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yI}-6,6-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(propan-2yljacetamîde	441.3

163

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
456	Y	2-[(2-{4-[2- (d i m ethyl am ino)ethoxy} py ridin-2yI}-7,7-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4- y ] )( m ethy l ) am i n o] -N -(propan -2y])acetamîde	441.3
457	o V Λ Ο Σ—/ b ^ZU	N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyndin-2yl}-7,7-dimethyl-5H_s6H,7Hcyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide	455.3
458	Ύ cVï	N-[(2R)-1 -hydroxypropan-2-y I]-2{[2-(4-methoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y l](methyl)am ino] acetam i de	372.2
459	Y yrv O .....( o d / s	N-[(2 S)-1 -hy droxypropan-2-y l ]-2{[2-(4-methoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4y l] ( m ethy l )am i η o} acetam i de	372.2
460	Y⁷ o ç > 0	N-tert-butyl-2-[methyl(2-{4-[2(morpholin-4-yl)ethoxy]pyridîn-2yl}-5H,6H,7Hcyclopenta[d]pyrtmidin-4yl)amino]acetamide	469.3

164

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
461	A Φ	N-tert-butyl-2-{methyl[2-(4-{2[(lS,4S)-2-oxa-5azabîcyclo[2.2.1 ]heptan-5y l ]ethoxy} pyridin-2-y l)5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino} acetamide	481.3
462	OlX a —'lAi '''N i] N A A	N-tert-buty l-2- {methyl [2-(4-{2κ l R,4R)-2-oxa-5azabicyclo[2.2.1 ]heptan-5yl]ethoxy}pyridin-2-yl)5H,6H,7Hcyc!openta[d]pyrimidin-4y]]amîno} acetamide	481.3
463	À ΓτΛι Ά ^Ύ^· /°	N-tert-buty l -2- {[2-(4-{2-[(3R)-3methoxypyrrolidin-1 yl]ethoxy}pyridin-2-yl)5H,6H,71-Icyclopenta[d\|pyrimîdin-4yl](methyl)amîno} acetamide	483.3
464	°γΎ Obi η b /	N-tert-buty l-2- {[2-(4- {2-[(3 S)-3 methoxypyrrolidin-1 y l ] ethoxy} py ri d i n -2 -y l)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino} acetamide	483.3
465	°Υ^Ύ 0(5 .-. .c . 'Ύ La	N-tert-butyl-2-\|(2-{4-(2-(lHimidazol-1 -yi)ethoxy]pyridm-2yl}-5H,6H,7Hcyclopenta[d]pyrimi di n-4ylXmethyl)amino]acetamide	450.2

165

Compound No.	Structure	IUPAC Naine	Mass Found (M+l)
466	VJ hA A	N-tert-butyl-2-[methy[(2-{4-[2( 1 H-1,2,3,4-tetrazol-1 y l)eth oxy ] py ri d in-2-y l} 5H,6H,7Hcyclopenta[d]pyrimidin-4y l)ammo]acetainide	452.2
467	H 'PT /^Y^hJ < E £ n	N-tert-butyl-2-{ [2-(4ethoxypyridin-2-yi)-5H,6H,7Hcyclopenta[d]pyriinidin-4yl](methyl)amino}acetamide	384.2
468	H W Ά N A	N-tert-buty 1-2- [methy 1(2- {4-[2(pyridazin-3yloxy)ethoxy]pyridin-2-yl}5H,6H,7Hcyc lopenta[d]pyrimi di n-4yl)amino]acetaniide	478.2
469	byj o \=z z=< z z Ly V_ < Aa o x z	2-({2-[4-(2-ethyl-2- hydroxybutoxy)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidin-4y 1} (methyl )amino)-N-[( 1 R,2S)-2hydroxycyclopentyl]acetamide	484.3
470	1 X z— o y. θ i—V 2—i Ά U 1	N-tert-butyl-2-[(2-{4-[2- (diniethylamino)ethoxy]pyridin-2yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(2,2,2- trifluoroeîhy!)amino]acetamide	495.3

166

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
471	x / O Q ό b Z-é ^z 'N	l -[(3R)-3-hydroxypyrrolidin-1 yl]-2-{[2-(4-methoxypyridin-2yl)-5H,6H,7H- cy c l openta [d ] py r im i d i n-4 yl](methyl)amino}ethan-l -one	384.2
472	X / O Q à b i—zA o z—/ z T	l-[(3 S)-3-hydroxypyrrolidin-1 -yl]2-{ [2-(4-methoxypy ridi n-2-y 1 )- 5H,6H,7H- cyclopenta[d]pyrimidin-4- y 1 ] (m ethyl )ami no} ethan-1 - one	384.2
473	Q y b ζΥ O Z A z '13	N-tert-butyl-2-{[2-(4-{2-[(3R)-3fluoropyrrolidin-ly 1 ] ethoxy} py rid i n-2 -y 1 )5H,6H,7Hcyclopenta[d] pyrimidin-4y]](methyl)amino}acetamide	471.2
474	A Z A— z o A A o A	N-tert-butyl-2-{[2-(4-{2-[(3S)-3fluoropyrrolîdin-1 yl]ethoxy}pyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidÎn-4yl](methyl)amino}acetamîde	471.2
475	r q OX s \	N-tert-butyl-2-[(2-{4-[3(dimethy lami no)propy 1 ] py ri din-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4y])(methyl)amino]acetamide	425.3

167

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
476	Z 0Z Q _^-Z O — z / X	N-[2-(dimeÎhylamino)ethyl]-2{[2-(4’iT>ethoxypyridin-2-yl)5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	385.2
477	/ o b à—* zA O Z-E ^z ' c	2-{[2-(4-methoxypyridin-2-yl)- 5H,6H,7H- cyclopenÎa[d]pyrimidin-4yl](methyl)amino}-1 -(morpholin4-yl)ethan-l-one	384.2
478	ü, ¥-Z ^λ—\ M h O TT —z X	2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(2,2,2tri fl uoroethy 1 )acetamide	453.2
479	b\ / P 0z '— H V *C	2-({2-[4-(2-hydroxy-2methylpropoxy)pyridin-2-yl]5H,6H,7Hcyciopenta[djpyrimidin-4yl}(methyl)ainino)-N-(2,2,2trifluoroethyl)aceÎamide	454.1

I68

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
480	T IO y_ O O z—i 'b	N-tert-buty l-2-[methyl(2-{4-[3( methylam ino)propy l] pyridin-2yl}-5H,6H₅7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	411.3
481	Z EU % h zz f=z o zR X ' b	N-tert-buty l-2-( {2-[4-(3 -hydroxy3-methylbutyl)pyridin-2-yl]5H,6H,7Hcyclopenta[d]pyrimidîn-4yl}(methyl)amino)acetainide	426.3
482	ü, Z O yT M c z	N-tert-butyl-2-{[2-(4- hydroxypyridin-2-yl)-5H₅6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acet amide	356.2
483	Ni r z o Ί^~ \=^ O^ z-/ \e 'b I	2-({2-[4-(2-aminoethoxy)pyridin- 2-yl]-5H,âH,7H- cyclopenta[d]pyrîmidin-4yl} ( methy l)amî no )-N-tertbutyl acet ami de	399.3
484	\ Γ Z b i—\ ^z~/ Ο Z—/ ^XZ R	N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyrîdin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	413.3

169

Compound No,	Structure	ÏUPAC Name	Mass Found (M+l)
485	X zz y: O E—4 ^XZ A	N-tert-butyl-2-[(2-{4-[2- (methylamino)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	399.2
486	\ o β Λ \ & o \ x \__f Z >=z H Z-/ Q Z A Z A	2-{[2-(4-{[(2R)-l(dimethylamino)propan-2yl]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[l(trifluoromethyl)cyclopropyl]aceta mide	493.3
487	zycFj o^Ah Ά αχ., no n-	2-{methyl[2-(4-{[(3R)-l- methylpyrrolidin-3- y l J oxy } pyridi n-2-y l )-5 H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}-N-[1- (trifluoromethyl)cyclopropyl]aceta mide	491.3
488	Aq Z=( zz Q Y o .....ç I	N-tert-butyl-2-{[2-(4-{[(3R,5R)- l,5-dimethylpyrrolidin-3yl]oxy}pyridin-2-yl)-5H,6H,7Hcycloperita[d]pyrimidin-4y ] J(methy 1 )amîno} acetamîde	453.3

170

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
489	\ I P o J ίχ )—y zA o z—d Z V	N-tert-butyl-2-{ methyl[2-(4{[(3 R)-1 -methy ! pi péri din-3 y l]oxy} pyridin-2-y l)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]ainino}acetamide	453.3
490	Nr OÔl n nTAy' Y'''n'' νΆ RJ	N-tert-buty!-2-{metbyl[2-(4{[(3S)-l-methyipiperidin-3yl]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl]amino}acetamide	453.3
491	Ά ΥΤΟφ	N-tert-butyl-2-{[2-(4-{[(3R)-l(2,2-difluoroeÎhyl)pyrroîidin-3yl]oxy}pyridm-2-yl.)-5H,6H,7Hcyclopetita[d]pyrimidin-4yl](methyl)amino}acetamide	489.3
492	Z o Ak V Y	N-tert-butyl-2-({2-[4-(2-hydroxy2-methylpropoxy)pyridin-2-yl]-5oxo-5H,6H,7Hcyc iopenta[d]pyrimi di n-4yl}(inethyl)amîno)acetamide	442.2

171

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
493	X z— O y- b zz ffiz. Q zM Z	N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridin-2yl}-5-hydroxy-5H,6H,7Hcyc]openta[d]pyrinnidin-4yl)(methyl)amino]acetamide	443.2
494	z )=\ / p v-z Q V O —z X	N-tert-buty !-2-[( 2- {4-[2- (dim ethyl amÎno)ethoxy]pyridin-2yl}-7-hydroxy-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methyi)amino]acetamide	443.3
495	Cf 2=/ I SŒ Q Y O — Z	N-tert-butyl-2-[(2-{4-[2- (dimethylamino)ethoxy]pyridîn-2yi}-5H,6H,7H- cyclopenta[b]pyridin-4- y l)( methy l)am ino] acetam ide	426.3
496	i □ X t) À—\ ^z-ÿ o V '0	N-tert-buty l-2- {[2-(4- {[(3 R)-1 ethYlpynOlidin-3-yl]oxy}pyridin- 2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	453.3
497	? p y- b zz >=z A I	N-tert-butyl-2-{[2-(4-{[(3R)-l-(2- fluoroethyl)pyrrolidin-3yl]oxy}pyridin-2-y])-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acet amide	471.3

172

Compound No.	Structure	IUPAC Name	Mass Fouud (M+l)
498	o N Y >4''	N-tert-butyl-2-[methyl( (2-[4(methylsul fany l )py ridin-2-y l]5H,6H,7Hcyclopenta[d]pyrimidin-4y l} )amino]acetam ide	386.2
499	A* ?~^z '—\ ω —Z \	N-tert-butyl-2-{[2-(4-{[2(dîmethylamino)ethyl]sulfany]}py ridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide	443.3
500	0' I Z A Z Q l Y² X Q d o J \	N-cyclopropyl-2-[(2-{4-[2(dimethy lam înojethoxy ]pyridin-2yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)(methy!)amino]acetamide	411.3
501	Z o \=z 2—Z 2 X Q A o o X	N-tert-buty l-2-( {2-[4-(2-hydroxy2-methylpropoxy )py ridin-2-y l ]-7oxo-5H,6H,7Hcyclopenta[d]pyrimidin-4yl} (methyl )amino)acet amide	442.3
502	AA / _Λ2 y—Z 0 \=z S— o l	N-tert-butyl-2-{[2-(4-{[(3R,5S)l,5-dimethylpyrrolidin-3yl] oxy} py ridin-2-y l )-5 H ,6H,7Hcyclopenta[d]pyrîmidin-4y ] ]( methy l)ami no} acetam ide	453.4

173

Compound No.	Structure	IUPAC Name	Mass Found (M+I)
503	H VA La	(2R)-N-tert-butyl-2- {methy! [2-(4{[{3 R)-1 -methylpyrrolidî n-3y l]oxy } pyridin-2-yl)-5H,6H,7Hcyciopenta[d]pyrîmidin-4' y 1 ]am îno} propanamîde	453.4
504	I P o XZ / yA j-=C o z—4 ,z V	(2R)-2-{methyi[2-(4-{[(3R)-lmethylpyrrolidin-3- yl]oxy}pyridin-2-yl)-5H,6H,7HcyctopenÎa[d]pyrimidin-4yl]amino}-N-(propan-2yl)propanamide	439.3
505	0 v °b X z >=z ° /^zjj	2-[methyl(2-{4-[2-(Îhiomorpholin4-y I (ethoxy] pyri din-2-y l} 5H,6H,7H- cyc lopentafd] pyrimidin-4yl)amino]-N-(propan-2yl (acetamide	471.3
506	H °Υ^Ν'Τ''· yîS W ,o.. ^·,, nyA ·Ά'_Τ> N.0J ¹	N-tert-butyl-2-[methy 1(2-{4-[2(methylsulfanyl)ethoxy]pyridin-2yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4yl)amino]acetamide	430.2
507	A' Z=/ Z3 Ύ O -(Îo ci	N-tert-buty 1-2-( {2-(4-(2methanesu[fonylethoxy)pyridin-2yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4yl}(methyl)amino)acetamide	462.3

174

Compound No.	Structure	IUPAC Name	Mass Found (M+l)
508	rY ta	N-tert-buty 1-2- {[2-(4- {2[di(2H3)methylamino]ethoxy}pyri din-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4yl](methyl)amino}acet amide	433.3
509	Z V- Z o Y* M Q % o d T	N-tert-buty 1-2-( {2-[4-(2-hydroxy2-methylpropoxy)pyridîn-2-yl]5H,6H,7H- cy c 1 openta[ d] py rim i d i n - 4 y 1} ((2 H3 )methy l)amino)acetamide	431

III. Pharmaceutical Compositions and Modes of Administration

[0121] Compounds provided herein are usualiy administered in the form of pharmaceutical compositions. Thus, provided herein are also pharmaceutical compositions that comprise one or more of 5 the compounds described herein or a pharmaceutically acceptable sait, a stereoisomer, or a mixture of stereoisomers thereof and one or more pharmaceutically acceptable vehicles selected from carriers, adjuvants and excipients. Suitabie pharmaceutically acceptable vehicles may include, for example, inert solid diluents and fillers, diluents, includîng stérile aqueous solution and various organic solvents, perméation 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 Modem Pharmaceutics, Marcel Dekker, Inc. 3rd Ed. (G.S. Banker & C.T. Rhodes, Eds.).

[0122] The pharmaceutical compositions may be administered in either single or multiple doses.

The pharmaceutical composition may be administered by various methods includîng, for example, rectal, buccal, intranasal and transdermal routes. In certain embodiments, the pharmaceutical composition may be administered by intra-arterial injection, intravenously, intraperitoneally, parenterally, intramuscularly, subcutaneously, orally, topically, or as an inhalant.

175

[ΟΙ23] One mode for administration is parentéral, for example, by injection. The forms in which the pharmaceutical compositions described herein may be incorporated for administration by injection include, for example, aqueous or oil suspensions, or émulsions, with sesame oil, com oil, cottonseed oil, or peanut oil, as well as élixirs, mannitol, dextrose, or a stérile aqueous solution, and similar pharmaceutical vehicles.

[0124] Oral administration may be another route for administration of the compounds described herein. Administration may be via, for example, capsule or enteric coated tablets. In making the pharmaceutical compositions that include at least one compound described herein or a pharmaceutically acceptable sait, a stereoisomer, or a mixture of stereoisomers thereof, the active ingrédient is usually diluted by an excipient and/or enclosed within such a carrier that can be in the form of a capsule, sachet, paper or other container. When the excipient serves as a diluent, it can be in the form of a solid, semisolid, or liquid material, which acts as a vehicle, carrier or medium for the active ingrédient. Thus, the compositions can be in the fonn of tablets, pills, powders, lozenges, sachets, cachets, élixirs, suspensions, émulsions, solutions, syrups, aérosols (as a solid or in a liquid medium), oîntments containing, for example, up to 10% by weight of the active compound, soft and hard gelatin capsules, stérile injectable solutions, and stérile packaged powders.

[0125] Some examples of suitable excipients include lactose, dextrose, sucrose, sorbitol, mannitol, starches, gum acacia, calcium phosphate, alginates, tragacanth, gelatin, calcium silicate, microcrystalline cellulose, polyvinylpyrrolidone, cellulose, stérile water, syrup, and methyl cellulose. The formulations 20 can additionally include lubricating agents such as talc, magnésium stéarate, and minerai oil; wetting agents; emulsifying and suspending agents; preserving agents such as methyl and propyIhydroxybenzoates; sweetening agents; and flavoring agents.

[0126] The compositions that include at least one compound described herein or a pharmaceutically acceptable sait, a stereoisomer, or a mixture of stereoisomers thereof can be formulated so as to provide 25 quick, sustained or delayed release of the active ingrédient after administration to the subject by employing procedures known in the art. Controlled release drug deIivery Systems for oral administration include osmotic pump Systems and dissolutional Systems containing polymer-coated réservoirs or drugpolymer matrix formulations. Examples of controlled release Systems are given in U.S. Patent Nos.

3,845,770; 4,326,525; 4,902,514; and 5,616,345. Another formulation for use in the methods disclosed herein employ transdermal delivery devices (“patches”). Such transdermal patches may be used to provide continuous or discontinuous infusion ofthe compounds described herein în controlled amounts.

176

The construction and use of transdermal patches for the delivery of pharmaceutical agents is well known in the art. See, e.g., U.S. Patent Nos. 5,023,252, 4,992,445 and 5,001,139. Such patches may be constructed for continuous, pulsatile, or on demand delivery of pharmaceutical agents.

[0127] For preparing solid compositions such as tablets, the principal active ingrédient may be mixed with a pharmaceutical excipient to form a solid preformulation composition containing a homogeneous mixture of a compound described herein or a pharmaceutically acceptable sait, a stereoisomer, or a mixture of stereoisomers thereof. When referring to these preformulation compositions as homogeneous, the active ingrédient may be dispersed evenly throughout the composition so that the composition may be readily subdivided into equaliy effective unit dosage forms 10 such as tablets, pills and capsules.

[0128] The tablets or pills of the compounds described herein may be coated or otherwise compounded to provide a dosage form affording the advantage of prolonged action, or to protect from the acid conditions of the stomach. For example, the tablet or pill can include an inner dosage and an outer dosage component, the latter being in the form of an envelope over the former. The two components can be separated by an enteric layer that serves to resist disintegration in the stomach and permit the inner component to pass intact into the duodénum or to be delayed in reiease. A variety of materials can be used for such enteric layers or coatings, such materials including a number of polymeric acids and mixtures of polymeric acids with such materials as shellac, cety! alcohol, and cellulose acetate. [0129] Compositions for inhalation or insufflation may include solutions and suspensions in pharmaceutically acceptable, aqueous or organic solvents, or mixtures thereof, and powders. The liquid or solid compositions may contain suitable pharmaceutically acceptable excipients as described herein. In some embodiments, the compositions are administered by the oral or nasal respiratory route for local or systemic effect. In other embodiments, compositions in pharmaceutically acceptable solvents may be nebulized by use of inert gases. Nebulized solutions may be înhaled directly from the nebulizing device 25 or the nebulizing device may be attached to a facemask tent, or intermittent positive pressure breathing machine. Solution, suspension, or powder compositions may be administered, preferably orally or nasally, from devices that deliver the formulation in an appropriate manner.

[0130] The spécifie dose level of a compound of the present application for any particular subject will dépend upon a variety of factors including the activity of the spécifie compound employed, the âge, 30 body weight, general health, sex, diet, time of administration, route of administration, and rate of excrétion, drug combination and the severity of the particular disease in the subject undergoing therapy.

177

For example, a dosage may be expressed as a number of milligrams of a compound described herein per kilogram of the subject’s body weight (mg/kg). Dosages of between about 0. ! and 150 mg/kg may be appropriate. In some embodiments, about 0.1 and 100 mg/kg may be appropriate. In other embodiments a dosage of between 0.5 and 60 mg/kg may be appropriate. Nonnalizing according to the subject’s body weight is particularly useful when adjusting dosages between subjects of widely disparate size, such as occurs when using the drug in both children and adult humans or when converting an effective dosage in a non-human subject such as dog to a dosage suitable for a human subject. A dose may be administered once a day (Q1D), twice per day (BID), or more frequently, depending on the phamiacokinetic and pharmacodynamie properties, including absorption, distribution, metabolism, and excrétion of the particular compound. In addition, toxicity factors may influence the dosage and administration regimen. When administered orally, the pill, capsule, or tablet may be ingested daily or less frequently for a specified period of time. The regîmen may be repeated for a number of cycles of therapy.

IV. Methods of Treatment

[0131] In certain embodiments, the subject matter described herein is directed to a method of inhibiting iron transport mediated by ferroportin in a subject, comprising administering to a subject an effective amount of a compound of Formula I or Formula Γ, or a pharmaceutically acceptable sait thereof.

[0132] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Fonnula 1 or Formula Γ. [0133] In certain embodiments, the disease is related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload.

[0134] In certain embodiments, the disease is related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin.

[0135] In certain embodiments, the disease is hemochromatosis.

[0136] In certain embodiments, the disease is related to or caused by a hemoglobinopathy.

[0137] In certain embodiments, the disease is thalassemia, hemoglobîn E disease, hemoglobin H disease, or sickle cell disease.

i 78

[0138] In certain embodiments, the disease is sickle cell disease.

[0139] In certain embodiments, the sickle cell disease is sickle cell anémia.

[0140] The methods described herein may be applied to cell populations in vivo or ex vivo. Ίη vivo means within a living individual, as within an animal or human. In this context, the methods described herein may be used therapeutically in an individual. “Ex vivo means outside of a living individual. Examples of ex vivo cell populations include in vitro cell cultures and biological samples including fluid or tissue samples obtained from individuals. Such samples may be obtained by methods well known in the art. Exemplary biological fluid samples include blood, cerebrospinal fluid, urine, and saliva. In this context, the compounds and compositions described herein may be used for a variety of purposes, including therapeutic and experimental purposes. For example, the compounds and compositions described herein may be used ex vivo to détermine the optimal schedule and/or dosing of administration of a compound of the present disclosure for a given indication, cell type, individual, and other parameters. Information gleaned from such use may be used for experimental purposes or in the clinic to set protocols for in vivo treatment. Other ex vivo uses for which the compounds and compositions described herein may be suited are described below or will become apparent to those skilled în the art. The selected compounds may be further characterized to examine the safety or tolérance dosage in human or non-human subjects. Such properties may be examined using commonly known methods to those skilled in the art.

[0141] The ferroportin inhibition activity ofthe compounds of Formula 1 or Formula Γ and pharmaceutically acceptable salts thereof provide methods particularly suitable for the use in the inhibition of iron transport medîated by ferroportin. As such, the compounds of Formula I or Formula Γ and pharmaceutically acceptable salts thereof are useful in the prophylaxis and/or treatment of a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, increased iron levels, increased iron absorption, iron overload, increased erythropoîesis, stress erythropoiesis, or ineffective erythropoiesis.

[0142] Further, the compounds of Formula 1 or Formula 1’ are suitable for the use in an adjunctive therapy by limitîng the amount of iron available to pathogenic microorganisms, e.g. the siderophilic bacteria Vibrio vulnificus and Yersinia enterocolitica, and common pathogens (e.g. Escherichia coli), thereby preventing or treating infections, inflammation, sepsis, and septic shock caused by said pathogenic microorganisms.

[0143] In certain embodiments, the subject matter described herein is directed to a method of

179 inhibiting iron transport mediated by ferroportin in a subject, comprising administering to the subject an effective amount of a compound of Formula I or Formula I’ or a pharmaceutically acceptable sait thereof.

[0144] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, increased ferroportin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, increased iron levels, increased iron absorption, iron overload (e.g. due to blood transfusions), increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis, comprising administering to the subject an effective amount of a compound of Formula I or Formula Γ or a pharmaceutically acceptable sait thereof. In aspects of these embodiemnts, the treating comprises inhibiting iron transport mediated by ferroportin in the subject.

[0145] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels, reduced sensitivity of ferroportin to hepcidin, a hemoglobinopathy, or iron overload.

[0146] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by reduced hepcidin levels or reduced sensitivity of ferroportin to hepcidin. In a certain aspect of this embodiment, the disease is hemochromatosis.

[0147] In certain embodiments, the subject matter described herein is directed to a method of treating a subject afflicted with a disease related to or caused by a hemoglobinopathy. In a certain aspects of this embodiment, the disease is thalassemia, hemoglobin E disease, hemoglobin H disease, or sickle cell disease. In certain aspects of this embodiment, the disease is sickle cell disease. In certain aspect of this embodiment. the disease ts sickle cell anémia.

[0148] In certain embodiments, the diseases being associated with, being related to, being caused by or leading to increased iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) or ineffective erythropoiesis comprise thalassemia, hemoglobinopathy, such as hemoglobin E disease (HbE), hemoglobin H disease (HbH), haemochromatosis, hemolytic anémia, such as sickle cell anémia and congénital dyserythropoietic anémia. Additional diseases being associated with, being related to, being caused by or leading to increased iron levels, increased iron absorption, iron overload (e.g., tissue iron overload) include neurodegenerative diseases, such as for example Alzheîmer's disease, Parkinson's disease, Huntington’s disease, multiple sclerosis, Wilson’s disease, amyotrophie latéral sclerosis (ALS),

180 and Friedreich’s Ataxia, wherein the compounds and methods are considered to be effective by limiting the déposition or increase of îron in tissue or cells; conditions associated with the formation of radicals, reactive oxygen species (ROS) and oxidative stress caused by excess iron or iron overload; cardiac, liver and endocrine damage caused by excess iron or iron overload; inflammation triggered by excess iron or 5 iron overload; diseases associated with ineffective erythropoiesis, such as myelodysplastic syndromes (MDS, myelodysplasia), polycythemia vera, and congénital dyserythropoîetic anémia; diseases, disorders and/or disease conditions that comprise iron overload caused by mutations in genes involved in sensing the systemic iron stores, such as hepcidin/hepcidin antimicrobial peptide (HAMP), hemochromatosis protein (HFE), hemojuvelin (HJV) and transferrin receptor 2 (TFR2), such as in particular diseases related to HFE and HJV gene mutations; diseases related to ferroportin mutations; chronic hemolysis associated diseases, sickle cell diseases (including sickle cell anémia (HbSS) as well as hemoglobin SC dîsease (HbSC), hemoglobin S beta-plus-thalasseinia (HbS/p+), and hemoglobîn S beta-zero-thalassemia (HbS/βΟ)), red cell membrane disorders, Giucose-6-phosphate dehydrogenase deficiency (G6PD deficiency), erythropoietic porphyria, Friedreich s Ataxia, as well as subgroups of iron overload such as transfusîonal iron overload, iron intoxication, pulmonary hemosiderosis, osteopenia, insulin résistance, African iron overload, Hallervordan Spatz disease, hyperferritinemia, ceruloplasmin deficiency, néonatal hemochromatosis and red blood cell disorders comprising thalassemia, including alpha thalassemia, beta thalassemia and delta thalassemia, thalassemia intermedia, sickle cell disease and myelodyplastic syndrome; liver diseases (e.g. hepatitis B virus infection, hepatitis C virus infection, alcoholic liver disease, autoimmune hepatitis), other conditions including ataxia, Friedreich's ataxia, age-related macular degeneration, age-related cataract, age-related retinal diseases and neurodegenerative disease, such as pantothenate kinase-associated neurodegeneration, restless leg syndrome and Huntington's disease. In certain embodiments, the disease is sickle cell anémia. The ferroportin inhibition activity, for instance by inducing internalization of ferroportin, of the compounds of Formula I and pharmaceutically acceptable salts thereof can be determined by the assays described herein as well as those described in WO2018/192973, incorporated herein by reference in its entirety. [0149] The activity of the compounds of Formula 1 or Formula Γ in the treatment of sickle cell anémia (sickle cell disease) can be determined by using a mouse model, such as e.g. described by Yulin Zhao et al. in MEK1/2 inhibitors reverse acute vascular occlusion in mouse models of sickle cell disease; The FASEB Journal Vol. 30, No. 3, pp 1171-1186, 2016. Said mouse model can be suitably adapted to détermine the activity of the compounds of Formula I or Formula I’ in the treatment of sickle

181 cell anémia. In certain embodiments, the disease is caused by a lack of hepcidin or iron metabolism disorders, particularly iron overload States, such as thalassemia, sickle cell disease and hemochromatosis. In certain embodiments, the disease is related to or caused by reduced hepcidin levels, increased iron levels, increased iron absorption, iron overload, increased erythropoiesis, stress erythropoiesis, or ineffective erythropoiesis. In certain embodiments, the disease is selected from the group consisting of thalassemia, hemoglobinopathy, hemoglobin E disease, hemoglobin H disease, haemochromatosis, and hemolytic anémia.

[0150] In certain embodiments, the methods of administering and treating described herein further comprise co-administration of one or more additional pharmaceutically active compounds or in combination with a blood transfusion,

[0151] In a combination therapy, the pharmaceutically active compounds can be administered at the same time, in the same formulation, or at different times. Such combination therapy comprises coadmînistration of a compound of Formula I or Formula Γ or a pharmaceutically acceptable sait thereof with at least one additional pharmaceutically active compound. Combination therapy in a fixed dose combination therapy comprises co-administration of a compound of Formula I or Formula Γ or a pharmaceutically acceptable sait thereof with at least one additional pharmaceutically active compound in a fixed-dose formulation. Combination therapy in a free dose combination therapy comprises coadministration of a compound of Formula 1 or Formula Γ or a pharmaceutically acceptable sait thereof and at least one additional pharmaceutically active compound in free doses of the respective compounds, either by simultaneous administration of the individual compounds or by sequentîal use of the individual compounds over a perîod of time.

[0152] The additional pharmaceutically active compound includes in particular drugs for reducing iron overload (e.g., Tmprss6-ASO or siRNA) or iron chelators, in particular curcutnin, SSP-004184, Deferîtrin, deferasirox, deferoxamîne and/or deferiprone, or antioxidants such as n-acetyl cysteine, anti- diabetics such as GLP-1 receptor agonists, antibiotics such as peniciliin, vancomycin (Van) or tobramycin, antifungal drugs, anti-viral drugs such as interferon-a or ribavirin, drugs for the treatment of malaria, anticancer agents, drugs for the treatment of neurodegenerative diseases such as Alzheimer's disease and Parkinson's disease (e.g., dopamine agonists such as Levodopa), or immunosuppressants (cyclosporine A or cyclosporine A dérivatives), iron suppléments, vitamin suppléments, red cell production stimulators (e.g., erythropoietin, Epo), anti-inflammatory agents, anti-thrombolytics, statins, vasopressors and inotropic compounds. A further object ofthe present invention relates to the use ofthe

182 above combinations for the prophylaxis and/or treatment of diseases caused by a lack of hepcidin or iron metabolism disorders, such as particularly iron overload States such as in particular thalassemia, sickle cell disease and hemochromatosis and other disorders as described in the present application,

[0153 J In certain embodiments, the subject matter described herein is directed to a method of treating beta-thalassemia (b-thalassemia) in a subject, comprising administering to the subject an effective amount of a compound of Formula l or a pharmaceutically acceptable sait thereof. The compounds of Formula I as defined herein, act as ferroportin inhibitors and can be used for treating severe forms of b-thalassemia, such as transfusion-dependent b-thalassemia, including in particular bthalassemia major and hemoglobin E b-thalassemia and the symptoms and pathological conditions associated therewith, such as in particular defective red blood cell production in the bone marrow, ineffective erythropoiesis, low hemoglobin levels / anémia, multiple organ dysfunction, iron overload, liver iron loading and cardiac iron overload, paleness, fatigue, jaundice, and splenomegaly.

[0154] In particular, a severe form of b-thalassemia is transfusion-dependent b-thalassemia (TDT), including in particular b-thalassemia major and severe forms of hemoglobin E b- thalassemia. Severe forms of b-thalassemia and hemoglobin E 13- thalassemia, require that patients suffering therefrom achieve regular blood transfusions / Red Blood Cell transfusions (RBC transfusions). Such severe forms of b-thalassemia are thus also summarized as transfUsion-dependent b-thalassemia (TDT). Thus the methods of treating severe forms of b-thalassemia, such as in particular transfusion-dependent bthalassemia (TDT), include in particular b-thalassemia major and severe forms of hemoglobin E b- thalassemia by administering to a subject in need thereof one or more of the compounds of Formula I as described herein.

[0155] The subject may be: suffering from b-thalassemia or haemoglobin E b-thalassemla and requiring regular blood transfusion; suffering from b-thalassemia major and/or severe haemoglobin E bthalassemia, more particularly to patients suffering from b-thalassemia major.

[0156] The methods of treating beta-thalassemia can resuit in: reduced NTBI levels in a subject;

reduced LPI levels in a subject; reduced alpha globin aggregate levels in a subject; reduced RO S levels in RBCs of a subject; a decrease in liver iron concentration in the subject; a decrease in myocardial iron concentration in the subject; an improvement of at least one of the parameters Hct, MCV, MCH, ROW and réticulocyte numbers in the subject; in an erythroîd response, which comprises a réduction in transfusion burden in the subject; a réduction of transfusion burden in the subject compared to the transfusion burden prior to treatment using the methods; achieving no longer requiring a transfusion in a

183 transfusion-dependent b-thalassemia subject; reduced sérum ferritin levels in the subject; a réduction of the symptoms associated with one or more transfusion-dependent b-thalassemia clinical complications. Nonlimiting examples of transfusion-dependent b-thalassemia symptoms include growth retardation, pallor, jaundice, poor musculature, genu valgum, hepatosplenomegaly, leg ulcers, development of masses from extramedullary hematopoiesis, skeletal changes resulting from expansion of the bone marrow, and clinical complications of chronic red blood cell transfusions, such as, for example hepatitis B virus infection, hepatitis C virus infection and human itnmunodefîcîency virus infection, alloimmunization, and organ damage due to iron overload, such as, for example, liver damage, heart damage and endocrine gland damage. Although the compounds of the formula (1) are not expected to directly affect growth différentiation factor 11 (GDFI1), decrease of skeletal deformities can also occur caused by reduced extramedullary erythropoiesis.

[0157] The foîlowing parameters can be determined to evaluate the efficacy of the compounds of the present invention in the new medical use: sérum iron, NTBI levels, LPI (Labile Plasma Iron) levels, erythropoietin, TSAT (transferrin saturation), Hb (hemoglobin), Hct (haematocrit), MCV (Mean Cell

Volume), MCH (Mean Cell Hemoglobin), RDW (Red Blood Cell Distribution Width) and réticulocyte numbers, complété blood counts, spleen and liver weight, erythropoiesis in spleen and bone marrow, spleen and liver iron content and alpha-globin aggregates in RBC membranes. The détermination can be carried ont using conventional methods of the art, in particular by those described below in more detail. The compounds (I) of the present invention are suitable to improve at least one of these parameters.

[0158] The methods can be prior to or accompanying blood transfusion to prevent or at least attenuate occurrence of transfusion-caused pathological conditions.

[0159] In certain embodiments, the subject matter described herein is directed to a method of preventing and treating kidney injuries in a subject, comprising administering to the subject an effective amount of a compound of Fonnula I or a pharmaceutically acceptable sait 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 injuries are those induced by catalytic free iron. In certain aspects of these embodiments, the kidney injuries are selected from rénal ischemia-reperfusion injury (IR1), ischémie injury and acute kidney injuries. In a further aspect, kidney injuries are selected from acute kidney injury (AK!), rénal ischemia-reperfusion injury (IRI), ischémie injury and AKI caused by ischémie injury, AK1 foîlowing surgery or surgical intervention, such as in particular foîlowing cardiac surgery most often with procedures involving cardiopulmonary bypass,

184 other major chest or abdominal surgery, and kidney injury associated with RBC transfusion.

[0160] The term “preventing” and the like includes the protection from ischémie renai injury, avoidance of occurrence of AKI or at least reducing the severity of AKI following ischémie injury, RBC transfusion or a surgery intervention e.g. by administering the compounds prior to or accompanying or shortly after an ischémie event, RBC transfusion or the surgery intervention to prevent or at least attenuate occurrence of kidney injuries induced by catalytic free iron.

[0161 ] Free catalytic iron or labile iron or NTBI is considered as a main cause of kidney injury, such as in particular AKI triggered by ischemia. The administration of the ferroportin inhibitor compounds of formula (I) as described herein can protect against the damaging effects of catalytic free iron. Without being bound to theory, the ferroportin inhibitors described herein can reduce or prevent the formation of catalytic free iron or NTBI by sequestering iron in macrophages of liver and spleen, therewith reducing its levels in plasma and reducing the risk of ROS formation. The compounds of Formula I described herein act as ferroportin inhibitors, and hâve the potentîal to sequester iron în macrophages, thereby interrupting the cycle of self-sustaining release of catalytic free iron. The compounds of the Formula I are suitable for the prévention and treatment of the kidney injuries described herein by 1 imiting reactive oxygen species (ROS) to avoid kidney tissue injury. Further to catalytic free iron, NTBI and LPI (Labile Plasma Iron) can cause kidney injuries. NTBI encompasses ail forms of sérum iron that are not tightly associated with transferrin and is chemtcally and functionally heterogeneous. LPI represents a component of NTBI that is both redox active and chelatable, capable of permeating into organs and inducing tissue iron overload.

[0162] The following parameters can be determined to evaluate the efficacy of the compounds for treating kidney injuries; plasma créatinine, glomerular filtration rate (including estîmated glomerular filtration rate eGFR), urine album in excrétion, urine neutrophil gelatinase-associated lipocaiin (NGAL), NTBI, LPI, RBC hemolysis, blood urea nitrogen (BUN), plasma hemoglobin (Llb), total plasma iron, plasma hepcidin, rénal neutrophil infiltration, sérum IL-6, spleen, kidney and/or liver iron content, rénal ferroportin, KIM-1 (Kidney Injury Molécule- 1) as an acute marker for kidney injury in blood and urine, and H-ferritin. Additionally or alternatively, the efficacy of the compounds of the present invention can be determined via the kidney tubular injury score, such as e.g. the CSA-NGAL score (Cardiac Surgery Associated NGAL Score) for detecting acute tubular damage as described in more detail below, the

KDIGO score described in more detail below or the EGTI score comprising Endothélial, Glomerular, Tubular and Interstitial (EGTI) components to evaluate histology (described e.g, by: Khalid et al.‘

185

Kidney ischaemia reperfusion injury in the rat the EGTl scoring system as a valid and reliable tool for histological assessment Journal of Histology & Histopatholoy, Vol. 3, 20I6).

[0163] The methods of treating or preventing kidney injury can resuit in a decrease of sérum créatinine (sCr) in the subject. The methods of treating or preventing kidney injury can resuit in a corrected (decreased) urine album in excrétion in the subject. The methods of treating or preventing kidney injury can resuit in a decrease of blood urea nitrogen (BUN) in the subject. The methods of treating or preventing kidney injury can resuit în a decrease of total plasma iron in the subject. The methods of treating or preventing kidney injury can resuit in a decrease of interleukin-6 (!L-6) levels in the subject. The methods of treating or preventing kidney injury can resuit in a decrease of KIM-1 levels in the subject. The methods of treating or preventing kidney injury can resuit in an increase in spleen and/or liver iron concentration in the subject. The methods of treating or preventing kidney injury can resuit in a decrease in kidney iron concentration in the subject. The methods of treating or preventing kidney injury can resuit in reduced NTBI levels. The methods of treating or preventing kidney injury can resuit in reduced LP1 levels in the subject. The methods of treating or preventing kidney injury can resuit in an inhibition of tubular injury, such as tubular necrosis. The methods of treating or preventing kidney injury can resuit in an inhibition of apoptosis. The methods of treating or preventing kidney injury can resuit in a reduced IRI-induced rénal neutrophil infiltration. The methods of treating or preventing kidney injury can resuit in reduced ROS levels in kidney tissue of the subject. The methods of treating or preventing kidney injury can resuit in corrected (increased) kidney H- ferritin levels in the subject. In particular, the methods of treating or preventing kidney injury can reduce the occurrence of AKI, rénal ischemia- reperfusion injury and AKI caused by ischémie injury, AKI following surgery or surgical intervention, such as in particular following cardiac surgery most often with procedures involving cardiopulmonary bypass, other major chest or abdominal surgery, and kidney injury associated with RBC transfusion. The methods of treating or preventing kidney injury can comprise a) decrease, accelerated decrease or prévention of increase of sérum créatinine; and/or b) increase or prévention of decrease of estimated glomerular filtration rate (eGFR); and/or c) decrease or prévention of increase of rénal ferroportin; and/or d) increase or prévention of decrease of H-ferritin levels; and/or e) decrease or prévention of increase of rénal neutrophil infiltration; and/or f) decrease or prévention of increase of sérum IL-6 levels.

V. Methods of Preparing Compounds of Formula 1 and Pharmaceutically Acceptable Salts

186

Thereof

[0164] Compounds can be synthesized by synthetic routes that include processes analogous to those well-known in the Chemical arts, particularly in light of the description contained herein, and those for other heterocycles described in: Comprehensive Heterocyclic Chemistry 11, Editors Katritzky and Rees, 5 Elsevier, ]997, e.g., Volume 3; Liebigs Annalen derChemie, (9):1910-16, (1985); Helvetica Chimica

Acta, 41:1052-60, (1958); Arzneimittel-Forschung, 40(12):1328-3 I, (1990), each of which are expressly incorporated by reference, Starting materials are generally available from commercial sources such as Aldrich Chemicals (Milwaukee, WI) or are readily prepared using methods well known to those skilled in the art (e.g., prepared by methods generally described in Louis F. Fieser and Mary Fieser, Reagents 10 for Organic Synthesis, v. 1-23, Wiley, N.Y. (1967-2006 ed.), or Beilsteins Handbuch der organischen

Chemie, 4, Aufl. ed. Springer-Verlag, Berlin, includîng suppléments (also available via the Beilstein online database). DTT refers to dithiothreitol. DH AA refers to dehydroascorbic acid,

[0165] Synthetic chemistry transformations and protecting group méthodologies (protection and deprotection) useful in synthesizing compounds and necessary reagents and intermediates are known in 15 the art and include, for example, those described in R, Larock, Comprehensive Organic

Transformations, VCH Publishers (1989); T. W. Greene and P. G ,M. Wuts, Protective Groups in Organic Synthesis, 3^rd Ed., John Wiley and Sons (1999); and L. Paquette, ed., Encyclopedia of Reagents for Organic Synthesis, John Wiley and Sons (1995) and subséquent éditions thereof.

[0166] Compounds may be prepared singly or as compound libraries comprising at least 2, for 20 example 5 to 1,000 compounds, or 10 to 100 compounds. Libraries of compounds of Formula I may be prepared by a combinatorial ‘split and mix’ approach or by multiple parallel synthèses using either solution phase or solid phase chemistry, by procedures known to those skilled in the art. Thus, according to a further aspect, there is provided a compound library comprising at least 2 compounds, or pharmaceutically acceptable salts thereof.

[0167] The subject matter described herein is directed to the following embodiments.

IA. A compound ofFormula (I):

187

or a pharmaceutically acceptable sait thereof; wherein,

Z isNorCH;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, Ci-

Cîalkyl, C1-C3 alkoxy-Ci-Cjalkyl, hydroxy-Ci-C& alkoxy, hydroxy-Ci-Cj-alkyl, cyano, C3-C7 cycloalkyl-Ci-Cî alkoxy, NR^GR^H, halo-Ci-C₃ alkoxy, and C3-C6 cycloalkyl;

wherein R° and R^H are each independently hydrogen or C1-C3 alkyl; or two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered 10 heterocyclyl, C3-C7 cycloalkyl, Cô-Cio aryl, or 5- to I O-membered heteroaryl;

n is 0, 1, 2, or 3;

Y¹, Y², Y³, and Y⁴ 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 Y¹, Y², Y³, and Y⁴ can be N, NH, O, or S;

f is 0 or 1 ;

p is 1 or 2;

R^x, in each instance, is halogen, Ci-Ce alkyl, C1-C3 alkoxy, hydroxy, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, C1-C3 alkyl, hydroxy-Ci-Ci alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to lO-membered monocyclic or bicyclic fused heteroaryl)-Ci-C3 alkyl branched or linear, or (6- or 7-membered monocyclic heterocycIyl)-Ci-C3 alkyl branched or linear;

wherein, when p is l, C1-C3 alkyl in the (5- to lO-membered monocyclic or bicyclic fused heteroaryl)-Ci-C3 alkyl is linear;

and,

R^4a R⁴^

I I

wherein,

R^4a and R^4ë are each independently selected from the group consisting of hydrogen, Ci-Cô alkyl, hydroxy-Cj-Ce alkyl, C1-C3 alkoxy-Ci-Ce alkyl, C3-C7 cycloalkyl, 5- to l O-membered monocyclic, bicyclic fused, or spiro heterocyclyl, Ce-Cio aryl, 5- to lO-membered monocyclic or bicyclic fused heteroaryl, (Ce-Cio aryl)-Ci-C3 alkyl, and (5to 10-membered monocyclic heteroaryl)-C,-C3 alkyl;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R^4aor R^4g is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl;

R^4b is hydrogen or Ci-Côalkyl; or

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 7membered heterocyclyl; or

R^4b and R^4c taken together with the atom to which each is attached form a 5- to Ίmembered heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halo, and C1-C3 alkyl; or

R^4e and R^4d are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyi-thio-Ci-C3 alkyl, hydroxy-Ci-Cô alkyl, CiC& alkoxy-Ci-Cs alkyl, C3-C7 cycloalkyl, and C1-C3 alkyl; or

or, when p is 1,

i. 7-membered bicyclic fused heterocyclyl, 7-membered bridged heterocyclyl, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, haloalkyl, and Ce-Cio aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ü. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom;

wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2)_sC(=O)NR^kR';

wherein, s is 0, 1, 2, or 3;

R^k is hydrogen or C1-C3 alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, Ci21052

190

C₃ alkyl, C3-C7 cycloalkyl, and Ce-Cioaryl;

wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Ci-C₃ alkoxy, oxo, halogen, cyano, and NR^qR^w;

wherein R^q is hydrogen or C1-C3 alkyl, and R^wis Cô-Cio aryl or C3C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy;

or;

iii. 8-, 9-, IO- or l l-membered bicyclic fused heterocyclyl, or 12-membered bicyclic bridged, fused heterocyclyl, wherein said 8-, 9-, or 1 l-membered heterocyclyl contains one heteroatom and said 10- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said 10-, 11-, or 12-membered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, Cj-C₃ alkoxy, and hydroxy;

or, when p is 2,

i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(Ci-Cô alkyl), hydroxy, oxo, and Ci-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9, 10-, or 1 l-membered bicyclic bridged, fused, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, oxo, cyano, Ci-C₃ alkyl, hydroxy, NR^GR^H, and -(CHshCAOjNR^R¹;

provided that when the structure of Formula (I) îs

I9l

and ** is ; or

and ** is ;

and, wherein the compound of Formula (I) is not:

?/-((l,4-dioxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[c/]pyrimidin-4amine;

4-(piperidin-l-yl)-2-(pyridin-2-yI)-5,6,7,8-tetrahydroquinazolÎne;

4-(azepan-l-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

1-propy 1-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pyrimidin-4-yi)-l,4-diazepan10 2-one; or

2-(2-(pyridîn-2-yl)-6,7-dihydro-5H-cyclopenta[c/]pyrimidin-4-yl)-l,2-oxazepane; or a sait thereof.

2A. The compound of embodiment 1 A, wherein,

Z isN;

192

R. , in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, CiC3 alkyl, C1-C3 alkoxy-Ci-C3 alkyl, hydroxy-Ci-Cô alkoxy, hydroxy-Ci-Cs-alkyl, and NR^GR^H;

wherein R^G and R^H are each independently hydrogen or Cj-Cj alkyl; or wherein two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6membered heterocyclyl, Cô-Cio aryl, or 5- to l O-membered heteroaryl;

n is 0, l, or 2;

Y’, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, N H, and C (when R⁶ is attached thereto), provîded that l or 2 of Y¹, Y², Y³, and Y⁴ can be N or NH;

f is 0 or I;

p is 1 or 2;

m is 0;

R³ is selected from the group consisting of hydrogen, Cj-Cî alkyl, and hydroxy-Ci-Cs-alkyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-Ci-C3 alkyl branched or linear;

wherein, when p is 1, C1-C3 alkyl in the (5- to lû-membered monocyclic or bicyclic fused heteroaryï)-Ci-C3 alkyl is linear;

and,

R^4a Fi

I I

wherein,

R^4a is selected from the group consisting of Ci-Cô alkyl, hydroxy-Ci-C& alkyl, C1-C3 alkoxy-Ci-Côalkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic heterocyclyl, Cô-Cio aryl, 5- to 1 O-membered monocyclic or bicyclic fused

193 heteroaryl, (Cé-Cio aryl)-Ci-C3 alkyl, and (5- to 10-membered monocyclic heteroaryl)-Ci-C3 alkyl;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyl of R^4a is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, haloalkyl, hydroxy, Ci-Csalkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl;

R⁴® is selected from the group consisting of C&-Cio aryl and Ci-Cï alkyl;

R^4b is hydrogen or Cj-Cô alkyl;

or, R^4a and R^4b taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl;

or, R^4b and R^4c taken together with the atom to which each îs attached form a 5- to 7- membered heterocyclyl optionally substituted with one or two substituents, each independently selected from C1-C3 alkyl;

R^4c and R^4d are each independently hydrogen or C1-C3 alkyl;

or, R^4c and R^4d taken together with the atom to which each is attached form a C3-C5 cycloalkyl;

or,

R³ and R⁴ taken together with the nitrogen atom to which each is attached form a:

i. 7-membered monocyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the

I94 group consisting of C1-C3 alkyl, cyano, oxo, halogen, haloalkyl, and Ce-Cio aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of Ci-C3alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom;

wherein said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH₂)₅C(=O)NR^kR';

wherein s is 0, l, or 2;

R^k is hydrogen or Ci-Cs alkyl; and

R¹ is selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl;

wherein said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and NR^qR^w;

wherein R^q is hydrogen or C1-C3alkyl and R^wis Cô-Cio aryl or C3C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy; or iii. 10- or 11-membered bicyclic fused heterocyclyl containing one heteroatom, 20 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.

3A. The compound of embodiment 1A or 2A, wherein Y¹, Y², Y³, and Y⁴ are each CH or C (to which R⁶ is bound).

4A. The compound of embodiment 1A or 2A, wherein Y³ is N and Y¹, Y², and Y⁴ are each CH or C 25 (to which R⁶ is bound).

5A. The compound of embodiment 1A or 2A, wherein Y² is N and Y¹, Y³, Y⁴ are each CH or C (to which R⁶ is bound).

6A. The compound of embodiment 1A or 2A, wherein Y¹ is N and Y², Y³, and Y⁴ are each CH or C (to which R⁶ is bound).

195

7A. The compound of any one of embodiments 1A-6A, wherein R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, Cj-C₃ alkoxy, C1-C3 alkyl, C1-C3 alkoxy-Ci-C₃ alkyl, hydroxyC1-C3alkoxy, hydroxy-Ci-C3-alkyl, and NR^GR^H;

wherein R^G and R^H are each independently hydrogen or C1-C3 alkyl.

SA. The compound of embodiment 7A, wherein R⁶, in each instance, is selected from the group consisting of methoxy, methyl, fluoro, chloro, ethyl, N(CH₃)2, hydroxy, -OCH2CH2OH, -CH2OH, CH2OCH3, and -CH2CH2OH.

9A. The compound of embodiment SA, wherein R⁶, in each instance, is methoxy or methyl.

10A. The compound of any one of embodiments 1A-6A, wherein two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered heterocyclyl, Cô-Cio aryl, or 5- to 10- membered heteroaryl.

A. The compound of embodiment 10A, wherein two R⁶ groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, or phenyl ring.

I2A. The compound of any one of embodiments 1 A-l IA, wherein n is 1.

13A. The compound of any one of embodiments 1 A-l 1 A, wherein n is 0.

14A. The compound of any one of embodiments 1A-13A, wherein f is 1.

A. The compound of any one of embodiments 1A-13A, wherein fis 0.

16A. The compound of any one of embodiments ] A-l5A, wherein R³ is selected from the group consisting of hydrogen, methyl, and -CH2CH2OH.

17A. The compound of embodiment 16A, wherein R³ is methyl.

18A. The compound of any one of embodiments 1A-17A, wherein R⁴is a (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyL

19A. The compound of embodiment ISA, wherein R⁴ is a (5- to 10-membered monocyclic or bicyclic fused heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point is a nitrogen or oxygen.

20A. The compound of embodiment 18A or 19A, wherein R⁴ is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, and benzoxazole-methyl.

R^4a y-vY

A. The compound of any one of embodiments 1A-17A, wherein, wherein R⁴ is ' R

196

22A. The compound of embodiment 2I A, wherein R^4c and R^4d are each independently hydrogen or methyl.

23A. The compound of embodiment 22A, wherein R^4c and R^4d are each hydrogen.

24A. The compound of any one of embodiments 21A-23A, wherein R^4b is hydrogen.

25A. The compound of any one of embodiments 21A-24A, wherein R^4a is Ci-Ce alkyl.

26A. The compound of embodiment 25A, wherein R^4a is tert-butyl.

27A. The compound of any one of embodiments 21A-24A, wherein R^4a is Cô-Cio aryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, haloalkyl, hydroxy, Ci-Cialkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl.

28A. The compound of embodiment 27A, wherein R^4a is phenyl optionally substituted with fluoro or methoxy.

29A. The compound of any one of embodiments 21A-24A, wherein R^4a is 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, Ci-Cô alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl. 30A. The compound of embodiment 29A, wherein R^4a is pyridinyl or quinolinyl, optionally substituted with fluoro, methoxy, or methy l.

A. The compound of any one of embodiments 21A-24A, wherein R^4a is C3-C7 cycloalkyl, optionally 20 substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cê alkyl, haloalky l, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl.

32A. The compound of embodiment 31 A, wherein R^4a is cyciopropyl, cyclobutyl, cyclopentyl, or cyclohexyl, optionally substituted with methyl, trifluoromethyl, fluoro, or hydroxy.

33A. The compound of any one of embodiments 21A-24A, wherein R^4a is a 5- or 6-membered heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cs alkyl, haloalkyl, hydroxy, Ci-Csalkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spîro heterocyclyl.

34A. The compound of 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.

197

35A. The compound of any one of embodiments 21A-24A, wherein R^4a is (Cê-Cio aryl)-Ci-C3 alkyl or (5- to 10-membered monocyclic heteroaryl)-Ci-C3 alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cé alkyl, haloalkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, bicyclic fused, or spiro heterocyclyl.

36A. The compound of embodiment 35A, wherein R^4a is phenyl-methyl or pyridinyl-methyl.

37A. The compound of any one of embodiments 21A-23A, wherein R^4a and R^4b taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl.

38A. The compound of embodiment 37A, wherein R^4a and R^4b taken together with the atom to which each is attached fonn a 6-membered heterocyclyl selected from the group consisting of piperidinyl, morpholinyl, and piperazinyl.

39A. The compound of any one of embodiments 21A or 25A-36A, wherein R^4b and R^ taken together with the atom to which each is attached form a 5- to 7-membered heterocyclyl optionally substituted one or two times with C1-C3 alkyl.

40A. The compound of embodiment 39A, wherein R^4b and R^4c taken together with the atom to which each is attached form a pipendin-2-one or a pyrrolidine-2-one, optionally substituted one or two times with C1-C3 alkyl.

I o

41A. The compound of any one of embodiments 1A-17A, wherein R⁴ is A

42A. The compound of embodiment 41A, wherein R⁴- is phenyl or methyl.

43A. The compound of any one of embodiments 1A-15A, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing one or two heteroatoms.

44A. The compound of embodiment 43A, wherein R³ and R⁴ taken together with the nitrogen atom to which each îs attached form a 7-membered monocyclic heterocyclyl containing one heteroatom, wherein said heterocyclyl îs optionally substituted once with methyl or oxo.

45A. The compound of embodiment 43A, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted once with phenyl,

I98 methyl, or oxo, and wherein said phenyl is optionally substituted with methoxy.

46A. The compound of any one of embodiments 1 A-l 5A, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form an 11-membered bicyclic fused heterocyclyl containing one heteroatom, optionally substituted with methoxy.

47A. The compound of any one of embodiments 1A-46A, wherein p is 1.

IB. A compound of Formula (F):

or a pharmaceutically acceptable sait thereof; wherein, Z is N or CH;

^N<-V^Y

Ring B is ^γ4 , wherein indicates the point of attachment to the remainder of the molécule;

R⁶, în each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-Ci-Cs alkyl, hydroxy-Ci-Ce alkoxy, hydroxy-Ci-Cj-alkyl, cyano, -NR^GR^H, halo-Ci-C3 alkoxy, -O-(CH2)U-R^bb, halo-Ci-C3 alkyl, -O-R^cc-O-R^dd, 5- to 7membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, u is an integer from 0 to 6;

R^bb is 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR^GR^H; R^cc and R^dd are each independently Ci-Csalkyl;

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

199 and,

R^G and R^H are each independently hydrogen, -C(O)R^Ga, or C1-C3 alkyl; wherein, R^Ga is Ci-C₃alkyl orhydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-Ci-C₃-alkyl, Ci-C₃ alkyl, C₃-C? cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1,2, or 3;

f is 0 or 1;

p is 1 or 2;

R^x, in each instance, is halogen, Ci-Cô alkyl, C1-C3 alkoxy, hydroxy, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, Ci-C₃ alkyl, hydroxy-Ci-C₃ alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C₃ alkyl branched or linear, or (6- or 7-membered monocyclic heterocyclyl)-Ci-C₃ alkyl branched or linear; wherein, said heteroaryl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Ce-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7membered monocyclic heterocyclyl, and wherein said aryl, cycloalkyl, heteroaryl, or heterocyclyl îs optionally substituted with one or two substituents, each individually

200 selected from the group consisting of Ci-Ca alkyi, halogen, and hydroxy; and, when p is 1, C1-C3 alkyi in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyi is linear;

and.

R^4aI I

wherein,

R^4a and R^4g are each independently selected from the group consisting of hydrogen, Ci-Cô alkyi, hydroxy-Ci-Côalkyi, C1-C3 alkoxy-Ci-Côalkyi, C3-C7 cycloalkyl, 5- to 1 Û-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, Cô-Cjo monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cio monocyclic or fused bicyclic aryI)-Ci-Cj alkyi, and (5- to 10membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyi;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl of R^4aor R^4g is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyi, halo-Ci-C3 alkyi, hydroxy, C1-C3 alkoxy, halo-Ci-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;

R^4b is hydrogen or Ci-Côalkyi; or

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyi, halo-Ci-Cj alkyi, hydroxy, and C1-C3 alkoxy; or

R^4b and R^4c taken together with the atom to which each is attached form a 5- to 7membered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and C1-C3 alkyi; or

R^4c and R^4d are each independently selected from the group consisting of

201 hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-C;-Cî alkyl, hydroxy-C ।-Cô alkyl, CiCô alkoxy-Ci-Cs alkyl, C3-C7 cycloalkyl, and C1-C3 alkyl; or

or, when p is l,

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-C3 alkyl, and Cô-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2)₃C(=O)NR^kR^l; wherein, s is 0, l, 2, or 3;

R^k is hydrogen or Cj-C? alkyl; and ’ R¹ is selected from the group consisting of hydrogen, hydroxy, CiC3 alkyl, C3-C7 cycloalkyl, and Cô-Cio monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted

202 with one or two substituents, each independently selected from the group consistîng of C1-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein, R^q is hydrogen or C1-C3 alkyl; and

R^wis Cô-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consistîng of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy;

or, iii. 8-,9-, 10-or H-membered fused bicyclic heterocyclyl, or 12-membered bicyclic bridged and fused heterocyclyl, wherein said 8-, 9-, or 11-membered heterocyclyl contains one heteroatom and said IO- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said ΙΟ-, l I-, or 12-membered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consistîng of halogen, Cj-Cs alkyl, C1-C3 alkoxy, and hydroxy;

or, when p is 2,

i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally substituted with one or two substituents, each independently selected from the group consistîng of halogen, hydroxy-(Ci-Cô alkyl), hydroxy, oxo, and Ci-Csalkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9-, 10-, or 11-membered bridged bicyclic, fused bicyclic, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consistîng of halogen, oxo, cyano, C1-C3 alkyl, hydroxy, -NR^GR^H, and -(CH2)sC(=O)NR^kR^l;

provided that when the structure of Formula (l) is

203

H * is and ** is ; or \ \ * is and ** is ;

and, wherein the compound of Formula (!) îs not:

N-((l,4-dÎoxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i7]pyrimidin-4amine;

4-(piperidin-l-yl)-2-(pyridin-2-yl)-5,6,7,8'tetrahydroquinazoline; 4-(azepan-l-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline; l-propyl-4-(2-(pyrîdin-2-yl)-6_s7-dihydro-5H-cyciopenta[i7]pyrimidin-4-yl)-1,4-diazepan-

2-one; or

2-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[<7|pyrimidin-4-yl)-l ,2-oxazepane; or a sait thereof.

C. A compound of Formula (Γ):

204

α^!) or a pharmaceutically acceptable sait thereof; wherein, Z is N or CH;

indicates the point of attachment to the remainder of the molécule;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 alkoxy-Ci-C3 alkyl, hydroxy-Ci-Cio alkoxy, hydroxy-Ci-Cjo-alkyl, cyano, -NR^GR^H, halo-Ci-C3 alkoxy, -O-(C]-Ce alkyl)-R^bb, -O-R^bb, -(Ci-Cô alkyl)NR^giR^hi, -S-C1-C3 alkyl, -S-C1-C3 alkyl-NR^G,R^H1, halo-Ci-C₃alkyl, -O-R^cc-O-R^dd, 5-to 7membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, the alkyl moiety in hydroxy-Ci-Cio alkoxy or -O-(Ci-C6alkyl)-R^bb is optionally substituted with cyano, hydroxy, hydroxy-Ci-Ca-alkyl, halogen, or C1-C3 alkoxy;

R^bb ts 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7 cycloalkyl, 5or 6-membered monocyclic heteroaryl, -SO2-C1-C3 alkyl, -S-C1-C3 alkyl, -C(O)NR^GlR^H1, or -NR^gR^h;

R^ccisCi-C₃ alkyl; and

R^dd is Ci-C3alkyl or a 6-membered heteroaryl;

wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶, R^bb, or R^dd is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, halo-Ci-Cs alkyl, oxo, C1-C3 alkoxy, and Ci-Csalkyl;

205

R^Gl and R^Hl are each independently hydrogen or C1-C3 alkyl;

and,

R° and R^H are each independently hydrogen, -C(O)R^Ga, or optionally deuterated C1-C3 alkyl; wherein,

R^Ga is C1-C3 alkyl or hydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting ofCi-C3 alkoxy, hydroxy, hydroxy-Ci-Cj-alkyl, C1-C3 alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1, 2, or 3;

Y^!, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R⁶, N-R⁶, and C-R⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N, N-R⁶, NH, O, SH or S-R⁶;

f is 0 or 1;

p is 1 or 2;

R^x, in each instance, is halogen, Ci-Ce alkyl, C1-C3 alkoxy, hydroxy, oxo, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, optionally deuterated C1-C3 alkyl, hydroxyC1-C3 alkyl, halo-Ci-Cs alkyl, cyclopropyl, and phenyl;

R⁴ is selected from the group consisting of:

i. (5- to 10-membered monocyclic or fused bicyclic heteroaryI)-Ci-C3 alkyl, or (6or 7-membered monocyclic heterocyclyl)-Ci-C3 alkyl; wherein, said heteroaryl or heterocyclyl îs optionally substituted with one or two substituents, each independently selected from the group consisting of Cô-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, -(Ci-C3alkyl)-T, and 5- to 7-membered monocyclic heterocyclyl;

206

T is selected from the group consisting of Ce-Cio monocyclic or fused bicyclic aryl, C3-C7 cycloalkyl, 5- or 6-membered heteroaryl, and 5- to 7membered monocyclic heterocyclyl; and, wherein T or said aryl, cycloalkyl, heteroaryl, or heterocyclyl substituent of R⁴ is optional ly substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy; and when p is l, Ci-Cj alkyl in the (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl is linear;

and,

R^4a R⁴9

wherein,

R^4a and R^4s are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, hydroxy-Ci-Cô alkyl, halo-Ci-C₃ alkyl, C1-C3 alkoxy-Ci-C& alkyl, -Ci-Cô alkyl-NR^JiR^J2, C3-C7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, Cô-Cjo monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl;

Rⁿ and R^J2 are independently hydrogen or Ci-C₃ alkyl;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl of R^4aor R^4g is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, halo-Ci-C₃ alkyl, hydroxy, C)-C₃ alkoxy, halo-Ci-C₃ alkoxy, oxo, C₃-C? cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;

R^4b is hydrogen or Ci-Côalkyl; or

R^4a and R^4b taken together with the atom to which each is attached form a 5- to

207

10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, halo-Ci-Ca alkyl, hydroxy, and C1-C3 alkoxy; or

R^4b and R^4c taken together with the atom to which each is attached form a 5- to 7membered monocyclic heterocyclyl 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 R⁴⁴ are each independently selected from the group consisting of hydrogen, C1-C3 alkoxy, hydroxy, C1-C3 alkyl-thio-Ci-C₃ alkyl, hydroxy-Ci-Cg alkyl, CiCb alkoxy-Ci-Cj alkyl, C3-C7 cycloalkyl, and C1-C3 alkyl; or

or, when p is 1,

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C;-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-Cs alkyl, and C^-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and Ci-C₃ alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4~membered monocyclic heterocyclyl is optionally

208 substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkoxy, oxo, and -(CH2)₅C(=O)NR^kR^l;

wherein, s is 0, l, 2, or 3;

R^k is hydrogen or C1-C3 alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, CiCa alkyl, C3-C7 cycloalkyl, and Cé-Cio monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting ofCi-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein,

R^q is hydrogen or C1-C3 alkyl; and

R^w is Cô-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Csalkyl, hydroxy, and C1-C3alkoxy;

or, iii. 8-, 9-, 10- or 1 l-membered fused bicyclic heterocyclyl, or 12-membered bicyclic bridged and fused heterocyclyl, wherein said 8-, 9-, or l l-membered heterocyclyl contains one heteroatom and said 10- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said 10-, 11-, or 12-membered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, C1-C3 alkoxy, and hydroxy;

or, when p is 2,

i. 6-membered monocyclic heterocyclyl containing one heteroatom, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, hydroxy-(Ci-Cû alkyl), hydroxy, oxo, and C1-C3 alkoxy; or ii. 4- or 7-membered monocyclic heterocyclyl containing one or two heteroatoms, or 7-, 8-, 9-, 10-, or 1 l-membered bridged bicyclic, fused bicyclic, or spiro heterocyclyl containing one, two, or three heteroatoms, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, oxo,

209

cyano, C1-C3 alkyl, hydroxy, -NR^GR^H, and -(CH_z)_sC(=O)NR^kR’; provîded that when the structure of Formula (I) is

wherein the compound of Formula (I) is not:

/V-((l_;4-d>oxan-2-yl)methyl)-2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pyrimidin-4amine;

4-(piperidîn-l-y l)-2-(pyridin-2-y 1)-5,6,7,8-tetrahydroquinazol ine;

4-(azepan-l-yl)-2-(6-propylpyridin-2-yl)-5,6,7,8-tetrahydroquinazoline;

-propyl-4-(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[i/]pyrimidin-4-yl)-1,4-diazepan2-one; or

2-(2-(pyridin-2-yl)-6,7-dîhydro-5H-cyclopenta[c/]pyrimidin-4-yI)-l,2-oxazepane; or a sait thereof.

2B. The compound of embodiment IB or IC, or a pharmaceutically acceptable sait thereof, wherein p is 1.

3B. The compound of embodiment IB, 2B, or IC, or a pharmaceutically acceptable sait thereof,

210 wherein Z is N.

4B. The compound of any one of embodiments 1B-3B or IC, or a pharmaceutically acceptable sait thereof, wherein Y¹, Y², Y³, and Y⁴ are each CH or C-R⁶.

5C. The compound of embodiment 4B or IC, or a pharmaceutically acceptable sait thereof, wherein Y¹ is CH, Y² is C-R⁶, Y³ is CH, and Y⁴ is CH.

5B. The compound of any one of embodiments 1B-3B or IC, or a pharmaceutically acceptable sait thereof, wherein Y³ is N and Y¹, Y², and Y⁴ are each CH or C-R⁶.

6B. The compound of any one of embodiments 1B-3B or 1C, or a pharmaceutically acceptable sait thereof, wherein Y² is N and Y¹, Y³, Y⁴ are each CH or C-R⁶.

7B. The compound of any one of embodiments IB-3B or 1 C, or a pharmaceutically acceptable sait thereof, wherein Y¹ is N and Y², Y³, and Y⁴ are each CH or C-R⁶.

8B. The compound of any one of embodiments 1B-7B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, Ci-C3 alkoxy, Ci-C3alkyl, Ci-C3 alkoxy-Ci-C3 alkyl, hydroxy-Ci-Cô alkoxy, hydroxy-Ci-C3 alkyl, -O-(CH2)U-R^bb, haloCi-C3 alkoxy, -O-R^cc-O-R^dd, halo-Ci-C₃ alkyl, and -NR^GR^H; wherein,

R^bb is -NR^GR^H;

u is an integer from 1 to 3;

R^g and R^H are each independently hydrogen or Ci-C₃ alkyl; and

R^cc and R^dd are each independently Ci-C₃ alkyl.

9C. The compound of any one of embodiments IC, 2B-8B or 5C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, CiC3 alkoxy, Ci-C3 alkyl, Ci-C3alkoxy-Ci-C3 alkyl, hydroxy-Ci-Cio alkoxy, hydroxy-Ci-Cioalkyl, -O-(Ci-C6 alkyl)-R^bb, halo-Ci-C3 alkoxy, -O-R^cc-O-R^dd, halo-Ci-C3 alkyl, -(Ci-C6 alkyl)NR^GIR^H1, -S-CH3, -S(CH₂)₂N(CH₃)₂, and -NR^gR^h; wherein,

R^bb is -NR^gR^h, -C(O)N(CH₃)₂, -S(O)₂CH₃, or -SCH₃;

R^g and R^h are each independently hydrogen, optionally deuterated Ci-C3 alkyl, or -C(O)R^Ga, wherein R^Ga is Ci-C3 alkyl;

R^Gî and R^['¹¹ are each independently hydrogen or Ci-C₃ alkyl;

R^ce and R^dd are each independently Ci-C₃ alkyl; and, wherein the alkyl moiety în hydroxy-Ci-Cio alkoxy is optionally substituted with hydroxy, halogen, or Ci-C₃ alkoxy.

2ll

9B. The compound of any one of embodiments 1B-8B, 5C, or 9C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH₃)₂, hydroxy, -OCH₂CH₂OH, -CH₂OH, CH2OCH3, -OCH2CH2NH2, -OCH₂CH₂N(CH₃)₂, -OCH₂C(CH₃)₂OH, -OCH₂CF₃₎ -OCHF₂, -OCF3, -oc

H₂CH2OCH₃, -OCH2CH2F, -OC(CH₃)₂CH₂OH, and -CH₂CH₂OH.

IOC. The compound of embodiment 9C, or a phannaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, N(CH₃)2, hydroxy, -OCH2CH2OH, -CH₂OH, CH₂OCH₃, -OCH₂CH₂NH₂, -OCH₂CH2N(CH3)₂, -OCH₂C(CH₃)₂OH, -OCH₂CF3, -OCHF2, -OCF₃, -OC

H₂CH₂OCH₃, -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(CH2 CH₃)₂OH, -OCH₂CH₂N(CH₂CH₃)2, -OCH(CH₃)CH₂N(CH₃)₂, -OCH₂C(O)N(CH₃)₂, -OCH₂C(CH₃)₂N(C H₃)_2î -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)₂CH_3î

-O(CH₂)₂SCH₃, -(CH₂)₂C(CH₃)₂OH, -OCH₂CH₂N(CD₃)₂, and -CH2CH2OH.

I0B. The compound of embodiment 9B, 9C, or 10C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is methoxy, -OCH₂CH₂OH, or -OCH₂C(CH₃)₂OH.

IC. The compound of embodiment 10C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is methoxy, -OCH₂CH₂N(CH₃)2, -OCH2CH2OH, or -OCH₂C(CH₃)₂OH.

12C. The compound of embodiment 1 IC, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is -OCH₂CH₂N(CH₃)₂ or -OCH₂C(CH₃)₂OH.

IB. The compound of any one of embodiments 1B-7B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of -O-(CH₂)u-R^bb, and Ca-Cô cycloalkyl; wherein, u is an integer from 0 to 3;

R^bb is 4- to 7-membered monocyclic heterocyclyl or C₃-C? cycloalkyl; and wherein said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, Ci-C₃ alkoxy, and Ci-C₃alkyl.

12B. The compound of embodiment 11 B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of cyclopropyl and -O-(CH₂)_U-R^bb; wherein,

212 u is 0, 1, or 2; and

R^bb is selected from the group consistîng of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl.

13C. The compound of any one of embodiments IC, 2B-8B or 5C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consistîng of-O-(Ci-Cs alkyl)-R^bb, -O-R^bb, -O-R^cc-O-R^dd, 5- to 7- membered monocyclic heteroaryl, and Cî-Cô cycloalkyl; wherein,

R^cc is C1-C3 alkyl and R^dd is 6-membered heteroaryl;

R^bb is 4- to 7-membered monocyclic or bridged heterocyclyl, 5- or 6- membered monocyclic heteroaryl, or C3-C7 cycloalkyl; and wherein said cycloalkyl, heteroaryl, or heterocyclyl of R⁶, R^bb, or R^dd is optionally substituted with one or two substituents, each independently selected from the group consistîng of hydroxy, halogen, C1-C3 alkoxy, oxo, halo-Ci-Ca alkyl, and C]-C3 alkyl.

14C. The compound of embodiment 13C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consistîng of cyclopropyl, -O-R^bb, -O-(CH2)-R^bb, and -O-(CH2)2-R^hb, -O-(CH2)2-O-pyridazinyl, optionally Cj-Cj alkyl-substituted imidazolyl; wherein,

R^bb is selected from the group consistîng of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranol, oxetanyl, dioxolanyl, azetidinyl, morpholinyl, piperazinyl, 2-oxa5-azabicyclo[2.2.1]heptane, imidazolyl, tetrazolyl, pyridazinyl, piperidinyl, thiomorpholinyl, and pyrrolidinyl, each optionally substituted with hydroxy, oxo, fluoro, -CFj, -CH2CF3, -CH2CHF2, -CH2CH2F, methoxy, ethyl, or methyl.

15C. The compound of embodiment 14C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in

214

to Ring B.

13B. The compound of embodiment 12B, 14C, or 15C, or a pharmaceutically acceptable sait thereof,

where ' indicates the point of attachment to Ring B.

16C. The compound of embodiment 15C, or a pharmaceutically acceptable sait thereof, wherein R⁶ is

215

14B. The compound of embodiment 13B or 13-I6C, or a pharmaceutically acceptable sait thereof.

I5B. The compound of any one of embodiments 1B-7B or IC, or a pharmaceutically acceptable sait thereof, wherein two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6- membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-Ci-Cs-atkyl, C1-C3 alkyi, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl.

16B. The compound of any one of embodiments 1B-7B or IC, or a pharmaceutically acceptable sait thereof, wherein two R^È groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyi, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl.

17B. The compound of embodiment 16B, or a pharmaceutically acceptable sait thereof, wherein two

R⁶ groups, taken together with the atom to which each is attached, form a ring selected from the group

216

attachment of the ring with Ring B.

18B. The compound of embodiment I7B, or a pharmaceutically acceptable sait thereof, wherein two

R⁶ groups, taken together with the atom to which each is attached, form a form a ring selected from the

18.bb The compound of any one of embodiments 15B-18B, wherein Ring B is selected from the group

2] 7

I9B. The compound of any one of embodiments l B-19B, IC, 5C, 9C, 10C, l IC, 12C, 13C, 14C, 15C, 5 or 16C, or a pharmaceutically acceptable sait thereof, wherein fis 1.

20B. The compound of embodiment 1 B, 2B, 3B, or IC, or a pharmaceutically acceptable sait thereof, wherein f is 0, and Ring B is

B. The compound of embodiment 20B, or a pharmaceutically acceptable sait thereof, wherein Ring

n is 0 or 1; and

Y² and Y³ are each independently selected from the group consisting of CH, N, NH, NR⁶, S, O, and CR⁶, provîded that only one of Y² and Y³ can be N, NH, NR⁶, S, or O.

22B. The compound of embodiment 20B or 21 B, or a pharmaceutically acceptable sait thereof,

23B. The compound of any one of embodiments 20B-22B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of C1-C3 alkyl and hydroxy-

C1-C3 alkyl.

24B. The compound of embodiment 23B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of methyl, ethyl, w-propyl, -CH2CH2OH, and CH2CH2CH2OH.

25B. The compound of any one of embodiments IB-24B, IC, 5C, 9C, IOC, 11C, 12C, 13C, I4C, 15C, 10 or 16C, or a pharmaceutically acceptable sait thereof, wherein n is 1.

26B. The compound of any one of embodiments 1B-24B1C, 5C, 9C, 10C, 1 IC, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable sait thereof, wherein n îs 0.

27B. The compound of any one of embodiments 1B-14B, IC, 5C, 9C, 10C, 1 IC, 12C, 13C, 14C, 15C, or 16C, or a pharmaceutically acceptable sait thereof, wherein n îs 2.

28B. The compound of embodiment 27B, wherein one R⁶ is selected from the group consisting of methyl and methoxy and the other R⁶ is selected from the group consisting of methyl, methoxy, halogen, and -OCH2CH2OH.

31C. The compound of any one of embodiments 1-28B or IC, 5C, 9C, 10C, 1 IC, 12C, 13C, 14C,

15C, or 16C, or a phannaceutically acceptable sait thereof, wherein R³ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, -CD3, -CH2CF3, and -CH2CH2OH.

29B. The compound of any one of embodiments 1B-28B IC, 5C, 9C, 10C, 1 IC, 12C, 13C, 14C, 15C, 16C, or 3 IC, or a pharmaceutically acceptable sait thereof, wherein R³ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH.

3ÛB. The compound of embodiment 29B or 31 C, or a phannaceutically acceptable sait thereof,

219 wherein R³ is methyl.

33C. The compound of any one of embodiments IB-30B or IC, 5C, 9C, 10C, I IC, I2C, I3C, 14C, 15C, 16C, or 3 i C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is a (5- ίο 1 O-membered monocyclic or fused bicyclic heteroaryl)-m ethyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7 cycloalkyl, -(Ci-Csalkylj-phenyl, and 5-to 7-membered monocyclic heterocyclyl, and wherein said phenyl either alone or în -(Ci-C3alkyl)-phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting ofCi-C3 alkyl, halogen, and hydroxy.

31 B. The compound of any one of embodiments 1B-30B or 33C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is a (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-methyl, wherein said heteroaryl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, C3-C7 cycloalkyl, and 5- to 7-membered monocyclic heterocyclyl, and wherein said phenyl, cycloalkyl, or heterocyclyl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkyl, halogen, and hydroxy.

32B. The compound of embodiment 3IB or 33C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is a (6-membered heteroaryl)-methyl, wherein at least one of the ring atoms ortho to the attachment point in said 6-membered heteroaryl is a nitrogen.

35C. The compound of embodiment 33C or 32B, or a pharmaceutically acceptable sait thereof, wherein R⁴ is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazolemethyl, oxazolyl-methyl, and triazolyl-methyl, each optionally substituted with phenyl or benzyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro.

33B. The compound of embodiment 31 B, 32B or 35C, or a pharmaceutically acceptable sait thereof, 25 wherein R⁴ is selected from the group consisting of pyridinyl-methyl, pyrimidinyl-methyl, benzoxazolemethyl, and triazolyl-methyl, each optionally substituted with phenyl, and wherein said phenyl is optionally substituted with one substituent selected from the group consisting of fluoro, methyl, and chloro.

36C. The compound of embodiment 35C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is

220

34B. The compound of embodiment 33B or 36C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is selected from the group consisting of

35B. The compound of any one of embodiments 1B-30B or IC, 5C, 9C, 10C, l IC, 12C, 13C, 14C, ] 5C, 16C, 3 ] C, 33C, 35C, or 36C, or a pharmaceutically acceptable sait thereof, wherein, wherein R⁴ is

R^4a

36B. The compound of embodiment 35B, or a pharmaceutically acceptable sait thereof, wherein R^4c is selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, -CH2ÛC(CH₃)₃, and -CHzCHaSCbh; and R^4d is selected from the group consisting of hydrogen and methyl; or, R^4c and R^4d taken together with the atom to which each is attached form a cyclopropyl ring,

37B. The compound of embodiment 36B, or a pharmaceutically acceptable sait thereof, wherein R^4c and R^4d are each hydrogen.

37bb. The compound of embodiment 36B, or a pharmaceutically acceptable sait thereof, wherein R^4c is hydrogen or methyl; and R^4d is hydrogen.

37bbb. The compound of embodiment 36B or 37bb, or a pharmaceutically acceptable sait thereof, wherein R^4c is methyl; and R^4d is hydrogen.

38B. The compound of any one of embodiments 35B-37B, or a pharmaceutically acceptable sait thereof, wherein R^4b is hydrogen.

39B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is Ci-C6alkyl.

42C. The compound of embodiment 39B, or a pharmaceutically acceptable sait thereof, wherein R^4a is 20 methyl, ethyl, isopropyl, tert-butyl, or 3-methylpentan-3-yl.

43C. The compound of embodiment 39B or 42C, or a pharmaceutically acceptable sait thereof,

222 wherein R^4a is tert-butyl or isopropyl.

40B. The compound of embodiment 39B or 42C, or a pharmaceutically acceptable sait thereof, wherein R^4a is tert-butyl.

4] B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cs alkyl, halo-Ci-Cs alkyl, hydroxy, C1-C3 alkoxy, C3C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl.

42B. The compound of embodiment 41B, or a pharmaceutically acceptable sait thereof, wherein R^4a is phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy.

43B. The compound of embodiment 42B, wherein R^4a is selected from the group consisting of

F

44B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is 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, Ci-Cô alkyl, haio-Ci-Cs alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to ΙΟ-membered monocyclic, fused bicyclic, or spiro heterocyclyl.

45B. The compound of embodiment 44B, or a pharmaceutically acceptable sait thereof, wherein R⁴³ is pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one

223

substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CFa, -OCF3, or methyl.

46B. The compound of embodiment 45B, or a pharmaceutically acceptable sait thereof, wherein R^4a is

χΟ +O

224

47B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is C3-C7 cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, halo-Ci-Cs alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to IO-membered monocyclic or fused bicyclic heterocyclyl.

48B. The compound of embodiment 47B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of cyclopropyi, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[l.l.l]pentan-l-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy.

52C. The compound of embodiment 48B, wherein R^4a is selected from the group consisting of

49B. The compound of embodiment 48B or 52C, wherein R^4a is selected from the group consisting of

53C. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is a 4- to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Cj-Ce alkyl, balo-Ci-Ca alkyl, hydroxy, C1-C3 alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10membered monocyclic or fused bicyclic heterocyclyl.

50B. The compound of any one of embodiments 35B-38B or 53C, or a pharmaceutically acceptable sait thereof, wherein R^4a is a 5- to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cê alkyl, halo-Ci-Cs alkyl, hydroxy, Ci-C₃alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10membered monocyclic or fused bicyclic heterocyclyl.

54C. The compound of embodiment 53C, or a pharmaceutically acceptable sait thereof, wherein R^4a îs selected from the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][I,3]dioxolyl, oxetanyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, methoxy, and oxo.

5IB. The compound of embodiment 50B, or a pharmaceutically acceptable sait thereof, wherein R^4a is

226

selected front the group consisting of tetrahydrofuranyl, pyrrolidinyl, benzo[d][l,3]dioxolyl, and tetrahydropyranyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, methoxy, and oxo.

55C. The compound of embodiment 54C, wherein R^4a is selected from the group consisting of

52B. The compound of embodiment 5lB or 55C, wherein R^4a is selected from the group consisting of

53B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is (Cô-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyi or (5- to 10-membered monocyclic or fused bicyclic heteroaryi)-Ci-C3 alkyi, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyi, halo-Ci-Cs

227 alkyl, hydroxy, C1-C3 alkoxy, C3-C7 cycloalkyl, and 5- to l O-membered monocyclic, fused bicyclic heterocyclyl.

54B. The compound of embodiment 53B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of phenyl-methyl, l-cyclobutyl-2-ethyl-5-methyl-lH-imidazolyl, and pyridinyl-methyl.

57C. The compound of claim 53B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of benzyl, 2-(l-cyclobutyl-5-methyl-lH-imidazol-2-yl)ethyl, and pyridinyl-methyl.

55B. The compound of embodiment 54B or 57C, or a pharmaceutically acceptable sait thereof,

59C. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of hydroxy-Ci-C&alkyl, halo-Ci-Cîalkyl, CiC3 alkoxy-Ci-Cô alkyl, and -Ci-Cè alkyl-NR^J1R¹², wherein R¹¹ and R^J2 are each independently hydrogen or Ci-Csalkyl.

60C. The compound of embodiment 59C, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of-C(CH₃)₂CH₂OH, -CH2CH2OH, -C(CH3)₂CH₂OCH₃, -CH(CH3)CH₂OH, -CH₂CH2N(CH3)₂, -CH2CF3. 56B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of -CCCHshCHbOH, -CH₂CH₂OH, and -C(CH3)₂CH₂OCH3.

228

6lC. The compound of embodiment 59C, 60C, or 56B, or a pharmaceutically acceptable sait thereof, wherein R^4a is -C(CH₃)₂CH₂OH.

57B. The compound of any one of embodiments 35B-38B, or a pharmaceutically acceptable sait thereof, wherein R^4a and R^4b taken together with the atom to which each is attached form a 5- to 105 membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Ce alkyl, haloC1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

63C. The compound of embodiment 57B, or a pharmaceutically acceptable sait thereof, wherein R^4aand R^4b taken together with the atom to which each is attached fonn a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1.1 ]heptanyl, 2,3-dihydro-l H-pyrralo[2,3-c]pyridine_} or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, methyl, fluoro, and methoxy.

58B. The compound of embodiment 57B or 63C, or a pharmaceutically acceptable sait thereof, wherein R^4a and R^4b taken together with the atom to which each is attached form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.1. l]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, and methoxy.

64C. The compound of embodiment 63C or 58B, or a pharmaceutically acceptable sait thereof,

Yuxr wherein R^4a and R^4b taken together with the atom to which each is attached form a । ,

59B. The compound of embodiment 5SB or 64C, or a pharmaceutically acceptable sait thereof,

wherein R^4a and R^4b taken together with the atom to which each is attached form a

60B. The compound of any one of embodiments 35B, 39B-56B, 42C, 43C, 52C, 53C, 54C, 55C, 59C, 60C, or 61 C, or a pharmaceutically acceptable sait thereof, wherein R^4b and R^4c taken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3 alkyl.

230

6lB. The compound of embodiment 60B, or a pharmaceutically acceptable sait thereof, wherein R^4band R^4c taken together with the atom to which each is attached form a piperidin-2-one or a pyrrolidine-2one, optionally substituted one or two times with methyl.

62B. The compound of any one of embodiments 1B-30B, 1C,5C,9C, 10C, l IC, 12C, 13C, 14C, 15C, _R4g

I o

16C, or 3 l C, or a pharmaceutically acceptable sait thereof, wherein R⁴ is * , wherein R^4s is selected from the group consisting of Cô-Cw monocyclic or fused bicyclic aryl and Ci-Cs alkyl.

63B. The compound of claim 62B, or a pharmaceutically acceptable sait thereof, wherein R^4g is selected from the group consisting of phenyl and methyl.

64B. The compound of claim any one of embodiments 1B-28B, IC, 5C, 9C, IOC, l IC, 12C, 13C, 14C, 15C, 16C, or 3 IC, or a pharmaceutically acceptable sait thereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered monocyclic or bridged bicyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and when said 7-membered heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-C₃ alkyl, and Cô-Cjo monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl.

65B. The compound of embodiment 64B, or a pharmaceutically acceptable sait thereof, wherein R³and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl or oxo; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein said

231

phenyl is optionally substituted with methoxy.

66B. The compound of embodiment 65B, or a pharmaceutically acceptable sait thereof, wherein R³

67B. The compound of any one of embodiments IB-28B, IC, 5C, 9C, lOC, l IC, I2C, I3C, I4C, 15C, 16C, or 31 C, or a pharmaceutically acceptable sait thereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a lO- or l l-membered fused bicyclic heterocyclyl

232

containing one heteroatom, or a 12-membered bicyclic fused and bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of

C1-C3 alkyl, Ci-Csalkoxy, hydroxy, and halogen.

68B. The compound of embodiment 67B, or a pharmaceutically acceptable sait thereof, wherein R³

and R⁴ taken together with the nitrogen atom to which each is attached form a

69B. The compound of any one of embodiments 1B-28B, IC, 8C, 9C, 10C, UC, I2C, 13C, 14C, 15C,

233

16C, or 3IC, or a pharmaceutically acceptable saitthereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(Ctb^CAOjNRkR¹; wherein, s is 0, 1, or 2;

R^k is hydrogen or C1-C3 alkyl; and

R¹ îs selected from the group consisting of hydrogen, methyl, phenyl, cyclopentyl, and cyclohexyl;

and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and -NR^qR^w; wherein,

R^q is hydrogen or C1-C3 alkyl;

R^w is Cô-Cio monocyclic or fused bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

70B. The compound of embodiment 69B, or a pharmaceutically acceptable sait thereof, wherein R³and R⁴ taken together with the nitrogen atom to which each is attached form a

B. The compound of any one of embodiments 1B-70B, IC, 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 sait thereof, wherein R^x, in each instance, is methyl.

234

72B. The compound of any one of embodiments 1B-71B, IC, 5C, 9C, 10C, l IC, 12C, 13C, 14C, 15C, 16C, 3 IC, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 6lC, 63C, or 64C, or a pharmaceutically acceptable sait thereof, wherein m is 0.

73B. The compound of any one of embodiments 1B-7IB, IC, 5C, 9C, 10C, l IC, 12C, I3C, 14C, 15C, 16C, 3 IC, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 6IC, 63C, or 64C, or a pharmaceutically acceptable sait thereof, wherein m is 2.

79C. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein,

Z isN;

p is 1;

f is 1;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, and CR⁶, provîded that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, CiC3 alkyl, C1-C3 alkoxy-Ci-Csalkyl, hydroxy-Ci-Cio alkoxy, hydroxy-Ci-Cw-alkyl, cyano, -NR^GR^H, halo-Ci-C3 alkoxy, -O-(Ci-C6aIkyl)-R^bb, -O-R^bb, -(Ct-C₆ alkyl)-NR^G1R^HI, halo-Ci-C₃alkyl, -O-R^cc-O-R^dd, 5- to 7-membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, the alkyl moiety in hydroxy-Ci-Cio alkoxy or -O-(Ci-Côalkyl)-R^bb is optionally substituted with hydroxy, hydroxy-Ci-C3-alkyl, halogen, orCi-C3 alkoxy;

R^bb is 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR^ÜR^H;

and R^dd are each independently Cj-Cj alkyl;

wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶ or R^bb is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, C1-C3 alkoxy, and Ci-Csaikyl;

and,

R^gi and R^H1 are each independently hydrogen or C1-C3 alkyl;

R^g and R^h are each independently hydrogen, -C(O)R^Ga, or optionally deuterated C1-C3 alkyl; wherein,

R^Ga is C1-C3 alkyl or hydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with

235

Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-Ci-Cî-alkyl, C1-C3 alkyi, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, phenyl, -CH2CH2OH, and optionally deuterated methyl or ethyl;

R^4a °Y^NA^b

R⁴ is ' ^R ; wherein,

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

R^4d is selected from the group consisting of hydrogen and methyl;

or,

R^4c and R^4d taken together with the atom to which each is attached form a cyclopropyl ring;

R^4b is hydrogen or methyl;

R^4a is selected from the group consisting of hydrogen, Ci-Cioalkyi, hydroxy-Ci-Cô alkyi, C1-C3 alkoxy-Cj-Côalkyi, -Ci-Cô alkyl-NR^JIR^J2, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, Cô-Cio monocyclic or fused bicyclic aryl, 4- to 10-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyi, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-CiC3 alkyi; wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, arylalkyl, or heteroaryl-alkyi of R^4a is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-C& alkyi, halo-Ci-Ca alkyi, hydroxy, C1-C3 alkoxy, halo-Ci-Cj alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl;

Rⁿ and R^J2 are independently hydrogen or C1-C3 alkyi;

236 or,

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 10membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consistîng of halogen, Ci-Cô alkyl, halo-Ci-Ca alkyl, hydroxy, and C1-C3 alkoxy;

R^x, in each instance, is Ci-Cs alkyl; and m is 0, l, or 2.

74B. The compound of embodiment IB, or a pharmaceutically acceptable sait thereof, wherein, Zis N;

p is l ;

f is l ;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consistîng of CH, N, and CR⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can be N;

R⁶, in each instance, is selected from the group consistîng of halogen, hydroxy, C1-C3 alkoxy, CjC3 alkyl, C1-C3 alkoxy-Ci-Caalkyl, hydroxy-Ci-C& alkoxy, hydroxy-Ci-C3 alkyl, cyano, -NR^GR^H, haloC1-C3 alkoxy, -O-(CH2)_U-R^bb, halo-Ci-C3 alkyl, -O-R“-O-R^dd, 5- to 7- membered monocyclic heteroaryl, and C3-C6 cycloalkyl; wherein, □ is an integer from 0 to 6;

R^bb is 4- to 7-membered monocyclic heterocyclyl, C3-C7 cycloalkyl, or -NR^GR^H;

R^cc and R^dd are each independently C1-C3 alkyl;

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

and,

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B is optionally substituted

237 with one or two substituents, each independently selected from the group consisting ofCi-C3 alkoxy, hydroxy, hydroxy-Ci-Cs-alkyl, C1-C3 alkyl, Cs-C? cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, l, or 2;

R³ is selected from the group consisting of hydrogen, methyl, ethyl, phenyl, and -CH2CH2OH;

R^4a °γ^Ν^

At^r4c

R⁴ is ' ^R4d ; wherein,

R^4c îs selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, CH₂OC(CH3)3, and -CH₂CH₂SCH₃;

R^4d is selected from the group consisting of hydrogen and methyl;

or,

R^4b is hydrogen or methyl;

R^4a is selected from the group consisting of hydrogen, Ci-Cs alkyl, hydroxy-Cj-Côalkyl, C1-C3 alkoxy-Ci-Cô alkyl, C3-C7 cycloalkyl, 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, Cs-Cio monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (C&-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-Cj-C3 alkyl; wherein the cycloalkyl, heterocyclyl, 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, Ci-Cô alkyl, halo-Ci-Cs alkyl, hydroxy, C1-C3 alkoxy, halo-Ci-Cs alkoxy, halo-Cj-Cs alkyl, oxo, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl;

or,

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 10membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen,

238

Ci-Ce alkyl, halo-Ci-Cs alkyl, hydroxy, and C1-C3 alkoxy;

R\ in each instance, is C1-C3 alkyl; and m is 0, l, or 2.

75B. The compound of embodiment 74B or 79C, or a pharmaceutically acceptable sait thereof, wherein m is 0,

76B. The compound of embodiment 74B or 79C, or a pharmaceutically acceptable sait thereof, wherein m is 2 and R^x, in each instance, is methyl.

77B. The compound of any one of embodiments 74B-76B or 79C, or a pharmaceutically acceptable sait thereof, wherein, Y¹, Y², Y³, and Y⁴ are each CH or C-R⁶;

Y³ is N and Y¹, Y², and Y⁴ are each CH or C-R⁶;

Y² is N and Y¹, Y³, Y⁴ are each CH or C-R⁶;

or

Y¹ îs N and Y², Y³, and Y⁴ are each CH or C-R^é.

77bb. The compound of any one of embodiments 74B-77B or 79C, or a pharmaceutically acceptable sait thereof, wherein, Y¹ is CH, Y² is C-R⁶, Y³ is CH, and Y⁴ is CH.

83C. The compound of any one of embodiments 79C or 75B-77bb, or a pharmaceutically acceptable sait thereof; wherein R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, CiC3 alkoxy, C1-C3 alkyl, Ci-C3alkoxy-Ci-C3 alkyl, hydroxy-C 1-Cé alkoxy, hydroxy-Ci-Cioalkyl, -O-R^bb, -O-(C!-C6alkyl)-R^bb, halo-Ci-C3 alkoxy, -O-R^cc-O-R^dd, halo-Ci-C3 alkyl, C₃-C₆cycloalkyl, and -NR^CR^H; wherein,

R^bb is -NR^gR^h, 4- to 6-membered monocyclic heterocyclyl, or C3-C7 cycloalkyl;

R^g and R^h are each independently hydrogen or C1-C3 alkyl;

R^cc and R^dd are each independently Ci-C₃ alkyl; and, wherein, said cycloalkyl or heterocyclyl of R⁶ or R^bb is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, Ci-C3 alkoxy, and Ci-C3 alkyl. 84C. The compound of embodiment 83C, wherein R^bbis selected from the group consisting of cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, morpholinyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl; or, R^bb is -N(CH3)2.

78B. The compound of any one of embodiments 74B-77B, or a pharmaceutically acceptable sait thereof; wherein R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C1-C3 alkoxy, C1-C3 alkyl, C1-C3 aIkoxy-Ci-C₃ alkyl, hydroxy-Ci-Cé alkoxy, hydroxy-C।-C₃

239 alkyl, -O-(CH₂)_U-R^bb, halo-Cj-C3 alkoxy, -O-R^cc-O-R^dd, halo-Ci-Ca alkyl, C3-C₆ cycloalkyl, and -NR^gR^h; wherein,

R^bb is -NR^gR^h, 4- or 5-membered monocyclic heterocyclyl, or C₃-C? cycloalkyl;

u is an integer from 0 to 3;

R^g and R^h are each independently hydrogen or C1-C3 alkyl;

R^cc and R^dd are each independently Ci-C₃ alkyl; and, wherein, said cycloalkyl or heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, Ci-C₃ alkoxy, and C1-C3 alkyl.

79B. The compound of embodiment 78B, wherein R^bb is selected from the group consisting of 10 cyclopropyl, cyclobutyl, tetrahydrofuranyl, oxetanyl, and pyrrolidinyl, each optionally substituted with hydroxy or methyl.

85C. The compound of any one of embodiments 79C, 75B-77B, or 84C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chlore, ethyl, -N(CH₃)₂, hydroxy,-OCH₂CH(CH₃)OH,-OCH₂CH₂N(CH₂CH₃)₂,-OCH₂C(CH₃)(CH₂CH₃)OH,-OCH₂CH(CH₂OC H₃)OH, -OCH₂CH₂OH, -CH2OH, -CH₂OCH₃, -OCH₂CH₂NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂C(CH₃)₂OH, -OCH₂CF₃, -OCHF₂, -0CF3, -OCH₂CH₂OCH₃, -OCH₂CH₂F, -OC(CH₃)₂CH₂OH, -ch₂ch₂oh,

240

indicates the point of attachment to Ring B,

80B. The compound of any one of embodiments 74B-79B, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CHfh, hydroxy, -OCH₂CH₂OH, -CH₂OH, -CH₂OCH₃, -OCH₂CH₂NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂C(CH₃)₂O

H, -OCH₂CF₃, -OCHF2, -OCF3, -OCH2CH₂OCH₃, -OCH₂CH₂F, -OC(CH₃)₂CH₂OH, -CH₂CH₂OH,

86C. The compound of embodiment 85C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is methoxy, -OCH₂CH₂OH, -OCH₂CH₂N(CH₃)₂, -OCH₂C(CH₃)₂OH,

241

C. The compound of embodiment 86C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is methoxy, -OCFbCHaNiCFhh, -OCRCfCHshOH,

B. The compound of embodiment 80B or 86C, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is methoxy, -OCH2CH2OH, -OCHzCHîNfCHsL, -OCHzCiCHjhOH, or

82B. The compound of any one of embodiments 74B-77B, or a pharmaceutically acceptable sait 10 thereof, wherein two R⁶ groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CH2OH, and methyl.

83B. The compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C, 86C, or 87C, or a 15 pharmaceutically acceptable sait thereof, wherein R³ is methyl.

84B. The compound of any one of embodiments 74B-82B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable sait thereof, wherein n is I.

85B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, or a phannaceutically acceptable sait thereof, wherein R^4b is hydrogen.

242

92C. The compound of any one of embodiments 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of: i. tert-butyl or isopropyl;

ii. phenyl optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methyl, and methoxy;

iii. pyridinyi, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, and methyl;

iv. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[l.l. l]pentan-l-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, and hydroxy;

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

vi. benzyl, 2-(l-cyclobutyl-5-methyl-lH-imidazol-2-yl)ethyl, and pyridinyl-methyl;

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

86B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of:

i. tert-butyl;

iii. pyridinyl, pyrimidinyl, pyrazolyl, isothiazolyl, pyradizinyl, or quinolinyl, optionally substituted with one substituent selected from the group consisting of fluoro, chloro, methoxy, azepanyl, cyclopropyl, -CF3, -OCF3, or methyl;

iv. cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and bicyclo[l.l.l]pentan-l-yl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, -CF3, fluoro, or hydroxy;

243 vi. phenyl-methyl, l-cyclobutyl-2-ethyl-5-methyl-î H-imidazolyl, and pyridinyl-methyl; and vii. -C(CH₃)2CH₂OH, -CH2CH2OH, and -C(CH₃)2CH₂OCH3.

87B. The compound of any one of embodiments 74B-84B, 79C, 83C, 84C, 85C, 86C, or 87C, wherein R^4a and R^4b taken together with the atom to which each is attached form a piperidinyl, morpholinyl, pyrrolidinyl, azepanyl, indolinyl, azabicyclo[3.l.l]heptanyl, or piperazinyl, optionally substituted with one or two substituents, each independently selected from the group consisting of methyl, fluoro, and methoxy.

88B. The compound of embodiment IB or IC, or a pharmaceutically acceptable sait thereof, wherein, Z isN;

fis l;

R⁶, in each instance, is selected from the group consisting of C1-C3 alkyl, -NR^GR^H, halogen, and C1-C3 alkoxy;

p is l n is 0 or l

R^g and R^h are each independently hydrogen or C1-C3 alkyl;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, and CR⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴ can beN;

m is 0; and

i. 7-membered fused bicyclic heterocyclyl, 7-membered bridged bicyclic heterocyclyl, or 7-membered monocyclic heterocyclyl containing one or two heteroatoms;

wherein when said 7-membered monocyclic heterocyclyl contains one heteroatom, said heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of oxo, halogen, hydroxy, C1-C3 alkoxy, cyano, and C1-C3 alkyl; and, when said 7-membered monocyclic heterocyclyl contains two heteroatoms, said heteroatoms are each independently N or O, and said heterocyclyl is optionally substituted with one, two, or three substituents, each

244 independently selected from the group consisting of C1-C3 alkyl, cyano, oxo, halogen, halo-Ci-Cs alkyl,, and Cô-Cio monocyclic or fused bicyclic aryl; and wherein said aryl is optionally substituted with one or two substituents, each individually selected from the group consisting of C1-C3 alkoxy, hydroxy, halogen, and C1-C3 alkyl;

ii. 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein said 4-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-Csalkoxy, oxo, and -(CH2)_$C(=O)NR^kR';

wherein, s is 0, l, 2, or 3;

R^k is hydrogen orCi-C₃alkyl; and

R¹ is selected from the group consisting of hydrogen, hydroxy, CiC3 alkyl, C3-C7 cycloalkyl, and Cô-Cio monocyclic or fused bicyclic aryl; wherein said 6-membered monocyclic heterocylyl is optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, oxo, halogen, cyano, and NR^qR^w; wherein,

R^q is hydrogen or C1-C3 alkyl; and

R^w is Ce-Cio monocyclic or bicyclic aryl or C3-C7 cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy;

or, iii. 8-, 9-, 10- or 11-membered fused bicyclic heterocyclyl, or 12-membered bicyclic bridged, fused heterocyclyl, wherein said 8-, 9-, or 11-membered heterocyclyl contains one heteroatom and said 10- or 12-membered heterocyclyl contains one or two heteroatoms; and wherein said 10-, 11-, or 12-mernbered heterocyclyl is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-Cî alkyl, C1-C3 alkoxy, and hydroxy.

89B. The compound of embodiment 88B, or a pharmaceutically acceptable sait thereof, wherein Y¹, Y², Y³, and Y⁴ are each CH or C-R⁶.

245

90B. The compound of embodiment 88B or 89B, or a pharmaceutically acceptable sait thereof, wherein R⁶, if présent, is selected from the group consisting of -N(CH₃)2, methyl, methoxy, fluoro, and chloro.

9lB. The compound of any one of embodiments 88B-90B, or a pharmaceutically acceptable sait thereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 7-membered heterocyclyl containing one heteroatom, wherein said heterocyclyl is optionally substituted once with methyl or oxo; or, a 7-membered monocyclic or bridged bicyclic heterocyclyl containing two heteroatoms, wherein said heteroatoms are N or O, and said heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of phenyl, methyl, and oxo, and wherein said phenyl is optionally substituted with methoxy.

92B. The compound of any one of embodiments 88B-90B, or a phannaceutically acceptable sait thereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 10- or 11-membered fused bicyclic heterocyclyl containing one heteroatom, or a 12-membered bicyclic fused, bridged heterocyclyl, each optionally substituted with one, two, or three substituents, each independently selected from the group consisting of Ci-C₃ alkyl, Ci-C₃ alkoxy, hydroxy, and halogen.

93B. The compound of any one of embodiments 88B-90B, or a pharmaceutically acceptable sait thereof, wherein R³ and R⁴ taken together with the nitrogen atom to which each is attached form a 4- or 6-membered monocyclic heterocyclyl containing one heteroatom; wherein, said 4-membered monocyclic heterocyclyl is optionally substituted with -(CH₂)_sC(=O)NR^kR^l; wherein, s is 0, l, or 2;

R^k is hydrogen or Ci-C₃ alkyl; and

and, said 6-membered monocyclic heterocyclyl is optionally substituted with one or two substituents, each independently selected from the group consisting of Ci-C₃alkoxy, oxo, halogen, cyano, and NR^qR^w; wherein,

R^q is hydrogen or Ci-C₃ alkyl;

R^w is Cé-Cio monocyclic or fused bicyclic aryl or C₃-C? cycloalkyl, wherein said aryl or cycloalkyl is optionally substituted with one or two substituents, each independently selected

246 from the group consisting of halogen, C1-C3 alkyl, hydroxy, and C1-C3 alkoxy.

94B. The compound of embodiment IB, 74B, or IC, or a pharmaceutically acceptable sait thereof, wherein,

Z isN;

p is I ;

fis l;

Y¹, Y², Y³, and Y⁴ are each independently CH or C-R⁶.

R⁶, in each instance, is selected from the group consisting of C1-C3 alkyl, hydroxy, C1-C3 alkoxy, C1-C3 alkoxy-Ci-C3 alkyl, hydroxy-C 1-C3 alkyl, hydroxy-C।-C& alkoxy, -O-(CH2)U-R^bb, halo-Ci-Cs alkyl, -O-R^cc-O-R^dd, and C3-Cé cycloalkyl; or, R⁶, in each instance, is -O-R^bb or -O-(Ci-Cô alkoxy)-R^bb, wherein, u is an integer from 0 to 6;

R^bb is 4- to 7-membered monocyclic heterocyclyl, C₃-C? cycloalkyl, or -NR^CR^H;

R^cc and R^dd are each independently Ci-Csalkyl;

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

R^G and R^H are each independently hydrogen, -CiOjR⁰³, or C1-C3 alkyl; wherein,

R^Ga is C1-C3 alkyl or hydrogen;

n is 0, 1, or 2;

R^4a °Y%4b

R⁴ is ' R^4d ; wherein, R^4c îs selected from the group consisting of hydrogen, methyl, isopropyl, -CH2OH, and -CH2OC(CH3)₃; R^4d is selected from the group consisting of hydrogen and methyl;

or,

R^4c and R^ taken together with the atom to which each is attached form a cyclopropyl ring;

247

R^4b is hydrogen or methyl;

R^4a is selected from the group consisting of hydrogen, Ci-Cô alkyl, hydroxy-Ci-Côalkyl, Ci-Cs alkoxy-Ci-Cô alkyl, C3-C7 cycloalkyl, 5- to l O-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, Cô-Cio monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cio monocyclic or fused bicyclic aryl)-Ci-C3 alkyl, and (5- to l O-membered monocyclic or fused bicyclic heteroaryl)-Ci-C3 alkyl; wherein the cycloalkyl, heterocyclyl, 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, Ci-Cô alkyl, halo-C;-C3 alkyl, hydroxy, C1-C3 alkoxy, halo-Ci-C3 alkoxy, halo-Ci-Cî alkyl, oxo, C3-C7 cycloalkyl, and 5- to lO-membered monocyclic or fused bicyclic heterocyclyl;

or,

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Cj-Cô alkyl, halo-Ci-Cs 15 alkyl, hydroxy, and C1-C3 alkoxy;

R^x, in each instance, is C1-C3 alkyl; and m is 0, l, or 2.

95B. The compound of embodiment 94B, or a pharmaceutically acceptable sait thereof, wherein, Y¹ is CH, Y² is C-R⁶, Y³ is CH, and Y⁴ is CH.

96B. The compound of embodiment 94B or 95B, or a pharmaceutically acceptable sait thereof, wherein R⁶ is selected from the group consisting of hydroxy-Ci-Cô alkoxy, and -O-(CH₂)u-R^bb; wherein, u is an integer from 0 to 6;

R^g and R¹⁴ are each independently hydrogen or C1-C3 alkyl; and n is 0, 1, or 2.

97B. The compound of embodiment 96B, or a pharmaceutically acceptable sait thereof, wherein R⁶ is 30 selected from the group consisting of -

248

-OCH2CH2OH , -OCH₂CH2N(CH3)2. -OCH₂C(CH3)2OH, and

98B. The compound of any one of embodiments 94B-97B, or a pharmaceutically acceptable sait thereof, wherein:

R³ is methyl;

R^4cand R^4d are each hydrogen;

R^4b is hydrogen; and,

R^4a is selected from the group consisting of Ci-Côalkyl, Cô-Cio monocyclic or fiised bicyclic aryl, and 5- to 10-membered monocyclic or fused bicyclic heteroaryl, optionally substituted with with one or two substituents, each independently selected from the group consisting of halogen, Ci-Cô alkyl, halo-Ci-C₃ alkyl, hydroxy, C1-C3 alkoxy, and halo-Ci-Cs alkoxy.

99B. The compound of embodiment 98B, or a pharmaceutically acceptable sait thereof, wherein R^4a is selected from the group consisting of Ci-Cô alkyl, phenyl, and pyridinyI, wherein said phenyl or pyrimidinyl is optionally substituted with C1-C3 alkoxy.

100B. The compound of embodiment 99B, or a pharmaceutically acceptable sait thereof, wherein R^4a is

selected from the group consisting of tert-butyl and ।

101 B. The compound of embodiment IA, IB, or IC selected from Table 1, or a pharmaceutically acceptable sait thereof.

102B. A pharmaceutical composition comprisîng a compound according to any one of embodiments 1B-101B, 1A-47A, IC, 5C, 9C, I0C, UC, I2C, 13C, I4C, 15C, 16C, 31 C, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 61C, 63C, 64C, 79C, 83C, 84C, 85C, 86C, or 87C, or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.

103B. A method of inhibiting iron transport mediated by ferroportin in a subject, comprisîng

249 administering to the subject an effective amount of a compound of any one of embodiments IB-IOIB, l A-47A, IC, 5C, 9C, 10C, l IC, 12C, 13C, 14C, 15C, 16C, 3lC, 33C, 35C, 36C, 42C, 52C, 53C, 54C, 55C, 6lC, 63C, 64C, 79C, 83C, 84C, 85C, 86C, or 87C, or the pharmaceutical composition of embodiment 102B.

[0168] The General Procedures and Examples provide exemplary methods for preparing compounds. Those ski lied in the art will appreciate that other synthetic routes may be used to synthesize the compounds. Although spécifie starting materials and reagents are depicted and discussed in the Schemes, General Procedures, and Examples, other starting materials and reagents can be easily substituted to provide a variety of dérivatives and/or reaction conditions. In addition, many of the exemplary compounds prepared by the described methods can be further modified in light of this disclosure using conventional chemistry well known to those skilled in the art.

General Synthetic Schemes

[0169] General synthetic approaches to FPNl compounds la and 1b. In certain embodiments, compound la can be synthesized as shown in Scheme 1, the core intermediate 2a could be displaced by various substituted amine 3a via method A to give intermediate 4a, which was then coupled with various organometallic reagent 5a to provide final compound la. Alternatively, final compound la could be synthesized as shown in Scheme 2. Intermediate 2a could be displaced by primary amine 6a to give intermediate 7a, after coupling with organometallic reagent 5a, the resulting intermediate 8a could then alkylated by a halîde to give compound la. Final compound lb could be synthesized according to scheme 3. Intermediate 2a was displaced by glycinate 9a to provide intermediate 10a, after coupling with organometallic reagent 5a, the resulting intermediate lia was saponified. The corresponding carboxylic acid intermediate 12a was coupled with various amine to form compound lb.

[0170] Modifications and variations to schemes 1-3 can be made based on the availability of starting materials and synthetic compatibility of reagents, starting materials, or intermediates. This should be obvious to those who are familiar with the art. For example, Ri and R₂ could be hydrogen, halogen, simple alkyl or could join to form a ring; R₃ could be hydrogen or alkyl; R4 could be alkyl substituted by aminocarbonyl, alkoxy; or R₃ and R4 could join together to form a cyclic amine. For method B, another available heteroaromatic Suzuki or Sti 11e reagent could be used to provide the final compound 1 a.

[0171] Scheme 1 depicts a method for preparing exemplary compounds using Method A and Method B.

Method A ^ΝΗ

I r₄

3a

Method B

5a

Scheme l

[0172] Scheme 2 depicts a method for preparing exemplary compounds using Method A, Method B, and Method C.

Scheme 2

[0173} Scheme 3 depicts a method for preparing exemplary compounds using Method A, Method B,

Method D, and Method E.

Scheme 3

[0174] The conditions and reagesnts for Methods A-E are provided in the below Examples. The foilowing examples are offered by way of illustration and not by way of limitation.

1. SYNTHETIC EXAMPLES

Example 1.1

IS Method A: General synthetic method for nucleophilic coupling of amine to intennediate 4a

251

[ΟΙ75] Into a ΙΟΟ-mL round-bottom flask, was placed dichloropynmidine intermediate 2a (1.00 equiv), CHaCN, amine 3a ( l. 10 equiv), and triethylamine (2.00 equiv). The resulting solution was stirred for 3 hr at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether to give intermediate 4a.

Example l .2 Method B: General synthetic method for métal mediated cross coupling

[0176] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed intermediate 4a (l .00 equiv), dioxane, organometallic reagent 5 (2.0 equiv) and Pd(dppf)Ch (, 0.05 equiv). The resulting solution was stirred overnight at l00°C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (I :l) or subjected to préparative HPLC purification to give compound la, 8a, or lia.

Example 1.3

Method C: General synthetic method for alkylation with halide to give compound la

[0177] Intermediate 8a (l .00 eq.) was dissolved in DMF and cooled in an ice bath. Sodium hydride (2.00 eq.) (60%) was added in two portions and the reaction was stirred for 45 min. Halide (2.00 eq.) was added slowly and the mixture was stirred for 1.5 h more. Water (20 ml) and ethyl acetate (100 ml) were added, the phases were separated, and the aqueous phase was extracted with more ethyl acetate The combined organic phases were washed with some water and dried over sodium sulfate. After évaporation of solvent, the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl8 column, 0-70% acetonitrile/O.l % aqueous formic acid gradient). The purified fractions were treated with l M HCl and freeze-dried to give compound la.

Example E4

Method D: General synthetic method for saponification to give I2a

[0178] Intermediate lia (l.OO eq.) was dissolved in THF and methanoL Lithium hydroxide (5.00 eq.) was dissolved in water and was added dropwise to the solution. After 7 h, the mixture was acidified carefully with 6 M HCl to pH 3 and evaporated to dryness. The residue was co-evaporated with toluene and dried under high vacuum to give 12a.

Example 1.5

Method E: General synthetic method for amide formation to give 1b [0179] Intermediate 12a (L00 eq.) was suspended in Ν,Ν-dimethylformamide, N,N21052

252

Di isopropy le thy lamine (2.50 eq.), amine (l .35 eq.) and then l-[bis(dimethylamino)methylene]-lHl,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, l .35 eq.) were added. After 40 h, ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After évaporation of the solvents, the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl8 column, 0-70% acetonitrile/Û.l % aqueous formic acid gradient) to give compound 1b.

Example 1.6

Experimental Procedures for Common Intermediates

[0180] Scheme 4 depicts a method for preparing Intermediate 1

Intermedite I

Scheme 4

[0181] Step 1

[0182] 2,4-Dich!oro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (2.00 g; 10.58 mmol; 1.00 eq.) was dissolved in acetonîtrile (36 ml). (2-Ethoxy-2-oxoethyl)(methyl)azanÎum chloride (2.11 g; 13.75 mmol;

1.30 eq., sarcosine ethyl ester HCl) was added, followed by Ν,Ν-diisopropylethy lamine (4.6 mL; 26.45 mmol; 2.50 eq.) slowly. The reaction 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/hexanes gradient) to give ethyl 2-({2-chloro-5H,6H,7H-cyclopenta(d]pyrimidin-4-yl}(methyl)amino)acetate (2.18 g, 76%) as a solid. ‘H NMR (400 MHz, Chloroform-c/) 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). [0183] Step 2

[ΟΙ 84] Ethyl 2-( {2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl} (methy i)amino)acetate (900.00 mg; 3.34 mmol; l .00 eq.) was dissolved in l,4-dioxane (9 ml) and purged with argon. 2(Tributylstannyl)pyridine (2.34 mL; 6.67 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (385.58 mg; 0.33 mmol; 0.10 eq.) were added, the reaction vessel was sealed, and then stirred in a heat bath at 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-yI)-5H,6H,7Hcyclopenta[d]pyrimidin-4-y!]amino}acetate (0.72 g, 62%) 'H NMR (400 MHz, Chloroform-d) δ 8.83 (d, J = 4.8 Hz, IH), 8.39-8.28(m, 1 H), 7.86 - 7.77 (m, 1 H), 7.41 -7.32 (m, IH), 4.37 (s, 2H), 4.20 (q, J =

7.2, L5 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.

[0185] Step 3

[0186] Ethyl 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4-yl]amino}acetate (0.72 g; 2.30 mmol; 1.00 eq.) was dissolved in THF (20 ml) and methanol (5 ml). Lithium hydroxide (0.28 g; 11.52 mmol; 5.00 eq.) dissolved in water (8 ml) was added dropwise to the solution. After 7 h, the mixture was acidified carefully with 6 M HCl to pH 3 and evaporated to dryness. The residue was co-evaporated with toluene and dried under high vacuum to give 2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetic acid hydrochloride (Intermediate I) as an off-white solid. ’H

NMR (400 MHz, DMSO-<76) δ 8.84 (d, .7= 4.7 Hz, IH), 8.41 (d, .7= 7.9 Hz, IH), 8.21 -8.12 (m, IH),

254

7.75 (40,7=7.8,4.8 Hz, IH), 3.28-3.27 (m, 2H), 3.07-3.01 (m, 2H), 2.15-2.05 (m, 2H). MS (ES+): (M+H)⁺ = 284.9.

Example 1.7

[0187] Scheme 5 depicts a method for preparing Intermediate 11

H θ \ HOBt, ËDCl.DCiyi _N ï JH ^Pd/C· ^H2· MeOH,

Cbz''^NΆ^_οη ⁺ hÀ rt, o/n ^Cbz N rt,o/n z > pi

[0188] Step 1

Cbz

HOBt, EPCI,DCM rt, o/n

[0189] Into a 1-L 3-necked round-bottom flask was placed 2-(benzyloxycarbonylamino)acetic acid 10 (20.0 g, 95.6 mmol, 1.00 equiv), DCM (500 mL), HOBt (15.5 g, 114.7 mmol, 1.20 equiv), EDC1 (22.0 g, 114.7 mmol, 1.20 equiv), and tert-butylamine (21.0 g, 286.8 mmol, 3.00 equiv). The resulting solution was stirred overnight at room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with PE/EA ether (0-50%). This resulted in 25.1 g (99%) of benzyl N-[(tert-butylcarbamoyl)methyl]-carbamate as a white solid. LCMS: (ES, m/z) : [M+H] + 265.

Pd/C, H₂, MeOH, H₂N rt,o/n H

[0190] Into a 250-mL round-bottom flask, was placed benzyl N-[(tertbutylcarbamoyl)methyl]carbamate (7.0 g, 26.48 mmol, 1.00 equiv), MeOH (50 mL), and Pd/C(10%) (0.70 g, 10%). The resulting solution was stirred overnight at room température under Hz (1 atm). The solids were filtered out. The resulting mixture was concentrated. This resulted in 3.3 g (95%) of 221052

255

amino-N-tert-butylacetamide as a colorless oil. LCMS; (ES, m/z): [M+H]+: 131.

Intermediate II

[0191] Into a 50-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidîne (0.80 g, 4.23 mmol, 1.00 equiv), THF (20 mL), TEA (0.51 g, 5.04 mmol, 1.19 equiv), and 2-amino-N-tert-butylacetamide (0.58 g, 4.44 mmol, 1.05 equiv). The resulting solution was stirred ovemight at room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/hexane (0-50%). This resulted in 0.688 g (57%) of N-tertbutyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidm-4-yl]amino)acetamide as a white solid. LCMS (ES, m/z): [M+H] ⁺: 283.1.

Example 1.8

[0192] Synthesis of l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 92).

[0193] Scheme 6 depicts a synthetic route for preparing an exemplary compound.

H

Scheme 6

[0194] Step 1

256

[ΟΙ95] Into a ΙΟΟ-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (500.00 mg, 2.645 mmol, l.OO equiv), acetonitrile (20.00 mL, 0.487 mmol,

0.18 equiv), azepane (314.78 mg, 3.174 mmol, l .20 equiv), and TEA (321.17 mg, 3.174 mmol, 1.20 equiv). The resulting solution was stirred for 2 hr at 80 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3) to give 600 mg (90.10%) of l-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yI]azepane as a solid. [0196] Step 2

[0197] Into a 100-mL round-bottom flask purged and maintained în an inert atmosphère of nitrogen, was placed l-[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)Cb (43.60 mg, 0.060 mmol, 0.05 equiv). The resulting solution was stirred ovemight at 100 degrees C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The crude product was purified by re-crystallization from EA (ethyl acetate). This resulted in 79 mg (24.16%) of l-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyriinidin-4-yl]azepane as a white solid. 'H NMR (300 MHz, DMSOA): δ 8.66 (d, .7=4.5Hz, IH), 8.25 (d, J=7.8Hz, IH), 7.882 (t, A7.8Hz, IH), 7.42 (dd, J=5.1Hz, 6.0 Hz ,1H), 3.78-3.64 (m, 4H), 3.11-3.00 (m, 2H), 2.83-2.78 (m, 2H), 2.08-1.97 (m, 2H), 1.76 (s, 4H), 1.49 (s, 2H).

LCMS:(ES) [M+l]⁺ m/z 295.2.

Example 1.9

[0198] Synthesis of 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4-oxazepane

257

(Compound 93).

[ΟΙ99] Scheme 7 depicts a synthetic route for preparing an exemplary compound.

[0201] Into a 100-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (500.00 mg. l.OO equiv), CHaCN (l0.00 mL), l,4-oxazepane hydrochloride (402.00 mg, 1.10 equiv), and TEA (534.00 mg, 2.00 equiv). The resulting solution was stirred for 3 hr at degrees C. The reaction progress was monitored by LCMS. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 600 mg (89.28%) of 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4oxazepane as a brown solid.

[0202] Step 2

258

[0203] Into a lOO-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 4-[2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4-oxazepane (0.30 g, l.18 mmol, l .00 equiv), dioxane (20 mL), 2-(tributylstannyl)pyrîdine (0.87 g, 2.36 mmol, 2.0 equiv), Pd(dppf)Cl₂(0.04 g, 0.035 mmol, 0.05 equiv). The resulting solution was stirred ovemight at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l : l). The crude product was purified by re-crystallization from EA. This resulted in 358.1 mg (90%) of 4-[2-(pyridin-2-yl)-5H_!6H,7H-l-Z-4-cyclopenta[d]pyrimidin-4-yl]1,4-oxazepane as a light brown solid. IH NMR (300 MHz, DMSO-d6): δ 8.66 (dd, J=0.9, 0.9Hz, IH), 8.25 (d, J=7.8Hz, IH), 7.91-7.86 (m, IH), 7.45-7.41 (m ,1H), 3.97-3.87 (m, 4H), 3.85-3.75 (m, 2H), 3.66-3.62 (m, 2H), 3.08 (t, J=7.5Hz, 2H), 2.85-2.80 (m, 2H), 2.06-1.96 (m, 4H). LCMS (ES) [M+l]+ m/z 297.2.

Example 1.10 [0204] Synthesis of l-[2-(3-f1uoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 71).

[0205] Compound 71 was synthesized similar to compound 92 replacing 2-(tributylstannyl)pyridine with 4-fluoro-2-(trîbutylstannyl)pyridine. ’ H NMR (400 MHz, Methanol-c/4) δ 8.46 (d, .7= 4.8 Hz, IH), 7.77 - 7.68 (m, IH), 7.54 (dt, J= 8.5, 4.3 Hz, IH), 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+lfi m/z 312.4.

Example L11

259

[0206] Synthesis of 5-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrîmidin-4-yl]-2-oxa-5azabîcyclo[2.2.l]heptane (Compound 72).

[0207] Compound 72 was synthesized similar to compound 92 replacing azepane with 2-oxa-5- azabicyclo[2.2. l]heptane. LCMS (ES+): (M+H)^4- = 295.0. 'HNMR (400 MHz, Chloroform-d) δ 8.85 (d, 7=4.8 Hz, IH), 8.40 (d, J= 7.9 Hz, IH), 7.89-7.79 (m, IH), 7.39 (dd, J = 7.5, 4.9 Hz, JH), 5.33 (s, IH), 4.71 (s, IH), 4.00-3.94 (m, 2H), 3.83-3.76 (m, 2H), 3.20-2.96 (m, 4H), 2.19- I.94 (m, 4H).

Example 1.12

[0208] Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]-5H,6H,7H10 cyclopenta[d]pyrimidin-4-amine (Compound 73)

[0209] Scheme 8 depicts a synthetic route for preparing an exemplary compound.

Scheme 8

[0210] Step 1

260

[0211] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (204.00 mg; l .08 mmol; l .00 eq.) was dissolved in acetonitrile (4 ml). 2-pyridinylmethanamine (0.15 mL; L40 mmol; L30 eq.) was added followed by N, N-diisopropylethylamine (0.28 mL; l .62 mmol; L50 eq.) slowly. The reaction was stirred at 25 °C for 18 h, 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-2ylmethyl)-5H,6H.7H-cyclopenta[d]pyrimidin-4-amine (277 mg, 98%) as a white solid.. *H NMR (400 MHz, Chloroform-i/) δ 8.58 (d, J= 5.2 Hz, IH), 7.97 - 7.88 (m, IH), 7.59 (d, J= 7.8 Hz, IH), 7.45 7.38 (m, l H), 6.63 (s, IH), 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).

[0212] Step 2

[0213] 2-Chloro-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (274.00 mg;

.05 mmol; 1.00 eq.) was suspended in 1,4-dioxane (5 ml) and mixture was purged with argon. 2- (Tributylstannyl)pyridine (0.74 mL; 2.10 mmol; 2.00 eq.) and then tetrakis(triphenylphosphane) palladium (121.44 mg; 0.11 mmol; 0.10 eq.) were added. The reaction vessel was sealed, and the contents stirred in a heat bath at 105 °C for 16 h. Solvent was evaporated and the residue was purified by silica gel chromatography (methanol/dichloromethane gradient) to give 2-(pyridin-2-yl)-N-(pyridin-2ylmethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (161 mg, 50%) as a white solid. ’H NMR (400

MHz, Chloroform-rf) δ 8.87 (d, J= 5.0 Hz, IH), 8.57 (d, J= 5.0 Hz, IH), 8.49 (d, J= 8.0 Hz, IH), 7.94 - 7.88 (m, 1 H), 7.80 - 7.73 (m, IH), 7.65 (d, J = 7.9 Hz, 1 H), 7.45 (dd, J= ΊΑ, 4.9 Hz, 1 H), 7.30 - 7.26 (m, 1 H), 7.13 (s, IH), 5.07 (d, 5.1 Hz, 2H), 3.11 (t, J = 7.8 Hz, 2H), 2.95 (t, J =1.5 Hz, 2H), 2.2421052

261

2.16 (m, 2H). MS (ES+): (M+H) = 304.0.

[0214] Step 3

[0215] 2-(Pyridin-2-yl)-N-(pyridin-2-ylmethyl)-5H,6H,7H-cyciopenta[d]pyrimidin-4-amine (046 g; 0.53 mmol; l .00 eq.) was dissolved in DMF (!0 mi) and cooled in an ice bath. Sodium hydride (42 mg; l .05 mmol; 2.00 eq.) (60%) was added in two portions and the reaction was stirred for 45 m. lodomethane (66 pL; l .05 mmol; 2.00 eq.) was added slowly and the mixture was stirred for l .5 h more. Water (20 ml) and ethyl acetate (100 ml) were added, the phases were separated, and the aqueous phase was extracted with more ethyl acetate (3 x 75 ml) and 3: l chlorofonniisopropanol (50 ml). The combined organic phases were washed with some water (5 ml) and dried over sodium sulfate. After évaporation of solvent, the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-70% acetonitrile/O.l % aqueous formic acid gradient). The purified fractions were treated with l M HCl and freeze-dried to give N-rnethyl-2-(pyridin-2-yl)-N-[(pyridin-2-yl)methyl]51-l,6H,7lΊ-cyclopenta[d]pyrimidin-4-amine hydrochloride (90 mg, 48%) as a white solid. 'H NMR. (400 MHz, Chloroformé δ 9.08 (d, 7=5.3 Hz, IH), 8.69 (d, 7= 5.5 Hz, i H), 8.62 (d,7=8.0 Hz, IH), 8.29

- 7.98 (m, 3H), 7.75 - 7.68 (m, IH), 7.55 - 7.47 (m, IH), 5.68 (s, 2H), 3.67 (s, 3H), 3.52 - 3.37 (m, 2H), 3.26 -3.14 (m, 2H), 2.23 - 2.I2 (m, 2H). MS (ES+): (M+H)⁺ = 317.9.

Example l .13

[0216] Synthesis of N-(4-methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)pyrimidin-4yl]amino]acetamide (Compound 75).

[0217] Scheme 9 depicts a synthetic route for preparing an exemplary compound.

Scheme 9

[0218] 2-{4-[(Carboxymethyl)(methyl)ammo]-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridin-lium chloride (Intermediate I) (150.00 mg; 0.35 mmol; 1.00 eq.) was suspended in N,N5 dimethylfbnnamide (3.5 ml). N,N-Diisopropylethylaniine (0.15 mL; 0.87 mmol; 2.50 eq.), 4methoxyaniline (57.5 mg; 0.47 mmol; 1.35 eq.) and then l-[bis(dîmethylamino)methylene]-l H-1,2,3triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 177.6 mg; 0.47 mmol; 1.35 eq.) were added. After 40 h, ethyl acetate (50 ml) and sodium bicarbonate solution (20 ml) were added, the phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organic phases were washed with sodium chloride solution and dried over sodium sulfate. After évaporation of the solvents, the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-70% acetonitrile/0.1 % aqueous formic acid gradient) to give N-(4-methoxyphenyl)-2{methyl[2-(pyridin-2-yl)-5H_f6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (fonnate sait, 46 mg, 34%) as a solid. Ή NMR (400 MHz, Chloroformas 10.18 (s, IH), 8.86 (d, J= 5.0 Hz, IH), 8.53 (d, J= 8.0 Hz, IH), 8.22 (s, IH), 8.04-7.93 (m, IH), 7.56 -7.46 (m, 3H), 6.76 (d, J= 8.6 Hz, 2H), 4.56 (s, 2H), 3.74 (s, 3H), 3.50 (s, 3H), 3.24 (t, J= 7.4 Hz, 2H), 2.99 (t, J= 7.9 Hz, 2H), 2.12 (p, J= 7.7 Hz, 2H). MS (ES+): (M+H)⁺ = 390.1.

Example 1.14

[0219] Synthesis of N-(3-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H20 cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 74).

263

[0220] Compound 74 was synthesized similar to Compound 75 replacmg 4-methoxyaniline with 3fluoroaniline. LCMS (ES+): (M+H)⁺ = 379.0.^lH NMR (400 MHz, Chloroform-iT) δ 10.80 (s, IH), 9.10 - 8.96 (m, IH), 8.67 (d, J=7.9 Hz, IH), 8.21-8.09 (m, IH), 7.72-7.58 (m, 2H), 7.40 (d, 8.2 Hz,

IH), 7.21 -7.11 (m, I H), 6.75 - 6.65 (m, 1 H), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J= 7.4 Hz, 2H), 2.97 (t, J= 7.9 Hz, 2H), 2.14 (p, J = 7.7 Hz, 2H).

Example 1.15

[0221] Synthesis of I-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yI]-l,2,3,4tetrahydroquinoline (Compound 76)

[0222] Scheme 10 depicts a synthetic route for preparing an exemplary compound.

Scheme 10

[0223] Step I

[0224] To a solution of 2,4-dichloro-6,7*dihydro-5H-cyclopenta[dJpyrimidine (100.00 mg; 0.53

264 mmol; l .00 eq.) in AcCN (2 mL) was added 1,2,3,4-tetrahydroquinohne (73.98 mg; 0.56 mmol; 1.05 eq.) followed by Hunig's base (0.19 mL; 1.06 mmol; 2.00 eq.). The mixture was heated at 75 °C for 2 h, the mixture was cooled and concentrated, the residue was diluted with water, the resulting precipitate was collected by filtration, and dried under vacuum to give l-{2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}-l,2,3,4-tetrahydroquinoline (25 mg). LCMS (ES⁺): (M+H)⁺ = 286.2, 288.2.

[0225] Step 2

[0226] To a solution of l-{2-chloro-5H,6H,7El-cyclopenta[d]pyrimidin-4-yl}-1,2,3,4tetrahydroquinoline (25.00 mg; 0.09 mmol; 1.00 eq.) in toluene (1.5 mL) was added 2(tributylstannyl)pyridine (48.31 mg; 0.13 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (10.11 mg; 0.01 mmol; 0.10 eq.). The mixture was degassed and heated at 110 ^QC for 15 h. The mixture was cooled and concentrated, diluted with AcCN and water, and subjected to purification by préparative HPLC to give l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,2,3,4-tetrahydroquinoline (36 mg). ’H NMR (400 MHz, MethanolA) δ 8.73 - 8.67 (m, IH), 8.42 (dt, J= 8.0, 1.2 Hz, IH), 7.96 (td, J=7.8, 1.8 Hz, IH), 7.50 (ddd, 7.5, 4.9, 1.3 Hz, IH), 7.17 (q, J= 7.5 Hz, 2H), 7.03 (td, J =1.5, 1.3 Hz, IH), 6.77 (d, J= 7.9 Hz, 1H),4.IO (t, J= 6.5 Hz, 2H), 2.97 (t, J =1.1 Hz, 2H), 2.82 (t, J=6.6 Hz, 2H), 2.3 ï (t, J= 7.3 Hz, 2H), 2.02 (dp, J= 36.1, 7.5, 7.0 Hz, 4H). LCMS (ES+): (M+H)⁺ = 329.1.

Example 1.16

[0227] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-Nphenylacetamide (Compound 77)

[0228] Compound 77 was synthesized similar to Compound 75 replacing 4-methoxyaniline with

265 aniline. LC MS (ES+): (M+H)⁺ = 360.0. Ή NMR (400 MHz, Chloroform-7) δ 10.39 (s, IH), 8.98 - 8.87 (m, IH), 8.58 (d, 7= 8.0 Hz, IH), 8.08-7.96 (m, lH), 7.62 (d, J= 8.0 Hz, 2H), 7.59-7.51 (m, IH), 7.25 - 7.I7 (m, 2H), 7.01 (t,./= 7.4 Hz, IH), 4.61 (s, 2H), 3.52 (s, 3H), 3.26 (t, 7 = 7.4 Hz, 2H), 2.98 (t, 7= 7.9 Hz, 2H), 2.18 - 2.07 (m, 2H).

Example 1.17

[0229] Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide (Compound 78)

[0230] Compound 78 was synthesized similar to Compound 75 replacing 4-methoxyaniline with cyclohexanamine. Ή NMR (400 MHz, Chloroform-7) δ 9.07 - 8.93 (m, IH), 8.59 (d,7= 8.0 Hz, IH), 8.12 - 8.01 (m, IH), 7.83 -7.64 (m, IH), 7.59 (d, 7= 6.7 Hz, lH), 4.47 (s, 2H), 3.78 - 3.68 (m, IH), 3.47 (s, 3H), 3.24 (t, J= 7.4 Hz, 2H), 3.00 (t, J= 7.9 Hz, 2H), 2.I7 -2.07 (m, 2H), 1.75 (d, 7- 12.0 Hz, 2H), l .65 - l .58 (m, 2H), 1.56 - 1.49 (m, IH), 1.28 - 1.06 (m, 5H). LCMS (ES+): (M+H)⁺ = 366.0.

Example 1.18

[0231 ] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N(oxan-4-yl)acetamide (Compound 79)

[0232] Compound 79 was synthesized similar to Compound 75 by replacing 4-methoxyaniline with 4-aminotetrahydropyran. LCMS (ES+): (M+H)⁺ = 368.I. Ή NMR (400 MHz, Chloroform-d) δ 9.32 (s, 1 H), 8.87 (d, J = 8.0 Hz, 1 H), 8.81 - 8.73 (m, I H), 8.45 - 8.35 (m, IH), 7.92 - 7.84 (m, IH), 4.76 (s, 2H), 3.93 - 3.84 (m, 3H), 3.58 (s, 3H), 3.40-3.30 (m, 4H), 2.96 (t, J = 7.9 Hz, 2H), 2.16 -2.11 (m, 2H), 1.75- 1.56 (m,4H).

Example 1.19

[0233] Synthesis of N-ethyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H21052

266

cyclopenta[d]pyrimidin-4-amine (Compound 80)

[0234] Compound 80 was synthesized similar to Compound 73 by replacing 2pyridinylmethanamine with 2-pyrimidinylmethylamine and replacing iodomethane with ethyl iodide.

LCMS (ES+): (M+H)⁺ = 333.0. ’H NMR (400 MHz, Chloroform-rf) δ 8.96 - 8.82 (m, 3H), 8.52 (d, J= 7.7 Hz, IH), 8.18-8.09 (m, IH), 7.75 - 7.68 (m, JH), 7.55 (s, JH), 5.43 (s, 2H), 4.01 (q, J=1A Hz, 2H), 3.32-3.13 (m, 4H), 2.28 - 2.17 (m, 2H), 1.37 (t, .7=6.9 Hz, 3H).

Example 1.20

[0235] Synthesis of N-methyl-2-(pyridin-2-yl)-N-[(pyrimidin-2-yl)methyl]-5H,6H,7H10 cyclopenta[d]pyrimidin-4-amine (Compound 81)

[0236] Compound 81 was synthesized similar to Compound 73 by replacing 2pyridinylmethanamine with 2-pyrimidinylmethylamine. LCMS (ES+): (M+H)⁺ = 319.1. *H NMR (400 MHz, Chloroform-ίΖ) δ 8.78 - 8.69 (m, 3H), 8.33 (s, IH), 8.18 (d, J= 8.0 Hz, 1 H), 7.79 - 7.72 (m, IH), 15 7.38-7.31 (m, 1 H), 7.22 - 7.17 (m, IH), 5.14 (s, 2H), 3.53 (s, 3H), 3.21 (t, J= 7.4 Hz, 2H), 3.15 - 3.10 (m,2H), 2.13-2.07 (m, 2H).

Example 1.21

[0237] Synthesis ofN-[(l,3-benzoxazol-2-yl)methyl]-N-methyl-2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine (Compound 82)

267

[0238] Compound 82 was synthesized similar to Compound 73 by replacing 2pyridinylmethanamine with l,3-benzoxazol-2-ylmethanamine. LCMS (ES+): (M+H)⁺ = 358.0. 'H NMR (400 MHz, Chloroform-i/) δ 8.82 (d, J =5.4 Hz, IH), 8.34 (d, J = 8.0 Hz, IH), 8.14 (s, IH), 7.86-7.77 (m, IH), 7.74-7.67 (m, IH), 7.54-7.47 (m, JH), 7.41 -7.35 (m, IH), 7.35 -7.29 (m, 2H), 5.25 (s,

2H), 3.54 (s, 3H), 3.29 (t, J= 7.3 Hz, 2H), 3.I8-3.11 (m, 2H), 2.I6-2.12 (m, 2H).

Example l .22

[0239] Synthesis of 3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2,3,4,5-tetrahydrol H-3-benzazepine (Compound 83)

[02 40] Compound 83 was synthesized similar to compound 92 by replacing azepane with 2,3,4,5tetrahydro-lH-benzo[d]azepine. LCMS (ES+); (M+H)⁺ = 343.0. Ή NMR (400 MHz, Chloroform-tT) δ 8.81 (d,J=4.8 Hz, IH), 8.41 (d, J = 7.9 Hz, III), 7.89 - 7.80 (m, IH), 7.39 (dd, J= 7.5, 4.9 Hz, IH), 7. L5 (s, 4H), 6.10 (s, 2H), 4.08 - 3.99 (m, 4H), 3.15 - 3.02 (m, 8H), 2.19 - 2.08 (m, 2H).

Example 1.23

[0241 ] Synthesis of N-(2-methoxyethyl)-N-methyl-2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîdin-4-amine (Compound 84)

[0242] Compound 84 was synthesized similar to compound 92 by replacing azepane with N-(2methoxyethyl)-N-methy lamine. LCMS (ES+): (M+H)⁺ = 285.0. NMR. (400 MHz, Chloroformé) δ

8.81 (dd, J= 4.7, 2.0 Hz, IH), 8.45 (d,7 = 1.5 Hz, l H), 8.34 (dd, 7= 8.2, 1.5 Hz, IH), 7.89-7.80 (m, 5 IH), 7.50 - 7.27 (m, 3H), 3.97 - 3.90 (m, 2H), 3.70 - 3.63 (m, 2H), 3.41 (s, 3H), 3.36 (s, 3H), 3.23 -

3.14 (m, 4H), 2.16- 2.07 (m, 2H).

Example 1.24

[0243] Synthesis of l-methyl-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4diazepane (Compound 85)

[0244] Compound 85 was synthesized similar to compound 92 by replacing azepane with l-methyl1,4-dîazepane. LCMS (ES+): (M+H)⁺ = 310.1. Ή NMR (400 MHz, Chloroformé) δ 8.79 (d, 7=4.8 Hz, 1 H), 8.29-8.21 (m, IH), 7.86- 7.76 (m, IH), 7.40- 7.34 (m, IH), 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, 7=7.8 Hz, 2H), 15 2.82 (s, 3H), 2.56 (s, 2H), 2.15 -2.04 (m, 2H).

Example 1.25

[0245] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]-l(morpholin-4-yl)ethan-1 -one (Compound 86)

269

[0246] Compound 86 was synthesized simîlar to Compound 75 by replacing 4-methoxy aniline with morpholine, LCMS (ES+): (M+H)⁺ = 354.0. Ή NMR (400 MHz, Chloroform-7) δ 8.96 - 8.86 (m, l H), 8.50-8.37 (m, IH), 8.21 -8.15 (m, IH), 8.07-7.93 (m, IH), 7.60-7.48 (m, lH), 4.86 - 4.75 (m, 2H), 5 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), 3.063.00 (m, 2H), 2,17- 2.05 (m, 2H),

Example 1.26

[0247] Synthesis ofN-methyl-N-(2-phenoxyethyl)-2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-amîne (Compound 87)

[0248] Compound 87 was synthesized similar to compound 92 by replacing azepane with N-methyl N-(2-phenoxyethyl)amine. LCMS (ES+): (M+H)⁺ = 285.0. 'H NMR (400 MHz, Chloroform-7) δ 9.09 (d, 7= 4.9 Hz, IH), 8.57 (d,7 = 7.8 Hz, IH), 8.16-8.00 (m, IH), 7.69-7.63 (m, IH), 7.29-7.25 (m, 2H), 6.98 - 6.91 (m, 111), 6.86 (d, 7= 8.0 Hz, 2H), 4.36 (s, 4H), 3.61 (s, 3H), 3.45 (t, 7= 7.8 Hz, 2H), 15 3.29 (t, 7= 7.3 Hz, 2H), 2.24 - 2.13 (m, 2H).

Example 1.27

[0249] Synthesis of2-{methyl[2-(pyridin-2-yl)-5H,6H,7H’Cyclopenta[d]pyrimidin-4-yl]amino}-l(piperidin-l-yl)ethan-l-one (Compound 88)

270

[0250] Compound 88 was synthesized similar to Compound 75 replacing 4-methoxyaniline with piperidine. LCMS (ES+): (M+H)⁺ = 352,1. Ή NMR (400 MHz, Chloroform-tT) δ 9.03 (d, J= 5.1 Hz, IH), 8.69-8.55 (m, IH), 8.23 - 8.07 (m, IH), 7.74-7.64 (m, IH), 5.17-4.78 (m, 2H), 3.64-3.56 (m, 5 2H), 3.52 (t, J= 5.6 Hz, 2H), 3.44 (s, 3H), 3.33 - 3.20 (m, 4H), 2.20 - 2.10 (m, 2H), 1.73 - 1.62 (m,

4H), 1.57- 1.49 (m, 2H).

Example 1.28

[0251] Synthesis ofN-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide (Compound 89).

[0252] Compound 89 was synthesized similar to Compound 75 by replacing 4-methoxyaniline with tert-butylamine. Ή NMR (400 MHz, Chloroform-rf) δ 9.33 - 9.18 (m, IH), 8.87 (d, J = 7.7 Hz, JH), 8.43 -8.33 (m, IH), 8.28 (s, 1 H), 7.91 - 7.79 (m, IH), 4.71 (s, 2H), 3.55 (s, 3H), 3.29 (t, J= 7.3 Hz, 2H), 3.00 (t, J= 7.9 Hz, 2H), 2.17 - 2.07 (m, 2H), 1.27 (s, 9H). MS (ES+): (M+H)⁺ = 340.0.

Example 1.29 (0253) Synthesis of N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}propanamide (Compound 91)

[0254] Step 1

[0255] 2-{[(Tert-butoxy)carbony[](methyl)amino[propanoic acid (500 mg; 2.5 mmol; l eq.) was dissolved in DMF (6 ml). N, N-diisopropylethy lamine (l.l mL; 6.15 mmol; 2.5 eq.) and then I[bis(dimethylamino)methyiene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

S (HATU, 1262 mg; 3.3 mmol; 1.35 eq.) were added. Cyclohexanamine (0.38 mL; 3.3 mmol; 1.35 eq.) was added and the reaction mixture was stirred at 25 °C. After 14 h, the reaction was diluted with ethyl acétate (50 ml), water (l 5 ml) and sodium bicarbonate solution (30 ml). The phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml), the combined organics were washed with sodium chloride solution (50 ml) and dried over sodium sulfate. After évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-[l(cyclohexylcarbamoyl)ethylj-N-methylcarbamate (0.48 g, 68%) as white crystals. LCMS (ES+): (M+H)⁺= 285.0.

[0256] Step 2

[0257] Tert-butyl N-[l-(cyclohexylcarbamoyl)ethyl]-N-methylcarbamate (0.48 g; 1.7 mmol; 1 eq.) was dissolved in dichloromethane (12 ml) and cooled in an ice bath. Trifluoroacetic acid (6 mL) was added slowly and the reaction was stirred at 20 °C. After 1.6 h, the reaction was evaporated to a residue and then co-evaporated from toluene (40 ml). The crude product of N-cyclohexyl-2(methylamino)propanamide; trifluoroacetic acid sait was used directly in the next step.

[0258] Step 3

272

[0259] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150 mg; 0.79 mmol; l eq.) was dissolved in acetonitrile (3 ml) containing N-cyclohexyl-2-(methylamino)propenamide trifluoroacetic acid sait (355 mg; 1.19 mmol; 1.5 eq.). Ν,Ν-diisopropylethy lamine (0.55 mL; 3.2 mmol; 4 eq.) was added and the reaction was stirred at 50°C for 14 h, then at 60°C for 6 h, and to 30°C over 18 h. After évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-cyclohexylpropanamide (174 mg, 65%) as a film. LCMS (ES+): (M+H)⁺ = 337.2.

[0261] 2-({2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-Ncyclohexylpropanamide (174 mg; 0.52 mmol; l eq.) was dissolved in 1,4-dioxane (4 ml), and the solution was purged with Ar gas. 2-(Tributylstannyl)pyridine (0.39 mL; 1.03 mmol; 2 eq.) was added followed by tetrakis(triphenylphosphane) palladium (60 mg; 0.05 mmol; 0.1 eq.) The reaction vessel was sealed and stirred in a heat bath at 110 °C for 15 h. After évaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1 % aqueous fonnic acid gradient) to give N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propenamide (86 mg, 43%) as an off-white solid. LCMS (ES+): (M+H)⁺= 380.0. Ή NMR (400 MHz, DMSO-76) δ 8.69 (d, 7= 4.8 Hz, IH), 8.34 (d,7=7.9 Hz, IH),

8.19(d,7= 8.3 Hz, IH), 7.96-7.84 (m, IH), 7.53 -7.42 (m, IH), 5.16 (q,7= 7.0 Hz, IH), 3.63-3.49 (m, IH), 3.25-3.16 (m, IH), 3.14-3.06 (m, 4H), 2.93-2.76 (m, 2H), 1.74 (s, IH), 1.65 (s, IH), 1.59 1.44 (m,3H), 1.33 (d, 7= 7.0 Hz, 3H), 1.25 - 1.12 (m, 3H), 1.07-0.93 (m, 2H).

273

Example 1.30

[0262] Synthesis of N-tert-butyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}propanam ide (Compound 90)

[0263] Compound 90 was synthesîzed similar to Compound 91 by replacing cyclohexanamine with tert-butyl ami ne. LCMS (ES+): (M+H)⁺= 354.4. Ή NMR (400 MHz, DMSO-i76) δ 8.80 - 8.74 (m, IH), 8.50 (d, J=7.9 Hz, IH), 8.09-8.01 (m, IH), 7.81 (s, IH), 7.66- 7.59 (m, IH), 5.14 (q, J= 7.0 Hz, IH), 3.26 (s, 3H), 3.24 - 3.10 (m, 2H), 3.05 - 2.88 (m, 2H), 2.15 - 1.97 (m, 3H), 1.40 (d, J= 7.1 Hz, 3H), 1.21 (s, 9H).

Example 1.31

[0264] Synthesis of'IO-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-IOazatricyclo[6.3.1.0'{2,7}]dodeca-2,4,6-triene (Compound 1)

[0265] Compound 1 was synthesîzed similar to compound 92 by replacing azepane with 10azatricyclo[6.3.1.0³,7]dodeca-2(7),3,5-triene. LCMS (ES+): (M+H)⁺ = 355.0. ‘H NMR (400 MHz, Chloroform-i/) δ 8.66 (s, IH), 8.45 - 8.12 (m, I H), 7.71 (s, 1 H), 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, IH), 2.01 - 1.76 (m, 3H).

Example 1.32

[0266] Synthesis of 7-methoxy-3-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimîdin-4-yi]-2,3,4,5tetrahydro-lH-3-benzazepîne (Compound 2)

274

[0267] Compound 2 was synthesized similar to compound 92 by replacing azepane with 7-methoxy2,3,4,5-tetrahydro-lH-3-benzazepine. LCMS (ES+): (M+H)⁺ = 373.1 *H NMR (400 MHz, Chloroform7) δ 8.90 - 8.70 (m, IH), 8.40 (d, 7= 7.1 Hz, 2H), 7.90-7.76(m, IH), 7.43-7.31 (m, IH), 7.07 (d, 7 =

8.2 Hz, IH), 6.77-6.60 (m, 2H), 4.10-3.91 (m, 4H), 3.79 (s, 3H), 3.15-2.91 (m, 8H), 2.19-2.07 (m,

2H).

Example 1.33

[0268] Synthesis of 6-tnethoxy-3-[2-(pyrÎdin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-2,3,4,5tetrahydro-lH-3-benzazepine (Compound 3)

[0269] Compound 3 was synthesized similar to compound 92 by replacing azepane with 6-methoxy2,3,4,5-tetrahydro-lH-3-benzazepine. LCMS (ES+): (M+H)⁺ = 373.0. 'H NMR (400 MHz, Chlorofonn7) δ 8,81 (dd, 7=4.8, 1.8 Hz, IH), 8.42 (d, 7= 7.9 Hz, IH), 7.86 - 7.77 (m, IH), 7.39 - 7.31 (m, JH), 7.14 - 7.07 (m, IH), 6.79 - 6.74 (m, 2H), 4.00 (dt, 7= 25.4, 4.9 Hz, 4H), 3.81 (s, 3H), 3.17 - 3.03 (m, 15 814), 2,15 - 2.06 (m, 2H).

Example 1.34

[0270] Synthesis of 1 -(3-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]1,4-diazepane (Compound 4)

275

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

[0273] Tert-butyl 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-L4-diazepane-lcarboxylate (200 mg; 0.51 mmol; l eq.) was dissolved in dichloromethane (5 mi). Trifluoroacetic acid (2.5 mL) was added slowly and the reaction was stirred at 25 °C. After l h, the reaction was evaporated 10 to dryness and the residue was co-evaporated with toluene. LCMS (ES+): (M+H)⁺ = 296.

[0274] Step 2

276

I

[0275] l42-(Pyridin-2-yl)-5H_s6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4-diazepane (108 mg; 0.37 mmol; l. 15 eq.) and l-iodo-3-methoxybenzene (75 mg; 0.32 mmol; l eq.) were mixed with 1,4-dioxane (1 ml) and tert-butanol (0.5 ml). The mixture was purged with Ar gas. 2-[2(Dicyclohexylphosphanyi)phenyl]-N,N-dimethylamime (25 mg; 0.06 mmol; 0.20 eq.), tris(dibenzylideneacetone)dipalladium(0) (15 mg; 0.02 mmol; 0.05 eq.) and sodium tert-butoxide (46 mg; 0.48 mmol; 1.50 eq.) were added and the reaction vessel was sealed and stirred at 100°C. After 19 h, additional portions of reagents (iodide, ligand, palladium catalyst and base) were added to drive product formation. The reaction mixture was then fîltered, concentrated and purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-50% acetonitrile/0.1 % aqueous formic acid gradient) to give 1 -(3-methoxyphenyI)-4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4dîazepane (19 mg, 15%) as ayellow solid.

[0276] MS (ES+): (M+H)⁺= 402.1. 'HNMR (400 MHz, Chloroform-rf) δ 8.94-8.87 (m, IH), 8.34 (d, J= 7.9 Hz, IH), 8.02-7.92 (m, IH), 7.62-7.53 (m, 1 H), 7.19 - 7.10 (m, IH), 6.41 (d, J= 8.3 Hz, IH), 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, 6.2 Hz,

2H), 3.36 (t, J= 8.0 Hz, 2H), 3.18 (t, J= 7.4 Hz, 2H), 2.27 - 2.15 (m, 4H).

Example 1.35

[0277] Synthesis ofN-(pyridin-2-yl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl] amino} acetamide (Compound 5)

277

[0278] Scheme 12 depicts a synthetic route for preparing an exempiary compound.

H o ^N

Boc

HATU, DIPEA, DMF 0 oC-rt, 2 h

HCI(g)/EA, rt

HCl O

Scheme 12

[0279] Step l

H ,N Boc

nh₂

0°C-rt, 2 h

ΌΗ HATU, DIPEA, DMF

[0280] Into a 50-mL 3-necked round-bottom flask, was placed [(tert-butoxycarbonyl)amino]acetic acid (2.0 g, 11.42 mmol, l.O equiv), DMF (20.0 mL), 2-aminopyridine (1.29 g, 13.7I mmol, 1.2 equiv) and DIPEA (3.69 g, 28.54 mmol, 2.5 equiv). This was followed by the addition of HATU (5.21 g, I3.70 mmol, 1.2 equiv) în several batches at 0 °C. The reaction solution was stirred for 2 h at room température. The reaction was then quenched by the addition of 50 mL of H_ZO, filtered and the collected solid was dried under infrared lamp. 2.4 g (84% yield) of tert-butyl N-[[(pyridin-2yl)carbamoyl]methyl]carbamate was obtained as white solid. LCMS (ES) [ΜΉ]⁺ m/z: 252.

[0281] Step

HCI(g)/EA, rt

78%

[0282] Into a 50-mL round-bottom flask, was placed tert-butyl N-[[(pyridin-2-

yl)carbamoyl]methyl]carbamate (2.40 g, 9.55 mmol, 1.0 equiv) and DCM (20.0 mL). To the above

278

mixture was added HCl (g) (2 M in EA) (19.0 mL) at 0 °C. The mixture was stirred for 2 h at room température. The mixture was concentrated to remove the solvent, 1.4 g (78% yield) of 2-amino-N(pyridin-2-yl)acetamide hydrochloride was obtained as white solid. LCMS (ES) [M-HCI+l]⁺ m/z: 152. [0283] Step 3

[0284] Into a 100-mL round-bottom flask, was placed 2-amino-N-(pyridin-2-yl)acetamide hydrochloride (l .40 g, 7.46 mmol, l .0 equiv), NMP (30.0 mL), 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (1.30 g, 6.88 mmol, 0.9 equiv), DIEA (2.70 g, 20.89 mmol, 2.80 equiv). The mixture was stirred for 12 h at 60 °C in an oil bath. After being cooled to room température, the reaction 10 was diluted with H₂O (50 mL) and extracted with 3x40 mL of ethyl acetate. The combined organic phase was washed with 3 x40 ml of brine, dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:2). 320 mg (14% yield) of 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino)-N-(pyridin-2-yl)acetamide was obtained as a white solid. LCMS (ES) [M+l]⁺ m/z: 304.

[0285] Step 4

[0286] Into a 50-mL round-bottom flask, was placed 2-([2-chloro-5H,6H,7Hcyclopenta[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)C12 (86 mg, 20 0.11 mmol, 0.1 equiv). The mixture was stirred for 12 h at 110 °C in an oil bath under N2 atmosphère.

279

The reaction mixture was cooled to room température and concentrated to remove the solvent. The residue was purified by silica gel column with ethyl acetate/petroleum ether (3: l). The crude product was further purified by Flash-Prep-HPLC with the following conditions: Column: HPH Cl8, 50*3.0 mm, 2.6 um, Mobile Phase A: Water/0.05% NH3H2O, Mobile Phase B: CH3CN, Flow rate: 1.2 mL/min, 5 Gradient: 5% B to 100% B within 1.1 min, hold 0.7 min. 78.9 mg (22% yield) ofN-(pyridin-2-yl)-2-[[2(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide was obtained as off-white solid. ’H-NMR (300 MHz, DMSO-A^pm): δ 10.60 (s, IH), 8.61 (d, 7=4.6 Hz, IH), 8.33 (dd,7=4.9, 1.1 Hz, IH) 8.23 (d, 7= 8.1 Hz, IH), 8.03 (d, 7= 8.4 Hz, IH), 7.78-7.69 (m, 2H), 7.40-7.35 (m, 2H), 7.09 (ddd, 7= 7.3, 4.8, 1.0 Hz, IH), 4.31 (d, 7= 5.8 Hz, 2H), 2.86 (t, 7= 7.7 Hz, 2H), 2.79 (t, 7= 7.4 Hz, 10 2H), 2,09 (p,7 = 7.5 Hz, 2H). LCMS: (ES, m/z): [M+H]⁺: 347.1.

Example 1.36

[0287] Synthesis ofN-(2-fluorophenyl)-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide (Compound 6)

Scheme 13

[0289] Into a 50-mL round-bottom flask, was placed [[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1.0 equiv), DMF (3.0 mL), 220 fluoroaniline (98 mg, 0.88 mmol, 1.5 equiv), DIEA (153 mg, 1.18 mmol, 2.0 equiv) and HATU (337

280 mg, 0,88 mmol, 1.5 equiv), The resulting solution was stirred for 2 h at room température. The reaction solution was diluted with 5 mL of CH3CN and fïltered. The fîltrate was purified by Prep-HPLC with the following conditions (SHIMADZU (HPLC-Ol)): Column, Welch Xtimate Cl 8, 21.2*250 mm, 5um, mobile phase, Water (10 mmol/L NH4HCO3) and MeOH: CHjCNM :l (25% Phase B up to 65% in 15 min), Detector, UV, 254 nm. This provided 117.3 mg of N-(2-fluorophenyl)-2-[[2-(pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as light yellow solid. Ή NMR (300 MHz, DMSO-Λ) δ 10.03 (br, IH), 8.63-8.61 (m, IH), 8.31-8.28 (m, IH), 7.88-7.75 (m, 2H), 7.50-7.37 (m, 2H), 7.29-7.18 (m, IH), 7.18-7.08 (m, 2H), 4.28 (d, J =5.4 Hz, 2H), 2.86 (t, J =7.8 Hz, 2H), 2.78 (t, J= 7,4 Hz, 2H), 2.14-2,04 (m, 2H). LCMS (ES)[M+1]⁺ m/z: 364.1.

Example 1.37

[0290] Synthesis of 2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrÎmidin-4-yl]amino}-N(quinolin-7-yl)acetamide (Compound 7)

[0291] Scheme 14 depicts a synthetic route for preparing an exemplary compound.

Scheme 14

[0292] Into a 50-mL round-bottom flask at 0 °C was placed [[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160 mg, 0.59 mmol, 1,0 equiv), DMF (3.0 mL),

281 quinolin-7-amine (128 mg, 0.88 mmol, 1.5 equiv), DIEA(l53 mg, t .18 mmol, 2.0 equiv) and HATU (337 mg, 0.88 mmol, 1.5 equiv). After addition, the mixture was stirred for 2 h at room température. The reaction solution was diluted with 5 mL of CHsCN and filtered. The filtrate was purified by Prep-HPLC with the following conditions: Column, Welch Xtimate Cl8, 21.2*250 mm, 5 uni, mobile phase, Water (10 mmol/L NH4HCO3) and MeOH: CH₃CN= 1:1 (25% Phase B up to 70% in 15 min); Detector, UV

254 nm. This provided 1 18.0 mg (50%) of 2-((2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)amino)-N-(quinolin-7-yl)acetamide was obtained as grey solid. Ή NMR (300 MHz, DMSO-r/e) δ 10.64 (s, 1 H), 8.82 (dd, J=4.2, 1.8 Hz, IH), 8.64-8.61 (m, 1 H), 8.43 (d, J= 1.8 Hz, 1 H), 8.29-8.25 (m, 2H), 7.92 (d, J= 8.7 Hz, IH), 7.81-7.69 (m, 2H), 7.54-7.50 (m, IH), 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+Tm/z: 397.1.

Example 1.38

[0293] Synthesis of N-tert-buty 1-2-{[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide (Compound 8)

[0294] Scheme 15 depicts a synthetic route for preparing an exemplary compound.

Scheme 15

[0295] Into a 10-mL sealed tube purged and maintained in an inert atmosphère of nitrogen, was placed N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)acetamide (0.30 g, 1.06 mmol, 1.00 equiv), dioxane (10 mL), 4-(tributylstannyl)pyrimidine (0.47 g, 1.27 mmol, 1.20 equiv), and

PdtdppfjCh.CHjCk (0.17 g, 0.20 equiv). The resulting solution was stirred ovemight at 130 °C. The

282 resulting mixture was concentrated. The residue was applied onto a silica gel column with MeOH/EA (l:9). The crude product was purified by Prep-HPLC with the following conditions: Column. welch Xtimate Cl 8,21,2*250mm, 5um; mobile phase; phase A water(lOmmol/L NH4HCO3), phase B

CH₃CN/MeOH(l : l) (l 5% B up to 60% in 15min); Detector, 220nm. This resulted in 57.7 mg (16.7%) 5 of N-tert-butyl-2-[[2-(pyrimidin-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide as a white solid. Ή-NMR: (300 MHz, DMSOé^ppm): δ 9.28 (s, IH), 8.93 (d, 7=5.1 Hz), 8.32 (d, 7=5.1 Hz, IH), 7.67 (s, IH), 7.29 (t, 7= 6.0 Hz, IH), 3.97 (d,7= 5.7 Hz, 2H), 2.87 (q, 7=7.8 Hz, 2H), 2.76 (q, 7=7.2 Hz, 2H), 2.13-2.06 (m, 2H),L24 (s, 9H). LCMS: (ES, m/z): [M+H]⁺: 327.2.

Example 1.39

[0296] Synthesis ofN-tert-butyl-2-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4yi]amino}acetamide (Compound 9)

[0297] Scheme 16 depicts a synthetic route for preparing an exemplary compound.

Scheme 16

[0298] Step 1

[0299] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen was placed

283

2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500,00 mg, 2.66 mmol, l.OO equiv), 2(tributylstannyl)pyridine (l272.53 mg, 3.46 mmol, l .30 equiv), dioxane (10.00 mL), and Pd(PPh3)4 (307.25 mg, 0.26 mmol, 0.10 equiv). The resulting solution was stirred ovemight at 110 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (1 g) was purified by Prep-HPLC with the foilowing conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH3.H2O) and CAN (50% Phase B up to 80% in 11 min); Detector, 254. This resulted in 350 mg (57.06%) of 2-[4-chloro-5H,6H,7Hcyclopenta[b]pyridin-2-yl]pyridine as white solid. LCMS (ES) [M+H]+ m/z: 231.

[0300] Step 2

[0301 ] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen was placed 2[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (160.00 mg, 0.69 mmol, 1.00 equiv), 2-aminoN-tert-butylacetamide (99.32 mg, 0.76 mmol, 1.10 equiv), Pd(OAc)2 (15.57 mg, 0.069 mmol, 0.10 equiv), Cs2CO3 (451.94 mg, 1.38 mmol, 2.00 equiv), BINAP (86.37 mg, 0.14 mmol, 0.20 equiv), dioxane (10.00 mL). The resulting solution was stirred for ovemight at lOOoC. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (300 mg) was purified by Prep-HPLC with the foilowing conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 167.7 mg (74.53%) of N-tert-butyl-2-[[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[b]pyridin-4-yl]amino]acetamîde as off-white solid. IHNMR (300 MHz, DMSO-d6) δ 8.59 (ddd, J =4.8, 1.9, 0.9 Hz, IH), 8.30 (dt, J = 8.0, 1.1 Hz, IH), 7.84 (td, J = 7.7, 1.8 Hz, IH), 7.66 (s, IH), 7.41-7.30 (m, 2H), 6.00 (t, J = 5.7 Hz, 1 H), 3.77 (d, J = 5.7 Hz, 2H), 2.88 (t, J = 7.6 Hz, 2H), 2.75 (t, J = 7.3 Hz, 2H), 2.12-2.02 (m, 2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H] +: 325.1.

Example 1.40

[0302] Synthesis of N-tert-buty 1-2-{[2-(pyridin-2-y 1)-5,6,7,8-tetrahydroquinazolin-4yl]amino}acetamide (Compound 10)

284

[0303] Scheme 17 depicts a synthetic route for preparing an exemplary compound.

Scheme 17

[0304] Step I

[0305] Into a 40-mL vial, was placed 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (1.00 g, 4.92 mmol, 1.00 equiv), 2-amino-N-tert-butylacetamide (0.71 g, 5.47 mmol, 1,11 equiv), DIEA (1.27 g, 9.85 mmol, 2.00 equiv), and CH3CN (10.00 mL). The resulting solution was stirred overnight at 80 °C. The reaction 10 mixture was cooled to room température, The crude product (2 g) was purified by Prep-HPLC with the following conditions; Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH3.H2O) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. This resulted in 1.1g (75.26%) of N-Îert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)amino]acetamide as a white solid. LCMS (ES) [M+H]+ m/z;297.

[0306] Step 2

285

[0307] Into a 40-mL vial purged and tnaintained with an inert atmosphère of nitrogen, was placed Ntert-butyI-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)Ch (123.26 mg, 0.17 mmol, 0.10 equiv). The resulting solution was stirred for ovemight at 110°C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (800 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 139.2 mg (24.34%) of N10 tert-butyl-2-[[2-(pyridin-2-y 1)-5,6,7,8-tetrahydroquinazolin-4-yl]amino]acetamide as white solid. ’HNMR(300 MHz, DMSO-<7(5) δ8.65 (ddd, J=4.8, 1.8, 0.9 Hz, IH), 8.33 (dt, 8.0, 1.1 Hz, IH), 7.87 (td, J =1.1, 1.8 Hz, 1 H), 7.71 (s, 1 H), 7.45-7.40 (m, IH), 6.88 (t, J = 5.6 Hz, 1 H), 3.95 (d, J= 5.6 Hz, 2H), 2.73-2.63 (m, 2H), 2.46-2.38 (m, 2H), 1.81-1.78 (m, 4H), 1.24 (s,9H). LCMS (ES, m/z); [M+H]⁺: 340.1

Example 1.41

[0308] Synthesis ofN-(4-methoxyphenyl)-l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]piperidin-3-amine (Compound 11)

286

[0309] Step l

Pd₂(dba)₃

[0310] l-Bromo-4-methoxybenzene (0.25 g; 1.34 mmol; l eq.) and tert-butyl 3-amino-lpiperidinecarboxylate (0.32 g; 1.6 mmol; 1.2 eq.) were dissolved in 1,4-dioxane (5 ml) and tert-butanol (2.5 ml). The solution was purged with Ar gas, and sodium tert-butoxide (0.26 g; 2.67 mmol; 2 eq.), 2[2-(dicyclohexylphosphanyl)phenyl]-N,N-dimethylanilîne (52.6 mg; 0.13 mmol; 0.1 eq.) and tris(dibenzylîdeneacetone)dipalladium(0) (61.2 mg; 0.07 mmol; 0.05 eq.) were added. The sealed reaction vessel was stirred in a heat bath at 100 °C for 6 h. After cooling and évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl 3-[(4methoxyphenyl)amino]piperidine-l-carboxylate (178 mg, 43%) as a solid. LCMS (ES+): (M+H)⁺ = 307.0. 'H NMR (400 MHz, Chloroform-if) δ 6.82 - 6.76 (m, 2H), 6.76 - 6.60 (m, 2H), 4.09 - 3.93 (m, IH), 3.76-3.67 (m, 4H), 3.33-3.22 (m, IH), 3.09 -2.95 (m, IH), 2.95 -2.75 (m, IH), 2.07- 1.95 (m,

H), 1.76 - 1.68 (m, 1 H), 1.45 (s, 9H).

[0311] Step 2

[0312] Tert-butyl 3-[(4-methoxyphenyl)amino]piperidine-l-carboxylate (178 mg; 0.58 mmol; 1 eq.) was dissolved in DCM (5 ml) and cooled in an ice bath. Trifluoroacetic acid (2.55 mL) was added slowly and the reaction was stirred at 20 °C for 1 h. The reaction was evaporated, and the residue was co-evaporated with toluene to give 3-[(4-methoxypheny!)amino]piperidin-1-ium trifluoroacetate, which was used directly in the next step.

287

[0313] Step 3

[0314] In a round bottom flask was added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (l00.00 mg; 0.53 mmoi; l.OO eq.), acetonitrile (3.5 ml), 3-[(4-methoxyphenyl)amino]piperidin-l-ium trifluoroacetate ( 186.38 mg; 0.58 mmol; L10 eq.) Hunig’s base (0.38 mL; 2.17 mmol; 4.10 eq.). The mixture was stirred at ~70°C. After cooling and évaporation, the residue was purified by silica gel chromatography (0 to 50% ethyl acetate/hexanes gradient) to give l-{2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}-N-(4-methoxyphenyl)piperidin-3-amine (I44mg, 76%). LCMS (ES+): (M+H)⁺ = 402.4.

[0315] Step 4

[0316] In a round bottom flask was added l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-N(4-methoxyphenyl)piperidin-3-amine (144.00 mg; 0.40 mmol; 1.00 eq.) in 1,4-dîoxane (dry, -3 ml). The solution was purged with Ar. To the mixture was added 2-(tributylstannyl)pyridine (0.26 mL; 0.80 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (46.37 mg; 0.04 mmol; 0.10 eq.) After being stirred in a heat block at 105°C for 15 h, the mixture was concentrated and the residue was purified by préparative HPLC to give N-(4-methoxypheny 1)-1-(2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]piperidin-3-amine (52 mg) as a yellow solid. LCMS (ES+): (M+H)⁺ = 402.4. Ή NMR (400 MHz, Chloroformé δ 9.01 -8.83 (m, IH), 8.38 (d, 7= 8.6 Hz, 1 H), 8.00 - 7.86

288 (m, IH), 7.55-7.43 (m, IH), 7.08-6.87 (m, 2H), 6.87-6.69 (m, 2H), 4.79 (s, IH), 4.16-4.00 (m, 1H), 3.74 (s, 3H), 3.62 - 3.44 (m, 3H), 3.17-2.87 (m, 4H), 2.17-1.99 (m, 3H), 1.99- 1.75 (m,2H), 1.70-1.52(m, IH).

Example 1.42

[0317] Synthesis of N-tert-buty l-2-{[2-(5-methoxypyrazin-2-y i)-5H,6H,7H-cyclopenta[d]pyrimidin4-yl](methyl)amino}acetamide (Compound 12)

[0318] Scheme 18 depicts a synthetic route for preparing an exemplary compound.

Scheme 18

[0319] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen was placed a mixture of N-(tert-buty 1)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide (200 mg, 0.674 mmol, 1.00 equiv), dioxane (10.0 ml), 2-methoxy-5(trimethylstannyl)pyrazine (275 mg, 1.01 mmol, 1.50 equiv), and Pd(PPh₃)4 (155 mg, 0.135 mmol, 0.20 equiv). The resulting solution was stirred for 16 hours at 110 °C. The resulting mixture was concentrated. The crude reaction mixture was filtered and subjected to reverse phase préparative MPLC (Prep-C 18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5 % MeCN in water to 35 % MeCN in water over a 15 min period, where both solvents contain 0.1% fonnic acid). This resulted in 71.7 mg (28 %) of N-(tert-butyl)-2-((2-(5-methoxypyrazin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as an off-white solid. ^JH NMR (300 MHz,

289

DMSO A,ppm); δ 9.12 (d, J= L4 Hz, 1H), 8.36 (d, J= 1.3 Hz, IH), 7.68 (s, IH), 4.13 (s, 2H), 3.98 (s, 3H), 3.27 (s, 3H), 3.14 (t, 7.3 Hz, 2H),2.81 (t, .7= 7.8 Hz, 2H), 2.00-1.95 (m, 2H), 1.25-1.22 (m,

9H). LCMS (ES) [M+l]⁺ m/z: 371.2.

Example 1.43A

[0320] Synthesis of N-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yi}(methyl)amino)acetamide (Compound 174)

[0321] Scheme 19A depicts a synthetic route for preparing an exemplary compound.

LiAIH_4r THF

74%

THRO

[0322] Step 1

PHP, PPTS DCM, rt 95%

[0323] Into a 250-mL 3-necked round-bottom flask was placed ethyl 2-hydroxy-2-methylpropanoate (10.0 g, 75.8 mmol, 1.00 equiv), 3,4-dihydro-2H-pyran (9.54 g, 113.7 mmol, 1.50 equiv) in dîchloromethane (100 mL), and pyridine 4-methylbenzenesulfonate (0.95 g, 3.79 mmol, 0.05 equiv).

The resulting solution was stirred for 3 h at room température. The reaction mixture was poured into

290 water and extracted with Et₂O. The organic layers were dried over Na₂SÛ4, fîltered, and the filtrate was concentrated in vacuo. The crude residue was purified by silica gel chromatography (hexane/ethyl acetate, 100:0 to 5:1) to give 15.6 g (95%) of ethyl 2-methyl-2-((tetrahydro-2H-pyran-2yl)oxy)propanoate as a coiorless oil.

[0324] Step 2

O

THPoVL_o^\ LîAIH₄, THF ^thPO^^o_HV 74% ^{Z X}

[0325] Into a 500-mL 3-round-bottom flask was placed ethyl 2-methyl-2-((tetrahydro-2H-pyran-2yl)oxy)propanoate (15.0 g, 69.4 mmol, 1.00 equiv) in THF (150.00 mL). Lithium aluminium hydride (69.4 mL, Imol/L, 69.4 mmol, 1.00 equiv) was added portion-wise at 0° C. The reaction mixture was stirred for 5 h, followed by the slow addition of Na₂SO4.10H₂O (22.3 g, 69.4 mmol, 1.00 equiv). After 30 minutes of stirring at 0°C, the mixture was fîltered and the filtrate was concentrated in vacuo to give 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol (8.9 g, 74%) as a coiorless oil which was used in the next step without further purification.

[0326] Step 3

[0327] Into a 250 mL 3-neck flask was placed 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propanl-ol (3.9 g, 22.4 mmol, 2.0 equiv) and DMF (50 mL), NaH (60% in minerai oil) (896 mg, 22.4 mmol, 2.0 equiv) was added portion-wise at 0-5 °C. The mixture was stirred for 1 h at room température. After that, N-(tert-butyl)-2-((2-(4-fiuoropyridin-2-yI)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide (4 g, 11.2 mmol, 1.00 equiv) was added at 0-5 °C. The reaction mixture was stirred for 5 h at 50 °C. (The reaction was repeated in 2 batches). The reaction mixture was cooled to room température, diluted with 150 mL of water, and extracted with 3x100 mL of ethyl acetate. The combined organic phase was washed with 3 xl50 mL of water and brine Ixl 00 mL, dried over anhydrous sodium sulfate, and concentrated to afford 10 g crude product (87% yield). This was directly used in the next step without purification. LCMS (ES) [M+l]⁺ m/z: 512.

291

[0328]

[0329] Into a 250 mL 3-neck flask was placed N-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2((tetrahy dro-2H-py ran-2-y l)oxy )propoxy)py rid i n-2-y l)-6,7-dihydro-5 H -cyc lopenta[d] py ri m id in-45 yl)amino)acetamide (crude product from step 3, 10 g, 19.5 mmol, l .00 equiv) and MeOH (50 mL). HCl (20 mL, IN) was added in portion wise at 0-5 °C. The mixture was stirred for 3 h at room température. The reaction mixture was concentrated, and the residue was purified by Prep-HPLC with the following conditions: column, Cl 8-800 g. Mobile phase, CH3CN/H2O (0,05% FA), from 10% increased to 70% within 27 min, Flow rate, 180 mL/min, Detector, 254 nm. The pH value of the fraction was adjusted to 10 7—8 with K2CO3 solid, and extracted with dichloromethane (3x300 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the fîltrate was concentrated under reduced pressure. The residue was freezing dried, and this resulted in 5.3 g (64%) of N-(tert-butyl)-2-((2-(4-(2hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a white solid. LCMS: (ES, m/z): [M+H]T 428.3. ¹H NMR (300 MHz, 15 DMSO-Λ): δ 8.47 (d, J= 5.6 Hz, IH), 7.82 (d, J= 2.5 Hz, IH), 7.67 (s, 1 H), 7.04 (dd, J= 5.7, 2.6 Hz,

IH), 4.69 (s, IH), 4.14 (s, 2H), 3.86 (s, 2H), 3.26 (s, 3H), 3.15 (t, 7.4 Hz, 2H), 2.81 (t, J= 7.8 Hz,

2H), 2.04-1.94 (m, 2H), l.25-1.24(m, 15H).

[0330] Example 1.43B (alternative method for preparing compound 174)

Scheme 19B

[0331] Into a 250 mL three-necked round bottom flask were added N-(tert-buty 1)-2-((2-(4chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (7.2 g, 19.3 mmol, 1.00 equiv) and DMSO (80 mL). This was followed by the addition of NaH (60% in minerai oil)

292 (l .5 g, 38.6 mmol, 2.00 equiv) at room température. The mixture was stirred for 0.5 h, and 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol (6.7 g, 38.6 mmol, 2.00 equiv) was added to the above mixture and stirred for an additional 3 h at 40 °C. The reaction mixture was cooled to room température, quenched with HjO (100 mL), and extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with brine (100 mL*2), dried over anhydrous sodium sulfate, and fïltered. The fîltrate was concentrated under reduced pressure and the residue was purified by Prep-HPLC with the following conditions: Cl8-500 g, CH3CN/H2O (NH4HCO3 0.1%), from 15% to 70% in 30 min, Flow rate, 150 mL/min, Detector, UV 254 nm. This resulted in 7.0 g (71%) N-(tert-butyl)-2-(methy 1(2-(4-(2methy 1-2-( (tetrahyd ro-2H -py ran-2-y l)oxy)propoxy )py rid i n -2-y 1 )-6,7-d ihy dro-5 H- cyclopenta[d]pyrimidin-4-yl)amino)acetamide as a brown solid. LCMS (ES, m/z): [M+H]⁺: 512.

[0332] Into a 250 mL three-necked round bottom flask were added N-(tert-butyl)-2-(methyl(2-(4-(2methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dîhydro-5Hcyclopenta[d]pyrimidin-4-yl)amino)acetamide (7.0 g, 13.7 mmol, 1.00 equiv) and methanol (70 mL), HCl (c) (5 mL). The mixture was stirred for 0.5 h, diluted with H₂O (200 mL), and the pH value was adjusted to 9 with K.2CO3 solid. The mixture was extracted with dîchloromethane (300 mL*2), the combined organic phase was dried over anhydrous sodium sulfate, fïltered, and the fîltrate was concentrated under reduced pressure. The residue 5.8 g (purity: 96.7%) was triturated in CH3CN (120 mL), fïltered, and 5.5 g (98.8% purity) was obtained. The crude product was dissolved in CH3CN (I 10 mL) at 60 ⁰ and then cooled to 20 °C in 20 min. The solid was collected by filtration and dried under an infrared lamp for 1 h. This resulted in 3.1 g (99.94% purity, 56.3% yield) N-(tert-butyl)-2-((2-(4-(2hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a white solid. LCMS: (ES, m/z): [M+H]^T: 428. ^lH-NMR (300 MHz, DMSO-^jPpm): δ 8.48 (d, J= 5.4 Hz, 1 H), 7.83 (d,J=2.7 Hz, IH), 7.67 (s, IH), 7.05 (dd, J= 5.7, 2.7 Hz, 1 H), 4.69 (s, 1 H), 4.14 (s, 2H), 3.86 (s, 2H), 3.26 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.8

Hz, 2H), 2.04-1.94 (m, 2H), 1.25 (s, 9H), 1.24 (s, 6H).

Example 1.44

[0333] Synthesis of2-[4-(azepan-l-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]-N,Ndi methy Ipy rid in-4-amine (Compound 13)

[0334] Compound 13 was synthesized similar to Compound 92, by replacing (2tributylstannyl)pyridine with N,N-dimethyl-2-(tributylstannyl)pyridin-4-amine. 'H NMR (400 MHz,

DMSO-ïfO δ 8.19 (d, 7= 7.2 Hz, IH), 7.75 (d, J = 3 J Hz, IH), 7.05 (dd, 7= 7.3, 2.9 Hz, IH), 3.86 (d, J = 3.4 Hz, IH), 3.86 - 3.72 (m, 3H), 3.26 (s, 6H), 3.12 (hept, 7 = 7.3, 6.7 Hz, 2H), 3.00 - 2.80 (m, 7= 8.0

Hz, 2H), 2.04 (h, 7= 8.2, 7.8 Hz, 2H), 1.73 (dq, 7= i 8.9, 7.4, 6.4 Hz, 4H), 1.48 (dq, 7= 7.4, 4.6, 3.7 Hz, 4H). LCMS (ES+): (M+H)⁺ = 338.1.

Example 1.45

[0335] Synthesis of 1 -[2-(4-methylpyridm-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 14)

[0336] Compound 14 was synthesized similar to Compound 92 replacing (2-tributylstannyl)pyridine with 4-methyl-2-(tributylstannyl)pyridine. ’H NMR (400 MHz, DMSOA) δ 8.69 (d, 7= 5.0 Hz, IH), 8.27 (d, 7= 1.7 Hz, IH), 7.64-7.58 (m, IH), 3.97 (s, 4H), 3.22 - 3.10 (m, 2H), 3.03 (t,7=7.9 Hz, 2H),

2.51 (s, 3H), 2.09 (p, 7 = 7.7 Hz, 2H), 1.82 (s, 4H), 1.54 (s, 4H). LCMS (ES+): (M+H)⁺ = 309.2.

Example 1.46

[0337] Synthesis ofN-(2-methoxyphenyi)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 15)

294

[0338] Scheme 20 depicts a synthetic route for preparing an exemplary compound.

Scheme 20

[0339] To a solution of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino]acetic acid (65.00 tng; 0.23 mmol; l .00 eq.) in DMF (l .5 mL) was added 2-methoxyaniline (33.79 mg; 0.27 mmol; 1.20 eq.) followed by Hunig's base (0.08 mL; 0.46 mmol; 2.00 eq.), and HATU (86.93 mg; 0.23 mmol; l .00 eq.). After being stirred for l h at room température, it was diluted with water and acetonitrile and the mixture was subjected to purification by préparative HPLC to give N-(210 methoxyphenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (9 mg). Ή NMR (400 MHz, DMSOA) δ 9.39 (s, IH), 8.66-8.59 (m, IH), 8.31 - 8.24 (m, IH), 7.92 (d, 7= 8.0 Hz, 1 H), 7.78 (td, 7= 7.7, 1.8 Hz, IH), 7.40 (ddd, 7= 7.5, 4.7, L2 Hz, IH), 7.07-6.95 (m, 2H), 6.85 (td, 7= 7.5, 7.0, 1.7 Hz, IH), 4.49 (s, 2H), 3.68 (s, 3H), 3.31 (s, 3H), 3.18 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.00 (dq, 7 = 15.2, 8.3, 7.8 Hz, 2H). LCMS (ES+): (M+H)⁺ = 390.3.

Example 1.47

[0340] Synthesis of N-tert-buty 1-2-{methy l[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[b]pyridin-4yl]amino}acetamide (Compound 16)

295

[0341] Scheme 21 depicts a synthetic route for preparing an exemplary compound.

Scheme 21

[0342] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed 2-[4chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyridine (l00.00 mg, 0.43 mmol, 1.00 equiv), N-tert-butyl2-(methylamino)acetamide (81.27 mg, 0.56 mmol, 1.30 equiv), Pd(OAc)₂ (9.73 mg, 0.04 mmol, 0.10 equiv), B1NAP (53.98 mg, 0.08 mmol, 0.20 equiv), Cs₂CO₃ (282.46 mg, 0.86 mmol, 2.00 equiv) and dioxane (6.00 mL). The resulting solution was stirred ovemight at IOÛ°C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (200 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and AcCN (30% Phase B up to 60% in 11 min); Detector, 254 nm. This resulted in 71.5 mg (48.74%) ofN-tert-butyl-2-[methyl[2-(pyridin-2-yl)5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamide as off-white solid. 'H-NMR (300 MHz, DMSO76) δ 8.62 (dd,7=4.8, 1.7 Hz, 2H), 8.31 (dt,7=8.0, 1.2 Hz, IH), 7.86 (td, 7= 7.7, 1.9 Hz, IH), 7.57 (s, IH), 7.55 (s, IH), 7.37 (ddd, 7= 7.5, 4.7, 1.2 Hz, IH), 3.94 (s, 2H), 3.07 (s, 3H), 3.03 (t, 7= 7.2 Hz, 2H), 2.86 (t, 7= 7.7 Hz, 2H), 2.05-1.95 (m, 2H), 1.28 (s, 9H). LCMS (ES, m/z): [M+H] ⁺: 339.2.

Example 1.48

[0343] Synthesis ofN-terÎ-buty[-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 245)

296

[0344] Scheme 22 depicts a synthetic route for preparing an exemplary compound.

Scheme 22

[0345] Step l

78%

[0346] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen was placed oxetan-3-ol (8.45 g, 114.04 mmol, 1.50 equiv) and THF (l 00.00 mL). This was followed by the addition ofNaH (60% in minerai oil) (6.84 g, 171.06 mmol, 1.50 equiv) in several batches at 0 °C. The mixture was stirred at 0 °C for 30 min. 2-ch loro-4-fluoro pyridine (10.00 g, 76.02 mmol, 1.00 equiv) was added dropwise with stirring at 0 °C. After addition, the resulting solution was stirred for 6 h at room température. The reaction mixture was cooled to 0 °C again, quenched carefully by the addition of 30 mL of water, extracted with 3x100 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced

297 pressure, The residue was purified by silica gel column with ethyl acetate/petroleum ether (l :2). This resulted in 11 g (78%) of 2-chloro-4-(oxetan-3-yloxy)pyridine as a white solid. LCMS (ES) [M+l]⁺m/z: 186.

[0347] Step 2

Sn₂Me₆, Pd(PPh₃)4 100°C,4h

Me₃Sn

[0348] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen was placed 2-chloro-4-(oxetan-3-yloxy)pyridine (2.00 g, 10.81 mmol, 1.00 equiv), toluene (60.00 mL), Sn₂Me6 (3.71 g, 11.31 mmol, 1.05 equiv), Pd(PPhs)4 (1.25 g, 1.08 mmol, 0.10 equiv). The mixture was stirred for 4 h at 100 °C in oil bath. The reaction mixture was cooled to room température and used to the next step without purification. This réaction was repeated three times. LCMS (ES) [M+l]⁺ m/z: 316.

[0349] Step 3

[0350] Into the reaction solution of step 3 purged and maintained with an inert atmosphère of nitrogen, N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (2.23 g, 7.54 mmol, 0.70 equiv) and Pd(PPh₃)4 (1.24 g, 1.07 mmol, 0.10 equiv) were added. The resulting solution was stirred for 12 h at 100 °C in oil bath. This parallel reaction was repeated three times. The reaction mixture was cooled and concentrated to remove the solvent. The residue was purified by silica gel column with ethyl acetate/petroleum ether (from 10% to 100%). This resulted in 7,2 g crude compound, which was further purified by Prep-HPLC with conditions: column, C18-800 g, Mobile phase, CHsCN/H₂O (0.05% FA), from 10% increased to 70% within 27 min, Flow rate, 180 mL/min, Detector, 254 nm, The pH value of the fraction was adjusted to 7~8 with K2CO3 solid, extracted with dichloromethane (3x300 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure. The residue was

298 triturated in dichloromethane/hexane (l :1O, 30 mL), filtered and the solid was freezing dried to give5.2 g (56 %) of N-tert-butyl-2-[methyl([2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl])amino]acetamide as a white solid. LCMS: (ES, m/z): [M+H]⁺: 412. 'HNMR: (300 MHz, DMSOé,ppm): Ô 8.49 (d,7=5.4 Hz, IH), 7.77 (d,7=2.4 Hz, IH), 7.70 (s, IH),

6.87 (dd, 7= 5.7, 2.4 Hz, I H), 5.52-5.45 (m, IH), 4.99 (t, 7= 6.6 Hz, 2H), 4.58 (dd, 7= 7.2, 4.8 Hz, 2H),

4.13 (s, 2H), 3.29 (s, 3H),3.15 (t,7=7.2 Hz, 2H), 2.82 (t,7=7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.26 (s, 9H).

Example 1.49

[0351] Synthesis of N-cyclohexyl-l-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-410 yl]amino]cyclopropane-l-carboxamide (Compound 17)

[0352] Scheme 23 depicts a synthetic route for preparing an exemplary compound.

Scheme 23

[0353] Step 1

299

[0354] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (500.00 mg; 2.64 mmol; l .00 eq.) in AcCN (5 mL) was added DIPEA (l ,l 5 mL; 6.61 mmol; 2.50 eq.) and ethyl laminocyclopropane-l-carboxylate (409.93 mg; 3.17 mmol; 1.20 eq.). The mixture was heated at 60 °C 5 for 24 h, and 80 °C for an additional 4 days (HPLC showed the conversion to be about 50%). The reaction was stopped and the mixture was concentrated, the resulting crude residue was purified by column chromatography (hexanes/EtOAc = l:l) to give ethyl l-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}amino)cyclopropane-l-carboxylate (135 ing). LCMS (ES⁺): (M+H)⁺ = 282.0, 284.1.

[0355] Step 2

[0356] To a solution of ethyl l-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}amino)cyclopropane-l-carboxylate (135.00 mg; 0.48 mmol; 1.00 eq.) in DMF (2 mL) was added sodium hydride (57.49 mg; 1.44 mmol; 3.00 eq.) at 0 °C. After being stirred for 10 min, to the mixture was added iodomethane (0.04 mL; 0.72 mmol; 1.50 eq.) and the solution was further stirred at ambient température until finished. The mixture was diluted with Sat. NaHCCb and EtOAc, the organic layer was separated, and the aqueous layer was further extracted with EtOAc (2X). The combined organic layer was washed with brine, dried, and concentrated to give ethyl l-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)cycîopropane-l-carboxylate (66 mg), which was used for the next step without further purification. LCMS (ESÔ: (M+H)⁺ = 296.1, 298.4. [0357] Step 3

[0358] To a solution of ethyl l-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-421052

300

y]}(methyl)amino)cyclopropane-l-carboxylate (66.00 mg; 0.22 mmol; I.00 eq.) in THF (l mL) was added MeOH (0.5 mL) and water (0.5 mL) followed by lithium hydroxide monohydrate (18.73 mg; 0.45 mmol; 2.00 eq.). The mixture was stirred for 2 h at room température and was heated to 60 °C and stirred for an additional 2 h. The mixture was cooled and concentrated under vacuum, the residue was acidified with IN HCl to pH =3, and the aqueous layer was freeze-dried to give l-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl] (methy l)amino)cyclopropane-l-carboxylic acid, which was used for the next step without purification. LCMS (ES⁺): (M+H)⁺ = 268.1, 270.2.

[0359] Step 4

[0360] To a solution of L({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)cyclopropane-l-carboxy lie acid (100.00 mg; 0.37 mmol; 1.00 eq.) and cyclohexanamine (0.05 mL; 0.45 mmol; 1.20 eq.) in DMF (1 mL) was added DIPEA (0.13 mL; 0.75 mmol; 2.00 eq.) and HATU (142.03 mg; 0.37 mmol; 1.00 eq.). After being stirred at room température for 1 h, the mixture was diluted with water and the precipitate was collected by filtration, and dried under vacuum to give l-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-Ncyclohexylcyclopropane-l-carboxamide (73 mg). LCMS (ES⁺): (M+H)⁺ = 268.1, 270.2. [0361] Step 5

[0362] To a solution of ]-({2-chloro-5H,6H,7H-cyclopenta[d]pyriinidin-4-yl}(methyl)amino)-Ncyclohexylcyclopropane-l-carboxamide (70.00 mg; 0.20 mmol; 1.00 eq.) and 2-(trîbutylstannyl)pyridine (110.80 mg; 0.30 mmol; 1.50 eq.) in Toluene (I mL) was added tetrakis(triphenylphosphane) palladium (23.19 mg; 0.02 mmol; 0.10 eq.). The solution was degassed with N₂ and heated at 105 °C for 15 h. The mixture was cooled and concentrated, and the residue was subjected to purification by préparative HPLC to give N-cyclohexyl-l-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}cyclopropane-l-carboxamide (23 mg). NMR (400 MHz, DMSO-î/ô) δ 8.69 — 8.62 (m, IH),

301

8.27 (d, 7= 7.9 Hz, l H), 7.88 (td, 7= 7.7, l.8Hz, 2H), 7.58 (ddd, 7 = I8.l, 10.7,6.9 Hz, 1H), 7.42 (ddd, 7=7.5,4.7, 1.2 Hz, IH), 3.62(s, 1 H), 3.13 (s, 3H), 2.93 - 2.81 (m, IH), 2.76 (s, 2H), 2.02 (s, IH), 1.84 (s, IH), 1.64 (m,4H), 1.56 (t, 7= 14.5 Hz, 2H), 1.33 (dd,7=24.0, 10.8 Hz, 2H), 1.19 (m, 4H), 1.02 (m, 2H). LCMS (ES⁺): (M+H)⁺ = 392.2.

S Example 1.50

[0363] Synthesis of N-tert-buty l-2-methyl-2-{methy l[2-(pyridîn-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 19)

[0364] Scheme 24 depicts a synthetic route for preparing an exemplary compound.

Scheme 24

[0365] Step 1

[0366] In a vial was added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (150.00 mg; 0.79 mmol; 1.00 eq,), acetonitrile (3 ml), l-ethoxy-2-methyl-l-oxopropan-2-aminium chloride (159.62 mg;

0.95 mmol; 1.20 eq.), and Hunig's base (0.58 mL; 3.33 mmol; 4.20 eq,). After being stirred in a heat

302

block at 60°C for 15 h, the mixture was evaporated and the residue was subjected to column chromatography eluting with (0 to 50% EtOAc in Hexanes) to give ethyl 2-({2-chioro-5H,6H,7IIcyclopenta[d]pyrimidin-4-yl]amino)-2-methylpropanoate (88 mg). LCMS (ES+): (M+H)⁺= 283.9.

[0367] Step 2

[0368] In an round bottom flask was added ethyl 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino)-2-methylpropanoate (88.00 mg; 0.31 mmol; l.OO eq.) in l,4-dioxane (dry, ~2 ml). The mixture was purged with Ar. To the mixture was added 2-(tributylstannyl)pyridine (0.20 mL; 0.62 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (35.84 mg; 0.03 mmol; 0.10 eq.) After being stirred in a heat block at 108 °C for 15 h, the mixture was cooled and concentrated, and the residue was purified by column chromatography (0-5% MeOH/DCM)to give Ethyl 2-methyl-2-{[2-(pyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanoate. LCMS (ES+): (M+H)⁺ = 327.0.

[0369] Step 3

1) LiOH

2) NaH, Mel

[0370] Ethyl 2-methyl-2-{[2-(pyridin-2-yl)-5H₅6H,7H-cyclopenta[d]pyrimÎdin-4yl]amino}propanoate (67 mg; 0.21 mmol; 1 eq.) was dissolved in tetrahydrofuran (2 ml) and methanol (0.5 ml). Lithium hydroxide (anhydrous, 25 mg; 1.03 mmol; 5 eq.) was dissolved in water (-0.8 ml) was added dropwise and stirred at 25 °C. After 4.5 h, the reaction was acidified carefully with 6 M HCl to pH <3 and evaporated to dryness. The residue of 2-methyi-2-{[2-(pyridin-2-yl)-5H,6H,7H20 cyclopenta[d]pyrimidin-4-yl]amino}propanoic acid hydrochloride was co-evaporated with toluene and dried under a high vacuum. This material was dissolved in N, N-dimethylformamide (3 ml) and cooled in an ice bath. lodomethane (39 pL; 0.62 mmol; 3 eq.) and potassium carbonate (142 mg; 1.03 mmol; 5

303 eq.) were added and the mixture was stirred at 60°C. After 7 h, additional portions of iodomethane and potassium carbonate were added several times to drive the reaction to product. The reaction was taken up in ethyl acetate (50 ml) and water (25 ml), the phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organics were washed with water (10 ml) and sodium chloride solution (10 ml). The combined aqueous phases were extracted with l : 3 isopropanol : chloroform (6 x 20 ml), combined with the organics, and dried over sodium sulfate. The residue from concentration was purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-80% acetonitrile/O.l % aqueous formic acid gradient) to give methyl 2-methyl-2-{methyl[2-(pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimÎdin-4-yl]amino]propanoate (10 mg, I5%) as a yellow solid. LCMS (ES+): (M+H)⁺= 327.0.

[0371] Step 4

[0372] Methyl 2-methy 1-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}propanoate (10 mg; 30.64 pmol; 1 eq.) was dissolved in tetrahydrofuran (0.5 ml) and methanol (0.2 mi). Lithium hydroxide (anhydrous, 3.67 mg; 0.15 mmol; 5 eq.) dissolved in water (-0.2 ml ) was added dropwise and the mixture was stirred for 2 h at 25°C. The reaction was then acidified carefully with 6 M HCl to pH <3 and evaporated to dryness. The residue was co-evaporated with toluene and dried under high vacuum. The residue of2-{4-[(l-carboxy-l-methylethyl)(methyi)amino]5H,6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridin-l-ium chloride (10.7 mg; 0.03 mmol; 1 eq.) was dissolved in N ,N-di methyl formant ide (1.5 ml). N, N-diisopropylethylamine (19 gL; 0.11 mmol; 3.5 eq.) and l-[bis(dimethylamino)methylene]-lH“l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 23 mg; 0.06 mmol; 2 eq.) were added, followed by tert-buty lamine (6 pL; 0.05 mmol; 1.5 eq.) After 15 h, additional portions of tert-butylamine, HATU and N, N-diisopropylethylamine were added to drive the reaction to completton. The reaction was partitioned into water (5 ml), ethyl acetate (50 ml) and sodium bicarbonate solution (10 ml). The phases were separated and the aqueous phase was extracted with ethyl acetate (50 ml) and 1:3 isopropanohchloroform (50 ml). The combined organic

304 phases were dried over sodium sulfate, evaporated, and purified by reverse phase chromatography (Waters XSelect CSH 08 column, 0-90% acetonitrile/O.i % aqueous formic acid gradient) to give Ntert-butyl-2-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}propenamide (6 mg, 50%) as a brown solid. LCMS (ES±): (M+H)⁺ = 368.1. 'H NMR (400

MHz, Chloroform-tT) δ 8.77 — 8.67 (m, IH), 8.52 - 8.43 (m, 2H), 8.11 - 8.00 (m, IH), 7.74 - 7.65 (m, 1H), 6.79-6.71 (m, 1 H), 4.73 (s, 3H), 3.00 - 2.91 (m, 4H), 2.21-2.12 (m, 2H), 1.62 (s, 6H), 1.18 (s.

9H).

Example 1.51

[0373] Synthesis of N-tert-buty 1-2-{phenyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4 yl]amino}propanamide (Compound 20)

[0374] Scheme 25 depicts a synthetic route for preparing an exemplary compound.

Scheme 25

[0375] Step l

305

[0376] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg; l .06 mmol; l eq.) was dissolved in acetonitrile (9.5 ml). Aniline (0.12 mL; l .27 mmol; l .2 eq.) and N, Ndiisopropylethylamine (0.55 mL; 3.17 mmol; 3 eq.) were added. The reaction was sealed and heated in a 5 microwave reactor at 12O°C for ] h. Additional aniline (1.2 eq.) and N, N-diisopropylamine (1.5 eq.) were added and heating continued at 100°C for 4 h, and then 90 °C in a heat block for 10 h. The reaction was then concentrated to approximately 2 ml in volume, more N, N-diisopropylethy lamine (0.75 ml) was added, and heating continued at 90 °C for 4 days. The reaction was evaporated and purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 2-chlorO'N-phenyl-5H,6H,71-l10 cyclopema[d]pyrimidin-4-amine (194 mg, 74%) as a light-yellow film. LCMS (ES+): (M+H)⁺ = 245.9.

[0377] Step 2

[0378] 2-Chloro-N-phenyl-5H,6H,7H-cyclopenta[d]pyrimidm-4-amine (60 mg; 0.24 mmol; 1 eq.) was dissolved in Ν,Ν-dimethylformamide (I ml). Potassium carbonate (67 mg; 0.49 mmol; 2 eq.) was added and the mixture was stirred în a heat block at 50 °C for 2 h. The reaction mixture was cooled to 20 °C and 2-bromo-N-tert-butylpropanamide (76 mg; 0.37 mmol; 1.5 eq.) in Ν,Ν-dimethylfonnamide (1 ml) was added and the reaction was stirred at 80 °C for 24 h. Additional amounts of bromo-amide (38 mg) and potassium carbonate (33 mg) were added and the reaction was heated for 24 b more. The reaction mixture was taken up in ethyl acetate (50 ml), water (10 ml), and sodium bicarbonate solution (10 ml). The phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The combined organics were washed with water (10 ml) and sodium chloride solution (10 ml), dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(phenyl)amino)propenamide (48mg, 52%) as a white solid. LCMS (ES+): (M+H)⁺ = 372.9.

[0379] Step 3

306

[0380] N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(phenyl)amino)propanamide (48 mg; 0.13 mmol; 1 eq.) was suspended in 1,4-dioxane (2 ml). The mixture was purged with Ar gas. 2-(Tributylstannyl)pyridine (0.08 mL; 0.26 mmol; 2 eq.) and tetrakis(triphenylphosphane) palladium (15 mg; 0.01 mmol; 0.1 eq.) were added and the mixture was stirred in a heat block at 108 °C for 18 h. Additional amounts of tin reagent (0.08 ml) and palladium catalyst (15 mg) were added and heating continued for 14 h. The reaction was evaporated, filtered, and purified by reverse phase chromatography (Waters XSelect CSH Cl8 column, 5-80% acetonitrile/0.1 % aqueous formic acid gradient) to give N-tert-butyl-2-{phenyl[2-(pyridin-2-yl)-5II,6H,7H10 cyclopenta[d]pyrimidin-4-yl]amino)propenamide (19 mg, 35%) as a white solid. LCMS (ES+): (M+H)⁺= 415.8. Ή NMR (400 MHz, Chloroform-rf) δ 8.82 (d, .7=4.8 Hz, IH), 8.49 (d, 8.0 Hz, 1 H), 7.927.83 (m, IH), 7.43 - 7.33 (m, 4H), 7.33 - 7.26 (m, 2H), 7.26 - 7.21 (m, 1 H), 5.44 (s, I H), 2.92 (t, J= ΊΧ Hz, 2H), 1.99 - 1.92 (m, 1 H), 1.80 - 1.63 (m, 3H), 1.33 (d, J= 7.1 Hz, 3H), 1.19 (s, 9H).

Example 1.52

[0381] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidiii-4-yl]amino}-N(quinolin-7-yl)acetamide (Compound 21)

[0382] Scheme 26 depicts a synthetic route for preparing an exemplary compound.

307

Scheme 26

[0383] into a 100-mL round-bottom flask, was placed N-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro5H-cycîopenta[d]pyrimidin-4-yl)glycine (250 mg, 0.879 mmol, 1.00 equîv), quinolin-7-amine (190.16 mg, 1.319 mmol, 1.5 equiv), HATU (501.50 mg, 1.319 mmol, 1.50 equiv), D1EA (227.29 mg, 1.759 mmol, 2 equiv), DCM (10.00 mL). The resulting solution was stirred for 4 hr at room température. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2&SHIMADZU (HPLC-01)): Column, Atlantis HILIC OBD Column, 19^J|1i50mm*5um; mobile phase, Water(0.05%NH₃H₂0) and ACN (25% PhaseB up to 42% in 14 min. This resulted in 137.7 mg (38.2%) of 2-(methy 1(2-(pyridin-2-y 1)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-y[)amîno)-N-(quinolin-7-yl)acetamide as an off-white solid. 'H NMR (300 MHz, DMSOA) δ 10.61 (s, IH), 8.86-8.80 (m, IH), 8.67-8.60 (m, IH), 8.39 (s, IH), 8.328.22 (m, 2H), 7.92 (d, J= 8.8 Hz, IH), 7.83-7.66 (m, 2H), 7.39 (td, J= 7.6, 4.5 Hz, 2H), 4.52 (s, 2H), 3.42 (s, 3H), 3.24 (t, J= 7.3 Hz, 2H), 2.85 (t, J = 7.8 Hz, 2H), 2.02 (p, J= 7.7 Hz, 2H). LCMS (ES) [M+l]⁺ m/z: 411.2.

Example 1.53 [0384] Synthesis of N-(2-fluorophenyI)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 22)

308

[0385] Scheme 27 depicts a synthetic route for preparing an exemplary compound.

Intermediate I

Scheme 27

[0386] Into a 50-mL round-bottom flask, was placed 2-[methyl[2-(pyridin-2-yl)-5H,6H,7H5 cyclopenta[d]pyrimidin-4-yl]amino]acetainide (Intermediate I, 100.00 mg, 0.353 mmol, I.00 equiv), dimethylformamide (8 mL), 2-fluoroaniline (39.22 mg, 0.353 mmol, L00 equiv), HATU (20L30 mg, 0.529 mmol, 1.50 equiv) and DIEA (l36.84 mg, l .059 mmol, 3.00 equiv). The resulting solution was stirred for 2 hr at 25 °C. The crude reaction mixture was filtered and subjected to reverse phase préparative HPLC (Prep-Cl8, 20-45M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of

30% MeCN in water to 40% MeCN in water over a 10 min period, water contains 0.1 % FA) to provide

N-(2-fluorophenyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide as a brown solid (45.7 mg, 34.31%). 'H NMR (300 MHz, DMSO-d6) δ 10.05 (s, 114),8.63 (d, 7=4.4 Hz, IH), 8.29 (d, 7= 7.8 Hz, IH), 7.89-7.64 (m, 2H), 7.47-7.34 (m, IH), 7.32-7.20 (m, IH), 7.14 (dt, 7= 6.4, 3.2 Hz, 2H), 4.50 (s, 2H), 3.36-3.32 (m, 3H), 3.21 (t, 7 = 7.4 Hz, 2H), 2.84 (t,

7 = 7.8 Hz, 2H), 2.01 (p, 7= 7.6 Hz, 2H). LCMS (ES) [M+l]⁺ m/z 378.2.

Example 1.54

[0387] Synthesis of N-tert-buty 1-2-{methyl[2-(pyridin-2-yl)-5,6,7,8-tetrahydroquinazoIin-4yl]amino}acetamide (Compound

23)

309

[0388] Scheme 28 depicts a synthetic route for preparing an exemplary compound.

ci

H

DIEA, MeOH rt, 16 h %

SnBu₃

Pd{PPh₃)₄, dioxane

110 0,16 h %

Scheme 28

[0389] Step 1

H

DIEA, MeOH rt, 16 h %

[0390] Into a 50-mL round-bottom flask, was placed a mixture of 2,4-dichloro-5,6,7,8tetrahydroquinazoline (300 mg, 1.477 mmol, 1.00 equiv), MeOH (10.00 mL), N-tert-butyl-2(methylamino)acetamide (319 mg, 2.21 mmol, 1.50 equiv), and DIEA (286 mg, 2.21 mmol, 1.50 equiv). The resulting solution was stirred for 16 hours at room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/3). This resulted in 260 mg (56.62%) of N-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4yl)(methyl)amino]acetamide as a white solid. LCMS (ES) [M+l]+ m/z: 311.

[0391] Step 2

Pd(PPh₃)₄, dioxane 110 °C,16 h 55%

[0392] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed a

3I0 mixture of N-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4-yl)(methyl)amino]acetamide (200 mg, 0.643 mmol, l.OO equiv), dioxane (I5.0 mL), 2-(tributylstannyl)pyridine (473 mg, L28 mmol, 2.00 equiv), and Pd(PPh3)4 (223 mg, 0.193 mmol, 0.30 equiv), The resulting solution was stirred for 16 hours at l ]0°C, The crude réaction mixture was filtered and subjected to reverse phase préparative

MPLC (Prep-C18, 20-45 mM, I20 g, Tianjin Bonna-Ageîa Technologies; gradient elution of 5 % MeCN in water to 26 % MeCN in water over a 12 min period, where both solvents contain 0.1% formic acid). This resulted in 127.1 mg (55.88%) of N-tert-butyL2-[inethyl[2-(pyridin-2-yI)-5,6,7,8tetrahydroquinazolin-4-yl]amino]acetamide as an off-white solid. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.70 (d, J = 4.3 Hz, IH), 8.37 (d, J = 7.9 Hz, IH), 7.93 (td, J = 7.7, 1,8 Hz, 1 H), 7.77 (s, IH),

7.52-7.47 (m, IH), 4.04 (s, 2H), 3.21 (s, 3H), 2.83-2.79 (m, 2H), 2.73-2.70 (m, 2H), 1.82-1.80 (m, 2H),

1.69- 1.67 (m ,2H), 1.23 (s, 9H). LCMS (ES) [M+l]+m/z: 354.2.

Example 1.55

[0393] Synthesis of N-tert-buty 1-2-{methy l[2-(4-m ethy lpyridin-2-y l)-5 H,6H,7 Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 24)

[0394] Scheme 29 depicts a synthetic route for preparing an exemplary compound.

Intermediate II

Scheme 29

[0395] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed N tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Intermediate

31L

11,0.30 g, 1.01 mmol, 1.00 equiv), dioxane (15 mL), Pd(dppf)Ch.CH2C12 (0.22 g, 0.30 mmol, 0.30 equiv), and 4-methyl-2-(tributylstannyl)-pyridine (0.58 g, 1.52 mmol, 1.50 equiv). The resulting solution was stirred overnight at 110 ° C. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1): Column, Cl8 silica gel; mobile phase, Phase A: Water (0.05% FA), Phase B CH₃CN( 0-30% in 6min); Detector, 220&254nm. This resulted in 0.1 g crude product. The crude product (O.lg) was further purified by Prep-HPLC with the following conditions: Column, X-Bridge Cl8 OBD, 5um, 19*150 mm; mobile phase, Phase A:Watwe(0.05% NH4OH), Phase B CH₃CN(25% B up to 45% in 8min); Detector, 220nm; Flow rate 20mL/min. This resulted in 88.9 mg (24.88%) of (N-tert-butyl)-2-(methyl(2-(4-methylpyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide as an off-white solid. 'H-NMR:(300 MHz, DMSO-^ppfflLÔ 8.50 (d,7= 4.9 Hz, IH), 8.16 (s, IH), 7.71 (s, 1 H), 7.26 (d, 7=4.2 Hz, IH), 4.14 (s, 2H), 3.27 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.41 (s, 3H), 2.0 -1.99 (m, 2H), 1.23 (s, 9H). LCMS: (ES, m/z): [M+H]⁺: 354.2.

Example L56 [0396] Synthesis of2-{methyi[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N(1-methy lcyclohexyl)acetam ide (Compound 25)

[0397] Scheme 30 depicts a synthetic route for preparing an exemplary compound.

Scheme 30

312

[0398] Into a 8-mL vial, was placed [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetic acid (Intermediate I, 150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL), 1methylcyclohexy lamine (66 mg, 0.58 mmol, 1.1 equiv), and DIPEA (341 mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU (301 mg, 0.79 mmol, 1.5 equiv) at 0 °C. The mixture was stirred for 1 h at room température. The mixture was fîltered, and the filtrate was purified by Prep-HPLC with the following conditions: 120 g Cia column, CH3CN/H2O (0.05% NH4OH), from 5% to 80% with 15 min, flow rate, 70 mL/min, detector, 254 nm. 101.6 mg (51%) of 2-[methyl[2-(pyridm-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino|-N-(l-methylcyclohexyl)acetamide was obtained as light yellow solid. 'H-NMR (300 MHz, DMSO-Λ., ppm): δ 8.66 (dd, J= 4.7, 1.8 Hz, IH), 8.34 (dt, J= 8.0,

1.1 Hz, IH), 7.86 (td, J= 7.7, 1.8 Hz, IH), 7.43 (ddd, 7.5, 4.7, 1.2 Hz, IH), 7.37 (s, 1 H), 4.20 (s,

2H), 3.28 (s, 3H), 3.16 (t, J = 7.2 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.02-1.96 (m, 4H), 1.33-1.24 (m, 8H), 1.19 (s, 3H). LCMS: (ES, m/z): [M+H]⁺: 380.3.

Example 1.57

[0399] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N15 (oxan-3-yl)acetamide (Compound 26)

[0400] Scheme 31 depicts a synthetic route for preparing an exemplary compound.

HATU, DIEA, DMF 0°C~rt, 1 h 56%

Scheme 31

[0401 ] Into an 8-mL vial, was placed [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-421052

313 yl]amino]acetic acid (Intermediate I, 150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL), oxan-3-amine hydrochloride (80 mg, 0.58 mmol, 1 1 equiv), and DIEA (341 mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU (301 mg, 0.79 mmol, 1.5 equiv) at 0 °C. The mixture was stirred for 1 h at room température, filtered, and the filtrate was purified by Prep-HPLC with conditions: Cl 8-120 g 5 column, CH3CN/H2O (0.05% NH4OH), from 5% to 80% with 15 min, flow rate, 70 mL/min, detector,

254 nm. This proived 108.5 mg (56%) of 2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cycîopenta[d]pyrimidin4-yl]amino]-N-(oxan-3-yl)acetamide as an off-white solid. 'H-NMR: (300 MHz, DMSO-iisp/wr): δ 8.67 (d, 7=4.2 Hz, IH), 8.29 (d, 7= 7.8 Hz, IH), 8.09 (d,7=7.5 Hz, IH), 7.90-7.85 (m, IH), 7.46-7.42 (m, 1 H), 4.20 (s, 2H), 3.71-3.63 (m, 3H), 3.33-3.29 (m, 11-1),3.26 (s, 3H) 3.15-3.05 (m, 3H), 2.82 (t,7= 10 7.8 Hz, 2H), 2.04-1.94 (m,2H), 1.79-1.71 (m, IH), 1.64-1.55 (m, IH), 1.49-1.43 (m, 2H). LCMS: (ES, m/z): [M+H]⁺:

368.2.

Example 1.58

[0402] Synthesis of N-benzyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4 yl]amino}acetamide (Compound 27)

[0403] Scheme 32 depicts a synthetic route for preparing an exemplary compound.

Scheme 32

[0404] Into an 8-mL vial, was placed [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrÎmidin-421052

314 yl]amino]acetic acid (200 mg, 0.70 mmol, l.O equiv), DMF (3.00 mL), benzylamine (83 mg, 0.77 mmol, Ll equiv), and DIEA (455 mg, 3.52 mmol, 5.0 equiv). This was followed by the addition of HATU (321 mg, 0.84 mmol, 1.2 equiv) at 0 ^ÜC. The reaction solution was stirred for l h at room température, fïltered, and the fîltrate was purified by Prep-HPLC with conditions: C18-120 g column, CH3CN/H2O (0.05% NH4OH), from 5% to 80% with 15 min, flow rate, 70 mL/min, detector, 254 nm. This provided 101.6 mg (39%) of N-benzyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetamide as an off-white solid. 1H-NMR (300 MHz, DMSO-d6, ppm): δ 8.64 (d, J=5.4 Hz 2H), 8.26 (d, J = 7.8 Hz, IH), 7.83 (td, J = 7.7, 1.9 Hz, IH), 7.43 (dd, J = 7.5, 4.9 Hz, IH), 7.22-7.10 (m, 5H), 4.31 (s, 2H), 4.30 (s, 2H), 3.32 (s, 3H), 3.17 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.03-1.93 (m, 2H). LCMS: (ES, m/z): [M+H]+: 374.2

Example 1.59

[0405] Synthesis of N-tert-buty l-2-{[2-(5-hydroxypyrazin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide (Compound 28)

[0406] Scheme 33 depicts a synthetic route for preparing an exemplary compound.

[0407] Into a 50-mL round-bottom flask, was placed a mixture of N-(tert-buty 1)-2-((2-(5methoxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (120 mg, 0.324 mmol, 1.00 equiv), DCM (20.0 mL), and AICh (431 mg, 3.23 mmol, 10.00 equiv). The resulting solution was stirred for 24 hours at room température. The reaction was then quenched by the addition

315 of 100 mL of water/ice. The resulting solution was extracted with 3x50 mL of dichloromethane. The organic layer was separated, dried over anhydrous magnésium sulfate, and concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep Cl8 OBD Column, l9xl50mm, 5um; mobile phase, phase A: H₂O (0.05 % NH3H2O); phase B: CH3CN (10%

CH3CN up to 30% CH3CN in 8 min). This resulted in 57.2 mg (49.54%) of N-(tert-butyl)-2-((2-(5hydroxypyrazin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a white solid. 'HNMR (300 MHz, DMSO-^,ppm): δ12.63 (br, IH), 8.26 (br, IH), 8.05 (d, J=l.3 Hz JH), 7.61 (s, IH), 4.08 (s, 2H), 3.3 (s, 3 H), 3.10 (t, J= 7.3 Hz, 2H), 2.76 (t, J= 7.8 Hz, 2H), 2.05-1.93 (m, 2H), 1.24 (s, 9H). LCMS (ES) [M+l]⁺ m/z :357.2.

Example 1.60

[0408] Synthesis of N-cyclohexyl-l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]azetidine-3-carboxamide (Compound 29)

[0409] Scheme 34 depicts a synthetic route for preparing an exemplary compound.

3Ï6

Scheme 34

[0411] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (300.00 mg; 1.59 mmol; 1.00 eq.) and methyl l-chloroazetidine-3-carboxylate HCl sait (300.71 mg; 1.98 mmol; 1.25 eq.) in AcCN (4 mL) was added triethylamine (0.44 mL; 3.17 mmol; 2.00 eq.) at room température. The reaction mixture was stirred for 30 min at room température and 3 h at 75 °C. The resulting mixture was cooled and diluted with water and EtOAc. The organic layer was collected and was concentrated, and the resulting residue was purified by column chromatography (Hexanes/EtOAc = 30:70) to give methyl l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylate (390 mg). LCMS (ES⁺):

(M+H)⁺ = 268.1,270.1.

[0412] Step 2

[0413] To a solution of methyl l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3 carboxylate (390.00 mg; 1.46 mmol; 1.00 eq.) in THF (2 mL) was added MeOH (1 mL) and water (1 mL), followed by lithium hydroxide monohydrate (122.26 mg; 2.91 mmol; 2.00 eq.). The mixture was stirred for 2 h and concentrated and the residue was acidified with IN HCl to pH = 3. The resulting précipitâtes were collected by filtration to give 1 -{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}azetidine-3-carboxylic acid (339 mg). LCMS (ES⁺): (M+H)” = 254.0, 256.2.

[0414] Step 3

317

[0415] To a solution of l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azetidine-3-carboxylic acid (156.00 mg; 0.61 mmol; 1.00 eq.) and cyclohexanamine (0.1 I mL; 0.92 mmol; 1.50 eq.) in DMF (2 mL) was added DIPEA (0.27 mL; 1,54 mmol; 2.50 eq.) and HATU (257.20 mg; 0.68 mmol; 1.10 eq.).

The reaction was stirred until completion, and the mixture was poured over Sat. NaHCO₃ and water. The resulting précipitâtes were collected by filtration to give l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin4-yl]-N-cyclohexylazetidine-3-carboxamide (198 mg). LCMS (ES⁺): (M+FI)^T = 335.0, 337.1.

[0416] Step 4

[0417] To a suspension of l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-Ncyclohexylazetidine-3-carboxamide (100.00 mg; 0.30 mmol; 1.00 eq.) in DMF (2 mL) was added 2(tributylstannyl)pyridine (164.92 mg; 0.45 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (34.51 mg; 0.03 mmol; 0.10 eq.). The mixture was heated at 115 °C for 15 h, the mixture was cooled and diluted with water and AcCN, the insoluble material was filtered off, and the filtrate was purified by préparative HPLC to give N-cyclohexyl-l-[2-(pyridin-2-y[)-5H,6H,7H-cycioper)ta[d]pyrimidin-4yl]azetidine-3-carboxamide (63 mg). ’H NMR (400 MHz, DMSOé) δ 8.66 (ddd, 7= 4.8, 1.8, 0.9 Hz, IH), 8.25 (dt, 7= 7.9, 1.2 Hz, IH), 7.89 (td, 7= 7.7, 1.8 Hz, 2H), 7.45 (ddd, 7= 7.6, 4.7, 1.2 Hz, IH), 4.33 (t, 7=8.6 Hz, 2H), 4.24 (t, 7= 7.4 Hz, 2H), 3.58 - 3.50 (m, IH), 3.48 - 3.39 (m, IH), 2.93 (t, 7= 7.4 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.01 (p, 7= 7.7 Hz, 2H), 1.77 - 1.62 (m, 4H), 1.53 (d,7= 12.3 Hz,

1 H), 1.32-1.03 (m, 5H). LCMS (ES⁺): (M+H)⁺ = 378.3.

Example 1.61

318

[04i 8] Synthesis of N-cyclohexyl-l-[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4yl]azetidine-3-carboxamide (Compound 30)

[0419] Compound 30 was synthesized similar to Compound 29 by replacing 2(tributylstannyl)pyridine with 4-methyl-2-(tributylstannyl)pyridine. ’H NMR (400 MHz, DMSO-7&) δ 8.51 - 8.46 (m, IH), 8.06 (dd, 7 = l .8, 0.9 Hz, IH), 7.88 (d, 7= 7.8 Hz, IH), 7.27 - 7.21 (m, IH), 4.29 (t, 7=8.5 Hz, 2H), 4.21 (t, 7= 7.3 Hz, 2H), 3.60- 3.48 (m, IH), 3.48 - 3.38 (m, IH), 2.92 (t,7=7.4 Hz, 2H), 2.78 (t, 7= 7.8 Hz, 2H), 2.37 (s, 3H), l .99 (p, 7= 7.7 Hz, 2H), 1.77 - I.73 (m, 2H), l .66 (dt, J = 12.6,3.7 Hz, 2H), 1.53 (d,7= 12.8 Hz, IH), 1.33- 1.18 (m, 2H), 1.22- 1.03 (m, 3H). LCMS (ES+): (M+H)⁺ = 392.4.

Example 1.62

[0420] Synthesis ofN-(l-methyi-2-oxopyrrolidin-3-yl)-2-{methyl[2-(pyridin-2-y 1)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 31)

[0421] Compound 31 was synthesized similar to compound 75 by replacing 4-methoxyaniline with 3amino-l-methylpyrrolidin-2-one. LCMS (ES+): (M+H)⁺ = 381.3. ^!H NMR (400 MHz, Acetonitrile-73) δ 8.60-8.55 (m, IH), 8.37 (d. 7= 8.0 Hz, IH), 8.02 (d,7= 8.3 Hz, IH), 7.90-7.84 (m, IH), 7.40 (ddd, 7= 7.6, 4.8, 1.2 Hz, IH), 4.43 (q, 7= 9.0 Hz, IH), 4.31-4.10 (m, 2H), 3.34 (s, 3H), 3.23-3.14 (m, 4H), 2.89-2.85 (m, 2H), 2.74 (s, 3H),2.28 (dddd, 7= 12.5,9.0, 6.9, 2.2 Hz, IH), 2.10- 1.99 (m, 2H), 1.79- 1.67 (m, IH).

Example 1.63

319

[0422] Synthesis ofN-(2,2-difluoro-2H-l,3-benzodioxol-5-yl)-2-{ methy l[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 32)

[0423] Compound 32 was synthesized similar to compound 75 by replacing 4-methoxyaniline with 2,2- difluoro-l,3-benzodioxol-5-amine. LCMS (ES+): (M+H)⁺ = 440.3. Ή NMR (400 MHz, Acetonitrile73)0 9.91 (s, lH), 8.68 (d, 7= 4.7 Hz, lH), 8.39 (d, 7= 8.0 Hz, IH), 7.92 - 7.84 (m, lH), 7.69 (d, 7= 2.1 Hz, IH), 7.46 (dd, J= 7.6, 4.9 Hz, IH), 7.24 (dd, 7= 8.7, 2.1 Hz, I H), 7.07 (d,7=8.7 Hz, 1 H), 4.35 (s, 2H), 3.43 (s, 3H), 3.28 - 3.22 (m, 2H), 2.96 - 2.90 (m, 2H), 2.11 - 2.06 (m, 2H).

Example 1.64

[0424] Synthesis ofN-tert-butyl-2-{[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4y 1] amino }acetam ide (Compound 33)

[0425] Scheme 35 depicts a synthetic route for preparing an exemplary compound.

320

POCI₃

100°C, 4 h %

DIÊA, MeOH 70“C,16 h 15 %

[0426] Step I

NaOMe(2.0 eq), MeOH °C, 24 h

S [0427] Into a 500-mL round-bottom flask, was placed a mixture of pyrimidine-2-carboximidamide hydrochloride (10.0 g, 63.0 mmol, 1.00 equiv), MeOH (200 mL), ethyl 2-oxocyclopentane-lcarboxylate (14.7 g, 94.5 mmol, 1.50 equiv), and NaOMe (6.81 g, 126 mmol, 2.00 equiv). The resulting solution was stirred for 16 hours at 60 °C. The resulting mixture was concentrated. The reaction was then quenched by the addition of 200 mL ofwater. The pH value ofthe solution was adjusted to 3 with 10 HCl (2 mol/L). The resulting solution was extracted with 3x150 mL of dichloromethane, the organic layers were separated and combined, dried over anhydrous sodium sulfate, and concentrated. This resulted in 1.1 g (8.14%) of 2-(pynmÎdin-2-yl)-3,5,6,7-tetrahydro-4H-cyclopenta[d]pyrimidin-4-one as an off-white oil. LCMS (ES) [M+l]+ m/z: 215. [0428] Step 2

32l

[0429] Into a 20-mL vîal was placed 2-(pyrimidin-2-yl)-3,5,6,7-tetrahydro-4Hcyclopenta[d]pyrîmidin-4-one (l.OO g, 4.66 mmol, l.OO equiv) and phosphorus oxychloride (10 mL). The resulting solution was stirred for 4 hours at 100 °C. The resulting mixture was concentrated. The reaction was then quenched by the addition of 50 mL of water. The pH value of the solution was adjusted to 9 with saturated sodium carbonate solution. The resulting solution was extracted with 3x50 mL of dichloromethane, the organic layer was separated and dried in an oven under reduced pressure. This resulted in 560 mg (51.56%) of 4-chloro-2-(pyrimidin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine as black oil. LCMS (ES) [M+l]+ m/z :233.

[0431] Into a 40-mL vial was placed 4-chloro-2-(pyrimidin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidine (500 mg, 2.14 mmol, 1.00 equiv), MeOH (10.0 mL), 2-amino-N-tertbutylacetamide (419 mg, 3.22 mmol, 1.50 equiv) and DIEA (416 mg, 3.22 mmol, 1.50 equiv). The resulting solution was stirred for 16 hours at 80 °C. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, SunFire Prep C18 OBD Column, 19x150mm, 5um; mobile phase, phase A: H2O (0.1% FA); phase B: CH3CN (5% CH3CN up to 35% CH3CN in 10 min). This resulted in 111 mg (15.82%) of N-(tert-butyl)-2-((2-(pyrimidin-2-yl)6,7-dihydro-5H-cyclopenta[d]Pyrimidîn-4-yl)amino)acetamide. 1HNMR (300 MHz, DMSO-d6, ppm): δ 8.91 (d, J = 4.9 Hz, 2H), 7.63 (s, 1 H), 7.56 (t, J = 4.9 Hz, IH), 7.08 (t, J = 5.8 Hz, 1 H), 3.97 (d, J = 5.8 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 2.76 (t, J = 7.4 Hz. 2H), 2.10-2.05 (m, 2H), 1.22 (s, 9H). LCMS (ES)

[M+l]+ m/z: 327.2.

322

Example 1.65

[0432] Synthesis of N-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin4-yl](methyl)amino}acetamide (Compound 34)

[0433] Scheme 36 depicts a synthetic route for preparing an exemplary compound.

Scheme 36

[0434] Step î

Me₃Sn

[0435] Into a lOO-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of argon, was placed 2-chloro-4-m ethoxy py ri dine (500 mg, 3.48 mmol, l .00 equiv), hexamethyldistannane (1.48 g, 4.527 mmol, 1.3 equiv), dioxane (20 mL), and Pd(PPhs)4 (804 mg, 0.69 mmol, 0.2 equiv). The resulting solution was stirred for 16 h at 110 ^ÜC in an oil bath. The solids were filtered out. The filtrate was concentrated to give 950 mg of 4-methoxy-2-(trimethylstannyl)pyridine. The crude product was 15 used for next step without further purification. LCMS (ES) [M+I ]⁺ m/z: 274.02.

[0436] Step 2

323

[0437] Into a 100-inL 3-necked round-bottom flask purged and maintained in an inert atmosphère of argon, was placed 4-methoxy-2-(trimethylstannyl)pyridine (947 mg, 3.48 mmol, l.OO equiv), N-tertbuty l-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Intermediate II, 5 310 mg, ].O4 mmol, 0.3 equiv), Pd(dppf)Ci₂ (254 mg, 0.35 mmol, O.l equiv) and dioxane (15 mL). The resulting solution was stirred for 16 hr at 100 C. The resulting mixture was concentrated under vacuum.

The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50 to 3:l). The crude product (160 mg) was purified by Flash-Prep-HPLC. This resulted in 50 mg (3.9%) of N-tertbuty l-2-[[2-(4-methoxypyridin-2 -y l)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide as a white solid. Ή NMR (300 MHz, DMSCM0 δ 8.49 (d, 7= 5.4 Hz, 1 H), 7.86 (d, 7= 2.4 Hz, 1 H), 7.69 (s, IH), 7.06 (dd, 7= 5.7, 2.4 Hz, IH), 4.14 (s, 2H), 3.92 (s, 3H), 3.27 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 1.99 (t, 7= 7.5 Hz, 2H), 1.23 (s, 9H). LCMS (ES) [M+l]⁺ m/z: 370.2.

Example 1.66

[0438] Synthesis ofN-tert-butyl-2-({2-[4-(methoxymethyl)pyridin-2-yl]-5H,6H,7H15 cyclopenta[d]pyrimidin-4-yl}(methyî)amino)acetamide (Compound 35)

[0439] Scheme 37 depicts a synthetic route for preparing an exemplary compound.

324

Scheme 37

[0440] Step 1

[0441 ] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed (2-chloropyridin-4-yl)methanol (5.00 g, 34.826 mmol, 1.00 equiv), THF (20 mL). The resulting solution was stirred for 40 min at 0 °C, andNaH (1.25 g, 52.088 mmol, 1.50 equiv) was added.

The resulting solution was allowed to stir for an additional 4 hr at room température. The reaction was quenched by the addition of water. The resulting mixture was extracted with ethyl acetate (3x30 mL), the organic layers were combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by silica gel column chromatography with ethyl acetate/petroleum ether (1:4). This resulted in 3.1 g (56.5%) of 2-chloro-4-(methoxymethyl)pyridine as a light yellow solid. LCMS (ES) [M+l]⁺ m/z: 158. [0442] Step 2

Sn_aMe₆, PdtdppfJClg, dioxane, 100°C

Me₃Sn

325

[0443] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 2-chloro-4-(methoxymethyl)pyridine (l.OO g, 6.345 mmol, I.OÛ equiv), hexamethytdistannane (2.49 g, 7.600 mmol, 1.20 equiv), Pd(dppf)Cl2 (0.93 g, 0.001 mmol, 0.2 equiv), and dioxane (20.00 mL). The resulting solution was stirred for 4 hr at 100 °C. The solution was cooled 5 and concentrated and the resulting 4-(methoxymethyl)-2-(trimethylstannyl)pyridine was used for next step directly. LCMS (ES) [M+l ] ⁺ m/z:288.

[0444] Step

[0445] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 4-(methoxymethy[)-2-(tnmethylstannyi)pyridine (In terni ediate Π, 500.00 mg, 1.748 mmol, 1.00 equiv), N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide (415.16 mg, 1.399 mmol, 0.8 equiv), Pd(dppf)C12 (255.87 mg, 0.350 mmol, 0.20 equiv), and dioxane (20.00 mL). The resulting solution was stirred for 16 seconds at 100 °C. The resulting solution was cooled and extracted with ethyl acetate (3x20 mL). The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2&SHIMADZU (HPLC-01)): Column, Welch Xtimate Cl 8, 21.2*250mm,5um; mobile phase, Water(0.Û5%TFA ) and MeOH:ACN=l:l (10%PhaseB up to 60% in 17 min. This resulted in 51.2 mg (7.6%) of N-(tert-butyl)-2-((2-(4- (methoxymethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)ammo)acetamide as a pink solid. Ή NMR (300 MHz, DMSO-î/₆) δ 8.83 (dd, J= 5.0, 0.8 Hz, IH), 8.46 - 8.39 (m, IH), 7.97 (s, IH), 7.73 (dd, J= 5.0, 1.7 Hz, lH),4.64(s, 2H), 4.41 (s, 2H), 3.49 (s, 3H), 3.42 (s, 3H), 3.323.18 (m, 2H), 3.07 (t, J=1S Hz, 2H), 2.11 Hz, 2H), 1.25 (s, 9H). LCMS (ES) [M+l] ⁺ m/z:

384.2.

Example 1.67

326

[0446] Synthesis of N-tert-buty l-2-{ethyl[2-(pyndin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide (Compound 36)

[0447] Scheme 38 depicts a synthetic route for preparing an exemplary compound.

K₂CO₃

78.0%

Scheme 38

[0448] Step I

I

K2CO3 78%

[0449] Into a 50-mL round-bottom flask, was placed a solution of N-(tert-butyl)-2-((2-chloro-6,710 dihydro-51-I-cyclopenta[d]pyrimidin-4-yl)amino)acetamide (500.00 mg, 1.768 mmol, 1.00 equiv) in

DMF (10 mL), ethyl iodide (303.36 mg, 1.945 mmol, 1.1 equiv) and K2CO3 (366.57 mg, 2.652 mmol, 1.5 equiv). The resulting solution was stirred for 3 hr at room température. The resulting solution was diluted with 50 mL of H2O and extracted with 2x50 mL of ethyl acetate. Organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 390 mg (78.00%) 15 ofN-(tert-buty 1)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamide as a light yellow solid. LCMS (ES) [M+1 ]⁺ m/z:311.

327

[045I] Into a 25-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed a solution of N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidîn-4yl)(ethyl)amino)acetamide (230.00 mg, 0.813 mmol, l.OO equiv) in Toi (8 mL), 2(tributylstannyl)pyridine (359.34 mg, 0.976 mmol, 1.2 equiv) and Pd(PPh3)4 (93.99 mg, 0.081 mmol, 0.1 equiv), The resulting solution was stirred for 12 hr at 100 °C in an oil bath. The resulting solution was diluted with 10 mL of H₂O and extracted with 2x15 mL of ethyl acetate. Organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). The collected crude product was further purified by Flash-PrepHPLC with the foîlowing conditions (IntelFlash-1): Column, C18 silica gel; mobile phase, CAN:H₂O=I :20 increasing to ACN:H₂O=1:4 within 15; Detector, 254 nm. product was obtaîned and concentrated. This resulted in 120 mg (41.74%) ofN-(tert-butyl)-2-((2-chloro-6,7-dîhydro-5Hcyclopenta[d]pyrimidin-4-yl)(ethyl)amino) acetamide as a solid. ’H NMR (300 MHz, DMSO-ùfc) 08.67 (dd, J= 4.8, 1.9 Hz, IH), 8.35 (d, J= 8.1 Hz, IH), 7.88 (td, J=7.7, 1.9 Hz, IH), 7.71 (s, IH), 7.44 (ddd, J= 7.5, 4.7, 1.2 Hz, IH), 4.10 (s, 2H), 3.66 (q, J= 7.1 Hz, 2H), 3.09 (t, J= 7.3 Hz, 2H), 2.83 (t, J= 7.8 Hz, 2H), 2.08-1.95 (m, 2H), 1.23 (s, 9H), 1.19 (t, J= 7.0 Hz, 3H). LCMS (ES) [M+l]⁺ m/z 354.2.

Example 1.68

[0452] Synthesis of N-tert-buty l-2-[(2-hydroxyethyl)[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetainide (Compound 37)

328

[0453] Scheme 39 depicts a synthetic route for preparing an exemplary compound.

O TH P

Pd(PPh3)_4ldixoane

100 °C

52.09%

K₂CO₃, DMF 100°C

57.8%

[0455] Into a 25-mL round-bottom flask purged and maîntained in an inert atmosphère of nitrogen, was placed N-(tert-butyl)-2-((2-chEoro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide.

The resulting solution was stirred for 12 hr at room température in an oil bath. The resulting solution was diluted with 25 mL of H2O. The resulting solution was extracted with 2x25 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroieum ether (1:3). The collected fractions were combined and concentrated. This resulted in 420 mg (57,8%) of N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)acetamide. LCMS (ES) [M+1]’ m/z:411.

[0456] Step 2

329

[0457] Into a 25-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen. was placed a solution of N-(tert-butyl)~2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(2((tetrahydro-2H-pyran-2-yl)oxy)ethyl)amino)acetamide (400 mg, 0.97 mmol, l.OO equiv) in dioxene (8 mL), 2-(tributylstannyl)pyridine (243 mg, 0.97 mmol, l equiv), and Pd(PPh3)4 (l 12 mg, 0.097 mmol, 0.1 equiv). The resulting solution was stirred for 12 hr at 100 °C in an oil bath. The resulting solution was diluted with 20 mL of H₂O and extracted with 3x20 mL of ethyl acetate. The organic layers were combined and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l :l). The collected fractions were combined and concentrated. This resulted in

230 mg (52.09%) of N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(ethyl)amino)acetamide as a solid, LCMS (ES) [M+l ]⁺ m/z:454.

[0458] Step 3

[0459] Into a 25-mL round-bottom flask, was placed a solution of N-(tert-butyl)-2-((2-chloro-6,715 dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(ethyl)amino)acetamide (150.00 mg, 0.331 mmol, 1.00 equiv) in MeOH (7 mL), pTSA (5.69 mg, 0.033 mmol, 0.1 equiv). The resulting solution was stirred for 12 hr at room température. The resulting mixture was concentrated. The crude product was purified by FlashPrep-HPLC with the foilowing conditions (IntelFlash-1): Column, silica gel; mobile phase, ACNTLO (0.01%TFA)=l:15 increasing to ACN:H₂O (0.01%TFA)=l :3 within 9 ; Detector, UV 254 nm. This

330 resulted in 80 mg (65.48%) of Nqtert-butylA-iAhydroxyethyOPHpyridin^-yO-ôjT-dmydro-SHcyclopentaldjpyrimidin^-yOaminojacetamide. LCMS (ES) [M+l]⁺ m/z: 370.2. ^fH NMR (300 MHz, DMSO-rf₆) δ 8.67 (d, J= 4.9 Hz, IH), 8.36 (d, J= 7.9 Hz, IH), 7.93-7.80 (m, 2H), 7.48-7.40 (m, IH), 5.15 (t, J=5.5 Hz, IH), 4.16 (s, 2H), 3.78-3.61 (m, 4H), 3.10 (t,J=7.3 Hz, 2H), 2.83 (t, J= 7.8 Hz, 2H), 2.06-1.96 (m, 2H), 1.22 (s, 9H).

Example 1.69

[0460] Synthesis of 2-{methyi[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N[(pyridin-2-yl)methyl]acetamide (Compound 38)

[0461] Scheme 40 depicts a synthetic route for preparing an exemplary compound.

Scheme 40

[0462] Into an 8-mL vial was placed [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetic acid (200 mg, 0.70 mmol, 1.0 equiv), DMF (3.0 mL), 2-pyridinemethaneamine (84 mg, 0.77 mmol, Ll equiv), and DIEA (455 mg, 3.52 mmol, 5.0 equiv). This was followed by the addition of HATU (401 mg, 1.06 mmol, 1.5 equiv) at 0 °C. The mixture was stirred for 1 h at room température, fïltered, and the fîltrate was purified by Prep-HPLC with conditions: Cl8-120 g column, CH3CN/H2O (0.05% NH4OH), from 5% to 80% with 15 min, flow rate, 70 mL/min, detector, 254 nm. This resulted in 62.8 mg (24%) of 2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amÎno]-N(pyridin-2-ylmethyl)acetamide formate as light brown solid. 1H-NMR (300 MHz, DMSO-d6, ppm):

331

δ8.72 (t, J = 6.0 Hz, IH), 8.64 (dd, J = 4.7, 1.8 Hz, IH), 8.43 (dd, J = 4.8, 1.9 Hz, IH), 8.28 (dt, J = 8.0, 1.1 Hz, I H), 8.16 (s, lH), 7.85 (td, J = 7.7, 1.8 Hz, IH), 7.44 (ddd, J = 7.5, 4.7, 1.2 Hz, 1 H), 7.35 (td, J = 7.7, 1.8 Hz, IH), 7.21-7.14 (m, 2H), 4.37 (d, >6.0 Hz, 2H), 4.34 (s, 2H), 3.34 (s, 3H), 3.20 (t, J = 7.2

Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 1.99 (p, J = 7.7 Hz, 2H). LCMS: (ES, m/z): [M+H]+: 375.2.

Example 1.70

[0463] Synthesis of N-tert-buty 1-2-( {2-[6-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidîn-4-yl}(methyl)amino)acetamide (Compound 39)

[0464] Scheme 41 depicts a synthetic route for preparing an exemplary compound.

Pd{PPh₃)_4r dioxane 100°C,16 h \ / —SnSn— / X

TH PO

Pd(dppf)CI_2r dioxane 100’C, 2 h

[0465] Step l

332

^Γ^'~ΟΤΗΡ

K₂CO₃, DMF, 75°C, 2 h

[0466] Into a 100-mL round-bottom flask, was placed 6-chloropyridin-2-ol (5.00 g, 38.59 mmol, l.OO equiv), DMF (50.0 mL), 2-(2-bromoethoxy)oxane (9.68 g, 46.31 mmol, 1.20 equiv), and K2CO3 (10.67 g, 77.19 mmol, 2.00 equiv). The mixture was stirred for 2 h at 70 °C. The reaction mixture was cooled and diluted with 200 mL of H2O, and extracted with 3x50 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure, The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/3) to give 9,0 g (90%) of 2-chloro-6-[2-(oxan-2-yloxy)ethoxy]pyridine as colorless oil. LCMS (ES) [M+l]⁺ m/z: 258.

[0467] Step

100°C,2 h

[0468] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-chloro-6-[2-(oxan-2-yloxy)ethoxy]pyridine (600 mg, 2.42 mmol, 1.00 equiv), dioxane (10.0 mL), hexamethyldistannane (872 mg, 2.66 mmol, 1.10 equiv) and Pd(dppf)C12 (177 mg, 0.24 mmol, 0.10 equiv). The mixture was stirred for 2 h at 100 °C. The reaction mixture was cooled and diluted with 20 mL of H₂O, and extracted with 3x10 mL of ethyl acetate. The organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This resulted in 500 mg of 2-[2-(oxan-2-yloxy)ethoxy]-6-(trimethylstannyl)pyridine as brown oil and the crude product was used to the next step directly without purification. LCMS (ES) [M+l]⁺ m/z: 388.

[0469] Step

[0470] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 2-[2-(oxan-2-yloxy)ethoxy]-6-(trimethylstannyl)pyridine (468 mg, l.2l mmol, l.20 equiv), dioxane (5.0 mL), N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino)acetamide (300 mg, LOI mmol, l .00 equiv), and Pd(PPh₃)4 (116 mg, 0.10 mmol, 0.10 equiv). The mixture was stirred for 16 h at 100 °C. The reaction mixture was cooled and diluted with 20 mL of EA, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (4/l). This resulted in 400 mg (82%) ofN-tertbutyl-2-[methyl(2-[6-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide as brown solid. LCMS (ES) [M+l]⁺ m/z: 484.

[0471] Step 4

[0472] Into a 100-mL round-bottom flask was placed N-tert-butyl-2-[methyl(2-[6-[2-(oxan-2yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yI)amino]acetamide (400 mg, 0.82

334 mmol, l.OO equiv), MeOH (5.0 mL), and TsOH (142 mg, 0.82 mmol, L00equiv). The resulting solution was stirred for l h at room température. The resulting mixture was concentrated and diluted with 5 mL of HzO. The pH value of the solution was adjusted to 8 with ΝΗ3Ή2Ο (30%). The mixture was extracted with 3x5 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, 5 filtered, and the filtrate was concentrated. The residue was purified by Prep-HPLC with the following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um, Mobile phase, Water (0.05%NH40H) and CHsCN (10% Phase B up to 65% in 15 min), Detector, UV 254 nm. This resulted in 121.1 mg (36.6%) ofN-tert-buty!-2-([2-[6-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)acetamide as white solid. Ή NMR (300 MHz, DMSOéa) δ 7.96 (d, 7= 7.2 Hz, IH), 10 7.79 (t, 7= 7.8 Hz, IH), 7.63 (s, IH), 6.89 (d, 7= 8.1 Hz, 1 H), 5.18 (br, IH), 4.43-4.39 (m, 2H), 4.16 (s,

2H), 3.79-3.75 (m, 2H), 3.27 (s, 3H), 3.13 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.04-1.96 (m,

2H), 1.23 (s, 9H). LCMS (ES) [M+l]⁺ m/z: 400.2.

Example 1.71

[0473] Synthesis of N-tert-butyl-2-({2-[5-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H15 cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 40)

[0474] Scheme 42 depicts a synthetic route for preparing an exemplary compound.

335

pTSA, MeOH

36.32%

Scheme 42

[0475] Step l

N^^Br ^THP0^''^Br qVVr

K₂CO₃, DMF ΤΗΡΟ^^θ

92.13%

[0476] Into a 250-mL round-bottom flask was placed 6-bromopyndin-3-ol (2.00 g, 11.49 mmol, .00 equiv), DMF (30.00 mL), 2-(2-bromoethoxy)oxane (2.88 g, 13.79 mmol, 1.20 equiv), and K2CO3 (3.18 g, 22.99 mmol, 2.00 equiv). The resulting solution was stirred for 2 h at 70 ^ÜC. The reaction mixture was cooled to room température. The reaction was then quenched by the addition of 50 mL of water. The resulting mixture was extracted with 3x50 mL of ethyl acetate, the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (15%). This resulted in 3.2 g (92.13%) of 2-bromo-5-[2(oxan-2-yloxy)ethoxy]pyridine as ayellow oil. LCMS (ES) [M+HJ-I- m/z: 302.

[0477] Step 2

[0478] Into a 100-mL round-bottom flask, was placed 2-bromo-5-[2-(oxan-2-yloxy)ethoxy]pyridine (l.OO g, 3.31 mmol, l.OO equiv), hexamethyldistannane (1.30 g, 3.97 mmol, 1.20 equiv), Pd(PPh3)4 (0.38 g, 0.33 mmol, 0.1 equiv), and dioxane (10,00 mL). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled to room température and was added N-tert-butyl-2-([2-chloro-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Intermediate II, 0.49 g, 1.65 mmol, 0.50 equiv) and Pd(dppf)Cl2 (0.24 g, 0.33 mmol, 0.10 equiv). The resulting solution was stirred for 5 h at 100 °C. The reaction mixture was cooled to room température. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm,

150mm, 5um; mobile phase, Water (0.1%NH4HCO3) and CAN (30% Phase B up to 60% in 11 min);

Detector, 254 nm. This resulted in 150 mg (9.37%) ofN-tert-butyl-2-[methyl(2-[5-[2-(oxan-2y]oxy)ethoxy]pyridm-2-yl]-5H,6H,7H-cyc]openta[d]pyrimidin-4-yl)amino]acetamide as yellow solid. LCMS (ES) [M+H]+ m/z: 484.

[0479] Step 3

CK, N H OyNH ^N |jV 36.32% ^N II η

N ^N ^ü

[0480] Into an 8-mL vial was placed N-tert-buty 1-2-[methy 1(2-[5-[2-(oxan-2-yloxy)ethoxy]pyridin2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (150.00 mg, 0.31 mmol, 1.00 equiv), MeOH (5.00 mL) and PTSA (10.68 mg, 0.06 mmol, 0.20 equiv). The resulting solution was stirred for I

337 h at room température. The crude product (150 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl 8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 45.0 mg (36.32%) ofN-tert-butyl-2-([2-[5-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](meÎhyl)amino)acetamide as a white solid. 1 H-NMR (300 MHz, DMSO-d6) S 8.38-8.27 (m, 2H), 7.68 (s, 1 H), 7.43 (dd, J = 8.8, 3.0 Hz, 1 H), 4.94 (t, J = 5.5 Hz, 1 H), 4.18-4.09 (m, 4H), 3.78-3.73 (m, 2H), 3.25 (s, 3H), 3.12 (t, J = 7.3 Hz, 2H), 2.79 (t, J = 7.8 Hz, 2H), 2.10-1.89 (m, 2H), 1.24 (s, 9H). LCMS: (ES, m/z): [M+H] +; 400.3.

Example 1.72 [0481] Synthesis ofN-tert-butyl-2-({2-[4-(hydroxymethyl)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidÎn-4-yl}(methyl)amino)acetamide (Compound 41 )

Scheme 43

[0483] Into a 50-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed N-(tert-buty 1)-2-( (2-(4-(methoxymethyl)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amîno)acetamide (100 mg, 0.261 mmol, 1.00 equiv), BBrs (0.78 mL, 0.780 mmol, 2.99 equiv), and DCM (10.00 mL). The resulting solution was stirred for 4 hr at -78 °C. The reaction was quenched by the addition of water. The resulting solution was extracted with dichloromethane (3x20 mL), the organic layers were combined, dried over anhydrous sodium sulfate,

338 and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#SHlMADZU (HPLC-01)): Column, Welch XB-CI8, 21.2*250mm,5um; mobile phase, Water (O.OSHNHsI-LO) and AcCN (5% Phase B up to 50% in 16 min). This resulted in 30.2 mg (31.4%) of N-(tert-butyl)-2-((2-(4-(hydroxymethyl)pyridin-2-yl)-6,7“dihydro-5H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino)acetamide as a white solid. ^rH NMR. (300 MHz, DMSO<L) δ 8.60 (d, J = 4.9 Hz,

IH), 8.26 (s, IH), 7.68 (s, IH), 139 (d, J= 5.0 Hz, III), 5.48 (br, IH), 4.62 (s, 2H), 4.16 (s, 2H), 3.32 (s, 3H), 3.14 (t, J = 13 Hz, 2H), 2.82 (t, J- 7.8 Hz, 2H), 1.99 (p, J- 7.5 Hz, 2H), 1.24 (s, 9H). LCMS (ES) [M+l] ⁺ m/z: 370.2.

Example 1.73

[0484] Synthesis of N-tert-butyl-2-{methyl[2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydroquinazolin4-yi]amino}acetamide (Compound 42)

Scheme 44

[0486] Step l

339

[0487] Into a 40-mL vial, was placed 2,4-dichloro-5,6,7,8-tetrahydroquinazoline (500.00 mg, 2.46 mmol, l .00 equiv), CH3CN (8.00 mL), DIEA (636.45 mg, 4.92 mmol, 2.00 equiv), and N-tert-butyl-2(methylamino)acetamide (390.60 mg, 2.71 mmol, l. I0 equiv). The resulting solution was stirred for 3 h at 80°C. The reaction mixture was cooled to room température. The crude product (l g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl8 OBD Column, I9cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (30% Phase B up to 60% in 11 min); Detector, 254. This resulted in 410 mg (53.57%) ofN-tert-butyl-2-[(2-chloro-5,6,7,8-tetrahydroquinazolin-4yl)(methyl)amino]acetamide as a white solid. LCMS (ES) [M+H]⁺ m/z:3l l.

[0488] Step

[0489] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed Ntert-butyl-2-[(2-chloro-5,6,7,8-letrahydroquinazolin-4-yl)(methyl)amino]acetamide (350.00 mg, 1.12 mmol, l .00 equiv), 4-methyl-2-(tributylstannyl)pyridine (559.44 mg, 1.46 mmol, 1.30 equiv), and dioxane (8.00 mL), Pd(dppf)Cb (82.39 mg, 0.11 mmol, 0.10 equiv). The resulting solution was stirred for overnight at 110 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (500 mg) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl 8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1%

NH4HCO3) and CAN (30% Phase B up to 60% in 11 min); Detector, 254. This resulted in 86.4 mg (20.88%) ofN-tert-butyl-2-[methyl[2-(4-methylpyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-

340

yi]amino]acetamide as an off-white solid. Ή-NMR (300 MHz, DMSO-76) δ 8.51 (d, J= 4.9 Hz, IH), 8.15 (d, J= 1.6 Hz, IH), 7.77 (s, IH), 7.31 -7.23 (m, IH), 3.99 (s, 2H), 3.15 (s, 3H), 2.78 (t, 7=6.4 Hz, 2H), 2.69 (t, 7= 6.0 Hz, 2H), 2.40 (s, 3H), 1.82 (s, 2H), 1.68 (d, 7= 6.9 Hz, 2H), 1.22 (s, 9H). LCMS (ES, m/z): [M+H] L 368.2.

Example 1.74

[0490] Synthesis of N-tert-butyl-2-({2-[5-(2-hydroxyethyl)pyridin-2-y 1]-5H,6EI,7H cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 43)

[0491 ] Scheme 45 depicts a synthetic route for preparing an exemplary compound.

Scheme 45

[0492] Step l

B_?H_fil THF 0oC~rt, 12 h

341

[0493J Into a 250-mL 3-necked round-bottom flask, was placed (6-chloropyridin-3-yl)aceticacid (5.0 g, 29.14 mmol, 1.0 equiv), THF (50.0 mL). This was followed by the addition of BzHé (I M in THF) (88.0 mL, 3.0 eq) at 0°C. After addition, the mixture was stirred for 12 h at room température. The reaction was then quenched by the addition of MeOH (30 mL), diluted with of HiO (100 mL), and extracted with 3x100 mL of dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This resulted in 3.09 g (67%) of 2-(6-chloropyridin-3-yl)ethanol as yellow oil. LCMS (ES) [M+l]⁺ m/z: 158.

[0494] Step .N. Al Al il Ί PHP. TsOH f| A

[0495] Into a 100-mL round-bottom flask, was placed 2-(6-chloropyridin-3-yl)ethanol (3.09 g, 19.61 mmol, 1.0 equiv), DCM(30.0 mL), DHP (3.30 g, 39.23 mmol, 2.0 equiv), and TsOH (340 mg, 1.97 mmol, 0.10 equiv). The reaction solution was stirred for 2 h at room température. The mixture was diluted with of saturated NazCOs (20.0 mL), and extracted with 3x50 mL of dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (7%). This resulted in 3.0 g (63%) of 2-chloro-5-(2-((tetrahydro-2H-pyran-2yl)oxy)ethyl)pyridine as a yellow oil. LCMS (ES) [M+l]⁺ m/z: 242, [0496] Step

100°C, 3 h

[0497] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 2-chloro-5-[2-(oxan-2-yloxy)ethyl]pyridine (1.17 g, 4.84 mmol, 1.0 equiv), dioxane (30.0 mL), hexamethyldistannane (1.60 g, 4.88 mmol, LO equiv), and Pd(PPhj)4 (L44 g, 1.25 mmol, 0.26 equiv). The mixture was stirred for 2 h at 100°C. The reaction was cooled to room température, filtered, and the filtrate was concentrated under reduced pressure. The crude product was used to the next step directly without further purification. LCMS (ES) [M+l]⁺ m/z: 372.

[0499] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 5-[2-(oxan-2-yloxy)ethyl]-2-(trimethylstannyl)pyridine (1.50 g, 4.05 mmol, l.O equiv), 5 dioxane (20.0 mL), N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyi)amino)acetamide (Intermédiare II, 700 mg, 2.36 mmol, 0.58 equiv), and Pd(PPh₃)₄ (932.00 mg, 0.81 mmol, 0.20 equiv). The mixture was stirred for 12 h at l00°C. The mixture was concentrated to remove the solvent, and the residue was purified by silica gel column with THF/petroleum ether (70%).

This resulted in 184 mg (9.7%) ofN-(tert-butyl)-2-(methyl(2-(5-(2-((tetrahydro-2H-pyran-2 yi)oxy)ethyl)pyridin-2-yI)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide as yellow oil.

LCMS (ES) [M+l]⁺ m/z: 468.

[0500] Step 5

[0501] Into a 20-mL vial, was placed N-tert-butyl-2-[methyl(2-[5-[2-(oxan-2-yloxy)ethyl]pyridin-215 yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (184 mg, 0.39 mmol, 1.0 equiv), methanol (5.0 mL), and TsOH (68 mg, 0.40 mmol, 1.0 equiv). The mixture was stirred for 1 h at room température. The crude product was purified by Prep-HPLC with the foilowing conditions: Column,

343

Atlantis HILIC OBD Column, 19*150 mm*5 uni, mobile phase, Water (10 mmol/L NH4HCO3) and MeOH:CH3CN=l :1 (33% Phase B up to 45% within 9 min); Detector, UV 254 nm. This resulted in 89.2 mg (59%) of N-(tert-buty!)-2-((2-(5-(2-hydroxyethyl)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as an off-white solid. ’H-NMR (300 MHz,

8.51 (d, J= 1.8 Hz, 1 H), 8.25 (d, J= 8.1 Hz, 1 H), 7.72 (dd, J = 8.1, 2.1 Hz, IH),

7.68 (s, IH), 4.72 (t, J= 5.1 Hz, 1 H), 4.13 (s, 2H), 3.70-3.63 (m, 2H), 3.26 (s, 3H), 3.14 (t, J=7.2Hz, 2H), 2.84-2.78 (m, 4H), 2.04-1.96 (m, 2H), 1.25 (s, 9H). LCMS: (ES, m/z): [M+H]⁺: 384.2.

Example 1.75

[0502] Synthesis of N-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H10 cyclopenta[d]pyrimidin-4-yl[(methyl)amino)acetamide (Compound 44)

[0503] Scheme 46a depicts a synthetic route for preparing an exemplary compound.

OH _{B r}^OT H P

K₂CO₃₁ DMF 80 °C, 16 h

Cl

I I —Sn-Sn—

I I

Pd(PPh₃)₄, dioxane 100°C, 16 h

100 °C, 16 h

Pd(PPh₃)₄, dioxane

TsOH, MeOH rt, 2 h

Scheme 46a

[0504] Step 1

344

OH

K₂CO₃, DMF 80 °C,16 h

Cl

[0505] Into a 50-mL round-bottom flask was placed a mixture of 2-chloropyridin-4-ol (2.00 g, 15.439 mmol, 1.00 equiv), DMF (20 ml), K₂CO₃ (4.27 g, 30.878 mmol, 2.00 equiv), and 2-(2bromoethoxy)oxane (4.84 g, 23.159 mmol, 1.50 equiv). The resulting solution was stirred for 16 hours at

70°C. The resulting solution was diluted with 100 mL of H₂O. The resulting solution was extracted with

3x100 mL of ethyl acetate. The organic layers were combined, washed with 100 ml of brine, dried over anhydrous sodium sulfate, and concentrated. This resulted in 2.15 g (54.04%) of 2-chloro-4-[2-(oxan-2yloxy)ethoxy]pyridine as a light yellow oil. LCMS (ES) [M+l]⁺ m/z:258. [0506] Step 2

Cl I I SnMe₃

I —Sn—Sn— n'A _____I I____ _r n'A

JA /\^OTHP Pd(PPh₃)₄, dioxane Vjx x-\^OTHP ₀ ⁰ 100 °C, 16 h ⁰

[0507] Into a 40-mL vial, was placed a mixture of 2-chloro-4-[2-(oxan-2-yloxy)ethoxy]pyridine (1.00 g, 3.88 mmol, 1.00 equiv), dioxane (10.0 mL), hexamethyldistannane (1.91 g, 5.82 mmol, 1.50 equiv), and Pd(PPhs)4 (896 mg, 0.776 mmol, 0.20 equiv). The resulting solution was stirred for 2 hours at 100°C. The resulting mixture was concentrated. This resulted product was used directly in the next step. LCMS (ES) [M+l]⁺ m/z: 388.

[0508]

Step 3

100 °C, 16 h

OTHP

[0509] Into a 40-mL vial, was placed a mixture of 4-[2-(oxan-2-yloxy)ethoxy]-2(trimethylstannyl)pyridine (800 mg, 2.07 mmol, I.00 equiv), dioxane (10.00 mL), N-(tert-buty 1)-2-((221052

345 chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methy!)amino)acetamide (Intermediate 11, 430 mg, 1.45 mmol, 0.70 equiv), and Pd(PPh₃)4(478 mg, 0.414 mmol, 0.20 equiv). The resulting solution was stirred for 16 hours at 100°C. The crude reaction mixture was fïltered and subjected to reverse phase préparative MPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 10 % MeCN in water to 48% MeCN in water over a 15 min period, where both solvents contain 0.1% NH4HCO₃). The resulting mixture was concentrated. This resulted in 280 mg (27.94%) of N-(tert-butyl)2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)amino)acetamide as a off-white solid. LCMS (ES) [M+l ]⁺ m/z: 484. [0510] Step 4

[0511] Into a 40-mL via! was placed a mixture of N-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2Hpyran-2-yl)oxy)ethoxy)pyridin-2-yI)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide (250 mg, 0.517 mmol, 1.00 equiv), MeOH (10.0 mL) and TsOH (89 mg, 0.52 mmol, 1.0 equiv). The resulting solution was stirred for 2 hours at room température. The resulting mixture was concentrated. The crude product was purified by Prep-HPLC with the foîlowing conditions: Column, Xbridge Prep Cl 8 OBD Column, 19x150mm, 5um; mobile phase, phase A: H?O (0.05 % NH3H2O); phase B: CH3CN (20%CH₃CN up to 70% CH₃CN in 13 min). This resulted in 72.6 mg (35.15%) ofN(tert-butyl)-2-((2-(4-(2-hydroxyethoxy)pyrÎdin-2-yl)-6,7-dihydro-5H-cyciopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a white solid. ¹H NMR (300 MHz, DMSO-îA ppm); δ 8.47 (d, J= 5.6 Hz, JH), 7.85 (d,J=2.5Hz, lH),7.68(s, 1 H), 7.04 (dd, J= 5.7, 2.6 Hz, IH), 4.92 (t, J= 5.4 Hz, IH), 4.19-4.10 (m, 4H), 3.76 (q, J= 5.1 Hz, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J= 7.8 Hz, 2H), 2.01-1.96 (m, 2H), 1.24 (s, 9H). LCMS (ES) [M+l]⁺m/z: 400.2.

[0512] Scheme 46b depicts a synthetic route for preparing an exemplary compound.

346

Boc A

HATU, DIEA

DMF

80%

(4N) HCI/Dioxane

86%

Bu₃Sn

Pd(Ph₃)₄, Toi

58%

NaH, DMF

41%

Scheme 46b

[0513] Step 1

HATU, DIEA

DMF

80%

[0514] Into a 50-mL 3-necked round-bottom flask was placed N-(tert-butoxycarbonyl)-Nmethylglycine (20.0 g, 0.105 mol, 1.00 equiv), DMF (200.00 mL), 2-methylpropan-2-amine (8.43 g, 0.115 mol, 1.10 equiv) and DIEA (27.21 g, 0.211 mmol, 2.00 equiv). This was followed by the addition of HATU (44.08 g, 0.115 mol, 1.10 equiv) in several batches at 0 °C. After addition, the resulting solution was stirred for 16 h at room température. The reaction was quenched with 200 mL of water, 10 extracted with 3x100 mL of ethyl acetate. The combined organic phase was washed with 2 x200 mL of water and Ix 200 mL brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column with ethyl acetate/petroleum ether (1:1) to give 20.6 g (80%) of tert-butyl (2-(tert-butylamino)-2oxoethyl)(methyl)carbamate as an off white solid. LCMS (ES) [M+1]⁺ m/z: 245.

[0515] Step 2

H ^x (4N) HCI/Dioxane

86%

HCl

H \

[0516] Into a 500-mL 3-round-bottom flask was placed tert-butyl (2-(tert-butylamino)-2oxoethyl)(methyl)carbamate (25 g, 102.4 mmol, 1.00 equiv) and DCM (100.00 mL). This was followed

347

by the addition of HCl (g) (4 M in dioxane) (200.00 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 16 h at room température, concentrated in vacuum to remove the solvent and washed with ethyl acetate(l50 mL). This resulted in 16 g (86%) of N-(tert-buty l)-2(methylamino)acetamide hydrochloride. LCMS (ES) [M-HCI+1]⁺ m/z: 145.

[0517] Step 3

[0518] Into a 500-mL 3 neck round-bottom flask was placed N-(tert-butyI)-2(methylamino)acetamide hydrochloride (16 g, 88.9 mmol, 1.00 equiv), NMP (200.00 mL), 2,4-dichloro6,7-dihydro-5H-cyclopenta[d]pyrimidine (16.8 g, 88.9 mmol, 1.00 equiv) and DIEA (40.6 g, 0.315 mol, 10 3.00 equiv). The resulting solution was stirred for 6 h at 50 °C in oil bath. The reaction mixture was cooled to room température, diluted with 200 mL of water and extracted with 3x200 mL of ethyl acetate.

The combined organic phase was washed with 3 x300 mL of water and brine 1 x200 mL, dried over anhydrous sodium sulfate and fîltered. The filtrate was concentrated under reduced pressure, the residue was triturated with ethyl acetate and fîltered. This resulted in 18.4 g (70%) ofN-(tert-butyl)-2-((215 chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z: 297.

[0519] Step 4

Pd(Ph₃)₄, Toi

58%

[0520] 4-fluoro-2-(tributylstannyl)pyridine was synthesized as following: To a solution of 2-bromo20 4-fluoropyridine (25 g, 142 mmol, 1.00 eq.) in Toluene (300 mL) was added butyllithium (62.5 mL, 2.50 mol/L, 156 mmol, 1.10 eq.) at -78 °C, after stirred for 1 h, the mixture was added tributyl(chloro)stannane (50.7 g, 156 mmol, 1.10 eq.) and was further stirred for 30 min at -78 °C and 3

348

h. at room température The mixture was quenched with ice water, extracted with hexane, organic layers were combined and washed with Sat. NaHCCh, brine, dried and fîltered. The filtrate was concentrated to give crude product (51 g) as clear yellow oil, which was used without purification. LCMS (ES) [Μ-Η]⁺m/z: 388.

[0521] Into a 250-mL three necked round bottom flask purged and maintained with an inert atmosphère of nitrogen was placed N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)(methyl)amino)acetamide (10 g, 33.8 mmol, l .00 equiv), toluene (l 50.00 mL), 4-fluoro-2(tributylstannyl)pyridine (21.7 g, 60.84 mmol, 1.8 equiv) and Pd(PPh₃)4 (3.57 g, 3.38 mmol, 0.10 equiv). The mixture was stirred for 60 h at H0 °C in oil bath. The reaction mixture was cooled to room température, concentrated to remove the solvent; the residue was purified by silica gel column with dichloromethane/methanol (10:1). This resulted in 7 g (58%) of N-(tert-butyl)-2-((2-(4-fluoropyridin-2yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as yellow solid. LCMS (ES) [M+l]⁺ m/z: 358.

[0522] Step 5

[0523] Into a 250mL 3-neck flask was placed ethane-l,2-diol (9.55g, 154 mmol, 10.0 equiv) and DMF (100 mL), NaH (60% in minerai oil) (6.16 g, 154 mmol, 10.0 equiv) was added in portion wise at 0-5 °C. The mixture was stirred for 1 h at room température and N-(tert-butyl)-2-((2-(4-fluoropyridin-2yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (5.5 g, 15.4 mmol, 1.00 equiv) was added at 0-5 °C. The reaction mixture was stirred for 5 h at 50 °C. (The reaction was repeated in 2 batches). The reaction mixture was cooled to room température, diluted with 200 mL of water, extracted with 3x200 mL of ethyl acetate. The combined organic phase was washed with 3 x300 mi of water and brine 1 x200 mL, dried over anhydrous sodium sulfate. The residue was purified by Prep-HPLC with conditions: column, Cl8-800 g, Mobile phase, CH₃CN/H₂O (0.05% FA), from 10% increased to 70% within 27 min, Flow rate, 180 mL/min, Detector, 254 nm. The pH value of the fraction was adjusted to 7-8 with K.₂CO₃ solid, extracted with dichloromethane (3x300 mL). The combined

349 organic phase was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure and the residue was freezing dried, this resulted in 5.03 g (41%) of N-(tert-buty 1)-2-((2(4-(2-hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a white solid. LCMS: (ES, m/z): [M+H]⁺: 400. ’H-NMR: (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J=5.6 Hz, IH), 7.86 (d,.7=2.5 Hz, IH), 7.68 (s, IH), 7.04 (dd,./= 5.6, 2.6 Hz, 1 H), 4.92 (t, J= 5.4 Hz, IH), 4.19-4.10 (m, 4H), 3.77 (q, J= 5.1 Hz, 2H), 3.26 (s, 3H), 3.13 (t, J= 7.3 Hz, 2H), 2.81 (t, J= 7.9 Hz, 2H), 2.01-1.96 (m, 2H), 1.24 (s, 9H).

[0524] Synthesis of Compound 44—Route 2.

Scheme 4-1

[0525] Into a 250-mL round-bottom flask were placed N-tert-butyl-2-[[2-(4-chloropyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methy[)amino]acetamide (7.40 g, 19,79 mmol, 1.00 equiv), 2(oxan-2-yloxy)ethanol (4.34 g, 29.69 mmol, 1.50 equiv), DMF (150.00 mL) and t-BuOK (6.66 g, 59.37 mmol, 3.00 equiv). The resulting solution was stirred for ovemight at 25 °C. The reaction was then quenched by the addition of water/ice. The resulting solution was extracted with 3x200 mL of ethyl acetate and the organic layers combined, dried over anhydrous sodium sulfate and concentrated. The crude product (8 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1%NH3H₂O) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. This resulted in 6 g (62.69%) ofN-tert-butyI-2-[methyl(2-[4-[2(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrÎmidin-4-yl)amino]acetamide as yellow solid. LCMS (ES) [M+l]⁺m/z: 484.

[0526] Into a 40-mL vial were placed N-tert-buty l-2-[methyl(2-[4-[2-(oxan-2-y loxy)ethoxy]pyridin2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (1.00 g, 2.07 mmol, 1.00 equiv), MeOH (10.00 mL) and HC1(6M) (1.00 mL). The resulting solution was stirred for 1 h at room température. The crude product (I g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1%NH₃ H₂O) and ACN (15% Phase B up to 60% in 11 min); Detector, 254 nm. This resulted in 613.5 mg (74.27%) of N-tert-buty l-2-([2-[4(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide as

350 white solid. LCMS (ES, m/z)\ [M+H]⁺: 400. H-NMR (300 MHz, DMSO-A/wO: δ 8.47 (d, J = 5.6 Hz, IH), 7.85 (d, J = 2.5 Hz, IH), 7.68 (s, IH), 7.04 (dd, J = 5.7, 2.6 Hz, IH), 4.92 (t, J = 5.4 Hz, IH), 4.2l4.07 (m, 4H), 3.76 (q, J = 5.1 Hz, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.01-1.96 (m, 2H), l .24 (s, 9H).

Example l .76

[0527] Synthesis of 4-[2-(pyridin-2-yl)-5l·L6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4-diazepan-2one (Compound 47)

[0528] Compound 47 was synthesized similar to compound 92 by replacing azapane with 1,4diazepan-2-one. LCMS (ES+): (M+H)⁺ = 310.0. Ή NMR (400 MHz, DMSO-rf6) δ 8.82 - 8.76 (m, 1 H), 8.52 (d, J= 7.9 Hz, IH), 8.12-8.05 (m, IH), 7.70-7.61 (m, 2H), 6.52 (s, 1 H), 4.48 (s, 2H), 4.16-4.06 (m, 2H), 3.27 - 3.22 (m, 4H), 2.99 (t, J= 7.9 Hz, 2H), 2.14- 2.03 (m, 2H), 1.92 - 1.83 (m, 2H).

Example 1.77

[0529] Synthesis of l-[2-(pyndin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]-l,4-diazepan-5-one (Compound 50)

[0530] Compound 50 was synthesized similar to compound 92 by replacing azapane with 1,4-diazepan5-one. LCMS (ES+): (M+H)⁺ = 309.9. ’H NMR (400 MHz, DMSO-c/6) δ 8.76 - 8.69 (m, IH), 8.34 (d, J = 7.9 Hz, 1H), 8.01 - 7.92 (m, IH), 7.73 - 7.64 (m, IH), 7.57 - 7.48 (m, IH), 3.98 - 3.92 (m, 4H), 3.29

- 3.26 (m, 2H), 3.10 - 3.03 (m, 2H), 2.93 - 2.87 (m, 2H), 2.65 - 2.60 (m, 2H), 2.09 - 2.00 (m, 2H).

Example 1.78

[0531] Synthesis of (2R)-N-tert-butyl-2-{methy![2-(pyridin-2-yl)-5H,6H,7H21052

351

cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 51)

[0532] Scheme 47 depicts a synthetic route for preparing an exemplary compound.

[0534] 2,4-dichloro-6,7-dîhydro-5H-cyclopenta[d]pyrimÎdine (130.00 mg; 0.69 mmol; 1.00 eq.) was dissolved in acetonitrile (2.5 ml), and to the solution was added methyl (2R)-210 (methylamino)propanoate hydrochloride (126.76 mg; 0.83 mmol; 1.20 eq.) and Hunig's base (0.48 mL; 2.75 mmol; 4.00 eq.). After being stirred at ~55°C for 15 h, the mixture was evaporated and the residue was subjected to column chromatography to give methyl (2R)-2-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidîn-4-yl}(methyl)atnino)propanoate (54 mg, 31%) as a film. LCMS (ES+); (M+H)⁺

352

= 270.2.

[0535] Step 2

[0536] Methyl (2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)propanoate (54 mg; 0.20 mmol; l eq.) was dissolved in THF (2 ml) and methanol (0.5 ml). Lithium hydroxide (anhydrous, 19 mg; 0.8 mmol; 4 eq.) dissolved in -0.8 ml of water was added dropwise and the reaction was stirred at 25 °C for L5 h. 6 M HCl was added carefully to acidify the reaction to pH <3. The solvents were evaporated and the residue was dried on high vacuum. The residue of (2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanoic acid (51 mg;

0.2 mmol; 1 eq.) was dissolved in Ν,Ν-dimethylfonnamide (2 ml). N, N-diisopropylethy lamine (0.12 mL; 0.7 mmol; 3.5 eq.) was added and the reaction was stirred in an ice bath. Tert-butylamine (32 pL; 0.3 mmol; 1.5 eq.) and l-[bis(dimethy)amÎno)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, ( 152 mg; 0.4 mmol; 2 eq.) were added. After 4 h, ethyl acetate (50 ml), water (10 ml), and sodium bicarbonate solution (10 ml) were added. The phases were separated, and the aqueous phase was extracted with ethyl acetate (50 ml). The organic phases were washed with water (10 ml) and sodium chloride solution (20 ml), and dried over sodium sulfate. After évaporation, the product was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give (2R)-N-tert-butyl-2({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propenamide (12.5 mg, 20%). MS (ES+): (M+H)⁺ = 310.9.

[0537] Step 3

[0538] (2R)-N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidÎn-4

353 yl}(methyl)amino)propanamide (30.00 mg; 0.10 mmol; l.OO eq.) was dissolved in l,4-dioxane (l ml) and the solution was purged with Ar gas. 2-(tributylstannyl)pyridine (0.06 mL; 0.19 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium ( 11.15 mg; 0.01 mmol; 0.10 eq.) were added The reaction vessel was sealed and stirred in a heat bath at 110°C for 15 h. After évaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-70% acetonitrile/0.1 % aqueous formic acid gradient) to give (2R)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrîmidin-4-yl]amino}propanamide (11 mg, 32%) as an off-white solid. LCMS (ES+): (M+H)⁺ = 354.4. ’HNMR (400 MHz, Methanol-74) δ 8.72 (ddd, J= 4.9, 1.8, 0.9 Hz, IH), 8.46-8.41 (m, IH), 8.02 -7.95 (m, IH), 7.68 (s, IH), 7.57-7.50 (m, IH), 5.26 (q, 7=7.1 Hz, IH), 3.38-3.33 (m, I H), 3.28 — 3.18 (m, I H), 3.08 - 2.91 (m, 2H), 2.24 - 2.06 (m, 2H), 1.48 (d, 7= 7.1 Hz, 3H), 1.25 (s, 9H).

Example 1.79 [0539] Synthesis of (2S)-N-tert-buty 1-2-{methy l[2-(pyridin-2-y l)-5 H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 52)

[0540] Compound 52 was synthesized similar to compound 51 by replacing (2R)-2(methylamino)propanoate with (2S)-2-(methylamino)propanoate. LCMS (ES+): (M+H)⁺ = 354.4. *H NMR (400 MHz, Methanol-74) δ 8.72 (ddd, 7 = 4.8, 1.8, 0.9 Hz, IH), 8.46 - 8.40 (m, IH), 8.02 - 7.95 (m, IH), 7.68 (s, IH), 7.54 (ddd, 7= 7.6, 4.8, 1.2 Hz, IH), 5.26 (q, J= 7.1 Hz, IH), 3.38 - 3.32 (m, IH), 3.28-3.18 (m, IH), 3.09 - 2.91 (m, 2H), 2.23 - 2.04 (m, 2H), 1.48 (d, 7= 7.2 Hz, 3H), 1.25 (s, 9H).

Example 1.80

[0541 ] Synthesis of l-[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 53)

354

[0542] Compound 53 was synthesized similar to Compound 92 by replacing (2-tributylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine. ’H NMR (400 MHz, Methanol-Æ) δ 8.48 (d, J= 5.8 Hz, IH), 7.86 (d, J= 2.6 Hz, IH), 7.06 (dd, J = 5.8, 2.6 Hz, IH), 3.94 (s, 3H), 3.86 (t, J= 6.1 Hz, 4H), 3.15 5 (t, J=13 Hz, 2H), 2.92 (t, J= 7.9 Hz, 2H), 2.16 - 2.04 (m, 2H), 1.83 (q, J =5.5 Hz, 4H), l.59(p,J =

2.7 Hz, 4H). LCMS (ES+): (M+H)⁺ = 325. L

Example LSI

[0543] Synthesis of (3R)-6,6-dimethyl-3-{ [2-(pyridin-2-yl)-5H,6H,7l·I-cyclopenta[d]pyrinlidin-4yl]amino}piperidin-2-one (Compound 55)

[0544] Scheme 48 depicts a synthetic route for preparing an exemplary compound.

355

Scheme 48

[0545] Step l

Zn, CuBrDMS DMF,

[0546] Into a 100-mL 3-necked round-bottom flask, Zn (2.98 g, 45.6 mmol, 3.0 equiv) was suspended in dry (DMF) (30 mL) under nitrogen atmosphère, and iodine (two crystals) was added immediately. A change in color from colorless to dark brown and colorless again was observed. Methyl (2S)-2-[(tert-butoxycarbonyl)amino]-3-iodopropanoate (5.0 g, 15.2 mmol, l .0 equiv), was added followed immediately by iodine (three crystals), the aforementioned color change was observed once more, and the insertion process was allowed to proceed for 2 h. A flask containing CuBr-Me₂S (0.3 i g, 1.53 mmol, 0.1 equiv), was placed under vacuum and heated vigorously until the gray CuBr-Me₂S became light green/yellow. The flask was then placed under a flow of nitrogen and allowed to cool to room température. This was repeated once more, and the flask was allowed to cool to room température. A prepared solution of Zn Reagent in DMF was transferred to the flask containing CuBr-Me₂S (2.06 g,

22.78 mmol, 2.0 equiv), and the reaction was stirred for 72 h at room température. The reaction mixture

356 was then filtered through a silica plug eluting with EtOAc. The organic phase was washed with water (2 x 50 mL) and brine (50 mL). The organic phase was dried with Na₂SÛ4, filtered, and the solvent removed under reduced pressure. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l :50 toi :l). This resulted in 3 g (76.7%) of methyl (2R)-2-[(tertbLitoxycarbonyl)amino]-5-methylhex-5-enoate as an oil. LCMS (ES) [M+1] ⁺ m/z: 258.2.

[0547] Step 2

Fe2(ox)3'6H2Q

NaN₃, NaBH₄

[0548] Into a 500-mL 3-necked round-bottom flask, Fe₂(OX)3.6H₂O (3.76 g, 7.77 mmol, 2.0 equiv) was stirred in H₂O (150 mL) until compietely dissolved (typically 2 h). The clear yellow solution was cooled to 0 °C and degassed with Ar for 10 min. NaN₃ (0.76 g, 11.66 mmol, 3.0 equiv) and éthanol (75 mL) were added. After 20 min, a solution of methyl (2R)-2-[(tert-butoxycarbonyl)amino]-5methylhex-5-enoate (l.OO g, 3.886 mmol, 1.00 equiv) in EtOH (75 mL) was added to the reaction mixture, followed by NaBH4 (l .03 g, 27.202 mmol, 7 equiv) at 0 °C. The resulting mixture was stirred for 30 min before being quenched by the addition of 30% aqueous NH4OH (4 mL). The mixture was extracted with 10% MeOH in CH₂Cl₂, the organic layer was dried over Na₂SO4 and concentrated. The residue was purified by flash chromatography (SiO₂, 20% EtOAc/PE) to give methyl (2R)-5-azido-2[(tert-butoxycarbonyl)amino]-5-methylhexanoate (450 mg, 38.5 %) as a colorless oil. LCMS (ES) [M+I]⁺ m/z: 30L2.

[0549] Step 3

[0550] To a solution of methyl (2R)-5-azido-2-[(tert-butoxycarbonyl)amino]-5-methylhexanoate (450 mg, l .50 mmol, l .0 equiv) in EtOAc ( 15 mL) was added Pd/C (200 mg) at room température. After the addition, the reaction was purged with H₂ three times. The resulting mixture was stirred for 16 hr at 25 °C under a H₂ atmosphère. The resulting mixture was filtered, and the filtrate was concentrated to give 220 mg (60.6%) of tert-butyl N-[(3R)-6,6-dimethyl-2-oxopiperidin-3-yl]carbamate as an off white solid. LCMS (ES) [M+l]⁺ m/z: 243.3.

[0551] Step 4

[0552] Into a 100-mL round-bottom flask, was placed tert-butyl N-[(3R)-6,6-dimethyl-2oxopiperidin-3-yl]carbamate (220 mg, 0.91 mmol, l .0 equiv), EtOAc (5 mL), and HCl/EtOAc (2 mL, 2 5 M, 4.0 mmol, 4,4 equiv). The resulting solution was stirred for 5 h at 25 °C. The resulting mixture was concentrated under vacuum. This resulted in 150 mg (100%) of (3R)-3-amino-6,6-dimethylpiperidin-2one as an off white solid. LCMS (ES) [M+l]⁺ m/z: 143.

[0553] Step 5

[0554] Into a 50-mL round-bottom flask, was placed (3R)-3-amino-6,6-dimethylpiperidin-2-one (150 mg, 1.05 mmol, L0 equiv), 2,4-dichloro-5H,6H,7El-cyclopenta[d]pyriniidine (199 mg, 1.05 mmol, 1.0 equiv), NMP (5 mL), and DIPEA (409 mg, 3.16 mmol, 3.0 equiv). The resulting solution was stirred for 16 h at 60°C in an oil bath. The reaction mixture was cooled to room température. The reaction was then quenched by the addition of 20 mL of water. The resulting solution was extracted with 3x30 mL of ethyl acetate, dried over anhydrous sodium sulfate, and concentrated, The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:50 to 1:1). This resulted in 160 mg (51.5%) of (3R)-3-([2chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-6,6-dimethylpiperidin-2-one as a white solid. LCMS (ES) [M+1 ]⁺ m/z: 295.2.

[0555] Step 6

358

[0556] To a solution of (3R)-3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino)-6,6dimethylpiperidin-2-one (l60mg, 0.54 mmol, l.O equiv) and 2-(tributylstannyl)pyridine (200 mg, 0.54 mmol, l .0 equiv) in dioxane (5 mL) was added Pd(PPh₃)4 (62 mg, 0.05 mmol, 0.1 equiv) at 25 C in one portion. After the addition, the resulting solution was stirred for î 6 hr at 100 °C under an Ar atmosphère. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l:50 to 10:1). The crude product (150 mg) was purified by FlashPrep-l-IPLC with the following conditions (IntelFlash-l): Column, Cl8 silica gel; mobile phase, MeCN = 10/90 increasing to MeCN=90/l0 within 15 min; Detector, 220. This resulted in 57.5 mg (3L4%) of (3R)-6,6-dimethyl-3-[[2-(pyridin-2-yL)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]piperidin-2-one as a white solid. Ή NMR (300 MHz, DMSOA, ppm) δ 8.65 (d, 7= 3.9 Hz, IH), 8.23 (d, 7= 7.8 Hz, 1H), 7.89 (dd,7= 1.5 Hz, 7.5 Hz, IH), 7.57 (s, I H), 7.44 (dd, 7= 1.2 Hz, 6.0 Hz, IH), 7.06 (d, 7= 8.1 Hz, IH), 4.67-4.52 (m, IH), 2.84 (t,7= 7.5 Hz,2H), 2.72 (t,7= 7.2 Hz, 2H),2.12-1.96 (m,4H), 1.781.76(m, 2H), 1.23 (d, 7= 10.8 Hz, 6H). LCMS (ES) [M+l]⁺ m/z: 338.2.

Example 1.82

[0557] Synthesis of (3S)-6,6-dimethyl·3-{[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]piperidin-2-one (Compound 56)

[0558] Compound 56 was synthesized similar to Compound 55 by replacing Methyl (2S)-2-[(tertbutoxycarbonyl)amino]-3-iodopropanoate with Methyl (2R)-2-[(tert-butoxycarbonyl)amino]-3iodopropanoate. Ή NMR (300 MHz, DMSO-ώ, ppm) δ 8.65 (d, 7= 3.6 Hz, IH), 8.23 (d, 7= 7.8 Hz, IH), 7.89 (dd, 7= 1.8 Hz, 7.8 Hz, IH), 7.57 (s, 1 H), 7.44 (dd, J= 0.9 Hz, 4.8 Hz, IH), 7.06 (d, 7= 8.1

359

Hz, I H), 4.71-4.53 (m, IH), 2.84 (t, 7= 8.1 Hz, 2H), 2.72 (t, 7= 7.2 Hz, 2H), 2.15-1.95 (m, 4H), 1.791.76(m, 2H), 1.25 (d,7= 10.8 Hz, 6H). LCMS (ES) [M+i]⁺ m/z: 338.2.

Example 1.83

[0559] Synthesis of N-tert-buty 1-2-{[2-(4-cyclopropylpyridin-2-y 1)-5H,6H,7H5 cyclopenta[d]pynmidin-4-yl](methyl)amino}acetamide (Copound 57)

[0560] Scheme 49 depicts a synthetic route for preparing an exemplary compound.

Scheme 49

[0561] Step 1

OH

A—b' ^B[_________OH

Pd(dppt)CI₂, Na₂CO₃

[0562] To a mixture of 2-chloro-4-methoxypyridine (1.0 g, 6.32 mmol, 1.00 equiv),

360 cyclopropylboronic acid (0.68 g, 6.9 mmol, 1.25 equiv) and NazCCh (1.68 g, 15.8 mmol, 2.50 equiv) in dioxane (20 mL)/HzO (1 mL) was added Pd(dppf)Ch.CH2Cb (50 mg, 0.064 mmol, 0.01 equiv) at room température. The resulting mixture was stirred for 16 h at 80^c'C in an oil bath under an Ar atmosphère. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100 to 1:10). This resulted in 500 mg (66.29%) of 4-cyclopropylpyridine as a solid. LCMS (ES) [M+l] ⁺ m/z: 120.L‘H NMR (300 MHz, CDC13, ppm) Ô 8.45 (d,7=5.1 Hz, 2H), 6.98 (dd, 7= 4.5, 1.5 Hz, 2H), 1.92-1.84 (m, IH), 1.28-1.10 (m, 2H), 0.84-0.81 (m, 2H).

[0563] Step 2

[0564] To a mixture of 2-(dimethylamino)ethan-l-ol (523 mg, 5.87 mmol, 2.0 equiv) in hexane (20 mL), was added n-BuLi (2.3 mL, 2.5 M,5.87 mmol, 2.0 equiv) at -78°C under a Nz atmosphère. After the reaction was stirred at -78°C for 20 min, BuîSnCl (1.9 g, 5.8 mmol, 2.0 equiv) and 4cyclopropylpyridine (350 mg, 2.94 mmol, 1.0 equiv) were added. The resulting mixture was stirred for 2 h between -78“C to room température. The reaction was then quenched by the addition of water. The resulting solution was extracted with 3x50 mL of ethyl acetate, the organic layers were combined, dried over NazSCh, and concentrated under vacuum to give 600 mg of the crude 4-cyclopropyl-2(tributylstannyl)pyridine as a yellow gum. LCMS (ES) [M+l]⁺ m/z: 410.1.

[0565] Step 3

H

[0566] Into a 50-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of argon was placed 4-cyclopropyl-2-(tributylstannyl)pyridine (200 mg, 0.49 mmol, 1.00 equiv), N-tertbuty 1-2-( [2-chloro-5 H, 6H, 7 H-cyclopenta[d] pyrimid in-4-yl](methyl)amino)acetamide (Intermediate II, 72.7 mg, 0.25 mmol, 0.5 equiv), Pd(PPhz)4 (56.6 mg, 0.05 mmol, 0.1 equiv) and dioxane (5 mL). The

361 resulting solution was stirred for 16 hr at 1OO°C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l: 10 to 10:1). The crude product (150 mg) was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-l): Column, Cl 8; mobile phase, Mobile phase : MeCN=5/lB:Water Flow rate: 20mL/min Column: DAICEL

CHIRALPAK IC, 250*20mm, 220 nm Gradient:50%B in 20min; 220nm; This resulted in 87.6 mg (47.1l%) ofN-tert-butyl-2-[[2-(4-cyclopropylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide as a white solid. 'H NMR (300 MHz, DMSOéô) δ 8.47 (d, J= 5.1 Hz, IH), 8.16 (s, IH), 8.08 (d, J= 1.8 Hz, IH), 7.68 (s, IH), 7.06 (dd,7=5.1, 1.8 Hz,Hz, 1 H), 4.15 (s, 2H), 3.50 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.28-1.97 (m, 3H), 1.23 (s, 9H), 1.13-1.07 (m, 2H), 0.88-0.82 (m, 2H). LCMS (ES) [M+l]⁺ m/z: 380.2.

Example 1.84 [0567] Synthesis ofN-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide (Compound 58)

[0568] Scheme 50 depicts a synthetic route for preparing an exemplary compound.

Scheme 50

[0569] Into a 50-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen.

was placed 4-fluoro-2-(trimethylstannyl)pyridine (1.00 g, 3.85 mmol, 1.00 equiv), N-tert-butyl-220 [5H,6H,7H-cyclopenta[d]pyrimidîn-4-yl(methyl)amino]acetamide (Intermediate II, 500 mg, 1.91 mmol, 0.50 equiv), Pd(dppf)Cl₂ (350 mg, 0.43 mmol, 0.10 equiv), and dioxane (20.0 mL). The mixture was stirred for 12 h at !00°C. The mixture was concentrated to remove the solvent, the resulting residue was

362 purified by silica gel column with THF/PE (70%) and the collected product was further purified by Prep-HPLC with conditions: Column, Welch Xtimate Cl 8, 21.2*250 mm, 5um, mobile phase, Water(10 mmol/L NH4HCO3) and MeOH: CHjCN=l :1 (25% Phase B up to 65% in 15 min), Detector, UV, 254 nm. This resulted in 42.9 mg (3%) of N-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-

5H-cyclopenta[d]pyrimidin-4-yl)(methyI)amino)acetamide as a white solid. ¹ H-NMR (300 MHz, DMSO-ds/Tpm): δ 8.69 (dd, J = 9.0, 5.4 Hz, IH), 8.16 (dd, J = 10.8,2.7 Hz, IH), 7.73 (s, 1 H), 7.427.37 (m, IH), 4.12 (s, 2H), 3.30 (s, 3H), 3.17 (t, J = 7.2 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.05-1.95(m, 2H), 1.24 (s, 9H).

[0570] LCMS (ES, m/z): [M+Hf:

358.1.

Example 1.85

[0571 ] Synthesis of -tert-butyl-2-{methyl[2-(6-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 59)

[0572] Scheme 51 depicts a synthetic route for preparîng an exemplary compound.

Scheme 5 i

[0573] To a solution of N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)acetamide (Intermediate II, 200,00 mg, 0,674 mmol, 1.00 equiv) and 2-methyl-621052

363 (tributylstannyl)pyridine (386.30 mg, LOI l mmol, L5 equiv) in dioxane (4 ml ) was added Pd(dppf)Ch (49.31 mg, 0.067 mmol, 0.I0 equiv). After stirring for 4 h at 1OO°C under a nitrogen atmosphère, the resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with ΡΕ/THF (l :5) to afford N-tert-butyl-2-[methyl[2-(65 methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide (125 mg, 52.48%) as a white solid. Ή NMR (300 MHz, DMSO-rfc) IH NMR (300 MHz, DMSO-d6) δ 8.15 (d, J = 7.8 Hz, IH), 7.75 (t, J= 7.7 Hz, IH), 7.66 (s, IH), 7.29 (d, J= 7.6 Hz, IH), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.83 (t, J= 7.8 Hz, 2H), 2.55 (s, 3H), 2.14-1.83 (m, 2H), 1.24 (s, 9H). LCMS (ES) [M+l] ⁺m/z: 354.3.

Example 1.86

[0574] Synthesis of N-tert-butyl-2-{[2-(4,5-dimethylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino} acetamide (Compound 60)

[0575] Scheme 52 depicts a synthetic route for preparing an exemplary compound.

Scheme 52

[0576] Step 1

Bu₃Sn

Bu₃SnCl, BuLi, THF, -78°C

364

[0577] Into a 250-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 3,4-dimethylpyridine (l.00 g, 9.332 mmol, l.OO equiv) and THF (20.00 mL). The mixture was stirred at 0°C, then butyllithium (l .76 mL, 27.448 mmol, 2 equiv) was added dropwise. The resulting solution was stirred at 0°C for l hr and dimethylaminoethanol (L25 g, I4.023 mmol, 1.50 equiv) was added dropwise. The resulting solution was stirred for an additional l hr at 0°C, cooled down to -78°C and tributyltin chloride (4.56 g, 13.998 mmol, l .5 equiv) was added dropwise. The resulting solution was stirred for an additional l h at -78°C. The reaction was then quenched by the addition of water. The resulting mixture was extracted with 3x30 mL of ethyl acetate and the organic layers were combined and dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 400 10 mg (10.82%) of 4,5-dimethyl-2-(tributylstannyl)pyndine as a solid. LCMS (ES) [M+l]⁺ m/z: 398.

[0578] Step

[0579] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, 15 was placed 4,5-dimethyl-2-(tributylstannyl)pyridine (400.48 mg, LOI 1 mmol, 1.20 equiv), N-(tert- butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (Intermedaite II, 250.00 mg, 0.842 mmol, 1.00 equiv), Pd(PPh3)4 (97.33 mg, 0.084 mmol, 0.10 equiv), LiCl (35.71 mg, 0.842 mmol, 1.00 equiv), and Toluene (10.00 mL). The resulting solution was stirred for 16 hr at 100°C. The reaction mixture was cooled and concentrated. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10:1). The collected crude product was further purified by Prep-HPLC with the foîlowing conditions (2#SHIMADZU (HPLC-01)): Column, Welch Xtimate Cl8, 21.2*250mm,5um; mobile phase, Water(0.05%TFA ) and MeOH:ACN=l:l (10% Phase 13 up to 60% in 17 min. This resulted in 68.3 mg (22.06%) of N-(tert-buty 1)-2-((2-(4,5dimethylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a white solid. 'H NMR (300 MHz, DMS04) δ 8.37 (s, IH), 8.14 (s, IH), 7.72 (s, IH), 4.14 (s, 2H), 3.27 (s, 3H), 3.14 (t, J= 7.3 Hz, 2H), 2.80 (t, J= 7.8 Hz, 2H), 2.34 (s, 3H), 2.27 (s, 3H), 2.03-1.92 (m, 2H), 1.24

365 (s, 9H). LCMS (ES) [M+l] ⁺ m/z: 368,2

Example 1.87

[0580] Synthesis ofN-(l-hydroxy-2-methy Ipropan-2-yl)-2-{methyl[2-(pyridin-2-y l)-5H,6H,7Hcyclopenta[djpyrimidin-4-yl]amino}acetamide (Compound 6I)

[0581] Scheme 53 depicts a synthetic route for preparing an exemplary compound.

HATU, DIEA, DMF

O°C-rt

38%

Scheme 53

[0582] Into a 20-mL vial was placed [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetic acid (Intermediate I, 200 mg, 0.70 mmol, l.O equiv), DMF (3.0 mL), 2-amino-2methyl-l-propanol (69 mg, 0.77 mmol, l.l equiv), and DIEA (455 mg, 3.52 mmol, 5.0 equiv). This was followed by the addition of HATU (401 mg, l .06 mmol, l .5 equiv) at 0°C. The reaction solution was stirred for l h at room température. The reaction solution was directly purified by C l 8-120 g column eluted with CH3CN/H2O (l% NH4OH), from 5% to 80% within 12 min, flow rate, 70 mL/min, detector, 254 nm. This resulted in 93.9 mg (38%) ofN-(l-hydroxy-2-methylpropan-2-yl)-2-[methyl[2-(pyrÎdin-2yl)-5H,6H,7H-cydopenta[d]pyrimidin-4-yl]ammo]acetamide as white solid. ‘H-NMR (300 MHz, DMSO-Appm):Ô8.66 (dd,7=4.7, 1.8 Hz, IH), 8.33 (dt,7=8.0, 1.1 Hz, IH), 7.88 (td, J= 7.7, 1.8 Hz, IH), 7.51 (s, IH), 7.44 (ddd, 7= 7.5, 4.8, 1.2 Hz, IH), 4.82 (t, 7= 6.0 Hz, IH), 4.16 (s, 2H), 3.37 (d, 7= 5.7 Hz, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.2 Hz, 2H), 2.82 (t,7= 7.8 Hz, 2H), 2.03-1.97 (m, 2H), 1.17 (s, 6H). LCMS (ES, m/z): [M+H]⁺: 356.2.

Example 1.88

366

[0583] Synthesis ofN-(l-hydroxy-2-methylpropan-2-y 1)-2-{rnethyl[2-(4-rnethylpyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 62)

[0584] Scheme 54 depicts a synthetic route for preparing an exemplary compound.

[0585] Step 1

[0586] Into a 250-mL round-bottom flask, was placed 2,4-dichloro-6,7-dihydro-5H10 cyclopenta[d]pyrimidine (10.00 g, 52,899 mmol, 1.00 equiv), NMP (100.00 mL), ethyl 2(methyiamino)acetate hydrochlorîde (8,13 g, 52.899 mmol, 1.00 equiv), and DIEA (13.67 g, 105.798 mmol, 2.00 equiv). The resulting solution was stirred for I hr at 60°C.The mixture was poured into 200

367

mL of ethyl acetate. The organic layer was separated and washed with 3 xl 00 ml of water. The organic layer was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). The collected fractions were combined and concentrated. This resulted in 8.2 g (57.47%) of ethyl ethyl N-(2-chloro-6,7-dihydro-5H5 cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate as a yellow solid. LCMS (ES) [M+l]⁺ m/z 270.

[0587] Step 2

[0588] Into a 250-mL round-bottom flask, was placed ethyl N-(2-chloro-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)-N-methylglycinate (8.00 g, 29.659 mmol, 1.00 equiv), dioxane (100.00 mL), 4-methyl-2-(tributylstannyl)pyridine( 13.60 g, 35.591 mmol, 1.20 equiv), and tetrakis(triphenylphûsphine)paIladium(O) (3.43 g, 2.966 mmol, 0.10 equiv). The resulting solution was stirred for 16 hr at 110°C. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:3). The collected fractions were combined and concentrated. This resulted in 7.5 g (77.5%) of ethyl N-methyl-N-(2-(4-methylpyridin-2-yl)-6,715 dihydro-5H-cyclopenta[d]pyrimidin-4-yl)gIycinate as a yellow solid. LCMS (ES) [M+l]⁴ m/z 327.

[0589] Step 3

[0590] Into a 250-mL round-bottom flask was placed ethyl N-methyl-N-(2-(4-methylpyridin-2-yl)6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate (3.80 g, 11.642 mmol, l equiv), tetrahydrofuran (30 mL), water (30 mL), and lithium hydroxide (0.56 g, 23.284 mmol, 2.00 equiv). The resulting solution was stirred for 2 hr at 25°C. The resulting mixture was concentrated. The resulting solution was

368 diluted with 50 mL of water. The pH value of the solution was adjusted to 4 with HCl (l mol/L). The precipitated solids were collected by filtration. This resulted in 3.4 g (97.89%) ofN-methyl-N-(2-(4methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yI)glycine as an off-whîte solid. LCMS (ES) [M+l]⁺ m/z 299.

[0591] Step 4

[0592] Into a 50-mL round-bottom flask, was placed N-methyl-N-(2-(4-methylpyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine (100.00 mg, 0.335 mmol, 1.00 equiv), dimethylformamide (4.00 mL), 2-amino-2-methyl-l-propanol (29.88 mg, 0.335 mmol, 1.00 equiv), HATU (191.17 mg, 0.503 mmol, 1.50 equiv), and DIEA (129.96 mg, 1.006 mmol, 3.00 equiv). The resulting solution was stirred for 2 hr at 25°C. The crude reaction mixture was filtered and subjected to reverse phase préparative HPLC (Prep-C 18, 20-45M, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 25% MeCN in water to 35% MeCN in water over a 10 min period, water contains 0.1% NH3H2O) to provide N-(l-hydroxy-2-methylpropan-2-yl)-2-{methyl[2-(4-methylpyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yI]amino}acetamide as a yellow solid (69.6 mg,56.20%). Ή NMR (300 MHz, DMSO-d6) δ 8.61 (d, J = 5.0 Hz, i H), 8.28 (s, IH), 7.72 (s, IH), 7.46 (d, J= 4.9 Hz, 1 H), 4.83 (s, IH), 4.30 (s, 2H), 3.32 (s, 5H), 3.21 (t, J= 7.4 Hz, 2H), 2.93 (t, J= 7.8 Hz, 2H), 2.47 (s, 3H), 2.11 -1.97 (m, 2H), 1J 7 (s, 6H). LCMS (ES) [M+1]⁺ m/z 370.1.

Example 1.89

[0593] Synthesis ofN-(4-hydroxy-2-methylbutan-2-y!)-2-{methy l[2-(pyrîdin-2-yl)-5H,6H,7Hcyclopenta[d]pyrîmidin-4-yl]amino}acetamide (Compound 63)

369

(0594] Scheme 55 depicts a synthetic route for preparing an exemplary compound.

Scheme 55

[0595] Into a 20-mL vial was placed [methy l[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-45 yl]amino]acetic acid (150 mg, 0.53 mmol, 1.0 equiv), DMF (3.0 mL), 3-amino-3-methylbutan-l-ol (60 mg, 0.58 mmol, 1.10 equiv), and DIEA (341 mg, 2.64 mmol, 5.0 equiv). This was followed by the addition of HATU (301 mg, 0.79 mmol, 1.5 equiv) at 0°C. The reaction solution was stirred for 1 h at room température. The reaction solution was purified by Prep-HPLC with conditions: C18-120 g column, CH3CN/H2O (0.5% NH4OH) from 5% to 80% within 15 min, flow rate: 70 mL/min, detector,

254 nm. This resulted in 86.5 mg (44%) of N-(4-hydroxy-2-methyIbutan-2-yl)-2-[methyl[2-(pyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidÎn-4-yl]amino]acetamide as an off-white solid. ¹ H-NMR (300 MHz, DMSO-^/jp/w): 8 8.67 (ddd, J=4.8, 1.8, 0.9 Hz, IH), 8.32 (dt, J=T9, 1.1 Hz, IH), 7.88 (td, J= 7.7, 1.8 Hz, H-I),7.69(s, IH), 7.44 (ddd, J= 7.5, 4.8, 1.3 Hz, IH), 4.40 (t, J= 4.8 Hz, lH),4.I4(s, 2H), 3.47-3.41 (m, 2H), 3.26 (s, 3H), 3.14 (t, J= 12 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.05-1.95 (m, 2H),

1.76 (t, J= 6.9 Hz, 2H), 1.23 (s, 6H). LCMS (ES, m/z): [M+H]⁺:

370.3.

Example 1.90

[0596] Synthesis of N-cyclopentyl-2-{methyl[2-(4-methylpyridm-2-yl)-5H,6Ll,7I-icyclopenta[d]pyrimidin-4-yl]amino)acetamide (Compound 64)

[0597] Compound 64 was synthesized similar to compound 62 by replacing 2-amino-2-methyl-lpropanol with cyciopentanamine. Ή NMR (300 MHz, DMSO-d6) δ 8.51 (d, J= 4.9 Hz, IH), 8.16-8.07

370 (m, 2H), 7.31-7.23 (m, IH), 4.17 (s, 2H), 4.06-3.95 (m, IH), 3.30-3.20 (m, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.40 (s, 3H), 2.03-1.93 (m, 2H), 1.85-1.68 (m, 2H), 1.70-1.30 (m, 6H). LCMS (ES)[M+1]⁺ m/z 366.2.

Example 1.91

[0598] Synthesis of 2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-N-(3-methyloxolan-3-yl)acetamîde (Compound 65)

[0599] Compound 65 was synthesized similar to compound 62 by replacing 2-amino-2-methyl-l propanoi with 3-methyloxolan-3-amine. Ή NMR (300 MHz, DMSO-7&) δ 8.51 (d, 7 = 4.9 Hz, IH), 8.20 (s, 1 H), 8.16 (d, 7= 1.8 Hz, 1 H), 7.27 (dd, 7= 5.1, 1.4 Hz, IH), 4.18 (s, 2H), 3.80 (d, 7= 8.7 Hz, IH), 3.77-3.67 (m, 2H), 3.49 (d,7=8.7 Hz, 1 H), 3.29 (s, 3H), 3.16 (t, 7= 7.4 Hz, 2H), 2.82 (t,7=7.8 Hz, 2H), 2.40 (s, 3H), 2.12-2.28 (m, IH), 1.81-2.02 (m, 2H), L71-L79 (m, IH), 1.31 (s, 3H). LCMS (ES) [M+l]⁺ m/z: 382.3.

Example L92

[0600] Synthesis ofN-(3-fluorophenyl)-2-{inethyl[2-(4-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]aniino}acetamide (Compound 66)

[0601] Compound 66 was synthesized similar to compound 62 by replacing 2-amino-2-methyl-l propanoi with 3-Huoroaniline. 'HNMR(300 MHz, DMSO-d₆) δ 10.49(s, IH), 8.47 (d, 7=4.9 Hz, IH), 8.03 (s, IH), 7.65-7.55 (m, i H), 7.39-7.26 (m, 2H), 7.25-7. J7 (m, 1 H), 6.93-6.80 (m, IH), 4.40 (s, 2H), 3,39 (s, 3H), 3.22 (t, J= 7.3 Hz, 2H), 2.83 (t, 7 = 7.8 Hz, 2H), 2.18 (s, 3H), 2.11-1.94 (m, 2H). LCMS (ES) [M+l]⁺ m/z 392.1.

371

Example 1.93

[0602] Synthesis of N-tert-butyl-2-[methyI[2-(pyrimidin-2-yi)~5El,6H,7H-cyclopenta[b]pyridin-4yl] amino] acetam i de (Compound 67)

[0603] Scheme 56 depicts a synthetic route for preparing an exemplary compound.

Scheme 56

[0604] Step l

[0605] Into a 40-mL vîal purged and maintained in an inert atmosphère of nitrogen was placed 2,4- dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, 1.00 equiv), 2(tributylstannyl)pyrîmidine (1275.94 mg, 3.46 mmol, 1.30 equiv), CsF (807.78 mg, 5.32 mmol, 2.00 equiv), Pd(PPh₃)4 (307.25 mg, 0.26 mmol, 0.10 equiv), Cul (50.64 mg, 0.26 mmol, 0.10 equiv), and DMF (10.00 mL). The resulting solution was stirred for 8 h at 110°C. The reaction mixture was cooled to room température. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (30% Phase B up to 60% in 11 min); Detector, 254 nm. This resulted in 200 mg (32.47%) of 2-[4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine as a brown solid. LCMS (ES) [M+H]⁺m/z: 232.

372

[0606] Step 2

[0607] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed 2-[4chloro-5H.6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine ( 150.00 mg, 0.65 mmol, l.OO equiv), N-tertbutyl-2-(methylamino)acetamide (121.39 mg, 0.84 mmol, I.30 equiv), Pd(OAc)₂ (I4.54mg, 0.06 mmol, 0.10 equiv), BINAP (80.63 mg, 0.13 mmol, 0.20 equiv), CS2CO3 (421,90 mg, 1.29 mmol, 2.00 equiv), and dioxane (8.00 mL). The resulting solution was stirred ovemight at 100°C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (500 mg) was purified by Prep-HPLC with the foilowing conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% HCOOH) and CAN (20% Phase B up to 50% in 11 min); Detector, 254 nm. This resulted in 82.1 mg (32.90%) of N-tert-buty 1-2-[methy l[2-(pyrim îdîn-2-y 1)5H,6H,7H-cyclopenta[b]pyridin-4-yI]amino]acetamide formate as a yellow oil. ’H-NMR (300 MHz, DMSO-76) Ô 8.91 (d,7=4.8 Hz, 2H), 8.17 (s, IH), 7.61 (s, IH), 7.57-7.45 (m, 2H), 3.98 (s, 2H), 3.09 (s, 3H), 3.04 (t, 7= 7.2 Hz, 2H), 2.88 (t, 7= 7.7 Hz, 2H), 2.09-1.93 (m, 2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H] ⁺:

340.L

Example 1.94

[0608] Synthesis of N-tert-butyl-2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[b]pyridin-4-yl]amîno}acetamide (Compound 68)

H

[0609] Scheme 57 depicts a synthetic route for preparing an exemplary compound.

373

Scheme 57

[06ΙΟ] Step l

[0611 ] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed 2,4- dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, l.OO equiv), 4-methyl-2(tributylstannyl)pyridine (1321.01 mg, 3.46 mmol, L30 equiv), Pd(PPh₃)4 (307.25 mg, 0.26 mmol, 0.10 equiv), and dioxane (10.00 mL). The resulting solution was stirred ovemight at 110°C. The réaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (1

g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl 8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1 % NH4HCO₃) and CAN (40% Phase B up to 70% in 11 min); Detector, 254. This resulted in 300 mg (46.11%) of 2-[4-chloro-5H,6H,7Hcyclopenta[b]pyridin-2-yl]-4-methylpyridine as a white solid. LCMS (ES) [M+H]⁺ m/z: 245. [0612] Step

2

[0613] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed 2-[4chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]-4-methylpyridine (200.00 mg, 0.82 mmol, 1.00 equiv), N21052

374 tert-butyl-2-(methyIamino)acetamide (153.22 mg, 1.06 mmol, 1.30 equiv), Pd(OAc)2 (18.35 mg, 0.08 mmol, 0.10 equiv), CS2CO3 (532.56 mg, 1.64 mmol, 2.00 equiv), BINAP (101.78 mg, 0.16 mmol, 0.20 equiv), dioxane (8.00 tnL). The resulting solution was stirred ovemight at 100 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The crude product (0.5 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3) and CAN (40% Phase B up to 70% in 11 min); Detector, 254 nm. This resulted in 118.1 mg (41.00%) of N-tert-butyl-2-[methyl[2-(4-methyipyridin-2yl)-5H,6H,7H-cyclopenta[b]pyridin-4-yl]amino]acetamide as a white solid. 'H-NMR (300 MHz, DMSCW6) δ 8.46 (d_; J = 4.9 Hz, IH), 8.16 (d, J = 1.8 Hz, IH), 7.56 (s, lH),7.54(s, IH), 7.19 (dd, J=

5.0, 1.8 Hz, IH), 3.93 (s, 2H), 3.06 (s, 3H), 3.02 (t, J = 7.1 Hz, 2H), 2.85 (t, J = 7.7 Hz, 2H), 2.39 (s,

3H), 2.08 - 1.95 (m, 2H), 1.27 (s, 9H). LCMS (ES, m/z): [M+H] ⁺: 353.2.

Example 1.95

[0614] Synthesis ofN-[2-( 1 -cyclobuty 1-5-methy 1-1 H-imidazol-2-yl)ethyl]-2-{methyl[2-(pyndin-215 yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide (Compound 69)

[0615] Scheme 58 depicts a synthetic route for preparing an exemplary compound.

375

33.18%

HCÎ in dioxane

77.92%

HATU, DIEA, DCM

33.10%

[0616] Step 1

[0617] Into a 250-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 3-((tert-butoxycarbonyl)amino)propanoic acid (7.56 g, 39.955 mmol, 1.00 equiv), DCM (100.00 mL), and CDI (6.48 g, 39.955 mmol, 1 equiv). The resulting solution was stirred for 2 h at room température. This was followed by the addition of 2-propynylamine (2.20 g, 39.942 mmol, l .00 equiv) dropwise with stirring at room température. The resulting solution was stirred overnight at room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with ΡΕ/THF (50%THF). This resulted in 3 g (33.18%) of tert-butyl (3-oxo-3-(prop-2-yn-lylamino)propyl)carbamate as an off-white solid. LCMS (ES) [M+l]⁺ m/z 227.

[0618] Step 2

crude

[0619] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen,

376 was placed tert-butyl (3-oxo-3-(prop-2-yn-l-ylamino)propyl)carbamate (500.00 mg, 2.210 mmol, l.OO equiv), cyclobuty lamine (] 88.59 mg, 2.652 mmol, 1.20 equiv), zinc trifluoromethanesulfonate (l 60.67 mg, 0.442 mmol, 0.20 equiv), and Toluene (30.00 mL). The resulting solution was stirred overnight at !00°C in an oil bath. The reaction mixture was cooled to room température with a water bath. The pH value of the solution was adjusted to 8 with K2CO3 (10%). The resulting solution was extracted with 3x100 mL of ethyl acetate, he organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. This resulted in 600 mg (crude) of tert-butyl (2-(l-cyclobutyl-5-methyl-lH-imidazol-2yl)ethyl)carbamate as a yellow oil. LCMS (ES) [M+l ]⁺ m/z 280.

[0620] Step 3

[0621 ] Info a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed tert-butyl (2-(l-cyclobutyl-5-methyl-l H-imidazol-2-yl)ethyl)carbainate (600.00 mg, 2.148 mmol, 1.00 equiv), HCl(gas)in EA (10.00 mL). The resulting solution was stirred overnight at room température. The resulting mixture was concentrated. The solids were îsolated by filtration and dried over vacuum. This resulted in 300 mg (77.92%) of 2—(T-cyclobutyl-5-methy 1-1 H-imidazol-2-yl)ethan-Iamine as a yellow solid. LCMS (ES) [M+1 ]⁺ m/z 180.

[0622]

[0623]

Into a 100-mL round-bottom flask, was placed N-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-yl)glycine (200.00 mg, 0.703 mmol, 1.00 equiv), 2-(l-cyclobutyl-5 methyl-1 H-imidazol-2-yl)ethan-l -amine (151.32 mg, 0.844 mmol, 1.20 equiv), HATU (294,21 mg,

0.774 mmol, LI0 equiv), DIEA (272.74 mg, 2.110 mmol, 3.00 equiv), and DCM (20.00 mL). The

377 resulting solution was stirred for 4 hr at room température. The resulting mixture was concentrated. The crude product was purified by Flash-Prep-HPLC (Prep-Cl8, 20-45M, 120 g, Tianjîn Bonna-Agela Technologies; gradient elution of 35% MeCN in water to 60% MeCN in water over a 10 min period, where both solvents contain 0. l% NH3H2O). This resulted in 100.6 mg (32.10%) ofN-(2-(l-cyclobutyl5 5-methyl-lH-imidazo!-2-yl)ethyl)-2-(methyl(2-(pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)amino)acetatnide as a white solid. Ή NMR (300 MHz, DMSOé.ppm) δ 8.66 (d, 7= 3.6 Hz, IH), 8.22-8.35 (m, 2H), 7.86 (td, 7= 7.7, 1.9 Hz, 1 H), 7.49-7.38 (m, 1 H), 6.40 (s, IH), 4.41-4.56 (m, IH), 4.19 (s, 2H), 3.25-3.39 (m, 2H), 3.28 (s, 3H), 3.15 (t, 7= 7.4 Hz, 2H), 2.82 (t, 7= 7.9 Hz, 2H), 2.70 (t,7 = 7.3 Hz, 2H), 2.45-2.23 (m, 4H),2.18 (s, 3H), 1.87-2.05 (m, 2H), 1.55-1.71 (m, 2H). LCMS (ES)

[M+l]⁺m/z 446.2.

Example 1.96

[0624] Synthesis ofN-[5-(azepan-l-yl)-l,3,4-thiadiazol-2-yl]-2-[methyl[2-(pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 70)

[0625] Scheme 59 depicts a synthetic route for preparing an exemplary' compound.

Scheme 59

[0626] Step I

378

82%

[0627] Into a 50-mL round-bottom flask was placed 5-bromo-l,3,4-thiadiazol-2-amine (500 mg, 2.78 mmol, 1.0 equiv), DMF (10.0 mL), K₂CO₃(I.15 g, 8.33 mmol, 3.0 equiv), and hexamethyleneimine (276 mg, 2.78 mmol, 1.0 equiv). The mixture was stirred for 12 h at 80°C in an oil 5 bath. After being cooled to room température, the reaction was diluted with 20 mL of water and extracted with 3x20 mL of ethyl acetate. The combined organic phase was washed with 3 x20 ml of brine, dried over anhydrous sodium sulfate, fïltered, and the fîltrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 450 mg (82%) of 5-(azepan-l-yl)-l,3,4-thiadiazol-2-amine obtained as a pink solid.

[0628] Step 2

[0629] Into a20-mL vial, was placed 5-(azepan-l-yl)-l ,3,4-thiadiazol-2-amine (230 mg, 1.16 mmol, 1.1 equiv), DMF (3.0 mL), [methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetic acid (300 mg, 1.06 mmol, 1.0 equiv), and DIEA (682 mg, 5.28 mmol, 5.0 equiv). This was followed by the addition ofEDC.HCl (243 mg, 1.27 mmol, 1.2 equiv) and HOBt (171 mg, 1.27 mmol, 1.2 equiv) at 0°C. The mixture was stirred for I h at room température. The reaction solution was purified by Prep-HPLC with conditions: C18-120 g column, CH3CN/ H₂O (0.5% NH4OH) from 5% to 80% within 15 min, flow rate: 70 mL/min, detector, 254 nm. 106.6 mg (22%) ofN-[5-(azepan-l-yl)1 _J3,4-thiadiazol-2-yl]-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino]acetamide was obtained as off-white solid. 'H NMR (300 MHz, DMSO-t/ό, j>/wi): δ 12.19 (br.

IH), 8.64(000,7=4.8, 1.8,0.9 Hz, IH), 8.19 (dt, 7 = 7.9, 1.1 Hz, 1 H), 7.77 (td, 7= 7.7, 1.8 Hz, IH), 7.41 (ddd, 7 = 7.5, 4.7, 1.2 Hz, IH), 4.50 (s, 2H), 3.48 (t, 7= 5.7 Hz, 4H), 3.36 (s, 3H), 3.20 (t, J= 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.06-1.96 (m, 2H), 1.73-1.67 (m, 4H), 1.50-1.46 (m, 4H). LCMS (ES, m/z): [M+H]⁺: 465.3.

Example 1.97

[0630] Synthesis of l-[2-(l,3-thiazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepane (Compound 94)

[0631] Compound 94 was synthesized similar to Compound 92 by replacing 2- (tributylstannyl)pyridine with 4-(tributylstannyl)thiazole. ’H NMR (400 MHz, DMSO-7ô) δ 9.13 (d, 7 = 2.1 Hz, IH), 8.32 (d, 7= 2.1 Hz, IH), 3.75 (t, 7= 6.1 Hz, 4H), 3.05 (t, 7= 7.3 Hz, 2H), 2.78 (t, 7= 7.9 Hz, 2H), 1.97 (p, 7= 7.7 Hz, 2H), 1.73 (q,7=5.5 Hz, 4H), 1.47 (p, 7= 2.8 Hz, 4H). LCMS (ES) [M+l] ⁺ m/z: 301.2.

Example 1.98

[0632] Synthesis of 3-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amîno}-lphenyIpyrrolidin-2-one (Compound 95)

[0633] Compound 95 was synthesized similar to Compound 73 by replacing 2pyridinylmethanamine with 3-amino-1 -phenylpyrrolidin-2-one LCMS (ES+): (M+H)⁺ = 386.3. 'HNMR (400 MHz, DMSO-î/6) δ 8.65 - 8.45 (m, IH), 8.23 - 8.06 (m, IH), 7.79 - 7.56 (m, 3H), 7.44 - 7.08 (m,

4H), 5.48 - 5.17 (m, IH), 4.01 - 3.85 (m, 2H), 3.24 (s, 5H), 2.90 - 2.79 (m, 2H), 2.44 - 2.27 (m, 2H),

380

2.09- 1.95 (m, 2H).

Example 1.99

[0634] Synthesis of l-[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]azepane(Compound 96)

[0635] Compound 96 was synthesized similar to Compound 92 by replacing 2(tributylstarmyi)pyridine with 4-chioro-2-(tributylstannyl)pyridine. 'H NMR (400 MHz, Methanol-Λ) δ 8.59 (d, 7= 5.3 Hz, IH), 8.30 (d,7=2.0 Hz, IH), 7.50 (dd, 7= 5.3, 2.1 Hz, 1 H), 3.81 (t,7=6.1 Hz, 4H),3.H (t, 7=7.3 Hz, 2H), 2.89 (t, 7= 7.9 Hz, 2H), 2.07 (p, 7= 7.7 Hz, 2H), 1.81 (dq, 7= 9.2, 4.0 Hz, 4H), 1.51 (m,4H). LCMS (ES) [M+l]⁺m/z: 329.3, 331.4.

Example 1.100

[0636] Synthesis of l-[2-(l -methyl-lH-imidazol-4-yl)-5H,6H,7H-cyciopenta[d]pyrimidin-4yl]azepane (Compound 97)

[0637] Compound 97 was synthesized similar to Compound 92 by replacing 2(tributylstannyl)pyridine with 1-methyl-4-(tributylstannyl)-lH-imidazole. 'H NMR (400 MHz, Methanol-ώ) δ 7.86 (d, 7= 1.3 Hz, 1 H), 7.73 (d, 7= 1.3 Hz, JH), 3.88 (t, 7= 6.1 Hz, 4H), 3.80 (s, 3H), 3.12 (t, 7= 7.4 Hz, 2H), 2.91 (t, 7= 7.9 Hz, 2H), 2.09 (h, 7= 8.1 Hz, 2H), 1.82 (q, 7= 5.7 Hz, 4H), 1.58 (p,7= 2.7 Hz, 4H). LCMS (ES) [M+l]⁺m/z: 298.2.

Example 1.101

[0638] Synthesis of 2-{methyl[2-(pyridin-2-yl)-5H,6H,7I-I-cyclopenta[d]pyrimidin-4-yl]amino}-N[l-(trifluoromethyi)cyclopropyl]acetamide (Compound 98)

381

[0639] Scheme 60 depicts a synthetic route for preparing an exemplary compound.

h o

HATU, DIPEA, DMF

HCI(g)/EA, rt

Scheme 60

[0640] Step l

HATU, DIPEA, DMF

H o Boc

[0641] To a solution of [(tert-butoxycarbony[)(methyl)amino]acetic acid (302.51 mg; 1.60 mmol;

l .OO eq.) in DMF (2.5 mL) was added l-(trifluoromethyl)cyclopropan-l-amine (200.00 mg; L60 mmol; l .00 eq.), followed by DIPEA (0.42 mL; 2.40 mmol; l .50 eq.) and HATU (607.92 mg; l .60 mmol; 1.00 eq.). After being stirred for 15 h at room température, it was diluted with water, and extracted with

EtOAc. The organic layers were combined, dried, and concentrated to give tert-butyl N-methyl-N-({[l(trifluoromethyl)cyclopropyl]carbamoyl}methy[)carbamate, which was used for the next step without purification. LCMS (ES) [M+l]⁺ m/z; 297.5.

[0642] Step 2

382

H

HCI(g)/EA, rt

HCl h₂n

H

[0643] To a solution of tert-butyl N-methyl-N-({[l(tnfluoromethyl)cyclopropyl]carbamoyl}methyl)carbamate (0.47 g; l .60 mmol; l.OO eq.) in DCM (4 mL) was added 4N HCl in dioxane (4 mL). The mixture was stirred further, concentrated, and lyophîlized to give 2-[chloro(methyl)amino]-N-[l-(trif1uoromethyl)cyclopropyl]acetamide, which was used directly for the next step without purification. LCMS (ES) [M+l]⁺ m/z: 197.3.

[0644] Step 3 zycF₃

[0645] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.13 g; 0.70 mmol;

1.00 eq.) in AcCN (2 mL) was added 2-[chloro(methyl)amino]-N-[l(trifluoromethyl)cyclopropyi]acetamide (0.19 g; 0.80 mmol; 1.15 eq.), and trîethylamine (0.29 mL; 2.10 mmol; 3.00 eq.). After being heated at 75 °C for 4 h, the mixture was cooled and concentrated, diluted with water, and the resulting précipitâtes were collected by filtration and dried to give 2-({2-chloro5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[l-(trifluoromethyl)cyclopropyl]acetamide (200 mg). LCMS (ES) [M+l]⁺ m/z: 349.0, 351.1.

[0646] Step 4

[0647] To a solution of 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-[l(trifluoromethyl)cyclopropyl]acetamide (50.00 mg; 0.20 mmol; 1.00 eq.) and 2-(tributylstannyl)pyridine

383 (190.01 mg; 0.52 mmol; 2.00 eq.) in toluene (1 mL) was added tetrakis(triphenylphosphane) palladium (29.82 mg; 0.03 mmol; 0.10 eq.). The mixture was heated at 115 °C for 15 h. The mixture was cooled and concentrated, and the crude residue was purified by préparative HPLC to give 2-{methyl[2-(pyridin2-yl)-5H,6H,7H-cyclopenta[d]pyrîmidin-4-yl]amino}-N-[l-(trifluoromethyl)cyclopropyl]acetamide (49.8 mg). ‘H NMR (400 MHz, DMSO-7₆) δ 9.05 (s, IH), 8.80 (d, 7= 4.7 Hz, IH), 8.35 (d, 7= 8.2 Hz, IH), 8.07 (s, IH), 7.70 (s, IH), 4.37 (s, 2H), 3.44 (s, 3H), 3.20 (m, 2H), 3.00 (t, 7= 7.9 Hz, 2H), 2.11 — 2.03 (m, 2H), 1.25 - 1.17 (m, 2H), 0.96 (s, 2H). LCMS (ES) [M+i] ⁺ m/z: 392.0.

Example 1.102

[0648] Synthesis of2-{[2-(4-methoxypyridin-2-yÎ)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amîno}-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 99)

CU^NH

[0649] Compound 99 was synthesized similar to Compound 98 by replacing 2(tributylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine. 'H NMR (400 MHz, DMSOéô) δ 9.04 (s, IH), 8.65 (d,7=6.1 Hz, 1H),7.91 (d,7=2.6 Hz, IH), 7.41 (dd, 7= 6.2, 2.6 Hz, IH),4.35 (s, 2H), 4.02 (s, 3H), 3.40 (s, 3H), 3.22 (m, 2H), 2.96 (t,7= 7.9 Hz, 2H), 2.11 - 1.99 (m, 2H), 1.23 - 1.09 (m, 2H), 0.96 (s, 2H). LCMS (ES) [M+l] ⁺ m/z: 421.7.

Example 1.103

[0650] Synthesis ofN-tert-butyl-2-{[2-(4-ethylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide(Compound 100)

[0651] Scheme 61 depicts a synthetic route for preparing an exemplary compound.

384

[0652] Step l

[0653] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 2-bromo-4-ethylpyridine (500 mg, 2.68 mmol, 1.00 equiv), dioxane (5.0 mL), hexamethyidistannane (l .06 g, 3.22 mmol, 1.20 equiv), and Pd(dppf)Cl₂ (196 mg, 0.26 mmol, 0.10 equiv). The mixture was stirred for 2 h at 100°C. The reaction mixture was cooled and diluted with 20 mL of H₂O and extracted with 3x10 mL of ethyl acetate. The combined organic phase was dried over lû anhydrous sodium sulfate, filtered, and the fîltrate was concentrated under reduced pressure. This resulted în 600 mg crude product of 4-ethyl-2-(trimethylstannyl)pyridine as a brown oil, which was used in the next step directly without further purification. LCMS (ESHM+l]⁴· m/z: 272.

[0654] Step

[0655] Into a 50-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed N-tert-butyl-2-([2-ch]oro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide

(300 mg, LOI mmol, l.00 equiv), dioxane (5.0 mL), 4-ethyl-2-(trimethylstannyl)pyridine (409 mg, l.5l mmol, L50 equiv), and Pd(dppf)Ch (73 mg, 0.10 mmol, 0.I0 equiv). The mixture was stirred for I6 h at l00°C. The reaction mixture was cooled and diluted with 20 mL of H2O and extracted with 3xl0 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated. The crude residue was purified by Prep-HPLC with the following conditions: Column, Kinetex EVO Ci8 Column, 21.2*150, 5 um, mobile phase, Water (0.1%FA) and CH3CN (10% Phase B up to 50% in 15 min); Detector, UV 254 nm. 29.6 mg (7.9%) of N-tert-buty 1-2-[[2-(4ethylpyridin-2-yl)-5H,6H,7H-cyclopcnta[d]pyrimidin-4-yl](methyl)amino]acetamide was obtained as a pink solid. 'H NMR (300 MHz, DMSO-Æ) δ 8.54 (d, ./=4.8 Hz, IH), 8.16 (s, IH), 7.69 (s, IH), 7.30 (dd, J=5.1, 1.7 Hz, IH), 4.16 (s, 2H), 3.27 (s, 3H), 3.15 (t, J= 7.5 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.72 (q, J =15 Hz, 2H), 2.08-1.91 (m, 2H), 1.30-1.19 (m, 12H). LCMS (ES) [M+l]⁺ m/z: 368.2.

Example 1.104

[0656] Synthesis of (2R)-N-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]propanamide (Compound 101)

[0657] Scheme 62 depicts a synthetic route for preparing an exemplary compound.

386

[0659] (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (0.5 g; 2.46 mmol; l eq.) was dissolved in dichloromethane (20 ml) and cooled in an ice bath. Tert-butylamine (0.28 mL; 2.71 mmol;

l.l eq.), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.03 g; 2.71 mmol; LJ eq.) and Ν,Ν-diisopropylethylamine (0.90 mL;

5.17 mmol; 2.1 eq.) were then added. The reaction was stirred to 25°C over 20 h and then taken up in ethyl acetate (100 ml), water (10 ml), and sodium bicarbonate solution (50 ml). The phases were separated, and the aqueous phase was extracted with more ethyl acetate (100 ml). The combined organics were washed with sodium chloride solution (30 ml), dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-[(lR)-l-(tert-butylcarbamoyl)ethyl]-N-methylcarbamate (0.61 g, 96%) as a white solid. LCMS (ES+):

(M+Na)⁺ = 281.0.

[0660] Step 2

387

[0661] Tert-butyl N-{l-[(1-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate (0.56 g; 1.66 mmol; 1 eq.) was dissolved in dichloromethane (8 ml) and cooled in an ice bath.

Trifluoroacetic acid (4 ml) was added slowly and the reaction was stirred to 25°C over 3 h. The reaction was evaporated, and the residue was co-evaporated with toluene and dried under high vacuum to give (2R)-N-tert-butyl-2-(methylamino)propanamide; trifluoroacetic acid, which was used dîrectly in the next step. LCMS (ES+): (M+Na)⁺= 159.0.

[0662] Step 3

o

[0663] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (400.00 mg; 2.12 mmol; 1.00 eq.) (Combi-Blocks) was dissolved in acetonitrile (7 ml), and to this was added (2R)-N-tert-butyl-2(methylamino)propanamide; trifluoroacetic acid (633.70 mg; 2.33 mmol; 1.10 eq.), and Hunig's base (1.84 mL; 10.58 mmol; 5.00 eq.). The mixture was stirred at 70°C for 15 h, the solvent was then evaporated under reduced pressure, and the residue was purified by column chromatography (50%

EtOAc in Hexanes) to give (2R)-N-tert-buty 1-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)propenamide (480 mg, 73%). LCMS (ES+): (M+H)⁺ = 310.9.

[0664] Step 4

388

[0665] (2R)-N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyi)amino)propanamide (140.00 mg; 0.45 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml) and the solution was purged with Ar gas. 4-methoxy-2-(tributylstannyl)pyridine (0.36 g; 0.90 mmol;

2.00 eq.) and tetrakis(triphenylphosphane) palladium (52.05 mg; 0.05 mmol; 0.10 eq.) were added. The reaction vessel was sealed and stirred in a heat bath at 110^uC for 15 h. After évaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1 % aqueous formic acid gradient) to give (2R)-N-tert-butyl-2-{[2-(4-meihoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide (67 mg, 39%) as a white solid. LCMS (ES+):

(M+H)⁺ = 384.4. 'H NMR (400 MHz, Methanol-74) Ô 8.51 (d, J= 5.8 Hz, IH), 7.95 (d, J= 2.6 Hz, IH),

7.63 (s, IH), 7.09 (dd, J= 5.8, 2.6 Hz, IH), 5.24 (q, J= 7.1 Hz, IH), 3.98 (s, 3H), 3.30-3.15 (m, 5H), 3.04-2.86 (m, 2H), 2.21 -2.01 (m, 2H), 1.45 (d, 7=7.1 Hz, 3H), 1.23 (s, 9H).

Example 1.105

[0666] Synthesis of N-tert-butyl-2-({2-[4-(dimethylamino)pyridin-2-yl]-5H,6H,7H15 cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide(Compound 102)

[0667] Scheme 63 depicts a synthetic route for preparing an exemplary compound.

389

Scheme 63

[0668] Step l

^HO—

I

Sn(Bu)₃CI, BuLi, THF

23.77%

[0669] Into a 100-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed ethanolamine (l.OO g, i6.371 mmol, 2.00 equiv) and THF (40.00 mL). This was followed by the addition of η-BuLi (l3.00 mL, 138.006 mmol, 16.86 equiv) dropwise with stirring at 0°C in 10 min. The resulting solution was stirred for 0.5 h at 0°C. To this was added a solution of 4dimethylaminopyridine (1.00 g, 8.185 mmol, 1.00 equiv) in THF (5 mL) dropwise with stirring at 0°C in

5 min. The resulting solution was stirred for Ih at 0°C. The resulting solution was stirred for 0.5 h at room température. To the mixture was added tributyltin chloride (6.66 g, 20.460 mmol, 2.50 equiv) dropwise with stirring at -78°C in 10 min. The resulting solution was then stirred ovemight at room température. The resulting solution was diluted with 50 mL of H₂O and extracted with 3x50 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (20%-50%EA). This resulted in 0.8 g (23.77%) ofN,N-dimethyl-2-(tributylstannyl)pyridin-4amine as a yellow oil. LCMS (ES) [M+l]⁺ m/z 413.2.

[0670] Step 2

390

Intermediate 11

Pd(PPh₃)₄, dioxane

11.55%

[0671] Into a 40-mL round-bottom flask purged and maintained in an inert atmosphère of argon, was placed N,N-dimethyl-2-(tributylstannyl)pyridin-4-amine (418.00 mg, 1.016 mmol, 1.00 equiv),N-(tertbuty 1)-2-((2-ch loro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (301.69 mg, 5 1.016 mmol, 1.00 equiv), Pd(PPh₃)4 (l 17.46 mg, 0.102 mmol, 0.10 equiv), and dioxane ( 10.00 mL). The resulting solution was stirred for 24 hr at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10%30%MeOH). The collected crude product was purified by Flash-Prep-HPLC (Prep-C18, 20-45M, 120 g, Tianjin Bonna-AgelaTechnologïes; gradient elution of 20% MeCN in water to 45% MeCN in water over 10 a 10 min period, where both solvents contain 0.1% FA). This resulted in 44.9 mg (11.55%) ofN-(tertbutyl)-2-((2-(4-(dimethylamino)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide formate as a light yellow solid. 'H NMR. (300 MHz, DMSO-TQ/wr) δ 8.23 (s, IH), 8.21 (d, 7=6.0 Hz, IH), 7.68 (s, IH), 7.59 (d,7=2.7 Hz, IH), 6.72 (dd,7=6.2, 2.8 Hz, 1 H), 4.17 (s, 2H), 3.13 (t,7=7.3 Hz, 2H), 3.07 (s, 6H), 2.82 (t,7=7.7 Hz, 2H), 1.89-2.08 (m, 2H), 1.22 15 (s, 9H). LCMS (ES) [M+l]⁺m/z 383.2.

Example 1.106

[0672] Synthesis ofN-tert-butyl-2-{methyl[2-(3-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 103)

H

[0673] Scheme 64 depicts a synthetic route for preparing an exemplary compound.

391

Pd(dppf)Cl₂, CsF, Dioxane, 120°C

Intermediate II

Scheme 64

[0674] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed N-tert-buty l-2-([2-chloro-5H,6H,7H-cyclopenta[d]py ri midin-4-yl](methyl)amino)acetamide (800.00 mg, 2.695 mmol, 1.00 equiv), 3-methyl-2-(tributylstannyl)pyridine (1.23g, 3.235 mmol, 1.20 equiv), Pd(dppf)CI₂ ( 197.22 mg, 0.270 mmol, 0.10 equiv), CsF (409.44 mg, 2.695 mmol, 1.00 equiv), and dioxane (20.00 mL). The resulting solution was stirred for 16 hr at 120°C. The reaction mixture was cooled. The resulting solution was extracted with 3x50 mL of dîchloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-002): Column, XBridge BEH130 Prep Cl 8 OBD Column, 19*150mm 5um 13nm; mobile phase, Water (0.05%FA) and ACN (10% PhaseB up to 50% in 8 min). This resulted in 41.3 mg (4.3%) ofN-tert-butyl-2-[methyl[2-(3methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide formate as a pink solid. Ή NMR (300 MHz, DMSO-7₆) δ 8.41 (d,7=4.7 Hz, IH), 8.19 (s, IH), 7.68 (4, J ^1.1 Hz, IH), 7.49 (s, IH), 7.31 (dd, 7= 7.7, 4.7 Hz, IH), 4.11 (s, 2H), 3.18 (s, 3H), 3.14 (d, 7= 7.4 Hz, 2H), 2.78 (t,7 = 7.8 Hz, 2H), 2.28 (s, 3H), 2.05-1.95 (m, 2H), 1.22 (s, 9H).LCMS (ES) [M+l] ⁺ m/z: 354.2.

Exampie 1.107

[0675] Synthesis of N-tert-buty 1-2-{methyl[2-(5-methylpyridin-2-y 1)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 104)

[0676] Scheme 65 depicts a synthetic route for preparing an exemplary compound.

392

Scheme 65

[0677] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed Ntert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (500 mg, l .69 5 mmol, 1.0 equiv), 5-methyl-2-(tributyistannyl)pyridine (712 mg, 1.86 mmol, 1.1 equiv), dioxane (5.0 mL), and Pd(PPh₃)4 (391 mg, 0.34 mmol, 0.2 equiv). The mixture was stirred for 12 h at 100°C. It was then concentrated to remove the solvent, and the crude product was purified by Prep-HPLC with the following conditions: Column, Atlantis HIL1C OBD Column, 19*150 mm*5 uni, Mobile phase, Water (0.1% FA) and CH₃CN (5% Phase B up to 35% in 8 min), Detector, UV 254 nm. This resulted 48.3 mg 10 (7%) of N-(tert-butyl)-2-(methyl(2-(5-methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)amino)acetamide formate as a light brown solid. ’HNMRQOO MHz, DMSO-7<),ppm)'· δ 8.50 (d, J —

2.1 Hz, IH), 8.26 (d, 7= 8.1 Hz, JH), 8.18 (s, IH), 7.70-7.68 (m, 2H), 4.13 (s, 2H), 3.26 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.36 (s, 3H), 2.01-1.96 (m, 2H), 1.24 (s, 9H). LCMS (ES, m/z): [M+H] ⁺:

354.1.

Example 1.108

[0678] Synthesisof2-{methyl[2-(4-methylpyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-N-(l-methy lcyclopentyl)acetamide (Compound 105)

[0679] Compound 105 was synthesized similar to compound 62 by replacing 2-amino-2-methyl-1propanol with 1-methy Icyclopentanamine. ^!H NMR (300 MHz, DMSO-cAjyim) δ 8.51 (d, 7= 4.9 Hz, IH), 8.16 (s, IH), 7.76 (s, IH), 7.27 (dd, 7= 5.2, 1.7 Hz, IH), 4.16 (s, 2H), 3.28 (s, 3H), 3.15 (t,7= 7.3

393

Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.41 (s, 3H), 2.07-1.89 (m, 4H), l.60-1.40 (m, 6H), 1.28 (s, 3H).

LCMS (ES) [M+lf m/z 380.2.

Example 1.109

[0680] Synthesis of N-tert-buty 1-2-{methyl[2-(pyrimidin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin5 4-yl]amino}acetamide (Compound 106)

[0681 ] Scheme 66 depicts a synthetic route for preparing an exemplary compound.

Cl

Pd(PPh₃)₄, Cul

32.47%

[0682] Step 1

Cl

Pd(PPh₃)₄, Cul

32.47%

Cl

[0683] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen, was placed 2,4dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, 1.00 equiv), 215 (tributylstannyl)pyrimidine (1275.94 mg, 3.46 mmol, 1.30 equiv), CsF (807.78 mg, 5,32 mmol, 2.00 equiv), Pd(PPh₃)₄ (307.25 mg, 0.26 mmol, 0.10 equiv), Cul (50.64 mg, 0.26 mmol, 0.10 equiv), and DMF (10.00 mL). The resulting solution was stirred for 8 h at 110°C. The reaction mixture was cooled to room température. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NH4HCO3)

394

and CAN (30% Phase B up to 60% in 11 min); Detector, 254. This resulted in 200 mg (32.47%) of 2-[4chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yI]pyriniidine as a brown solid. LCMS (ES) [M+H]⁺ m/z: 232.

[0684] Step

2

[0685] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen was placed 2-[4chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl]pyrimidine (150.00 mg, 0.65 mmol, 1.00 equiv), N-tertbuty 1-2-(methylamino)acetamide (121.39 mg, 0.84 mmol, 1.30 equiv), Pd(OAc)₂ (14.54 mg, 0.06 mmol, 10 0.10 equiv), ΒΓΝΑΡ (80.63 mg, 0.13 mmol, 0.20 equiv), CS2CO3 (421.90 mg, 1.29 mmol, 2.00 equiv), and dioxane (8.00 mL). The resulting solution was stirred overnight at 100°C. The reaction mixture was cooled to room température and concentrated. The crude product (500 mg) was purified by Prep-HPLC with the foîlowing conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% HCOOH) and CAN (20% Phase B up to 50% in 11 min); Detector, 254. This 15 resulted in 82.1 mg (32.90%) of N-tert-buty l-2-[methyl [2-(pyrimidin-2-yl)-5 H,6H,7Hcyclopenta[b]pyridin-4-yl]amino]acetamide formate as a yellow oil. ’HNMR (300 MHz, DMSO-76) δ 8.91 (d, 7= 4.8 Hz, 2H), 8.17 (s, IH), 7.61 (s, IH), 7.57-7.45 (m, 2H), 3.98 (s, 2H), 3.09 (s, 3H), 3.04 (t, J= 7.2 Hz, 2H), 2.88 (t, 7 = 7.7 Hz, 2H), 2.09-1.93 (m, 2H), 1.27 (s, 9H). LCMS (ES, m/zy [M+H] ⁺: 341.2.

Example L110

[0686] Synthesis ofN-tert-butyl-2-({2-[5-(2-hydroxyethyl)-l,3-thiazol-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 107)

395

[0687] Scheme 67 depicts a synthetic route for preparing an exemplary compound.

Br

Zn, Zn(CN)₂, Pd(dppf)CI₂DMA, 100°C, 2 h

(NH₄)₂S,TEA, DMF rt, 30 min

Scheme 67

[0688] Step 1

PCC, DCM, rt, 16 h

[0689] Into a 250-mL round-bottom flask, was placed 4-(benzyloxy)butan-l-ol (5.00 g, 27.74 mmol, 1.00 equiv), DCM (100 mL), and PCC (11.96 g, 55.47 mmol, 2.00 equiv). The mixture was stirred for 16 h at room température, filtered, and the fïltrate was concentrated under reduced pressure. The residue

396

was purified by silica gel column and eluted with ethyl acetate/petroleum ether (1/10). This resulted in 2.5 g (50%) of 4-(benzyloxy)butanal was obtained as a colorless solid. LCMS (ES)[M+l]⁺ m/z: 179. [0690] Step

Br

[0691] Into a 100-mL 3-necked round-bottom flask, was placed 4-(cyclohexylmethoxy)butan-I-ol (2.50 g, 13.42 mmol, 1.00 equiv), DMSO (30 mL). This was followed by the addition of bromotrimethylsilane (2.05 g, 13.42 mmol, 1.00 equiv) dropwise with stirring at 0°C. The resulting solution was stirred for 6 h at room température. The reaction was quenched with 100 mL of H₂O, 10 extracted with 3x30 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the fîltrate was concentrated. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 1.5 g (43.4%) of 4-(benzyioxy)-2bromobutanal as light brown oil. LCMS (ES) [M+l]⁺ m/z: 257.

[0692] Step

3

[0693] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (600 mg, 2.02 mmol, 1.00 equiv), DMA (6.0 mL), Zn(CN)₂ (474 mg, 4.04 mmol, 2.00 equiv), Zn (264 20 mg, 4.04 mmol, 2.00 equiv), and Pd(dppf)Cl₂ (147 mg, 0.20 mmol, 0.10 equiv). The mixture was stirred for 2 h at 100^ûC. The reaction mixture was cooled and filtered. The fîltrate was diluted with 20 mL of

H₂O, extracted with 3x20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the fîltrate was concentrated. The residue was purified by silica gel cohimn with ethyl acetate/petroleum ether (1/1). This resulted in 550 mg (95%) of N-tert-butyl-221052

397

([2-cyano-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide as a yellow solid. Ή NMR (300 MHz, DMSO-7₀) δ 7.64 (s, IH), 4.10 (s, 2H), 3.18 (s, 3H), 3.13 (t, 7= 7.5 Hz, 2H), 2.78 (t, 7= 7.8 Hz, 2H), 2.04-1.88 (m, 2H), 1.27 (s, 9H). LCMS (ES) [M+l]⁺ m/z: 288.

[0694] Step 4

[0695] Into a 100-mL round-bottom flask was placed N-tert-butyl-2-([2-cyano-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (530 mg, 1.84 mmol, 1.00 equiv), DMF (6.0 mL), (NH₄)₂S (251 mg, 3.68 mmol, 2.00 equiv), and TEA (373 mg, 3.68 mmol, 2.00 equiv). The resulting solution was stirred for 0.5 h at room température. The reaction solution was diluted with 20 10 mL of H₂O, extracted with 3x20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was washed with 30 ml of hexane. This resulted in 500 mg (84.3%) ofN-tert-butyl-2-([2-carbamothioyl-5H,6H,7Hcyclopcnta[d]pyrimidin-4-yl](methyl)amino)acetam!de as a yellow solid. 'H NMR (300 MHz, DMSOdb) δ 10.10 (br, IH), 9.45 (br, IH), 7.60 (s, 1 H), 4.01 (s,2H),3.25 (s, 3H), 3.12 (t,7=7.5 Hz, 2H), 2.79 15 (t, 7=7.8 Hz, 2H), 2.04-1.88 (m, 2H), 1.25 (s, 9H). LCMS (ES) [M+l ]⁺m/z: 322.

[0696] Step 5

[0697] Into a 100-mL round-bottom flask, was placed Ν-tert-buty 1-2-([2-carbamothioy 1-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (400 mg, 1.24 mmol, 1.00 equiv), DMF (5.0

398 mL), DIEA (321 mg, 2.48 mmol, 2.00 equiv), and 4-(benzyloxy)-2-bromobutanal (383 mg, 1.49 mmol, 1.20 equiv). The resulting solution was stirred for 16 h at room température. The reaction was diluted with 20 mL of H₂O, extracted with 3x20 mL of ethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated. The residue was purified 5 by silica gel column with ethyl acetate/petroleum ether (1/10). This resulted in 380 mg (61%) of2-[[2([[4-(benzyloxy)-l-oxobutan-2-yl]sulfanyl]methanimidoyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]-N-tert-butylacetamide as a brown solid. LCMS (ES) [M+l]⁺ m/z: 498.

[0698]

[0699] Into a 100-mL round-bottom flask, was placed 2-[[2-([[4-(benzyloxy)-l-oxobutan-2yl]sulfanyl]methanimidoyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-tertbutylacetamide (380 mg, 0.76 mmol, ] .00 equiv), and AcOH (4.0 mL). The mixture was stirred for 1 h at 100°C. The reaction mixture was cooled to room température, and diluted with 10 mL of H₂O. The pH value ofthe solution was adjusted to 8 withNal-ICO₃ (10 %), extracted with 3x10 mL ofethyl acetate, the organic layers were combined and dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/1). 180 mg (49%) of 2-[(2-[5-[2-(benzyloxy)ethyl]-1,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-tert-butylacetamide was obtained as a brown solid. LCMS (ES) [M+l]⁺ m/z: 480.

[0700] Step 6

399

[0701 ] Into a 50-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-[(2-[5-[2-(benzyloxy)ethyl]-l,3-thiazol-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin4-yl)(methyl)amino]-N-tert-butylacetamide (180 mg, 0.37 mmol, 1.00 equiv), and DCM (3.0 mL). This was followed by the addition of BBn (1.8 mL, 1.80 mmol, 4.80 equiv) dropwise with stirring at -78°C. The resulting solution was stirred for 2 h at 0°C. The reaction was then quenched by the addition of 10 mL of water, and extracted with 3x5 mL of dichloromethane. The organic layers were combined, dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The crude product was purified by Prep-HPLC with the following conditions: Column, Welch XB-C18, 21.2*250 mm, 5 um, Mobile phase, Water (0.05%NH4ÛH) and CHaCN (10% Phase B up to 65% in 15 min), Detector, UV 254 nm. This resulted in 53.0 mg (36.2%) ofN-tert-butyl-2-([2-[5-(2-hydroxyethyl)-l,3-thiazol-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide as a white solid. Ή NMR (300 MHz, DMSO-Æ) § 7.68 (s, IH), 7.62 (s, IH), 4.91 (t, 7= 5.1 Hz, 1 H), 4.14 (s, 2H), 3.65 (q,7=6.3 Hz, 2H), 3.22 (s, 3H), 3.10 (t, 7= 7.5 Hz, 2H), 2.98 (t, 7= 6.3 Hz, 2H), 2.79 (t, 7= 7.8 Hz, 2H), 2.06-1.90 (m, 2H), 1.26 (s, 9H). LCMS (ES) [M+1 ]⁺ m/z: 390.2.

Example 1.111

[0702] Synthesis of (2R)-N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4-yl]armno}propanamide (Compound 108)

[0703] Stepl

400

[0704] (2R)-2-[(tert-butoxycarbonyl)(methyl)amino]propanoic acid (0.50 g; 2.46 mmol; l.OO eq.) was dissolved in dichloromethane (20 ml) and cooled in an ice bath. Cyclohexanamine (0.31 mL; 2.71 mmol; 1.10 eq.), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 1.03 g; 2.71 mmol; 1 JO eq.)), and Hunig's base (0.90 mL; 5.17 mmol;

.10 eq.) were then added. The reaction was stirred to 25°C over 20 h and then taken up in ethyl acetate (100 ml), water (10 ml), and sodium bicarbonate solution (50 ml). The phases were separated, and the aqueous phase was extracted with more ethyl acetate (100 ml). The combined organics were washed with sodium chloride solution (30 ml), dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-{1-[(1hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate (0.7 g, 99%) as a white solid. LCMS (ES+): (M+Na)⁺ = 307.0.

[0705] Step 2

[0706] Tert-butyl N-{l-[(l-hydroxy-3-phenylpropan-2-yl)carbamoyl]ethyl}-N-methylcarbamate (0.56 g; 1.66 mmol; 1.00 eq.) was dissolved in dichloromethane (8 ml) and cooled in an ice bath. Trifluoroacetic acid (4 ml) was added slowly and the reaction was stirred to 25°C over 3 h. The reaction was evaporated, and the residue was co-evaporated with toluene and dried under high vacuum to give (2R)-N-cyclohexyl-2-(methylamino)propanamide; trifluoroacetic acid which was used directly in the next step.

[0707] Step 3

40]

[0708] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (420.00 mg; 2.22 mmol; l.OO eq.) was dissolved in acetonitrîle (7 mi), andto this was added (2R)-N-cyclohexyl-2-(methylamino)propanamide; trifluoroacetic acid (729.02 mg; 2.44 mmol; 1.10 eq.), and Hunig’s base (1.93 mL; 11.11 mmol; 5.00 eq.). The mixture was stirred at 70°C for 15 h, the solvent was then evaporated under reduced pressure, and the residue was purified by column chromatography (50% EtOAc in Hexanes) to give (2R)-N-tertbutyl-2-({2-chloro-5H,6H,7H-cyciopenta[d]pyrimidin-4-yl}(methyl)amino)propenamide (480 mg, 73%). LCMS (ES+): (M+Hf = 336.9.

[0709] Step 4

[0710] (2R)-2-({2-chloro-5H,6H,7H-cycIopenta[d]pyrimidin-4-yl} (methy l)amino)-Ncyclohexylpropanamide (150.00 mg; 0.45 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml), and the solution was purged with Ar gas. 2-(tributylstannyl)pyridine (0.29 mL; 0.89 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (51.46 mg; 0.04 mmol; 0.10 eq.) were added. The reaction vessel was sealed and stirred in a heat bath at 110°C for 15 h. After évaporation, the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1 % aqueous formic acid gradient) to give (2R)-N-cyclohexyl-2-{methyl[2-(pyridin-2-yl)-5I-l,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]propanamide (132 mg) as a white solid. LCMS (ES+): (M+H)' = 380.4. Ή NMR (400 MHz, DMSO-76) δ 8.82 - 8.56 (m, I H), 8.44 - 8.27 (m, IH), 8.27 - 8.07 (m, IH),

7.99-7.77 (m, 1 H), 7.57 - 7.36 (m, IH), 5.26-5.04 (m, 1 H), 3.65 -3.50 (m, IH), 3.23 - 34 5 (m, 2H),

402 .09 (s, 3H), 2.93 -2.72 (m,2H),2.Il - l.89(m, 2H), 1.78- 1.6) (m, 2H), l.61 - 1.47 (m, 3H), 1.351.12 (m, 6H), 1.06 - 0.89 (m, 2H).

Example

1.112

[0711] Synthesis of (2R)-N-(3,3-difluorocyclobutyl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yI]amino}propanamide (Compound 109)

[0712] Compound 109 was synthesized similar to Compound 108 by replacing cyclohexylamine with 3,3-difluorocyclobutanamine. LCMS (ES+): (M+H)⁺ = 388.3. 'H NMR (400 MHz, DMSO-r/6) δ

8.82 (d, 7=7.1 Hz, IH), 8.72-8.66 (m, IH), 8.31 (d,7= 7.9 Hz, IH), 7.95 -7.88 (m, IH), 7.51-7.43 (m, IH), 5.15 (q, 7= 7.0 Hz, IH), 4.17 - 4.04 (m, IH), 3.24 - 3.14 (m, 2H), 3.10 (s, 3H), 2.95 - 2.58 (m, 5H), 2.49 - 2.41 (m, 1 H), 2.09 - 1.90 (m, 2H), 1.34 (d, J = 7.0 Hz, 3H).

Example 1.113

[0713] Synthesis of N-tert-butyl-2-[methy 1(2-{lH-pyrazolo[3,4-c]pyridin-5-y 1}-5H,6H,7H15 cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 110)

[0714] Scheme 68 depicts a synthetic route for preparing an exemplary compound.

403

DHP, p-TsOH

1) Pd(PPh₃)₄, 1Û0°C, 2 h

2) Pd(PPh₃}₄, CsF, 100°G, 16 h

Intermedlate II

Scheme 68

[0715] Step 2

[0716] To a stirred solution of 5-bromo-i H-pyrazolo[3,4-c]pyridine (4.00 g, 20.200 mmol, 1.00 equiv) in DCM (32.00 mL), THF (32.00 mL), and DMF (2.00 mL) were added DHP (3.80 g, 45.175 mmol, 2.24 equiv) and p-Toluenesulfonic acid (0.35 g, 0.002 mmol, 0.1Û equiv) at room température under an air atmosphère. The resulting mixture was stirred for 12 h at 50°C under an air atmosphère.

The mixture was allowed to cool down to room température. The resulting mixture was concentrated under reduced pressure. The residue was dissolved in 10% NaHCOj (100 mL). The resulting mixture was extracted with EtOAc (3 xlOO mL). The combined organic layers were washed with brine (1x100 mL) and dried over anhydrous Na2SÛ4. After filtration, the filtrate was concentrated under reduced pressure. This resulted in 5-bromo-i-(oxan-2-yl)pyrazolo[3,4-c]pyridine (3 g, 52.64%) as ayellow solid.

LCMS (ES) [M+l] ⁺ m/z: 282.

[0717] Step 3

404

1) Pd(PPh₃)₄, 100°C, 2 h

2) Pd(PPh₃)₄, CsF, 100°C, 16 h

Intermediate II

[0718] To a solution of 5-bromo-1 -(oxan-2-yl)pyrazolo[3,4-c]pyridine (71.30 mg, 0.253 mmol, 1.5 equiv) and Sn₂Me₆ (91.07 mg, 0.278 mmol, 1.65 equiv) in dioxane (2.00 mL) was added Pd(PPh₃)₄(19.5 mg, 0.017 mmol, 0.1 equiv) after stirring for 2 h at 100°C under a nitrogen atmosphère. The mixture was cooled to room température. To the above mixture was added N-tert-butyl-2-([2-chloro5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Intermediate II, 50.00 mg, 0.168 mmol, 1.00 equiv), CsF (51.18 mg, 0.337 mmol, 2 equiv), and Pd(PPh₃)₄ (19.5 mg, 0.017 mmol, 0.1 equiv) at room température. The resulting mixture was stirred for an additional 16 h at !00°C under a nitrogen atmosphère. The resulting mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography and eluted with PE/THF (1:1 ) to afford N-tert-butyl-2[methyl([2-[l-(oxan-2-yl)pyrazolo[3,4-c]pyrtdin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl])amino]acetamide (50 mg, 64.02%) as a yellow solid. LCMS (ES) [M+l ]⁺ m/z: 464.

[0719] Step 4

[0720] A solution of N-tert-butyl-2-[methyl([2-[l-(oxan-2-yl)pyrazolo[3,4-c]pyridin-5-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl])amino]acetamide (400.00 mg, 0.863 mmol, ! .00 equiv) in 4NHCl(g) in MeOH (4,00 mL, 131.648 mmol, 152.57 equiv) was stirred for 2 h at 60°C under an air atmosphère. The mixture was cooled to room température. The resulting mixture was concentrated under reduced pressure. The crude product (500 mg) was purified by Prep-HPLC to afford N-tert-buty 1-220 [methyl(2-[lH-pyrazolo[3,4-c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide

405 formate (76 mg, 23.21%) as a white solid. ’H NMR (300 MHz, DMSOA) ^lH NMR (300 MHz, DMSOd&) δ 13.71 (br, 3H), 9.09 (s, IH), 8.81 (d, 7= 1.2 Hz, IH), 8.28 (s, IH), 8.15 (s, 1 H), 7.77 (s, IH), 4.15 (s, 2H), 3.30 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.06-1.92 (m, 2H), 1.22 (s, 9H). LCMS (ES) [M+l] ⁺ m/z: 380.2.

Example 1.114

[0721] Synthesis of 2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 111)

[0722] Compound 111 was synthesized similar to Compound 98 by replacing 2(tributylstannyl)pyridine with l-methyl-4-(tributylstannyl)-lH-imidazole. 'H NMR (400 MHz, DMSO7₆)Ô9.I5 (s, IH), 8.34 (s, 1 H), 8.22 (s, I H), 4.35 (s,2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.14 (s, 2H), 2.92 (t, 7= 7.9 Hz, 2H), 2.02 (p, 7= 7.9 Hz, 2H), 1.24 - 1.16 (m, 2H), 0.98 (s, 2H). LCMS (ES) [M+1R m/z: 395.2.

Example 1.115

[0723] Synthesis of (2R)-N-tert-buty 1-2-{methy 1[2-(1-methyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-y!]amino}propanamide (Compound 112)

[0724] Compound J 12 was synthesized similar to Compound 101 replacing with l-methyl-4(tributylstannyl)-lH-imidazole. 'H NMR (400 MHz, DMSO-7ô) δ 8.09 (s, IH), 8.02 (s, IH), 7.75 (s, 1 H), 5.17 (q, 7= 7.0 Hz, IH), 3.75 (s, 3H), 3.15 (s, 3H), 3.24 - 3.01 (m, 3H), 2.87-2.78 (m, 2H), 2.06 1.90 (m, IH), 1.31 (d, 7= 7.1 Hz, 3H), 1.20 (d,7= 1.1 Hz, 9H). LCMS (ES) [M+l] ⁺ m/z: 357.4.

406

Example El 16

[0725] Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethyl)pyndin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yJ}(methyl)amino)acetamide (Compound 113)

[0726] Scheme 69 depicts a synthetic route for preparing an exemplary compound.

LD A, THF

-7B°C-rt, 4 h

NaBH₄, EtOH DHP, TsOH

O 0°C-rt, 3 h N DCM, rt, 2 h

Clc|+^+++^OH

TsOH, MeOH rt. 1 h

Scheme 69

[0727] Step 1

O

-78°C-rt, 4 h

[0728] Into a 250-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 2-ch!oro-4-methylpyridine (10.0 g, 78.39 mmol, 1.0 equiv) and THF (100 mL).

407

This was followed by the addition of LDA (2 M in THF) (l 17.5 mL, 235.17 mmol, 3.0 equiv) at -78 C. After addition, the reaction solution was stirred for 2 hr at -78^ÛC. To this, diethyl carbonate (13.9 g, ] 17.66 mmol, l .50 equiv) was added. The mixture was stirred for 3 h at room température. The reaction was then quenched by the addition of NHæl (aq) (200 mL) and extracted with 3x100 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (4:1). This resulted in 10.0 g (64%) of ethyl 2-(2-chloropyridin-4-yl)acetate was obtained as a yellow oil. LCMS (ES) [M+l ]⁺ m/z: 200.

[0729] Step 2

NaBH₄, EtOH N η O 0°C~rt, 3 h _: Ί

[0730] Into a 25Û-mL 3-necked round-bottom flask was placed ethyl 2-(2-chloropyridin-4-yl)acetate (10.0 g, 50.09 mmol, LO equiv) and EtOH (100 mL). This was followed by the addition ofNaBH₄ (9.50 g, 251.10 mmol, 5.0 equiv) in several batches at Û°C. After addition, the mixture was stirred for 3 h at room température. The reaction was then quenched by the addition of water (300 tnL) and extracted with 3x100 mL of dichloromethane. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This resulted in 7.5 g (95%) of 2-(2chloropyridin-4-yl)ethan-l-ol as a yellow oil, which was used in the next step directly without further purification. LCMS (ES) [M+l]⁺ m/z: 158.

[0731] Step 3

DHP, TsOH NV DCM, rt, 2 h ^Ν|Ύ

Cl

[0732] Into a 100-mL round-bottom flask was placed 2-(2-chloropyridin-4-yl)ethan-l-ol (4.78 g, 30.33 mmol, 1.0 equiv), DCM (40 mL), DHP (5.10 g, 60.63 mmol, 2.0 equiv), and TsOH (524 mg, 3.04 mmol, 0.1 equiv). The reaction was stirred for 2 h at room température. The solution was concentrated to remove the solvent, and the residue was purified by silica gel column with ethyl acetate/petroleum ether (1/3) to vield 2.0 g (27%) of 2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine as a colorless oil. LCMS (ES) [M+l] m/z: 242.

408

[0733]

Step 4

[0734] Into a 50-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethyl)pyridine (800 mg, 3.31 mmol, LO equiv), dioxane (10.0 mL), hexamethyldistannane (1.3 g, 3.97 mmol, 1.2 equiv), and Pd(PPha)4 (765 mg, 0.66 mmol, 0.2 equiv). The mixture was stirred for 2 h at l00°C. After being cooled to room température, the reaction solution was used in the next step directly without purification. LCMS (ES)

[M+l]⁺ m/z: 372.

[0735] Step 5

[0736] Into a 40-mL vial purged and maintained in an inert atmosphère of nitrogen was placed 4-(2((tetrahydro-2H-pyran-2-yl)oxy)ethyl)-2-(trimethylstannyl)pyridine (the reaction solution of last step), dioxane (10.0 mL), N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](meÎhyl)amino)acetamide (Intermediate II, 385 mg, L30 mmol, 0.6 equiv), and Pd(PPh3)4 (500 mg, 0.43 mmol, 0.2 equiv). The mixture was stirred for 12 h at l00°C. The mixture was cooled and concentrated to remove the solvent, and the residue was purified by silica gel column with THF/ΡΕ (2/l) to yield 500 mg (50%) ofN-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2y|)oxy)ethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide as a yellow oiL LCMS (ES) [M+lf m/z: 468.

[0737] Step 6

[0738] Into a 20-mL vial was placed N-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro-2H-pyran-2y|)oxy)ethy])pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide (l 84 mg, 0.39 mmol, l .0 equiv), methanol (5.0 mL), and para-toluene sulfonic acid (68 mg, 0.39 mmol, 1.0 equiv).

S The reaction solution was stirred for 1 h at room température. The reaction solution was purified by Prep-HPLC with the foîlowing conditions: Column, Atlantis HIL1C OBD Column, 19*150 mm*5 uni, mobile phase, Water(10 mmol/L) with (0.5 HCOOH) and MeOH:ACN=l:l (33% Phase B up to 45% within 9 min), Detector, UV 254 nm. This resulted in 89.2 mg (59%) ofN-(tert-butyl)-2-((2-(4-(2hydroxyethyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide formate as an off-white solid. 'H NMR (300 MHz, DMSO-Ts, ppm): δ 8.53 (d, J⁼ 4.8 Hz, IH), 8.24 (br, IH), 8.17 (s, IH), 7.70 (s, IH), 7.32 (d, J= 3.6 Hz, 11-1), 4.16 (s, 2H), 3.70 (t, 7= 6.6 Hz, 2H), 3.27 (s, 3H), 3.15 (t, J= 7.2 Hz, 2H), 2.86-2.79 (m, 4H), 2.04-1.94 (m, 2H), 1.23 (s, 9H). LCMS (ES, m/z): [M+H]⁺: 384.2.

Example 1.117

[0739] Synthesis of (2R)-N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H.7Hcyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 114)

[0740] Scheme 70 depîcts a synthetic route for preparing an exemplary compound.

Scheme 70

[0741] Step 1

[0742] (2R)-2-[(tert-butoxycarbonyl)amino]-3-methylbutanoic acid (0.50 g; 2.30 mmol; 1.00 eq.) was dissolved in dichloromethane (23 ml) and cooled in an ice bath. Tert-butylamine (0.27 mL; 2.53 mmol; 1.10 eq.), l-[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate (HATU, 0.96 g; 2.53 mmol; 1.10 eq.), and Hunig's base (0.84 mL; 4.83 mmol; 2.10 eq.) were then added. The reaction was stirred to 25°C over 20 h and then taken up in ethyl acetate 10 (100 ml), water (10 ml), and sodium bicarbonate solution (50 ml). The phases were separated, and the aqueous phase was extracted with more ethyl acetate (100 ml). The combined organics were washed with sodium chloride solution (30 ml), dried over sodium sulfate, and evaporated. The residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-{ 1 -[( 1 hydroxy-3-phenylpropan-2-yI)carbamoyl]ethyl]-N-methylcarbamate (0.6 g, 96%) as a white solid.

[0743] Tert-butyl N-{ 1-[(1-hydroxy-3-phenyl propan-2-y l)carbamoyl] ethyl]-N-methyl carbamate (0.56 g; 1.66 mmol; 1.00 eq.) was dissolved in dichloromethane (7 ml) and cooled in an ice bath.

Trifluoroacetic acid (3.7 ml) was added slowly and the reaction was stirred to 25°C over 3 h. The reaction was evaporated, and the residue was co-evaporated with toluene and dried under high vacuum to give (2R)-2-amino-N-tert-butyl-3-methylbutanamide; trifluoroacetic acid, which was used directly in the next step. LCMS (ES+): (M+H)⁺ = 172.9.

[0744]

Step 2

[0745] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200.00 mg; l .06 mmol; l.OO eq.) was dissolved in acetonitrile (4 ml), and to this was added (2R)-2-amino-N-tert-butyl-3-methylbutanamide, trifluoroacetic acid (333.18 mg; Llômmol; l.lOeq.), and Hunig's base (0.92 mL; 5.29 mmol; 5.00 eq.). The mixture was stirred at 70°C for 15 h, the solvent was then evaporated under reduced pressure, and the residue was purified by column chromatography (50% EtOAc in Hexanes) to give (2R)-N-tert-butyl2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-3-methylbutanamide (266 mg, 77%).

LCMS (ES+): (M+H)⁺= 324.9. ΉNMR (400 MHz, DMSO-rf6) δ 7.64 (s, IH), 6.85 (d, J= 8.3 Hz, IH), 4.32 - 4.24 (m, l H), 2.75 - 2.65 (m, 4H), 2.09 - i .96 (m, 3H), l .25 (s, 9H), 0.92 - 0.86 (m, 6H).

[0746] Step 3

[0747] (2R)-N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidm-4-yl}amino)-3methylbutanamide (262 mg; 0.81 mmol; I eq.) was dissolved in N,N-dimethylfonnamide (15 ml) and cooled in an ice bath. Sodium hydride (34 mg; 0.85 mmol; l .05 eq., 60%) was added and the mixture was stirred for 20 min. lodomethane (53 pL; 0.85 mmol; l .05 eq.) was then added and the reaction was stirred to 25 “C over ] .5 h. The reaction was quenched by the addition of water (90 ml) and then extracted with ethyl acetate (2 x 100 ml). The combined organic phases were washed with water (30 ml) and sodium chloride solution (30 ml), and then dried over sodium sulfate. After évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give (2R)-N-tert-butyl-221052

412

({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-3-methylbutanamide (255 mg, 93%) as a film. MS (ES+): (M+H)⁺ = 339.3.

[0748] Step 4

[0749] (2R)-N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-y!}(methyl)ammo)-3methylbutanamide (147.00 mg; 0.43 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (3.5 ml), and the solution was purged with Ar gas. 2-(tributylstannyl)pyridine (0.28 mL; 0.87 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (50.13 mg; 0.04 mmol; 0.10 eq.) were added The reaction vessel was sealed and stirred in a heat bath at 110°C for 15 h. After évaporation, the residue was purified by reverse phase chromatography (Waters XSeiect CSH C18 column, 0-70% acetonitrile/0.1 % aqueous formic acid gradient) to give (2R)-N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]butanamîde (98 mg, 59%) as a Light yellow solid. LCMS (ES+): (M+H)⁺ = 382.0. 'H NMR (400 MHz, DMSO-76) S 8.72 (ddd, J= 4.8, l .8, 0.9 Hz, IH), 8.41 (dt, J = 8.0, 1.1 Hz, IH), 7.98-7.89 (ni, 2H), 7.52-7.46 (m, IH), 4.56 (d, 7= 11.0 Hz, IH), 3.27-3.20 (m,

IH), 3.14 (s, 3H), 3.10-3.00 (m, IH), 2.99-2.88 (m, IH), 2.85-2.76 (m, IH), 2.36-2.25 (m, IH), 2.06- 1.89 (m, 2H), 1.18 (s, 9H), 0.95 (d,7= 6.4 Hz, 3H), 0.86 (d, 7= 6.6 Hz, 3H).

Example 1.118

[0750] Synthesis of (2S)-N-tert-butyl-3-methyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7I-Icyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 115)

[0751] Compound 115 was synthesized similar to compound 114 by replacing (2R)-2-[(tert

4I3 butoxycarbonyl)amino]-3-methylbutanoic acid with (2S)-2-[(tert-butoxycarbonyl)ammo]-3methylbutanoic acid. LCMS (ES+): (M+H)⁺ = 382.0. Ή NMR (400 MHz, DMSO-76) δ 8.73 (ddd, 7 = 4.8, 1.8,0.9 Hz, IH), 8.45 -8.40 (m, IH), 7.98 - 7.90 (m, 2H), 7.51 (ddd, 7= 7.5, 4.8, 1.2 Hz, IH),4.57 (d,7= 11.0 Hz, IH), 3.28-3.21 (m, IH), 3.16 (s, 3H), 3.10 - 3.00 (m, IH), 2.99-2.88 (m, IH), 2.862.76 (m, IH), 2.37-2.26 (m, I H), 2.15- 1.91 (m, 2H), 1.19 (s, 9H), Û.95 (d,7= 6.5 Hz, 3H), 0.86 (d, 7 = 6.6 Hz, 3H).

Example 1.119

[0752] Synthesis of(2R)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}-4-(methylsulfanyI)butanamide (Compound 116)

[0753] Compound 116 was synthesized similar to Compound 114 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-3-methylbutanoic acid in with (2R)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoîc acid. LCMS (ES+): (M+H)⁺ = 414.0. ^!H NMR (400 MHz, DMSO-76) δ 8.70 (ddd, 7= 4.7, 1.8, 0.9 Hz, IH), 8.43 -8.35 (m, IH), 7.97-7.88 (m, 2H), 7.48 (ddd, 7= 7.5, 4.8, 1.2 Hz, lH), 5.11 (dd, 7= 8.9, 6.2 Hz, 1 H), 3.26-3.17 (m, IH), 3.13-3.04 (m, 4H), 2.97-2.87 (m, IH), 2.87 -2.77 (m, IH), 2.48-2.36 (m, 2H),2.15 - 1.92 (m, 7H), 1.20 (s, 9H).

Example 1.120

[0754] Synthesis of (2S)-N-tert-butyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimîdin-4-yl]amino]-4-(methylsulfanyl)butanamide (Compound 117)

414

[0755] Compound 117 was synthesized similar to Compound l 14 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-3-methylbutanoic acid in with (2S)-2-[(tert-butoxycarbonyI)amino]-4(methylsulfanyl)butanoic acid. LCMS (ES+): (M+H)⁺ = 414.1. 'H NMR (400 MHz, DMSO-î/6) δ 8.72 (ddd, 7=4.8, 1.8,0.9 Hz, IH), 8.45 -8.36 (m, 1 H), 7.99 - 7.87 (m, 2H), 7.51 (ddd, J= 7.5, 4.7, 1.2 Hz, 5 1 H), 5.13 (dd, 7=8.9, 6.1 Hz, IH), 3.25 - 3.19 (m, IH), 3.15-3.05 (m, 4H), 3.00-2.78 (m, 2H), 2.48

-2.37 (m, 2H), 2.16-1.93 (m, 7H), 1.20 (s, 9H).

Example 1.121

[0756] Synthesis of(2R)-N-cyclohexyl-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 118)

[0757] Scheme 71 depicts a synthetic route for preparing an exemplary compound.

Scheme 71

[0758] To a solution of (2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl} (methy l)amino)15 N-cyclohexylpropanamide (134.00 mg; 0.40 mmol; 1.00 eq.) and 1 -methyl-4-(tributyIstannyl)-1Himidazole (251.17 mg; 0.63 mmol; 2.00 eq.) in Toluene (2 mL) was added tetrakis(triphenylphosphane) palladium (45.97 mg; 0.04 mmol; 0.10 eq.). The solution was heated at 105°C for 15 h, cooled to room température, and concentrated to remove solvent. The residue was purified by préparative HPLC to give (2R)-N-cyclohexyl-2-{methyl[2-(l-methyl-]H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-421052

415 yl]amino}propenamide (135 mg). 'H NMR (400 MHz, DMSO-ifc) S 8.15 - 8.05 (m, 2H), 8.01 (d, J 8.I Hz, IH), 5.23 (q, J= 6.9 Hz, IH), 3.76 (s, 3H), 3.52 (s, IH), 3.15 (s, 3H), 3.24 - 3.03 (m, 2H), 2.94 -2.76 (m,2H), 1.99 (ddt, J= 20.4, 13.0, 5.5 Hz, 2H), 1.72 - 1.62 (m, 2H), 1.62 - 1.54 (m, 2H), 1.51 (d, J= 12.3 Hz, IH), 1.33 (d, J= 7.0 Hz, 3H), 1.30 - 1.12 (m, 3H), 1.08 (ddd. J= 19.3, 14.8, 8.6 Hz, 2H).

LCMS (ES, m/z): [M+H]⁺: 383.2.

Example 1.122

[0759] Synthesis of (2R)-N-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide (Compound 119)

[0760] Scheme 72 depicts a synthetic route for preparing an exemplary compound.

Scheme 72

[0761] To a solution of (2R)-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)N-cyclohexylpropanamide (125.00 mg; 0.37 mmol; 1.00 eq.) and 4-methoxy-2-(tributylstannyl)pyridine (251.17 mg; 0.63 mmol; 2.00 eq.) in Toluene (2 mL) was added tetrakis(triphenylphosphane) palladium (42.88 mg; 0.04 mmol; 0.10 eq.). The solution was heated at 105°C for 15 h, cooled to room température, and concentrated to remove solvent. The residue was purified by préparative HPLC to give (2R)-N-cyclohexyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}propenamide (62 mg). ‘H NMR (400 MHz, DMSO-c/ô) δ 8.54 (d, J= 5.8 Hz, IH),

416

8. H (4,7=8.0 Hz, IH), 7.91 (4,7=2.6 Hz, IH), 7.16 (dd, 7= 5.8, 2.6 Hz, 1 H), 5.07 (q,7=7.0 Hz, IH), 3.94 (s, 3H), 3.53 (d,7= 6.6 Hz, IH), 3.25-3.17 (m, IH), 3.15 (s, 3H), 3.15-3.05 (m, IH), 2.87 (tdd, 7= 16.9, 13.0, 7.0 Hz, 2H), 2.12-1.90 (m, 2H), 1.71 (s, IH), 1.51 (d, 7 = 12.2 Hz, IH), 1.50 (s, 3H), 1.34 (d, 7 = 7.1 Hz, 3H), 1.20 (t, 7=9.7 Hz, 2H), 1.16- 1.06 (m, IH), 0.99 (s, 2H). LCMS (ES, m/z): [M+H]⁺: 410.1.

Example L123

[0762] Synthesis of (2S)-3-(tert-butoxy)-N-tert-butyl-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 120)

[0763] Compound 120 was synthesized similar to Compound 114 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-3-methylbutanoic acid with (2S)-3-tert-butoxy-2-{[(9H-fluoren-9yhnethoxy)carbonyl]amino)propanoic acid. MS (ES+): (M+H)' = 426.1. 'H NMR (400 MHz, DMSO76)0 8.68 (ddd, 7=4.8, 1.8,0.9 Hz, IH), 8.41 - 8.33 (m, IH), 7.94-7.86 (m, 1 H), 7.81 (s, 1 H), 7.46 (ddd, 7= 7.5, 4.7, 1.2 Hz, 1 H), 5.00 (dd, 7= 8.0, 5.9 Hz, IH), 3.83 - 3.75 (m, IH), 3.73-3.65 (m, IH), 3.29-3.20 (m, 2H), 3.18 (s, 3H), 3.12 - 3.02 (m, 1 H), 2.93 - 2.74 (m, 2H), 2.10 - 1.90 (m, 2H), 1.19 (s, 9H), 1.14 (s, 9H).

Example 1.124

[0764] Synthesis of (2R)-3-(tert-butoxy)-N-tert-butyL2-{methyl[2-(pyridin-2-yI)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 121)

CU.NH

417

[0765] Compound I2l was synthesized similar to Compound 114 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-3-methyl butanoic acid with (2R)-3-tert-butoxy-2-{[(9H-fluoren-9ylmethoxy)carbonyl]amino}propanoic acid. MS (ES+): (M+H)⁺ = 426.1. 'H NMR (400 MHz, DMSO76) δ 8.69 (ddd, 7=4.7, 1.8,0.9 Hz, IH), 8.41 -8.33 (m, IH), 7.94 - 7.85 (m, IH), 7.81 (s, 1 H), 7.46 (ddd, 7=7.5, 4.7, 1.2 Hz, IH), 5.00 (dd, 7= 7.9, 5.9 Hz, 1 H), 3.82 - 3.76 (m, 1 H), 3.70 (dd, 7= 9.5, 8.0 Hz, IH), 3.26-3.20 (m, IH), 3.18 (s, 3H), 3.12-3.02 (m, IH), 2.93-2.75 (m, 2H), 2.10-1.90 (m, 2H), 1.19 (s, 9H), 1.14 (s, 9H).

Example 1.125

[0766] Synthesis of N-tert-butyl-2-[(2-[2H,3H-[l,4]dioxino[2,3-c]pyridin-7-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 122)

[0767] Scheme 73 depicts a synthetic route for preparing an exemplary compound.

Scheme 73

[0768] Step 1

418

LDA, l₂THF, -78°C, 2 h

F

[0769] Into a 250-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-bromo-5-fluoropyridine (9.80 g, 55.68 mmol, l.OO equiv) and THF (100 mL). This was followed by the addition of LDA (33.4 mL, 66.80 mmol, 1.20 equiv) dropwise with stirring at 78°C. The reaction solution was stirred for 0.5 hr at -78°C. To this was added a solution of iodine (14.13 g, 55.68 mmol, l.OO equiv) in THF (20 mL) dropwise with stirring at -78“C and stirred for 1.5 hr at 78°C. The reaction was then quenched by the addition of 100 mL ofNHÆl (aq) and extracted with 3x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with petroleum ether/THF (10/1) to give 16.0 g (95%) of 2-bromo-5-fluoro-4-iodopyridine as a white solid. LCMS (ES)[M+l]⁺ m/z: 302. [0770] Step 2

_F t-BuOK, NMP, 65°C, 3 h

[0771] Into a 250-mL round-bottom flask was placed 2-bromo-5-fluoro-4-iodopyridine (8.0 g, 26.50 mmol, l .00 equiv), ethylene glycol (50.0 mL), NMP (50.0 mL), and /-BuOK (5.95 g, 53.00 mmol, 2.0 equiv). The reaction was stirred for 3 h at 65°C. The mixture was cooled and diluted with 100 mL of H₂O and extracted with 3x50 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate, fîltered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with petroleum ether/THF (3/1) to yield 4.9 g (53.7%) of 2-[(6-bromo4-iodopyridin-3-yl)oxy]ethanol as an off-white solid. LCMS (ES) [M+l]⁺ m/z: 344. [0772] Step 3

80°C,2 h

419

[0773] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-[(6-bromo-4-iodopyridin-3-yl)oxy]ethanol (4.90 g, 14.24 mmol, 1.00 equiv), isopropyl alcohol (50.00 mL), 3,4,7,8-tetramethyl-l,10-phenanthroline (673 mg, 2.84 mmol, 0.20 equiv), tertbutoxypotassium (3.20 g, 28.49 mmol, 2.00 equiv), and copper(I) iodide (542 mg, 2.84 mmol, 0.20 equiv). The mixture was stirred for 2 h at 80°C. After being cooled to room température, the reaction solution was diluted with 50 mL of FhO and extracted with 3x50 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with petroleum ether/THF (4/1) to give 2.0 g (65%) of 7-bromo-2H,3H-[l,4]dioxino[2,3-c]pyridine as a light yellow solid. LCMS (ES)

[M+lf m/z: 216.

[0774]

Step 4 —SnSn—

Pd(PPh₃)₄, dioxane, 100°C, 2 h

[0775] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 7-bromo-2H,3H-[l,4]dioxino[2,3-c]pyridine (500 mg, 2.31 mmol, L00 equiv), dioxane (8.0 mL), hexamethyldistannane (909 mg, 2.77 mmol, 1.20 equiv), and Pd(PPh₃)₄ (267 mg, 0.23 mmol, 0.10 equiv). The mixture was stirred for 2 h at l00°C. The réaction mixture was cooled and diluted with 10 mL of H₂O, and extracted with 3x10 mL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. 60Û mg crude product of 7-(trimethylstannyl)-2H,3H-[l,4]dioxino[2,3-c]pyridine was obtained as a brown oil and used to the next step without purification. LCMS (ES) [M+l]⁺ m/z: 302. [0776] Step 5

[0777] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen,

420 was placed 7-(trimethylstannyl)-2H,3H-[l,4]dioxino[2,3-c]pyridine (454 mg, l.5l mmol, L50 equiv), dioxane (5.0 mL), N-tert-buty l-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)acetamide (300 mg, LOI mmol, l.OO equiv), and Pd(PPh₃)4 (l 16 mg, 0.10 mmol, 0.10 equiv). The mixture was stirred for 16 h at 100°C. The reaction mixture was cooled and concentrated.

The residue was purified by silica gel column with dichloromethane/methanol (10/1). The collected crude product was further purified by Prep-HPLC with the foîlowing conditions: Column, Atlantîs HILIC OBD Column, 19*150 mm*5 um, Mobile phase, Water (0.05%NH4OH) and CHsCN (20% Phase B up to 45% in 15 min, hold 45% in 5 min), Detector, UV 254 nm. This resulted in 98.1 mg (24.4%) of N-tert-butyl-2-[(2-[2H,3H-[l,4]dioxino[2,3-c]pyridin-7-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-410 yl)(methyl)amino]acetamide as a white solid. 'H NMR (300 MHz, DMSO-7é) δ 8.17 (s, IH), 7.86 (s, 1H), 7.69 (s, IH), 4.40-4.36 (m, 4H), 4.10 (s, 2H), 3.26 (s, 3H), 3.12 (t, J = 7.5 Hz, 2H), 2.79 (t, 7= 7.8 Hz, 2H), 2.02-1.95 (m, 2H), 1.25 (s, 9H). LCMS (ES) [M+l]⁺ m/z: 398.2.

Example 1.126

[0778] Synthesis of (2S)-N-tert-butyl-3-hydroxy-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H15 cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 123)

[0779] Scheme 74 depicts a synthetic route for preparing an exemplary compound.

[0780] (2S)-3-(tert-butoxy)-N-tert-buty 1-2-{methyl [2-(pyridin-2-y l)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide and formîc acid (62.5 mg; 0.13 mmol; 1 eq.) were

421 dissolved in dichloromethane (l ml) and cooled in an ice bath. Trifluoroacetic acid (0.75 mL; 0.2 mol/L; 0.15 mmol; LI3 eq.) (I ml) was added and the reaction was stirred at 25°C for 3.5 h. The solution was then evaporated, the residue was co-evaporated with toluene and purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-90% acetonitrile/O.l % aqueous formic acid gradient) to give (2S)-N-tert-butyl-3-hydroxy-2-[methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}propanamide (40 mg, 81%) as an off-white solid. LCMS (ES+): (M+H)⁺= 369.9. 'H NMR (400 MHz, DMSO-76) δ 8.79 - 8.74 (m, IH), 8.48 (d, 7= 7.9 Hz, IH), 8.077.99 (m, IH), 7.87 (s, IH), 7.61 (ddd, 7= 7.6, 4.7, L2 Hz, IH), 5.10 (t, 7= 7.3 Hz, IH), 5.01 (s, IH), 3.91-3.81 (m, 2H), 3.31 - 3.26 (m, 4H), 3.17-3.10 (m, IH), 3.02 - 2.87 (m, 2H), 2.15-1.96 (m, 2H),

1.20 (s, 9H).

Example 1.127

[0781] Synthesis of (2R)-N-tert-butyl-3-hydroxy-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]propanamide (Compound 124)

[0782] Scheme 75 depicts a synthetic route for preparing an exemplary compound.

Scheme 75

[0783] Compound 124 was synthesized similar to compound 123 by replacing (2S)-3-(tert-butoxy)N-tert-butyl-2-{ methyl [2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yt]amino}propenamîde with (2R)-3-(tert-butoxy)-N-tert-butyl-2-[methyl[2-(pyrÎdin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}propenamide. LCMS (ES+): (M+H)⁺ = 370.0. Ή NMR (400 MHz, DMSO-76) δ 8.88 - 8.81

422 (m, lH), 8.59 (d, 7= 7.8 Hz, IH), 8.l9-8.l2(m, IH), 7.89 (s, IH), 7.76 (ddd, 7= 7.6, 4.8, 1.2 Hz, IH), 5.34-5.00 (m, 2H), 3.92 (d, 7=7.1 Hz, 2H), 3.45 (s, 3H), 3.36 - 3.34 (m, 1 H), 3.23 - 3.16 (m, IH), 3.08-3.01 (m, 2H), 2.20 - 2.02 (m, 2H), 1.22 (s, 9H).

Example 1.128

[0784] Synthesis of N-tert-butyl-2-{methyl[2-(] -methy 1-1 H-imidazol-4-y 1)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 125)

[0785] Scheme 76 depicts a synthetic route for preparing an exemplary compound.

Scheme 76

[0786] Step 1

-SnSn— Me₃Sn,_

N — ---------------—‘ ‘ N—

N^/ Pd(PPh₃)₄, dioxane, 100°C, 2 h N^/

[0787] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 4-bromo-l-methylimidazole (500 mg, 3.10 mmol, 1.00 equiv), dioxane (8.0 mL), hexamethyldistannane ( 1.22 g, 3.72 mmol, 1.20 equiv), and Pd(PPh₃)4 (358 mg, 0.31 mmol, 0.10 equiv).

The mixture was stirred for 4 h at 100°C. The reaction mixture was cooled and concentrated. This resulted in 600 mg crude product of 1 -methyl-4-(trimethyistannyl)imidazole as brown oil. LCMS (ES)

423

[M+l] m/z: 247.

[0788] Step

[0789] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed N-tert-butyl-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (300 mg, LOI mmol, l.OO equiv), dioxane (5.0 mL), l-methyl-4-(trimethylstannyl)imidazole (371 mg, l.5l mmol, L50 equiv), and Pd(PPh₃)4 ( 116 mg, 0.I0 mmol, 0.10 equiv). The mixture was stirred for 20 h at !00°C. The reaction mixture was cooled and concentrated to remove the solvent. The residue was purified by silica gel column with dichloromethane/methanol (l 0/l). The product was further purified by Prep-HPLC with the following conditions: Column, Welch Xtimate Cl8, 21.2*250 mm, 5 um, Mobile phase, Water ( 10 mmol/L NPkHCOj) and MeOH: CH₃CN=1:1 (25% Phase B up to 65% in 15 min); Detector, UV 254 nm. This resulted in 47.0 mg (13.5%) of N-tert-butyl-2-[methyl[2-(l-methylimidazol4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yi]amino]acetamide as a white solid. Ή NMR (300 MHz, DMSOéé) δ 7.73 (d, J= 1.5 Hz, 1 H), 7.67-7.52 (m, 2H), 4.09 (s,2H), 3.69 (s, 3H), 3.21 (s, 3H), 3.06 (t, J= 7.5 Hz, 2H), 2.73 (t, J = 7.8 Hz, 2H), 2.02-1.86 (m, 2H), 1.25 (s, 9H). LCMS (ES) [M+l]⁺ m/z: 343.2.

Example 1.129

[0790] Synthesis of N-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 126)

424

[0791] Scheme 77 depicts a synthetic route for preparing an exemplary compound.

[0792] Step l

[0793] To a stirred solution of tert-butylam ine (3.89 g, 53.186 mmol, l.OO equiv) and K2CO3 (7.34 g, 53.126 mmol, l .00 equiv) in DCM (l20.00 mL) was added chloroacetyl chloride (6.00 g, 53.126 mmol, l .00 equiv) dropwise at 0°C under an air atmosphère. The resulting mixture was stirred for 16 h at room température under an air atmosphère. The reaction was quenched with water at room température. The resulting mixture was extracted with CH2CI2 (2 xlOO mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous NajSOi, and fïltered. The fîltrate was concentrated under reduced pressure to afford N-tert-butyl-2-chloroacetamide (4 g, 50.32%) as a yellow

425 solid. LCMS (ES) [MH]⁺ m/z: 150. [0794] Step 2

[0795] A solution ofN-tert-butyl-2-chloroacetamide (4.00 g, 26.734 mmol, L00 equiv) and ethylamine in EtOH (80 mL) was stirred for 16 h at 80°C under an air atmosphère. The resulting mixture was concentrated under reduced pressure. The resulting mixture was diluted with water (50 mL) and extracted with DCM:MeOH=10:1 (3 x 100 mL). The combined organic layers were washed with brine (Ixl 00 mL), dried over anhydrous Na₂SO4, and filtered. The fïltrate was concentrated under reduced pressure to yieid N-tert-buty l-2-(ethylamino)acetamide (3.3 g, 78.00%) as a yellow solid. LCMS (ES)

[MH] ⁺ m/z: 159.

[0796] Step 3

H

[0797] A solution of 2,4-dichloro-5H_J6H,7H-cyclopenta[d]pyrimidine (3.00 g, 15.870 mmol, 1.00 equiv), DIEA (6.15 g, 47.609 mmol, 3 equiv) and N-tert-butyl-2-(ethylamino)acetamide (3.01 g, 19.044 mmol, 1.20 equiv) in NMP (30.00 mL, 311.103 mmol, 19.60 equiv) was stirred for 2 h at 60°C under an air atmosphère. The mixture was cooled to room température. The resulting mixture was extracted with EtOAc (3 x 100 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na₂SÛ4, and filtered. The fïltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/EtOAc (1:1 ) to yieid N-tert-buty l-2-([220 chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](ethyl)amino)acetamide (2.2 g, 44.60%) as a white solid. LCMS (ES) [MH]⁺ m/z: 311.

[0798] Step 4

426

[0799] To a solution of 2-bromo-4-methoxypyridine (453.68 mg, 2.413 mmol, 1.5 equiv) and 2-tertbutyl-l,l,l-trÎmethyldistannane (906.82 mg, 2.654 mmol, 1.65 equiv) in dioxane (2.00 mL ) were added Pd(PPh₃)4 (186 mg, 0.161 mmol, 0.1 equiv). After being stirred for 2 h at l00°C under a nitrogen atmosphère, the mixture was cooled to room température. To the above mixture was added N-tert-butyl2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](ethyl)amino)acetamide (500.00 mg, l .609 mmol, l.OO equiv), CsF (488.70 mg, 3.217 mmol, 2.00 equiv), and Pd(PPh₃)4 (186 mg, 0.161 mmol, 0.1 equiv) at room température. The resulting mixture was stirred for an additional 16 h at l00^ûC under a nitrogen atmosphère. The resulting mixture was cooled and concentrated under reduced pressure. The residue was purified by silica gel column chromatography eluting with PE/THF (1:1) to afford N-tert-butyl-2[ethyl[2-(4-methoxypyridin-2-yI)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide (89 mg , 13%) as a yellow solid. Ή NMR (300 MHz, DMSO-rfô) δ 8.49 (d, J= 5.6 Hz, IH), 7.87 (d, J= 2.6 Hz, IH), 7.68 (s, IH), 7.16-6.82 (m, 1H),4.O9 (s,2H), 3.90 (s, 3H), 3.65 (q, 7= 7.0 Hz, 2H), 3.08 (t, J= 7.2 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.23- 1.92 (m, 2H), 1.23 (s, 9H),3.65 (t, 7= 7.0 Hz, 3H). LCMS (ES) [M+1]⁺ m/z: 384.1.

Example 1.130

[0800] Synthesis ofN-(6-fluotOpyridin-3-yl)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 127)

[0801] Scheme 78 depicts a synthetic route for preparing an exemplary compound.

427

1. HATU DI ΡΕΑ

2. HCl

Scheme 78

[0802] Step i

[0803] To a solution of [(tert-butoxycarbonyl)(methyl)amino]acetic acid (2.00 g; 10.57 mmol; 1.00 eq.) in DMF (15 mL) was added 6-fluoro-3-pyridînylamine (1.18g; 10.57 mmol; 1.00 eq.) followed by Hunig's base (2.77 mL; 0.02 mol; 1.50 eq.) and HATU (4.02 g; 0.01 mol; 1.00 eq.). After being stirred for 15 h at room température, it was extracted with EtOAc. The organic layers were combined, dried, 10 and concentrated to give tert-butyl (2-((6-fluoropyridin-3-yl)amino)-2-oxoethyl)(methyl)carbamate as a crude product (5.6 g). The crude product was diluted with DCM (10 mL), to which 4N HCl in dioxane (10 mL) was added. After completion, the mixture was concentrated and diluted with Sat. NaHCOa. The aqueous layer was extracted with EtOAc, the organic layers were combined, dried, and concentrated to give 2-[chloro(methyl)amino]-N-(6-fluoropyridin-3-yl)acetamide (2.5 g). LCMS (ES) [M+l] ⁺ m/z: 184.

[0804] Step 2

[0805] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (l .00 g; 5.29 mmol; l.OO eq.) in AcCN (15 mL) was added triethylamine (L48 mL; 10.58 mmol; 2.00 eq.) and 2[chloro(methyl)amino]-N-(6-fluoropyridin-3-yl)acetamide (L74 g; 7.93 mmol; L50 eq.). After being heated at 80°C for 15 h, it was concentrated and diluted with Sat. NaHCCh, and extracted with EtOAc. The organic layers were combined, washed with brine, dried, and concentrated to give the crude product, which was purified by column chromatography (0 to 100% EtOAc) to give 2-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-fluoropyridin-3-yl)acetamide (1.78 g). LCMS (ES) [M+lpm/z: 336.0.

[0806] Step 3

[0807] To a solution of 2-({2-chloro-5H,61-I,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6tluoropyridin-3-yl)acetamide (95.00 mg; 0.28 mmol; 1.00 eq.) in Toluene (2 mL) was added 2(tributylstannyl)pyridine (156.24 mg; 0.42 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium 15 (32.70 mg; 0.03 mmol; 0.10 eq.). After being heated at 105°C overnight, HPLC indicated starting material left. The mixture was concentrated and was added DMF (1 mL), additional tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol; 0.10 eq.), and 2-(tributylstannyl)pyridine (156.24 mg; 0.42 mmol; 1.50 eq.). The mixture was heated for 5 h at 105°C. It was diluted with water and subjected to purification by prep HPLC to give N-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)20 5H,6H,7H-cyclopenta[d]pyrÎmidin-4-yl]amino}aceiamide (28.7 mg). 'H NMR (400 MHz, DMSOA) δ 10.83 (s, IH), 8.81 (d,7=4.9 Hz, IH), 8.47 - 8.40 (m, 2H), 8.19 - 8.10 (m, IH), 8.05 (t, .7= 7.5 Hz, IH), 7.71 (dd, 7= 7.7, 4.8 Hz, 1 H), 7.15 (dd, 7= 8.8, 3.2 Hz, IH), 4.69 (s, 2H), 3.54 (s, 3H), 3.04 (t, 7= 7.9 Hz, 2H), 2.49 (m, 2H), 2.16- 2.03 (m, 2H). LCMS (ES) [M+l ]⁺ m/z: 379.1.

429

Example 1.131

[0808] Synthesis ofN-(6-fluoropyridin-3-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 128)

[0809] Scheme 79 depicts a synthetic route for preparing an exemplary compound.

Scheme 79

[0810] To a solution of 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-ylKmethyl)amino)-N-(6fluoropyridin-3-yi)acetamide (95.00 mg; 0.28 mmol; 1.00 eq.) in DMF (1 mL) was added 4-methoxy-210 (tributylstannyl)pyrîdine (168.99 mg; 0.42 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol; 0.10 eq.). After being heated at 110°C ovemight, the mixture was cooled to room température and diluted with water and AcCN, and subjected to purification by préparative HPLC to give N-(6-fluoropyridin-3-yl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide (25.9 mg). Ή NMR (400 MHz, DMSO-7_È) δ 10.56 (s, IH), 8.45 (d, 7=5.7

Hz, 1 H), 8.39 (d, 7= 3.3 Hz, IH), 8.12 (td, 7= 8.4, 7.9, 2.7 Hz, IH), 7.77 (d, 7= 2.6 Hz, IH), 7.13 (dt, 7 = 8.8,3.5 Hz, IH), 7.05 (dd, 7= 5.7, 2.6 Hz, 1 H), 4.44 (s, 2H), 3.79 (s, 3H), 3.21 (t,7=7.4 Hz, 2H), 3.11 (t, 7= 7.3 Hz, IH), 2.85 (t, 7= 7.9 Hz, 3H), 2.72 (t, 7= 7.9 Hz, 1 H), 2.04 (d, 7= 11.3 Hz, 2H).

LCMS (ES) [M+l]⁺ m/z: 409.2.

Example 1.132

[0811] Synthesis of N-(6-fluoropy ridin-3-yl)-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 129)

430

[0812] Scheme 80 depicts a synthetic route for preparing an exemplary compound.

Scheme 80

[0813] To a solution of 2-({2-chloro-5H,6H,7H-cyc]openta[d]pyrimidm-4-yl}(methyl)amino)-N-(6fluoropyridin-3-yl)acetamide (95.00 mg; 0.28 mmol; l.OO eq.) in DMF (I mL) was added l -methy I-4(tributylstannyl)-lH-imidazole (l 57.52 mg; 0.42 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (32.70 mg; 0.03 mmol; 0. ]0 eq.). After being heated at l l0°C ovemight, the mixture was cooled to room température and diluted with water and AcCN. The mixture was subjected to purification by préparative HPLC to give N-(6-fluoropyndin-3-yl)-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)5H,6H,7H-cyclopenta[d]pyrîmîdin-4-yl]amino}acetamide. 'H NMR (400 MHz, DMSO-7&) δ 10.86 (s, IH), 10.76 (s, IH), 8.47 (s, IH), 8.30 (s, JH), 8.18 (s, 2H), 7.16 (dd, 7= 8.8, 3.2 Hz, IH), 4.62 (d, 7 = 4.0 Hz, 2H), 3.75 (s, 4H), 3.19 (s, IH), 2.91 (t,7=7.9 Hz, 2H), 2.78 (s, IH), 2.09- 1.97 (m, 2H). LCMS (ES) [M+l]⁺ m/z: 382.2.

Example 1.133

[0814] Synthesis of (3R)-3-{methyl[2-(pyridîn-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-l-phenylpyrrolidin-2-one (Compound 130)

431

[0815] Scheme 81 depicts a synthetic route for preparing an exemplary compound.

Scheme 81

[0816] Step l

432

[0817] (2R)-2-[(tert-butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid (0.50 g; 2.01 mmol;

.00 eq.) was dissolved in DCM (20 ml). The mixture was cooled in an ice water bath and HATU (0.84 g; 2.2 i mmol; 1.10 eq.), Hunîg's base (0.73 mL; 4.21 mmol; 2.10 eq.) and aniline (0.20 mL; 2.21 mmol;

1.10 eq.) were added. After being stirred at 0°C to r.t for 15 h, the mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried, and concentrated. The residue was purified by column chromatography (Hexanes/EtOAc= 3:1) to give tert-butyl N-[(1R)3-(methylsulfanyl)-l-(phenylcarbamoyl)propyl]carbamate (0.58 g, 89%) as a solid. LCMS (ES+): (M+Na)⁺ = 347.1.

[0819] Tert-butyl N-[(lR)-3-(methylsulfanyl)-l-(phenylcarbamoyl)propyl]carbamate (0.58 g; 1.78 mmol; 1 eq.) was dissolved in iodomethane (2.66 mL; 43 mmol; 24 eq.) and the solution was stirred at 25 °C. After 19 h, the residue was dried under vacuum and used directly in the next step. LCMS (ES+):

(M+H)⁺= 338.8.

[0820] Step 3

[0821] Tert-butyl N-[(l R)-3-(dimethylsulfaniumyl)-l-(phenylcarbamoyl)propyl]carbamate iodîde

433 (0.83 g; 1.78 mmol; l eq.) was suspended in tetrahydrofuran (35 ml) and cooled in an ice bath. Lithium bis(trimethylsilyl)azanide (L78 mL; l mol/L; 1.78 mmol; l eq.) was added dropwise slowly. After stirring at 0 °C for 3 h, ammonium chloride solution (l 0 ml) was added slowly. The solvent was evaporated and the remainder was taken up in dichloromethane (100 ml) and sodium bicarbonate solution (50 ml). The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 50 ml), and the combined organic phases were dried over sodium sulfate. After évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give tert-butyl N-[(3R)-2oxo-l-phenylpyrroIidin-3-yl]carbamate (0.41 g, 82%) as a white solid.MS (ES+): (M+Na)^T = 299.0. ’H NMR (400 MHz, Chloroform-rZ) δ 7.67 - 7.60 (m, 2H), 7.42 - 7.34 (m, 2H), 7.21 - 7.14 (m, IH), 5.28 10 5.17 (m, 1 H), 4.41 - 4.27 (m, 1 H), 3.85 - 3.76 (m, 2H), 2.85 - 2.74 (m, IH), 2.06 - 1.93 (m, IH), 1.47 (s, 9H).

[0822] Step 4

[0823] Tert-butyl N-[(3R)-2-oxo-l-phenylpyrrolidîn-3-yl]carbamate (0.41 g; 1.48 mmol; 1 eq.) was dissolved in dichloromethane (5 ml) and cooled in an ice bath. Trifluoroacetic acid (2.5 mL) was added slowly and the reaction was stirred at 25 °C. After 1.5 h. the reaction was evaporated, the residue was co-evaporated with toluene and then dried under high vacuum to give (3R)-3-ammo-l-phenylpyrrolidin2-one; trifluoroacetic acid.

[0824] Step 5

[0825] 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (0.25 g; 1.32 mmol; 1.00 eq.) was dissolved in acetonitrîle (4.5 ml, dry), and to the solution was added (3R)-3-amino-l-phenylpyrrolidin-221052

434 one; trifluoroacetic acid (0.42 g; 1.45 mmol; 1.10 eq.) and Hunig's base (1.15 mL; 6.61 mmol; 5.00 eq.) (dry). After being stirred at ~70°C for 20 h, the mixture was cooled and the solvent was evaporated, the residue was purified by column chromatography (Hexanes/EtOAc = 1:1) to give (3R)-3-({2-chloro5H,6H,7H-cyclopenta[d]pyrimidir)-4-yl}amino)-l-phenylpyrrolidin-2-one (170 mg, 39%). LCMS (ES+): (M+H)⁺= 342.9.

[0826] Step 6

[0827] (3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}amino)-l-phenylpyrrolidin-2-one (170.00 mg; 0.52 mmol; 1.00 eq.) was dissolved in DMF (3 ml) and cooled in an ice bath. Sodium hydride (62.04 mg; 1.55 mmol; 3.00 eq.) was added and the mixture was stirred in an ice bath for 30 min before iodomethane (96.56 pL; 1.55 mmol; 3.00 eq.) was added. After being stirred at room température for 1.5 h, the mixture was diluted with water and extracted with EtOAc. The combined organic phase was washed with brine, dried, and concentrated. The residue was purified by column chromatography (Hexanes/EtOAc = 1:1) to give (3R)-3-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amfno)-J-phenylpyrrolidin-2-one (161 mg, 91%). LCMS (ES+): (M+H)⁺ = 342.9. [0828] Step 7

[0829] (3R)-3-({2-chlorO'5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-lphenylpyrrolidin-2-one (100.00 mg; 0.29 mmol; 1.00 eq.) was dissolved in 1,4-dioxane (2.4 ml) and purged with Ar gas. 2-(tributylstannyl)pyridine (0.19 mL; 0.58 mmol; 2.00 eq.) and

435 tetrakis(triphenylphosphane) palladium (33.71 mg; 0.03 mmol; 0.10 eq.) were added and the mixture was stirred in a heat bath at l08°C for 20 h. The solvent was evaporated, the residue taken up in acetonitrile, filtered, and purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-70% acetonitrile/O.l % aqueous formic acid gradient) to give (3R)-3-{methyl[2-(pyridin-2-yl)5 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-l-phenylpyrrolidin-2-one (64 mg, 57%) as a white solid. LCMS (ES+): (M+H)⁺ = 386.0. Ή NMR (400 MHz, DMSO-76) δ 8.57 (dd, 7= 4.8, 1.8 Hz, IH), 8.17 (d, J= 7.9 Hz, IH), 7.75 - 7.68 (m, 2H), 7.67 - 7.58 (m, IH), 7.43-7.34 (m, 3H), 7.20- 7.12 (m, IH), 5.46-5.25 (m, IH), 4.00-3.82 (m, 2H), 3.27-3.22 (m, 5H), 2.86 (dd, 7= 8.7, 7.0 Hz, 2H), 2.45 - 2.30 (m, 2H), 2.07 - 1.97 (m, 2H).

Example 1.134

[0830] Synthesis of (3S)-3-{methyI[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-l -phenylpyrrolidin-2-one (Compound 131)

[0831] Compound 131 was synthesized similar to compound 130 by replacing (2R)-2-[(tert15 butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with (2S)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoic acid. LCMS (ES+): (M+H)⁺ = 386.0. NMR (400 MHz, DMSO-76) δ 8.57 (dd, 7=4.9, 1.8 Hz, IH), 8.17 (d, 7= 7.9 Hz, IH), 7.74 - 7.68 (m, 2H), 7.66-7.57 (m, IH), 7.43-7.33 (m, 3H), 7,19-7.12 (m, IH), 5.44 - 5.26 (m, 1 H), 3.92 (dtd, 7= 18.6, 9.5, 7.4 Hz, 2H), 3.26 - 3.21 (m, 5H), 2.86 (dd, 7 = 8.7, 7.0 Hz, 2H), 2.47 - 2,29 (m, 2H), 2.08 - 1,98 (m, 2H).

Example 1.135

[0832] Synthesis of (3R)-3-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-l-pheny]pyrroIidin-2-one (Compound 132)

436

[0833] Scheme 82 depicts a synthetic route for preparing an exemplary compound.

Scheme 82

[0834] (3R)-3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl] (methy l)amino)-lphenylpyrrolîdin-2-one (60 mg; 0.18 mmol; l eq.) was dissolved in l,4-dioxane (2 ml) and purged with Ar gas. 4-Methoxy-2-(tributylstannyl)pyridine (0.14 g; 0.35 mmol; 2 eq.) and then tetrakis(triphenylphosphane) palladium (20 mg; 0.02 mmol; 0.1 eq.) were added and the mixture was stirred in a heat bath at 108°C for 20 h. The solvent was evaporated, the residue taken up in acetonitrile, 10 filtered, and purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-70% acetonitrile/0.1 % aqueous formîc acid gradient) to give (3R)-3-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}-l-phenylpyrrolidin-2-one (25 mg, 35%) as a white solid. LCMS (ES+): (M+H)⁺ = 415.9. Ή NMR (400 MHz, DMSO-76) δ 8.37 (d, 5.6 Hz, IH), 7.72 (d, J=

2.6 Hz, IH), 7.71 - 7.65 (m, 2H), 7.41 - 7.33 (m, 2H), 7.18 - 7.11 (m, IH), 6.97 (dd, 7= 5.6, 2.6 Hz, 15 IH), 5.40 (s, IH), 3.92 (dtd, 7= 16.7,9.4,7.3 Hz, 2H), 3.78 (s, 3H), 3.24 - 3.19 (m, 5H), 2.84 (td, 7 =

7.5 , 1.6 Hz, 2H), 2.48 - 2.29 (m, 2H), 2.06 - 1.97 (m, 2H).

Example 1.136 [0835] Synthesis of N-(2-hydroxyethyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 133)

437

[0836] Scheme 83 depicts a synthetic route for preparing an exemplary compound.

Scheme 83

[0837] Step i

Sn2(Me)g

Pd(dppf)Cl2_T dioxane

[0838] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen.

was placed 2-bromo-4-methoxypyridine (500.00 mg, 2.659 mmol, I.00 equiv), hexamethyldistannane (l045.49 mg, 3.191 mmol, l .20 equiv), Pd(dppf)Ch (l94.58 mg, 0.266 mmol, 0.1 equiv), and dioxane (20.00 mL). The resulting solution was stirred for 4 hr at 100°C. The solution was cooled and then used for the next step directly. LCMS (ES) [M+l]⁺ m/z: 274.

[0839] Step

438 (Bu)₃Sn

[0840] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen, was placed 4-methoxy-2-(tributylstannyl)pyridine (590.48 mg, l .483 mmol, l .00 equiv), ethyl 2-([2chloro-5H,6H,7H-cyciopenta[d]pyrimidin-4-yl](methyl)amino)acetate (400.00 mg, l .483 mmol, l .00 equiv), Pd(dppf)Cl₂ (l 08.51 mg, 0.148 mmol, 0.10 equiv), and dioxane (20.00 mL). The resulting solution was stirred for 16 hr at l00°C. The reaction mixture was cooled. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with dichloromethane/methanol (10: l). This resulted in 300 mg (59.08%) of ethyl N-(2-(410 methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate as brown oil. LCMS (ES) [M+l] ⁺ m/z: 343.

[0841] Step 3

[0842] Into a 50-mL round-bottom flask, was placed ethyl N-(2-(4-methoxypyridin-2-yl)-6,715 dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate (300.00 mg, 0.876 mmol, 1.00 equiv), ethanolamine (64.22 mg, 1.051 mmol, 1.20 equiv), A1CE ( 1 ] .68 mg, 0.088 mmol, 0.10 equiv), and toluene (20.00 mL). The resulting solution was stirred for 16 hr at 90°C. The reaction mixture was cooled. The resulting solution was extracted with 3x30 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#SHIMADZU (HPLC-ÛI)): Column, Atlantis HILIC OBD Column, 19*150mm*5um; mobile phase, Water(0.05%NHsH₂0) and ACN (5% PhaseB up

439 to 18% in 8 min). This resulted in 47.2 mg (15.07%) of N-(2-hydroxy ethy 1)-2-( (2-(4-m ethoxypyridin-2yO-ôJ-dihydro-SH-cyclopentafdJpyrimidinAylXmethyljaminojacetamide as a white solid. '1-1 NMR (300 MHz, DMSO-Æ) δ 8.48 (d, J= 5.7 Hz, 1 H), 8.14 (t, 7= 5.7 Hz, JH), 7.81 (d, 7= 2.6 Hz, 1 H), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 4.65 (s, IH), 4.20 (s, 2H), 3.90 (s, 3H), 3.44-3.35(m, 2H), 3.28 (s, 3H), 3.21 5 3.11 (m,4H), 2.83 (t, 7= 7.8 Hz, 2H), 2.01-1.96 (m, 2H).LCMS (ES) [M+l] ⁺ m/z: 358.2.

Example 1.137

[0843] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(oxan-4-yl)acetamide (Compound 134)

H

[0844] Scheme 84 depicts a synthetic route for preparing an exemplary compound.

Scheme 84

[0845] To a stirred solution of [[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetic acid (200 mg, 0.63 mmol, 1.0 equiv), DIEA (411 mg, 3.18 mmol, 5.0 equiv), 15 and HATU (1.21 g, 3.181 mmol, 5.0 equiv) in THF (10 mL) was added oxan-4-amine (321 mg, 3.18 mmol, 5.0 equiv) in portions at 20°C. The resulting mixture was stirred for 5 h at 60°C. The reaction was concentrated under reduced pressure. The residue was purified by Flash-Prep-HPLC with the following conditions (IntelFlash-1 ): Column, Cl 8; mobile phase, Mobile phase : MeCN=5/1 B:Water Flow rate: 20mL/min Column: DA1CEL CHIRALPAK IC, 250*20mm, 220 nm Gradient:50%B in

20min; 220nm. This resulted in 47 mg (18.5%) 2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(oxan-4-yl)acetamide as a white solid. ’HNMR (300

MHz, DMSO-Λ) S 8.49 (d, 7= 5.7 Hz, IH), 8.13 (d, 7= 7.5 Hz, IH), 7.8J (d,7=2.4Hz, JH), 7.05 (dd, 7= 2.4 Hz, 5.7 Hz, IH), 4.18 (s, 2H), 3.89 (s, 3H), 3.81-3.77 (m, 3H), 3.31-3.28 (m, 2H), 3.18-3.16 (m, 3H), 3.15 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.67-1.63 (m, 2H), 1.47-1.39 (m, 2H). LCMS (ES) [M+l]⁺ m/z: 398.2.

Example 1.138

[0846] Synthesis of2-{[2-(4-methoxypyridm-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(oxolan-3-yl)acetamide (Compound 135)

H

[0847] Scheme 85 depicts a synthetic route for preparing an exemplary compound.

SnBüjCI, n-BuLi i-PrMgBr Toi, -78°C, 3 h 1 II T ---------------------------

Y o^o /él N ) \ 1 1 N V-VaC. 1 LiOH.THF, H₂O ^{N Cl} /-Yn rt, 16 h

N^J Pd(PPh₃}₄, Toi 100°C,16 h °^^0H _o [ | H₂N Y L / Ύ f ‘-Q N ΥΤ ? ₀ HATU, DIEA, THF, 50°C, 4 h Vf । Y _r 10 ^r Scheme 85 [0848] Step 1 ^Br0YY° ' SnBu₃CI, n-BuLi fil J i-PrMgBr, Toi, -78°C, 3 h '

1 Ii Y B u ₃S n O ii T

[0849] Into a 250-mL 3-necked round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed 2-bromo-4-methoxypyridine (7.0 g, 37.22 mmol, l .0 equiv) and toluene (70.0 mL). This was followed by the addition of n-BuLi (16.4 mL, 4LO mmol, L10 equiv) and /-PrMgBr (22.3 mL, 22.30 mmol, 0.60 equiv) dropwise with stirring at -78°C. After addition, the resulting solution was stirred for 2 hr at -78°C. To the mixture tributyltin chloride (l 4.54 g, 44.68 mmol, l .20 equiv) was added at -78°C. The reaction was stirred for I h at room température. The reaction was then quenched by the addition of 200 mL ofNLLCl (aq), and extracted with 3x100 mL of toluene. The combined organic phase was dried over anhydrous sodium sulfate, filtered, and the fîltrate was concentrated under reduced pressure. 16.0 g crude product of 4-methoxy-2-(tributylstannyl)pyridine was obtained as a brown oil and used in the next step without purification. LCMS (ES) [M+l]⁺ m/z: 400.

[0850] Step 2

[0851] Into a 250-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed ethyl 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate (7.0 g, 25.95 mmol, 1.00 equiv), toluene (100.0 mL), 4-methoxy-2-(tributyIstannyl)pyridine (15.5 g, 38.92 mmol, 1.50 equiv), and Pd(PPh3)4 (3.0 g, 2.59 mmol, 0.10 equiv). The mixture was stirred for 16 h at lOO^C. The reaction mixture was cooled and concentrated to remove the solvent. The residue was purified by silica gel column with dichloromethane/methanol (10/1). This resulted in 3.5 g (39%) of ethyl 2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetate as a brown oil. LCMS (ES) [M+l]⁺ m/z: 343.

[0852] Step

[0853] Into a IOO-mL round-bottom flask, was placed ethyl 2-[[2-(4-methoxypyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetate (3.5 g, 10.22 mmol, l.OO equiv), THF (30.0 mL), H₂O (10.0 mL), and LiOH H₂O (857 mg, 20.44 mmol, 2.00 equiv). The reaction solution was 5 stirred for 16 h at room température. The solids were collected by filtration and dried under an infrared lamp. 2.5 g (77%) of N-(2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-Nmethy(glycine was obtained as a yellow solid. LCMS (ES)[M+1]⁺ m/z: 315.

[0854] Step 4

H

[0855] Into a 50-mL round-bottom flask, was placed N-(2-(4-methoxypyridin-2-yI)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)-N-methylgiycine (200 mg, 0.63 mmol, 1.00 equiv), THF (5.0 mL), oxolan-3-amine (83 mg, 0.95 mmol, 1.50 equiv), DIEA (246 mg, 1.90 mmol, 3.00 equiv), and HATU (362 mg, 0.95 mmol, 1.50 equiv). The mixture was stirred for 4 h at 50°C. The reaction mixture was cooled and concentrated to remove the solvent. The residue was diluted with 5 mL of MeOH and purified by Prep-HPLC with the following conditions: Column, Welch Xtimate Cl8, 21.2*250 mm, 5 um, Mobile phase, Water(10 mmol/L NH4HCO3) and MeOH: CHsCN=l :1 (25% Phase B up to 65% in 15 min), Detector, UV 254 nm. This resulted in 30 mg (12%) of 2-[[2-(4-methoxypyrîdin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(oxolan-3-yl)acetamide as a white solid. ’H NMR (300 MHz, DMSO-T.) δ 8.47 (d, J = 5.7 Hz, IH), 8.35 (d, J= 6.9 Hz, IH), 7.80 (d,7=2.7 Hz,

IH), 7.03 (dd, 7= 5.7, 2.7 Hz, IH), 4.33-4.22 (m, IH), 4.18 (d,7= 2.4 Hz, 2H), 3.89 (s, 3H), 3.80-3.67 (m, 2H), 3.70-3.57 (m, IH), 3.43 (dd, 7= 8.7, 3.9 Hz, IH), 3.27 (s, 3H), 3.16 (t, 7= 7.5 Hz, 2H), 2.82 (t,

443

7= 7.8 Hz, 2H), 2.13-1.9 i (m, 3H), L77-L67 (m, IH). LCMS(ES)[M+l]⁺m/z: 384.1.

Example l. 139

[0856] Synthesis ofN-(l-hydroxy-2-methylpropan-2-yl)-2-{[2-(4-methoxypyrîdin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-y]](methyl)amino}acetamide (Compound 136)

[0857] Scheme 86 depicts a synthetic route for preparing an exemplary compound.

Scheme 86

[0858] Into a 100-mL round-bottom flask was placed N-(2-(4-methoxypyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-y!)-N-methy [glycine (150.00 mg, 0.477 mmol, 1.00 equiv), 2-amino-2methyl-l-propanol (85.07 mg, 0.954 mmol, 2.00 equiv), HATU (272.16 mg, 0.716 mmol, 1.50 equiv), D1EA (l 85.02 mg, 1.432 mmol, 3.00 equiv), and DCM (20.00 mL). The resulting solution was stirred for 6 hr at room température. The resulting solution was extracted with 3x20 mL of dîchloromethane and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated. The crude product was purified by Prep-HPLC with the foîlowing conditions (2#SHIMADZU (HPLC-0I)): Column, Atlantis HILIC OBD Column, 19* I50mm*5um; mobile phase, Water(0.05%NHsH20) and ACN (5% PhaseB up to 18% in 8 min). This resulted in 66.9 mg (36.37%) ofN-(l-hydroxy-2methylpropan-2-y 1)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a white solid. 'H NMR (300 MHz, DMSO-7&) S 8.68 (d, J— 6.1 Hz, 1 H), 8.04 (d, 7= 2.7 Hz, IH), 7.69 (s, IH), 7.44 (dd, 7= 6.1, 2.6 Hz, IH), 4.88 (br, 1 H), 4.35 (s,2H), 4.06 (s, 3H), 3.52-3.41 (s, 3H), 3.39-3.25 (m, 2H), 3.22-3.17 (m, 2H), 3.01 (t,7= 7.9 Hz, 2H), 2.15-1.99 (m,

444

2H), 1.17 (s, 6H). LCMS (ES) [M+l] ⁺ m/z: 386.2,

Example L140

[0859] Synthesis of N-cyclohexyl-2-{[2-(4-methoxypyridîn-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yI](methyl)amino}acetamide (Compound 137)

Scheme 87

[0861] Into a 50-mL round-bottom flask, was placed [[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]acetic acid (100.00 mg, 0.318 mmol, 1.00 equiv), dimethylformamide (4 mL), cyclohexylamine (31.55 mg, 0.318 mmol, 1.00 equiv), HATU (181.44 mg, 0.477 mmol, 1.50 equiv), and DIEA (123.35 mg, 0.954 mmol, 3.00 equiv). The resulting solution was stirred for 2 hr at 25°C. The crude reaction mixture was filtered and subjected to reverse phase préparative HPLC (Prep-C18, 20-45uM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 25% MeCN in water to 35% MeCN in water over a 10 min period, water contaîns 0.1% NH3H2O) to provide N-cyclohexyl-2- {[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide as a white solid (65 mg,51.66%). ’H NMR (300 MHz, DMSO-d6) S 8.48 (d, 7= 5.6 Hz, IH), 7.98 (d, 7= 8.0 Hz, 1 H), 7.81 (d,7=2.6 Hz, IH), 7.04 (dd,7= 5.6, 2.7 Hz, IH), 4.16 (s, 2H), 3.89 (s, 3H), 3.54 (s, 1H), 3.26 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.82 (t,7 = 7.8 Hz, 2H), 1.89-2.07 (m, 2H), 1.81-1.45 (m, 5H), 1.12-1.32 (m, 5H). LCMS (ES) [M+l]⁺ m/z 396.2.

Example 1.141

445

[0862] Synthesis of N-(3-iluorophenyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidm-4-yl](methyl)amino}acetamide (Compound 138)

[0863] Scheme 88 depicts a synthetic route for preparing an exemplary compound.

Scheme 88

[0864] Into a 50-mL round-bottom flask, was placed [[2-(4-methoxypyrîdin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]acetic acid ( 100.00 mg, 0.318 mmol, l .00 equiv), dimethylformamide (4 mL), 3-fluoroaniline (35.35 mg, 0.318 mmol, 1.00 equiv), HATU (181.44 mg, 10 0.477 mmol, 1.50 equiv), and DIEA (123.35 mg, 0.954 mmol, 3.00 equiv). The resulting solution was stirred for 2 hr at 25°C. The crude réaction mixture was filtered and subjected to reverse phase préparative HPLC (Prep-C 18, 20-45uM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 25% MeCN in water to 35% MeCN in water over a 10 min period, water contains 0.1 % NH3H2O) to provide N-(3-fluorophenyl)-2-{[2-(4-methoxypyridir)-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-415 yl](methyl)amino}acetamide as a white solid (62 mg, 47.83%). ’H NMR (300 MHz, DMSO-d6) δ 10.43 (s, IH), 8.44 (d, J= 5.6 Hz, IH), 7.77 (d, J= 2.6 Hz, IH), 7.57 (d, 7= 11.5 Hz, IH), 7.40-7.28 (m, 2H), 6.99 (dd, J=5.6, 2.6 Hz, IH), 6.86-6.92 (m, IH), 4.43 (s, 2H), 3.76 (s, 3H), 3.37 (s, 3H), 3.21 (t, J=7.4 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 1.94-2.09 (m, 2H). LCMS (ES) [M+l Y m/z 408.2.

Example 1.142

[0865] Synthesis of N-(l-methoxy-2-methylpropan-2-yl)-2-{[2-(4-methoxypyridin-2-yi)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yI](methyl)amino}acetamide (Compound 139)

446

[0866] Scheme 89 depicts a synthetic route for preparing an exemplary compound.

Scheme 89

[0867] Into a 100-mL round-bottom flask, was placed N-(2-(4-methoxypyridin-2-yl)-6,7-dihydro5l-I-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine (150.00 mg, 0.493 mmol, l.OO equiv), l-methoxytert-butylamine (76.27 mg, 0.739 mmol, 1.5 equiv), HATU (28l.l0mg, 0.739 mmol, 1.5 equiv), DIEA (I9l .09 mg, l .479 mmol, 3 equiv), and THF (20.00 mL). The resulting solution was stirred for 4 hr at room température. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers were combined, dried over anhydrous sodium sulfate, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2&SHIMADZU (HPLC-01)): Column, Welch Xtimate Cl8, 21.2*250mm,5um; mobile phase, Water(0.05%FA ) and MeOH:ACN=l:l (10% PhaseB up to 60% in 17 min. This resulted in 55.8 mg (29.07%) ofN-(lhydroxy-2-methylpropan-2-yl)-2-((2-(4-methoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-

4-yl)(methyl)amino)acetamide as an off-white solid. 'FI NMR (300 MHz, DMSO-ô/e) δ 8.48 (d, J= 5.6 Hz, 1 H), 7.85 (d, J= 2.5 Hz, 1 H), 7.57 (s, 1 H), 7.04 (dd, J= 5.6, 2.6 Hz, i H), 4.17 (s, 2H), 3.90 (s, 3H), 3.34 (s, 2H), 3.25 (s, 3H), 3.18 (s, 3H), 3.14 (t, J= 7.3 Hz, 2H), 2.82 (t, J= 7.9 Hz, 2H), 2.09-1.92 (m, 2H), 1.19 (s, 6H). LCMS (ES) [M+1 ] ⁺ m/z: 400.2.

Example 1.143

[0868] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxan-4-yl)acetamîde (Compound 140)

447

[0869] Scheme 90 depicts a synthetic route for preparing an exemplary compound.

Scheme 90

[0870] Step

[0871 ] Into a 50-mL round-bottom flask was placed [methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin2-yl]-5H,6FL7H-cyclopenta[d]pyrimidin-4-yl)amino]acetic acid (200 mg, 0.46 mmol, l.OO equiv), THF (5 mL), HATU (266 mg, 0.70 mmol, 1.50 equiv), DfEA (180 mg, L40 mmol, 3.00 equiv), and oxan-4- ainine (70 mg, 0.70 mmol, 1.50 equiv). The resulting solution was stirred for 3 hr at 60°C. The reaction was then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3x100 mL of ethyl acetate and ihe organic layers were combined, washed with 3 xlOO ml of brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 90 mg (37.69%) of 215 [methy l(2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyc!openta[d]pyrimidin-4-yl)amîno]-N(oxan-4-yl)acetamide as a yellow oil. LCMS (ES) [M+l]⁺ m/z 512.

[0872] Step 2

448

[0873] Into a 50-mL round-bottom flask, was placed 2-[methyl(2-[4-[2-(oxan-2yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]-N-(oxan-4-yi)acetamide (90 mg, 0.17 mmol, l.00 equiv), MeOH (3 mL), and TsOH (15 mg, 0.08 mmol, 0.5 equiv). The resulting solution was stirred for 2 hr at 25°C. The crude product was purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5um, I9*l50mm; mobile phase, Water (0.1% FA) and CHaCN (30% CHsCN up to 42% in 15 min); Detector, UV 254nm. This resulted in 38.6 mg (51.33%) of 2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)-N-(oxan-4-yl)acetamide as a yellow solid. 'H NMR. (300 MHz, DMSO-7&) δ 8.47 (d, 10 7=5.6 Hz, 1 H), 8.29-8.05 (m, 2H), 7.81 (d, 7= 2.6 Hz, IH), 7.05 (dd, 7= 5.7, 2.6 Hz, IH), 4.24-4.09 (m, 4H), 3.84-3.72 (m, 5H), 3.36-3.30 (m, 2H), 3.28 (s, 3H), 3.15 (t, 7 = 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.00 (q, 7=7.6 Hz, 2H), 1.67 (d,7= 11.3 Hz, 2H), 1.49-1.37 (m, 2H). LCMS (ES) [M+l]⁺ m/z 428.2.

Example L144

[0874] Synthesis of N-[(lR,2R)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 141)

[0875] Scheme 91 depicts a synthetic route for preparing an exemplary compound.

449

[0876] Into a I00-mL round-bottom flask, was placed N-(2-(4-methoxypyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidîn-4-yl)-N-methylglycîne (l50.00 mg, 0.477 mmol, l.OO equiv), 2aminocyclohexan-l-ol (82.44 mg, 0.716 mmol, 1.50 equiv), HATU (272.16 mg, 0.716 mmol, 1.5 equiv), DIEA (185.02 mg, 1.432 mmol, 3 equiv), and DCM (20.00 mL). The resulting solution was stirred for 4 hr at 4°C. The resulting solution was extracted with 3x20 mL of dichloromethane and the organic layers were combined, dried in an oven under reduced pressure, and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions (2#SH1MADZU (HPLC-01)): Column, Atlantis HILIC OBD Column, 19*150mm*5um; mobile phase, Water (0.05%NH₃H₂0) and ACN (5% PhaseB up to 18% in 8 min). This resulted in 95.2 mg (48.48%) ofN-((ÎR,2R)-2hyd roxycyc lohexy l)-2-((2-(4-m ethoxy py rid in-2-y I )-6,7-d ihy dro-5 H -cyc 1 openta[d] pyrimîd in-4yl)(methyl)amino)acetamide as a white solid. 'H NMR (300 MHz, DMSO-c/e) δ 8.48 (d, J - 5.6 Hz, IH), 7.91 (d,7=8.1 Hz, IH), 7.82 (d, 7= 2.6 Hz, IH), 7.04 (dd,7= 5.7, 2.6 Hz, 1H),4.54 (d, 7= 4.8 Hz, II-I), 4.25 (d, 7= 16.4 Hz, IH), 4.15 (d, 7= 16.3 Hz, IH), 3.89 (s, 3H), 3.48-3.36 (m, IH), 3.313.22 (m, 4H), 3.14 (t, 7= 4.7 Hz, 2H), 2.82 (t, 7= 7.9 Hz, 2H), 2.03-1.93 (m, 2H), 1.86-1.49 (m, 4H), 1.32-1.05 (m, 4H). LCMS (ES) [M+l]⁺ m/z: 412.3.

Example 1.145

[0877] Synthesis of N-cydohexyl-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 142)

450

[0878] Scheme 92 depicts a synthetic route for preparing an exemplary compound.

Scheme 92

[0879] Into a 20-mL vial, was placed [methyl[2-(l-methylimidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetic acid hydrochloride (150 mg, 0.46 mmol, l.OO equiv), DMF (3.0 mL), cyclohexylamine (51 mg, 0.51 mmol, L10 equiv), and D1EA (240 mg, l .85 mmol, 4.00 equiv). This was followed by the addition of HATU (264 mg, 0.69 mmol, 1.50 equiv) at 0°C. The reaction solution was stirred for 2 h at room température. The crude product was purified by Flash-Prep-

HPLC with the following conditions: Column, Cl8-120 g, CH3CN/H2O (0.05% NH4OH) from 10% to 80% within 12 min, flow rate, 70 ml/min, Detector, UV 254 nm. 83.8 mg (49%) ofN-cyclohexyî-2[methyl[2-(l-methylimidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetamide was obtained as a white solid. ’HNMR (300 MHz, DMSO-7<5,ppm): δ 7.95 (d, J= 8.1 Hz, I H), 7.71 (d, J= 1.5 Hz, IH), 7.60 (d, 7= 1.5 Hz, IH), 4.12 (s, 2H), 3.69 (s, 3H), 3.57-3.53 (m, IH), 3.21 (s, 3H), 3.06 (t,

7=7.5 Hz, 2H), 2.73 (t, 7= 7.8 Hz, 2H), 1.99-1.89 (m, 2H), 1.68 (t, 7= 10.8 Hz, 4H), 1.54 (d, 7= 12.3

Hz, IH), 1.27-1.07 (m, 5H). LCMS (ES, m/z): [M+H]⁺:

369.2.

Example 1.146

[0880] Synthesis ofN-(l-hydroxy-2-methylpropan-2-yl)-2-{methyi[2-(i-methyl-lH-imidazol-4-yl)20 5H,6H,7H-cyclopenta[d]pyrimidm-4-yl]amino}acetamide (Compound 143)

451

[0881 ] Scheme 93 depicts a synthetic route for preparing an exemplary compound.

HATU, DlEA, DMF O°C~rt, 1.5 h 62%

Scheme 93

[0882] Into a 20-mL vial, was placed [methyl[2-(l-methylimidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino] acetic acid hydrochloride (150 mg, 0.46 mmol, 1.00 equiv), DMF (3.00 mL), 2-amino-2-methyl-l-propanol (45 mg, 0.51 mmol, 1.10 equiv), and DIEA (240 mg, 1.85 mmol, 4.00 equiv), This was followed by the addition of HATU (264 mg, 0.69 mmol, 1.50 equiv) at 0^üC. The resulting solution was stirred for 2 h at room température. The crude product was purified by

Flash-Prep-HPLC with the foilowing conditions: Column, Cl 8-120 g, CH3CN/H2O (0.05% NH₄OH) from 10% to 80% within 12 min, flow rate, 70 ml/min, Detector, UV 254 nm. 102.8 mg (62%) of N-(lhydroxy-2-methylpropan-2-yl)-2-[methyl[2-(l-methylimidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yi]amino]acetamide was obtained as a white solid. 'H-NMR (300 MHz, DMSOA^wO: ô 7.74 (d, J= 1.5 Hz, IH), 7.59 (d, J= 1.5 Hz, IH), 7.46 (s, 1 H), 4.93 (br, lH),4.10(s,

2H), 3.69 (s, 3H), 3.37 (d, J= 3.9 Hz, 2H), 3.21 (s, 3H), 3.07 (t, 7= 7.5 Hz, 2H), 2.73 (t, 7= 7.8 Hz,

2H), 1.99-1.89 (m, 2H), L18 (s, 6H). LCMS (ES, m/z): [M+H]⁺: 359.2.

Example 1.147

[0883] Synthesis ofN-cyclohexyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pynmidin-4-yl}(methyl)amino)acetamide (Compound 144)

ΌΗ

[0884] Scheme 94 depicts a synthetic route for preparing an exemplary compound.

Scheme 94

[0886] Into a 100-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed a mixture of 4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (2.00 g, 5.1S mmol, l.OO equiv), dioxane (40.0 mL, 454 mmol), ethyl N-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin10 4-yl)-N-methylglycÎnate (1.40 g, 5.180 mmol, 1.00 equiv), and Pd(PPh₃)4 (598 mg, 0.518 mmol, 0.10

453 equiv). The resulting solution was stirred for 16 hours at 100°C. After cooling, the solution was concentrated. The residue was applied onto a silica gel column eluting with dichloromethane/methanol (10/1). This resulted in 826 mg (34.93%) of ethyl N-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyc!openta[d]pyrimidin-4-yl)glycinate as a brown crude oil. LCMS (ES) [M+l ]* m/z: 457.

[0888] Into a 20-mL vial was placed a mixture of ethyl N-methyl-N-(2-(4-(2-((tetrahydro-2Hpyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yI)glycmate (800 mg, 1.75 mmol, 1.00 equiv), MeOH (8.00 mL), H₂O (2.00 mL), and LiOH (83.9 mg, 3.50 mmol, 2.00 equiv). The resulting solution was stirred for 2 hours at room température. The crude reaction mixture was fîltered and subjected to reverse phase préparative MPLC (Prep-C18, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 5 % MeCN in water to 27% MeCN in water over a 12 min period, where both solvents contain 0.1% NH3H2O). This resulted in 568 mg (75.65%) of N-methylN-(2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-y!)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)glycine as a red solid. LCMS (ES) [M+l]⁺ m/z: 429.

[0889] Step 3

[0890] Into an 8-mL vial, was placed N-methyl-N-(2-(4-(2-((tetrahydro-2H-pyran-2 yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)giycine (150 mg, 0.350 mmol, 1.00 equiv), DMF (2.00 mL), cyclohexylamine (34.7 mg, 0.350 mmol, ! .00 equiv), DIEA (135 mg, 1.05 mmol, 3.00 equiv) and HATU (159 mg, 0.420 mmol, 1.20 equiv). The resulting solution was stirred for

454 hours at room température, The crude reaction mixture was filtered and the filtrate was subjected to reverse phase préparative MPLC (Prep-CI8, 20-45 mM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 8 % MeCN in water to 33% MeCN in water over a 12 min period, where both solvents contain 0,]%NH₃H2O). This resulted in 126 mg (70.62%) ofN-cyclohexyl-2-(methyl(2-(4-(2((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4y!)amino)acetamide as a brown oil. LCMS (ES) [M+l]⁺ m/z: 510.

[0891] Step 4

[0892] Into an 8-mL vial was placed a mixture of N-cyclohexyl-2-(methyl(2-(4-(2-((tetrahydro-2Hpyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide ( 120 mg, 0.235 mmol, l .00 equiv), MeOH (3.00 mL), and TsOH (20.2 mg, 0.118 mmol, 0.50 equiv). The resulting solution was stirred for 2 hours at room température. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep Cl8 OBD Column, l9xl50mm, 5um; mobile phase, phase A: H₂O (O.l % FA); phase B: CH3CN (5% CH3CN up to 20% CH3CN in 8 min). This resulted in 22.5 mg (22.46%) of N-cyclohexyl-2-((2-(4-(2-hydroxyethoxy)pyridîn-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as an off-white solid. ’H NMR (300 MHz, DMSOA, ppm): δ 8.55 (d, J= 5.9 Hz, IH), 8.14 (s, 0H), 8.03 (d,7= 7.9 Hz, IH), 7.89 (d,7=2.6 Hz, IH), 7.22 (dd, 7= 5.9, 2.6 Hz, IH), 4.96 (br, IH), 4.24-4.20 (m, 4H), 3.77-3,68 (m, 2H), 3.62-3.47 (m, IH), 3,33 (s, 3H),3.18 (t, 7= 7,3 Hz, 2H),2.89 (t,7= 7,8 Hz, 2H), 2.07-1.97 (m, 2H), 1.72-1.52 (m, 5H), 1.31-1.07 (m, 5H). LCMS (ES) [M+l]⁴ m/z: 426.2.

Example 1.148

[0893] Synthesis of N-tert-buty 1-2-{[2-(4,5-dimethoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 145) [0894]

455

[0895] Scheme 95 depicts a synthetic route for preparing an exemplary compound.

90.23% mCPBA DCM

72.41%

H₂SO₄, hno₃

44%

NaOMe

58.78%

Scheme 95

[0896] Step I

K₂CO₃

90.23%

[0897] Into a 25-mL round-bottom flask was placed a solution of 6-bromopyridin-3-ol (800.00 mg, 4.598 mmol, 1.00 equiv) in DMF (10 mL), methyl iodide (717.86 mg, 5.058 mmol, 1.10 equiv), and K2CO3 (762.53 mg, 5.517 mmol, 1.2 equiv). The resulting solution was stirred for 12 hr at room température. The resulting solution was diluted with 50 mL of H₂O, extracted with 2x50 mL of ethyl acetate, the organic layeres were combined, dried over anhydrous sodium sulfate, and concentrated. This resulted in 780 mg (90.23%) of 2-bromo-5-methoxypyridine as a light yellow oil. LCMS (ES) [M+l]⁺m/z: 188.

[0898] Step 2

456

mCPBA DCM

72.41%

[0899] Into a 25-mL round-bottom flask, was placed a solution of 2-bromo-5-methoxypyridine (700.00 mg, 3.723 mmol, 1.00 equiv) in DCM (15 mL), and mCPBA (770.94 mg, 4.468 mmol, 1.2 equiv). The resulting solution was stirred for 10 hr at room température. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 2x20 mL of dichloromethane. The combined organic layers were washed with 3x20 mL of aq Na₂SO3, dried over anhydrous sodium sulfate, and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:2). This resulted in 550 mg (72.41%) of 2-bromo-5-methoxypyridîne 1-oxide as a light yellow solid. LCMS (ES) [M+l]⁺ m/z:204.

[0900] Step 3 h₂so₄, _r ^Bryv

HNO₃ n JE / 44% ⁰

[0901] Into a 50-mL round-bottom flask, was placed H₂SÛ4 (12.00 mL), 2-bromo-5methoxypyridine 1-oxide (500.00 mg, 2.451 mmol, 1.00 equiv). This was followed by the addition of HNO₃ (8.00 mL, 0.127 mmol, 0.05 equiv) dropwise with stirring at 0°C in 30 min. The resulting solution was stirred for 30 min at 0°C in an ice/salt bath. The resulting solution was stirred for an additional 12 hr while the température was maintained at 100°C in an oil bath. The resulting solution was diluted with 100 mL of ice water. The pH value ofthe solution was adjusted to 10 with NaOH (5 mol/L). The resulting mixture was extracted with 3x30 mL of ethyl acetate, and the combined orgaic layers were dried and concentrated, The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 220 mg of 2-bromo-5-methoxy-4-mtropyridine as a light yellow solid. LCMS (ES) [MH]⁺ m/z:233.

[0902] Step 4

NaOMe ^Br

58.78%

[0903] Into a 20-mL round-bottom flask was placed a solution of 2-bromo-5-methoxy-425 nitropyridine (200.00 mg, 0.858 mmol, 1.00 equiv) in MeOH (5 mL) and sodium methoxîde (69.55 mg, 1.287 mmol, 1.50 equiv). The resulting solution was stirred for 3 hr at room température. The resulting

457 solution was diluted with 20 mL of H₂O, extracted with 2x20 mL of dichloromethane. The combined organic layers were dried over anhydrous sodium sulfate and concentrated. This resulted in 110 mg (58.78%) of 2-bromo-4,5-dimethoxypyridine as an off-white solid. LCMS (ES) [M+l]⁺ m/z:2l8.

[0904] Step 5

PdCI₂(dppf), Tol,Sn₂Me₆37.34% (Bu)₃Sn

OMe

[0905] Into a 25-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed a solution of 2-bromo-4,5-dimethoxypyridine (300.00 mg, 1.376 mmol, l.OO equiv) in Toi ( mL), Sn₂Mee (450.76 mg, 1.376 mmol, l.OO equiv), and Pd(dppf)Cl₂ (1006.70 mg, l.376 mmol, l equiv). The resulting solution was stirred for 3 hr at I00°C in an oil bath. The resulting solution was diluted with 20 mL of H₂O, extracted with 2x20 mL of ethyl acetate. The combined organic layers were dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 220 mg (37.34%) of 4,5-dimethoxy-2-(tributylstannyl)pyridine as a brown solid. LCMS (ES) [M+l]⁺ m/z:430.

[0906] Step 6 (Bu)₃Sn

OMe

38.98%>

[0907] Into a 20-mL round-bottom flask purged and maintained in an inert atmosphère of nitrogen was placed a solution of 4,5-dimethoxy-2-(tributylstannyl)pyridine (220.00 mg, 0.514 mmol, l.OO equiv) in Toi (6 mL), tert-butyl 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate (l 52.99 mg, 0.514 mmol, l equiv), and Pd(dppf)Cl₂ (37.59 mg, 0.051 mmol, 0.10 equiv). The resulting solution was stirred for 12 hr at !00°C in an oil bath. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l: l). The collected fractions were combined and concentrated. The crude product was purified by Flash-Prep-HPLC with the following conditions (IntelFLash-l): Column Cl8; mobile phase, ACN:H₂O (0.0l%TFA)=l :20 increasing to ACN:H₂O(0.0l%TFA)=l:5 within 15 min; Detector, UV 254 nm . This resulted in 80 mg

(38.98%) ofN-(tert-butyl)-2-((2-(4,5-dimethoxypyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)(methyl)amino)acetamide as a white solid. H NMR (300 MHz, DMSO-7&) δ 8.24 (s, IH), 7.92 (s, IH), 7.64 (s, IH), 4.16 (s, 2H), 3.93 (s, 3H), 3.91 (s, 3H), 3.25 (s, 3H),3.13 (t, J= 13 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.03-1.95 (m, 2H), 1.22 (s, 9H). LCMS (ES) [M+1 ]⁺ m/z: 400.2.

Example 1.149

[0908] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4y l](methy l)am i no} -N-(3 -methy loxo lan-3-y l)acetainide(Compound 146)

H

[0909] Scheme 96 depicts a synthetic route for preparing an exemplary compound.

Cl zXn

1. HATU

i II DIPEA x,.Z\_z o^o⁰ + X p —---~ π 2. HCl ⁿ CI O 1 H O. VT A Ά ++ γ Pd(pph₃)₄ JL + ’ /A'N * Γ T VU A ] N Cl A 10 Scheme 96 [0910] Step 1 'Xy^0H 1.HATU ï 0 ^H2^NV^N ^{dipea x} oV + A p - _H- A 2. HCl

Cl A] o ------ C-/ TEA H AA N ¹ VA A ^N vV H

459

[0911] To a solution of [(tert-butoxycarbonyl)(methyl)amino] acetic acid (l.OO g; 5.29 mmol; l.OO eq.) in DMF (I5 mL) was added 3-methyloxolan-3-amine (0.53 g; 5.29 mmol; l .00 eq.), followed by Hunig's base (L38 mL; 0.01 mol; 1.50 eq.) and HATU (2.01 g; 0.01 mol; 1.00 eq.). After being stirred for 15 h at room température, the mixture was extracted with EtOAc, the organic layers were combined, 5 dried, and concentrated to give desired crude product. The crude product was diluted with DCM (10 mL), to which was added 4N HCl in dioxane (10 mL). After completion, the mixture w^ras concentrated and diluted with Sat. NaHCOs. The aqueous layer was extracted with EtOAc, and then the organic layers were combined and concentrated to give 2-[chloro(methyl)amino]-N-(3-methyloxolan-3-yl)acetamide (2.80 g). LCMS (ES) [M+l]⁺ m/z: 173.4.

[0912] Step 2

Cl

[0913] To a solution of 2,4-dichloro-6₎7-dihydro-5H-cyclopenta[d]pyrimidine (0.66 g; 3.50 mmol;

.00 eq.) in AcCN (10 mL) was added 2-[chloro(methyl)amino]-N-(3-methyloxolan-3-yl)acetamide (1.10g; 5.25 mmol; 1.50 eq.) and triethylamine (1.96 mL; 14.00 mmol; 4.00 eq.). After being stirred at

80°C for 15 h, the mixture was cooled to room température and concentrated to remove solvent. The residue was purified by column chromatography (DCM/MeOH = 10:1) to give 2-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyloxolan-3-yl)acetamide. LCMS (ES) [M+l]⁺m/z:325.1,327.2.

[0914] Step 3

[0915] To a solution of 4-methoxy-2-(tributylstannyl)pyridine (183.88 mg; 0.46 mmol; 1.50 eq.) and

2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl] (methy l)amino)-N-(3-methyloxolan-3yl)acetamide (100.00 mg; 0.31 mmol; 1.00 eq.) in Toluene (L0 mL) was added

460

tetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol; 0.10 eq.). The mixture was degassed and heated at !05°C for 15 h. HPLC indicated slow conversion. The mixture was concentrated and was added DMF (ImL) more 4-methoxy-2-(tributylstannyl)pyndme (183.88 mg; 0.46 mmol; 1.50 eq.) and tetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol; 0.10 eq.). The mixture was heated further for 15 hr at 100°C, cooled. and diluted with water and AcCN and was subjected to purification by préparative FIPLC to give N-tert-butyl-2-{ethyl[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]ami no [acetamide (16 mg). 'H NMR (400 MHz, Methanol-Ti) δ 8.62 (d, J = 6.1 Hz, IH), 8.06 (d, J= 2.6 Hz, IH), 7.35 (dd, J= 6.1, 2.7 Hz, IH), 4.49-4.33 (m, 2H), 4.07 (s, 3H), 3.96 (dd, 7 = 13.9, 8.8 Hz, 1 H), 3.94 - 3.81 (m,2H), 3.61 (t,7=8.3 Hz, IH), 3.51 (s,3H), 3.33 (d,7=

7.3 Hz, 2H), 3.13- 2.94 (m, 2H), 2.30 (dq, 7=13.3, 6.7 Hz, 1 H), 2.26 -2.13 (m, 2H), 2.07 - 1.86 (m,

ÏH), 1.45 (d, 7= 15.2 Hz, 3H). LCMS (ES) [M+l]⁺m/z:398.0.

Example 1.150

[0916] Synthesis of 2-{methyl[2-( 1 -methyl-1 H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino[-N-(3-methyloxolan-3-yl)acetamide (Compound 147)

[0917] Scheme 97 depicts a synthetic route for preparing an exemplary compound.

Scheme 97

[0918] To a solution of l-methyl-4-(tributyistannyl)-lH-imidazole (171.40 mg; 0.46 mmol; 1.50 eq.) and 2-({2-ch]oro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyloxolan-3yl)acetamide (100.00 mg; 0.31 mmol; 1.00 eq.) in DMF (LO mL) was added tetrakis(triphenylphosphane) palladium (35.58 mg; 0.03 mmol; 0.10 eq,). The mixture was degassed and

461 heated at !05°C for 15 h. The solution was cooled to room température and diluted with water and AcCN, and purified by préparative HPLC to give 2-{methyl[2-(l-inethyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pynmidin-4-yl]amino}-N-(3-methyloxolan-3-yl)acetainide (26.6 mg). *H NMR (400 MHz, Methanol-7₄) δ 8.74 (s, IH), 8.37 (s, IH), 4.60 (d, J= 16.7 Hz, IH), 4.52 (d, J= 16.7 Hz, IH), 4.02 (d, J = 9.0 Hz, IH), 4.00 (s, 3H), 3.96 - 3.82 (m, 2H), 3.56 (d, J= 9.0 Hz, IH), 3.51 (s, 3H), 3.30 (d, J= 12.2

Hz, 2H), 3.10 (t, J= 7.9 Hz, 2H), 2.33 (ddd, J= 12.9, 7.6, 5.3 Hz, IH), 2.23 (p, J= 7.8 Hz, 2H), 1.95 (dt, J= 12.9, 8.1 Hz, IH), 1.46 (s, 3H). LCMS (ES) [M+l]⁺ m/z:37L0.

Example 1.151

[0919] Synthesis of 2-[methyl({2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5H,6H,7H10 cyclopenta[d]pyrimidin-4-yl})amino]-N-(l -methyl-lH-pyrazol-4-yl)acetamide (Compound 177)

[0920] Scheme 98 depicts a synthetic route for preparing an exemplary compound.

Cl

Br

OCH₂CF₃ BuLI Bu₃Sn

Bu₃SnCI

OCHgCFa

462

Scheme 98

[0921] Step l

[0922] To a solution of [(tert-butoxycarbonyl)(methyl)amino [acetic acid (2.00 g; 10.57 mmol; 1.00 eq.) in DMF (15 mL) was added ]-methyl-lH-pyrazol-4-ylamine (1.54 g; 15.86 mmol; 1.50 eq.), followed by Hunig's base (2.77 mL; 15.86 mmol; 1.50 eq.) and HATU (4.82 g; 12.68 mmol; 1.20 eq.). After being stirred for 4 h, the mixture was diluted with Sat. NaHCOj, and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried, and concentrated to give the crude product, which was purified by silica gel column chromatography (Hexanes/EtOAc = 1:3) to give tert-butyl N-methy 1-N-{[(1-methyl-lH-pyrazol-4-yl)carbamoyl]methyl}carbamate (2.75 g, 97% yield). LCMS (ES⁺): (M+Na)⁺ = 291.1.

[0923] Step 2

[0924] To a solution of tert-butyl N-methyl-N-{[(l-methyl-IH-pyrazol-4yl)carbamoyl]methyl}carbamate (2.75 g; 10.25 mmol; 1.00 eq.) in DCM (5 mL) was added 4N HCl in dioxane (5 mL). The mixture was stirred for 2 h. HPLC was used to check that the reaction was finished.

The suspension was concentrated to give 2-[chloro(methyl)amino]-N-(l-methyl-lH-pyrazol-4yl)acetamide (2.15 g). LCMS (ES⁺): (M+H)⁺= 169.1.

[0925] Step 3

[0926] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (1.32 g; 7.00 mmol;

.00 eq.) in AcCN (15 ml) was added triethylamine (2.94 mL; 21.01 mmol; 3.00 eq.) and 2-

[chloro(methyl)amino]-N-( 1-methyl-lH-pyrazol-4-yl)acetamide (2.15 g; 10.51 mmol; 1.50 eq.). The mixture was heated at 80 °C for 3 h and diluted with water. AcCN was removed under vacuum and the aqueous layer was extracted with EtOAc. The organic layers were combined, washed with brine, dried and concentrated. The resulting crude solid was washed with EtOAc, fïltered, and dried to give 2-({2cliioro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(l-methyl-lH-pyrazol-425 yl)acetamide as a white solid (1.61 g). LCMS (ES⁺): (M+H)⁺ = 32 ï. 1.

[0927] Step 4

[0928] Synthesis of the Stille tin reagent: To a solution of 2-bromo-4-(2,2,2-trifluoroethoxy)pyridine (310.00 mg; 1.21 mmol; 1.00 eq.) in toluene (10 ml) at -78 °C was added butyllithium (0.54 mL; 2.70 mol/L; 1.45 mmol; 1.20 eq.). After being stirred for 30 min at -78 °C, to the mixture was added tributyl(chloro)stannane (0.36 mL; 1.33 mmol; 1.10 eq.). After being stirred for 30 min at -78 °C, the solution was warmed to room température and further stirred for 2 h. The mixture was quenched with

ice water and brine and extracted with hexane. The organic layers were combined, dried, and concentrated to give 2-(tributylstanny 1)-4-(2,2,2-trifluoroethoxy)pyridine (590 mg).

[0929] To a solution of 2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(1methyl-lH-pyrazol-4-yl)acetamide (175.00 mg; 0.55 mmol; 1.00 eq.) in DMF (2 mL) was added the above synthesîzed 2-(tributylstannyl)-4-(2,2,2-trifluoroethoxy)pyridine (508.64 mg; 1.09 mmol; 2.00 eq.) and tetrakis(triphenylphosphane) palladium (63.04 mg; 0.05 mmol; 0.10 eq.). After being degassed with N2, the mixture was heated at 110 degree for 15 h. The mixture was cooled and diluted with AcCN/water, fïltered, and the filtrate was subjected to purification by préparative HPLC to give 2[methyl({2-[4-(2,2,2-trif1uoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimîdin-4-yl})amino]-N10 (1-methyl-1 H-pyrazol-4-yl)acetamide (11.4 mg). LCMS (ES⁺); (M+H)⁺ = 462.1. ¹H NMR (400 MHz,

DMSO-Αδ 10.74 (s, IH), 8.68 (d, J= 5.8 Hz, lH),7.94(s, IH), 7.50 (d, 7=2.3 Hz, IH), 7.43 (dd,7 = 5.8, 2.6 Hz, IH), 6.33 (d,7=2.2 Hz, IH), 5.01 (dd, J= 9.3, 4.1 Hz, 2H), 4.61 (s, 2H),3.69(s, 3H), 3.51 (s, 3H), 3.31 (m, 2H), 3.01 (t, 7= 7.9 Hz, 2H), 2.14-2.03 (m, 2H).

Example 1.152

[0930] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyfidin-2-yî]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyI)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 187)

[0931 ] Scheme 99 depicts a synthetic route for preparing an exemplary compound.

464

DMSO, NaH 41%

Scheme 99

[0932] Step 1

□MF

64%

HATU, DIEA

[0933] Into a 1 L 3-necked round-bottom flask was placed N-(tert-butoxycarbonyl)-N-methylglycine (40.0 g, 0.211 mol, 1.00 equiv), DMF (300 mL), 6-methoxypyridin-3-amine (28.8 g, 0.232 mol, 1.10 equiv), DIEA (54.4 g, 0.422 mmol, 2.00 equiv). This was followed by the addition of HATU (88.16 g, 0.232 mol, 1.10 equiv)in several batches at 0 °C. After addition, the resulting solution was stirred for 16 h at room température. The reaction was quenched with 400 mL of water, extracted with 3x200 mL of ethyl acetate. The combined organic phase was washed with 2x400 mL of water and lx 400 mL brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column with ethyl acetate/petroleum ether (E i). This resulted in 40 g (4%) of tert-butyl (2-((6-methoxypyridin-3-yl)amino)-2-oxoethyl)(methy!)carbamate as an off white solid. LCMS (ES) [M+l]⁺m/z: 296.

[0934] Step 2

Into a 500-mL 3-round-bottom flask was placed tert-butyl (2-((6-methoxypyridin-3-yl)amino)-2oxoethyl)(methyl)carbamate (40 g, 0.101 mol, 1.00 equiv), DCM (200.00 mL). This was followed by the addition of HCl (g) (2 M in ethyl acetate) (300.00 mL) dropwise with stirring at 0 °C. The resulting

465 solution was stirred for 16 h at room température, concentrated in vacuum to remove the solvent and washed with ethyl acetate (150 mL). This resulted in 25.5 g (8I%) ofN-(6-methoxypyridin-3-yl)-2(methylamino)acetamide hydrochloride. LCMS (ES) [M-HCl+l]⁺m/z: I96.

[0935] Step 3

[0936] Into a I L 3 neck round-bottom flask was placed N-(6-methoxypyridin-3-yl)-2(methylamino)acetamide hydrochloride(38.6 g, 0.167 mol, L05 equiv), NMP (300.00 mL) , 2,4dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (30 g, 0.158 mol, l.OO equiv), DIEA (6L15 g, 0.474 10 mol, 3.00 equiv).. The resulting solution was stirred for 18 h at 50 °C in oil bath. The reaction mixture was cooled to room température, diluted with 200 mL of water, extracted with 3x200 mL of ethyl acetate. The combined organic phase was washed with 3 x3ÛO ml of water and brine 200 mL, dried over anhydrous sodium sulfate and filtered. The fïltrate was concentrated under reduced pressure, the residue was purified by silica gel column with THF/petroleum ether (1:1). This resulted in 35 g (63%) of 2-((215 chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(inethyl)amino)-N-(6-inethoxypyridin-3yl)acetamide as a white solid. LCMS (ES) [M+f]* m/z: 348.

[0937] Step 4

[0938] Into a 500-mL three necked round boltom flask purged and maintained with an inert atmosphère of nitrogen was placed 2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (10 g, 28.8 mmol, 1.00 equiv), toluene (150 mL), 4-fluoro-2-(tributylstannyl)pyridine (20 g, 51.84 mmol, 1.8 equiv) and Pd(PPh3)₄ (3.04 g, 2.88

466 mmol, 0.10 equiv). The mixture was stirred for 36 h at 110 °C in oil bath. The reaction was repeated in 2 batches. The reaction mixture was cooled to room température, concentrated to remove the solvent, the residue was purified by silica gel column with PE/THF (100:1 to 1:10). This resulted in 12.1 g (51.5%) of 2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6methoxypyridin-3-yl)acetamide as yellow oil. LCMS (ES) [M+l]⁺ m/z: 409.

[0939] Step 5

[0940] Into a 250mL 3-neck flask was placed ethane-l,2-diol (4.78 g, 77.0 mmol, 5.0 equiv) and DMSO (100 mL), NaH (60% in minerai oil) (3.08 g, 77.0 mmol, 5.0 equiv) was added in portion wise at 5°C. The mixture was stirred for 1 h at room température. After which 2-((2-(4-fluoropyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrinridin-4-yl)(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (6.3 g, 15.4 mmol, 1.00 equiv) was added at 5°C. The reaction mixture was stirred for 5 h at room température. (The reaction was repeated in 2 batches). The reaction mixture was poured into 200 mL of stirred water, extracted with 3x200 mL of ethyl acetate. The combined organic phase was washed with 3 x300 ml of water and brine 1 x200 mL, dried over anhydrous sodium sulfate. The residue was purified by PrepHPLC with conditions: column, C18-800 g, Mobile phase, CH3CN/H2O (0.05% FA), from 10% increased to 70% within 27 min, Flow rate, 180 mL/mîn, Detector, 254 nm. The pH value of the fraction was adjusted to 7-8 with K2CO3 solid, extracted with dichloromethane (3x300 mL). The combined organic phase was dried over anhydrous sodium sulfate and filtered. The fîltrate was concentrated under reduced pressure. The residue was freeze dried to give5.7 g (41%) of2-((2-(4-(2hydroxyethoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(6methoxypyridin-3-yl)acetamide as a white solid. LCMS: (ES, m/z); [M+H]⁺: 451.2. 'H-NMR: (300 MHz, DMSO^^m): δ 10.27 (s, IH), 8.44 (d, J= 5.6 Hz, IH), 8.35 (d, J= 2.6 Hz, IH), 7.89 (dd, 7 = 8.9, 2.7 Hz, 1 H), 7.79 (d,7=2.5 Hz, IH), 7.01 (dd,7= 5.7, 2.6 Hz, IH), 6.78 (d,7= 8.9 Hz, IH), 4.91 (t, 7= 5.4 Hz, 11-1),4.41 (s, 211),4.04 (t, 7= 4.8 Hz, 2H), 3.80 (s, 3H), 3.69 (q,7=5.1 Hz, 2H), 3.37 (s, 3H), 3.20 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.08-1.96 (m, 2H).

Example 1.153

467

[0941] Synthesis of N-tert-buty l-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5 H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 348)

[0942] Scheme 100 depicts a synthetic route for preparing an exemplary compound.

Scheme 100

[0943] Step 1 : Addition of fluoropyridine:

NaH, DMF

Scheme 100-1

[0944] Into a 250-mL three-necked round bottom flask purged and maintained with an inert atmosphère of nitrogen were placed N-(tert-butyl)-2-((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-y[)(methyl)amino)acetamide (10 g, 33.8 mmol, 1.00 equiv), toluene (150.00 mL), 4-fiuoro-2(tributylstannyl)pyridine (21.7 g, 60.84 mmol, 1.8 equiv), and Pd(PPh3)₄ (3.57 g, 3.38 mmol, 0.10 equiv). After being stirred for 60 h at 110 °C in an oil bath, the reaction mixture was cooled to room

468

température, and concentrated to remove the solvent; the residue was purified by silica gel column with dichloromethane/méthanol (10:1). This resulted in 7 g (58%) ofN-(tert-butyI)-2-((2-(4-fluoropyridin-2yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl) amino)acetamide as a yellow solid. LCMS (ES) [M+l]⁺ m/z: 358.

[0945] Step 2: Addition of 2-(dimethylamino)ethan-l-ol:

Scheme 100-2

[0946] Into a 50 mL 3-neck flask were placed 2-(dimethylamino)ethan-l-ol (112 mg, 1.26 mmol, 3.0 equiv) and DMF (2 mL). NaH (60% in minerai oil) (33.6 mg, 0.84 mmol, 2.0 equiv) was added portion10 wise at 0-5 °C. After being stirred for 1 h, to the mixture was added N-(tert-butyl)-2-((2-(4f]uoropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yi)(methyl)amino)acetamide ( 150 mg, 0.42 mmol, 1.00 equiv) at 0-5 °C. The reaction mixture was then stirred for 5 h at 50 °C. After being cooled down to ambient température, the reaction mixture was concentrated, and the residue was purified by Prep-HPLC with the following conditions: column, Cl 8-800 g, Mobile phase, CH3CN/H2O (0.05% FA), from 10% increased to 70% within 27 min, Flow rate, 80mL/min, Detector, 254 nm. The pH value of the fraction was adjusted to 7-8 with NazCOa, and the mixture was extracted with dichloromethane (3x300 mL). The combined organic phases were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated under reduced pressure. This resulted in 100.9 mg (56%) of N(tert-buty 1)-2 -((2-(4-(2 -(d imethy lam ino)ethoxy )py rid in -2-y l)-6,7-dihydro-5 H-cyc lopenta[d]py rimid in-4- yl)(methyl)amino)acetamide as a white solid. LCMS (ES, m/z): [M+H]⁺: 427. H NMR (300 MHz, DMSOA) δ 8.47 (d, J = 5.6 Hz, IH), 7.83 (d, J = 2.5 Hz, IH), 7.67 (s, IH), 7.05 (dd, J = 5.6, 2.6 Hz, lH), 4.20 (t, J = 5.7 Hz, 2H), 4.12 (s, 2H), 3.31 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 2.05 - 1.94 (m, 2H), 1.25 (s, 9H).

[0947] Alternative Method: For Preparing Compound 348

469

Scheme 100-3

[0948] Into a 500 mL round-bottom flask were added 4-chioropicolinonitrile (50 g, 360 mmol, 1.00 equiv) in MeOH and NaOMe (1.95 g, 36.1 mmol, 0.1 equiv). The mixture was stirred for 8 hours at room température under a nitrogen atmosphère, and NH4CI (29.0 g, 541 mmol, 1.5 equiv) was added. The resulting mixture was further stirred for 16 hours at room température under a nitrogen atmosphère. The resulting mixture was fîltered, the filtrate was concentrated under reduced pressure. This resulted in 4-chloropicolinimidamide hydrochloride (63.0 g, 90.90%) as a brown solid. LCMS (ES) [M-HC1+1]⁺m/z 156.

[0949] Into a 1 L round-bottom flask were added 4-chloropicolinimidamide hydrochloride (60.0 g, 312 mmol, 1.00 equiv) in MeOH (600 mL), methyl 2-oxocyclopentane-l-carboxylate (66.6 g, 468 mmol, 1.5 equiv), and NaOMe (42.18 g, 781 mmol, 2.5 equiv) in MeOH at room température. The mixture was stirred for 40 hours at 70 °C under a nitrogen atmosphère. The precipitated solids were collected by filtration and washed with MeOH (Ixl 500 mL). This resulted in 2-(4-chloropyridin-2-yl)6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (62 g, 80.12%) as a brown solid, LCMS (ES) [M+l]⁺m/z 248.

470

Scheme 100-5

[0950] Into a IL 3-necked round-bottom flask were added 2-(4-chloropyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-ol (60 g, 242 mmol, l.OO equiv) in DCM and TEA (123 g, I2l l mmol, 5,0 equiv). A stirred mixture of Tf₂O (137 g, 484 mmol, 2.0 equiv) in DCM was added dropwise at 0 °C. The resulting mixture was stirred for an additional 2 hours at 0 °C. The reaction was quenched by the addition of NH4CI (aq. 500 mL) at room température. The resulting mixture was extracted with DCM (3 x 600 mL), and the organic layers were combined and dried over anhydrous Na₂SO4- The resulting mixture was fîltered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:l) to afford 2-(4-chloropyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate (63 g, 68.48%) as an off-white solid. LCMS (ES) [M+ff m/z 380.

Scheme 100-6

[0951] Into a 500 mL three-necked round bottom flask were added 2-(4-chloropyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate (24.0 g, 63.3 mmol, l.OO equiv), TEA (25.6 g, 253.2 mmol, 4.00 equiv), and dichloromethane (300 mL). This was followed by the addition ofN-(tert-butyl)-2-(methylamino)acetamide hydrochloride (14.8 g, 82.3 mmol, L30 equiv) at room température. After being stirred for 12 h, the reaction was quenched with H₂O (200 mL), extracted with dichloromethane (100 mL* l), and the organic layer was separated and dried over anhydrous sodium sulfate. The mixture was fîltered, and the filtrate was concentrated under reduced pressure. The residue was triturated in ethyl acetate/ hexane (l :3). The solid was collected by filtration and dried under an infrared lamp for 3 h. This resulted in 2L3 g (90%) N-(tert-butyl)-2-((2-(4-chloropyridin-2-yl)-6,721052

dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 374.

Scheme 100-7

[0952] Into a 250 mL three-necked round bottom flask were added 2-(dimethylamino)ethan-l-ol (2.86 g, 32.17 mmol, 2.00 equiv) and DMF (80 mL). This was followed by the addition of t-BuOK (3.6 g, 32.17 mmol, 2.00 equiv) at room température. The mixture was stirred for 0.5 h, N-(tert-butyl )-2-((2(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (6.0 g, 16.08 mmol, 1.00 equiv) was added to the above mixture and stirred for additional 5 h at 60 °C. The reaction mixture was cooled to room température, quenched with H₂O (100 mL), and extracted with ethyl acetate (100 mL*2). The combined organic phases were washed with brine (100 mL*2) and dried over anhydrous sodium sulfate. The mixture was fîltered, and the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: Cl8-500 g, CH3CN/H2O (NH4HCO3 0.1%), from 15% to 70% in 30 min, Flow rate, 150 mL/min, Detector, UV 254 nm. This resulted in 5.5 g (80.29%) N-(tert-butyl)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide as a brown solid. The solid was triturated in CH3CN (120 mL), collected by filtration and dried to give N-tert-butyl-2-[(2-{4-[2(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (5.5 g, 98.8%). LCMS (ES, m/z): [M+H]⁺: 427. *H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, 20 IH), 7.84 (d, J = 2.5 Hz, IH), 7.68 (s, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.20 (t, J = 5.7 Hz, 2H), 4.12 (s, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.67 (t, J = 5.6 Hz, 2H), 2.23 (s, 6H), 2.01-1.96 (m, 2H), 1.24 (s, 9H).

Example 1.154

[0953] Synthesis of N-(2,3-dihydro-IH-inden-l-yl)-N-methyl-2-(pyrîdin-2-yl)-5H,6H,7H2S cyclopenta[d]pyrimidin-4-amine

472

[0954] The title compound was synthesized in a similar manner to that of compound 92 by replacing azapane with N-methyl-l-indanamine. MS (ES+); (M+H)⁺ = 342.9. ’H NMR (400 MHz, Chloroformé) δ 8.78 (d, J= 5.6 Hz, IH), 8.38 (d, J= 7.9 Hz, IH), 7.83 - 7.74 (m, IH), 7.36 (dd, J= 7.6, 4.8 Hz, IH), 5 7.32 - 7.27 (m, JH), 7.25 - 7.14 (m, 2H), 6.44 (t, J = 8.2 Hz, IH), 3.21 (t, J= 7.3 Hz, 2H), 3.14 -3.03 (m, 3H), 3.03-2.91 (m, 4H), 2.56-2.43 (m, 1H), 2.18-2.05 (m, 3H).

Example 1.155

[0955] Synthesis of 2-{4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl}pyridine (Compound 18)

lîaih₄

THF

Scheme 101

473

Step 1

N H Boc

THF °C

[0956] To a solution of tert-butyl N-[(l S,2S)-2-hydroxycyclopentyl]carbamate (1.24 g; 6.16 mmol;

l .00 eq.) in tert-butanol (20 mL) and tert-butyl prop-2-enoate (20 mL) was added césium carbonate (2.0 g; 6.16 mmol; l.OO eq.), the mixture was stirred at room température for 15 h, heated up to 50 °C and stirred for 8 h. The solution was diluted with EtOAc, washed with brine, and extracted with EtOAc.

Organic layers were combined, dried and concentrated, the residue was purified by column chromatography to give tert-butyl 3-{[(l S,2S)-2-{[(tertbutoxy)carbonyl]amino}cyclopentyl]oxy]propanoate (1.22 g, 60.1%).

[0957] Step 2 p>.,_lCVy₀ 0°0^^OH

O \— Dioxane θ

NHBoc ^{Z x NH}2

[0958] A solution of tert-butyl 3-{[(l S,2S)-2-{[(tertbutoxy)carbonyl]amino)cyclopentyl]oxy}propanoate (1.22 g; 3.70 mmol; 1.00 eq.) in 4N HCl in dioxane (20 mL) was stirred for 15 h at room température, the mixture was concentrated to give 3{[(lS,2S)-2-(chloroamino)cyciopentyl]oxy)propanoic acid as thick oil (0.98 g, 126%), which was used for next step without purification. LCMS (ES) (M+H)⁺ = 174.4.

[0959] Step 3

[0960] To a solution of 3-{[(] S,2S)-2-aminocyclopentyl]oxy}propanoic acid (LOÛ g; 5.77 mmol;

.00 eq.) in DCM (125 mL) was added Hunig's base (5.03 mL; 28.87 mmol; 5.00 eq.) and 2,4,6-

474 tripropyl-l,3,5,2,4,6-trioxatriphosphinane 2,4,6-trioxide (5.16 mL; 8.66 mmol; 1.50 eq.), after stirred at room température for 15 h, HPLC check desired mass found. The mixture was concentrated and the residue was purified by column chromatography (DCM/MeOH = 10: l) to give (5aS,8aS)-octahydro-2Hcyclopenta[b][l,4]oxazepin-4-one (460 mg, 51%). LCMS (ES) (M+H)⁺ = 156.2.

Step 4

LiAIH₄

THF

[0961] To a solution of (5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepin-4-one (200.00 mg; 1.29 mmol; l.OO eq.) in THF (4.5 mL) was added lithium aluminum hydride (1.29 mL; 2.00 mol/L; 2.58 mmol; 2.00 eq.) at room température. The mixture was then heated at 55 °C for 2 h, additional l eq of L1AH4 was added. After 30 min, l more eq of LiAH₄ was added, after stirred for another 30 min, the mixture was cooled in ice batch, added 0,4 mL of water and O.l mL of 4M NaOH, the suspension was diluted with EtOAc (30 mL) and filtered through celite, the filtrate was concentrated to give (5aS,8aS)octahydro-2H-cyclopenta[b][i,4]oxazepane (l 75 mg, 96%), which was used for next step without further purification. LCMS (ES) (M+H)⁴ = I42.2.

Step 5

[0962] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (l 00.00 mg; 0.53 mmol; l.OO eq.) and (5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepine (93.37 mg; 0.66 mmol; 1.25 eq.) in AcCN (l mL) was added DIPEA (0.18 mL; l .06 mmol; 2.00 eq.) at room température. The reaction mixture was stirred for 30 min at ambient température, and 80 °C degree for overnight. The solution was concentrated and the crude oil was purified by column chromatography (Hexanes/EtOAc = 2:l) to give 4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-2'Chloro-5H,6H,7Hcyclopenta[d]pyrimidine (130 mg, 83.6% yield). LCMS (ES) (M+H)⁺ = 293.5.

475

[0963] Step 6

[0964] To a solution of 4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-2-chloro5H,6H,7H-cyclopenta[d]pyrîmidine (136.00 mg; 0.46 mmol; l.OO eq.) in Toluene (2 mL) was added 2(tributylstannyl)pyridine (255.63 mg; 0.69 mmol; L50 eq.) followed by tetrakis(triphenylphosphane) palladium (53.49 mg; 0.05 mmol; 0.10 eq.). The solution was heated at 105 °C for 15 h, cooled and concentrated to give crude product, which was purified by préparative HPLC to give 2-{4-[(5aS,8aS)octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H_s6H,7H-cyclopenta[d]pyrimidin-2-yl}pyridine (101 mg, 64.5%). LCMS (ES) (M+H)⁺ = 337.3. Ή NMR (400 MHz, DMSO-d6) δ 8.74 (d, J = 4.7 Hz, l H), 8.31 (d, J = 7.9 Hz, IH), 8.01 (td, J = 7.7, L8 Hz, IH), 7.57 (dd, J = 7.5, 4.8 Hz, IH), 4.40 (dd, J = 15.3, 5.9 Hz, lH), 4.23 (tt, J = 17.0, 10.0 Hz, 2H), 3.91 -3.83 (m, lH), 3.73 (dd, J = 15.4, 10.9 Hz, 1 H), 3.52 (td, J = 12.1,2.5 Hz, IH), 3.12 (dp, J = 29.5, 7.3, 6.9 Hz, 2H), 2.91 (t, J = 7.9 Hz, 2H), 2.44 - 2.32 (m, IH), 2.03 (dd, J= 10.8, 5.0 Hz, 2H), 2.01 - 1.83 (m, 2H), 1.78 (q, J = 9.5, 8.4 Hz, IH), 1.71 (t, J = 4.3 Hz, IH), 1.70- 1.63 (m, IH), 1.56 (p, J = 10.2 Hz, IH), 1.44- 1.30 (m, IH).

Example 1.156

[0965] Synthesis of 2-{4-[(5aS,8aS)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl]-4-methylpyridine (Compound 45)

[0966] Compound 45 was synthesized similar to Compound 18 by replacing 2(tributylstannyl)pyridine with 2-(tributylstannyl)pyridine. LCMS (ES) [M+l]⁺ m/z 351. ’H NMR (400 MHz, DMSO-dô) δ 8.52 (d, J = 4.9 Hz, IH), 8.10 (d, J = 15.7 Hz, IH), 7.28 (d, J = 4.9 Hz, IH), 4.38

476

(dd, J = 15.1,5.9 Hz, IH), 4.18 (dtd, J = 23.0, 10.0, 7.0 Hz, 2H), 3.91 - 3.82 (m, 1 H), 3.64 (dd, J = 15.3, 10.8 Hz, IH), 3.49 (td, .1 = 12.0, 2.5 Hz, IH), 3.16-3.00 (m,2H), 2.83 (dd, J = 8.7, 7.1 Hz, 2H), 2.4! (s, IH), 2.39 (s, 3H), 2.00 (p, J = 7.6 Hz, 2H), 1.94-1.84 (m, 2H), 1.79- 1.63 (m, 3H), 1.55 (p, J = 10.3 Hz, IH), 1.40- 1.25 (m, IH).

Example 1.157

[0967] Synthesis of l-[2-(pyridm-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]azepan-2-one (Compound 46)

Scheme 102

Step I

[0968] To a solution of 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (100.00 mg; 0.53 mmol; 1.00 eq.) and 2-azepanone (65.84 mg; 0.58 mmol; 1.10 eq.) in Dioxane (2 mL) was added

Césium carbonate (258.53 mg; 0.79 mmol; 1.50 eq.), Xantphos (30.61 mg; 0.05 mmol; 0.10 eq.) and Tris(dibenzylideneacetone)dipalladium(0) (24.22 mg; 0.03 mmol; 0.05 eq.). After heated at 100 °C for 3h, the mixture was diluted with AcCN, filtered through celite, the filtrate was concentrated and purified by préparative HPLC to give l-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azepan-2-one (16 mg,

477 % yieid). LCMS (ES) (M+H)⁺ = 342.7.

Step 2

Cl

Pd(PPh₃)₄

[0969] To a solution of 2-(tributylstannyl)pyridine (44.33 mg; 0.12 mmol; 2.00 eq.) and l-{2chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}azepan-2-one (16.00 mg; 0.06 mmol; 1.00 eq.) in toluene (1 mL) was added tetrakis(triphenylphosphane) palladium (6.96 mg; 0.01 mmol; 0.10 eq.), after degassed and heated at 100 °C ovemight, it was concentrated and the residue was subjected to purification by preparative HPLC to give l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]azepan-2-one (5.4 mg, 29.1%). LCMS (ES) (M+Hf = 308.9. Ή NMR (400 MHz, DMSO-^) δ 8.77 -8.71 (m, IH), 8.30 (d, J= 8.0 Hz, ! H), 7.99 (dd, 7= 8.5, 6.8 Hz, IH), 7.54 - 7.47 (m, 1 H), 3.92 (d,7= 8.4 Hz, 2H), 2.95 (t, 7= 7.8 Hz, 2H), 2.64 (d, 7= 10.5 Hz, 2H), 2.15-2.03 (m, 2H), 1.80-1.68 (m, 8H).

Example 1.158

[0970] Synthesis of 2-{4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl}pyridine (Compound 48)

[0971] Compound 48 was synthesized similar to Compound 18 by replacing tert-butyI N-[(lS,2S)-2hydroxycyclopentyî]carbamate with tert-butyl N-[(lS,2R)-2-hydroxycyclopentyl]carbamate. LCMS (ES)[M+1]⁺ m/z: 337.1. Ή NMR (400 MHz, Methanol-Λ) δ 8.69 (dt, 7= 4.8, 1.3 Hz, IH), 8.33 (dd, 7 = 8.0, 1.1 Hz, IH), 7.95 (td,7=7.8, 1.8 Hz, IH), 7.50 (ddd, 7= 7.6, 4.8, 1.2 Hz, I H), 5.04 - 4.93 (m, IH), 4.16 (dt, 7= 14.1,4.1 Hz, 1 H), 4.00 (s, 1H), 4.02-3.92 (m, IH), 3.68 (ddd, 7= 15.2, 10.6,5.2 Hz,

478 lH), 3.43 (ddd, J= 12.5,9.9,6.2 Hz, 1 H), 3.22 - 3.11 (m, 2H), 3.14 - 3.04 (m, IH), 2.97 (t, J= 7.9 Hz, 2H), 2.23- 1.84 (m, 7H), 1.81-1.58 (m, 2H).

Example 1.159

[0972] Synthesis of 2-[4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl}-4-methylpyridine (Compound 49)

[0973] Compound 49 was synthesîzed similar to Compound 18 by replacing tert-butyl N-[(lS,2S)-2hydroxycyclopentyl] carbamate with tert-butyl N-[(lS,2R)-2-hydroxycyclopentyl]carbamate and replacing 2-(tributylstannyl)pyridine with 2-(tributylstannyl)pyridine. LCMS (ES) [M+l]⁺ m/z: 351.3. Ή NMR (400 MHz, Methanol-7₄) δ 8.54 (d,7=5.0 Hz, IH), 8.15 (s, IH), 7.37 (dd,7= 5.2, L6 Hz, IH), 5.00 (dq, 7= 10.5, 4.5 Hz, IH), 4.19 (dt, 7= 14.6, 4.2 Hz, IH), 3.99 (ddd, 7= 15.8, 6.6, 3.4 Hz, 2H), 3.69 (ddd, 7= 15.2, 10.5,5.3 Hz, 1 H), 3.44 (ddd, 7= 12.5,9.9,6.3 Hz, 1 H), 3.23 - 3.12 (m, IH), 3.16-3.05 (m, 2H), 2.98 (t, 7= 7.9 Hz, 2H), 2.47 (s, 3H), 2.24 - 1.85 (m, 7H), 1.82- 1.58 (m, 2H).

Example 1.160 [0974] Synthesis of 2-{4-[(5aS,8aR)-octahydro-2H-cyclopenta[b][l,4]oxazepin-5-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl}-4-methoxypyridine (Compound 54)

[0975] Compound 54 was synthesîzed similar to Compound 18 by replacing tert-butyl N-[(lS,2S)-2hydroxycyclopentyl]carbamate with tert-butyl N-[(lS,2R)-2-hydroxycyclopentyl]carbamate and replacing 2-(trîbutylstannyl)pyridine with 4-methoxy-2-(tributylstannyl)pyridine. LCMS (ES) [M+l]⁺

479 m/z: 367.2. Ή NMR (400 MHz, Methanol-7₄) ô 8.50 (d, J= 5.8 Hz, IH), 7.87 (d, J= 2.6 Hz, IH), 7.10 (dd, J= 5.9, 2.6 Hz, lH), 4.98 (td, 7= 9.7, 8.9,4.3 Hz, IH), 4.14 (dt, 7= 14.6,4.2 Hz, 1 H), 4.05 - 3.93 (m, 2H), 3.96 (s, 3H), 3.68 (ddd, 7= 15.2, 10.5, 5.2 Hz, IH), 3.44 (ddd, 7= 12.5, 10.0, 6.2 Hz, IH), 3.22 -3.12 (m, IH), 3.14-3.04 (m, IH), 2.95 (t,7= 7.9 Hz, 21-1),2.23-1.84 (m, 5H), 2.03 (s, 3H), 1.81 1.69 (m, IH), 1.69- 1.59 (m, IH).

Example 1.161

[0976] Synthesis of N-(1-hydroxy-2-methylpropan-2-y 1)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-y 1]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)ammo)acetamide (Compound 148)

H

[0977] Compound 148 was synthesized similar to Compound 144 by replacing cyclohexylamine with 2-amino-2-methyl-l-propanol. LCMS (ES) [M+l]⁺ m/z 416. 'H NMR (300 MHz, DMSO-7ê) δ 8.47 (d,7= 5.6 Hz, IH), 7.84 (d,7=2.6 Hz, IH), 7.50 (s, IH), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 4.90 (br, IH), 4.28-4.07 (m, 4H), 3.76 (t, 7= 5.0 Hz, 2H), 3.37 (s, 2H), 3.25 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.18 (s, 6H).

Example 1.162 [0978] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxolan-3-yl)acetamide (Compound 149)

[0979] Compound 149 was synthesized similar to Compound 144 by replacing cyclohexylamine with oxolan-3-amine hydrochloride. LCMS (ES) [M+l]⁺ m/z 414. Ή NMR (300 MHz, DMSO-7₆, ppm): δ 8.46 (d, 7= 5.6 Hz, IH), 8.37 (d, J= 6.9 Hz, 1 H), 7.80 (d, 7= 2.6 Hz, IH), 7.04 (dd, 7= 5.6, 2.6

480

Hz, IH), 5.22-4.75 (m, IH), 4.34-4.12 (ni, 5H), 3.83-3.52 (m, 5H), 3.49-3.39 (m, IH), 3.27 (s,3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.15-1.89 (m, 3H), 1.79-1.68 (m, IH).

Example 1.163

[0980] Synthesis of N-cyclopentyl-2-{methyl[2-(] -methyl-1 H-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidm-4-yl]amino}acetamide (Compound 150)

[0981] Compound 150 was synthesized similar to Compound 142 by replacing cyclohexylamine with cyclopentanamine. LCMS (ES, m/z); [M+H]⁺: 355. ’H-NMR(300 MHz, DMSO-ί/ά,/γ™): δ 8.05 (d,7=7.5 Hz, 1 H), 7.71 (s, 11-1), 7.60 (s, 1 H), 4.11 (s, 21-1),4.02 (q,7=6.6, 13.5 Hz, IH), 3.69 (s, 3H), 3.22 (s, 3H), 3.07 (t, 7=7.5 Hz, 2H), 2.73 (t, 7= 7.8 Hz, 2H), 1.99-1.89 (m, 2H), 1.80-1.72 (m, 2H), 1.63-1.34 (m, 6H).

Example 1.164

[0982] Synthesis of 2-{[2-(4-methoxypyndin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide (Compound 151)

[0983] Compound i 51 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES, m/z); [M+H]⁺: 421. Ή-NMR (300 MHz, DMSO-7_d,ppm): δ 10.26 (s, IH), 8.45 (d,7=5.4 Hz, 1H),8.34 (d, 7= 2.7 Hz, IH), 7.87 (dd, 7= 9.0, 2.7 Hz, IH), 7.79 (d,7 = 2.7 Hz, IH), 7.01 (dd, 7= 5.4, 2.4 Hz, IH), 6.78 (d, 7= 9.0 Hz, IH), 4.40 (s, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.37 (s, 3H), 3.21 (t, 7= 7.5 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.08-1.94 (m, 2H).

Example 1.165

481

[0984] Synthesis of N-(5-methoxypyndin-2-yl)-2-{[2-(4-methoxypyndin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 152)

[0985] Compound 152 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 5-methoxypyridin-2-amine. LCMS (ES, m/z): [M+H]⁺: 42L 'H-NMR (300 MHz, DMSOée,^™): δ 10.55 (s, IH), 8.43 (d, 7= 5.7 Hz, lH), 8.03 (d, 7= 3.0 Hz, IH), 7.96 (d, 7= 8.7 Hz, IH), 7.76 (d,7= 2.7 Hz, IH), 7.39 (dd, J = 9.0, 3.0 Hz, ]H), 6.96 (dd, 7= 5.7, 2.7 Hz, IH), 4.49 (s, 2H),3.79 (s, 3H), 3.73 (s, 3H), 3.35 (s, 3H), 3.20 (t, 7= 7.5 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.08-L95 (m, 2H).

Example l. 166

[0986] Synthesis of 2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(2-methoxypyrimidin-5-yl)acetamide (Compound 153)

[0987] Compound 153 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 5-methoxypyridin-2-amine. LCMS (ES, m/z): [M+H]⁺: 42L 'H-NMR (300 MHz, DMSOé>,ppm): δ 10.55 (s, IH), 8.43 (d, 7= 5.7 Hz, IH), 8.03 (d, 7= 3.0 Hz, IH), 7.96 (d, 7= 8.7 Hz, IH), 7.76 (d, 7 = 2.7 Hz, ] H), 7.39 (dd, 7= 9.0, 3.0 Hz, IH), 6.96 (dd, 7= 5.7, 2.7 Hz, I H), 4.49 (s, 2H), 3.79 (s, 3H), 3.73 (s, 3H), 3.35 (s, 3H), 3.20 (t, J= 7.5 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example l .167

[0988] Synthesis of2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 154)

482

N-N

[0989] Compound 154 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 1methylpyrazol-4-amine. LCMS (ES, m/z): [M+H]⁺: 394. Ή NMR (300 MHz, DMSO-î/ô) δ 10.24 (s, IH), 8.47 (d, 7 = 5.4 Hz, lH), 7.83 (s, IH), 7.78 (d, 7= 2.4 Hz, IH), 7.38 (s, IH), 7.01 (dd,7= 5.7, 2.4

Hz, 1H), 4.35 (s, 2H), 3.82 (s, 3H), 3.76 (s, 3H), 3.34 (s, 3H), 3.19 (t, 7= 7.5 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.168

[0990] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N~(l-methylcyclopentyI)acetamide (Compound 155)

[0991] Compound 155 was synthesized similar to Compound 135 by replacing 2 oxolan-3-amine with 1-methylcyclopentan-l-amine hydrochloride. LCMS (ES, m/z): [M+H]⁺: 396. 'H NMR (300 MHz, DMSO-t&) δ 8.48 (d,7= 5.7 Hz, IH), 7.84 (d, 7= 2.4 Hz, IH), 7.74 (s, IH), 7.04 (dd, 7= 5.7, 2.7 Hz, IH), 4.14 (s, 2H), 3.89 (s, 3H), 3.26 (s, 3H), 3.14 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.06-1.87 (m,4H), 1.63-1.38 (m, 6H), 1.27(s,3H).

Example 1.169

[0992] Synthesis of N-tert-buty l-2-{[2-(4-methoxypyridin-2-y l)-5H,6H,7H-cyclopenta[d]pyrimidin4-yl](methyl)amino}-N-methylacetamide (Compound 156)

483

[0993] Compound 156 was synthesized similar to Compound 135 by replacing oxolan-3-amine with tert-butyl(methyl)amine. LCMS (ES, m/z): [M+H]⁺: 384. Ή NMR (300 MHz, DMSO-7₆) δ 8.48 (d, J = 5.7 Hz, IH), 7.79 (d, J= 2.4 Hz, IH), 7.03 (dd, J= 5.7, 2.7 Hz, IH), 4.43 (s, 2H), 3.89 (s, 3H), 3.25 (s,

3H), 3.ll (t, 7=7.5 Hz, 2H), 2.93 (s, 3H), 2.80 (t, 7= 7.8 Hz, 2H), 2.08-1.95 (m, 2H), 1.32 (s, 9H).

Example 1.170

[0994] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yi](methyl)amino}-N,N-dimethyIacetamide (Compound 157)

[0995] Compound 157 was synthesized similar to Compound 135 by replacing oxolan-3-amine with di methy lamine hydrochloride. LCMS (ES, m/z): [M+H]⁺: 342. Ή NMR (300 MHz, DMSO-Æ) δ 8.47 (d,7= 5.7 Hz, IH), 7.74 (d, 7= 2.4 Hz, IH), 7.02 (dd, 7= 5.7, 2.7 Hz, IH), 4.51 (s, 2H), 3.89 (s, 3H), 3.25 (s, 3H), 3.12 (t,7= 7.5 Hz, 2H), 3.05 (s, 3H), 2.85 (s, 3H),2.8I (t, 7= 7.8 Hz, 2H), 2.03-1.93(m, 2H).

Example 1.171

[0996] Synthesis ofN-tert-butyl-2-n2-(4-cyanopyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide (Compound 158)

[0997] Compound 158 was synthesized similar to Compound 24 by replacing 4-methyl-2(tributylstannyl)-pyridine with 2-(trimethylstannyl)pyridine-4-carbonitrile. LCMS (ES) [M+l]⁺ m/z 365. Ή NMR (300 MHz, DMSOA) δ 8.92 (d, J= 4.9 Hz, IH), 8.66 (s, IH), 7.92 (dd, 7=5.0, 1.6 Hz, IH),

7.76 (s, IH), 4.14 (s, 2H), 3.32 (s, 3 H), 3.19 (t, 7= 7.3 Hz, 2H), 2.84 (t,7= 7.8 Hz, 2H), 2.01 (t, 7= 7.6

Hz, 2H).

Example 1.172

[0998] Synthesis ofN-tert-butyl-2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyi)amino)acetamide (Compound 159)

[0999] Compound 159 was synthesized similar to Compound 24 by replacing 4-methyl-2(tributylstannyl)-pyridine with 4-(cyclopropylmethoxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+l]⁺ m/z 410. Ή NMR (300 MHz, DMSOA) δ 8.45 (d,7= 5.6 Hz, IH), 7.85 (d, 7= 2.5 Hz, IH), 7.69 (s, 1 H), 7.01 (dd, 7= 5.7, 2.6 Hz, IH), 4.12 (s, 2H), 3.97 (d, 7= 7.1 Hz, 2H), 3.27 (s, 3H), 3.15 (t, 7 = 7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.04-1.88 (m, 2H), 1.25 (s, 9H),1.25-1.20 (m, IH), 0.66-0.54 (m,

2H), 0.43-0.32 (m, 2H).

Example 1.173

[1000] Synthesis of N-tert-butyl-2-{methy i[2-(l-methy 1-1 H-pyrazo 1-3-y l)-5 H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 160)

[lOOl] Compound 160 was synthesized similar to Compound 24 by replacing 4-methyL2(tributylstannyl)-pyridine with 1 -methy 1-3-(4,4,5,5-tetramethyl-l ,3,2-dioxaborolan-2-yl)pyrazole.

LCMS (ES) [M+l]⁺ m/z: 343, ^lH NMR (300 MHz, DMSO-d6) δ 7.69 (d, 2,2 Hz, IH), 7.60 (s, IH),

6.81 (d, 7= 2.2 Hz, IH), 4.09 (s, 2H), 3.89 (s, 3H), 3.21 (s, 3H), 3.08 (t, 7 = 7.3 Hz, 2H), 2.75 (t, 7= 7.8

Hz, 2H), 2.13-1.84 (m, 2H), 1.24 (s, 9H).

Example 1.174

[1002] Synthesis of 2-{methy 1(2-(1-methyl-lH-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-N-(l-methylcyclopentyI)acetamide (Compound 161)

[1003] Compound 161 was synthesized similar to Compound 142 by replacing cyclohexylamine with i -methyIcyclopentan-1 -amine. LCMS (ES, m/z): [M+H]⁺: 369. Ή-NMR (300 MHz, DMSOA, pjpm):8 8.16(s, IH), 7.74 (d, 7 = 1.5 Hz, IH), 7,71(br, IH), 7.61 (d,7= 1.5 Hz, 1 H), 4.10 (s, 2H), 3.69 (s, 3H), 3.22 (s,3H), 3.07 (t, 7=7.5 Hz, 2H), 2.74 (t,7= 7.8 Hz, 2H), L99-L89 (m, 4H), 1.60-1.44 (m, 15 6H), 1.29 (s, 3H).

Example 1.175

[1004] Synthesis of N-tert-butyl-2-{methyl[2-(l-methyl-lH-imidazol-2-yl)-5H,6H,7Hcyclopenta(d]pyrimidin-4-yl]amino}acetamide (Compound 162)

486

[l 005] Compound 162 was synthesized similar to Compound 24 by replacing 4-methyl-2(trîbutylstannyl)-pyridine with l-methyl-2-(tributylstannyl)-lH-imidazole. LCMS (ES) [M-M]⁺ m/z: 343, Ή NMR (300 MHz, DMSO-d6) δ 7,68 (d, J = L2 Hz, IH), 7.62-7.54 (m, 2H), 4.11 (s, 2H), 3.97 (s, 5 3H), 3.21 (s, 3H), 3.09 (t, J = 7.2 Hz, 2H), 2.75 (t, J = 7.8 Hz, 2H), 1.95 (m, 2H), 1.25 (s, 9H).

Example 1.176

[1006] Synthesis of N-tert-buty 1-2-{methyl[2-(l,3-oxazol-4-y 1)-5H,6H,7H-cyclopenta[d]pyrimidin-

4-yl]amino}acetamide (Compound 163)

[1007] Compound 163 was synthesized similar to Compound 24 by replacing 4-methyl-2(tributylstannyl)-pyridine with 2-(triisopropylsilyl)-4-(trimethylstannyI)oxazole. LCMS (ES) [M+l] ⁺m/z: 330. ‘H NMR (300 MHz, DMSO-d6) δ 8.62 (d, .1=1.1 Hz, IH), 8.42 (d, J=L1 Hz, IH), 7.60 (s, IH), 4.10 (s, 2H), 3.23 (s, 3H), 3.10 (t, 1=7.3 Hz, 2H), 2.77 (t, J=7.9 Hz, 2H), 2.05-1.92 (m,, 2H), 1.24 (s, 9H).

Example 1.177

[1008] Synthesis of N-tert-butyl-2-{methyl[2-(l,3-oxazol-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin4-yl]amino}acetamide (Compound 164)

487

[1009] Compound 164 was synthesized similar to Compound 24 by replacing 4-methyl-2- (tributylstannyl)-pyridine with 2-(trimethylstannyl)-l,3-oxazole. LCMS (ES) [M+l] ⁺ m/z: 330. Ή NMR (300 MHz, DMSO-d6) δ 8.23 (d, J=0.7 Hz, IH), 7.60 (s, IH), 7.40 (d, J=0.8 Hz, IH), 4.16 (s, 2H),

3.20 (s, 3H), 3.H (t, J =7.3 Hz, 214), 2.80 (t, J=7.9 Hz, 2H), L98-L85 (m, 2H), 1.25 (s, 9H).

Example L178

[ 1010] Synthesis of N-tert-butyl-2-{[2-(isoqumolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4y!](methyl)amino}acetamide (Compound 165)

[1011] Compound 165 was synthesized similar to Compound 24 by replacing 4-methyl-2(tnbutylstannyl)-pyridine with 3-(trimethylstannyl)isoquinolÎne. LCMS (ES) [M+l] m/z: 390. 'H NMR (300 MHz, DMSO-îÆ) δ 9.40 (s, IH), 8.86 (s, IH), 8.21-8.16 (m, 2H), 8.12 (d, 7= 8.2 Hz, IH), 7.87-7.69 (m, 3H), 4.20 (s, 2H),3.32(s, 314),3.18 (t,7=7.3 Hz, 2H), 2.86 (t,7=7.8 Hz, 2H), 2.10-1.93 (m, 2H), l .23 (s, 9H).

Example 1.179

[1012] Synthesis ofN-tert-butyl-2-[(2-{imidazo[l,2-a]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 166)

488

[1013] Compound 166 was synthesized similar to Compound 24 by replacing 4-methyl-2- (tributylstannyl)-pyridine with 2-(trimethylstannyl)imidazo[l,2-a]pyndine. LCMS (ES) [M+]]⁺ m/z 379, *H NMR (300 MHz, DMSO-d6) δ 8.52 (d, >7.l Hz, 2H), 7.68 (s, IH), 7.57 (d, >9.l Hz, IH),

7.31-7.19 (m, lH), 6.92 (td, >6.7, l.2 Hz, IH), 4.16 (s, 2H), 3.25 (s, 3H), 3.H (t, >7.3 Hz, 2H), 2.79 (t, >7.9 Hz, 2H), L99-L85 (m, 2H), I.25 (s, 9H).

Example L180

[ 1014} Synthesis of N-(3-fluoropheny 1)-2-({2-(4-(2-hydroxyethoxy)pyridin-2-y 1]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 167)

[1015] Compound 167 was synthesized similar to Compound 144 by replacing 1-cyclohexylamine with 3-fluoroaniline. LCMS (ES) [M+l]* m/z 438. Ή NMR (300 MHz, DMSO-d6) δ 10.46 (br, IH), 8.43 (d, 7= 5.6 Hz, IH), 7.78 (s, IH), 7.57 (d,7= 11.2 Hz, 1 H), 7.41-7.25 (m, 2H), 7.04-6.96 (m, IH), 6.85 (dd, 7= 8.4, 4.9 Hz, IH),5J 8-4.62 (br, IH), 4.55-4.31 (m, 2H), 4.15-3.95 (m, 2H), 3.71-3.62 (m, 15 2H), 3.35 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H) 2.83 (t, J= 7.9 Hz, 2H), 2.22-1.98 (m, 2H).

Example 1.181

[1016] Synthesis ofN-[(lR,2S)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pynmidin-4-yl](methy])amino}acetamide (Compound 168)

489

[ΙΟΙ7] Compound 168 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (lR,2S)-2-aminocyclohexan-l-ol. LCMS (ES) [M+l] ⁺ m/z: 412. Ή NMR (300 MHz, DMSO-rfs) δ 8.48 (d, 7= 5.6 Hz, IH), 7.80 (d, 7= 2.6 Hz, IH), 7.61 (d,7=7.9 Hz, IH), 7.03 (dd, 7= 5.6, 2.6 Hz, IH), 4.59 (d, 7= 3.9 Hz, 1H),4.31 (d,7= 16.6 Hz, 1 H), 4.18 (d, 7= 16.6 Hz, IH), 3.89 (s, 3H), 3.713.58 (m, 2H), 3.25 (s 3H),3.14 (t, 7= 7.1 Hz, 2H), 2.82 (t, 7= 7.9 Hz, 2H), 2.03-1.91 (m, 2H), 1.67L15(m, 8H).

Example 1.182 [1018] Synthesis ofN-[(l S,2R)-2-hydroxycyclohexyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyc!openta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 169)

H QH

[1019] Compound 169 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (lS,2R)-2-aminocyclohexan-l-ol. LCMS (ES) [M+l] ⁺ m/z: 412. Ή NMR (300 MHz, DMSO-7₆) δ 8.48 (d, 7=5.6 Hz, IH), 7.80 (d, 7= 2.6 Hz, IH), 7.61 (d,7=8.0 Hz, IH), 7.03 (dd, 7= 5.6, 2.6 Hz, 1 H), 4.59 (d, 7= 3.9 Hz, 1H),4.31 (d, J = 16.7 Hz, IH), 4.18 (d, J = 16.7 Hz, 1 H), 3.89(s, 3H), 3.71-3.63 (m, 2H), 3.25 (s, 3H),3.14 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.9 Hz, 2H), 2.06-1.92 (m, 2H), 1.69-1.32 (m, 6H), 1.31-1.14 (m, 2H).

Example 1.183a and Example 1.183b

[1020] Synthesis of N-[( 1 R,2S)-2-hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyciopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 170) and N-[(lS,2R)-2-

hydroxycyclopentyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}acetamide (Compound I7l)

H OH

[l 021 ] Into a 50-mL round-bottom flask were placed [[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]acetic acid (120 mg, 0.38 mmol, l.OO equiv), DMF (5.00 mL), HATU (174 mg, 0.45 mmol, 1.20 equiv), DIEA (148 mg, 1.145 mmol, 3.00 equiv), and (IS,2R)-2aminocyclopentan-l-ol hydrochloride (63.04 mg, 0.45 mmol, 1.20 equiv). The resulting solution was stirred for 3 hr at 25 °C. The crude product was purified by Prep-HPLC with the following conditions: Column, Xbridge Prep C18 OBD column, 5um, 19* 150mm; mobile phase, Water (0.05% NH3.H2O) and CH3CN (35% CH3CN up to 50% in 10 min); Detector, UV 254 nm. The collected fractions were combined and concentrated under vacuum.

[1022] The resulting product was separated by Chiral HPLC with the following conditions: Column:

491

CHIRALPAK IC, 20*250mm, 5um; Mobile phase: A: n-Hexane/DCM=5:l, B: Ethanol+O.l% DEA; Flow rate: 90 mL/min; Gradient: 30%B in 20 min. This resulted in 35.1 mg (23.13%) ofN-[(lR,2S)-2hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide as a white solid and 37.2 mg (24.52%) ofN-[(lS_s2R)-2hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide as a white solid. The compounds were analyzed by analytica) chiral HPLC with the following conditions: Column: CHIRALPAK IC, 4,6*50mm, 3um; Mobile phase: A: nHexane/DCM=5:1, B: Ethanol+0.1% DEA; Flow rate: 1 mL/min; Gradient: 30%B in 6 min.

[1023] Compound 170: CHIRAL_HPLC: Rétention time 3.09 min. LCMS (ES, m/z): [M+H]⁺: 398. 'hNMR (300 MHz, DMSO-76, ppm): δ 8.48 (d, J= 5.6 Hz, IH), 7.81 (d, J= 2.6 Hz, IH), 7.65 (d,7=7.8 Hz, IH), 7.03 (dd, J= 5.6, 2.6 Hz, 1H),4.65 (d, 7= 3.9 Hz, IH), 4.32 (d, J= 16.7 Hz, IH), 4.19 (d, 7= 16.7 Hz, IH), 3.89 (s, 3H), 3.98-3.79 (m, 2H), 3.26 (s, 3H), 3.15 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.74-1.68 (m, 3H), 1.58-1.39 (m, 3H). Compound 171: CHIRAL_HPLC: Rétention time 3.88 min. LCMS (ES, m/z): [M+H] ⁺: 398. ‘h-NMR (300 MHz, DMSO-76, ppm): δ ^]HNMR: (300 MHz, DMSO-76, ppm): δ 8.48 (d, 7= 5.6 Hz, IH), 7.81 (d,7=2.6 Hz, IH), 7.65 (d,7=7.8 Hz, IH), 7.03 (dd, 7= 5.6, 2.6 Hz, 1H),4.65 (d,7=3.9 Hz, IH), 4.32 (d, 7= 16.7 Hz, IH), 4.19 (d, 7 = 16.7 Hz, IH), 3.89 (s, 3H), 3.98-3.79 (m, 2H), 3.26 (s, 3H), 3.15 (t, 7= 7.5 Hz, 2H), 2.82 (t,7= 7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.74-1.68 (m, 3H), 1.58-1.39 (m, 3H).

Example 1.183c and Example 1.183d

[1024] Synthesis of N-[(IR,2R)-2-hydroxycyclopentyI]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino} acetamide (Compound 172) and N-[(lS,2S)-2hydroxycyclopentyl]-2-{[2-(4-methoxypyridîn-2-yl)-5H,6H,7H-cyclopenta[d]pyrîmidm-4yl](methyl)amino}acetamide (Compound 173)

492

Scheme 103

[1025] To a stirred solution of [[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)ami no] acetic acid (300 mg, 0.95 mmol, l.O equiv), DIEA (6I6 mg, 4.77 mmol, 5.0 equiv), and HATU (LSI9 g, 4.77 mmol, 5.0 equiv) in THF (30 mL) was added (lR,2R)-2-aminocyclopentan-lol (482 mg, 4.77 mmol, 5.0 equiv) in portions at 20 °C. The resulting mixture was stirred for 5 h at 60 °C. The reaction was concentrated under reduced pressure. The residue was purified by Flash-PrepHPLC with the foîlowing conditions (IntelFlash-l): Column, Cl8; mobile phase A: CH₃CN, Mobile phase B: Water; Flow rate: 20mL/min Column to give 200 mg of the racemate product, which was separated by Chiral-HPLC with the foîlowing conditions: Column: Lux Amylose-l, 50*250mm, 10 um; Mobile phase A: n-Hexane, Mobile phase B: Ethanol; Flow rate: 90 mL/min; Gradient:50%B in 36min; 220nm. This resulted in N-[(] R,2R)-2-hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide (85 mg, 22.41%) and N-[(lS,2S)-2hydroxycyclopentyl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide (80 mg, 21.09%) as a white solid. The compounds were subjected to analytical chiral HPLC with the foîlowing conditions: CHIRALPAK IC, 4.6*50mm, 3um; Mobile phase: A: n-Hexane, Mobile phase B: Ethanol; Flow rate: I mL/min; Gradient: 50%B in 6 min.

[1026] Compound 172: CH1RAL_HPLC: Rétention time 4.594 min. LCMS (ES, m/z): [M+H] ⁺: 398.2; ΉNMR (300 MHz, CDC1₃, ppm): δ 8.53 (d,7=5.7Hz, IH), 8.21 (s, IH), 7.95 (d, 7= 2.4 Hz, IH), 6.88 (dd, 7= 5.4, 2.4 Hz, I H), 4.46 (br, 1H),4.22 (s, 2H), 3.90(s, 3H), 3.89-3.82 (m, IH), 3.80-3.78 (m, I H), 3.40 (s, 3H), 3.19(t, 7= 7.2 Hz, 2H), 2.99(t, 7= 7.8 Hz, 2H), 2.15-2.08 (m, 2H), 2.05-1.96 (m, 2H), 1.71-1.57 (m,3H), 1.48-1.38 (m, IH).

[1027] Compound 173: CHIRAL HPLC: Rétention time 5.942 min. LCMS (ES, m/z): [M+H] ⁺: 398.2; Ή NMR (300 MHz, CDCh, ppm): δ 8.52 (d, 7= 8.7 Hz, IH), 8.20 (s, IH), 7.95 (d, 7= 2.4 Hz, IH), 6.88 (dd, 7=2.7, 5.7 Hz, IH), 4.48 (br, IH), 4.22 (br, 2H), 3.90(s, 3H), 3.89-3.82 (m, JH), 3.803.78 (m, IH), 3.40 (s, 3H), 3.18(t, 7= 8.4 Hz, 2H), 2.99(t, 7= 6.6 Hz, 2H), 2.15-2.07 (m, 2H), 2.05-1.94

493

(m, 2H), 1.71-1.55 (m, 3H), 1.48-1.38 (m, IH).

Example 1.184

[1028] Synthesis of N-tert-buty 1-2-{methyl[2-(pyridazin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino}acetamide (Compound 175)

[1029] Compound 175 was synthesized similar to Compound 24 by replacing 4-methyi-2(trimethylstannyl)pyridine with 3-(tributylstannyl)pyridazine. LCMS (ES) [M+l] ⁺ m/z: 341, ^lH-NMR (300 MHz, DMSO-7é)ô 10.00 (dd,7=2.3, 1.3 Hz, 1 H), 9.36 (dd, 7= 5.3, 1.3 Hz, IH), 8.37 (dd, 7 = 5.3, 2.3 Hz, IH), 7.77 (s, IH), 4.15 (s, 2H), 3.32 (s, 3H), 3.18 (t, 7= 7.3 Hz, 2H), 2.85 (t, 7= 7.9 Hz, 10 2H), 2.15-1.82 (m, 2H), 1.25 (s, 9H).

Example 1.185

[1030] Synthesis of N-tert-butyl-2-[methy 1(2-{lH-pyrazolo[4,3-c]pyridin-6-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 176)

[1031] Compound 176 was synthesized similar to Compound 24 by replacing 4-methyl-2(trimethylstannyl)pyridine with 6-(trimethylstannyl)-!H-pyrazolo[4,3-c]pyridine. LCMS (ES) [M+l] ⁺m/z: 380.2. Ή NMR (300 MHz, DMSO-d6, ppm): 9.16 (s, IH), 8.45 (s, IH), 8.33 (s, IH), 7.69 (s, IH), 4.18 (s, 2H), 3.26 (s, 3H),3.13 (t, J = 7.2 Hz, 2H), 2.84 (t, J = 7.9 Hz, 2H), 2.06-1.93 (m, 2H), 1.25 (s, 9 H).

Example l. 186

[1032] Synthesis of2-[methyl([2-[4-(2,2,2-trifluoroethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]-N-(l -methyl-lH-pyrazol-4-yl)acetamide (Compound 178)

[1033] Compound 178 was synthesized similar to Compound 135 by replacing oxolan-3-amine with

5-pyrimidînamine. LCMS (ES) [M+l] ⁺ m/z: 392. Ή NMR (300 MHz, DMSO-Λ) δ 10.69 (s, IH), 9.00 (s, 2H), 8.87 (s, IH), 8.42 (d, J= 5.4 Hz, IH), 7.74 (d, J= 2.4 Hz, IH), 7.00 (dd, 7= 5.4, 2.4 Hz, IH), 4.45 (s, 2H), 3.78 (s, 3H), 3.39 (s, 3H), 3.22 (t, 7= 7.5 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.10-1.95 (m, 2H).

Example 1.187

[1034] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(l-methylcyclopentyl)acetamide (Compound 179)

[1035] Compound 179 was synthesized similar to Compound 144 by replacing cyclohexylamine with 1-methy lcyclopentan-1 -amine hydrochloride. LCMS (ES) [M+l] ⁺ m/z: 426.3. ’H NMR (300 MHz, DMSO-Λ) § 8.46 (d, 7= 5.4 Hz, IH), 7.84 (d, 7= 2.4 Hz, IH), 7.74 (s, IH), 7.04 (dd, 7= 5.4, 2.4 Hz, IH), 4.93 (br, IH), 4.21-4.09 (m, 4H), 3.76 (t, 7= 4.8 Hz, 2H), 3.26 (s, 3H), 3.14 (t, 7= 7.5 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.07-1.89 (m,4H), 1.60-1.40 (m, 6H), 1.28 (s, 3H).

495

Example 1.188

[1036] Synthesis of N-tert-buty 1-2-{[2-(3-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-

4-yl](methyl)amino}acetamide (Compound 180)

[1037] Compound 180 was synthesized similarto Compound 24 by replacing 4-methyl-2(trimethylstannyl)pyridine with 3-methoxy-2-(trimethylstannyl)pyridine. LCMS (ES) [M+l] ⁺ m/z: 370. Ή NMR (300 MHz, DMSO-î/ô) δ 8.12 (dd, J= 4.6, 1.3 Hz, IH), 7.55-7.36 (m, 3H), 4.09 (s, 2H), 3.74 (s, 3H), 3.15-3.07 (m, 5H), 2.74 (t, J = 7.8 Hz, 2H), 2.06-1.87 (m, 2H), 1.22 (s, 9H).

Example 1.189

[1038] Synthesis of N-tert-butyl-2-{[2-(3-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin4-yl](methyl)amino}acetamide (Compound 181)

[1039] Into a 50-mL round-bottom flask were placed N-tert-butyl-2-[[2-(3-methoxypyridin-2-yl)21052

496

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](meÎhyl)amino]acetamide (50 mg, 0.135 mmol, l.OO equiv), DCE (5 mL) and AlCb (54 mg, 0.406 mmol, 3.00 equiv). The resulting solution was stirred for 7 h at 65 °C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 4 mL of MeOH and purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep Cl 8 OBD column, 5um, 19* 150mm; mobile phase, Water (0.05% FA) and CHsCN (5% CH3CN up to 35% in 15 min); Detector, UV 254 nm. This resulted in 17.1 mg (35.6%) ofN-tert-butyl-2-[[2-(3hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z 356. 'H NMR (300 MHz, DMSOéô) δ 14.21 (s, IH), 8.31-8.13 (m, IH), 7.88-7.69 (m, IH), 7.38-7.31 (m, 2H), 4.21 (s, 2H), 3.25 (s, 3H), 3.21-3.09 (m, 2H), 2.99-2.81 (m, 2H), 2.11-1.89 (m, 2H), 1.25 (s, 9H).

Example 1.190 [1040] Synthesis of N-tert-butyl-2-{[2-(lH-imidazoI-4-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4- yl](methyl)amino}acetamide (Compound 182)

[1041] Compound 182 was synthesized similar to Compound 24 by replacing 4-methyl-2(trimethylstannyl)pyridine with l-(triphenylmethyl)imidazol-4-ylboronic acid. LCMS (ES) [M+l]⁺ m/z: 329; Ή NMR (300 MHz, DMSOéô) δ 12.44 (br, IH), 7.67 (s, IH), 7.61 (s, IH), 7.55 (s, IH), 4.12 (s, 2H), 3.25 (s, 3H), 3.09 (t, ΊΑ Hz, 2H), 2.76 (t, J= Ί.8 Hz, 2H), 2.15-1.77 (m, 2H), 1.24 (s, 9H).

Example L191

[1042] Synthesis of (2R)-N-tert-butyl-2-[methyl(2-{ lH-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]propanamide (Compound 183)

497

H

[1043] Compound 183 was synthesized similar to Compound 101 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 5-(trimethylstannyl)-lH-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+l] ⁺m/z: 394,2; Ή NMR (300 MHz, DMSO-de./^m) δ 13.75 (s, IH), 9.12 (s, IH), 8.85 (d, J= L3 Hz, IH),

8.30 (d, 7=0.9 Hz, IH), 7,92 (s,lH), 5.17 (q, 7= 7.0 Hz, IH), 3.22 (dt,7= 15.6, 7.9 Hz, IH), 3,16-3.08 (m, 4H), 2.99-2,72 (m, 2H), 2.11-1.88 (m, 2H), 1.34 (d, 7= 7.1 Hz, 3H), 1.20 (s, 9H).

Example 1.192

[1044] Synthesis of 2-[methyl(2-{ IH-pyrazoio[3,4-c]pyridin-5-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(l-methylcyclopentyl)acetamide (Compound 184)

[1045] Compound 184 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 1-methylcyclopentan-l-amine hydrochloride and by replacing 4-methoxy-2-(trimethylstannyl)pyridine with 5-(tnmethylstannyl)-lH-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 406.2; 'HNMR (300 MHz, DMSO-dû.^m) δ 13.40 (s, IH), 9.09 (d,7 = 1.1 Hz, IH), 8.80 (d, 7= 1.3 Hz, IH), 8.26 (d, J= 0.9

Hz, IH), 7.82 (s, ]H), 4.17 (s, 2H), 3.30 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.091.97 (m, 4H), 1.48 (dt, 7= 16.7,7.2 Hz, 6H), 1.28 (s, 3H).

Example 1.193

[1046] Synthesis of 2-[methyl(2-{ lH-pyrazolo[3.4-c]pyridin-5-yl[-5H,6H,7H-

498

cyciopenta[d]pyrimidin-4-yl)amino]-N-(3-methyloxolan-3-yl)acetamide (Compound 185)

[ 1047] Compound 185 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 3-methyloxolan-3-amine and by replacing 4-methoxy-2-(trimethylstannyl)pyridine with 5- (trimethylstannyl)-l H-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 408,2; Ή NMR (300 MEIz, DMSO-de.^m) 813.71 (br, IH), 9.09 (s, IH), 8.78 (d, J = 1.3 Hz, IH), 8.26 (d,7=7.9 Hz, 2H),4.19 (s, 2H), 3.82 (d, 7= 8.7 Hz, IH), 3.77-3.66 (m, 2H), 3.49 (d,7= 8.7 Hz, IH), 3.31 (s, 3H), 3.15 (t, 7= 7.4 Hz, 2H), 2,83 (t, 7= 7.8 Hz, 2H), 2,25 (dt, 7= 12.9, 6.5 Hz, IH), 2.01 (h, 7= 8.1, 7.5 Hz, 2H), 1.80 (dt,7 = 12.5,7.6 Hz, IH), 1.32 (s, 3H).

Example 1.194

[1048] Synthesis of N-(2-methoxypyrimidin-5-yl)-2-{methyl[2-(!-methyl-lH-imidazol-4-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]ainino}acetamide (Compound 186)

[1049] Compound 186 was synthesized similar to Compound 142 by replacing cyclohexylamine with 2-methoxypyrimidin-5-amine. LCMS (ES) [M+l]⁺ m/z: 395; ’H-NMR: (300 MHz, DMSOA, ppm): δ 10.49 (s, IH), 8.79 (s, 2H), 7,69 (d,7= 1.2 Hz, IH), 7.61 (d, 7= 1.2 Hz, 1 H), 4.37 (s, 2H), 3.87 (s, 3H), 3.66 (s, 3H), 3.32 (s, 3H), 3.12 (t, 7= 7,2 Hz, 2H), 2.74 (t, 7= 7.8 Hz, 2H), 2.00-1.90 (m, 2H).

Example 1.195

[1050] Synthesis of 1-(4-nnethoxyphenyl)-4-[2-(pyridÎn-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-

499

yl]-l,4-diazepan-2-one (Compound 188)

Scheme J 04

[l 051 ] To a solution of 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (200 mg; 1,06 mmol; l eq.) in acetonitrile (3.5 ml) was added l,4-Diazepan-2-one hydrochloride (191 mg; 1.27 mmol; 1.2 eq.) and Hunig's base (0.74 mL; 4.23 mmol; 4 eq.). The reaction was stirred at 70 °C for 24 h. The reaction was evaporated, and the residue was purified by silica gel chromatography

500

(methanoi/dichloromethane gradient) to give 4-{2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-l,4diazepan-2-one (279 mg, 98%) as a white solid. LCMS (ES+): [M+H]⁺ = 266.9.

Step 2

[1052] 4-{2-Chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}-l,4-diazepan-2-one (279 mg; 1.05 mmol; l eq.) was suspended in l,4-dioxane (4 ml) and the mixture was purged with Argon gas. 2(Tributylstannyl)pyridine (0.68 mL; 2.09 mmol; 2 eq,) and tetrakis(triphenyiphosphane) palladium (I2l mg; O.l mmol; 0.1 eq.) were added and the reaction was stirred in a heat block at 108 °C for 18 h. The reaction mixture was evaporated and purified by reverse phase chromatography (Cl 8, acetonitrile/0.1%

HCOOH-water gradient) to give 4-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidîn-4-yl]-l,4diazepan-2-one (66 mg) as a white solid. LCMS (ES+): [M+H]⁺ = 310.0.

Step 3

[1053] 4-[2-(Pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrÎmidin-4-y!]-l,4-diazepan-2-one (59 mg;

0.19 mmol; 1 eq.), l-iodo-4-methoxybenzene (54 mg; 0.23 mmol; 1.2 eq.), 1-N,2-Ndimethylcyclohexane-l,2-diamine (13.5 mg; 0.1 mmol; 0.5 eq.), potassium phosphate tribasic (121 mg; 0.57 mmol; 3 eq.) were suspended in 1,4-dioxane (3.5 ml). The mixture was purged with Argon gas. Copper(I) iodide (12.7 mg; 0.07 mmol; 0.35 eq.) was added, the vessel was sealed and stirred in a heat

501 block at 120 °C for 48 h, The reaction was cooled, filtered, evaporated and the residue was purified by reverse phase chromatography (Waters XSelect CSH C18 column, 0-100% acetonîtrile/0.1 % aqueous fonnic acid gradient) to give l-(4-methoxyphenyl)-4-[2-(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]-l,4-diazepan-2-one (33 mg, 42%) as a brown solid. LCMS (ES+): [M+H]⁺ = 416. L Ή NMR (400 MHz, DMSO-Λ, 80^üC) δ 7.18-6.65 (m, 8H), 4.43 - 4.11 (m, 2H), 3.87 - 3.54 (m, HH), 2.15- 1.96 (m, 4H).

Example 1.196

[1054] Synthesis of N-(4-fluorophenyl)-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 189)

H Ck_zN

[1055] Compound 189 was synthesized similar to Compound 135 by replacing oxo lan-3-amine with 4-fluoroaniline. LCMS (ES) [M+1] ⁺ m/z: 408. ^lH NMR (300 MHz, DMSO-Λ) δ 10.34 (s, IH), 8.45 (d, 7= 5.4 Hz, IH), 7.79 (d, 7= 2.7 Hz, IH), 7.72-7.47 (m, 2H), 7.16-7.10 (m, 2H), 7.00 (dd,7=5.7, 2.7 Hz, IH), 4.42 (s, 2H), 3.77 (s, 3H), 3.37 (s, 3H), 3.21 (t,7= 7.2 Hz, 2H), 2.84 (t,7= 7.8 Hz, 2H), 2.081.95 (m, 2H).

Example 1.197

[1056] Synthesis ofN-(5-methoxypyridin-2-yl)-2-{methyl[2-(l-methyl-lH-iinidazol-4-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 190)

H

CK

NA

[1057] Compound 190 was synthesized similar to Compound 142 by replacing cyclohexylamine

502 with 4-methoxypyridin-2-amine. LCMS (ES) [M+1 ]^T m/z: 394; H NMR: (300 MHz, DMSO-dd, ppm)\ δ 10.51 (s, IH), 8.06 (d, 7= 2.7 Hz, l H), 7.95 (d, 7= 9.0 Hz, IH), 7.66 (d,7= 1.2 Hz, IH), 7.55 (d, 7 = 1.2 Hz, IH), 7.41 (dd, 7= 9.0, 3.0 Hz, 1 H), 4.43 (s, 2H), 3.80 (s, 3H), 3.62 (s, 3H),3.30(s, 3H), 3.12 (t, 7 = 7.2 Hz, 2H), 2.74 (t, J= 7.8 Hz, 2H), 2.00-1.90 (m, 2H).

Example 1.198

[1058] Synthesis ofN-tert-butyl-2-({2-[4-(2-hydroxyethoxy)-5-methylpyridin-2-yl]-5H,6H,7Hcyc lopenta[d] pyrim i d in-4-y 1} (methy l)amino)acetam ide (C ompo und 191)

[1059] Compound 191 was synthesized similar to Compound 44 by replacing 2-chloropyridin-4-ol with 2-chloro-5-methylpyridin-4-ol. LCMS (ES) [M+l] ⁺ m/z: 414. *H NMR (300 MHz, DMSO-7ô) δ 8.31 (s, IH), 7.85 (s, IH), 7.65 (s, IH), 4.93 (t, J = 5.5 Hz, IH), 4.20-4.17 (m, 4H), 3.83-3.78 (m, 2H), 3.25 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.20 (s, 3H), 2.11-L93 (m, 2H), 1.23 (s, 9H).

Example 1.199

[1060] Synthesis ofN-tert-butyl-2-{[2-(4-methoxy-5-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 192)

[1061] Compound 192 was synthesized similar to Compound 24 by replacing 4-methyl-2(trimethylstannyl)pyridine with 4-methoxy-5-methyl-2-(trimethylstannyl)pyridine. LCMS (ES) [M+l] ⁺m/z: 384. Ή NMR (300 MHz, DMSO-R,) δ 8.31 (s, IH), 7.88 (s, IH), 7.65 (s, IH), 4.17 (s, 2H), 3.96

503

(s, 3H), 3.26 (s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.18 (s, 3H), 2.04-1.94 (m, 2H),

1.23 (s, 9H).

Example 1.200 and Example 1.201

[l062] Synthesis ofN-tert-butyl-2-{[2-(l -ethyl-IH-imidazol-4-yl)-5H,6H,7H- cyclopenta[djpyrimidin-4-yl](methyl)amino}acetamide (Compound 193) and N-tert-butyl-2-{[2-(lethyl-lH-imidazol-5-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound

194)

Scheme 105

[1063] A solution ofN-tert-butyl-2-[[2-(3H-imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide (300.00 mg, 0.913 mmol, 1.00 equiv), K2CO3 (252.49 mg, 1.827 mmol, 2 equiv) and bromoethane (149.30 mg, 1.370 mmol, 1.50 equiv) in DMF (5.00 mL) was stirred for 2 h at 50 °C under air atmosphère. The crude product was purified by Prep-HPLC to afford N-tert-butyl-2-[[2- (3-ethy]imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyI)amino]acetamide (Compound

192, 86 mg, 26.41%)and N-tert-buty l-2-[[2-(l-ethyl imidazol-4-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide (Compound 193, 102 mg, 31.32%) as a white solid.

[1064] Compound 193: LCMS (ES) [M+]]⁺m/z: 357; Ή NMR (300 MHz, DMSO-Æ) δ 7.80 (d, J

504 = I.4 Hz, IH), 7.66 (d, 7 = l.4Hz, IH), 7.64 (br, lH),4.09(s, 2H), 4.03 (q,7=7.3 Hz, 2H), 3.22 (s, 3H), 3.08 (t, 7= 7.2 Hz, 2H), 2.73 (t, 7= 7.8 Hz, 2H), 2.05-i .86 (m, 2H), 1.39 (t, 7= 7.3 Hz, 3H), 1.25 (s, 9H).

[1065] Compound 194: LCMS (ES) [M+l] ⁺ m/z: 357; Ή NMR (300 MHz, DMSO-7₆) δ 7.75 (d, J 5 = 1.3 Hz, IH), 7.61 (d,7= 1.2 Hz, lH),7.58(br, 1 H), 4.53 (q,7=7.1 Hz, 2H), 4.11 (s, 2H), 3.19 (s,

3H), 3.08 (t,7= 7.3 Hz, 2H), 2.75 (t,7=7.8 Hz, 2H), 2.03-1.82 (m, 2H), 1.31 (t,7= 7.1 Hz, 3H), 1.24 (s, 9H).

Example 1.202 and Example 1.203

[1066] Synthesis of N-tert-buty 1-2-( {2-[l-(2-hydroxyethyI)-lH-imidazol-4-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 195) and N-tert-butyl-2-({2-[l-(2hydroxyethyl)-lH-irnidazol-5-yl]-5H,6H,7H-cyclopenta[d]pynmidin-4-yl}(methyl)amino)acetamide (Compound 196)

Compound 195

[1067] Compound 195 and Compound 196 were synthesized similar to Compound 193 and

Compound 194 by replacing bromoethane with 2-(2-iodoethoxy)oxane.

[1068] Compound 195: LCMS (ES) [M+l] ⁺ m/z: 373; 'H NMR (300 MHz, DMSOA) Ô7.77 (d, 7 = 1.4 Hz, IH), 7.62 (br, IH), 7.61 (d,7= 1.4 Hz, IH), 5.00 (t, 7= 4.5 Hz, lH),4J0(s, 2H), 4.03 (t,7=5.4 Hz, 2H), 3.69 (q, 7= 5.1 Hz, 2H), 3.20 (s, 3H), 3.06 (t, 7= 7.3 Hz, 2H), 2.73 (t, J= 7.8 Hz, 2H), 2.0220 1.79 (m, 2H), 1.25 (s, 9H).

[1069] Compound 196: LCMS (ES) [M±l]⁺m/z: 373; Ή NMR (300 MHz, DMSOA) Ô7.66 (d, 7 = 1.2 Hz, I H), 7.62 (d, 7= 1.2 Hz, IH), 7.57 (s, IH), 4.89 (t, 7= 5.3 Hz, 1 H), 4.56 (t,7= 5.5 Hz, 2H), 4.09 (s, 2H), 3.67 (d, 7= 5.3 Hz, 2H), 3.18 (s, 3H), 3.08 (t, J= 7.3 Hz, 2H), 2.75 (t, 7= 7.8 Hz, 2H), 2.00-1.90 (m, 2H), 1.26 (s, 9H).

505

Example 1.204

[1070] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide (Compound 197)

[1071] Compound 197 was synthesized similar to Compound 144 by replacing cyclohexylamine with 2-methoxypyrimidin-5-amine. LCMS (ES) [M+1 ] ⁺ m/z: 452. ’H NMR (300 MHz, DMSO-^) δ 10.51(s, IH), 8.77 (s, 2H), 8.44-8.42 (d,7= 5.6 Hz, IH), 7.77-7.76 (d, J= 2.5 Hz, ΐH), 7.03-7.0l(dd, 7= 5.6, 2.6 Hz, IH), 4.92 (t, 7= 5.4 Hz, IH), 4.42 (br, 2H), 4.05 (t, 7=4.9 Hz, 2H), 3.88 (s, 3H), 3.70 (q,7 = 5.1 Hz, 2H), 3.38 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H), 2.83 (t, 7= 7.9 Hz, 2H), 2.10-2.00 (m, 2H).

Example 1.205

[1072] Synthesis ofN-(4-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-y]}(methyl)amino)acetamide (Compound 198)

[1073] Compound 198 was synthesized similar to Compound 144 by replacing cyclohexylamine with 4-fluoroaniline. LCMS (ES) [M+1] ⁺ m/z: 438. ‘H NMR (300 MHz, DMSO-7₆) δ 10.28 (s, IH), 8.43 (d, 7=5.6 Hz, IH), 7.78 (d, 7= 2.5 Hz, 1 H), 7.60 (dd, 7= 9.1, 5.1 Hz, 2H), 7.12 (t, 7= 8.9 Hz, 2H), 7.00 (dd, 7= 5.6, 2.6 Hz, IH), 4.90 (s, IH), 4.41 (s, 2H), 4.02 (t, 7= 4.8 Hz, 2H), 3.67 (t,7= 4.8 Hz, 2H), 3.36 (s, 3H), 3.21 (t,7=7.3 Hz, 2H), 2.83 (t,7=7.9 Hz, 2H), 2.08-1.95 (m, 2H).

Example 1.206

[1074] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyT)amino)-N-(6-methylpyridin-3-yl)acetamide (Compound I99)

[1075] Compound 199 was synthesized similar to Compound 144 by replacing cyclohexylamine with 6-methylpyridin-3-amine. LCMS (ES) [M+l] ⁺ m/z: 435. 'H NMR (300 MHz, DMSO-Λ) δ 10.37 (s, lH), 8.62 (d, J = 2.5 Hz, IH), 8.43 (d, J = 5.6 Hz, IH), 7.91 (dd, J = 8.4, 2.6 Hz, IH), 7.77 (d, J = 2.5 5 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 7.01 (dd, J = 5.7, 2.6 Hz, IH), 5.02 (t, J = 5.5 Hz, IH), 4.42 (s, 2H),

4.0 3 (t, J = 4.8 Hz, 2H), 3.69 (q, J = 5.1 Hz, 2H), 3.38 (s, 3H), 3.21 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.40 (s, 3H), 2.08-2.01 (m, 2H).

Example 1.207

[1076] Synthesis of 2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino]-N-(6-methylpyridin-3-yl)acetamide (Compound 200)

[1077] Compound 200 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 6-methylpyridin-3-amine. LCMS (ES) [M+l] ⁺ m/z: 405. Ή NMR (300 MHz, DMSO-Λ) δ 10.36 (s, IH), 8.60 (d, J= 2.7 Hz, IH), 8.44 (d,7=5.7 Hz, IH), 7.89 (dd,7= 8.4, 2.7 Hz, IH), 7.78 (d, 7= 2.1

Hz, IH), 7.17 (d,7= 8.4 Hz, IH), 7.00 (dd, 7= 5.7, 2.7 Hz, 1H),4.43 (s, 2H), 3.78 (s, 3H), 3.37 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.40 (s, 3H), 2.11-1.96 (m, 2H).

Example 1.208

[1078] Synthesis of N-(6-methoxypyridin-3-yl)-2-{methyl[2-(l -methyl- lH-imtdazol-4-y 1)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 20 !)

[1079] Compound 201 was synthesized similar to Compound 142 by replacing cyclohexylamine with 5-amino-2-methoxypyridine. LCMS (ES) [M+l] ⁺ m/z: 394; Ή-NMR: (300 MHz, DMSO-ekj/y™): δ 10.27 (s, lH), 8.38 (d, 7= 2.7 Hz, lH), 7.92 (dd, 7= 8.7, 2.7 Hz, IH), 7.69 (d,7= 1.2 Hz, IH), 7.60 (d,

7= L2Hz, IH), 6.79 (d, 7= 8.7 Hz, IH), 4.35 (s, 2H), 3.80 (s, 3H), 3.64 (s, 3H), 3.3l(s, 3H), 3.13 (t,7=

7.2 Hz, 2H), 2.74 (t, 7= 7.8 Hz, 2H), 2.00-1.90 (m, 2H).

Example L209

[] 080] Synthesis of N-(4-fluorophenyl)-2-{methyl[2-(l-methy l-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrîmidin-4-yl]amino}acetamide (Compound 202)

[1081 ] Compound 202 was synthesized similar to Compound 142 by replacing cyclohexylamine with 4-fluoroaniline. LCMS (ES) [M+I] ⁺ m/z: 381; Ή-NMR: (300 MHz, DMSO-^/^m): δ I0.28 (s, IH), 7.70-7.60 (m, 4H), 7.I7-7.H (m, 2H), 4.35 (s, 2H), 3.63 (s, 3H), 3.31 (s, 3H), 3.12 (t, 7= 7.2 Hz, 2H), 2.74 (t, 7= 7.8 Hz, 2H), 2.00-1.90 (m, 2H).

Example l .210

[1082] Synthesis of 4-(4-methoxyphenyI)-l-[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yî]-l,4-diazepan-5-one (Compound 203)

508

[ 1083] Compound 203 was synthesized similar to Compound 188 by replacing l,4-diazepan-2-one hydrochloride with l,4-diazepan-5-one hydrochloride. LCMS (ES+): [M+H]⁺ = 416.1. *H NMR (400 MHz, MethanolA) δ 7.16 - 6.73 (m, 8H), 4.29 - 3.76 (m, 11H), 3.06 - 2.85 (m, 6H).

Example l.2l l

[1084] Synthesis of (2R)-2-{methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-N-(l-methy lcyclopropyl)propanamide (Compound 204)

[ ! 085] Compound 204 was synthesized similar to Compound I08 by replacing cyclohexylamîne with 1-methylcyclopropan-1-amine. LCMS (ES+): [M+H]⁺ = 352.1. Ή NMR (400 MHz, DMSOA) δ 8.78-8.71 (m, IH), 8.51 (s, IH), 8.43 -8.35 (m, IH), 8.06-7.96 (m, IH), 7.59 (ddd, J= 7.6,4.7, 1.2 Hz, IH), 5.02 (q, J= 7.0 Hz, IH), 3.25-3.14 (m, 5H), 2.99-2.87 (m, 2H), 2.14-1.93 (m, 2H), 1.37 (d, 7= 7.0 Hz, 3H), 1.17 (s, 3H), 0.61-0.41 (m, 4H).

Example 1.212

[1086] Synthesis of (3S)-3-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-l-phenylpyrrolidin-2-one (Compound 205)

[ 1087] Compound 205 was synthesized similar to Compound 130 by replacing (2R)-2-[(tert- butoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with (2S)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoic acid and replacing 2-(tributylstannyl)pyridine with 4-methoxy-25 (tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 416.3. Ή NMR (400 MHz, DMSO-7₆) δ 8.37 (d, J= 5.6 Hz, IH), 8.15 (s, IH), 7.72 (d, IH), 7.70 - 7.66 (m, 2H), 7.40 - 7.34 (m, 2H), 7.17 - 7.12 (m, IH), 6.97 (dd, 7= 5.6, 2.6 Hz, IH), 5.49-5.31 (m, IH), 3.99 - 3.86 (m, 2H), 3.78 (s, 3H), 3.24-3.19 (m, 5H), 2.87 - 2.81 (m, 2H), 2.46 - 2.30 (m, 2H), 2.07 - 1.97 (m, 2H).

Example 1.213

[1088] Synthesis of (3S)-]-(4-fluorophenyl)-3-{methyl[2'(pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}pyrrolidin-2-one (Compound 206)

[1089] Compound 206 was synthesized similar to Compound 130 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with (2S)-2-[(tert-butoxycarbonyl)amino]-4- (methylsulfanyl)butanoic acid and replacing aniline with 4-fluoroaniline. LCMS (ES+): [M+H]⁺ = 404.2. Ή NMR (400 MHz, DMSO-7₆) δ 8.54 (d, 7= 4.7 Hz, 1 H), 8.15 (d, 7= 2.5 Hz, 1 H), 7.73 (dd,J= 9.0, 4.9 Hz, 2H), 7.68-7.56 (m, IH), 7.39 - 7.33 (m, IH), 7.26 - 7.18 (m, 2H), 5.29 (s, IH), 3.99 - 3.84 (m, 2H), 3.25 - 3.21 (m, 5H), 2.88 - 2.80 (m, 2H), 2.46 - 2.27 (m, 2H), 2.06 - 1.96 (m, 2H).

Example 1.214

510

[1090] Synthesis of (3S)-3-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidtn-4- yl]amino}-1 -( l-methylcyciopentyI)pyrrolidin-2-one (Compound 207)

[1091] Compound 207 was synthesized similar to Compound 130 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with (2S)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoic acid and replacing aniline with 1-methylcyclopentan-l-aminium chloride. LCMS (ES+): [M+H] = 392.2. Ή NMR (400 MHz, DMSOéô) δ 8.77 - 8.56 (m, IH), 8.25 (d, 7 = 7.8 Hz, IH), 7.95 -7.79 (m, 1H),7.51 - 7.34 (m, IH), 5.36-5.12 (m, IH), 3.63 - 3.46 (m, 2H), 3.22 - 3.14 (m, 2H), 3.06 (s, 3H), 2.82 (t,7=8.0 Hz, 2H), 2.33-2.22 (m, IH), 2.14- 1.93 (m, 5H), 1.78-1.54 (m, 6H), 1.21 (s, 3H).

Example 1.215 [1092] Synthesis of (3S)-3-[methyl[2-(pyndîn-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}-l-(pyridin-4-yl)pyrrolidin-2-one (Compound 208)

[1093] Compound 208 was synthesized similar to Compound 130 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-4-(methylsulfanyl)butanoic acid with (2S)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoic acid and replacing aniline with 4-pyridinamine. LCMS (ES+): [M+H]⁺ = 386.9. Ή NMR (400 MHz, Methanolé) δ 8.53 (d, 7= 4.9 Hz, IH), 8.48-8.44 (m, 2H), 7.97 (d,7= 7.9 Hz, IH), 7,84-7.78 (m, 2H), 7.49-7.42 (m, IH), 7.35 -7,29 (m, IH), 4.14 - 3.91 (m, 3H), 3.44 (s, 3H), 2.99 - 2.93 (m, 2H), 2.62 - 2.51 (m, 2H), 2.17 - 2.11 (m, 2H).

Example l .216

[1094] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide (Compound 209)

[1095] Compound 209 was synthesized similar to Compound 144 by replacing cyclohexylamine with 5-methoxyl-2-aminopyridine. LCMS (ES) [M+l] ⁺ m/z: 451. Ή NMR (300 MHz, DMS0-7ô) δ 10.54(s, 1 H), 8.44-8.42 (d, J= 5.6 Hz, IH), 8.04-8.03(d, 7= 3.0Hz, 1 H), 7.98-7.95 (d, 7= 9,1 Hz, IH), 7.77-7.76 (d,7=2.5 Hz, IH), 7.42-7.38 (dd,7=9.1, 3.0 Hz, IH), 6.99-6.96 (dd,7= 5.6, 2.7 Hz, IH), 4.90-4.87 (t, 7= 5.4 Hz, IH), 4.50 (s, 2H), 4.02-3.96 (q, 7= 7.4 Hz, 2H), 3.80 (s, 3H), 3.69-3.64 (q, 7=

5.4 Hz, 2H), 3.34 (s, 3H), 3.22-3.17 (t, 7= 7.3 Hz, 2H), 2.85-2.80 (t, 7= 7.8 Hz, 2H), 2.05-1.98 (m,

2H).

Example 1.217

[1096] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl} (methy l)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 210)

512

Scheme 106

Step l

[l 097] Into a 50-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen were placed l-[(2-chloropyridin-4-yl)oxy]-2-methylpropan-2-ol (l.OO g, 4.96 mmol, l.OO equiv), Toluene (30 mL), SnsMeô (L7l g, 5.22 mmol, L05 equiv) and Pd(PPhs)4 (0,57 g, 0.49 mmol, 0.10 equiv). The resulting solution was stirred for 2 h at I00 °C. To this mixture was added ethyl 2-((2chioro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate (0.94 g, 3.48 mmol, 0.70 equiv) and Pd(PPh₃)4 (0.57 g, 0.49 mmol, 0.10 equiv), The resulting solution was stirred overnight at 100 °C. After cooled to ambient température the resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 300 mg (15.11%) of ethyl 2-([2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate as brown oil. LCMS (ES) (M+l]⁺ m/z 401.

Step 2

5I3

[ 1098] Into a 50-mL round-bottom flask were placed ethyl 2-([2-[4-(2-hydroxy-2methy]propoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate (300 mg, 0.75 mmol, l.OO equiv) and MeOH (3 mL). This was followed by the addition of a solution of LiOH (36 5 mg, L50 mmol, 2.00 equiv) in H₂O (l mL) dropwise with stîrring at 25 °C. The resulting solution was stirred for 2 hr at 25 °C and concentrated under vacuum. The resulting solution was extracted with 2x20 mL of dîchloromethane and the aqueous was separated and concentrated under vacuum. This resulted in 150 mg (52.92%) of lithio 2-([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yI](methyl)amino)acetate as a brown solid. LCMS (ES) [M-Li+H+l]⁺ m/z

373.

Step 3

[1099] To a stirred solution of ([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)acetic acid (200.00 mg, 0.537 mmol, 1.00 equiv), 5-amino-

2-methoxypyridine (80 mg, 0.64 mmol, 1.2 equiv) and DIEA (138.8 mg, 1.07 mmol, 2.0 equiv) in DMF (3 mL) was added HATU (265.4 mg, 0.69 mmol, 1.3 equiv) in one portion at 0 °C. After stirred for 5 h at 0-25 °C, the resulting mixture was purified by préparative

HPLC (Column, Cl 8; mobile phase A: CH3CN, Mobile phase B: Water. Flow rate: 20 mL/min) to give 2-[2-[(2S)-2-(2-formyl-3-hydroxyphenoxymethyl)piperidine-l20 carbonyl]phenyl]acetamide (123.1 mg, 12.3%) as an off white solid. LCMS (ES) [M+l]⁺ m/z: 479. 'H NMR (300 MHz, DMSO-d6) δ 10.27 (s, IH), 8.45 (d, J = 5.6 Hz, IH), 8.34 (d, J = 2.6 Hz, IH), 7.87

514 (dd, J = 8.9, 2.7 Hz, IH), 7.79 (d, J = 2.6 Hz, IH), 7.03 (dd, J = 5.7, 2.6 Hz, IH), 6.77 (d, J = 8.9 Hz, IH), 4.67 (s, IH), 4.41 (s, 2H), 3.82-3.78 (m, 5H), 3.37 (s, 3H), 3.21 (t, J = 7-3 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.04-I.99 (m, 2H), 1.17 (s, 6H).

Example 1.218

[1100] Synthesis of N-tert-buty l-2-[methyl(2-{4-[(oxetan-3-yl)methoxy]pyridin-2-y l}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 211)

[1101] Compound 211 was synthesized similar to Compound 24 replacing 4-methyl-2(tributylstannyl)-pyridine with 4-(oxetan-3-ylmethoxy)-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 426.2. Ή NMR (400 MHz, DMSO-d6) S 8.60 (d, J= 5.8 Hz, IH), 7.95 (d, 7= 2.6 Hz, IH), 7.82 (s, IH), 7.29 (dd, 7= 5.9, 2.6 Hz, IH), 4.77 - 4.69 (m, 2H),4.51 -4.42 (m, 4H), 4.22 (s, 2H),3.48 -3.43 (m, IH), 3.37 (s, 3H), 3.22-3.17 (m, 2H), 2.96-2.87 (m, 2H), 2.09- 1.98 (m, 2H), 1.24 (s, 9H).

Example 1.219

[1102] Synthesis of (2R)-N-tert-butyl-2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-y]}(methyl)amino)-4-(methylsulfanyl)butanamide (Compound 212)

[1103] Compound 212 was synthesized similar to Compound 114 by replacing (2R)-2-[(tertbutoxycarbonyl)amino]-3-methylbutanoic acid with (2R)-2-[(tert-butoxycarbonyl)amino]-4(methylsulfanyl)butanoic acid and by replacing 2-(tributylstannyl)pyridine with 4-(difluoromethoxy)-2(tributylstannyl)pyridine. LCMS (ES+): [Μ+ΗΓ = 480.4. Ή NMR (400 MHz, DMSO-7₆) δ ppm 1.16 -

515

1.20 (m, 9 H) l .89 - 2.15 (m, 7 H) 2.34 - 2.46 (m, 2 H) 2.74 - 2.95 (m, 2 H) 3.00 - 3.14 (m, 4 H) 3.18 3.25 (m, 2 H) 4.97 - 5.09 (m, 1 H) 7.29 (dd, 7=5.48, 2.35 Hz, 1 H) 7.57 (t, 7=72.78 Hz, 1 H) 7.81 - 7.87 (m, 1 H) 8.09 (d, 7=1.96 Hz, 1 H) 8.68 (d, 7=5.87 Hz, I H).

Example 1.220

[1104] Synthesis of 2-({2-[4-(dif]uoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 213)

[1105] Compound 213 was synthesized similar to Compound 177 by replacing 2-(tributylstannyl)-4(2,2,2-trifluoroethoxy)pyndine with 4-(difluoromethoxy)-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 429.9. Ή NMR (400 MHz, DMSO-Λ) δ ppm 2.04 - 2.16 (m, 2 H) 3.04 (br t, 7=7.83 Hz, 2 H) 3.26 - 3.28 (m, 2 H) 3.52 (s, 3 H) 3.70 - 3.74 (m, 3 H) 4.61 - 4.69 (m, 2 H) 6.32 - 6.38 (m, 1 H) 6.36 (d, 7=1.57 Hz, 1 H) 7.42 - 7.47 (m, 1 H) 7.43 - 7.83 (m, 2 H) 7.63 (t, 7=73.17 Hz, 1 H) 8.04 - 8.12 (m, 1 H) 8.77 - 8.85 (m, 1 H) 10.78 - 10.86 (m, 1 H).

Example 1.221

[1106] Synthesis of 2-({2-[4-(2-hydroxy-2-methyIpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide (Compound 214)

[1107] Compound 214 was synthesized similar to Compound 210 replacing 5-amino-2-methoxypyridine with 5-methoxypyndin-2-amme. LCMS (ES) [M+l] ⁺ m/z: 479.3. Ή NMR (300 MHz, DMSO-d6) δ

5I6

10.51 (s, IH), 8.44 (d, J = 5.6 Hz, IH), 8.28 (s, IH), 8.02 (d, J = 3.1 Hz, IH), 7.95 (d, J = 9.1 Hz, IH), 7.76 (d, J = 2.5 Hz, IH), 7.39 (dd, 1 = 9.1,3.1 Hz, IH), 7.00 (dd, J = 5.7, 2.5 Hz, 1H),4.51 (s,2H),3.813.76 (m, 5H), 3.34 (s, 3H), 3.19 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.08-1.95 (m, 2H), 1.15 (s, 6H).

S Example 1.222

[1108] Synthesis of2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 215) /

N-N

[ 11091 Compound 215 was synthesized similar to Compound 177 replacing 2-bromo-4-(2,2,210 trifluoroethoxy)pyridine with 2-bromo-4-(cyclopropylmethoxy)pyridine. LCMS (ES) [M+l] ⁺ m/z: 443.1.'H NMR (400 MHz, DM SO-Λ) δ 10.58 (s, IH), 8.47 (d, J= 5.8 Hz, 1 H), 7.78 (d, J = 2.6 Hz, IH), 7.50 (d, 7= 2.2 Hz, IH), 7.10 (dd, 7= 5.9, 2.6 Hz, IH), 6.34 (d,7= 2.2 Hz, 1 H), 4.46 (s, 2H), 3.92 (d, 7 = 7.1 Hz, 2H), 3.71 (s, 3H), 3.36 (s, 3H), 3.20 (d, 7= i4.8 Hz, 2H), 2.87 (t, 7= 7.9 Hz, 2H), 2.09 - 1.94 (m, 2H), 1.21 (s, IH), 0.63 - 0.52 (m, 2H), 0.40 - 0.29 (m, 2H).

Example 1.223

[1110] Synthesis of2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4y]} (methy l)amino)-N-(6-fluoropyrîdin-3-yl)acetamide (Compound 216)

5I7

[l 111] Compound 216 was synthesized similar to Compound 24 replacing 4-methyl-2(tributylstannyl)-pyridine with 4-(difluoro methoxy )-2-(tributylstannyl)pyridine and by replacing tertbutylamine with 6-fluoro-3-pyridiny lamine. LCMS (ES+): [M+H]⁺ — 445.1. ¹H NMR (400 MHz,

DMSO-de) δ ppm 2.03 -2.16 (m, 2 H) 3.02 (br t, 7=7.83 Hz, 2 H) 3.26 - 3.29 (m, 2 H) 3.53 (s, 2 H) 4.62 -4.70 (m, 2 H) 7.11 - 7.18 (m, 1 H) 7.60 (t, 7=71.99 Hz, 1 H) 7.45-7.51 (m, 1 H) 8.05 (br s, 1 H) 8.108.18 (m, 1 H) 8.45 (br s, 1 H) 8.73 - 8.81 (m, 1 H) 10.80 - 10.89 (m, 1 H).

Example 1.224

[1112] Synthesis of' 2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pynmidin-4- yl}(methyl)amino)-N-(5-methoxypyridin-2-yl)acetamide (Compound 217)

[1113] Compound 2)7 was synthesized similar to Compound 24 replacing 4-methy 1-2(tributylstannyl)-pyridine with 4-(difluoromethoxy)-2-(tributylstannyl)pyridine and by replacing tertbutylamine with 5-methoxypyridin-2-amine. LCMS (ES+): [M+H]⁺ = 456.9. ’H NMR (400 MHz,

DMSO-C&) δ ppm 2.04 - 2.13 (m, 2 H) 3.00 (br t, 7=7.83 Hz, 2 H) 3.28 (br d, 7=7.04 Hz, 2 H) 3.50 (s, 3 H) 3.77 - 3.80 (m, 3 H) 4.65 -4.72 (m, 2 H) 7.39 (dd, 7=9.00, 3.13 Hz, 1 H) 7.41 - 7.80 (m, 1 H) 7.46

518 (dd, 7=5.48, 2.35 Hz, l H) 7.87 - 7.96 (m, l H) 8.03 (d, 7=2.74 Hz, l H) 8.04 - 8.08 (m, l H) 8.77 (d, 7=5.87 Hz, l H) 10.73 - 10.79 (m, l H).

Example l .225

[l 114] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-45 yl](methyl)amino}-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 218)

N-N^Z

[1115] Compound 218 was synthesized similar to Compound 177 by replacing 2-(tributylstannyl)-4(2,2,2-trifluoroethoxy)pyridine with 3-(tnbutylstannyl)isoquinoline. LCMS (ES+): [M+H]⁺ = 414.0. ^!H

NMR (400 MHz, DMSO-7₆) δ ppm 2.08 - 2.19 (m, 2 H) 3.10 (br t, 7=7.83 Hz, 2 H) 3.30 - 3.36 (m, 2 H)

3.61 (br s, 3 H) 3.75 - 3.83 (m, 3 H) 4.61 - 4.72 (m, 2 H) 6.32 - 6.42 (m, 1 H) 7.45 - 7.54 (m, 1 H) 7.86 -

7.95 (m, 1 H) 7.95 - 8.08 (m, 2 H) 8.33 (br d, 7=8.22 Hz, 1 H) 8.79 - 8.98 (m, 1 H) 9.52 - 9.62 (m, 1 H) 10.98 - 11.15 (m, 1 H)

Example 1.226

[1116] Synthesis of N-(6-methoxypyrîdin-3-yl)-2-[methyl(2-{ lH-pyrazoIo[3,4-c]pyridin-5-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 219)

519

[l 117] Compound 219 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 5-amino-2-methoxypyridine and by replacing 4-methoxy-2-(trimethylstannyl)pyridine with 5(trimethylstannyl)-lH-pyrazolo[3,4-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 431.2; *HNMR (300 MHz, DMSO-d₆,ppm) δ 13.70 (s, IH), 10.37 (s, IH), 9.06 (s, IH), 8.70 (d, J= 1.2 Hz, IH), 8.41 (t,7=2.4 Hz, 5 IH), 8.09 (s, IH), 7.95 (ddd, 7= 8.9, 2.8, 1.5 Hz, IH), 6.80 (d,7=8.9 Hz, IH), 4.42 (s, 2H), 3.80 (s, 3H), 3.39 (s, 3H), 3.20 (t, 7= 7.3 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.11-1.93 (m, 2H).

Example 1.227

[1118] Synthesis ofN-(l-methy 1-1 H-pyrazol-4-yl)-2-{methyl[2-(l-methy 1-1 H-imidazol-4-yl)5H,6H,7H-cyclopenta[dJpyrimidin-4-yl]amino}acetamide (Compound 220) /

[1119] Compound 220 was synthesized similar to Compound 177 by replacing 2-(tributylstannyI)-4(2,2,2-trifluoroethoxy)pyridine with l-methyl-4-(tributylstanny!)-lH-imidazole. LCMS (ES) [M+l] ⁺m/z: 367.2; Ή NMR (400 MHz, dmso) δ 10.73 (s, IH), 8.29 (s, IH), 8.16 (s, IH), 7.53 (d, 7= 2.2 Hz, IH), 6.35 (d, 7= 2.2 Hz, 1 H), 4.58 (s, 3H), 4.55 (s, 2H), 3.77 (s, 3H), 3.73 (s, 3H), 3.16 (s, 2H), 2.92 (t,

7= 7.9 Hz, 2H), 2.09 - 1.96 (m, 2H).

Example 1.228

[1120] Synthesis ofN-(6-fluoropyridin-3-yl)-2-{[2-(isoquinolin-3-yl)-5H,6l·L7I^cyclopenta[d]pyrimtdin-4-yl](methyl)amino}acetamide (Compound 221)

520

[1121] Compound 221 was synthesized similar to Compound 135 by replacing 4-methoxy-2- (tri methy lstannyî)pyridine with 3-(tributylstannyl)isoquinoline and by replacing oxolan-3-amine with 6fluoro-3-pyridiny lamine. LCMS (ES+): [M+H]⁺ = 429.2. Ή NMR (400 MHz, DMSO-7₆) δ ppm L99 5 2.08 (m, 2 H) 2.84-2.91 (m, 2 H) 3.20 - 3.26 (m, 2 H) 3.42 (s, 3 H) 4.46 - 4.5I (m, 2 H) 7.10 - 7.16 (m, l H) 7.67 - 7.73 (m, l H) 7.73 - 7.79 (m, I H) 7.81 - 7.86 (m, l H) 8.13 - 8.17 (m, l H) 8.I7 - 8.24 (m, l H) 8.43 - 8.48 (m, l H) 8.7] - 8.75 (m, ] H) 9.32 - 9.37 (m, l H) 10.67 - 10.74 (m, 1 H)

Example 1.229

[1122] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide (Compound 222)

[1123] Compound 222 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 3-(tributylstannyl)isoquinoline and by replacing oxolan-3-amine with 5methyl-2-pyridinamine. LCMS (ES+): [M+H]⁺ = 425.2. Ή NMR (400 MHz, DMSO-Æ) δ ppm 2.09 -

2.19 (m, 2 H) 2.52-2.60 (m, 3 H) 3.11 (br t, 7=7.83 Hz, 2 H) 3.35 - 3.37 (m, 2 H) 3.64 (s, 3 H) 4.84 4.97 (m, 2 H) 7.66 - 7.75 (m, 1 H) 7.85 - 7.93 (m, 1 H) 7.93 - 8.00 (m, l H) 8.28 - 8.37 (m, 2 H) 8.45 8.65 (m, 1 H) 9.02-9.10 (m, 1 H) 9.18 - 9.28 (m, 1 H) 9.51 - 9.60 (m, 1 H) 12.14-12.47 (m, 1 H)

521

Example 1.230

[1124] Synthesis of 2-[[2-(4-ethoxypyridin-2-yl)-5I-L6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide (Compound 223)

[1125] Compound 223 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethyIstannyOpyridine with in situ made 4-ethoxy-2-(trimethylstannyi)pyridine and replacing oxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+l ] ⁺ m/z: 435. 'H NMR (300 MHz, DMSO-d6) 5 10.28 (s, IH), 8.46 (d, 7= 5.7 Hz, I H), 8.35 (d, 7= 2.6 Hz, IH), 7.89 (dd, 7= 8.9, 2.7 Hz, 1 H), 7.78 (d, 7= 2.6 Hz, I H), 7.06 (dd, 7= 5.6, 2.6 Hz, IH), 6.78 (d, 7= 8.8 Hz, IH), 4.42 (s, 2H), 4.06 (q, 7= 7.0 Hz, 2H), 3.80 (s, 3H), 3.40 (s, 3H), 3.23 (t, 7= 7.3 Hz, 2H), 2.86 (t, 7= 7.7 Hz, 2H), 2.111.97 (m, 2H), 1.28 (t, 7= 6.9 Hz, 3H).

Example 1.231

[1126]

Synthesis of 2-({2-[4-(cyclopropylmethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 224)

( 1127] Compound 224 was synthesized similar to Compound 135 by replacing 4-methoxy-2(tnmethylstannyl)pyridine with in situ made 4-cyciopropylmethoxy-2-(trimethylstannyl)pyridine and replacing oxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+l] ⁺ m/z: 461. 'H NMR (300 MHz, DMSO-d6) δ 10.25 (s, IH), 8.42 (d, J= 5.6 Hz, IH), 8.33 (d, 7= 2.7 Hz, IH), 7.86 (dd, 7 = 8.9, 2.7 Hz, 1 H), 7.76 (d, 7= 2.5 Hz, 1 H), 6.98 (dd, 7= 5.6, 2.6 Hz, IH), 6.77 (d, 7= 8.9 Hz, IH), 4.39

522 (s,2H), 3.86 (d, 7=7.1 Hz, 2H), 3.80 (s, 3H), 3.37 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.10-1.911 (m, 2H), 1.38-1.09 (m, IH), 0.56 (q,7 = 5.5 Hz, 2H), 0.30 (d,7=5.2 Hz, 2H).

Example 1.232

[1128] Synthesis of 2-({2-[4-(difluoromethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 225)

[1129] Compound 225 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trirnethylstannyl)pyridine with in situ made 4-(difluoromethoxy)-2-(trimethylstannyl)pyridine and replacing oxo lan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+1] ⁺ m/z: 457. 'H NMR (300 MHz, DMSO-d6) δ 10.23 (br, IH), 8.63 (d, 7= 5.7 Hz, IH), 8.35 (d, 7= 2.7 Hz, IH), 7.98 (d, 7 = 2.4 Hz, IH), 7.88 (dd, 7= 9.0, 2.7 Hz, IH), 7.49 (t, 7= 72.6 Hz IH, C//F2), 7.26 (dd, 7= 5.7, 2.4 Hz, IH), 6.75(d,7= 9.0 Hz, IH), 4.43 (s, 2H), 3.80 (s, 3H), 3.37(s, 3H), 3.21 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.07-1.96 (m, 2H).

Example 1.233

[1130] Synthesis of N-tert-butyl-2-[(2-{2H-[l,3]dioxolo[4,5-c]pyridin-6-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 226)

[1131] Compound 226 was synthesized similar to Compound 24 by replacing 4-methyl-2(tributylstannyl)pyridine with 6-(trimethylstannyl)-[l,3]dioxolo[4,5-c]pyridine. LCMS (ES) [M+l]⁺m/z: 384. Ή NMR (300 MHz, DMSO-7_É) δ 8.20 (s, 1 H), 7.95 (s, IH), 7.71 (s, 1 H), 6.20 (s, 2H), 4.10 (s,

523

2H), 3.32 (s, 3H), 3.14 (t, J= 7.4 Hz, 2H), 2.79 (t, 7= 7.9 Hz, 2H), 2.05 - 1.89 (m, 2H), 1.25 (s, 9H).

Example l .234

[l 132] Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide (Compound 227)

[l 133] Compound 227 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 3-(tributylstannyl)isoquînoline and replacing oxo lan-3-amine with 5amino-2-methoxypyridine. LCMS (ES) [M+l] ⁺ m/z: 457. 'H NMR (300 MHz, DMSO-d6) δ 10.23 (br, IH), 8.63 (d, 7= 5.7 Hz, IH), 8.35 (d,7= 2.7 Hz, IH), 7.98 (d,7 = 2.4 Hz, IH), 7.88 (dd, 7= 9.0, 2.7 Hz, IH), 7.49 (t,7= 72.6 Hz 1H,C/7F2), 7.26 (dd,7=5.7, 2.4 Hz, IH), 6.75(d, 7= 9.0 Hz, IH), 4.43 (s, 2H), 3.80 (s, 3H), 3.37(s, 3H), 3.21 (t, 7= 7.5 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.07-1.96 (m, 2H).

Example 1.235

[1134] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyc]openta[d]pyrimidin-4 yl](methyl)amino}-N-(6-methoxypyridin-3-yl)acetamide (Compound 228)

[1135] Compound 228 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 3-(tributylstannyl)isoquincline and replacing oxolan-3-amine with 3aminopyridine. . LCMS (ES) [M+l] ⁺ m/z: 411. Ή NMR (300 MHz, DMSO-d6) δ 9.48 (s, IH), 9.28 (d, J = 2.4 Hz, IH), 9.14 (s, IH), 8.82 (s, IH), 8.52 (s, IH), 8.33-8.20(m, 2H), 8.00 (t, J = 7.1 Hz, 1H), 7.937.79 (m, 2H), 4.90 (s, 2H), 3.57 (s, 3H), 3.38-3.19 (s, 2H), 3.18-2.99 (m, 2H), 2.09-2.00 (m, 2H).

524

Example L236 |Ί I36] Synthesis of N-(6-niethoxypyridin-3-yl)-2-[methyl([2-[4-(trifluoiOmethoxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 229)

[l 137] Compound 229 was synthesized similar to Compound 135 by replacing 4-methoxy-2(tri methy lstannyl)py ri dîne with 4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine and replacing oxolan3-amine with 5-amino-2-methoxypyridtne . LCMS (ES) [M+l] ⁺ m/z: 475. 'H NMR (300 MHz.

DMSO-d6) δ 10.22 (s, IH), 8.75 (d, 7= 5.5 Hz, 1 H), 8.36 (t, 7= 2.2 Hz, IH), 8.09 (d, 7= 2.37 Hz IH), 7.87 (ddd,7=8.9, 2.8, 1.3 Hz, 1 H), 7.46 (dd, 7= 5.3, 2.1 Hz, 1 H), 6.77 (d, 7= 8.8 Hz, 1 H), 4.41 (s, 2H), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t,7= 7.3 Hz, 2H), 2.85 (t, 7= 7.8 Hz, 2H), 2.10-1.922 (m, 2H).

Example 1.237

[1138] Synthesis ofN-(6-methoxypyridin-3-yl)-2-[methyI({2-[4-(trifluoromethoxy)pyridin-2-yI]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 230)

[1139] Compound 230 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 4-(trifluoromethoxy)-2-(trimethylstannyl)pyridine and replacing oxolan3-amine with 5-amino-2-methoxypyridine . LCMS (ES) [M+l] ⁺ m/z: 475. NMR (300 MHz, DMSO-d6)Ô 10.22 (s, IH), 8.75 (d,7= 5.5 Hz, IH), 8.36 (t, 7= 2.2 Hz, IH), 8.09 (d, 7= 2.37 Hz IH), 7.87 (ddd, 7= 8.9, 2.8, 1.3 Hz, 1 H), 7.46 (dd, 7= 5.3, 2.1 Hz, IH), 6.77 (d, 7= 8.8 Hz, l H), 4.41 (s, 2H), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t, 7= 7.3 Hz, 2H), 2.85 (t, 7= 7.8 Hz, 2H), 2.10-1.922 (m, 2H).

525

Example 1.238

[l 140] Synthesis of2-[methyl({2-[4-(trifluoromethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 231)

[1141 ] Compound 231 was synthesized similar to Compound 135 by replacing 4-methoxy-2- (trimethylstannyl)pyridine with 4-(trifluorornethoxy)-2-(trimethyIstannyl)pyridine and replacing oxolan3-amine with I-methy Ipyrazol-4-amine. LCMS (ES) [M+l] ⁺ m/z: 448, *H NMR (300 MHz, DMSOd6) δ 10.16(s, IH), 8.78 (d, J= 5,6 Hz, IH), 8,l0(d,7=2.3 Hz, IH), 7.82 (s, IH), 7.47 (dd, 7= 5.7, 1.4 Hz, IH), 7.39 (s, IH), 4.36 (s, 2H), 3.75 (s, 3H), 3.28 (s, 3H), 3.26-3.13 (m, 2H), 2.85 (t, 7= 7.8 Hz,

2H), 2.10-1.93 (m,2H).

Example 1.239

[1142] Synthesis of 2-[methyl(2-{ lH-pyrazolo[3,4-c]pyndîn-5-yl}-5H,6IL7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(l-methyl-lH-pyrazol-3-yI)acetamide (Compound 232)

[1 143] Compound 232 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 5-(trimethylstannyl)-l H-pyrazolo[3,4-c]pyridine and replacing oxolan3-amine with 2-methylpyrimidin-5-amine. LCMS (ES) [M+l] ⁺ m/z: 404. 'H NMR (300 MHz, DMSOd6) δ 13.67 (s, IH), 10.68 (s, IH), 9.08 (s, IH), 8.68 (d,7= 1.4 Hz, IH), 8.12 (s, IH), 7,52 (d,7= 2.3 Hz, IH), 6.41 (d,7=2.3 Hz, JH), 4.41 (s, 2H), 3.76 (s, 3H), 3.38 (s, 3H),3.I8 (t,7= 7.4 Hz, 2H), 2.83 (t,7=

7.8 Hz, 2H), 2.03-1.98 (m, 2H).

526

Example 1.240

[l 144] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(5-methoxypyridin-2-yl)acetamide (Compound 233)

H

Cto „ N

[l 145] Compound 233 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with 5methoxypyridin-2-amine. LCMS (ES) [M+l] ⁺ m/z: 441. Ή NMR (300 MHz, DMSO-d6) δ 10.71 (s, IH), 9.35 (s, IH), 8.72 (s, IH), 8.16 (0.4 HCOOH), 8.14 (d, J= 7.8 Hz, IH), 8.10 (d, 7= 3.0 Hz, IH), 7.99 (d, 7= 9.0 Hz, IH), 7.85-7.63 (m, 3H), 7.38 (dd, 7= 9.1, 3.1 Hz, IH), 4.51 (s,2H), 3.79 (s, 3H), 3.41 (s, 3H), 3.22 (t, 7= 7.3 Hz, 2H), 2.87 (t, 7= 7.8 Hz, 2H), 2.07-1.98 (m, 2H).

Example 1.241

[1146] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4 yl](methyl)amino}-N-[6-(trifluoromethoxy)pyridin-3-yl]acetamide (Compound 234)

[1147] Compound 234 was synthesized similar to Compound 135 by replacing 4-methoxy-2- (trimethylstannyl)pyridine with 3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with 6 (trifluoromethoxy)pyridin-3-amine. LCMS (ES) [M+l] ⁺ m/z: 495. 'H NMR (300 MHz, DMSO-d6) δ 11.51 (br, IH), 9.56 (s, IH), 9.10 (s, 1 H), 8.70 (s, IH), 8.32 (d, 7= 8.1 Hz, 2H), 8.10 (s, IH), 7.98-7.85 (m, 2H), 7.27 (d, J = 8.8 Hz, IH), 4.83 (s, 2H), 3.63 (s, 3H), 3.37-3.22 (m, 2H), 3.11 (t, J = 8.0 Hz, 2H), 2.20-2.09 (m, 2H).

527

Example l .242

[l 148] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(5-methylpyridin-3-yl)acetamide (Compound 235)

[l 149] Compound 235 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridtne with 3-(trîbutylstannyl)isoquinoline and replacing oxolan-3-amine with 5methylpyridin-3-amine. LCMS (ES) [M+l] ³ m/z: 425. ’HNMR (300 MHz, DMSO-d6) δ 10.52 (s, IH), 9.36 (s, IH), 8.72 (s, 1H),8.6I (d, 7=2.4 Hz, I H), 8.20-8.11 (m, 2H), 8.08 (d,7= 1.9 Hz, IH), 7.92 (s, IH), 7.85-7.64 (m, 3H), 4.48 (s, 2H), 3.43 (s, 3H), 3.24 (s, 2H), 2.88 (t, J= 7.8 Hz, 2H), 2.21 (s, 3H), 2.07-2.01 (m, 2H).

Example 1.243

[1150] Synthesis of2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](tnethyl)amino}-N-(l-methyl-lH-imidazol-4-yl)acetamide (Compound 236)

[1151] Compound 236 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 3-(tnbutylstannyl)isoquinoline and replacing oxoIan-3-amine with 1methylimidazol-4-amine. LCMS (ES) [M+l ] ⁺ m/z: 414.3. ^!H NMR (300 MHz, DMSO-d6) δ 10.61 (s, iH), 9.37 (d, 7= 3.1 Hz, IH), 8.71 (d, 7= 2.9 Hz, IH), 8.15 (dd, 7= 8.1, 3.1 Hz, 1 H), 7.95-7.86 (m, IH), 7.82-7.64 (m, 2H), 7.41 (t,7= 2.1 Hz, IH), 7.20- 7.11 (m, IH), 4.44 (s, 2H), 3.57 (s, 3H), 3.38 (s, 3H), 3.19 (t, 7= 7.4 Hz, 2H), 2.86 (d, 7= 7.7 Hz, 2H), 2.05-2.01 (m, 2H).

528

Example 1.244

[l 152] Synthesis of2-{[2-(isoquinolin-3-yI)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(l-methyl-lH-pyrazol-3-yl)acetamide (Compound 237)

[l 153] Compound 237 was synthesîzed similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridîne with 3-(tributylstannyl)isoquinoline and replacing oxolan-3-amine with lmethylpyrazol-3-amine. LCMS (ES) [M+l] ⁺ m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 10.75 (s, IH), 9.37 (s, IH), 8.69 (s, IH), 8.15 (d, 7=8.3 Hz, IH), 7.88 (d, 7= 8.1 Hz, IH), 7.83-7.74 (m, IH), 7.74-7.66 (m, IH), 7.52 (d, 7= 2.3 Hz, IH), 6.42 (d,7= 2.2 Hz, IH), 4.42 (s, 2H), 3.77 (s, 3H), 3.40 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H), 2,86 (t, 7= 7.8 Hz, 2H), 2.08-2.00 (m, 2H).

Example l .245

[l 154] Synthesis of 2-({2-[4-(2-methoxyethoxy)pyridm-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(metbyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 238)

[l 155] Compound 238 was synthesîzed similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine and replacing oxolan-3-amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+l] ⁺ m/z: 465. *H NMR (300 MHz, DMSO-d6) δ 10.29 (s, IH), 8.46 (d,7=5.7 Hz, IH), 8.35 (d, 7= 2.7 Hz, IH), 8.l4(s, HCOOH), 7.89 (dd, 7=9.0, 2.7 Hz, IH), 7.79 (d, 7= 2.7 Hz, IH), 7.05 (dd, J= 5.7, 2.7 Hz, I H), 6.78 (d, 7= 9.0 Hz, IH), 4.42 (s, 2H), 4.16-4.09 (m, 2H), 3.81 (s, 3H), 3.62-3.60 (m, 2H), 3.39 (s, 3H), 3.29 (s, 3H), 3.22 (t, 7= 7.2 Hz, 2H), 2.85 (t, 7= 7.8 Hz, 2H), 2.07-1.96 (m, 2H).

529

Example l .246

[l156] Synthesis of N-tert-buty 1-2-( {2-[4-(2-methoxy ethoxy )pyridin-2-y l]-5 H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 239)

[Il 57] Compound 239 was synthesized similar to Compound 24 by replacing 4-methyl-2(trimethylstannyl)pyridine with 4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+l] ⁺m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 8.48 (d, J= 5.7 Hz, IH), 8.14 (s, HCOOH), 7.86 (d, 7 = 2.4 Hz, JH), 7.69 (s, IH), 7.06 (dd, 7= 5.7, 2.7 Hz, IH), 4.27-4.24 (m, 2H), 4.13 (s, 2H), 3.72-3.69 (m, 2H), 3.32 (s, 3H), 3.27 (s, 3H), 3.15 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.05-1.94 (m, 2H), 1.25 (s, 9H).

Example 1.247

[1158] Synthesis of N-(5-fluoropyridin-3-yl)-2-{[2-(isoquinoiin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 240)

[Il 59] Compound 240 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyridine with 4-(2-methoxyethoxy)-2-(trimethylstannyl)pyridine and replacing oxolan-3-amine with 5-fluoropyridin-3-amine. LCMS (ES) [M+l] ⁺ m/z: 429.2. *H NMR (300 MHz, DMSO-d6) δ 10.87 (s, IH), 9.35 (s, IH), 8.71 (s, IH), 8.63 (t,7= 1.7 Hz, IH), 8.25 (d,7= 2.6 Hz, IH), 8.20-8.03 (m, 3H), 7.81 (d,7=8.3 Hz, IH), 7.82-7.64 (m, 2H), 4.51 (s, 2H), 3.43 (s,3H), 3.24 (t,7=7.3

Hz, 2H), 2.88 (t, 7= 7.8 Hz, 2H), 2.04 (p, 7= 7.6 Hz, 2H).

530

Example L248

[ Η 60] Synthesis of N-tert-buty 1-2-( {2-[4-(2-fluoroethoxy)pyridin-2-yl]-5 H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 241)

[1161] Compound 241 was synthesized similar to Compound 24 by replacing 4-melhyl-2(trimethylstannyl)pyridine with 4-(2-fluoroethoxy)-2-(trimethyIstannyl)pyridine. LCMS (ES) [M+l] ⁺m/z: 429.2. Ή NMR (300 MHz, DMSO-d6) δ 8.50 (d, J= 5.6 Hz, IH), 7.89 (d, J= 2.6 Hz, IH), 7.69 (s, IH), 7.08 (dd, J= 5.6, 2.6 Hz, IH), 4.91-4.82 (m, 1 H), 4.75-4.66 (m, 1 H), 4.48-4.44 (m, IH), 4.404.31 (m, IH), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J= 7.4 Hz, 2H), 2.81 (t, J= Ί.9 Hz, 2H), 2.02-1.97 (m, 2H), 1.24 (s, 9H).

Example 1.249

[1162] Synthesis of 2-({2-[4-(2-fluoroethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 242)

[1163] Compound 242 was synthesized similar to Compound 135 by replacing 4-methoxy-2(trimethylstannyl)pyndine with 4-(2-(1 uoroethoxy)-2-(trimethylstannyl)pyridîne and replacing oxolan-3amine with 5-amino-2-methoxypyridine. LCMS (ES) [M+l] ⁺ m/z: 453. 'H NMR (300 MHz, DMSOd6) δ 10.27 (s, 1 H), 8.46 (d, 7= 5.6 Hz, 1 H), 8.36 (d,7= 2.6 Hz, 1 H), 7.88 (dd, 7= 8.9, 2.7 Hz, IH), 7.80 (d, J= 2.6 Hz, IH), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 6.77 (d, 7= 8.9 Hz, IH), 4.84-4.75 (m, IH), 4.65-4.62 (m, IH), 4.40 (s, 2H), 4.37-4.30 (m, IH), 4.28-4.19 (m, IH), 3.80 (s, 3H), 3.38 (s, 3H), 3.22 (t, 7= 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.04-1.99 (m, 2H).

l

Exampie L250

[l 164] Synthesis of 2-({2-[4-(2-iluüiOethoxy)pyridin-2-yl]-5H,6H,7H-cyc!openta[d]pyrimidin-4yl}(methyl)amino)-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 243)

[l165] Compound 243 was synthesized similar to Compound I35 by replacing 4-methyl-2(trimethylstannyl)pyridine with 4-(2-fluoroethoxy)-2-(trimethylstannyl)pyridine and replacing oxo lan-3 amine with l-methylpyrazol-4-amine. LCMS (ES) [M+l] ⁺ m/z: 426. Ή NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1H), 8.48 (d, 7= 5.6 Hz, IH), 7.84 (s, IH), 7.78 (d, 7= 2.6 Hz, IH), 7.40 (s, IH), 7.05 (dd,7= 5.6, 2.6 Hz, 1 H), 4.85-4.79 (m, 11-1),4.69-4.62 (m, 1 H), 4.36-4.32 (m, 3H), 4.28-4.21 (m, IH), 3.76 (s,

3H), 3.35 (s, 3H), 3.20 (t, 7= 7.4 Hz, 2H), 2.83 (t, 7= 7.9 Hz, 2H), 2.05-1.95 (m, 2H).

Example 1.251

[1166] Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(l,7-naphthyridin-6-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 244)

532

NB S, CCI₄B0°C. 5 h

TMSCN.KjCOj

CH₃CN, 50°C. 12 h NC

NaNOj, HCl CuCI, 0-50°C

Pd/C, H₂KOH, EtOH, rt 2h

Sn₂Me₆. Pd(dppf)CI_;dioxane, 100°C, 12 h

Scheme 107

Step 1

NBS, CCI₄80°C, 5 h

[1167] Intoa IL round-bottom flask were placed 3-methylpyridine-2-carbonîtrile (12.00 g, 101,58 mmol, 1.00 equiv), NBS (36.10 g, 203,16 mmol, 2.00 equiv), CCU (500.00 mL) and AIBN (1.67 g, 10.16 mmol, 0.10 equiv). The resulting solution was stirred for 5 h at 80 °C. The reaction solution was cooled to room température, concentrated to remove the solvent. The residue was purified by silica gel column with ethyl acetate/petroleum ether (1/2). This resulted in 9.0 g (45%) of 310 (bromomethyl)pyridine-2-carbonitrile as yellow oil. LCMS (ES) [M+l]⁺ m/z: 197.

Step 2

TMSCN,K₂CO₃CH₃CN, 50°C, 12 h

[1168] Into a 250-mL round-bottom flask were placed 3-(bromomethyl)pyridine-2-carbonitrile (9.00 g, 45.68 mmol, 1.00 equiv), CH3CN (100.00 mL), TMSCN (13,59 g, 136.99 mmol, 3,00 equiv) and

K2CO3 (12.62 g, 91.31 mmol, 2.00 equiv). The resulting solution was stirred for 12 h at 50 °C. The

533 reaction was cooled to room température, filtered and the fîltrate was concentrated, the residue was purified by silica gel column with ethyl acetate/petroleum ether (2/3). This resulted in 3.0 g (46%) of3( cy anomethy l)pyridine-2-carbon itri le as a yellow solid. LCMS (ES) [M+l]⁺ m/z: ]44.

Step 3

HBr, HOAc rt, 1 h

[ 1169] Into a 100-mL 3-necked round-bottom flask were placed HBr (40% in H₂O) (20.00 mL), HOAc (20.00 mL), 3-(cyanomethyI)pyridine-2-carbonitrîle (3.00 g, 20.96 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room température. The solution was filtered, and the fîltrate was diluted with of H₂O (20.00 mL), the pH value of the solution was adjusted to 7 with NaHCOs solid, extracted with 3x50 inL of ethyl acetate. The combined organic phase was dried over anhydrous sodium sulfate, filtered and the fîltrate was concentrated in vacuum. This resulted în 2.2 g (47%) of 8-bromol,7-naphthyrîdin-6-amine as yellow oil. LCMS (ES) [M+1 ]^r m/z: 224.

Step 4

Pd/C, H₂

KOH, EtOH, rt

[1170] Into a 250-mL round-bottom flask were placed 8-bromo-l,7-naphthyridin-6-amîne (2.20 g, 9.82 mmol, 1.00 equiv), EtOH (100.00 mL), KOH (663 mg, 11.82 mmol, 1.20 equiv), Pd/C (300 mg). The mixture was stirred for 2 h at room température under atmosphère of hydrogen at pressure at 2~3 atm, filtered through the celite and the fîltrate was concentrated in vacuum. This resulted in 1.3 g (92%) of l,7-naphthyridin-6-amine as yellow oil. LCMS (ES) [M+l]⁺ m/z: 146.

Step 5

NaNO₂, HCl O°C-rt

[1171] Into a 250-mL 3-necked round-bottom flask were placed l,7-naphthyridin-6-amine (1.30 g,

534

8.97 mmol, 1.00 equiv), HCl (c) (40.00 mL). This was followed by the addition of NaNCb (1.36 g, 19.73 mmol, 2.20 equiv) at 0 °C and stirred for 30 min. To this mixture was added CuCl (897 mg, 8.97 mmol, 1.00 equiv), the resulting solution was stirred for an additional 2 h at room température. The pH value of the solution was adjusted to 7 with NaOH (4 N) at 0 °C, extracted with 3x50 mL of ethyl acetate. The combined organic phases were dried over anhydrous sodium sulfate, fïltered and the fîltrate was concentrated under reduced pressure. The residue was purified by silica gel column with ethyl acetate/petroleum ether (40%). This resulted in 530 mg (36%) of 6-chloro-l,7-naphthyridine as yellow oil. LCMS (ES) [M+l]⁺ m/z: 165.

Step 6

SriaMeg, dioxane 100°C,3 h

Me₃Sn

[1172] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen were placed 6chloro-l,7-naphthyridine (530 mg, 3.22 mmol, 1.00 equiv), dioxane (10.00 mL), SnsMeô (1.16 g, 3.54 mmol, 1.10 equiv) and Pd(dppf)Ch (234 mg, 0.32 mmol, 0.10 equiv). The mixture was stirred for 3 h at 100 °C. The mixture was used to the next step directly without purification. LCMS (ES) [M+l]⁺ m/z;

295.

Step 7

[1173] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen were placed 6(trimethylstannyl)-l,7-naphthyridine (reaction solution of last step), dioxane (5.00 mL), ethyl 2-([2chloro-5H,6H,7H-cyciopenta[d]pyrimidin-4-yl](methyl)amino)acetate (350 mg, 1.30 mmol, 0.70 equiv) and Pd(dppf)Ch (139 mg, 0.19 mmol, 0.10 equiv). The mixture was stirred for 12 h at 100 °C. The resulting mixture was cooled to room température, concentrated to remove the solvent. The residue was

535 purified by silica gel column with THF/PE (80%). This resulted in 507 mg (75%) of ethyl N-(2-(l,7naphthyridin-6-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate as yellow oil.

LCMS (ES) [M+i]⁺ m/z: 364.

Step 8

[l 174] Into a 40-mL vial were placed ethyl 2-[methyl[2-(l,7-naphthyridin-6-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino] acetate (507 mg, 1.40 mmol, 1.00 equiv), EtOH (5.00 mL), LiOHELO (117 mg, 2.79 mmol, 2.00 equiv) and H₂O (10.00 mL). The resulting solution was stirred for 1 h at room température. The reaction solution was concentrated and purified by Prep-HPLC with the following conditions: Column, C 18-120 g, Mobile phase, Water and CH3CN 5% increased to 10% within 9 min, Detector, 254 nm. The fraction was freezing dried, this resulted in 161 mg (34%) of lithio 2-[methyl[2-(l,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetate as a white solid. LCMS (ES) [M-Li+1]⁺ m/z: 336.

Step 9

[1175] Into a 8-mL vial were placed lithio 2-[methyl[2-(l,7-naphthyridin-6-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetate (161 mg, 0.47 mmol, 1.00 equiv), DMF (4.00 mL), 5-amino2-methoxypyridine (70 mg, 0.57 mmol, 1.20 equiv), DIEA (122 mg, 0.95 mmol, 2.00 equiv) and HATU (215 mg, 0.57 mmol, 1.20 equiv). The resulting solution was stirred for 2 h at room température. The reaction solution was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep C18

~ 536

OBD Column, 50*250 mm 5um, Mobile phase, Water (O.l%FA) and CH₃CN (5% Phase B up to 30% in 15 min), Detector, UV 254 nm. This resulted in 89.6 mg (43.02%) ofN-(6-methoxypyridin-3-yl)-2{methyl[2-(l,7-naphthyridin-6-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide as an offwhite solid. LCMS: (ES, m/z) [M+H]⁺: 442. Ή NMR (300 MHz, DMSO-d6) δ 10.35 (s, IH), 9.44 (s, 5 IH), 9.07 (dd, 7= 4.2, L5 Hz, IH), 8.82 (s, IH), 8.39 (d, 7= 2.7 Hz, IH), 8.33 (d, 7= 8.4 Hz, IH), 8.15 (s, IH), 7.93 (dd, 7= 9.0, 2.7 Hz, IH), 7.79 (dd, 7= 8.4, 4.2 Hz, IH), 6.77 (d, 7= 9.0 Hz, IH), 4.48 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.24 (t, 7= 7.5 Hz, 2H), 2.88 (t, 7= 7.8 Hz, 2H), 2.09-1.98 (m, 2H).

Example L252

[1176] Synthesis of (2R)-3-methyl-N-(l-methyl-lH-pyrazol-4-yl)-2-{methyI[2-(pyridin-2-yi)10 5H,6H,7Il-cyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 246)

cy Oz¹ Y Çi h₂n+'Z 1 . , ZY J* D1EA, NMP NaH. DMF ^N '^c| \ JL JL 'n Za V^H NaOH/MeOH/H,O 'N'Y ί R Il NU CC3A + f j n.A <

O j NH Μ Λ J । Assumed B] ^N A 0^0^ °γ°^~ ^{e u} X vy U Ύι Pd(dppf)CI₂, dioxane /A| T \Jl JL A+Zî ^{N Cl} nJI φ Φ ^σγ^ΝΗ CHIRAL-HPLC °y^NH xJ] 1 Assumed + zj

Scheme 108

537

Step l

[l 177] Into a 40-mL vial were placed 2,4-dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (2.00 g, 10.58 mmol, l.OO equiv), methyl (2R)-2-amino-3-methyIbutanoate (1.67 g, 12.73 mmol, 1.20 equiv),

NMP (20.00 mL) and DIEA (4.10 g, 31.74 mmol, 3.00 equiv). The resulting solution was stirred for ovemight at 80 °C. The crude product (4 g) was purified by Prep-HPLC with the foilowing conditions: Column, XBridge Prep Cl 8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% HCOOH) and CAN (50% Phase B up to 90% in 11 min); Detector, 254 nm. This resulted in 2.2 g (73.28%) of methyl (2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinate as a yellow solid. LCMS (ES)

[M+l]⁺ m/z: 284.

Step

[1178] Into a 100-mL 3-necked round-bottom flask were placed methyl (2-chloro-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)valinate (2.20 g, 7.75 mmol, 1.00 equiv), DMF (30.00 mL). This was followed by the addition of NaH (0.28 g, 11.67 mmol, 1.50 equiv) in portions at 0 °C. To this was added methyl iodide ( 1.32 g, 9.30 mmol, 1.20 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 2 h at room température. The reaction was then quenched by the addition of 20 mL of water/ice, extracted with 3x30 mL of ethyl acetate. The organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (6%). This resulted in 1.9 g (82.30%) of methyl N-(2-chloro-6,7-dihydro-5H-

538 cyclopenta[d]pyrimidin-4-yl)-N-methylvalinate as yellow solid. LCMS (ES) [M+l]* m/z: 298.

Step

[1179] Into a 100-mL round-bottom flask were placed methyl N-(2-chloro-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-y!)-N-methylvalinate (1.90 g, 6.38 mmol, 1.00 equiv), 2(tributylstannyl)pyrîdine (3.05 g, 8.28 mmol, 1.30 equiv), dioxane (30.00 mL) and Pd(dppf)Ch (0.47 g, 0.64 mmol, 0.10 equiv). The resulting solution was stirred for ovemight at 100 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF/PE (70-100%). This resulted in 1.5 g (69.06%) of methyl N-methyl-N-(2-(pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)valinate as yellow oil. LCMS (ES) [M+l]+ m/z: 341.

Step 4

[1180] Into a 100-mL round-bottom flask were placed methyl N-methyl-N-(2-(pyridin-2-yl)-6,715 dihydro-5H-cyclopenta[d]pyrimidin-4-yl)valinate (1.50 g, 4.41 mmol, 1.00 equiv), MeOH (10.00 mL),

H2O (10.00 mL). This was followed by the addition ofNaOH (0.35 g, 8.85 mmol, 2.00 equiv), in portions at 0 °C. The resulting solution was stirred for ovemight at room température. The pH value of the solution was adjusted to 5-6 with citric acid. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl8 OBD Column, 19cm, 150mm, 5um; mobile 20 phase, Water (0.1 % HCOOH) and CAN ( 10% Phase B up to 40% in 11 min); Detector, 254 nm. This resulted in 800 mg (55.63%) of 3-methyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin21052

539

4-yl]amino]butanoic acid as yellow solid. LCMS (ES) [M+l]' m/z: 327.

Step 5

[l 181 ] Into a 40-mL vial were placed 3-methyl-2-[methyl[2-(pyridin-2-yl)-5H,6H,7H5 cyclopenta[d]pyrimidin-4-yl]amino]butanoic acid (330.00 mg, LOI mmol, 1.00 equiv), 5-amino-2methoxypyridine (125.51 mg, 1.01 mmol, 1.00 equiv), DMF (5.00 mL) and DIEA (261.34 mg, 2.02 mmol, 2.00 equiv). This was followed by the addition of TjP (386.03 mg, 1.21 mmol, 1.20 equiv) in portions at 0°C. The resulting solution was stirred for 3 h at room température. The crude product (1 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 10 19cm, 150mm, 5um; mobile phase, Water (0.1%NHyH2O) and CAN (50% Phase B up to 90% in 11 min); Detector, 254 nm. This resulted in 310 mg (70.89%) ofN-(6-methoxypyridin-3-yl)-3-methyl-2[methy![2-(pyridin-2-yI)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]butanamide as white solid.

LCMS (ES) [M+lf m/z: 433.

[1182] The crude product (310 mg) was purified by Prep-CHIRAL-HPLC with the following conditions: Column, CH1RALPAK IC, 20*250 mm, 5pm; mobile phase, n-Hexane/DCM=5/l and IPA (15% in 25 min); Detector, 254 nM. This resulted in 83.7mg (27.00%) of (2R)-3-methyl-N-(l-methyl21052

540 l H-pyrazol-4-y 1)-2 -{methy l[2-(pyrid in-2-y 1)-5 H, 6H,7H-cyc lopenta[d]pyrim idin-4yl]amino}butanamide as white solid. Chiral HPLC rétention time: 3.83 min (condition: Column, YMC Cellulose-SB, 100*4.6 mm, 3μιη; mobile phase, n-Hexane/DCM=5/l and isopropanol (10% in 6 min)). LCMS (ES, m/z): [M+H]⁺: 433. Ή NMR (300 MHz, DMSO-d6) δ 10.75 (s, IH), 8.80-8.71 (m, IH),

8.42 (d, J = 7.9 Hz, IH), 8.31 (d, J = 2.6 Hz, IH), 8.04-7.87 (m, 2H), 7.60-7.50 (m, IH), 6.76 (d, J = 8.9

Hz, IH), 4.75 (d, J = 1L1 Hz, 1H),3.78 (s, 3H), 3.29-3.21 (m, IH), 3.18 (s, 3H), 3.15-3.01 (m, IH), 3.01-2.74 (m, 2H), 2.49-2.39 (m, 1 H), 2.14-1.95 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H).

Example 1.253

[Il 83] Synthesis of (2S)-N-(6-methoxypyridin-3-yl)-3-methyl-2-{methyl[2-(pyridin-2-y!)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 247)

[Il 84] The crude product from compound 246 step 1(310 mg) was purified by Prep-CHIRALHPLC with the following conditions: Column, CHIRALPAK IC, 30*250 mm, 5gm; mobile phase, n21052

~ 541

Hexane/DCM=5/l and IPA (15% in 25 min); Detector, 254. This resulted in lO5.5mg (34.03%) (2S)-N(6-methoxypyridin-3-yl)-3-methyl-2-{methyl[2-(pyridin-2-yE)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}butanamide as white solid. Chiral HPLC rétention time: 5.19 min (condition: Column, YMC Cellulose-SB, 100*4.6 mm, 3pm; mobile phase, n-Hexane/DCM=5/l and isopropanol (10% in 6 min)).

LCMS (ES, m/z): [M+H]⁺:433. Ή NMR (300 MHz, DMSO-d6) δ 10.74 (s, 1H),8.75 (dt, J = 4.6, 1.5 Hz, IH), 8.42 (dt, J = 8.0, 1.2 Hz, IH), 8.31 (d, J = 2.6 Hz, IH), 8.04-7.87 (m, 2H), 7.55 (ddd, J = 7.5, 4.8, 1.3 Hz, IH), 6.76 (d, J = 8.9 Hz, 1 H), 4.75 (d, J = 11.0 Hz, IH), 3.78 (s, 3H), 3.30-3.20 (m, IH), 3.18 (s, 3H), 3.15-3.01 (m, IH), 3.01-2.74 (m, 2H), 2.51-2.37 (m, 1 H), 2.17-1.91 (m, 2H), 1.02 (d, J = 6.4 Hz, 3H), 0.94 (d, J = 6.6 Hz, 3H).

Example 1.254

[1185] Synthesis of (2R)-3-methyl-N-( 1-methyl-l H-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 248)

[1186] Compound 248 was synthesized similar to Compound 246 replacing 5-amino-2- methoxypyridine with l-methylpyrazol-4-amine. Chiral HPLC rétention time: 3.68 min (condition: Column, YMC Cellulose-SB, 100*4.6 mm, 3pm; mobile phase, n-Hexane and éthanol (10% in 8 min)). LCMS (ES) [M+l] ⁺ m/z: 406. Ή NMR (300 MHz, DMSO-d6) δ 10.78 (s, IH), 8.85 (ddd, J = 4.8, 1.7, 0.7 Hz, IH), 8.41 (dt, J = 7.9, 1.2 Hz, IH), 7.99 (td, J = 7.7, 1.8 Hz, IH), 7.88 (s, 1 H), 7.57 (ddd, J = 7.5, 4.8, 1.3 Hz, IH), 7.34 (s, IH), 4.70 (d, J = 1L1 Hz, 1 H), 3.75 (s, 3H), 3.23 (dt, J = 15.9, 8.0 Hz, IH),

3.16 (s, 3H), 3.14-3.00 (m, IH), 3.00-2.74 (m, 2H), 2.49-2.35 (m, IH), 2.15-1.90 (m, 2H), 0.97 (d, J =

6.4 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H).

Example 1.255

[1187] Synthesis of (2R)-3-methyl-N-(l-methyl-lH-pyrazol-4-yl)-2-{methyl[2-(pyridin-2-yl)-

542

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}butanamide (Compound 249)

[l 188] Compound 249 was synthesized similar to Compound 247 replacing 5-amino-2methoxypyridine with l-methylpyrazol-4-amine. Chiral HPLC rétention time: 4.82 min (condition:

Column, YMC Cellulose-SB, 100*4,6 mm, 3gm; mobile phase, n-Hexane and éthanol (10% in 8 min)). LCMS (ES) [M+l] ⁺ m/z: 406. Ή NMR (300 MHz, DMSO-d6) Ô 10.78 (s, IH), 8.85 (dt, J = 5.1, 1.2 Hz, IH), 8.41 (dt,J = 7.9, 1.1 Hz, IH), 7.99 (td, J = 7.7, 1.7 Hz, 11-1),7.88 (s, 1 H), 7.57 (ddd, J = 7.5, 4.7, 1.3 Hz, IH), 7.35 (s, 1 H), 4.70 (d, J = 11.0 Hz, 1H),3.75 (s, 3H), 3.23 (dt, J = 16.0, 8.1 Hz, IH), 3.16 (s, 3H), 3.14-3.00 (m, 1 H), 3.00-2.74 (m, 2H), 2.49-2.35 (m, IH), 2.16-1.90 (m, 2H), 0.97 (d, J =

6.4 Hz, 3H), 0.93 (d, J = 6.6 Hz, 3H).

Example 1.256

[1189] Synthesis of (2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N-(6-methoxypyridin-3-yl)propanamide (Compound 250)

[1190] Compound 250 was synthesized similar to Compound 108 replacing Cyclohexanamine with

5-amino-2-methoxypyridine and replacing 2-(tributylstannyl)pyridine with 3(trimethylstannyl)isoquinoline. LCMS (ES) [M+l] ⁺ m/z: 455. ’H NMR (300 MHz, DMSO-d6) δ 10.61 (s, IH), 9.42 (s, 1 H), 8.85 (s, IH), 8.38 (d, J = 2.7 Hz, IH), 8.20 (d, 7= 8.4 Hz, IH), 8.17 (s, HCOOH), 8.03 (d, 7= 8.1 Hz, IH), 7.94 (dd, J= 8.7, 2.7 Hz, IH), 7.84-7.72 (m, 2H), 6.75 (d, 7= 8.7 Hz, IH), 5.38

543 (q, 7= 6.9 Hz, JH), 3.77 (s, 3H), 3.29-3.13 (m, 2H), 3.25 (s, 3H), 2.95-2.86 (m, 2H), 2.08-1.98 (m, 2H), 1.50 (d, J= 6.9 Hz, 3H).

Example 1.257

[1191] Synthesis of (2R)-N-(3-fluorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H cyclopenta[dJpyrimidin-4-yl}(methyl)amino)propanamide (Compound 251 )

Boc

HATU, DIEA, DMF 0*0 rt, 1 h

HCI(g)/ÊA rt, 1 h

DIEA, NMF, 60^aC_r4B h

Scheme 108

Step 1

Boc

HATU, DIEA, DMF

O°C~rt, 1 h

Boc

[1192] Into a 50-mL 3-necked round-bottom flask were placed (2R)-2-[(tertbutoxycarbonyl)(methyl)amino]propanoic acid (2.00 g, 9.84 mmol, 1.00 equiv), DMF (20.00 mL), 315 fluoroaniline (1.20 g, 10.82 mmol, L10 equiv) and DIEA (2.54 g, 19.68 mmol, 2.00 equiv). This was

544 followed by the addition of HATU (4.12 g, 10.82 mmol, l. 10 equiv) in several batches at 0 °C. After addition, the resulting solution was stirred for l h at room température. The reaction was quenched with 20 mL of water, extracted with 3x20 mL of ethyl acetate. The combined organic phase was washed with 3 x20 ml of brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated under 5 reduced pressure, the residue was purified by silica gel column with ethyl acetate/petroleum ether (1: l).

This resulted in 2.2 g (75%) of tert-butyl N-[(lR)-l-[(3-fluorophenyl)carbamoyl]ethyl]-Nmethylcarbamate as a white solid. LCMS (ES) [M+l]⁺ m/z: 297.

Step 2

HCI(g)/EA rt, 1 h

[1193] Info a 50-mL round-bottom flask were placed tert-butyl N-[(lR)-l-[(3fluorophenyl)carbamoyI]ethyl]-N-methylcarbamate (2.20 g, 7.42 mmol, 1.00 equiv) and DCM (10.00 mL). This was followed by the addition of HCl (g) (2 M in EA) (19.00 mL, 37.10 mmol, 5.00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 1 h at room température. The mixture was concentrated in vacuum to remove the solvent. This resulted in 1.6 g (93%) of (2R)-N-(315 f1uorophenyl)-2-(methylamino)propanamide hydrochloride as a white solid. LCMS (ES) [M-HC1+1]⁺m/z: 197.

Step 3

[1194] Into a 50-mL round-bottom flask were placed (2R)-N-(3-fluorophenyl)-2- (methy lamino)propanamide hydrochloride (1.00 g, 4.29 mmol, 1.00 equiv), NMP (20.00 mL), 2,4dichloro-5H,6H,7H-cyclopenta[d]pyrimidine (1.06 g, 5.58 mmol, 1.30 equiv) and DIEA (2.78 g, 21.49 mmol, 5.00 equiv). The resulting solution was stirred for 48 h at 60 °C in oil bath. The reaction mixture was cooled to room température, diluted with 20 mL of water and extracted with 3x20 mL of ethyl

545 acetate. The combined organic phases were washed with 3 x20 ml of brine, dried over anhydrous sodium sulfate and fîltered. The filtrate was concentrated under reduced pressure, the residue was purified by silica gel column with ethyl acetate/petroleum ether (l : l). This resulted in 1.0 g (67%) of (2R)-2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(35 fluorophenyl)propanamide as a white solid. LCMS (ES) [M+l]⁺ m/z: 349.

Step 4

[1195] Into a 100-mL three necked round bottom flask purged and maintained with an inert atmosphère of nitrogen were placed 4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyridine (Made in- situ from 2-chloro-4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridine with hexamethyldistannane) (1.60 g, 4.14 mmol, 1.00 equiv), toluene (60.00 mL), (2R)-2-([2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)propanamide (1.01 g, 2.90 mmol, 0.70 equiv), Pd(PPh₃)4 (479 mg, 0.41 mmol, 0.10 equiv). The mixture was stirred for 12 h at 105 °C in oil bath. The reaction mixture was cooled to room température, concentrated to remove the solvent, the residue was purified by silica gel column with dichloromethane/methanol (10:1). This resulted in 190 mg (9%) of (2R)-N-(3-fluorophenyl)-2-[methyl([2-[(2E)-3-[2-(oxan-2-yloxy)ethoxy]but-2-enimidoyl]5H,6H,7H-cyclopenta[d]pyrimidin-4-y!])amino]propanamide as yellow oil. LCMS (ES) [M+l] m/z: 536.

Step 5

[1196] Into a 8-mL vial were placed (2R)-N-(3-fluorophenyi)-2-[methyl(2-[4-[2-(oxan-2-

546 yloxy)ethoxy]pyndin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amîno]propanamide (l90 mg, 0.35 mmol, l.OO equiv), MeOH (4.00 mL) and TsOH (73 mg, 0.42 mmol, 1.20 equiv). The resulting solution was stirred for l h at room température. The reaction solution was purified by Flash-Prep-HPLC with the following conditions: Column, Weich XB-C18, 21.2*250 mm, 5 um, Mobile phase, Phase A: Water (0.05%NH₄OH) and Phase B: CHjCN (10% Phase B up to 65% in 15 min), Detector, UV 254 nm. The fraction was freezing dried, this resulted in 108.1 mg (68%) of (2R)-N-(3-fluorophenyl)-2-({2-[4-(2hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)propanamide as a white solid. LCMS (ES, m/z): [M+H]⁺: 452. Ή-NMR (300 MHz, DMSO-Jé,ppm): δ 10.58 (br, IH), 8.49 (d, 7= 5.7 Hz, IH), 7.88 (d, 7= 2.7 Hz, 1 H), 7.57-7.52 (m, I H), 7.36-7.22 (m, 2H), 7.07 (dd, 7 =

5.7, 2.7 Hz, JH), 6.86-6.80 (m, IH), 5.28 (q,7=7.2 Hz, IH), 4.92 (t,7= 5.4 Hz, IH), 4.13(t, 7= 4.2 Hz,

2H), 3.77-3.72 (m, 2H), 3.30-3.06 (m, 5H), 2.94-2.77 (m, 2H), 2.06-1.95 (m, 2H), 1.46 (d, 7= 7.2 Hz, 3H).

Example 1.258

[1197] Synthesis of N-(3-fluorophenyl)-2-[methy l(2-{4-[2-(pyrrolidin-I-yl)ethoxy]pyridin-2-yl}

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 252)

NaH_rTHF o to rt, ovemight

Pd(pphj)_4J toluene 100 °C. ovemight Crude —3n Sn— I I

Pd(dppf)CI_£

1,4-dloxano

100 ^DC, ovemight Crude

H

547

Scheme 109

Step 1

NaH, THF 0 to rt, ovemight

[1198] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère 5 of nitrogen was placed a solution of 1 -(2-hydroxyethyI)pyrrolidine (4.82 g, 41.816 mmol, 1.1 equiv) in

THF (50 mL). This was followed by the addition of NaH (60%) (1.83 g, 45.750 mmol, 1.2 equiv), in portions at 0 °C in 15 min. The resulting solution was stirred for 1 hr at 0 °C. To this was added 2chloro-4-fluoropyridine (5.00 g, 38.014 mmol, 1.00 equiv) dropwise with stirring at 0 °C in 20 min. The resulting solution was stirred ovemight at room température. The reaction was then quenched by the 10 addition of 50 mL of water/ice. The resulting solution was extracted with 3x50 mL of ethyl acetate and the organic layers combined, washed with 1 xlOO mL of brine. After filtration, the fîltrate was dried over anhydrous sodium sulfate and concentrated. The residue was purified by silica gel column eluted with ethyl acetate/petroleum ether (1/4). This resulted in 5.5 g (63.95%) of 2-chloro-4-[2-(pyrrolidin-lyl)ethoxy]pyridine as brown oil. LCMS (ES) [M+l]⁺ m/z: 227.

Step

—Sn Sn— I I

Pd{dppQCI₂

1,4-dioxane

100 °C, ovemight

Crude

[1199] Into a 40-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen were placed a solution of 2-chloro-4-[2-(pyrrolidin-l-yl)ethoxy]pyridine (1.80 g, 7.940 mmol, 1.00 equiv) in 1,4-Dioxane (20 mL), hexamethyldistannane (2.86 g, 8.734 mmol, 1.1 equiv) and Pd(dppf)C12 (400.00 mg, 0.547 mmol, 0.07 equiv). The resulting solution was stirred ovemight at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. This resulted in 5.0 g( crude) of 4-[2(pyrrolidin-l-yl)ethoxy]-2-(trimethyistannyl)pyridine as a solid. It was used directly in next step. LCMS

548 (ES) [M+l] ⁺ m/z: 357.

Step 3

Pd(pph₃)₄, toluene 100 “C, ovemight Crude

[l 200] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen were placed a solution of 4-[2-(pyrrolidin-l-yl)ethoxy]-2-(trimethylstannyl)pyridine (5.00 g crude, 14.082 mmol, 1.00 equiv) in toluene (50 mL), ethyl 2-([2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](meÎhyl)amino)acetate (2.28 g, 8.449 mmol, 0.6 equiv) and Pd(PPh₃)4 (1.00 g, 0.865 mmol, 0.06 equiv). The resulting solution was stirred ovemight at 100 °C in an oil bath. The resulting mixture was concentrated. The residue was purified by silica gel column eluted with dichloromethane/méthanol (10/1). This resulted in 400 mg (crude) of ethyl 2-[methyl(2-[4-[2(pyrrolidin-l-yl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetate as brown oil. LCMS (ES) [M+l] ⁺ m/z: 426.

Step

[1201] Into a 40-mL round-bottom flask were placed ethyl 2-[methyl(2-[4-[2-(pyrrolidin-lyl)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetate (390.00 mg, 0.916 mmol, 1.00 equiv), MeOH/H₂O (3/1) (4 mL) and L1OH.H2O (76.92 mg, 1.833 mmol, 2 equiv), The resulting solution was stirred ovemight at room température. The resulting mixture was concentrated. This

549 resulted în 350 mg(crude) of lithio 2-[methyl(2-[4-[2-(pynOlidin-l-yl)ethoxy]pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetate as a brown solid. LCMS (ES) [M-Li+H+l]⁺ m/z: 398.

Step 5

[1202] Into a 40-mL round-bottom flask were placed a solution of lithio 2-[methyl(2-[4-[2(pyrrolidin-l-yl)ethoxy]pyridin-2-y]]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetate (320.00 mg, 0.805 mmol, 1.00 equiv) in DCM (4 mL), TEA (162.93 mg, 1.610 mmol, 2 equiv), T3P (512.32 mg, 1.610 mmol, 2 equiv) and 3-fluoroaniline (107.35 mg, 0.966 mmol, 1.2 equiv). The resulting solution was stirred overnight at room température. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column with THF/petroleum ether (10:1). The collected fractions were combined and concentrated under vacuum. The residue was dissolved in 4 mL of MeOH and was further purified by Prep-HPLC with the following conditions (Waters I): Column, Xbridge Prep C18 OBD column, 5um, 19* 150mm; mobile phase, Water (0.1% TFA) and CHjCN (30% CH3CN up to 40% in 13 min); Detector, UV 254nm. This resulted in 35.0 mg (8.99%) ofN-(3-fluorophenyl)-2-[methyl(2-{4-[2- (pyrrolidin-l-yl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide as a light yellow solid. LCMS (ES) [M+l]⁺ m/z: 491. 'HNMR (300 MHz, Chloroform-7) δ 10.68 (s, IH), 8.64 (s, IH), 8.12 (s, IH), 7.56 (d, J= 11.4 Hz, IH), 7.43 (d,7=8.3 Hz, IH), 7.24-7.14 (m, IH), 7.14 (s, IH), 6.77-6.72 (m, 1 H), 4.70 (s, 2H), 4.56 (s, 2H), 3.83 (s, 2H), 3.64 (s, 3H), 3.58 (s, 2H), 3.42-3.26 (m, 2H), 3.11-3.06 (m, 4H), 2.23- 2.16 (m, 6H).

Example 1.259

[1203] Synthesis of N-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]5H,6I-l,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 253)

550

Scheme l ΙΟ

Step l

[l204] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen were placed a mixture of 4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine (1.00 g. 3.185 mmol, 1.00 equiv), toluene (20.0 mL), ethyl 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrirnidin-4-yl](methyl)amino)acetate (859 mg, 0.003 mmol, 1.00 equiv), Pd(PPh₃)4 (368 mg, 0.319 mmol, 0.10 equiv). The resulting solution was stirred for 16 hours at 100 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with dichloromethane/m éthanol (10/1). This resulted in 540 mg (44.10%) of ethyl Nmethyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)gIycinate as brown oil. LCMS (ES) [M+l]⁺ m/z 385.

Step 2

[1205] Into a 20-mL vial were placed a mixture of ethyl N-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin15 2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate (500 mg, 1.30 mmol, 1.00 equiv), MeOH (10.00 mL), H₂O (2.00 mL) and NaOH (104.04 mg, 2.602 mmol, 2.00 equiv). The resulting solution was stirred for 2 hours at room température. The resulting mixture was concentrated and diluted with 20 mL

55J of H₂O. The pH value of the solution was adjusted to 6 with HCl (2 mol/L). The resulting solids were collected by filtration. This resulted in 420 mg (90,61%) of N-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine as a white solid, LCMS (ES) [M+l]⁺ m/z 357.

Step 3

[1206] Into a 8-mL vial were placed a mixture ofN-methyl-N-(2-(4-(oxetan-3-yloxy)pyridin-2-yl)6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine (150 mg, 0,421 mmol, 1.00 equiv), DMA (5.00 mL), 5-amino-2-methoxy pyridine (104 mg, 0.842 mmol, 2.00 equiv), T3P (267 mg, 0.842 mmol, 2.00 equiv) and Et₃N (127 mg, 1.26 mmol, 3.00 equiv). The resulting solution was stirred for 2 hours at room température. The crude product was purified by Prep-HPLC with the foîlowing conditions: Column, Xbridge Prep C18 OBD Column, 19x150mm, 5um; mobile phase, phase A; H₂O (0.05 %NH₃H₂O); phase B: CH₃CN/MeOH=l/l (15% CH₃CN/MeOH up to 65% CH₃CN/MeOH in 15 min). This resulted in 52.7 mg (27.1 %) ofN-(6-methoxypyridin-3-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide as an off-white solid. LCMS (ES) [M+l] ⁺m/z: 463. Ή NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, IH), 8.37 (d, J = 2.7 Hz, IH), 7.91 (dd, J = 8.9, 2.8 Hz, 1 H), 7.64 (d, J = 2.6 Hz, IH), 6.85 (dd, J = 5.6, 2.6 Hz, 1 H), 6.78 (d, J = 8.8 Hz, IH), 5.38-5.32 (m, IH), 4.91 (t, J = 6.7 Hz, 2H), 4.53 (dd, J = 7.4, 4.8 Hz, 2H), 4.39 (s, 2H), 3.80 (s, 3H), 3.37 (s, 3H)3.21 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.07-1.96 (m. 2H).

Example 1.260

[ 1207] Synthesis of 2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 254)

[1208] Compound 254 was synthesîzed similar to Compound 135 replacing of 4-methoxy-2- (tributylstannyl)pyridine with 4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine and replacing oxolan-321052

552 amine with l-methyl-lH-pyrazol-4-amine. LCMS (ES) [M+l] ⁺ m/z: 436. ^lH NMR (300 MHz, DMSOd6) δ 8.48 (d, J = 5.5 Hz, IH), 7.86 (s, IH), 7.58 (d, J = 2.6 Hz, IH), 7.42 (s, IH), 6.88 (dd, J = 5.9, 2.6 Hz, IH), 5.48-5.35 (m, IH), 4.92 (t, J = 6.7 Hz, 2H), 4.55 (dd, J = 7.4, 4.8 Hz, 2H), 4.35 (s, 2H), 3.76 (s, 3H), 3.41 (s, 3H), 3.19 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.13-1.95 (m, 2H), 1.86 (s, IH).

Example 1.261

[1209] Synthesisof2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-l-(piperidin-l-yl)ethan-l-one (Compound 255)

[1210] Compound 255 was synthesized similar to Compound 135 replacing of 4-methoxy-2- (tributylstannyl)pyridine with 3-(trimethylstannyl)isoquinoline and replacing oxolan-3-amine with piperidine. LCMS (ES) [M+l] ⁺ m/z: 402. 'H NMR (300 MHz, DMSO-d6) δ 9.39 (s, IH), 8.71 (s, IH), 8.23-8.15 (m, IH), 8.05 (d, J = 8.1 Hz, 1 H), 7.82 (ddd, J = 8.2, 6.9, 1.3 Hz, IH), 7.73 (ddd, J = 8.1, 6.9, 1.3 Hz, IH), 4.59 (s, 2H), 3.54-3.39 (m, 4H), 3.30 (s, 3H), 3.16 (t, J = 7.2 Hz, 2H), 2.92-2.80 (m, 2H), 2.05-1.95 (m,2H), 1.72-1.59 (m, 4H), 1.48-1.38 (m, 2H).

Example 1.262

[1211] Synthesis of 2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyc!openta[d]pyrimidin-4- yl](methyl)amino}-l-(4-methylpiperazin-l-yl)ethan-l-one (Compound 256)

[1212] Compound 256 was synthesized similar to Compound 135 replacing of 4-methoxy-2-

553 (tributylstannyl)pyridine with 3-(tri methy lstannyl)isoqu incline and replacing oxolan-3-amine with 4methylpiperazine. LCMS (ES) [M+l] ⁺ m/z: 417. 'H NMR (300 MHz, DMSO-d6) δ 9.40 (s, IH), 8.71 (s, IH), 8.19 (d, J = 8.0 Hz, IH), 8.09 (d, J= 8.1 Hz, IH), 7.82 (ddd,7 = 8.2, 6.9, 1.3 Hz, IH), 7.73 (ddd, 7= 8.1, 6.9, 1.2 Hz, IH), 4.60 (s, 2H), 3.57 (s, 2H), 3.45 (s, 2H), 3.30 (s, 3H), 3.16 (t,7= 7.3 Hz, 5 2H), 2.86 (t, 7= 8.1 Hz, 2H), 2.42 (s, 2H), 2.24 (s, 2H), 2.18 (s, 3H), 2.02 (td, 7 = 14.8, 14.1,6.5 Hz,

2H).

Example 1.263

[1213] Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(l,6-naphthyridin-7-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 257)

Scheme 1 11

Step 1

Pd<dppQCh

ZnCN. K₂CO₃

IS [1214] To a stirred mixture of ethyl 2-(3-bromopyridin-2-yl)acetate (14 g, 57.3 mmol, 1.0 equiv), Zn(CN)₂ (10.1 g, 86.03 mmol, 1.5 equiv) and K2CO3 (15.8 g, 114.7 mmol, 2.0 equiv) in NMP (100 mL) was added Pd(dppf)C12.CH2Cl₂ (4.7 g, 5.73 mmol, 0.10 equiv) at 20 °C. The resulting mixture was

554 heated to 70 °C and stirred at this température for 16 h under N₂ atmosphère. The resulting mixture was cooled to 25 °C and quenched with water, extracted with EtOAc (100 mLx3), organic layer was combined, concentrated, the residue was purified by silica gel column chromatography to give ethyl 2(3-cyanopyridin-2-yl)acetate (9.0 g, 81.8% yield) as a yellow gum. LCMS (ES) [M+1]⁺ m/z: 191.

Step 2

[1215] To a stirred mixture of ethyl 2-(3-cyanopyridin-2-yl)acetate (6.0 g, 31.5 mmol, 1.0 equiv) in AcOH (12 mL) and EtOH (60 mL) was added Pd/C (600 mg) at 20 °C. The resulting mixture was heated to 40 °C and stirred at that température for 16 h under H2 atmosphère (10 atm). The resulting mixture was cooled to 25 °C, filtered and concentrated. The residue was purified by silica gel column chromatography to give 6,8-dihydro-5H-l,6-naphthyridin-7’One (4.0 g, 85.6%) as a yellow solid. LCMS (ES) [M+l] ⁺ m/z: 149.

Step 3

[1216] To a stirred solution of 6,8-dihydro-5H-L6-naphthyridin-7-one (1.5 g) in phenylphosphonic dichloride (10 mL) was heated to 130 °C and stirred at this température for 16 h . The resulting mixture was cooled to 25 °C, poured into 50 mL of water and adjusted pH to 8 with solid NaHCOi. The mixture was extracted with EtOAc, organic layer was separated and concentrated. The residue was purified by silica gel column chromatography to give 7-chloro-l,6-naphthyridine (400 mg, 25.5% yield) as a yellow solid. LCMS (ES) [M+1 ]⁺ m/z: 165.

Step 4

Sn₂Me₆, Pd(PPh₃)4

Toluene

[1217] To a stirred solution of 7-chloro-l,6-naphthyridine (200 mg, 1.21 mmol, L0 equiv) in

Toluene (5 mL) was added Sn₂Meô (438 mg, 1.33 mmol, 1.1 equiv) and Pd(dppf)Cb.CH2Cb (89 mg.

555

0.12 mmol, 0.1 equiv) at room température. The reaction was stirred at 100 °C for 3 h under Nz atmosphère. The reaction m ixture was used for next step without further purification (7(trimethylstannyi)-l,6-naphthyridine: theoretical weight 358 mg). LCMS (ES) [M+l] ⁺ m/z: 295.

Step 5

[l218] To a mixture of 7-(trimethylstannyl)-l,6-naphthyridine (358 mg, L2l mmol, LO equiv) in toluene (10 mL) were added 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N(6-methoxypyridin-3-yl)acetamide (296 mg, 0.85 mmol, 0.70 equiv) and Pd(PPhs)4 (l 40 mg, 0.12 mmol, 0,l equiv) at room température. The reaction was purged and maintained with an inert atmosphère of argon for 2 min. The resulting solution was stirred for 16 hr at 100 °C, cooled and concentrated under vacuum. The residue was applied onto a silica gel column with THF/petroleum ether (1:50 to 10:1) to give 150 mg crude product, which was further purified by preparatory HPLC (Column, Cl8; Flow rate: 20mL/min Column: DAICEL CHIRALPAK IC, 250*20mm, 220 nm) to give N-(6-methoxypyridin-3yl)-2-[methyl[2-(l,6-naphthyridin-7-yl)-5H,6H,7H-cyclopenta[d]pyrîmidin-4-yl]amino]acetamide (55 mg, 10.24%) as an off white solid. LCMS (ES) [M+l] ⁺ m/z: 442. Ή NMR (300 MHz, DMSO-7&) δ 10.31 (s, IH), 9.46(s, IH), 9.16 (d, 7= 4.2 Hz, IH), 8.82 (s, IH), 8.62 (d, 7= 8.3 Hz, IH), 8.38 (d, 7 = 2.7 Hz, 1 H), 7.92 (dd, 7= 8.6, 2.7 Hz, IH), 7.72 (dd, 7= 8.3, 4.2 Hz, 1 H), 6.75 (d, 7= 8.9 Hz, IH), 4.49 (s, 2H), 3.78 (s, 3H), 3.40 (s, 3H), 3.23 (t, 7= 7.4 Hz, 2H), 2.88 (t, 7= 7.8 Hz, 2H), 2.09-2.02 (m, 2H).

Example L264

[1219] Synthesis of N-(6-methoxypyridin-3-yl)-2-{methyl[2-(2,6-naphthyridin-3-yI)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 258)

556

HATU. DIEA, DMF

Scheme 12

Step 1

mCPBA

CHCI₃, rt

[1220] Into a 500 mL 3-necked round-bottom flask were placed ethyl 2-(pyridin-3-yl)acetate (20.00 g, 121.07 mmol, 1.00 equiv) and CHCh (300.00 mL). This was followed by the addition of mCPBA (31.34 g, 181.61 mmol, L50 equiv) in portions at 0 °C. The resulting solution was stirred for 5 h at room température. The reaction was then quenched by the addition of Sat. Na2SO₃. The pH value ofthe solution was adjusted to 8-9 with Sat. Na₂CO₃. The resulting solution was extracted with 3x300 mL of dîchloromethane and the organic layers were combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with dîchloromethane/methanol (100/5).

557

This resulted in 20 g (91.17%) of 3-(2-ethoxy-2-oxoethyl)pyridin-l-ium-l-olate as off-white solid.

LCMS (ES) [M+I]⁺m/z: 182.

Step

[1221] Into a 500 mL round-bottom flask, was placed 3-(2-ethoxy-2-oxoethyl)pyridin-l-ium-l-olate (20.00 g, 110.38 mmol, 1.00 equiv), ethyl iodide (51.65 g, 331.16 mmol, 3.00 equiv). The resulting solution was stirred for 6 h at 45 °C. The resulting solution was added CH₃CN (350.00 mL), K₂CO₃(45.77 g, 331.14 mmol, 3.00 equiv), TMSCN (32.85 g, 331.14 mmol, 3.00 equiv). The resulting solution 10 was stirred for ovemight at 50 °C. The reaction mixture was cooled to room température. The solids were fîltered out and the filtrate was concentrated. The residue was applied onto a silica gel column with THF/PE (10%). This resulted in 10 g (47.63%) of ethyl 2-(4-cyanopyridin-3-yl)acetate as yellow oil. LCMS (ES) [M+lfm/z: 191.

Step

3

[ 1222] Into a 250 mL pressure tank reactor were placed ethyl 2-(4-cyanopyridin-3-yl)acetate ( 10.00 g, 52.57 mmol, 1.00 equiv), EtOH (80.00 mL), AcOH (20.00 mL) and Pd/C (0.56 g, 5.26 mmol, 0.10 equiv). The resulting solution was stirred for 6 h at 35 °C. The solids were fîltered out and the filtrate was concentrated. The crude product (10 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NHyHzO) and CAN (10% Phase B up to 30% in 11 min); Detector, 254 nM. This resulted in 6 g (77 %) of 2,4dihydro-1 H-2,6-naphthyridin-3-one as yellow solid. LCMS (ES) [M+l ]+ m/z: 149.

Step 4

558

ο

[1223] Into a 25Û mL round-bottom flask were placed 2,4-dihydro-lH-2,6-naphthyridin-3-one (6.00 g, 40.49 mmol, 1.00 equiv) and phenylphosphonic dichloride (60.00 mL). The resulting solution was stirred for 3 h at 125 °C. The reaction mixture was cooled to room température. The pH value ofthe solution was adjusted to 8 with Sat. NaHCO₅. The resulting solution was extracted with 3x300 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (30%). This resulted in 350 mg (5.25%) of 3-chloro-2,6-naphthyridme as yellow solid. LCMS (ES) [M+l]⁺ m/z: 165.

Step 5

[1224] Into a40-mL vial were placed 3-chloro-2,6-naphthyridine (350.00 mg, 2.13 mmol, 1.00 equiv), hexamethyldistannane (905.72 mg, 2.76 mmol, 1.30 equiv), toluene (10.00 mL) and Pd(dppf)Ch (155.60 mg, 0.21 mmol, 0.10 equiv). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled to room température and added ethyl 2-([2-chloro-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetate (401.51 mg, 1.49 mmol, 0.70 equiv). The resulting solution was then stirred for overnight at 100 °C. The reaction mixture was cooled to room température and concentrated. The residue was applied onto a silica gel column with THF/PE (50%). This resulted in 300 mg (38.82%) of ethyl 2-[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetate as yellow solid. LCMS (ES) [M+l]* m/z: 364.

Step 6

559

[l 225] Into a 100-mL round-bottom flask were placed ethyl 2-[methyl[2-(2,6-naphthyridin-3-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino]acetate (300.00 mg, 0.83 mmol, l .00 equiv), MeOH (5.00 mL) and H₂O (5.00 mL). This was followed by the addition of LiOH H₂O (69.28 mg, 1.65 mmol, 5 2.00 equiv) in portions at 0 °C. The resulting solution was stirred for 3 h at room température and the pH value ofthe solution was adjusted to 7 with citric acid. The crude product (0.5 g) was purified by PrepHPLC with the foilowing conditions: Column, XBridge Prep Cl8 OBD Column, 19cm, 150mm, 5um;

mobile phase, Water and AcCN (10% Phase B up to 30% in 11 min); Detector, 254 nm. This resulted in

160 mg (57.79%) of [methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl]amino]acetic acid as yellow solid. LCMS (ES) [M+l]⁺ m/z: 336.

Step 7

[1226] Into a 40 mL vial was placed [methy l[2-(2,6-naphthyridin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino]acetic acid (160.00 mg, 0.47 mmol, 1.00 equiv), DMF (5.00 mL), 15 DIEA (123.32 mg, 0.95 mmol, 2 equiv) and 5-amino-2-methoxypyridine (59.23 mg, 0.47 mmol, 1.00 equiv). This was followed by the addition of HATU (217.68 mg, 0.57 mmol, 1.20 equiv) in portions at 0 °C. The resulting solution was stirred for 2 h at room température. The crude product (1 g) was purified by Prep-HPLC with the foilowing conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% ΝΗ3Ή2Ο) and AcCN/MeOH= 1:1 (30% Phase B up to 70% in

11 min); Detector, 254 nm. This resulted in 127 mg (33.97%) ofN-(6-methoxypyridin-3-yl)-2[methyl[2-(2,6-naphthyridin-3-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4-yl]amino]acetamide;

tris(trifluoroacetic acid) as orange soiid, LCMS (ES, m/z): [M+H]⁺: 442. Ή-NMR (300 MHz, DMSOd_6ippm): δ 10.6I (s, IH), 9.70 (s, IH), 9.43 (s, IH), 9.l4(s, IH), 8.91 (d, J = 5.6 Hz, IH), 8.44 (d, J = 2.7 Hz, lH), 8.22 (d, J = 5.7 Hz, IH), 7.96 (dd, J = 8.9, 2.8 Hz, IH), 6.79 (d, J =8.9 Hz, lH), 4.75 (s, 2H), 3.78 (s, 3H), 3.63 (s, 3H), 3.36-3.30 (m, 2H), 3.11 (t, J = 7.8 Hz, 2H), 2.19-2.02 (m, 2H).

Example 1.265

[1227] Synthesis of 2-{[2-(4-ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4- yl](methyl)amino}-N-(2-methoxypyrimidm-5-yl)acetamide (Compound 259)

[ 1228] Compound 259 was synthesized similar to Compound 135 by replacing of 4-methoxy-2- (tributylstannyl)pyridine with 4-ethoxy-2-(tributylstannyl)pyndine and replacing oxo lan-3-amine with 2methoxypyrimidin-5-amine. LCMS (ES) [M+l] ⁺ m/z: 436. Ή NMR (300 MHz, DMSO-d6) δ 10.49 (s, IH), 8.76 (s, 2H), 8.42 (d, J= 5.5 Hz, IH), 7.72 (d, .7=2.5 Hz, IH), 6.98 (dd, .7= 5.7, 2.5 Hz, IH), 4.39 (s, 2H), 4.05 (q, 4= 6.9 Hz, 2H), 3.87 (s, 3H), 3.38 (s, 3H), 3.21 (t, J = 7.4 Hz, 2H), 2.83 (t, J= 7.8 Hz, 2H), 2.07-1.96 (m, 2H), 1.29 (t, J = 7.0 Hz, 3H).

Example 1.266

[1229] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2-methoxypyrimidin-5-yl)acetamide (Compound 260)

N O

[1230] Compound 260 was synthesized similar to Compound 210 by replacing 5-amino-2- methoxypyridine with 2-methoxypyrimidin-5-amine. LCMS (ES) [M+l ] ⁺ m/z: 480. 'H NMR (300

MHz, DMSO-d6) δ 10.47 (s, IH), 8.74 (s, 2H), 8.43 (d, 7 = 5.6 Hz, IH), 7.77 (d, 7=2.5 Hz, IH), 7.03 (dd, 7= 5.7, 2.6 Hz, IH), 4.66 (s, IH), 4.42 (s, 2H), 3.87 (s, 3H), 3.80 (s, 2H), 3.38 (s, 3H), 3.22 (t, 7= 7.3 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.08-1.99 (m, 2H), 1.16 (s, 6H).

Example 1.267

[1231] Synthesis of N-tert-buty 1-2-{[2-(6-methoxyisoquinoiin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 261)

H

[1232] Compound 261 was synthesized similar to Compound 24 by replacing 4-methy 1 -2(tributylstannyl)pyridine with 6-methoxy-3-(trimethylstannyl)isoquinoline. LCMS (ES) [M+l]⁺ m/z 10 420. Ή NMR (300 MHz, DMSO-rfû) δ 9.23 (s, IH), 8.80 (s, JH), 8.16 (HCOOH), 8.08 (d, 7= 9.0 Hz,

H), 7.81 (s, IH), 7.50 (s, IH), 7.33 (dd, 7= 8.9, 2.5 Hz, IH), 4.19 (s, 2H), 3.94 (s, 3H), 3.33 (s,3H), 3.17 (t, 7= 7.5 Hz, 2H), 2.85 (t, 7= 7.9 Hz, 2H), 2.04-1.99 (m, 2H), 1.23 (s, 9H).

Example 1.268

[1233] Synthesis of N-tert-butyl-2-{[2-(7-methoxyisoquinolin-3-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 262)

[1234] Compound 262 was synthesized similar to Compound 24 by replacing 4-methy 1-2(tributylstannyl)pyridine with 7-methoxy-3-(trimethyIstannyl)isoquinoline. LCMS (ES) [M+I]⁺ m/z

420. Ή NMR (300 MHz, DMSOA) δ 9.28 (s, IH), 8.79 (s, 1 H), 8.17 (HCOOH), 8.03 (d,7=9.0 Hz,

562

IH), 7.79(s_s IH), 7.59 (d, 7=2.5 Hz, IH), 7.48 (dd, 7= 9.0, 2.5 Hz, IH), 4.19 (s, 2H), 3.95 (s, 3H), 3.32 (s, 3H), 3.17 (t, 7= 7.3 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.06-1.99 (m, 2H), 1.23 (s, 9H).

Example 1.269

[1235] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4 yl}(methyl)amino)-l-(piperidin-l-yl)ethan-l-one (Compound 263)

[1236] Compound 263 was synthesized similar to Compound 144 by replacing cyclohexylamine with piperidine. LCMS (ES) [M+l]⁺ m/z 4I2. 'H NMR (300 MHz, DMSO-i/ô) 5 8.45 (d, 7= 5.7 Hz, IH), 7.75 (d, 7=2.7 Hz, IH), 7.03 (dd,7=5.7, 2.7 Hz, lH), 4.92 (t,7= 5.4 Hz, IH), 4.51 (s, 2H), 4.13 10 (1,7=4.8 Hz, 2H), 3.75 (q,7 = 5.1 Hz, 2H), 3.47-3.37 (m, 4H), 3.25 (s, 3H), 3.13 (t,7= 7.5 Hz, 2H),

2.81 (t, 7= 7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.61 (s, 4H), 1.44 (s, 2H).

Example 1.270

[1237] Synthesis ofN-(6-fIuoropyridin-3-yl)-2-[methyl({2-[l-(oxan-2-yl)-lH-pyrazolo[3,4c]pyridin-5-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 264)

[1238] Compound 264 was synthesized similar to Compound 135 by replacing 4-methoxy-2(tributylstannyl)pyridine with l-(oxan-2-yl)-5-(tributyIstannyl)-lH-pyrazolo[3,4-c]pyridine and replacing oxolan-3-amine with 6-fluoro-3-pyridiny lamine. LCMS (ES) [M+l]⁴ m/z: 503.2. ’H NMR

(400 MHz, DMSO-d6) δ 9.39 (s, IH), 9.10-8.94 (ni, IH), 8.52 (d,7=2.3 Hz, IH), 8.37 (s, IH), 8.22 (ddd, 7=8.8, 7.3, 2.8 Hz, IH), 7.17 (dd,7 = 8.8,3.2 Hz, IH), 6.18 (dd, 7= 9.2, 2.5 Hz, IH), 4.73 (s, 2H), 3.92 - 3.76 (m, 2H), 3.58 (s, 3H), 3.25 (m, 2H), 3.08 (t, 7= 7.9 Hz, 2H), 2.45 - 2.30 (m, IH), 2.16 -2.01 (m, 4H), 1.82-1.70 (m, IH), l.66-l.57(m, 2H).

Example l.271

[1239] Synthesis ofN-(5-methoxypyridin-2-yl)-2-[methyl(2-{ lH-pyrazolo[3,4-c]pyndin-5-yI}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 265)

[1240] Compound 265 was synthesized similar to Compound 266 by replacing 6-fluoropyridine-310 amine with 5-methoxypyridin-2-amine. LCMS (ES+): [M+H]⁺ = 431.1. Ή NMR (400 MHz, DMSO-d6) δ 13.88 (s, IH), 10.77 (s, 1H),9.U (s, IH), 8.78 (d,7= 1.3 Hz, IH), 8.16-8.09 (m, 2H), 7.96 (d,7= 9.0 Hz, IH), 7.39 (dd, 7= 9.1, 3.1 Hz, IH), 4.58 (s, 2H), 3.78 (s, 3H), 3.30-3.18 (m, 9H), 2.92 (t, 7 = 7.8 Hz, 2H), 2.05 (p, 7= 7.9 Hz, 2H).

Example 1.272

[1241 ] Synthesis ofN-(5-methoxypyridm-2-yl)-2-[methy!(2-{ lH-pyrazolo[3,4-c]pyridin-5-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 266)

564

Scheme 112

[1242] N-(6-Fluoropyndin-3-yl)-2-[methyl({2-[l-(oxan-2-yl)-lH-pyrazolo[3,4-c]pyridin-5-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (53 mg; 0.11 mmol; 1 eq.) was dissolved in methanol (1 ml) and cooled in an ice water bath. Hydrogen chloride solution (1 mL; 6 mol/L isopropanol) was added slowly and the reaction was stirred at 25 °C. After 3 h, more HCl (0.2 ml) was added and the reaction stirred for an additional 1.5 h. The reaction solvent was evaporated and the residue was purified by reverse phase chromatography (Waters XSelectCSH C18 column, 0-60% acetonitrile/O.l % aqueous formic acid gradient) to give N-(6-fluoropyridin-3-yl)-2-[methyl(2-{lH- pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl)amino]acetamide (22 mg, 49%) as a white solid. LCMS (ES+): [M+H]⁺ = 419.0. Ή NMR (400 MHz, dmso) δ 13.83 (s, IH), 10.73 (s, IH), 9.08 (s, IH), 8.78-8.73 (m, IH), 8.48 (d,7=2.8 Hz, IH), 8.21 (ddd,7= 8.8,7.3,2.8 Hz, IH), 8.16 (s, IH), 7.16 (dd, 7= 8.9, 3.2 Hz, IH), 4.52 (s, 2H), 3.45 (s, 3H), 3.27 - 3.19 (m, 2H), 2.95-2.86 (m, 2H), 2.11 - 1.98 (m, 2H).

Example L273

[1243] Synthesis of 2-[methyl(2-{lH-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(6-methylpyridin-3-yl)acetamide (Compound 267)

565

[1244] Compound 267 was synthesized similar to Compound 266 by replacing 6-fluoropyridine-3amine with 6-methylpyridin-3-amine. LCMS (ES+): [M+H]⁺ = 415.1. 'H NMR (400 MHz, dmso) δ 11.81 (s, IH), 9.22 (s, IH), 9.09 (s, IH), 9.02 (s, IH), 8.50 - 8.31 (m, 2H), 7.69 - 7.63 (m, IH), 4.83 (s, 5 2H), 3.61 (s, 3H), 3.09 (t, J= 7.9 Hz, 2H), 2.55 (s, 3H), 2.17-2.09 (m, 2H).

Example 1.274

[1245] Synthesis ofN-(6-methoxypyridin-3-yl)-2-{methyl[2-(2,7-naphthyridin-3-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 268)

2) Me₂CO₃, rt

1) LiHDMS, -78°C

Scheme 113

566

Step l

1) LiHDMS, -78°C

2) Me₂CO₃, rt

[1246] To a solution of 4-methylpyridine-3-carbonitrile (10 g, 84.646 mmol, 1.00 equiv) in THF (100 mL) was added dropwise LiHDMS(1.0 M in THF, 170 mL, 169.292 mmol, 2 equiv)) at -78 °C under N2 atmosphère. The reaction mixture was stirred at -78 °C for 1 h. A solution of dimethyl carbonate (9.50 g, 105.464 mmol, 1.25 equiv) in 50 mL THF was added dropwise and the mixture was stirred for another 1 h at -78 °C. The resulting mixture was stirred for 2 h at -78 °C to 0 °C under nitrogen atmosphère. The reaction was quenched with NHÆl (200 mL) and the resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with water (1x100 mL), 10 dried over anhydrous NaïSOiand filtered. The fiItrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (10:1) to yield methyl 2-(3-cyanopyridin-4-yl)acetate (10.1 g, 67.73%) as a yellow oil. LCMS (ES) [M+l] ⁺ m/z: 177;

Step 2

___Pd/C___.

EtOH, HOAC

[1247] To a solution of methyl 2-(3-cyanopyridin-4-yl)acetate (10.00 g, 56.762 mmol, 1.00 equiv) in

EtOH (200.00 mL) and AcOH (20.00 mL) was added Pd/C (1.21 g, 11.352 mmol, 0.20 equiv) under nitrogen atmosphère in a 500 mL 3-necked round-bottom flask. The mixture was charged with Hs (latm) at 40 °C for ovemight. The resulting mixture was filtered; the fîlter cake was washed with MeOH (3x100 mL). The fîltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CHzCh / MeOH (10:1) to afford 2,4-dihydro-lH-2,7-naphthyridin3-one (4 g, 47.56%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 149;

Step 3

DDQ, POCI₃, Toluene

[1248] A solution of 2,4-dihydro-lH-2,7-naphthyridin-3-one (1.00 g, 6.749 mmol, 1.00 equiv) and

567

DDQ(L69 g, 7.424 mmol, 1.10 equiv) in Toluene (30.00 mL) was stirred for Ih at room température under air atmosphère. To the above mixture was added POCk (10.00 mL, 65.236 mmol, 15.90 equiv) . The resulting mixture was stirred for additional 16 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The reaction was quenched with water at room température. The mixture was adjusted to pH 8 with saturated NaHCOs (aq.). The resulting mixture was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with brine (1x100 mL), dried over anhydrous Na₂SO4 and filtered. the fïltrate was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/EtOAc (1:1) to afford 3-chloro-2,7-naphthyridine (50 mg, 4.50%) as a yellow solid. LCMS (ES) [M+l]^T m/z: 165.

Step 4

[1249] To a solution of 3-chloro-2,7-naphthyridine (220.00 mg, 1.337 mmol, 1.00 equiv) and hexamethyldistannane (481.72 mg, 1.471 mmol, 1.10 equiv) in toluene (5.00 mL, 46.995 mmol) were added Pd(dppf)C12 CH2CI2 (108.89 mg, 0.134 mmol, 0.10 equiv). After stirring for 2 h at 100 °C under a nitrogen atmosphère, the mixture was allowed to cool down to room température. The mixture was then added 2-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methoxypyridin3-yl)acetamide (325.42 mg, 0.936 mmol, 0.70 equiv) and Pd(PPh₃)₄( 108.89 mg, 0.134 mmol, 0.10 equiv). The resulting mixture was stirred for additional 16 h at 100 °C. After cooling the resulting mixture was concentrated under reduced pressure and the residue was purified by silica gel column chromatography, eluted with PE/THF (1:10) to provide N-(6-methoxypyridin-3-yl)-2-[methyl[2-(2,7naphthyridin-3-yl)-5H,6H,7H-cyclopenta[dJpyrimidin-4-yl]amino]acetamide (30 mg, 7.3%) as a white solid. LCMS (ES) [M+l] + m/z: 442; IH NMR (300 MHz, DMSO-d6) δ 10.35 (s, IH), 9.58 (d, J = 5.2 Hz, 2H), 8.87-8.62 (m, 2H), 8.39 (d, J = 2.7 Hz, IH), 7.93 (dd, J = 8.9, 2.7 Hz, IH), 7.74 (d, J = 5.8 Hz, IH), 6.77 (d, J = 8.9 Hz, IH), 4.47 (s, 2H), 3.79 (s, 3H), 3.42 (s, 3H), 3.31-3.11 (m, 2H), 2.89 (t, J =

568

7.8 Hz, 2H), 2.07-2.02 (m, 2H).

Example 1.275

[ 1250] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cycloρenta[d]pyπmidin-4yl}(rnethy])amino)-N-(4-methoxyphenyl)acetarmde (Compound 269)

( 1251 ] Co m pound 269 was synthesized sim i lar to Compound 144 by replacing cyc lohexy l am ine with 4-methoxy aniline. LCMS (ES) [M+l ]^k m/z 450. Ή NMR (300 MHz, DMSOés) δ 10.07 (s, IH), 8.44 (d, J = 5.6 Hz, IH), 7.80 (d, J = 2.6 Hz, IH), 7.55-7.43 (m, 2H), 7.00 (dd, J = 5.6, 2.6 Hz, IH), 6.92-6.79 (m, 2H), 4.90 (t, J = 5.4 Hz, JH), 4.39 (s, 2H), 4.03 (t, J = 4.7 Hz, 2H), 3.71 (s, 3H), 3.77-3.62 10 (m, 2H), 3.35 (s, 3H), 3.20 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.01 (p, J = 7.8 Hz, 2H).

Example 1.276

[1252] Synthesis of2-({2-[5-(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyciopenta[d]pyrimidin4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide (Compound 270)

569

Scheme 114

Step l

ACN

NBS

[l253] Into a 1000-mL round-bottom flask was placed l ,3-dichloroisoquinoline (30.00 g, 151.477 mmol, l.OO equiv), NBS (28.3 I g, 159.051 mmol, l .05 equiv), AcCN (600.00 mL) and H2SO4 (30.00 10 mL). The resulting solution was stirred for 90 h at room température. The solids were collected by filtration. This resulted in 18 g (42.91%) of 5-bromo-l,3-dichloroisoquinoline as a yellow solid. LCMS (ES) [M+l]⁺ m/z 276.

Step

[1254] Into a 500-mL round-bottom flask was placed 5-bromo-l,3-dichloroisoquinoline (15.00 g, 54.163 mmol, 1.00 equiv), AcOH (150.00 mL), HCl (30.00 mL) and Sn (19.34 g, 162.490 mmol, 3 equiv). The resulting solution was stirred for 0.5 hr at 60 °C. The resulting solution was extracted with 5 3x200 mL of ethyl acetate, organic layers were combined, washed with 3 x200 ml of brine and fîltered.

The filtrate was concentrated and the residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:5). This resulted in 5.5 g (41.87%) of 5-bromo-3-chloroisoquinoline as a light yellow solid. LCMS (ES) [M+l]⁺ m/z 242.

Step

3

[1255] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 5-bromo-3-chloroisoquinoline (3.00 g, 12.371 mmol, L00 equiv), THF (30.00 mL). This was followed by the addition of n-BuLi in hexanes (5.9 mL, 14.862 mmol, 1.20 equiv) dropwise with stirring at -78 °C. The resulting solution was stirred for 0.5 hr at -78 °C. To this was added DMF (2.71 g, 37.113 mmol, 3.00 equiv) dropwise with stirring at -78 °C. The resulting solution was warmed up to room température and stirred for an additional 2 hr. The reaction was then quenched by the addition of 100 mL of NH₄C1. The resulting solution was extracted with 2x50 mL of ethyl acetate. Organic layers were combined, washed with brine and dried over anhydrous sodium sulfate. The mixture was fîltered, and the filtrate was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 730 mg (30.7%) of 3-chloroisoquinoline-5carbaldehyde as a light yellow solid. LCMS (ES) [M+l]⁺ m/z 192.

Step

571

OH

[1256] Into a 40-mL round-bottom flask was placed 3-chloroisoquinoline-5-carbaldehyde (730.00 mg, 3.810 mmol, l.OO equiv), THF (l0.00 mL) and NaBH₄ (432.4! mg, 11.429 mmol, 3 equiv). The resulting solution was stirred for 2 hr at room température. The reaction was then quenched by the addition of 10 mL of water and extracted with 3x20 mL of ethyl acetate. The combined organic layers were washed with 3 x20 mL of brine, dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (l: l). This resulted in 730 mg (98.9%) of (3-chloroisoquinolin-5-yl)methanol as a light yellow solid. LCMS (ES) [M+l]⁺ m/z 194.

Step

[1257] Into a 40-mL round-bottom flask were placed (3-chloroisoquinolin-5-yl)methanol (730.00 mg, 3.770 mmol, 1.00 equiv), DCM (10 mL), TBSC1 (852.35 mg, 5.655 mmol, 1.50 equiv), imidazole 15 (513.31 mg, 7.540 mmol, 2 equiv). The resulting solution was stirred for 12 hr at room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:10). This resulted in 800 mg (68.9%) of 5-[[(tertbutyldimethylsilyl)oxy]methyl]-3-chloroisoquinoline as yellow oii. LCMS (ES) [M+l]⁺ m/z 308.

Step

6

572

[1258]

Into a 40-mL round-bottom flask were placed 2-([2-chioro-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)-N-(6-methyipyridin-3-yl)acetamide <215.53 mg, 0.650 mmol, 1.00 equiv), hexamethyldistannane (212.82 mg, 0.650 mmol, 1 equiv), Dioxane (6 mL) and Pd(dppf)Ch-CH2C12 (52.92 mg, 0.065 mmol, 0.10 equiv). The resulting solution was stirred for 3 h at 100 °C and was cooled and added 5-[[(tert-butyldimethylsilyl)oxy]methyl]-3-chloroisoquinoline (200.00 mg, 0.650 mmol, 1.00 equiv) and Pd(dppf)CI₂.CH₂Cl₂ (52.92 mg, 0.065 mmol, 0.10 equiv), The resulting solution was then stirred for ovemight at 100 °C. The resulting mixture was concentrated, the residue was applied onto a silica gel column with dichloromethane/methanol (1:0-10:1). This resulted in 120 mg (8.12%) of 2-((2(5-(((tert-butyldimethylsilyl)oxy)methyl)isoquinolin-3-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide as a brown solid. LCMS (ES) [M+l]⁺ m/z 569. Step 7

[ 1259] Into a 40 mL round-bottom flask were placed 2-[[2-(5-[[(tertbutyldimethylsilyl)oxy]inethyl]isoquinoLin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimÎdin-4yl](methyl)amino]-N-(6-methylpyridin-3-yl)acetaniide (120.00 mg, 0.211 mmol, 1.00 equiv), THF (3.00 mL) and EtaNTHF (170.05 mg, 1.055 mmol, 5.00 equiv). The resulting solution was stirred for 12 h at room température. The pH value of the solution was adjusted to 7~8 with NH3H2O. The resulting mixture was concentrated and the crude product was purified by Prep-HPLC with the following

conditions: Column, SunFire Prep C18 OBD Column, 19*l50mm 5um lOnm; mobile phase, Water(Û.l%FA) and ACN (48.0% ACN up to 53.0% in 7 min, hold 95.0% in l min, down to 48.0% in l min, hold 48.0% in 1 min); Detector, UV 220 nm. This resulted in 41.6 mg (43.38%) of2-({2-[5(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(65 methyipyrîdin-3-yl)acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z 455. Ή NMR (300 MHz, DMSO-d6) δ 10.40 (s, IH), 9.37 (s, IH), 8.88 (s, IH), 8.61 (d, J = 2.6 Hz, IH), 8.07 (d, J = 8.1 Hz, IH), 7.90 (dd, J = 8.4, 2.6 Hz, IH), 7.82 (d, J = 7.1 Hz, IH), 7.74-7.63 (m, IH), 7.16 (d, J= 8.5 Hz, IH), 5.40 (br, IH), 4.98 (d, J = 4.2 Hz, 2H), 4.51 (s, 2H), 3.39 (s, 3H), 3.23 (t, J = 7.1 Hz, 2H), 2.90 (t, J = 7.9 Hz, 2H), 2.38 (s, 3H), 2.09-1.97 (m, 2H).

Example 1.277

[1260] Synthesis ofN-(3-fluorophenyl)-2-{methyl[2-(l-methyl-lH-imidazol-4-yi)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 271)

[1261] Compound 271 was synthesized similar to compound 142 by replacing cyclohexylamine with 15 3-fluoroaniJine. LCMS (ES) [M+l] ⁺ tn/z: 381; Ή-NMR (300 MHz, DMSOé^pm): δ 10.43 (s, IH),

7.69-7 .55 (m, 3H), 7.41-7.26 (m, 2H), 6.93-6.80 (m, IH), 4.36 (s, 2H), 3.61 (s, 3H), 3.32 (s, 3H), 3.13 (t, 7=7.2 Hz, 2H), 2.75 (t, 7= 7.8 Hz, 2H), 2.01-1.91 (m, 2H).

Example 1.278

[1262] Synthesis ofN-(3-methoxyphenyl)-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl]amino]acetamide (Compound 272)

[1263] Compound 272 was synthesized similar to compound 142 by replacing cyclohexylamine with

3-methoxyaniline. LCMS (ES) [M+l] ' m/z: 393; 'H-NMR (300 MHz, DMSO-Appm): δ 10.19 (s, IH), 7.67 (d, J= L5 Hz, IH), 7.58 (d, J = 1.2 Hz, IH), 7.33 (t, 7=2.1 Hz, IH), 7.25-7.H (m, 2H), 6.63-6.59 (m, IH), 4.35 (s, 2H), 3.69 (s, 3H), 3.61 (s, 3H), 3.31 (s, 3H),3.13 (t, 7=7.2 Hz, 2H), 2.74 (t, 7= 7.8 Hz, 2H), 2.01-1.90 (m, 2H).

Example 1.279

[1264] Synthesis of (2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyî)amino}-N-(pyridazin-4-yl)propanamide (Compound 273)

O_X,NH

[1265] Compound 273 was synthesized similar to compound 108 by replacing cyclohexylamine with 10 4-pyridazinylamîne and by replacing 2-(tributylstannyl)pyridine with 3-(tributylstannyl)isoquinoline.

LCMS (ES+): [Μ+ΗΓ = 426. Ή NMR (400 MHz, DMSO-d6) δ 11.87 (s, IH), 9.62 - 9.55 (m, 2H), 9.15 (s, IH), 9.09 (d,7=6.2 Hz, IH), 8.39 - 8.26 (m, 2H), 8.22 (dd, 7= 6.2, 2.7 Hz, IH), 7.96 (dddd, 7 = 34.5, 8.1, 7.0, 1.2 Hz, 2H), 5.66 (d,7=7.7 Hz, 1 H), 3.54 (s, 3H), 3.47 - 3.29 (m, 2H), 3.17 - 3.06 (m, 2H), 2.26-2.08 (m, 2H), 1.70 (d,7=7.1 Hz, 3H).

Example 1.280

[1266] Synthesis of (2R)-2-{[2-(isoquinolin-3-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[6-(trifluoromethyi)pyridin-3-yl]propanamide (Compound 274)

575

[1267] Compound 274 was synthesîzed similar to compound 10S by replacing cyclohexy lamine with 6-trifluoropyridin-3-amine. LCMS (ES+); [M+H]⁺ = 426. 'H NMR (400 MHz, DMSO-d6) δ l L87 (s, 5 IH), 9.62 - 9.55 (m, 2H), 9.15 (s J H), 9.09 (d, 7= 6.2 Hz, I H), 8.39 - 8.26 (m, 2H), 8.22 (dd, J= 6.2,

2.7 Hz, IH), 7.96 (dddd, 7= 34.5, 8.1, 7.0, 1.2 Hz, 2H), 5.66 (d,7= 7.7 Hz, IH), 3.54 (s, 3H), 3.47-

3.29 (m, 2H), 3.17 - 3.06 (m, 2H), 2.26-2.08 (m, 2H), 1.70 (d,7= 7.1 Hz, 3H).

Example 1.281

[1268] Synthesis of N-(l-hy droxy-2-methylpropan-2-y 1)-2-( {2-[l-(3-hydroxy propyl)-lH-im idazol-

4-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 275)

576

Pd(dppf)Cl_ib Κ₃Ρ0<, H₂O dioxane, 100°C, 16h

NaOH, THF, H₂0 rt_b 2h

HATU, DIEA, DMF rt, 2h

H

HCI/dloxane rt, 2h

jqCQa, DMF

TO^C, 4Ôh

TBAE THF rt, 2h

Scheme 115

Step 1

[1269] Into a 100-mL round-bottom flask were placed ethyl N-(2-chloro-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate (2.00 g, 7.415 mmol, 1.00 equiv), dioxane (20.00 mL, 236.082 mmol, 31.84 equiv), water (2 mL), I-(triphenylmethyl)imidazol-4-ylboronic acid (3.94 g, 11.122 mmol, 1.50 equiv), K3PO4 (3.15 g, 14.830 mmol, 2.00 equiv) and Pd(dppf)Ch (0.54 g, 0.741 mmol, 0.10 equiv). The resulting solution was stirred for 16 hr at 100 °C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:3).

This resulted in 0.88 g (21.83%) of ethyl N-methyl-N-(2-(l-trityl-lH-imidazol-4-yl)-6,7-dihydro-5Hcyc]openta[d]pyrimidin-4-yl)glycinate as a yellow solid. LCMS (ES) [M+1 ]⁺ m/z:544.

Step 2

[1270] Into a 100-mL round-bottom flask were placed ethyl N-methyl-N-(2-(l-trityl-lH-imidazol-4yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycinate (800.00 mg, 1.471 mmol, 1.00 equiv), THF 15 (5.00 mL, 61.715 mmol, 41.94 equiv), HjO (5.00 mL, 277.542 mmol, 188.61 equiv) and NaOH ( 117.71 mg, 2.943 mmol, 2.00 equiv). The resulting solution was stirred for 2 hr at 25 ’C. The resulting solution ~ 577 was diluted with 20 mL of water. The pH value of the solution was adjusted to 6 with HCl (l mol/L).

The solids were collected by filtration. This resulted in 640 mg (84.35%) ofN-methyl-N-(2-(l-trityIlH-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine as an off-white solid. LCMS (ES)[M+lf m/z: 5 16.

Step 3

[1271] Into a 25-mL round-bottom flask were placed N-methyl-N-(2-(1 -trityl-lH-imidazol-4-yL)6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)glycine (640.00 mg, 1.241 mmol, 1.00 equiv), DMF (10 mL), 2-amîno-2-methyl-l-propanol (110.64 mg, 1.241 mmol, 1.00 equiv), HATU (707.93 mg, 1.862 mmol, 1.50 equiv) and DIEA (481.26 mg, 3.724 mmol, 3.00 equiv). The resulting solution was stirred 10 for 2 hr at 25 °C. The crude reaction mixture was filtered and subjected to reverse phase préparative

HPLC (Prep-C18, 20-45uM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 40% MeCN in water to 50% MeCN in water over a 10 min period, water contains 0.1% NH3H2O). This resulted in (250 mg, 34.33%) N-( 1-hydroxy-2-methylpropan-2-yl)-2-(methy 1(2-(1-trityl-lH-imidazol-4-y 1)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide as a light yellow solid. LCMS (ES) [M+l]' 15 m/z: 587.

Step 4

[1272] Into a 25-mL round-bottom flask were placed N-(I-hydroxy-2-methylpropan-2-yl)-2(methyl(2-(l-trityl-lH-imidazol-4-yI)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide (250.00 mg, 0.426 mmol, 1.00 equiv), HCl(gas) in 1,4-dioxane (10.00 mL). The resulting solution was 20 stirred for 2 hr at 25 °C. The solids were collected by filtration. This resulted in 150mg(92.43%)of2- ((2-(1 H-imidazol-4-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(l-hydroxy-2methylpropan-2-yl)acetainide hydrochloride as a yellow solid. LCMS (ES) [M+l]⁺ m/z: 381.

Step 5

[1273] Into a 100-mL round-bottom flask were placed 2-((2-(1 H-imidazol-4-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(l-hydroxy-2-methylpropan-2-yl)acetamide hydrochloride (150.00 mg, 0.394 mmol, 1.00 equiv), dimethylformamide (10 mL), DIEA (152.70 mg, 1.181 mmol, 3.00 equiv) and t-butyldimethylchlorosilane (71.23 mg, 0.473 mmol, 1.20 equiv). The resulting solution was stirred for 16 hr at 25 °C. The crude reaction mixture was filtered and subjected to reverse phase préparative HPLC (Prep-C18, 20-45uM, 120 g, Tianjin Bonna-Agela Technologies;

578 gradient elution of 50% MeCN in water to 60% MeCN in water over a 10 min period, water contains 0.l%NH₃H₂O) to provide -((2-(lH-imidazol-4-yl)-6_J7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)-N-(l-((tert-buty ldi methy lsilyl)oxy)-2-methylpropan-2-yl)acetamide as a light yellow solid (120 mg, 66.43%). LCMS (ES) [M+l]⁺ m/z: 459.

Step 6

[l 274] Into a 100 mL round-bottom flask were placed 2-((2-(1 H-imidazol-4-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-y[)(methyJ)arnino)-N-(l-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2yl)acetamide (120.00 mg, 0.262 mmol, 1.00 equiv), diméthylformamide (10 mL), 3-bromopropanol (72.73 mg, 0.523 mmol, 2.00 equiv), K₂CO₃ (108.47 mg, 0.785 mmol, 3.00 equiv). The resulting solution was stirred for 48 hr at 70 °C. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). The collected fractions were combined and concentrated. This resulted in 80 mg (59.17%) ofN-(l-((tert-butyldimethylsilyl)oxy)-2-methylpropan-2-yl)-2-((2-(l-(3hy droxy propyl)-lH-imidazo!-4-y l)-6,7-dihydro-5 H-cyclopenta[d]py rimidin-4yl)(methyl)amino)acetamide as a yellow solid. LCMS (ES) [M+l]⁺ m/z:517.

Step 7

[1275] Into a 100-mL round-bottom flask were placed N-(l-((tert-butyldimethylsiIyl)oxy)-2methylpropan-2-yl)-2-((2-(l-(3-hydroxypropyl)-lH-imidazol-4-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(m ethy l)amino)acetam ide (80.00 mg, 0.155 mmol, 1.00 equiv), tetrahydrofuran (5 mL), TB AF (4.05 mg, 0.015 mmol, 0.10 equiv). The resulting solution was stirred for 20 2 hr at 25 °C. The crude reaction mixture was fîltered and subjected to reverse phase préparative HPLC (Prep-C18, 20-45uM, 120 g, Tianjin Bonna-Agela Technologies; gradient elution of 25% MeCN in water to 35% MeCN in water over a 10 min period, water contains 0.1% NH₃H₂O). This resulted in (18.6 mg, 29.85%) N-(l-hydroxy-2-methylpropan-2-yl)-2-((2-(l-(3-hydroxypropyl)-lH-imidazol-4-yl)6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yI)(methyl)amino)acetamide as an off-white solid LCMS (ES) [M+1 ]⁺ m/z: 403. ¹H NMR (300 MHz, DMSO-d6) δ 7.77 (d, J = 1.4 Hz, 1 H), 7.63 (d, J = 1.4 Hz, IH), 7.47 (s, 1 H), 4.95 (t, J = 5.9 Hz, 1 H), 4.65 (t, J = 5.1 Hz, IH), 4.10 (s, 2H), 4.05 (t, J = 7.0 Hz, 2H), 3.49-3.35 (m, 4H), 3.21 (s, 3H), 3.08 (t, J = 7.2 Hz, 2H), 2.73 (t, J = 7.8 Hz, 2H), 1.92 (dt, J = 13.2, 7.3 Hz, 4H), ] .18 (s, 6H).

Example 1.282

[1276] Synthesis of 2-[(2-[4-[(l-hydroxy-2-methylpropan-2-yl)oxy]pyridin-2-yl}-5H,6H,7H21052

579 cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(2-methoxypyrimidin-5-yl)acetam (Compound 276)

[1277] Compound 276 was synthesized similar to compound 144 by replacing cyclohexylamine with 2-methoxypyrimidin-5-amine and replacing 4-[2-(oxan-2-yloxy)ethoxy]-2-(trimethylstannyl)pyrîdine with 4-[[2-methyl-l-(oxan-2-yloxy)propan-2-yl]oxy]-2-(trimethylstannyl)pyridine. LCMS (ES) [M+l] ⁺m/z: 480; 'H-NMR (300 MHz, DMSO-7₆,ppm/. Ô 10.49 (s, LH), 8.74 (s, 2H), 8.43 (d, 7= 5.4 Hz, ll-I), 7.77 (d, 7 = 2.4 Hz, IH), 7.03 (dd,7= 5.7, 2.7 Hz, IH), 4.67 (s, LH), 4.42 (s, 2H), 3.87 (s, 3H), 3.80 (s, 2H), 3.24 (s, 3H), 3.22 (t, 7= 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.07-1.99 (m, 2H), 1.16 (s, 6H).

Example 1.283

[1278] Synthesis of (2R)-N-(3-fluorophenyl)-2-{methyl[2-(l-methyl-lH-imidazol-4-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yi]amino}propanamide (Compound 277)

[ 1279] Compound 277 was synthesized similar to compound 108 by replacing 1-cyclohexylamine with 3-fluoroaniline and by replacing 2-(tributylstannyl)pyridine with l-methyl-4(tributylstannyl)imidazole. LCMS (ES) [M+l] ⁺ m/z: 395;¹ H-NMR (300 MHz, DMSO-7,5,ppm)\ δ 10.60 (s, IH), 8.14 (s, HCOOH), 7.78 (d, 7= 1.2 Hz, IH), 7.69 (d, J= 1.5 Hz, IH), 7.66 (dt. 7= 12.0, 2.4 Hz, IH), 7.45-7.40 (m, IH), 7.32-7.24 (m, IH), 6.83 (td,7= 8.4, 2.7 Hz, IH), 5.26 (q,7=7.2 Hz, IH), 3.68 (s, 3H), 3.22-3.14 (m, IH), 3.13 (s, 3H), 3.08-2.97 (m, IH), 2.86-2.66 (m, 2H), 2.06-1.86 (m, 2H), 1.43 (d, 7=7.2 Hz, 3H).

Example 1.284

[1280] Synthesis of (2R)-N-(3-methoxyphenyl)-2-{methyl[2-(l-methyl-1 H-imidazol-4-yl)5H,6H,7H-cyclopenta[d]pyrimidîn-4-yl]amino}propanamide (Compound 278)

[1281 ] Compound 278 was synthesized similarto compound 108 by replacing 1-cyclohexylamine with 3-methoxyaniline and by replacing 2-(tributylstannyl)pyridine with l-methyl-4(tributylstannyl)imidazole.. LCMS (ES) [M+l] ⁺ m/z: 407; 'H-NMR (300 MHz, DMSO-rfe, ppm): δ

10.58 (s, IH), 8.17 (s, HCOOH), 7.81 (d, J= 1.5 Hz, IH), 7.72 (d, J= 1.2 Hz, IH), 7.31 (t,7=2.1 Hz,

IH), 7.29-7.23 (m, IH), 7.14 (t,7=8.1 Hz, IH), 6.60-6.55 (m, IH), 5.29 (q,7=7.2 Hz, IH), 3.69 (s, 3H), 3.63 (s, 3H), 3.21-3.10 (m, IH), 3.13 (s, 3H), 3.06-2.96 (m, IH), 2.86-2.66 (m, 2H), 2.03-1.86 (m, 2H), 1.42 (d,7=7.2 Hz, 3H).

Example 1.285

[1282] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(3-methoxyphenyl)acetamide (Compound 279)

581

T₃P. D1EA, DMF

Scheme 116

Step 1

[1283] Into a 250 mL three necked round bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed ethyl N-(2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrirnidin-4-yl)-Nmethylglycinate (2.0 g, 7.4 mmol, 1.00 equiv), toluene (40.00 inL), 4-fluoro-2-(tributylstannyl)pyridine (4.3 g, 11.1 mmol, 1.5 equiv), Pd(PPhs)4 (780 mg, 0.74 mmol, 0.10 equiv). The mixture was stirred for 36 h at 110 °C in oil bath. The reaction mixture was cooled to room température, concentrated to remove the solvent; the residue was purified by silica gel column with dichloromethane/methanol (25:1). This resulted in 1.4 g (57% yield) of ethyl N-(2-(4-fluoropyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)-N-methylglycinate as yellow solid. LCMS (ES) [M+l]+ m/z: 331.

Step 2

[1284] Into a 250 mL round-bottom flask, was placed ethyl N-(2-(4-11 uoropyridin-2-yl)-6_s7-dihydro5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate (1.4 g, 4.2 mmol, 1 equiv), tetrahydrofuran (30 mL), water (15 mL), lithiumol (0.21 g, 8.4 mmol, 2.00 equiv). The resulting solution was stirred for 2 hr at 25 °C. The resulting mixture was concentrated. The resulting solution was diluted with 50 mL of water. The pH value of the solution was adjusted to 4 with HCl (1 mol/L). The solids were collected by filtration. This resulted in 0.68 g (53%) of N-(2-(4-fluoropyrtdin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)-N-methylglycine as an off-white solid. LCMS (ES) [M+l]⁺ m/z 303.

Step 3

582

[1285] Into a 8 mL viai were placed m-anisidine (102 mg, 0.83 mmol, l.OO equiv), DMF (5 mL), 3-

[2-(4-fluoropyrÎdin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidÎn-4-yl]butanoic acid (250 mg, 0.83 mmol, l .00 equiv) and DlEA (322 mg, 2.49 mmol, 3.00 equiv). This was followed by the addition of T3P (317 mg, l.OO mmol, L20 equiv) at 0°C. The resulting solution was stirred for 2 hr at 25 °C. The reaction was 5 then quenched by the addition of 50 mL of water. The resulting solution was extracted with 3 x 100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3 x 100 ml of brine and concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:l). This resulted in 180 mg (53.25%) of2-[[2-(4-fluoropyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin~4-yl](methyl)amino]-N-(3-methoxyphenyl)acetamide as light brown oil. LCMS (ES) [M+l]⁺ m/z 408.

Step 2

[1286] Into a 50 mL 3-necked round-bottom flask were placed ethylene glycol (114 mg, 1.84 mmol, 5.00 equiv), THF (5 mL). This was followed by the addition ofNaH (18 mg, 0.74 mmol, 2.00 equiv) at 0 °C. The resulting solution was stirred for 30 min at 0°C. To this was added 2-[[2-(4-fluoropyridin-2- yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yi](methyI)amino]-N-(3-methoxyphenyl)acetamide (150 mg, 0.37 mmol, 1.00 equiv) at 0 °C. The resulting solution was stirred for 1 hr at 25 °C. The reaction was then quenched by the addition of 30 mL of water. The resulting solution was extracted with 2x50 mL of ethyl acetate, the organic layers were combined and concentrated under vacuum. The residue was dissolved in 5 mL of MeOH. The crude product was purified by Prep-HPLC with the following conditions (Prep-HPLC-001): Column, Sunfire Prep C18 OBD Column, 50*250 mm, 5pm lOnm; mobile phase, Water (0.1% FA) and ACN (5% PhaseB up to 35% in 15 min). This resulted in 61.0 mg (36.86%) of 2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidm-4yl](methyl)amino)-N-(3-methoxyphenyl)acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z 450. ^!H NMR (300 MHz, DMSO-<7û) δ 10.22 (s, IH), 8.46 (d, J= 5.7 Hz, IH), 8.14 (s, 0.4HCOOH), 7.80 (d, J= 25 2.5 Hz, 1 H), 7.30 (t, 7= 2.2 Hz, IH), 7.19 (t, 7= 8.0 Hz, 1 H), 7.15-7.08 (m, 1 H), 7.04 (dd, 7= 5.7, 2.6

Hz, IH), 6.67-6.57 (m, IH), 4.90 (t, 7= 5.4 Hz, IH), 4.44 (s, 2H), 4.03 (t, J= 4.7 Hz, 2H), 3.69 (s, 3H), 3.69-3.64(m, 2H), 3.37 (s, 3H), 3.21 (t, 7= 7.3 Hz, 2H), 2.85 (t, 7= 7.8 Hz, 2H), 2.05-1.93 (m, 2H).

Example 1.286

[1287] Synthesis ofN-(3-f1uorophenyl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(inethyl)amÎno)acetamide (Compound 280)

583

Sn_sMe_e

Pd(PPh₃)₄, Toluene

Step l

[1288] Into a 100-mL round-bottom flask were placed a mixture of ethyl N-(2-chloro-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycinate (3.00 g, l l.l mmol, l.OO equiv), MeOH (30.0 mL), H2O (6.00 mL), NaOH (889 mg, 0.022 mmol, 2.00 equiv). The resulting solution was stirred for 2 hours at room température. The resulting mixture was concentrated. The resulting solution was diluted with 50 mL of H₂O. The pH value of the solution was adjusted to 4 with HCl (2 mol/L). The solids were collected by filtration and concentrated. This resulted in 1.3 g (48.36%) of N-(2-chloro-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)-N-methylglycine as a white solid. LCMS (ES) [M+ ! ]+ m/z 270.

Step 2

[1289] Into a 50-mL round-bottom flask were was placed N-(2-chloro-5H,6H,7H cyclopenta[d]pyrimidin-4~yl)-N-methylglycine (3.7 g, 15.29 mmol, 1.00 equiv), DMF (30.00 mL),

HATU (6.97 g, 18.34 mmol, 1.20 equiv), DIEA (5.92 g, 45.86 mmol, 3.00 equiv), 3-fluoroaniline(2.04

584 g, 18.34 mmol, 1.20 equiv). The resulting solution was stirred for 2 hr at 25 °C. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3 xlOO of brine and concentrated under vacuum. The residue was applied onto a silica gel column with DCM/MeOH (10:1). This resulted in 3.20 g (62.50%) of 2-([2-chloro-5H,6H,7H5 cyclopenta[d]pyrimidin-4-yl](melhyl)amino)-N-(3-fluorophenyl)acetamide as yellow solid. LCMS (ES) [M+lf m/z 335.

Step 3

[1290] Into a40-mL vial purged and maintained with an inert atmosphère of nitrogen were placed l-[(2-chloropyridin-4-yl)oxy]-2-methyipropan-2-ol (1.00 g, 4.96 mmol, 1.00 equiv), Sn₂Me& (1.71 g, 10 5.21 mmol, 1.05 equiv), toluene (30 mL), Pd(PPh₃)₄ (0.57 g, 0.50 mmol, 0.10 equiv). The resulting solution was stirred for 2 hr at 100 °C. To this was added 2-([2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)acetamide (1.16 g, 3.471 mmol, 0.7 equiv), Pd(PPh₃)₄ (0.57 g, 0.496 mmol, 0.10 equiv). The resulting solution was stirred for overnight at 100 °C. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1 ). The crude product was purified by Prep-HPLC with the foîlowing conditions : Column, Sunfire Prep Cl 8 OBD Column, 50*250 mm, 5pm 1 Onm; mobile phase A, Water(0.1% FA) and mobile phase B, AcCN (5% mobile Phase B up to 40% in 15 min); This resulted in 48.2 mg (2.09%) ofN-(3-fluorophenyl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]5H,6H,7H-cyciopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z 466. Ή NMR (300 MHz, DMSCM0 δ 10.43 (s, IH), 8.44 (d, 7= 5.6 Hz, IH), 7.78 (d, 7= 2.5 Hz, IH), 7.60-7.49 (m, IH), 7.37-7.24 (m, 2H), 7.02 (dd, 7= 5.6, 2.6 Hz, IH), 6.92-6.80 (m, 1H),4.65 (s, IH), 4.44 (s, 2H), 3.80 (s, 2H),3.36 (s, 3H), 3.21 (t, 7= 7.3 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.071.99 (m,2H), 1.17 (s, 6H).

Example 1.287

[1291] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-(l-methyI-6-oxo-l,6-dihydropyridin-3-yl)acetamide (Compound 281)

[1292] Compound 281 was synthesized similar to compound 135 replacing oxolan-3-amine with 5amino-l-methylpyridin-2-one. LCMS (ES) [M+l]⁺ m/z: 42J; 'H-NMR (300 MHz, DMSO-Λ,ppm)\ δ lO.Ol (s, IH), 8.46 (d, J = 5.6 Hz, IH), 8.07 (d, J = 2.8 Hz, IH), 7.78 (d, J = 2.6 Hz, IH), 7.40 (dd, J =

9.7, 2.9 Hz, JH), 7.02 (dd, J = 5.6, 2.6 Hz, IH), 6.38 (d, J = 9.6 Hz, IH), 4.35 (s, 2H), 3.83 (s, 3H), 3.37 (s, 3H), 3.35 (s, 3H), 3.20 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.04-1.99 (m, 2H).

Example 1.288

[1293] Synthesis of2-[(2-{2H,3H-[1,4]dioxino[2,3-c]pyridin-7-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(3-fluorophenyl)acetamide (Compound 282)

[1294] Compound 282 was synthesized similar to compound 280 by replacing l-[(2-chloropyridin4-yl)oxy]-2-methylpropan-2-ol with 7-bromo-2H,3H-[l,4]dioxino[2,3-c]pyridine. LCMS (ES) [M+l] ⁺m/z: 436; 'H-NMR (300 MHz, DMSO-Λ, p/wt): δ 10.42 (s, IH), 8.16(0.3 HCOOH), 8.14 (s, IH), 7.77 (s, 1 H), 7.55 (dd,7 = 12.0,2.1 Hz, 1 H), 7.38-7.25 (m, 2H), 6.92-6.80 (m, 1 H), 4.45 (s, 2H), 4.4] (s, 4H), IS 3.35 (s, 3H), 3.18 (t, 7= 7.3 Hz, 2H), 2.80 (t, 7= 7.8 Hz, 2H), 2.04-1.94 (m, 2H).

Example 1.289

[1295] Synthesis of 2-{[2-(Îsoquinolin-3-yl)-5H,6H,7H-cycîopenta[d]pyrimidin-4yl](methyl)amino}-N-[5-(tritluoromethoxy)pyridin-3-yl]acetamide (Compound 283)

586

[1296] Compound 283 was synthesized similar to compound 135 by replacing of 4-methoxy-2(tributylstannyl)pyridîne with 3-(trimethylstannyl)isoquinoline and replacing oxolan-3-amine with 3amino-5-trifluoromethoxypyridine. LCMS (ES) [M+l]⁺ m/z: 495. ’H NMR (300 MHz, Chloroform-7) δ 10.96 (s, lH), 9.33 (s, lH), 8.80 (d, 7=2.1 Hz, IH), 8.71 (s, IH), 8.33 (d,7=2.5 Hz, IH), 8.23 (s, IH), 8.14 (d, 7 = 7.7 Hz, IH), 7.78-7.69 (m, 3H), 4.51 (s, 2H), 3.44 (s, 3H), 3.24 (m, 2H), 2.88 (m, 2H), 2.05 (m, 2H).

Example 1.290

[1297] Synthesis of2 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin4-yl}(methyl)amino)-N-(5-methylpyrazin-2-yl)acetamide (Compound 284)

[1298] Compound 284 was synthesized similar to compound 44 by replacing oftert-buty lamine with 5-methyipyrazin-2-amine. LCMS (ES) [M+l]⁺ m/z: 436.2. 'H NMR (300 MHz, Chloroform-7) δ 9.59 (br, IH), 9.40 (s, IH), 8.62-8.61 (m, IH), 8.08 (s, IH), 7.92 (s, IH), 6.89-6.88 (s, IH), 4.43-4.42 (m, 2H), 4.21-4.20 (m, 2H), 4.01-4.00 (m, 2H), 3.28 (s, 3H), 3.03-3.01 (m, 2H), 2.76-2.75 (m, 2H), 2.49 (s, 3H), 2.13-4.11 (m, 2H).

Example 1.291

[1299] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyc]openta[d]pyrimidin-4yl}(methyl)amino)-N-(6-methoxypyridazin-3-yl)acetamide (Compound 285)

587

[1300] Compound 285 was synthesized similar to compound 44 by replacing of tert-buty lamine with 6-methoxypyridazin-3-amine. LCMS (ES) [M+l]⁺ m/z: 452. Ή NMR (300 MHz, DMSO-Λ, ppm) δ l Ll5 (s, IH), 8.41 (d,7=5.7Hz, IH), 8.21 (d,7=9.6 Hz, IH), 8.15 (HCOOH), 7.74 (d, 7= 2.7 Hz,

IH), 7.22 (d, 7= 9.6 Hz, l H), 6.98 (dd,7= 5.7,2.7 Hz, 1H),4.85 (br, IH), 4.55 (s, 2H), 4.00-3.97 (m, 5H), 3.66 (t, 7= 4.8 Hz, 2H), 3.36 (s, 3H), 3.21 (t, 7= 7.2 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.07-L96 (m, 2H).

Example l .292

[1301 ] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-410 yl}(methyl)amino)-N-(6-methylpyridazin-3-yl)acetamide (Compound 286)

[1302] Compound 286 was synthesized similar to compound 44 by replacing tert-butylamine with 615 methypyridazin-3-amine. LCMS (ES) [M+l ]⁺ m/z: 436. Ή NMR (300 MHz, DMSO-Λ, ppm δ 11.23 (s, IH), 8.40 (d, J = 5.6 Hz, IH), 8.15(d, 9.4 Hz), 8.14 (HCOOH), 7.71 (d, J = 2.6 Hz, IH), 7.52 (d, J = 9.2 Hz, 1 H), 6.96 (dd, J = 5.6, 2.5 Hz, IH), 4.86 (s, IH), 4.55 (s, 2H), 3.97 (t, J = 4.8 Hz, 2H), 3.63 (s, 2H), 3.35 (s, 2H), 3.21 (t, J = 7.5 Hz, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.55 (s, 3H), 2.06-1.95 (m, 2H).

Example 1.293

[1303] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pynmidin-4-

588 yl](methyl)amino}-N-(l-methyl-2-oxo-l,2-dihydropyridin-4-yl)acetamide (Compound 287)

[l 304] Compound 287 was synthesized similar to compound 135 by replacing oxolan-3-amine with 4-amino-l-methylpyridin-2-one hydrochloride. LCMS (ES) [M+l] ⁺ m/z: 421;¹ H-NMR (300 MHz, DMS0-7_à,/W δ 10.36 (s, IH), 8.44 (d, J = 5.6 Hz, IH), 7.74 (d, J = 2.5 Hz, IH), 7.58 (d, J = 7.4 Hz, IH), 7.00 (dd, J = 5.6, 2.6 Hz, IH), 6.71 (d, J =2.2 Hz, IH), 6.39 (dd, J = 7.4, 2.3 Hz, IH), 4.42 (s, 2H), 3.80 (s, 3H), 3.36 (s, 3H), 3.33 (s, 3H), 3.20 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.7 Hz, 2H), 2.04-1.99 (m, 2H).

Example 1.294

[1305] Synthesis of 2-[methyl(2-{ IH-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pyrimidm-4-yl)amino]-N-[6-(trifluoromethyl)pyridin-3-yl]acetamide (Compound 288)

[1306] Compound 288 was synthesized similarto compound 135 by replacing 4-methoxy-2(tributylstannyl)pyridine with 1 -(oxan-2-yl)-5-(tributylstannyl)-1 H-pyrazolo[3,4-c]pyridine and by replacing oxolan-3-amine with 6-trifluoropyridin-3-amine. LCMS (ES+): [M+H]⁺ = 469.1. 'H NMR (400 MHz, DMSO-d6) δ 11.71 (s, lH),9.20(s, IH), 9.11 (s, IH), 9.05 (s, IH), 8.40 (d, J= 8.7 Hz, IH), 8.29 (s, IH), 7.86 (d, 7= 8.6 Hz, IH), 4.83 (s,2H), 3.61 (s, 2H), 3.35 - 3.32 (m, 2H), 3.11 - 3.04 (m, 2H), 2.18 - 2.05 (m, 2H).

Example 1.295

[1307] Synthesis of N-(4-fluorophenyl)-2-[methyl(2-{lH-pyrazolo[3,4-c]pyridin-5-yl}-5H,6H,7Hcyclopenta[d]pynmîdin-4-yl)amino]acetamide (Compound 289)

[l 308] Compound 289 was synthesized similar to compound î35 by replacing 4-methoxy-2(tributylstannyl)pyridîne with l-(oxan-2-yl)-5-(tributylstannyl)-lH-pyrazolo[3,4-c]pyridine and by replacing oxolan-3-amine with 4-fluoroaniline. LCMS (ES+): [M+H]⁺ = 4l8.L ’HNMR (400 MHz,

DMSO-d6) δ 10.65 (s, IH), 9.15 (s, IH), 8.88 (s, IH), 8.20 (s, IH), 7.73 - 7.67 (m, 2H), 7.18 - 7.12 (m, 2H), 4.60 (s, 2H), 3.5 J (s, 3H), 3.26-3.24 (m, 2H),3.0l -2.96 (m, 2H), 2.12 -2.03 (m, 2H).

Example 1.296

[1309] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyndin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(5-methoxypyrazin-2-yl)acetamide (Compound 290)

[1310] Compound 290 was synthesized similar to compound 44 by replacing tert-butylamine with 5methoxypyrazin-2-amine. LCMS (ES) [M+l]⁺ m/z: 452. ’H NMR (300 MHz, DMSO-Z, ppm) δ 10.79 (s, 1 H), 8.81 (s, IH), 8.41 (d, J = 5.5 Hz, IH), 8.11 (d, J = 1.5 Hz, IH), 7.73 (d, J = 2.6 Hz, IH), 6.97 (dd, J = 5.6, 2.6 Hz, 1 H), 4.85 (br, lH),4.58(s, 2H), 4.00 (t, J = 4.7 Hz, 21-1),3.85 (s, 3H), 3.71-3.63 (m, 15 2H), 3.41 (s, 3H), 3.33-3.15 (m, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.08-1.88 (m, 2H).

Example 1.297

[131 l] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl] (methyl)amino)-N-(2-methylpyrimidin-5-yl)acetamide (Compound 291)

590

[l 312] Compound 291 was synthesized similar to compound 44 by replacing tert-buty lamine with 2methylpyrimidin-5-amine. LCMS (ES) [M+l] ⁺ m/z: 436. 'H NMR (300 MHz, DMSOée, ppm) δΐ0.73 (s, l H), 8.89 (s, 2H), 8.42 (d,7=5.6 Hz, IH), 8.36 (s, IH), 7.76 (d,7=2.5 Hz, IH), 7.01 (dd,7=5.7, 5 2.6 Hz, IH), 4.45 (s, 2H), 4.04 (t, 7= 4.8 Hz, 2H), 3.70 (q, J= 5.0 Hz, 2H),3.36 (s, 3H), 3.22 (t, 7 = 7.3

Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.55 (s, 3H), 2.15-1.96 (m, 2H).

Example 1.298

[1313] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)arnino)-N-(3-methylphenyl)acetamide (Compound 292)

[1314] Compound 292 was synthesized similar to compound 44 by replacing tert-butylamîne with m-toiuidine. LCMS (ES) [M+l] ⁺ m/z: 434. Ή NMR (300 MHz, DMSOé_& ppm) δ 10.12 (s, IH), 8.44 (d, .1=5.6 Hz, IH), 7.79 (d, J=2.5 Hz, IH), 7.46-7.33 (m, 2H), 7.19-7.13(m, IH), 7.00 (dd, J=5.6, 2.5 Hz, IH), 6.85 (d, J=7.5 Hz, 1 H), 4.88 (t, J=5.4 Hz, IH), 4.42 (s, 2H), 4.02 (t, J =4.7 Hz, 2H), 3.66 (q, J=5.0 15 Hz, 2H), 3.36 (s, 3H), 3.20 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.9 Hz, 2H), 2.25 (s, 3H), 2.07-1.96 (m, 2H).

Example 1.299

[1315] Synthesis of 2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(3-fluorophenyl)acetamide (Compound 293)

591

Scheme 118

Step l

[1316] Into a 50-mL 3-necked round-bottom flask were placed tert-butyl N-(2hydroxyethyl)carbamate (l .47 g, 9.12 mmol, 1.20 equiv) and THF ( 10 mL). This was followed by the addition ofNaH (0.22 g, 9.17 mmol, 1.20 equiv) at 0 ^QC. The resulting solution was stirred for 30 min at 0 °C and was added 2-chloro-4-fluoropyridine (1.00 g, 7.60 mmol, 1.00 equiv). After stirred for 2 hr at 25 °C, the reaction was quenched by the addition of 50 mL of water. The resulting mixture was extracted with 3x100 mL of ethyl acetate, the organic layers were combined, washed with 3x100 ml of brine, dried over anhydrous sodium sulfate. The solids were filtered out and the fîltrate was concentrated under vacuum. This resulted in 1.5 g (49.34%) of tert-butyl N-[2-[(2-chloropyridin-4yl)oxy]ethyl]carbamate as yellow oil. LCMS (ES) [M+l]⁺ m/z 273.

[1317] Step 2. Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen were placed tert-butyl N-[2-[(2-chloropyridin-4-yI)oxy]ethyl]carbamate (1.00 g, 3.67 mmol, 1.00 equiv),

Toluene (30 mL), Sn₂Mee(l.26 g, 3.85 mmol, l.05 equiv) and Pd(PPh₃)₄ (0.42 mg, 0.36 mmol, O.l equiv). The resulting solution was stirred for 4 h at I00 °C. To this was added C2-([2-chloro5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(3-fluorophenyl)acetamide (0.86 g, 2.57 mmol, 0.7 equiv), Pd(PPh₃)4 (0.42 g, 0.36 mmol, O.l equiv). After stirred for overnight at 100 °C, the 5 mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (20:1). This resulted in 300 mg (15.25%) of tert-butyl N-[2~([2-[4-([[(3fluorophenyl)carbamoyl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4yl]oxy)ethyl]carbamate as brown oil. LCMS (ES) [M+l]⁺ m/z 537.

Step 3 lû [1318] Into a 50-mL round-bottom flask were placed tert-butyl N-[2-([2-[4-([[(3fluorophenyl)carbamoyl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4yl]oxy)ethyl]carbamate (300 mg, 1.00 equiv), DCM (2 mL) and HCl (gas) in 1,4-dioxane (2 mL). The resulting solution was stirred for 2 hr at 25 °C. The resulting mixture was concentrated under vacuum. The residue was dissolved in 5 mL of MeOH. The crude product was purified by Prep-HPLC with the 15 following conditions: Column, Sunfire Prep C18 OBD Column, 50*250 mm, 5pm 1 Onm; mobile phase

A, Water (0.1% FA) and mobile phase B, AcCN (5% mobile Phase B up to 35% in 15 min); Detector, UV 254 nm. This resulted in 60.5 mg of 2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-fluorophenyl)acetamide as a white solid. LCMS (ES) [M+l]⁺ m/z 437. Ή NMR (300 MHz, DMSO-7₆): δ 10.56 (s, IH), 8.69 (d, J= 6.0 Hz, IH), 8.07 (br, 20 3H), 7.96 (d,7=2.6 Hz, IH), 7.65-7.54 (m, IH), 7.44-7.27 (m, 3H), 6.97-6.84 (m, 1H),4.65 (s, 2H),

4.37 (s, 2H), 3.48 (s, 3H), 3.26 (s, 4H), 3.00 (t, 7= 7.9 Hz, 2H), 2.08-3.02 (m, 2H).

Example 1.300

[1319] Synthesis of 2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(3-fluorophenyl)acetamide (Compound 294)

[1320] Compound 294 was synthesized similar to compound 348 replacing tert-butylamine with 3-

593 fluoroaniline. LCMS (ES) [M+l] ⁺ m/z: 465. Ή NMR (300 MHz, DMSO-Æ) δ 10.44 (s, IH), 8.43 (d, J = 5.6 Hz, IH), 8.18 (s, IH), 7.75 (d, 7=2.5 Hz, IH), 7.60-7.50 (m, IH), 7.38-7.25 (m, 2H), 7.00 (dd,7= 5.6, 2.6 Hz, JH), 6.93-6.80 (m, IH), 4.43 (s, 2H), 4.07 (t, 7= 5.5 Hz, 2H), 3.37 (s, 3H),3.2l (t,7= 7.3 Hz, 2H), 2.83 (t, 7 = 7.8 Hz, 2H), 2.59 (t, 7= 5.5 Hz, 2H), 2.21 (s, 6H), 2.06-1.96 (m, 2H).

Example l .301

[1321] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyndin-2-yI]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(5-methoxypyrimidin-2-yl)acetamide (Compound 295)

[1322] Compound 295 was synthesized similar to compound 44 replacing tert-buty lamine with 5methoxypyrimidin-2-amine. LCMS (ES) [M+1] ⁺ m/z: 452. 'H NMR (300 MHz, DMSO-7&) δ 10.67 (s, IH), 8.47-8.39 (m, 3H), 7.77 (d, 7=2.6 Hz, IH), 6.98 (dd,7= 5.6,2.6 Hz, 1 H), 4.88 (s, IH), 4.62 (s, 2H), 4.02 (t, 7= 4.7 Hz, 2H), 3.88 (s, 3H), 3.67 (t, 7= 4.7 Hz, 2H), 3.33 (s, 3H), 3.19 (t, 7= 7.4 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.15-1.96 (m, 2H).

Example 1.302

[1323] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(l-methyl-lH-pyrazol-4-yl)acetamide (Compound 296)

[1324] Compound 296 was synthesized similar to compound 44 replacing tert-buty lamine with 1methylpyrazol-4-amine. LCMS (ES) [M+1 ]⁺ m/z: 424. 'H NMR (300 MHz, DMSO-d6) δ 10.23 (s, 1 H), 8.46 (d, J=5.7Hz, IH), 7.84 (s, IH), 7.77 (d, J=2.5 Hz, 1 H), 7.40 (s, IH), 7.02 (dd, J = 5.7, 2.3 Hz, 1 H), 4.92 (t, J=5.4-Hz, 1 H), 4.35 (s, 2H), 4.06 (t, J=4.8 Hz, 2H), 3.76 (s, 3H), 3.72 (d, J=5.0 Hz, 2H), 3.32(s, 3H), 3.19 (t, J=7.3 Hz, 2H), 2.83 (t, J=7.8 Hz, 2H), 2.06-1.95 (m, 2H).

594

Examp Le 1.303

[1325] Synthesis of2-({2-[6-(hydroxymethyl)isoquinolin-3-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-

4-yl} (methy l)amino)-N-(6-methylpyridin-3-yl)acetamide (Compound 297)

[1326] Compound 297 was synthesized similar to compound 270 replacing 5-[[(tertbutyldimethylsi!yl)oxy]methyl]-3-(trimethylstannyl)isoquinoline with 6-(((tertbutyldimethylsilyl)oxy)methyl)-3-(trimethylstannyl)isoquinoline. LCMS (ES) [M+l]⁺ m/z: 455. Ή NMR (300 MHz, DMSO-d6) δ 10.51 (s, IH), 9.33 (s, IH), 8.69 (d, J = 2.3 Hz, 2H), 8.13 (d, J = 8.6 Hz, LH), 7.96 (dd, J = 8.4, 2.6 Hz, IH), 7.70-7.64 (m, 2H), 7.18 (d, J = 8.4 Hz, IH), 5.49 (t, J = 5.5 Hz, IH), 4.68 (d, J = 5.3 Hz, 2H), 4.49 (s, 2H), 3.45 (s, 3H), 3.29-3.22 (m, 2H), 2.96-2.85 (m, 2H), 2.39 (s, 3H), 2.11 -2.00 (m, 2H).

Example L304

[1327] Synthesis of 2-{[2-(5-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4y]](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide (Compound 298)

[1328] Compound 298 was synthesized similar to Compound 24 by replacing 2tributylstannylpyridine with 5-fluoro-2-(tributylstannyl)pyridine and by replacing tert-bytylamine with 6-methylpyridin-3-amine. LCMS (ES+): [M+H]⁺ = 393.1 . *H NMR (400 MHz, DMSO-d6) δ 10.77 (s, IH), 8.75 (d, 7= 2.8 Hz, IH), 8.69 (d, 7= 2.6 Hz, IH), 8.51 (dd, 7= 8.9, 4.6 Hz, 1 H), 7.98 - 7.87 (m, 2H), 7.25 (d, 7 = 8.4 Hz, 1 H), 4.64 (s, 2H), 3.49 (s, 3H), 3.27 - 3.24 (m, 2H), 3.00 - 2.95 (m, 2H), 2.42 (s, 3H), 2.12-2.03 (m, 2H).

595

Example l .305

[1329] Synthesis of N-tert-butyl-2-{[2-(5-fluoropyridin-2-yI)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}acetamide (Compound 299)

[ 1330] Compound 299 was synthesized similar to Compound 24 by replacing 2tributylstannylpyridine with 5-fluoro-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 358. L ’H NMR (400 MHz, dmso) δ 8.79 (d, 7= 2.8 Hz, IH), 8.55 (dd, 7= 8.8, 4.6 Hz, l H), 8.02 (td, 7= 8.7, 2.9 Hz, IH), 7.88 (s, IH), 4.30 (s, 2H), 3.40 (s, 3H), 3.22-3.18 (m, 2H), 3.01 -2.93 (m, 2H), 2.12-2.01 (m, 2H), L24 (s, 9H).

Example L306

[133 i ] Synthesis of N-tert-buty i-2-{[2-(5-c h loropyridin-2-y l)-5 H,6H,7H-cy cl openta[d|pyrimidin-4yi](methyl)amino}acetamide (Compound 300)

[ 1332] Compound 300 was synthesized similar to Compound 24 by replacing 2tributylstannylpyridine with 5-chloro-2-(trîbutylstannyl)pyridine. LCMS (ES+); [M+H]⁺ = 374. ’H NMR (400 MHz, DMSO-d6) δ 8.71 (dd, 7= 2.5, 0.7 Hz, IH), 8.38 (dd, 7= 8.5, 0.7 Hz, IH), 8.03 (dd, J = 8.5,2.5 Hz, IH), 7.68 (s, l H), 4.15 (s, 2H), 3.27 (s, 3H), 347 - 3.10 (m, 2H), 2.86 - 2.79 (m, 2H), 2.04 - l .94 (m, 2H), l .23 (s, 9H).

Example L307

[1333] Synthesis of N-tert-butyl-2-[methyl(2-{[l,3]thiazolo[4,5-c]pyridin-6-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 301 )

596

[1334] Compound 301 was synthesized similar to compound 245 replacing 2-chloro-4-(oxetan-3yloxy)pyridine with 6-bromo-[l,3]thiazolo[4,5-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 397. 'H NMR (300 MHz, DMSO-d6) δ 9.58 (s, IH), 9.42 (d, J = 0.9 Hz, IH), 9.25 (d, J = 0.9 Hz, IH), 8.14 (0.5 HCOOH), 5 7.79 (s, 1 H), 4.18 (s, 2H), 3.34 (s, 3H), 3.18 (l, J = 7.3 Hz, 2H), 2.86 (t, J = 7.8 Hz, 2H), 2.05-1.99 (m,

2H), 1.22 (s, 9H).

Example 1.308

[1335] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide (Compound 302)

[1336] Compound 302 was synthesized similar to compound 210 replacing 5-amino-2methoxypyridine with 6-methylpyridin-3-amine. LCMS (ES) [M+l] ⁺ m/z: 463. ^!H NMR (300 MHz, DMSOA) δ 10.36 (s, IH), 8.60 (d, J= 2.6 Hz, IH), 8.45 (d, 7 = 5.7 Hz, IH), 8.14 (s, tfCOOH), 7.88 (dd, 7= 8.4, 2.6 Hz, IH), 7.79 (d, 7= 2.5 Hz, IH), 7.17 (d, 7= 8.4 Hz, IH), 7.05 (dd, 7= 5.8, 2.6 Hz, 15 IH), 4.73 (s, IH), 4.43 (s, 2H), 3.81 (s, 2H), 3.38 (s, 31-1),3.22 (t,7=7.2 Hz, 2H), 2.85 (t, 7= 7.8 Hz,

2H), 2.39 (s, 31-1), 2.04-1.96 (m, 2H), 1.17 (s, 6H).

Example 1.309

[1337] Synthesis ofN-tert-butyl-2-{[2-(5-fluoro-4-methylpyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 303)

597

H

[1338] Compound 303 was synthesized similar to compound 24 by replacing 2tributylstannylpyridine with 5-fluoro-4-methyl-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 372.2. ‘HNMR (400 MHz, DMSO-d6) δ 8.50 (d, J= l.l Hz, IH), 8.30 (dd, 7=6.5, 0.9 Hz, IH), 7.69 (s, IH), 4.14 (s, 2H), 3.27 (s, 3H), 3.17 - 3.11 (m, 2H), 2.83 - 2.76 (m, 2H), 2.37 (dd, 7= L7, 0.7 Hz,

3H), 2.02 - 1.93 (m, 2H), L22 (s, 9H).

Example 1.310

[]339] Synthesis of N-(6-methoxypyridin-3-yI)-2-[methyl(2-{[i,3]thiazolo[4,5-c]pyridin-6-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 304)

[1340] Compound 304 was synthesized similar to compound 258 replacing 3-chloro-2,6naphthyridine with 6-bromo-[l,3]thiazolo[4,5-c]pyridine. LCMS (ES) [M+l]⁺ m/z: 448. 'H NMR (300 MHz, DMSO-d6) δ 10.34 (s, IH), 9.55 (s, IH), 9.38 (d, J = 0.9 Hz, IH), 9.11 (d, J = 0.9 Hz, IH), 8.39 (d, J = 2.6 Hz, IH), 7.92 (dd, J = 8.9, 2.7 Hz, IH), 6.78 (d, J = 8.9 Hz, IH), 4.44 (s, 2H), 3.79 (s, 3H), 15 3.42 (s, 3H), 3.23 (t, J = 7.2 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.12-1.95 (m, 2H).

Example 1.311

[1341] Synthesis (2R)-N-tert-butyl-2-[methyi({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]propanamide (Compound 305)

H

[1342] Compound 305 was synthesîzed similar to compound 101 byreplacing4-methoxy-2(tributylstannyl) pyridine with 4-(oxetan-3-yloxy)-2-(trimethylstannyl)pyridine. LCMS (ES) [M+i] ⁺m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.6 Hz, IH), 8.15 (s, 7/COOH), 7.90 (d, J = 2.5 5 Hz, IH), 7.81 (s, IH), 7.06 (dd, J = 5.7, 2.6 Hz, IH), 5.09 (q, J = 7.0 Hz, IH), 4.16 (t, J = 4.9 Hz, 2H),

3.77 (t, J = 4.9 Hz, 1 H), 3.21-3.01 (m, 2H), 3.11 (s, 3H), 2.95-2.72 (m, 2H), 2.13-1.84 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H), 1.20 (s, 9H).

Example 1.312

[1343] Synthesis 2-{[2-(5-fluoro-4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N-(6-methylpyridin-3-yl)acetamide (Compound 306)

[1344] Compound 306 was synthesîzed similar to compound 24 by replacing 2tributylstannylpyridine with 5-fluoro-4-methoxy-2-(tributylstannyl)pyridine and by replacing tertbuty lamine with 6-methylpyridin-3-amine. LCMS (ES+): [M+H]⁺ = 423.1. 'H NMR (400 MHz, DMSO15 d6) δ 11.74 (s, IH), 8.97-8.91 (m, IH), 8.71 (d, 7= 2.7 Hz, IH), 8.28 (d, 7 =8.1 Hz, 1 H), 8.03 (s, IH),

7.62 (d, 7=8.6 Hz, IH), 4.82 (s, 2H), 3.90 (s, 3H), 3.60 (s, 3H), 3.50-3.46 (m, 2H), 3.09-3.05 (m, 2H), 2.57 (s, 3H), 2.17- 2.08 (m, 2H).

Example 1.313

[1345] Synthesis N-(3-fluorophenyl)-2-[(2-{4-[(l-hydroxycyclopropyl)methoxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 307)

599

[l346] Compound 307 was synthesized simiiar to compound 252 by replacing l-(2- hydroxyethyl)pyrrolidine with {l-[(tert-butyldimethylsilyl)oxy]cyclopropyl}methanol. LCMS (ES) [M+l]⁺m/z: 464.2. Ή NMR (300 MHz, DMSO-7₆) δ 10.41 (s, 1 H), 8.43 (d, 7= 5.6 Hz, IH), 7.84 (d, 7 = 2.5 Hz, 1 H), 7.55 (ddd, 7= 11.4, 3.4, 1.9 Hz, IH), 7.45 - 7.21 (m, 2H), 7.10 (dd, 7= 5.6, 2.5 Hz, IH), 6.86 (ddt, 7= 8.8, 5.5, 2.9 Hz, IH), 4.98 (s, IH), 4.45 (s, 2H), 3.65 (s, 2H), 3.34 (s, 3H), 3.20 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7 = 7.8 Hz, 2H), 2.05-1.96 (m, 2H), 0.93 (t,7= 6.6 Hz, 2H), 0.86 (d, 7= 5.0 Hz, 2H).

Example 1.314

[1347] Synthesis ofN-(6-cyclopropylpyridin-3-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl} (methy l)amino)acetamide (Compound 308)

[1348] Compound 308 was synthesized similar to compound 44 by replacing tert-butylamine with 6cyclopropyl-3-aminopyridine. LCMS (ES) [M+l]⁺ m/z: 461. *H NMR (300 MHz, DMSO-7ô, ppm) δ 10.34 (s, IH), 8.55 (d, 7 =2.5 Hz, IH), 8.44 (d, 7= 5.6 Hz, IH), 8.14(HCOOH), 7.88 (dd, 7= 8.5, 2.6 Hz, IH), 7.78 (d, 7= 2.5 Hz, IH), 7.20 (d, 7= 8.5 Hz, IH), 7.02 (dd, 7= 5.6, 2.6 Hz, IH), 4.95 (s, IH), 4.42 (s, 2H), 4.03 (t, 7= 4.8 Hz, 2H), 3.68 (t, 7= 4.8 Hz, 2H), 3.37 (s, 3H), 3.21 (t, 7= 7.3 Hz, 2H), 2.84 (t, 7= 7.9 Hz, 2H), 2.06-1.97 (m, 3H), 0.95-0.77 (m, 4H).

Example 1.315

[1349] Synthesis of (2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,61-1,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)propanamide (Compound 309)

600

[1350] Compound 309 was synthesized similar to compound 251 replacing 3-fluoroaniline with 5- amino-2-methoxypyridine. LCMS (ES) [M+l]⁺ m/z: 465. 'H NMR (300 MHz, DMSO-A ppm) δ 10.43 (s, IH), 8.48 (d, J = 5.6 Hz, IH), 8.33 (d, J = 2.6 Hz, IH), 7.93-7.83 (m, 2H), 7.07 (dd, J = 5.6, 2.6 Hz, IH), 6.76 (d, J = 8.9 Hz, IH), 5.26 (q, J = 6.9 Hz, IH), 4.94 (t, J = 5.4 Hz, IH), 4.13 (t, J = 4.8 Hz, 2H), 3.79 (s, 3H), 3.74 (q, J = 4.9 Hz, 2H), 3.20 (s, 3H), 3.24-3.06 (m, 2H), 2.98-2.78 (m, 2H), 2.12-1.92 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

Example 1.316

[1351] Synthesis of (2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl] (methy l)amino)-N-(l-methy l-lH-pyrazoi-4-yl)propanam ide (Compound 310)

N

[1352] Compound 310 was synthesized similar to compound 25 i replacing 3-fluoroaniline with 1methylpyrazol-4-amine. LCMS (ES) [M+l]⁺ m/z: 438. 'H NMR (300 MHz, DMSO-A ppm) δ 10.41 (s, IH), 8.54 (d,7 = 5.7 Hz, IH), 7.88 (d, 7= 2.6 Hz, IH), 7.84 (s, IH), 7.38 (s, IH), 7.12 (dd, 7= 5.9, 2.7 Hz, IH), 5.26 (q, 7= 7.1 Hz, 1 H), 4.96 (t,7=5.2 Hz, 1 H), 4.17 (s, 2H), 3.87-3.68 (m, 5H), 3.23-3.09 (m, 5H), 3.03-2.77 (m, 2H), 2.23-1.91 (m, 2H), 1.44 (d, 7= 7.0 Hz, 3H).

Example 1.317

[1353] Synthesis of (2R)-N-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yi]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino)propanamide (Compound 311) ί

[ 1354] Compound 31 J was synthesized similar to compound 251 replacing 3-fluoroaniline with 2- methylpropan-2-amine. LCMS (ES) [M+l] ⁺ m/z: 414. 'H NMR (300 MHz, DMSOéû, ppm) δ 8.49 (d, J = 5.6 Hz, IH), 8.15 (s, ÆCOOH), 7.90 (d, J = 2.5 Hz, IH), 7.81 (s, IH), 7.06 (dd, J = 5.7, 2.6 Hz, IH), 5.09 (q, J = 7.0 Hz, IH), 4.16 (t, J =4.9 Hz, 2H), 3.77 (t, J = 4.9 Hz, IH), 3.21-3.0! (m, 2H), 3.11 (s, 3H), 2.95-2.72 (m,2H), 2.13-L84 (m, 2H), l.32 (d, J = 7.0 Hz, 3H), l.20(s,9H).

Example L318

[1355] Synthesis of (2R)-N-(6-methoxypyridin-3-yl)-2-[methyi({2-[4-(oxetan-3-yloxy)pyridin-2yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]propanamide (Compound 3 ] 2)

[l 356] Compound 312 was synthesized similar to compound 245 replacing N-tert-butyl-2-([2chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide with (2R)-2-([2-chloro5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyI)amino)-N-(6-methoxypyridin-3-yl)propanamide.

LCMS (ES) [M+l] ^h m/z: 477. Ή NMR (300 MHz, DMSOéû, ppm) δ 10.35 (s, IH), 8.50 (d, 7= 5.6 Hz, IH), 8.33 (d,7= 2.6 Hz, IH), 8.15 (s, ÆCOOH), 7.89 (dd, 7= 8.9, 2.7 Hz, IH), 7.73 (d, 7= 2.6 Hz, IH),6.9l (dd, 7= 5.6, 2.6 Hz, IH), 6.75 (d,7=8.9 Hz, IH), 5.50-5.42 (m, IH), 5.20 (q,7=7.0 Hz, IH), 4.97 (td, 7= 6.7, 4.1 Hz, 2H), 4.64-4.53 (m, 2H), 3.79 (s, 3H), 3.33-3.05 (m, 5H), 2.96-2.73 (m, 2H), 2.18-l .86 (m, 2H), i .47 (d, 7= 7.0 Hz, 3H).

Example L319 [1357] Synthesis ofN-(4-fluorophenyl)-2-[methyl(2-{l-methy l-lH-pyrazolo[3,4-c]pyridm-5-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 313)

602

[1358] Compound 313 was synthesized similar to compound 24 by replacing 2tributylstannylpyridine with 1 -methyl-5-(tributylstannyl)-l H-pyrazolo[3,4-c]pyridine and by replacing tert-butylamine with 4-fluoroanÎline. LCMS (ES+): [M+H]⁺ = 432.1. 'H NMR (400 MHz, DMSO-d6) δ

10.70 (s, I H), 9.37 (s, IH), 8.95 (s, 1H), 8.26 (s, IH), 7.71 (dd, J= 8.9, 5.0 Hz, 2H), 7.16 (dd, 7= 8.9

Hz, 2H), 4.69 (s, 2H), 4.27 (s, 3H), 3.58 (s, 3H), 3.39 - 3.38 (m, 2H), 3.11- 3.04 (m, 2H), 2.17 - 2.06 (m, 2H).

Example 1.320

[1359] Synthesis of N-(4-fluorophenyl)-2-[methyl(2-{2-methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 314)

H

[1360] Compound 314 was synthesized similar to compound 24 by replacing 2tributylstannylpyridine with 2-methyl-5-(tributylstannyl)-IH-pyrazoio[3,4-c]pyridine and by replacing tert-butylamine with 4-fluoroaniline. LCMS (ES+): [M+H]⁺ = 432.1. Ή NMR (400 MHz, DMSO-d6) δ

10.77- 10.64 (m, 1 H), 9.30 (s, I H), 8.93 (d, 7= 1.3 Hz, IH), 8.69 (s, IH), 7.74 - 7.65 (m,2H),7.15 (dd, 7= 8.9 Hz, 2H), 4.65 (s, 2H), 4.33 (s, 3H), 3.53 (s, 3H), 3.04 - 2.99 (m, 2H), 2.13 - 2.05 (m, 2H).

Example 1.321

[1361] Synthesis of 2-({2-[4-({[l-(3-fluorophenyl)-lH-l,2,4-triazol-5-yl]methyl}(methyl)amino)“ 5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-l -ol (Compound 315)

603

DMF-DMA

THF. 60°C. 2 h

Mel N a H

DMF, O’C-rt. 1.5 h

Scheme 119

Step 1

[1362] Into a 50 mL round-bottom flask were added tert-butyl N-(carbamoylmethyl)carbamate (2.0 g, 11.48 mmol, 1.00 equiv), THF (20 mL) and DMF-DMA (2.74 g, 22.99 mmol, 2.00 equiv) at room température. The resulting mixture was stirred for 2 h at 60 °C. The resulting mixture was cooled to room température and concentrated under reduced pressure. This resulted in 2.5 g of tert-butyl (2(((dimethylamino)methylene)amino)-2-oxoethyl)carbamate as a yellow oil. The crude product was used 10 to the next step directly without further purification. LCMS (ES) [M+l]^4- m/z; 230.

Step 2

[1363] Into a 100 mL round-bottom flask were added tert-butyl (2- (((dimethylamino)methylene)amino)-2-oxoethyl)carbamate (2.5 g, 10.90 mmol, 1.00 equiv), HOAc (30

604 mL) and (3-fluorophenyl)hydrazine hydrochloride (1.77 g, 10.90 mmol, l.OO equiv) at room température. The resulting mixture was stirred for l h at 60 °C. The resulting mixture was cooled to room température and concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (5:l) to afford tert-butyl ((l-(3-fluorophenyl)-lH-l,2,45 triazol-5-yl)methyl)carbamate (1.5 g, 45% in total from step one) as a brown solid. LCMS (ES) [M+l]⁺m/z: 293.

Step 3

[l 364] Into a 100 mL 3-necked round-bottom flask were added tert-butyl ((1-(3-fluorophenyl)-lHl,2,4-triazol-5-yl)methyl)carbamate (1.5 g, 5.13 mmol, 1.00 equiv) and DMF (30 mL). To the above 10 mixture was added NaH (60% in minerai oil) (190 mg, 7.92 mmol, 1.50 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 30 min at the same température. To the above mixture was added CH₃1 (1.75 g, 12.31 mmol, 2.4 equiv) dropwise at 0 °C. The resulting mixture was stirred for additional Ih at room température. The reaction was quenched by the addition of water (30 mL), extracted with EtOAc (50 mL*2). The combined organic phases were washed with brine (30 mL*3), 15 dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford tert-butyl ((l-(3-fluoropheny 1)-11-1-1,2,4-triazol-5-yl)methyl)(methyl)carbamate (1.5 g, 95%) as a yellow oil. LCMS (ES) [M+1]⁺ m/z: 307.

Step 4

[1365] Info a 100 mL round-bottom flask were added tert-butyl ((l-(3-fluorophenyl)-lH-l,2,4triazol-5-yl)methyl)(methyl)carbamate (1.5 g, 4.90 mmol, 1.00 equiv), DCM (30 mL) and HCl (g) (2 M in EtzO) (30 mL) at room température. The resulting mixture was stirred for 6 h at room température. The resulting mixture was concentrated under vacuum. This resulted in 1.5 g crude of 1 -(1-(3fluorophenyl)-lH-l,2,4-triazol-5-yl)-N-methylmethanamine hydrochloride as a yellow solid used in the next step directly without further purification. LCMS (ES) [M-HC1+1 ]⁺ m/z: 207.

Step 5

[1366] Into a 100 mL round-bottom flask were added 2,4-dichloro-5H,6H,7H- cyclopenta[d]pyrimidine (777 mg, 4.11 mmol, 1.00 equiv), NMP (30 mL), l-(l-(3-fluorophenyl)-lHl,2,4-triazol-5-yl)-N-methylmethanamine hydrochloride (1.56 g, 6.17 mmol, 1.5 equiv) and DIEA (1.6

605 g, 12.38 mmol, 3.00 equiv) at room température. The resulting mixture was stirred for 16 h at 60 °C. The reaction was cooled to room température and quenched by the addition of water (30 mL), extracted with EtOAc (50 mL*2). The combined organic phases were washed with brine (30 mL), concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE /

EA (kl) to afford 2-chloro-N-((l-(3-fluorophenyl)-1H-l,2,4-triazol-5-yl)methyl)-N-methyl-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-amine (LO g, 68%) as a yellow oil. LCMS (ES) [M+l] m/z: 359.

Step 6

[1367] Into a 40 mL vial were added 2-chloro-N-((l-(3-fluorophenyl)-lH-l,2,4-triazol-5-yl)methyl)N-methy]-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (650 mg, 1.81 mmol, 0.70 equiv), toluene (30 mL), 4-[2-(oxan-2-yioxy)ethoxy]-2-(trimethylstannyl)pyridine (1 g, 2.59 mmol, 1.00 equiv) and

Pd(PPh₃)₄ (300 mg, 0.26 mmol, 0.10 equiv) at room température. The resulting mixture was stirred for 12 h at 100 °C under nitrogen atmosphère. The reaction mixture was cooled to room température, concentrated under reduced pressure to remove the solvent, the residue was purified by silica gel column chromatography, eluted with CH₂Ch / MeOH (10:1) to afford N-((l-(3-fluorophenyl)-l H-l,2,4-triazol15 5-yl)methyl)-N-methyl·2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)ρyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-amine (300 mg, 21%) as a yellow oil. LCMS (ES) [M+l]⁺ m/z: 546.

Step 7

[1368] into a 20 mL vial were added N-((l-(3-fluorophenyl)-IH-l,2,4-triazol-5-yl)methyl)-Nmethyl-2-(4-(2-((tetrahydro-2H-pyran-2-yl)oxy)ethoxy)pyridin-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-amine (300 mg, 0.55 mmol, i.00 equiv), MeOH (5 mL) and TsOH (95 mg, 0.55 mmol, 1.00 equiv) at room température. The resulting solution was stirred for 1 h at room température. The reaction solution was purified by Prep-HPLC with the following conditions: Sunfire Prep Cl 8 OBD Column, 50*250 mm, 5 pm, 10 nm, mobile phase, water (0.1% FA) and CH3CN (5% Phase B up to 23% in 12 min), Detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in 158.4 mg (57%) of 2-((2-(4-(((1 -(3-fluorophenyl)-! H-1,2,4-triazo 1-5yl)methyl)(methyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl)oxy)ethan-l-ol formate as a brown semi-solid. LCMS [M+H]⁺: 462. 'H NMR (300 MHz, DMSO-c/e) δ 8.41 (d, J = 5.6 Hz, ! H), 8.07 (s, IH), 7.66 (dt, J = 9.0, 1.8 Hz, IH), 7.66-7.47 (m, 3H), 7.39-7.26 (m, IH), 7.01 (dd, J = 5.6, 2.6 Hz, IH), 5.15 (s, 2H), 4.11 (t, J = 4.8 Hz, 2H), 3.77 (t, J = 4.8 Hz, 2H), 3.29 (s, 3H), 3.06 (t, J =

7.3 Hz, 2H), 2.79 (t, J = 7.8 Hz, 2H), 2.00-1.90 (p, J = 7.6 Hz, 2H).

606

Example 1.322

[1369] Synthesis of (2R)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yi]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(6-methylpyridin-3-yl)propanamide (Compound 316)

H

[1370] Compound 316 was synthesized similar to compound 251 by replacing 3-fluoroaniIine with 6-methylpyridin-3-am. LCMS (ES) [M+l] ⁺ m/z: 449. 'H NMR (300 MHz, DMSO-Υί, ppm) δ 10.58 (s, IH), 8.61 (d,J = 2.6 Hz, 1H),8.47 (d,J = 5.6Hz, IH), 8.16 (s, WCOOH), 7.91 (dd, J = 8.4, 2.6Hz, IH), 7.86 (d, J = 2.5 Hz, I H), 7.15 (d, J = 8.4 Hz, 1 H), 7.06 (dd, J = 5.6, 2.6 Hz, 1 H), 5.26 (q, J = 6.9 Hz, IH), 4.12 (t, J = 4.8 Hz, 2H), 3.75 (t, J = 4.7 Hz, 2H), 3.19 (s, 3H), 3.26-3.00 (m, 2H), 2.96-2.70 (m, 2H), 2.37 (s, 3H), 2.17-1.84 (m, 2H), 1.46 (d, J = 7.0 Hz, 3H).

Example 1.323

[1371] Synthesis of N-tert-butyl-2-[methyI(2-[4-[(3S)-oxolan-3-yloxy]pyridin-2-yI)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 317)

[1372] Compound 317 was synthesized similar to compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with (3S)-oxolan-3-ol. LCMS (ES) [M+l] ⁺ m/z: 426. Ή NMR (300 MHz, DMSO-7_ft ppm) δ 8.48 (d, J= 5.6 Hz, IH), 7.84 (d, J= 2.6 Hz, IH), 7.69 (s, IH), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 5.22 (t,7=3.2 Hz, 1 H), 4.11 (s, 2H), 3.95 (dd,7= 10.3,4.5 Hz, 1 H), 3.93 3.73 (m, 3H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.39-2.21 (m, IH), 2.041.97 (m, 3H), 1.25 (s, 9H).

Example 1.324

[1373] Synthesis of N-tert-butyl-2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7H-

607 cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 318)

[1374] Compound 318 was synthesized similar to compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with (3R)-oxolan-3-ol. LCMS (ES) [M+l] ⁴ m/z: 426. ^lH

NMR (300 MHz, DMSO-ώ. ppm) δ 8.48 (d, J = 5.6 Hz, IH), 7.84 (d, J = 2.6 Hz, IH), 7.69 (s, IH), 7.04 (dd, J = 5.7, 2.6 Hz, I H), 5.22 (t, J = 3.2 Hz, 1 H), 4.11 (s, 2H), 3.95 (dd, J = 10.3,4.5 Hz, 1 H), 3.93 3.73 (m, 3H), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.39-2.21 (m, IH), 2.041.97 (m,3H), 1.25 (s, 9H).

Example 1.325

[1375] Synthesis of2-({2-[4-({[4-(3-fluorophenyl)-4H-1,2,4-triazol-3-yl]methyl} (methy I)amino)5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yî}oxy)ethan- l-ol (Compound 319)

608

1)ÊtOH, M^eC

2}NaOH, H_£O_r 100*C

HaOa.

AgOH

DCM

MeNH_a/ ElOH

6D ^QC. 4h

DIEA, MaOH. RT

PdfdpptyCl?, DMF

Scheme 120

NaH_r DMSO

Step 1

[1376] Into a 250-mL round-bottom flask, was placed l-fluoro-3-isothiocyanatobenzene (5 g, 32.643 5 mmol, 1.00 equiv), 2-methoxy acetohydrazide (3.98 g, 38.229 mmol, 1.17 equiv) and EtOH (60.00 mL).

The resulting solution was stirred for 1 hr at 80 degrees C. The precipitate was collected and recrystallized from H₂O. The solid andNaOH (130.57 mL, 261.144 mmol, 8.00 equiv) was placed into a 250 mL round-bottom flask. The resulting solution was allowed to react, with stirring, for an additional 1 hr at 100 degrees C. The resulting solution was transferred to abeaker, neutralized to 6 with 10 HCl (2 mol/L), applied to suction filtration, washed with water.This resulted in 6 g(76.9%) of 4-(3fluorophenyl)-5-(methoxymethyl)-2H-l,2,4-triazole-3-thione as a white solid. LCMS (ES) [M+l] ⁺ m/z: 240.

Step 2

[1377] A solution of starting 4-(3-fluorophenyi)-5-(methoxymethyl)-2H-l,2,4-triazole-3-thione (5.5 15 g, 22.987 mmol, 1.00 equiv) in CH₂CI₂ (40 mL) was cooled to 0 °C, and a 30% aqueous solution of

H₂O₂ (1.18 mL, 50.649 mmol, 2.20 equiv) in AcOH (27 mL) was added in portions under cooling and stirring. Then the ice bath was removed, and the stirring was continued at ambient température for 3 h. The reaction mixture was alkalized under cooling with NaOH to pH 10. The organic layer was separated, and the aqueous one was washed with CH₂C1₂ (2 x 100 mL). The combined extracts were

609 dried with Na₂SO4 and evaporated. The residue was purified by column chromatography (DCM/MeOH, 100:0—70:30). This resulted in 3.2 g (67.18%) of 4-(3-(1 uorophenyl)-3-(methoxymethyl)-1,2,4-triazole as a off-white solid. LCMS (ES) [M+l]⁺ m/z: 208.

Step 3

[1378] Into a 250-mL round-bottom flask, was placed 4-(3-fiuorophenyl)-3-(methoxymethy 1)-1,2,4trîazole (3.00 g, 14.478 mmol, 1.00 equiv), AICh (19.31 g, 144.782 mmol, 10 equiv), AcCN (100.00 mL). The resulting solution was stirred for 16 hr at 80 °C. The reaction mixture was cooled, and the crude product was purified by Flash-Prep-HPLC with the foîlowing conditions (IntelFlash-1 ): Column, Cl 8 silica gel; mobile phase, H₂O(FA)/ACN=10:l increasing to FI₂O(FA)/ACN=5:1 within 15 min. This resulted in 1.2 g (42.90%) of [4-(3-fluorophenyl)-l,2,4-triazol-3-yl]methanol as a yellow solid. LCMS (ES) [M+l]⁺m/z: 194.

Step 4

[1379] Into a 100-mL round-bottom flask were placed [4-(3-fl uoropheny 1)-1,2,4-triazo 1-3yl]methanol (1.20 g, 6.212 mmol, 1.00 equiv), SOC1₂ (1.1 l g, 9.330 mmol, 1.50 equiv), DCM (30.00 15 mL). The resulting solution was stirred for 6 hr at room température. The resulting mixture was concentrated under vacuum. The resulting solution was extracted with 3x30 mL of dîchloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in 1.28 g (97.37%) of 3-(chloromethyl)-4-(3-fluorophenyl)-l,2,4-triazole as colorless oil. LCMS (ES) [M+l]⁺ m/z:212.

Step 5

[1380] Into a 100-mL round-bottom flask were placed 3-(chloromethyl)-4-(3-fluorophenyl)-1,2,4triazole (1.20 g, 5.671 mmol, 1.00 equiv), Methylamine in éthanol (30wt. % 0.86 g, 8.372 mmol, 1.48 equiv), EtOFI (30.00 mL). The resulting solution was stirred for 4 hr at 60 °C. The resulting solution was extracted with 3x30 mL of dîchloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. This resulted in LO g (85.51%) of[[4-(3-fl uoropheny 1)-1,2,4-triazo 1-3yl]methyl](methyl)amine as a white solid. LCMS (ES) [M+l]⁺ m/z: 207.

Step 6

[1381 ] Into a 100 mL round-bottom flask were placed [[4-(3-fluorophenyl)-l,2,4-triazol-3yl]methyl](methyl)amine ( 1.00 g, 4.849 mmol, 1.00 equiv), 2,4-dichloro-5H,6H,7H21052

610 cyclopenta[d]pyrimidine (LIO g, 5.819 mmol, L20 equiv), DIEA (1.25 g, 9.698 mmol, 2 equiv), MeOH (20.00 mL). The resulting solution was stirred for 8 hr at room température. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with 5 ethyl acetate/petroleum ether (3:l). This resulted in l g (57.47%) of2-chloro-N-[[4-(3-fluorophenyl)- l,2 ,4-triazol-3-yl]methyl]-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine as a white solid. LCMS (ES) [M+l]⁺ m/z: 359.

Step 6

[1382] Into a 100-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed 2-chloro-N-[[4-(3-fluorophenyl)-l,2,4-triazol-3-yl]methyl]-N-methyl-5H,6H,7Hcyclopenta[d]pynmidin-4-amîne (700.00 mg, 1.951 mmol, 1.00 equiv), 4-fluoro-2(tributylstannyl)pyridine (903.99 mg, 2.341 mmol, 1.20 equiv), Pd(dppf)Ch (285.49 mg, 0.390 mmol, 0.2 equiv), DMF (30.00 mL). The resulting solution was stirred for 16 hr at 120 °C. The reaction mixture was cooled. The residue was applied onto a silica gel colutnn with dichloromethane/m éthanol (10:1). This resulted in 230 mg (28.11%) of N-[[4-(3-fiuoropheny 1)-1,2,4-triazol-3-yl]methyl]-2-(4fluoropyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine as brown oil. LCMS (ES) [M+l ] ⁺m/z: 420.

Step 7

[1383] Into a 100-mL round-bottom flask, was placed N-[[4-(3-fluorophenyl)-1,2,4-triazol-3- yl]methyl]-2-(4-fluoropyridin-2-yl)-N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (200.00 mg, 0.477 mmol, 1.00 equiv), NaH (57.21 mg, 2.384 mmol, 5 equiv), DMSO (10.00 mL). The resulting solution was stirred for 30 min at 0 °C and ethylene glycol (147.98 mg, 2.384 mmol, 5.00 equiv) was added, the solution was stirred for 2 hr at room température. The resulting solution was extracted with 3x30 mL of dichloromethane and the organic layers combined, dried over anhydrous sodium sulfate and concentrated. The residue was purified by prep-HPLC with the following conditions: Column: Sunfire Prep Cl 8 OBD Column, 50*250 mm, 5pm lOnm; Mobile Phase A: Water (0.1%FA), Mobile Phase B: AcCN; Flow rate: 90 mL/min; Gradient: 5% B to 35% B in 15 min, 35% B; Wave Length: 220 nm. This resulted in 63.9 mg (29.04%) of 2-([2-[4-([[4-(3-fluorophenyl)-l,2,4-triazol-3yl]methyl](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl]oxy)ethanol 2-([2-[4- ³⁰ ([[4-(3-fluorophenyl)-l,2,4-triazol-3-y]]methy[](methyl)amino)-5H,6H,7H-cyclopenta[d]pyrimidin-221052

611 yl]pyridin-4-yl]oxy)ethanol formate a brown solid. LCMS (ES) [M+l] ⁺ m/z: 462. ’H NMR (300 MHz, DMSOA) δ 8.72 (s, t H), 8.43 (d, J = 5.6 Hz, IH), 7.67 (d, 7= 2.6 Hz, IH), 7.63 - 7.53 (m, ! H), 7.48 7.33 (m, 2H), 7.25-7.19 (m, IH), 7.02 (dd, 7= 5.7, 2.6 Hz, IH), 5.13 (s, 2H), 4.16 (t, 7= 4.9 Hz, 2H), 3.78 (t, 7= 4.8 Hz, 2H), 3.14 (s, 3H), 2.99 (t, 7= 7.3 Hz, 2H), 2.77 (t, 7= 7.8 Hz, 2H), 1.98-1.88 (m,

2H).

Example 1.326

[1384] Synthesis of (3S)-l-(3-fluorophenyl)-3-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyc1openta[d]pyrimidin-4-yl}(methyl)amino)piperidin-2-one (Compound 320)

612

Et₃N 3HF

Scheme I2l

Step l

[l 385] Into a 250-mL round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed tert-butyi N-(2-oxopiperidin-3-yI)carbamate (10.00 g, 46.67 mmol, l.OO equiv), methyl [(methy lamino)methyl]amine (0.69 g, 9.31 mmol, 0.20 equiv), l-fluoro-3-iodobenzene (l2.43 g, 56.Oï mmol, 1.20 equiv), dioxane (100.00 mL), K3PO4 (19.81 g, 93.34 mmol, 2.00 equiv), Cul (0.89 g, 4.67 mmol, 0.10 equiv). The resulting solution was stirred for ovemight at 110 °C. The reaction mixture 10 was cooled to room température. The solids were filtered out. The resulting mixture was concentrated.

The residue was applied onto a silica gel column with THF/PE (15%). This resulted in 8 g (55.59%) of

613 tert-butyl N-[l-(3-fluorophenyl)-2-oxopiperidin-3-yl]carbamate as yellow solid. LCMS (ES) [M+l] ’ m/z:

309.

Step 2

[1386] Into a 250-mL 3-necked round-bottom flask, was placed tert-butyl N-[l-(3-fluorophenyl)-2oxopiperidin-3-y 1]carbamate (8.00 g, 25.94 mmol, 1.00 equiv), DMF (100.00 mL). This was followed by the addition of NaH (0.93 g, 38.75 mmol, 1.49 equiv), in portions at 0 °C. To this was added Mel (4.42 g, 31.13 mmol, 1.20 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room température. The reaction was then quenched by the addition of 50 mL of water/ice. The resulting solution was extracted with 3x100 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (20%). This resulted in 6.5 g (77.71%) of tert-butyl N-[l-(3-fluorophenyl)-2-oxopiperidin3-yl]-N-methylcarbamate as coiorless oil. LCMS (ES) [M+l ]⁺ m/z:

323.

Step 3

[1387] Into a 250-mL round-bottom flask, was placed tert-butyl N-[l-(3-fluorophenyl)-2oxopiperidin-3-yl]-N-methylcarbamate (6.50 g, 20.16 mmol, 1.00 equiv), DCM (20.00 mL). This was followed by the addition of HCl(gas)in 1,4-dioxane (10.08 mL, 40.32 mmol, 2,00 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room température. The solids were collected by filtration. This resulted in 5 g (95.85%) of l-(3-fluorophenyl)-3-(methylamino)piperidin-2-one hydrochloride as a white solid. LCMS (ES) [M-HC1+I]+ m/z: 223.

Step 4

[1388] Into a 100-mL round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (2.00 g, 10.58 mmol, 1.00 equiv), l-(3-fluorophenyl)-3(methylamino)piperidin-2-one hydrochloride (2.74 g, 10.58 mmol, 1.00 equiv), NMP (20.00 mL), DIEA (4.10 g, 31.74 mmol, 3.00 equiv). The resulting solution was stirred for 5 h at 60 ^OC. The reaction mixture was cooled to room température. The crude product (5 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep CI8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% ΝΗ3Ή2Ο) and CAN (30% Phase B up to 80% in 11 min); Detector, 254. This resulted in 2 g (50.43%) of 3-([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-l-(3-

614 fluorophenyl)piperidin-2-one as yellow solid. LCMS (ES) [M+l ] m/z: 375.

Step 5

[1389] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed 3([2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-l-(3-fluorophenyl)piperidin-2-one (2.00 g, 5.34 mmol, 1.00 equiv), DMF (20.00 mL), 4-fiuoro-2-(tributylstannyl)pyridine (2.68 g, 6.94 mmol, L30 equiv), Pd(PPh3)₄ (0.62 g, 0.54 mmol, 0.10 equiv). The resulting solution was stirred for ovemight at 120 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF/PE (60%). This resulted in 1 g (43.04%) of l-(3-fluorophenyl)-3-[[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]piperidin-2-one as yellow oil. LCMS (ES) [M+l]⁺ m/z: 436.

Step 6

[1390] Into a 100-mL 3-necked round-bottom flask, was placed 2-(oxan-2-yloxy)ethanol (0.30 g, 2.05 mmol, 1.00 equiv), DMF (10.00 mL). This was followed by the addition ofNaH (0.10 g, 4.17 mmol, 2.03 equiv), in portions at 0 °C. To this was added l-(3-fluorophenyl)-3-[[2-(4-fluoropyndin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]pîperidin-2-one (0.98 g, 2.26 mmol, 1.10 equiv) dropwise with stirring at 0 °C. The resulting solution was stirred for 3 h at room température. The reaction was then quenched by the addition of 10 mL of water/ice. The resulting solution was extracted with 3x20 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (50%). This resulted in 0.7 g (60.73%) of ]-(3-fluorophenyl)-3-[methyl(2-[4-[2-(oxan-2-yloxy)ethoxy]pyndin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]piperidin-2-one as a yellow oil. LCMS (ES) [M+l]⁺ m/z; 562.

Step 7

[1391] Into a 40-mL vial, was placed I -(3-fluorophenyl)-3-[methyl(2-[4-[2-(oxan-2yloxy)ethoxy]pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidÎn-4-yl)amino]piperidin-2-one (700.00 mg, 1.25 mmol, 1.00 equiv), MeOH ( 10.00 mL), PTSA (42.92 mg, 0.25 mmol, 0.20 equiv). The resulting solution was stirred for 3 h at room température. The crude product (0.8 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep CI8 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1% NHs H2O) and CAN (30% Phase B up to 70% in 11 min); Detector, 254. This resulted in 400 mg (67.21%) of l-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-

615 cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one as white solid. LCMS (ES) [M+l ]⁺ m/z: 478.

Step 8

[1392] Into a 100-mL round-bottom flask, was placed l-(3-f!uorophenyl)-3-([2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pynmidin-4-yl](methyl)amino)piperidin-2-one (400.00 mg, 0.84 mmol, 1.00 equiv), DCM (6.00 mL), imidazole (85.54 mg, 1.26 mmol, 1.50 equiv). This was followed by the addition of t-butyldimethylchlorosilane (151.50 mg, LOI mmol, 1.20 equiv), in portions at 0 °C. The resulting solution was stirred for 5 h at room température. The resulting mixture was concentrated. The crude product (500 mg) was purified by Prep-CHIRAL-HPLC with the following conditions: Column, YMC Cellulose-SC, 250*21.5 mm, 5qm; mobile phase, Acetonitrile and Ethanol (0.2%DEA) (70% in 10 min); Detector, 254. This resulted in 220 mg (44.38%) of (3S)-3-[[2-(4-[2-[(tertbutyldimethylsilyl)oxy]ethoxy]pyndin-2-yl)-5H,6H,7H-cycIopenta[d]pyrimidin-4-yI](methyl)amino]-l(3-fluorophenyl)piperidin-2-one as white solid. LCMS (ES) [M+l]⁺ m/z: 592.

Step 9

[1393] Into a 40-mL vial, was placed (3S)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyI)amino]-l-(3-fluorophenyl)piperidin-2-one (220.00 mg, 0.37 mmol, 1.00 equiv), THF (6.00 mL), Et₃N3HF (299.64 mg, 1.86 mmol, 5.00 equiv). The resulting solution was stirred for ovemight at room température. The crude product (0.3 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm,

150mm, 5utn; mobile phase, Water (0.1% FA) and CAN (5% Phase B up to 40% in 11 min); Detector,

254. This resulted in 130 mg (73.23%) of(3S)-l-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one as white solid. Chiral analytical HPLC condition: Column, (R,R)-WHELK-O1 50*4.6mm,3.5um; mobile phase, n-hexane and Ethanol(0.2%DEA) (50% in 6 min); Detector, 254, Rétention time: 3.233 min. LCMS (ES, m/z):

[M+H]⁺: 478. Ή-NMR (300 MHz, DMSO-é,^/H): δ 8.45 (d, J = 5.6 Hz, IH), 7.76 (d, J = 2.6 Hz, IH),

7.34-7.23 (m, 1 H), 7.12-6.93 (m, 4H), 4.92 (d, J = 6.3 Hz, IH), 4.61 (s, IH), 4.14 (t, J = 4.9 Hz, 3H), 3.75 (d, J = 5.1 Hz, 2H), 3.56 (d, J = 11.6 Hz, 1 H), 3.30 (s, 3H), 3.21 (q, J = 6.8 Hz, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.55 (s, IH), 2.10-1.98 (m, 511).

Example 1.327

[1394] Synthesis of (3R)-l-(3-fluorophenyl)-3-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H21052

616

cyclopenta[d]pyrimidin-4-yl}(methyl)amino)piperidm-2-one (Compound 321)

Scheme 122

Step 1

[1395] Into a lOO-mL round-bottom flask, was placed l-(3-fluorophenyl)-3-([2-[4-(2- hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one (400.00 mg, 0.84 mmol, 1.00 equiv), DCM (6.00 mL), imidazole (85.54 mg, 1.26 mmol, 1.50 equiv). This was followed by the addition of t-butyldimethylchlorosilane (151.50 mg, 1.01 mmol, 1.20 equiv), 10 in portions at 0 °C. The resulting solution was stirred for 5 h at room température. The resulting mixture was concentrated. The crude product (500 mg) was purified by Prep-CHIRAL-HPLC with the following conditions: Column, YMC Ceîlulose-SC, 250*21.5 mm, 5pm; mobile phase, Acetonitrile and

Ethanol(0.2%DEA) (70% in 10 min); Detector, 254. This resulted in 220 mg (44.38%) of (3R)-3-[[2-(4[2-[(tert-buty[dimethylsilyl)oxy]ethoxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-415 yl](methyl)amino]-I-(3-fluorophenyl)piperidin-2-one as a white solid. LCMS (ES) [M+]]⁺ m/z: 592.

Step 2

[1396] Into a 40-mL vial, was placed (3S)-3-[[2-(4-[2-[(tert-butyldimethylsilyl)oxy]ethoxy]pyridin2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-l-(3-fluorophenyl)piperidin-2-one

617 (220.00 mg, 0.37 mmol, l.OO equiv), THF (6.00 mL), Et₃N 3HF (299.64 mg, 1.86 mmol, 5.00 equiv). The resulting solution was stirred for ovemight at room température. The crude product (0.3 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl8 OBD Column, I9cm, 150mm, 5um; mobile phase, Water (0.1% FA) and CAN (5% Phase B up to 40% in 11 min); Detector, 254. This resulted in 109 mg (61.40%) of (3R)-I-(3-fluorophenyl)-3-([2-[4-(2-hydroxyethoxy)pyridin-2yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)piperidin-2-one as white solid. Chiral analytical HPLC condition: Column, (R,R)-WHELK-OI 50*4.6mm,3.5um; mobile phase, n-hexane and Ethanol(Û.2%DEA) (50% in 6 min); Detector, 254, Rétention time: 2.274 min. LCMS (ES, m/z): [M+Hf: 478. ‘H-NMR (300 MHz, DMSW₀,/>/m): δ 8.45 (d, J = 5.7 Hz, IH), 7.76 (d, J = 2.6 Hz, IH), 7.30 (q, J = 8.1, 7.3 Hz, 1 H), 7.10-6.94 (m, 4H), 4.94 (s, IH), 4.63 (s, IH),4.15 (t, J = 4.9 Hz, 3H), 3.75 (d, J = 4.7 Hz, 2H), 3.56 (d, J = 11.4 Hz, 1H),3.31 (s, 3H), 3.19 (dt, J = 11.9, 7.8 Hz, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.55 (s, IH), 2.10-1.98 (m, 5H).

Example 1.328 [1397] Synthesis of N-tert-butyl-N-methyl-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 322)

[ 1398] Compound 322 was synthesized similar to compound 253 by replacing 5-amino-2- methoxypyridine with tert-butyl(methyl)amine. LCMS (ES) [M+l] ⁺ m/z: 426. NMR (300 MHz,

DMSO-Rδ 8.41 (d,7=5.7Hz, IH), 7.59 (d, 7= 2.6 Hz, IH), 6.79 (dd, 7= 5.8, 2.6 Hz, IH), 5.41-5.31 (m, 1 H), 4.97 (t, 7= 6.7 Hz, 2H), 4.55 (dd, 7= 7.7, 4.5 Hz, 2H), 3.20 (s, 3H), 3.07 (t,7=7.5 Hz, 2H), 2.90 (s, 3H), 2.77 (t,7=7.8 Hz, 2H), 1.99-1.88 (m, 2H), 1.25 (s, 9H).

Example 1.329

[1399] Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]-l-(piperidin-l-yl)ethan-l-one (Compound 323)

[1400] Compound 323 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridine with piperidine. LCMS (ES) [M+l] ⁺ m/z: 424. 'H NMR (300 MHz, DMSO-Λ, ppm) δ 8.48 (d, J = 5.6 Hz, l H), 7.65 (d, J = 2.6 Hz, IH), 6.86 (dd, J = 5.6, 2.6 Hz, IH), 5.49-5.43 (m, 1H),4.97 (t, J = 6.7 Hz, 2H), 4.58 (dd, J = 7.5, 4.9 Hz, 2H), 4.51 (s, 2H), 3.50-3.38 (m, 4H), 3.25(s, 3H), 3.14 (t, J = 7.4 Hz, 2H), 2.81 (t, J = 7.9 Hz, 2H), 2.04-L96 (m, 2H), l .69-1.57 (m, 4H), 1.51-1.40 (m, 2H).

Example 1.330

[1401] Synthesis of 2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl])amino]-N-(6-methylpyridin-3-yl)acetamide (Compound 324)

[1402] Compound 324 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridine with 6-methylpyridin-3-amine. LCMS (ES) [M+l]⁺ m/z: 447. *H NMR (300 MHz, DMSO-rf^/mi) δ 10.35 (s, IH), 8.62 (d, J = 2.5 Hz, IH), 8.45 (d, J = 5.6 Hz, IH), 7.92 (dd, J = 8.4, 2.6 Hz, 1 H), 7.63 (d, J = 2.5 Hz, IH), 7.18 (d, J = 8.4 Hz, IH), 6.84 (dd, J = 5.6, 2.6 Hz, IH), 5.36-5.33 (m, 15 IH), 4.95-4.85 (m, 2H), 4.52 (dd, J = 7.6, 4.8 Hz, 2H), 4.42 (s, 2H), 3.37 (s, 3H), 3.21 (t, J = 7.4 Hz, 2H), 2.83 (t, J= 7.8 Hz, 2H), 2.40 (s, 3H), 2.04-1.99 (m, 2H).

Example 1.331

[1403] Synthesis of N-(4-chlorophenyl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 325)

619

H

Ck N

[1404] Compound 325 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridine with 4-chloroaniline. LCMS (ES) [M+l]⁺ m/z: 466. 'H NMR (300 MHz, DMSO-7s, ppm) Ô 10.36 (s, IH), 8.46 (d, J = 5.6 Hz, IH), 7.65 (d, J = 8.8 Hz, 2H), 7.62 (d, J = 2.6 Hz, IH), 7.35 (d, J = 8.8 Hz, 2H), 6.85 (dd, J = 5.6, 2.6 Hz, IH), 5.41-5.28 (m, IH), 4.90 (t, J = 6.7 Hz, 2H), 4.51 (dd, J = 7.5, 4.7 Hz, 2H), 4.42 (s, 2H), 3.21 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.08 - 1.93 (m, 2H).

Example 1.332

[1405] Synthesis of 2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]-N-(4-methylphenyl)acetamide (Compound 326)

[ 1406] Compound 326 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridîne wilh 4-methylaniline. LCMS (ES) [M+l]* m/z: 446. 'H NMR (300 MHz, DMSO-A ppm) δ 10.11 (s, 1 H), 8.46 (d, J = 5.7 Hz, 1 H), 7.64 (t, J = 1.9 Hz, IH), 7.49 (d, J = 8.0 Hz, 2H), 7.10 (d, J= 8.0 Hz, 2H), 6.91-6.82 (m, IH), 5.38-5.29 (m, IH), 4.90 (t, J = 6.7 Hz, 2H), 4.51 (dd, J = 7.4, 4.7 Hz, 2H), 4.41 (s, 2H), 3.36 (s, 3H), 3.21 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.9 Hz, 2H), 2.24 (s, 3H), 2.11-1.93 (m, 2H).

Example 1.333

[1407] Synthesis ofN-(4-methoxyphenyl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridm-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amÎno]acetamide (Compound 327)

[ 1408] Compound 327 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyrîdine with p-anisidine. LCMS (ES) [M+l] ⁺ m/z: 462. 'H NMR (300 MHz, DMSO-A, ppm) δ 10.05 (s, l H), 8.46 (d, J = 5.6 Hz, IH), 7.64 (d, J = 2.5 Hz, IH), 7.57-7.46 (m, 2H), 6.93-6.82 (m, 3H), 5 5.38-5.31 (m, IH), 4.96-4.85 (m, 2H), 4.52 (dd, J = 7.5, 4.7 Hz, 2H), 4.38 (s, 2H), 3.71 (s, 3H), 3.31 (s,

3H), 3.20 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.11-1.93 (m, 2H).

Example 1.334

[1409] Synthesis ofN-tert-butyl-2-[methyl(2-[[l,3]thiazolo[5,4-c]pyndin-6-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 328)

[1410] Compound 328 was synthesized similar to compound 245 by replacing 2-chloro-4-(oxetan-3yloxy)pyridine with 6-ch!oro-[l,3]thiazolo[5,4-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 397. ^]H NMR (300 MHz, DMSO-d6) δ 9.71 (s, IH), 9.51 (d, J = 0.9 Hz, IH), 9.01 (d, J = 0.9 Hz, IH), 8.12 (HCOOH), 7.84 (s, 1 H), 4.18 (s,2H), 3.34 (s, 3H), 3.18 (t, J = 7.3 Hz, 2H), 2.87 (d, J = 7.8 Hz, 2H), 2.05-1.97 (m, 2H),

1.24 (s, 9H).

Example 1.335

[1411] Synthesis of N-(6-methoxypyridin-3-yl)-2-[methyl(2-{[l,3]thiazolo[5,4-c]pyridin-6-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 329)

621

[ [412] Compound 329 was synthesized similar to compound 258 by replacing 3-chloro-2,6naphthyridine with 6-chloro-[l,3]thiazolo[5,4-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 448, 'H NMR (300 MHz, DMSO-d6) δ 9.71 (s, IH), 9.49 (d, J = 0,9 Hz, IH), 8.93 (d, J = 0.9 Hz, IH), 8.37 (d, J = 2.7 Hz, IH), 7.91 (dd, J = 8.9, 2.7 Hz, IH), 6.76 (d, J = 8.9 Hz, IH), 4.47 (s, 2H), 3.79 (s, 3H), 3.40 (s, 3H), 3.22 (t, J = 7.8 Hz, 2H), 2.87 (t, J = 7.8 Hz, 2H), 2.07-2,01 (m, 2H).

Example 1.336

[1413] Synthesis of2-[(2-{4-[(l-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methylpyndin-3-yl)acetamide (Compound 330)

[1414] Compound 330 was synthesized similar to Compound 252 by replacing 1 -(2hydroxyethyl)pyrrolidine with {l-[(tert-butyldimethylsilyl)oxy]cyclopropyl}methanol and repacing 3fluoroaniline with 6-methyi-3-aminopyridine. LCMS (ES) [M+l]⁺ m/z: 461.2. 'H NMR (300 MHz, DMSO-Æ) δ 10.34 (s, IH), 8.59 (d, 7=2.6 Hz, 1 H), 8.43 (d, 7= 5.6 Hz, IH), 8.17 (s, IH), 7.99-7.75 (m, 2H), 7.38-6.94 (m, 2H), 4.43 (s, 2H), 3.67 (s, 2H), 3.35 (s, 3H), 3.20 (t, 7= 7.1 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.40 (s, 3H), 2.05-1.95 (m, 2H), 0.93 (d, 7= 5.1 Hz, 2H), 0.87 (d, 7= 5.2 Hz, 2H).

Example 1.337

[1415] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyi-5l·I,6H,7I-Icyclopenta[d]pyrimidin-4-y[}(methyl)amino)-N-(6-methylpyridin-3-yl)acetamide (Compound 331)

622

Scheme 123

Step 1

[1416] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed NaH (6.82 g, 284.19 mmol, 1.10 equiv), THF (300.00 mL). To this was added methyl acetoacetate (30.00 g, 258.36 mmol, 1.00 equiv) dropwise at 0 °C. The resulting solution was stirred for 15 min at 0 °C. Tothis was added n-BuLi (108.51 mL, 271.27 mmol, 1.05 equiv) dropwise with stirring at 0 °C in 15 min. To the mixture was added l-iodo-2-methy [propane (71.32 g, 387.54 mmol, 1.50 equiv) dropwise with stirring at 0 °C in 30 min. The resulting solution was stirred for 30 min at room température. The pH value of the solution was adjusted to 6 with HCl (1 mol/L). The resulting solution was extracted with 3x500 mL of ether and the organic layers combined. The resulting solution

623 was extracted with 3x500 mL of NaCI and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with PE/THF (4%). This resulted in 18 g (40.45%) of methyl 6-methyl-3-oxoheptanoate as a yellow liquid.

Step 5 2

[ 1417] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed methyl 6-methyl-3-oxoheptanoate (18.00 g, 104.52 mmol, l.OO equiv), CH₃CN (400.00 mL), 4-acetamidobenzenesulfonyl azide (25.Il g, 104.52 mmol, l.OO equiv). This was followed by the addition of Et₃N (31.73 g, 313.55 mmol, 3.00 equiv) dropwise with stirring at 0 °C. The resulting 10 solution was stirred for overnight at room température. The resulting mixture was concentrated. The resulting solution was diluted with 300 mL of ether/n-hexane=l :1. The solids were fîltered out. The resulting mixture was concentrated. The residue was applied onto a silica gel column with TIIF/PE (10%). This resulted in 17.8 g (85.92%) of methyl 2-diazo-6-methyl-3-oxoheptanoate as a yellow oil.

Step 3

[1418] Into a 500-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed Rh₂(OAc)4 (0.39 g, 0.87 mmol, 0.01 equiv), DCM (250.00 mL). This was followed by the addition of a solution of methyl 2-diazo-6-methyl-3-oxoheptanoate (17.30 g, 87.27 mmol, 1.00 equiv) in DCM (50 mL) dropwise with stirring at 0 °C. The resulting solution was stirred for 20 4 h at room température. The resulting solution was extracted with 3x200 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (5.6%). This resulted in 12.57 g (84.62%) of methyl 2,2dimethyl-5-oxocyclopentane-l-carboxylate as a dark green liquid. LCMS (ES) [M+1]^T m/z: 171.

Step 4

[1419] Into a 500-mL round-bottom flask, was placed methyl 2,2-dimethyl-5-oxocyclopentane-lcarboxylate (12.00 g, 70.50 mmol, 1.00 equiv), urea (12.70 g, 211.47 mmol, 3.00 equiv), EtOH (225.00 mL), HCI(gas)in 1,4-dioxane (45.00 mL). The resulting solution was stirred for 3 h at 100 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The resulting solution was diluted with 200 mL of 5%NaOH. The resulting solution was stirred for 1 h at 80 °C. The

624 réaction mixture was cooled to 0 °C. The pH value ofthe solution was adjusted to 3 with HCl (l mol/L). The solids were collected by filtration. This resulted in 6.5 g (51.16%) of 5,5-dimethyl-lH,3H,6H,7Hcyclopenta[d]pyrimîdine-2,4-dione as a grey solid. LCMS (ES) [M-l]⁺ m/z; 179.

Step 5

[1420] Into a 250-mL round-bottom flask, was placed 5,5-dimethyl-IH,3H,6H,7Hcyclopenta[d]pyrimidine-2,4-dione (6.50 g, 36.07 mmol, l.OO equiv), EfN (3.65 g, 36.07 mmol, l.OO equiv). This was followed by the addition of POCh (80.00 mL) dropwise with stirring at room température. The resulting solution was stirred for 2 h at 80 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The resulting solution was diluted with 200 10 mL of water/ice. The pH value of the solution was adjusted to 7-8 with Na₂CO3. The resulting solution was extracted with 3x200 mL of dichloromethane and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The residue was applied onto a silica gel column with THF/PE (10%). This resulted in 7.15 g (91.31%) of 2,4-dichloro-5,5-dimethyl-6H,7Hcyclopenta[d]pyrimidine as light yellow liquid. LCMS (ES) [MH]⁺ m/z: 217.

Step 6

[1421] Into a 40-mL vial, was placed 2,4-dichloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidine (1.00 g, 4.61 mmol, LOÛ equiv), 2-(methylamino)-N-(6-methylpyridin-3-yl)acetamide (1.07 g, 5.97 mmol, 1.30 equiv), NMP (20.00 mL), DIEA (2.98 g, 23.03 mmol, 5.00 equiv). The resulting solution was stîrred for 6 h at 60 °C. The reaction mixture was cooled to room température. The crude product (3 20 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD

Column, 19cm, 150mm, 5um; mobile phase, Water (0.1 %FA) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. This resulted in 500 mg (30.16%) of2-([2-chloro-5,5-dimethyl-6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)ammo)-N-(6-methylpyridin-3-yl)acetamide as off-white solid. LCMS (ES) [M+l]* m/z:

360.

Step 7

[ 1422] Into a 40-mL vial, was placed 2-([2-chloro-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamide (500.00 mg, 1.39 mmol, 1.00 equiv), toluene (10.00 mL), 4-f1uoro-2-(tributylstannyl)pyridine (804.78 mg, 2.08 mmol, 1.50 equiv), Pd(PPh₃)₄ (160.56

625 mg. 0J4 mmol, O.IO equiv). The resulting solution was stirred for ovemight at 120 °C. The reaction mixture was cooled to room température. The resulting mixture was concentrated. The residue was applied onto a silica gel column with THF/PE (45%). This resulted in 300 mg (51.35%) of 2-[[2-(4fluoropyridin-2-yl)-5,5-dimethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]-N-(6- methy lpyridin-3-yl)acetamide as white solid. LCMS (ES) [M+l]⁺ m/z:

421.

Step 8

[I423] Into a 40-mL vial, was placed 2-(oxan-2-yloxy)ethanol (208.59 mg, 1.43 mmol, 2.00 equiv), DMF (10.00 mL). This was followed by the addition ofNaH (42.80 mg, 1.78 mmol, 2.50 equiv), in portions at 0 °C. The resulting solution was stirred for 0.5 h at room température. To this was added 2[[2-(4-fluoropyridin-2-yl)-5,5-dimethyl-6H,7H-cyclopenta[d]pyrirnidin-4-yl](methyi)amino]-N-(6methylpyridin-3-yl)acetamide (300.00 mg, 0.71 mmol, 1.00 equiv), in portions at 0 °C. The resulting solution was stirred for 2 h at room température. The reaction was then quenched by the addition of 20 mL of water/ice. The resulting solution was extracted with 3x40 mL of ethyl acetate and the organic layers combined and dried over anhydrous sodium sulfate and concentrated. The crude product (0.5 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep C18 OBD Column, 19cm, 150mm, 5um; mobile phase, Water (0.1%NH3 Η₂Ο) and CAN (20% Phase B up to 60% in 11 min); Detector, 254. This resulted in 230 mg (58.97%) of2-[(5,5-dimethyl-2-[4-[2-(oxan-2yloxy)ethoxy]pyridin-2-yl]-6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)ammo]-N-(6-methylpyridin-320 yl)acetamide as off-white solid. LCMS (ES) [M+1 ]⁺ m/z: 547.

Step 9

[1424] Into a 20-mL vial, was placed 2-[(5,5-dimethyl-2-[4-[2-(oxan-2-yloxy)ethoxy]pyridin-2-yl]6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methylpyridin-3-yI)acetamide (230.00 mg, 0.42 mmol, 1.00 equiv), MeOH (5.00 mL), PTSA (36.23 mg, 0.21 mmol, 0.50 equiv). The resulting solution was stirred for 1 h at room température. The crude product (0.2 g) was purified by Prep-HPLC with the following conditions: Column, XBridge Prep Cl8 OBD Column, 19cm, 150mm, 5um; mobile phase A, Water (0.1%ΝΗ3 H2O) and mobile phase B, AcCN (20% Phase B up to 60% in 11 min);

Detector, 254 nm. This resulted in 166.5 mg (85.56%) of 2-([2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5dîmethyl-6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)-N-(6-methylpyridin-3-yl)acetamide as white solid. LCMS (ES, m/z): [M+H]⁺: 463. ‘H-NMR (300 MHz, DMSO-^^pm): δ 10.51 (s, IH), 8.59

626

(d, J = 2.6 Hz, l H), 8.42 (d, J = 5.7 Hz, IH), 7.89 (dd, J = 8.4, 2.5 Hz, IH), 7.77 (d, J = 2.5 Hz, IH), 7.16 (d, J = 8.4 Hz, IH), 7.01 (dd, J = 5.6, 2.5 Hz, IH), 5.00 (t, J = 5.1 Hz, 1 H), 4.30 (s, 2H), 4.01 (t, J = 4.8 Hz, 2H), 3.67 (q, J = 4.9 Hz, 2H), 3.32 (s, 3H), 2.88 (t, J = 7.3 Hz, 2H), 2.39 (s, 3H), 1.89 (t, J = 7.3 Hz, 2H), 1.46 (s, 6H).

Example 1.338 and 1.339

[1425] Synthesis of Racemic N-tert-butyl-2-{methyl[2-(4-{[(2S,3S)-2-methyloxetan-3- yljoxy} pyridin-2-y 1)-51-1,6H,7H~cyclopenta[d]pyrimidin-4-yl]amino} acetamide (Compound 332) and Racemic N-tert-butyl-2-{methyl[2-(4-{[(2R,3S)-2-methyloxetan-3-yl]oxy} pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 333)

Scheme 124

[1426] Into a 50-mL 3-necked round-bottom flask, was placed 2-methyloxetan-3-ol (222 mg, 2.52 mmol, 3.00 equiv), DMSO (5 mL). This was followed by the addition ofNaH (101 mg, 2.52 mmol, 3.00 15 equiv, 60%) at 0 °C. The resulting solution was stirred for 30 min at 25 °C. To this was added a solution of N-tert-buty l-2-[[2-(4-fluoropyridin-2-y l)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino]acetamide (300 mg, 0.84 mmol, 1.00 equiv) in DMSO (2 mL) dropwise with stîrring

627 at 0 °C. The resulting solution was stirred for l hr at 25 °C. The reaction was then quenched by the addition of l mL of water. The crude product was purified by Prep-HPLC with the following conditions (2#SHlMADZU (HPLC-Ol)): Column, Atlantis Prep T3 OBD Column, l9*l50mm 5um; mobile phase, Water (0.05% TFA) and ACN (16% Phase B up to 30% in 15 min); Detector, UV. 254 nm. This resulted in 108.8 mg (33.78%) of racemic N-tert-butyl-2-[methyl[2-(4-[[(2R,3S)-2-methyloxetan-3yl]oxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-y[]amino]acetamide (Compound 332); tris(trifluoroacetic acid sait) as an off-white solid and 53.7 mg (23.72%) of racemic N-tert-butyl-2[methyl[2-(4-[[(2S,3S)-2-methyloxetan-3-yl]oxy]pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino]acetamîde (Compound 333); trifluoroacetic acid as an off-white solid.

[1427] Compound 332: LCMS (ES) [M+lf m/z 426. Ή NMR (300 MHz, DMSO-Λ) δ 8.48 (d, 7= 5.6 Hz, IH), 7.79 (d, 7= 2.5 Hz, lH), 7.69 (s, IH), 6.91 (dd, 7= 5.6, 2.6 Hz, IH), 5.44 (q, 7= 5.7 Hz, IH), 5.21 (p, 7= 6.3 Hz, IH), 4.93-4.83 (m, IH), 4.49 (dd, J= ΊΑ, 4.8 Hz, I H), 4.23-4.04 (m, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.4 Hz, 2H), 2.8i (t, 7= 7.8 Hz, 2H), L98 (q, 7= 7.8 Hz, 2H), L30(d,7=6.5 Hz, 3H), l .26 (s, 9H).

[I428] Compound 333: LCMS (ES) [M+lf m/z 426. Ή NMR (300 MHz, DMSO-Λ) δ 8.69 (d,7= 5.8 Hz, IH), 8.04-7.98 (m, 2H), 7.22 (dd, 7= 5.9, 2.7 Hz, IH), 5.26 (t, J= 53 Hz, IH), 4.89 (t, 7= 6.5 Hz, 2H), 4.40 (t,7= 6.4 Hz, IH), 4.35 (s, 2H), 3.47 (s, 3H), 3.25 (s, 2H), 3.04 (t, J= 7.9 Hz, 2H), 2.10 (t, 7 = 7.6 Hz, 2H), L50 (d, 7= 6.3 Hz, 3H), 1.27 (s, 9H).

Example 1.340

[1429] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyriinidin-4yl}(methyl)amino)-N-(4-methoxyphenyl)-N-methylacetamide (Compound 334)

[1430] Compound 334 was synthesized similar to compound 44 by replacing tert-buty lamine with 4methoxy-N-methyianiline. LCMS (ES) [M+l] ⁺ m/z: 464. 'H NMR (300 MHz, DMSO-d6) δ 8.52 (d, 7 = 5.7 Hz, IH), 7.78 (s, IH), 7.48 (d, 7= 8.4 Hz, 2H), 7.05-7.03 (m, 3H), 4.95 (t7= 5.5 Hz, IH), 4.19-4.15 (m, 4H), 3.79 (s, 5H), 3.29 (s, 3H), 3.27-3.22 (m, 5H), 3.14 (s, 2H), 2.92-2.71 (m, 2H), 2.13-1.85 (m,

628

2H).

Example 1.341

[1431] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-l-(5-methoxy-2,3-dihydro-lH-indol-l-y1)ethan-l-one (Compound 335)

[1432] Compound 335 was synthesized similar to compound 44 by replacing tert-butylamine with 5methoxy-2,3-dihydro-lH-indole. LCMS (ES) [M+l] ⁺ m/z: 476. Ή NMR (300 MHz, DMSO-d6) δ 8.42 (d, 7=5.6 Hz, IH), 7.90 (d,7= 8.7 Hz, iH), 7.70 (d,7= 2.5 Hz, l H), 6.98 (dd,7= 5.8, 2.6 Hz, IH), 6.87 (d, 7= 2.6 Hz, IH), 6.68 (d, 7= 8.7 Hz, lH), 4.88 (t, 7= 5.3 Hz, lH), 4.57 (s, 2H), 4.25 (t,7=8.3 Hz, 2H), 3.97 (d, 7= 4.9 Hz, 2H), 3.71 (s, 3H), 3.63 (q, 7= 4.6 Hz, 2H), 3.33(s, 3H), 3.18 (t, 7= 7.7 Hz, 4H), 2.82 (t, J= 7.9 Hz, 2H), 2.02-1.96 (m, 2H).

Example 1.342

[1433] Synthesis of N-tert-butyl-2-[methyl(2-{2'methyl-2H-pyrazolo[3,4-c]pyridin-5-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 336)

[1434] Compound 336 was synthesized similar to compound 24 by replacing 2tributylstannylpyridine with 2-methyl-5-(tributylstannyl)-2H-pyrazolo[3,4-c]pyridine. LCMS (ES+): [M+H]* = 394.1. Ή NMR (400 MHz, DMSO-d6) δ 9.37 (s, IH), 9.03 (s, 1 H), 8.84 (s, 1 H), 8.06 (s, IH), 4.45 - 4.32 (m, 6H), 3.51 (s, 2H), 3.09 - 3.03 (m, 2H), 2.15 - 2.07 (m, 2H), 1.25 (s, 9H).

629

Example l .343

[1435] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl} (methy l)amino)-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 337)

[1436] Compound 337 was synthesized similar to compound 280 by replacing 3-fluoroaniline with l-(trifluoromethyl)cyclopropan-l-amine hydrochloride. LCMS (ES) [M+1]' m/z: 480. 'H NMR (300 MHz, DMSO-d6) δ 9.07 (s, IH), 8.46 (d, J = 5.6 Hz, IH), 8.18 (s, HCOOH), 7.76 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.69 (s, IH), 4.18 (s, 2H), 3.87 (s, 2H), 3.28 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.08-1.92 (m, 2H), 1.24 (s, 6H), 1.22-1.07 (m, 2H), 1.04-0.94 (m, 2H).

Example 1.344

[1437] Synthesis of2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 338)

[1438] Compound 338 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridine with l-(trifluoromethyl)cyclopropan-l-amine hydrochloride. LCMS (ES) [M+1] ⁺ m/z: 464. Ή NMR (300 MHz, DMSO-d6) δ 8.98 (s, IH), 8.48 (d, J = 5.5 Hz, IH), 7.63 (d, J = 2.6 Hz, IH), 6.89 (dd, J = 5.6, 2.6 Hz, 1 H), 5.54-5.41 (m, IH), 5.15-4.91 (m, 2H), 4.64-4.54 (m, 2H), 4.18 (s, 2H), 3.33(s, 3H), 3.16 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.07-1.94 (m, 2H), 1.25-1.14 (m, 2H), 1.03-0.96 (s, 2H).

Example 1.345

630

[1439] Synthesis ofN-(4-chlorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl] (methy l)amino)acetam ide (Compound 339)

[1440] Compound 339 was synthesized similar to compound 44 by replacing tert-butylamine with 4- chloroaniline. LCMS (ES) [M+l] ⁺ m/z: 454. Ή NMR (300 MHz, DMSO-d6) δ 10.37 (s, IH), 8.45 (d, J = 5.7 Hz, IH), 8.14 (s, 0.5HCOOH), 7.78 (d, J = 2.4 Hz, IH), 7.64 (d, J= 8.9 Hz, 2H), 7.36 (d, J= 8.9 Hz, 2H), 7.02 (s, I H), 4.93 (t, 5.3 Hz, IH), 4.43 (s, 2H), 4.05 (t, J= 4.7 Hz, 2H), 3.69 (d, J= 5.0 Hz,

2H), 3.37 (s, 3H), 3.24 (t, J= 7.1 Hz, 2H), 2.87 (t, J= 1.9 Hz, 2H), 2.04-1.93 (m, 2H).

Example 1.346

[1441] Synthesis of N-(4-chlorophenyl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 340)

[1442] Compound 340 was synthesized similar to compound 253 by replacing 5-amino-2methoxypyridine with bicyclo[l.l. l]pentan-l-amine hydrochloride. LCMS (ES) [M+l] ⁺ m/z: 422. 'H NMR (300 MHz, DMSOé₆ ppm) δ 8.70 (s, IH), 8.50 (dd, J = 5.6, 1.4 Hz, IH), 7.68 (d, J = 2.4 Hz, IH), 6.90 (dt, J = 5.6, 2.8 Hz, IH), 5.58-5.43 (m, 1 H), 5.05-4.94 (m, 2H), 4.59 (dd, J = 7.7, 4.8 Hz, 2H), 4.13 (s, 2H), 3.30 (s, 3H), 3.16 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.38 (s, 1 H), 2.08-1.97 (m, 2H), 1.98 (s, 6H).

Example 1.347 [1443] Synthesis of N-tert-butyl-2-[(2-{furo[3,2-c]pyridin-6-yl}-5H,6H,7H-cyclopenta[d]pyrimidin4-yl)(methyl)amino]acetamide (Compound 341)

631

[ 1444] Compound 341 was synthesized similar to compound 245 replacing 2-chloro-4-(oxetan-3yloxy)pyridine with 6-chlorofuro[3,2-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 380. ’H NMR (300 MHz, DMSO-d6) δ 9.03 (s, IH), 8.60 (s, IH), 8.20 (d,J = 2.2Hz, 2H),8.l5 (s, 0.5HCOOH), 7.79 (s, IH), 7.207.13 (m, IH), 4.15 (s, 2H), 3.32 (s, 3H), 3.17 (t, J = 7.4 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.05-1.96 (m, 2H), 1.25 (s, 9H).

Example l .348

[1445] Synthesis of 2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-l-(piperidin-l-yl)ethan-l-one (Compound 342)

[1446] Compound 342 was synthesized similar to compound 318 by replacing tert-butylamine with piperidine. LCMS (ES) [M+l]⁺ m/z: 438. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.6 Hz, IH), 8.15 (s, 0.5Z7COOH), 7.71 (d, 7= 2.5 Hz, IH), 7.04 (dd,7= 5.7, 2.6 Hz, IH), 5.25-5.16 (m, IH), 4.49 (s, 2H), 3.94 (dd, 7= 10.3,4.5 Hz, IH), 3.90-3.73 (m, 3H), 3.52-3.40 (m, 4H), 3.25 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7=7.9 Hz, 2H), 2.38-2.20 (m, 1 H), 2.04-1.94 (m, 3H), 1.71-1.61 (m, 4H), 1.52-1.43 (m, 2H).

Example 1.349

[1447] Synthesis of 2-[methyl(2-[4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-l-(piperidin-l-yl)ethan-l-one (Compound 343)

632

[1448] Compound 343 was synthesized similar to compound 317 by replacing tert-butylamine with piperidine. LCMS (ES) [M+l]⁺m/z: 438. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.6 Hz, III), 8.15 (s, 0.57/COOH), 7.71 (d,7=2.5 Hz, IH), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 5.25-5.I6 (m, IH), 4.49 (s, 2H), 3.94 (dd, 7= 10.3, 4.5 Hz, IH), 3.90-3.73 (m, 3H), 3.51-3.41 (m, 4H), 3.25 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7=7.9 Hz, 2H), 2.38-2.20 (m, IH), 2.04-1.94 (m, 3H), 1.71-1.61 (m, 4H), 1.52-1.43 (m, 2H).

Example 1.350

[1449] Synthesis of 2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(6-methoxypyridin-3-yl)acetamide (Compound 344)

[4450] Compound 344 was synthesized similar to compound 187 by replacing ethane-1,2-diol with dimethylaminoethanol. LCMS (ES) [M+l] ⁺ m/z: 478. Ή NMR (300 MHz, DMSO-d6) δ 10.27 (s, IH), 8.44 (d, 7= 5.6 Hz, IH), 8.34 (d, 7= 2.6 Hz, IH), 8.17 (s, 0.7HCOOH), 7.89 (dd, 7= 8.9, 2.7 Hz, IH), 7.76 (d, 7=2.6 Hz, IH), 7.01 (dd,7= 5.6, 2.6 Hz, IH), 6.78 (d,7= 8.9 Hz, IH), 4.39 (s, 2H), 4.07 (t,7 = 5.6 Hz, 2H), 3.81 (s, 3H), 3.38 (s, 3H), 3.22 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.58 (t, 7= 5.6 Hz, 2H), 2.20 (s, 6H), 2.06-1.99 (m, 2H).

Example 1.351

[1451] Synthesis of N-(3-fluorophenyl)-2-[methyl(2-{4-[(ls,3s)-3-hydroxycyclobutoxy]pyridîn-2-

633 yl}-5H,6H,7H-cyciopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 345)

[1452] Compound 345 was synthesized similar to compound 280 replacing l-[(2-chloropyridin-4yl)oxy]-2-methylpropan-2-ol with 4-((ls,3s)-3-(benzyloxy)cyclobutoxy)-2-chloropyridine. LCMS (ES) [M+l] ⁺ m/z: 464. Ή NMR (300 MHz, DMSO-d6) δ 8.55 (d, J = 6.0 Hz, IH), 7.89 (d, J = 2.5 Hz, IH), 7.55 (d, J = ί I.5 Hz, IH), 7.43-7.28 (m, 2H), 7.17 (dd, J = 6.1, 2.7 Hz, IH), 6.92-6.81 (m, IH), 4.60 (s, 2H), 4.53-4.37 (m, IH), 4.03-3.87 (m, IH), 3.59 (s, 3H), 3.39 (t, J = 7.4 Hz, 2H), 3.08 (t, J = 7.9 Hz, 2H), 3.00-2.85 (m, 2H), 2.30-2.16 (m, 2H), 2.13-1.98 (m, 2H).

Exampie 1.352

[1453] Synthesis of N-(6-methoxypyridin-3-yl)-2-[methyl(2-{4-[(3R)-oxolan-3-yloxy]pyridin-2-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 346)

[1454] Compound 346 was synthesized similar to compound 187 by replacing ethane-l,2-diol with (3R)-oxolan-3-ol. LCMS (ES) [M+l] ^h m/z: 477. Ή NMR (300 MHz, DMSO-d6) δ 10.26 (s, IH), 8.45 (d. 7=5.6 Hz, IH), 8.35 (d, 7= 2.6 Hz, 1 H), 7.89 (dd, 7= 8.9, 2.7 Hz, IH), 7.73 (d,7=2.5 Hz, IH), 7.00 (dd, 7= 5.7, 2.6 Hz, IH), 6.78 (d, 7= 8.9 Hz, IH), 5.13-5.06 (m, 1 H), 4.39 (s, 2H), 3.80 (s, 3H), 3.90-3.65 (m, 4H), 3.37 (s, 3H), 3.21 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.29-2.11 (m, IH), 2.09-1.85 (m,3H).

Example 1.353

[1455] Synthesis of N-(6-methoxypyridin-3-yI)-2-[methyl(2-{4-[(3S)-oxolan-3-yloxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 347)

634

[l456] Compound 347 was synthesized similar to compound 187 by replacing ethane-l,2-diol with (3S)-oxolan-3-ol. LCMS (ES) [M+l]⁺ m/z: 477. ^lH NMR (300 MHz, DMSO-d6) δ l0.26(s, IH), 8.45 (d, J= 5.6 Hz, IH), 8.35 (d, J =2.6 Hz, IH), 7.89 (dd, J= 8.9, 2.7 Hz, IH), 7.73 (d,7=2.5 Hz, IH), 7.00 (dd, 7= 5.7, 2.6 Hz, IH), 6.78 (d, 7= 8.9 Hz, IH), 5.13-5.06 (m, IH), 4.39 (s, 2H), 3.80 (s, 3H), 3.90-3.65 (m, 4H), 3.37 (s, 3H),3.2l (t,7=7.3 Hz, 2H), 2.83 (t,7=7.8 Hz, 2H), 2.29-2.Il (m, IH), 2.09-1.85 (m, 3H).

Example l .354

[1457] Synthesis of N-{bicyclo[l .1.1 ]pentan-l-yl}-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 349)

[1458] Compound 349 was synthesized similar to compound 187 replacing 6-methoxypyridin-3amine with bicyclo[l.1.l]pentan-l-amine hydrochloride. LCMS (ES) [M+l]⁴ m/z: 410. 'H NMR(300 MHz, DMSO-d6) δ 8.73 (s, IH), 8.47 (d, 7= 5.6 Hz, IH), 8.15 (s, 0.5//COOH), 7.81 (d, 7=2.6 Hz, IH), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 4.93 (s, IH), 4.20-4.09 (m, 4H), 3.77 (s, 2H), 3.27 (s, 3H), 3.16 (t, 7 = 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.37 (s, IH), 2.05-1.93(m, 2H), 1.92 (s, 6H).

Example 1.355

[1459] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(3-methyl-l,2-thiazol-5-yl)acetamide (Compound 350)

635

[1460] Compound 350 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amine with 3-methylisothiazol-5-amine hydrochloride. LCMS (ES) [M+1 ]⁺ m/z: 441. ’HNMR (300 MHz, DMSO-d6) δ 12.11 (s, IH), 8.45 (d,7=5.7 Hz, IH), 8.14 (s, HCOOH), 7.68 (d, 7= 2.7 Hz, IH),

7.01 (dd, J= 5.7, 2.4 Hz, IH), 6.75 (s, IH), 4.92 (br, IH), 4.53 (s, 2H), 4.03 (t, 7= 4.8 Hz, 2H), 3.73- .70 (m, 2H), 3.39 (s, 3H), 3.22 (t, 7= 7.5 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.30 (s, 3H), 2.04-1.99 (m, 2H).

Example 1.356

[1461 ] Synthesis of 2-({2-[4-({[l-(3-fluoropheny])-lH-l,2,4-triazol-3-yl]methyl}(methyl)amino)10 5H,6H,7H-cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-l-ol (Compound 351)

636

HCl, NaNO₂. NaOAc, H₂O,0°C-RT

Scheme 125

Step l

[1462] A solution of 3-fluoroaniline (10.00 g, 89.994 mmol, 1.00 equiv) in a mixture of water (50,00 5 mL) and concentrated hydrochloric acid (30.00 mL) was cooled to 0 degrees C. A solution of sodium nitrite (7.45 g, 107.992 mmol, L20 equiv) in water ( i 0.00 mL) was added maintaining the température between 0 degrees C and 5 degrees C. Stîrring was continued for 5 min at 0 °C. This solution was added drop wise to a mixture of acetic acid sodium sait (55.37 g, 674.952 mmol, 7.50 equiv) and ethyl 2isocyanoacetate (i 1.20 g, 99.013 mmol, 1.10 equiv) in a mixture of water (100.00 mL) and methanol (10.00 mL).The reaction mixture was stirred at 0 °C for 30 min and was allowed to warm to room température. Stîrring was continued for overnight. The resulting solution was extracted with 2x300 mL of ethyl acetate. The resulting mixture was washed with 2 x300 of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (EA). This resulted in 5.5 g (25.98%) of ethyl l-(315 fluorophenyl)-lH-l,2,4-tnazole-3-carboxylate as a light yellow solid. LCMS (ES) [M+l]⁺ m/z: 236.

Step 2

637

[1463] Into a 250-mL 3-necked round-bottom flask, was placed ethyl l-(3-fluorophenyl)-lH-l,2,4triazole-3-carboxylate (5.50 g, 23.383 mmol. l.OO equiv), THF (60.00 mL). This was followed by the addition of L1AIH4 (1.33 g, 35.042 mmol, 1.50 equiv) at 0 °C. The resulting solution was stirred for l h at 0 °C. The reaction was then quenched by the addition of L5 mL of water, l .5 mL of !5%NaOH, 4.5 mL of water. The mixture was dried over anhydrous magnésium sulfate. The solids were filtered out. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (EA). This resulted in 2.2 g (48.70%) of (l-(3-fluorophenyl)-ll-l1,2,4-

Step 3

[1464] Into a 100-mL 3-necked round-bottom flask, was placed (l-(3-fluorophenyl)-lH-l,2,4triazol-3-yl)methanol (2.00 g, 10.353 mmol, 1.00 equiv), DCM (30.00 mL), PCI5 (4.31 g, 20.697 mmol, 2.00 equiv). The resulting solution was stirred for 1 h at room température. The reaction was then quenched by the addition of 30 mL of NH4CI (aq). The resulting solution was extracted with 2x40 mL of dichloromethane. The resulting mixture was washed with 2 x40 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:1). This resulted in 2 g (91.29%) of 3-(chloromethyl)-l(3-fluorophenyl)-lH-l,2,4-triazole as a light yellow solid. LCMS (ES) [M+l]⁺ m/z: 212. Step 4

[1465] Into a 40-mL round-bottom flask, was placed 3-(chloromethyl)-l-(3-fluorophenyI)-lH-l,2,4triazole (2.00 g, 9.451 mmol, 1.00 equiv), MeOH (20.00 mL), Methylamine (2M in methanol, 20.00 mL). The resulting solution was stirred for 4 h at 50 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/m éthanol (10:1). This resulted in 1.5 g (76.96%) of 1 -(l-(3-fluorophenyl)-lH-l,2,4triazol-3-yl)-N-methylmethanamine as a off-white solid. LCMS (ES) [M+l]⁺ m/z: 207. Step 5

[1466] Into a 100-mL 3-necked round-bottom flask, was placed 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (1.38 g, 7.300 mmol, 1.00 equiv), MeOH (30.00 mL), D1EA (2.35 g, 18.184 mmol, 2.50 equiv). This was followed by the addition of l-(l-(3-fluorophenyl)-lH-l,2,4-triazol-3-yl)-Nmethylmethanamine (1.50 g, 7.274 mmol, 1.00 equiv) at 0 °C.The resulting solution was stirred for 16 h at room température. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This resulted in 1.8 g (68.97%) of 2-

638 chloro-N-((l-(3-flLiorophenyl)-lH-l,2,4-triazol-3-yl)methyl)-N-methyl-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-amine as light yellow oil. LCMS (ES) [M+l]⁺ m/z: 359. Step 6

[1467] Into a 40-mL sealed tube purged and maintained with an inert atmosphère of nitrogen, was placed 2-chloro-N-((l-(3-fluorophenyl)-[H-l,2,4-triazol-3-yl)methyl)-N-methyl-6,7-dihydro-5Hcyclopenta[d] pyrimidin-4-amine (200.00 mg, 0.557 mmol, l.OO equiv), Toluene (6.00 mL), 4-f1uoro-2(tributylstannyl)pyridine (322.85 mg, 0.836 mmol, 1.50 equiv), Pd(PPh₃)₄ (64.41 mg, 0.056 mmol, 0.10 equiv). The resulting solution was stirred for 16 h at 100 °C in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with dichloromethane/methanol (10:1). This reaction was repeated 10 times and obtained 650 mg (69.44%) of N-((l-(3-f1uorophenyl)-l H-l,2,4-triazol-3-yl)methyl)-2-(4-fluoropyridin-2-yl)-N-methyl-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-amine as a light yellow oil. LCMS (ES) [M+l]⁺ m/z: 420.

Step 7

[1468] Into a 50-mL 3-necked round-bottom flask, was placed ethylene glycol (887.87 mg, 14.305 mmol, 20.00 equiv), DMF (3mL). This was followed by the addition ofNaH (85.82 mg, 3.576 mmol, 5.00 equiv) at 0 degrees C. To this was added N-((l-(3-fluorophenyl)-lH-l,2,4-triazol-3-yl)methyl)-2(4-fluoropyridin-2-yl) -N-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-amine (300.00 mg, 0.715 mmol, 1.00 equiv) at degrees C. The resulting solution was stirred for 2 h at room température. The resulting solution was extracted with 2x20 mL of dichloromethane/methanol (10:1). The resulting mixture was washed with 2 x20 ml of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep C18 OBD Column, 50*250mm 5um lünm; mobile phase, phase A: FhO (0.05 %NH₃.H₂O); phase B: CH₃CN (10% CH₃CN up to 50% CH₃CN in 15 min). This resulted in 216.1 mg (65.47%) of 2-({2-[4-({[l-(3-fluorophenyl)-lH-I,2,4-triazol-3-yl]methyl}(inethyl)amino)-5H,6H,7H25 cyclopenta[d]pyrimidin-2-yl]pyridin-4-yl}oxy)ethan-l-ol as a white solid. LCMS (ES) [M+l]⁺ m/z: 462. Ή NMR (300 MHz, DMSO-Ts, ppm): δ 9.27 (s, IH), 8.45 (d, J= 5.6 Hz, IH), 7.86 (d,7=2.6 Hz, IH), 7.80-7.66 (m,2H), 7.63-7.55 (m, 1 H), 7.32-7.19 (m, IH), 7.02 (dd, 7= 5.7, 2.6 Hz, 1 H), 5.00 (s, 2H), 4.93 (t, 7= 5.5 Hz, 1 H), 4.13 (t, 7= 4.9 Hz, 2H), 3.77-3.72 (m, 7= 5.0 Hz, 2H), 3.38 (s, 3H), 3.25 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.9 Hz, 2H), 2.06-1.95 (m, 2H).

Example 1.357

[1469] Synthesis of N-tert-buty l-2-[methyl({2-[4-(l-methy 1-1 H-pyrazol-4-yl)pyridin-2-yl]-

639

5H,6H,7H-cyclopenta[d]pyrimidin-4-y[})amino]acetamide (Compound 352)

[1470] Compound 352 was synthesized similar to compound 245 by replacing 2-chloro-4-(oxetan-3yloxy)pyridine with 2-chloro-4-(l-methyl-IH-pyrazol-4-yl)pyridine. LCMS (ES) [M+I] ⁺ m/z: 420. 'H

NMR (300 MHz, DMSO-d6) δ 8.57 (dd, 7= 5.I, 0.8 Hz, IH), 8.47 (s, IH), 8.41 (dd,7= 1.8,0.8 Hz,

H), 8.14 (d, 7= 0.8 Hz, 1 H), 7.65 (s, IH), 7.60 (dd,7=5.1, 1.8 Hz, lH), 4.19 (s, 2H), 3.91 (s, 3H), 3.30 (s, 3H), 3.17 (t, 7 = 7.4 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.18 (s, 9H).

Example 1.358

[1471] Synthesis ofN-(1 -cyclopropy 1-1 H-pyrazo!-4-y 1)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yΠ-

ΙΟ 5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 353)

H

[1472] Compound 353 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amine with l-cyclopropylpyrazol-4-amine. LCMS (ES) [M+l]^d m/z: 450. ^!H NMR (300 MHz, DMSOd6) δ 10.28 (s, IH), 8.46 (d, J = 5.6 Hz, IH), 7.87 (s, 1 H), 7.77 (d, J = 2.6 Hz, 1 H), 7.40 (s, 1 H), 7.02 (dd, J = 5.6, 2.6 Hz, IH), 4.94 (s, IH), 4.35 (s, 2H), 4.07-4.04 (m, 2H), 3.71-3.66 (m, 2H), 3.65-3.62 (m, 111),3.30 (s, 3H), 3.22-3.16 (m, 2H), 2.85-2.80 (m, 2H), 2.02-1.98 (m, 2H), 0.98-0.95 (m, 4H).

Example 1.359

[1473] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl} (methy l)amino)-l -(pyrrolidin-l-yl)ethan-l-one (Compound 354)

640

[1474] Compound 354 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amine with pyrrolidine. LCMS (ES) [M+l]⁺ m/z: 398. ^]H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J= 5.6 Hz, IH), 8.I5 (s, IH), 7.72 (d, J= 2.5 Hz, IH), 7.03 (dd, J= 5.8, 2.5 Hz, IH), 4.93 (br, IH), 4.39 (s,

2H), 4.13 (t, 7= 4.8 Hz, 2H), 3.75 (t, 7= 4.9 Hz, 2H), 3.54 (t, J = 6.8 Hz, 2H), 3.34-3.29 (m,5H), 3.2l-

3.14 (t, J = 7.4 Hz, 2H), 2.92-2.81 (m, 2H), 1.96-1.85 (m, 4H), 1.79 1.68(m, 2H).

Example 1.360

[1475] Synthesis of l-(4,4-difluoropiperidin-!-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-l-one (Compound 355)

[1476] Compound 355 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amîne with 4,4-difluoropiperidine. LCMS (ES) [M+l]⁺ m/z: 448. Ή NMR (300 MHz, DMSO-d6) δ 8.42 (d, 7=5.6 Hz, IH), 8.16 (s, 0.67/COOH), 7.77 (d,7=2.6 Hz, IH), 7.03 (dd, J = 5.7, 2.6 Hz, IH), 4.57 (s,2H), 4.12 (t, J = 5.0 Hz, 2H), 3.75 (t, J = 4.9 Hz, 2H), 3.69-3.52 (m, 4H),3.28 (s, 3H),3.16(t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.9 Hz, 2H), 2.23-2.14 (m, 2H), 1.99-2.83 (m, 4H).

Example 1.361

[1477] Synthesis of 2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin4-yl}(methyl)amino)-N-(3-fluorophenyl)acetamide (Compound 356)

641

[1478] Compound 356 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3- amine with 3-fluoroaniline and replacing ethane-l,2-diol with N-(2-hydroxyethy!)acetamide. LCMS (ES) [M+l]⁺ m/z: 479. 'H NMR (300 MHz, DMSO-d6) δ 10.45 (s, IH), 8.45 (d, J = 5.6 Hz, IH), 8.07 (t, J = 5.3 Hz, IH), 7.78 (d, J = 2.5 Hz, IH), 7.64-7.53 (m, IH), 7.40-7.27 (m, 2H), 7.02 (dd, J = 5.7, 2.6

Hz, IH), 6.86 (ddt, J = 8.9, 7.2, 2.6 Hz, IH), 4.45 (s, 2H), 4.05 (t, J = 5.5 Hz, 2H), 3.39 (d, J = 5.5 Hz, 2H), 3.36 (s, 3H), 3.21 (t, J = 7.3 Hz, 2H), 2.84 (t, J = 7.8 Hz, 2H), 2.05-1.96 (m, 2H), 1.83 (s, 3H).

Example 1,362

[1479] Synthesis of 1 -(azepan-l-yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyc lopenta[d]pyrimidin-4-yl] (methy l)amino)ethan-l-one (Compound 357)

[1480] Compound 357 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amine with azepane. LCMS (ES) [M+l]⁺ m/z: 426. ‘H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J= 5.6 Hz, IH), 8.14 (s, IH), 7.72 (d, J =2.6 Hz, IH), 7,02 (dd, J= 5,6, 2.6 Hz, 1 H), 4.92 (s, IH), 4.54 (s, 2H),

4.12 (t, 7 = 4.9 Hz, 2H), 3.80-3.72 (m, 2H), 3.50 (t, 7=6.0 Hz, 2H), 3.41 (t,7 = 5.9 Hz, 2H), 3,26 (s,

3H), 3,15 (t,7= 7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.03-1.98 (m, 2H), 1.84-1.72 (m, 2H), 1.61-1.40 (m, 6H).

Example 1.363

[1481] Synthesis of l-(azepan-l-yl)-2-[methyl({2-[4-(oxetan-3-yloxy)pyridin-2-ylJ-5H,6H,7H-

642 cyclopenta[d]pyrimidin-4-yl})amino]ethan-l-one (Compound 358)

[1482] Compound 358 was synthesized similar to compound 187 replacing 6-methoxypyridin-3amine with azepane and replacing ethan-l,2-diol with oxetan-3-ol. LCMS (ES) [M+l] ⁺ m/z: 438. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.6 Hz, IH), 7.61 (d, 7= 2.6 Hz, IH), 6.87 (dd, 7= 5.6, 2.6 Hz, IH), 5.50-5.43 (m, IH), 5.02-4.91 (m, 2H), 4.63-4.52 (m, 4H), 3.50 (t, 7= 6.0 Hz, 2H), 3.42 (t, 75.9 Hz, 2H), 3.26 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.88-1.79 (m, 2H), 1.62-1.43 (m,6H).

Example 1.364

[1483] Synthesis of l-(4-fluoropiperidin-l-y 1)-2-( {2-(4-(2-hydroxyethoxy)pyridin-2-y 1]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-l-one (Compound 359)

[1484] Compound 359 was synthesized similar to compound 187 by replacing 6-methoxypyridin-3amîne with 4-fluoropiperidine. LCMS (ES) [M+l] ⁺ m/z: 430. 'H NMR (300 MHz, DMSO-d6) δ 8.45 (d, 7= 5.4 Hz, IH), 7.75 (s, IH), 7.02 (dd, 7= 5.4, 2.5 Hz, 1 H), 5.00-4.84 (m, 2H), 4.63-4.45 (m, 2H), 4.13-4.10 (m, 2H), 3.76-3.74 (d, 7= 6 Hz, 2H), 3.70-3.40 (m, 4H), 3.27 (s, 3H), 3.17-3.12 (m, 2H), 2.832.78 (m, 2H), 2.20-1.50 (m, 6H).

Example 1.365

[1485] Synthesis of N-tert-butyl-2-[ethyl({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 360)

643

[I486] Compound 360 was synthesized similarto compound 126. LCMS (ES) [M+l] ⁺ m/z: 414. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 7.86 (d, J = 2.5 Hz, 1 H), 7.70 (s, IH), 7.04 (dd, J = 5.7, 2.5 Hz, 1 H), 4.92 (s, IH), 4.19-4.06 (m, 4H), 3.76 (t, J = 4.9 Hz, 2H), 3.65 (q, J = 7.0 Hz, 2H),

3.07 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.23-1.16 (m, 12H).

Example 1.366

[ 1487] Synthesis of N-tert-buty 1-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yi]-5,5-dimethyl-5H,6H,7Hcyclopenta[d]pynmidin-4-yl}(methyl)amino)acetamide (Compound 361)

[1488] Compound 361 was synthesized similar to compound 331 by replacing 2(methylamino)-N-(6-methylpyridin-3-yl)acetamide with N-tert-butyl-2-(methylamino)acetamide hydrochloride. LCMS (ES) [M+l]⁺ m/z: 428. Ή NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 5.6 Hz, IH), 7.86 (d, J = 2.6 Hz, IH), 7.67 (s, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.91 (s, IH), 4.15 (t, J = 5.0 Hz, 2H), 4.03 (s, 2H), 3.77 (s, 2H), 3.18 (s, 3H), 2.86 (t, J = 7.2 Hz, 2H), 1.87 (t, J = 7.3 Hz, 2H), 1.43 (s, 6H), 1.21 (s, 9H).

Example 1.367

[1489] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-l-(piperidin-l-yI)ethan-l-one (Compound 362)

644

[1490] Compound 362 was synthesized similar to compound 33] by replacing 2-(methylamino)-N(6-methylpyridin-3-yl)acetamide with 2-(methylamino)-l-(piperidin-l-yl)ethanone hydrochloride.

LCMS (ES) [M+1]⁺ m/z: 440. 'H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, IH), 7.72 (d, J = 2.6 Hz, IH), 7.04 (dd, J = 5.6, 2.5 Hz, I H), 4.91 (t, J = 5.4 Hz, lH),4.38(s, 2H),4.13 (t, J = 4.9 Hz, 2H), 3.76 (q, J = 5.1 Hz, 2H), 3.44 (d, J = 17.6 Hz, 4 H), 3.21 (s, 3H), 2.85 (t, J = 7.3 Hz, 2H), 1.87 (t, J = 7.2 Hz, 2H), 1.61 (s, 4H), 1.44 (s, 8H).

Example 1.368

[1491] Synthesis of2-({2-[4~(2-hydroxyethoxy)pyridin-2-yl]-5,5-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin'4'yl}(methyl)amino)-N-(6-methoxypyridin-3-yl)acetamide (Compound 363)

[1492] Compound 363 was synthesized similar to compound 331 by replacing 2-(methylamino)-N(6-methylpyridin-3-yl)acetamide with N-(6-methoxypyridin-3-yl)-2-(methylamino)acetamide hydrochloride. LCMS (ES) [M+l ] ⁺m/z: 479. 'H NMR (300 MHz, DMSO-d6) δ 10.44 (s, IH), 8.42 (d, J = 5.6 Hz, IH), 8.33 (d, J = 2.6 Hz, IH), 7.87 (dd, J = 9.0, 2.6 Hz, IH), 7.79 (d, J = 2.5 Hz, IH), 7.02 (dd, J = 5.7, 2.5 Hz, IH), 6.77 (d, J = 8.8 Hz, IH), 4.91 (s, IH), 4.29 (s, 2H), 4.02 (t, J = 4.8 Hz, 2H), 3.80 (d, J = 1.5 Hz, 3H), 3.68 (t, J = 4.7 Hz, 2H), 3.30 (s, 3H), 2.88 (t, J = 7.2 Hz, 2H), 1.89 (t, J = 7.2 Hz, 2H), 1.46 (s, 6H).

Example ] ,369

[1493] Synthesis of l-{3-azabicyclo[3.1.1]heptan-3*yl}-2-({2-[4“(2-hydroxyethoxy)pyridin-2-y[]-

645

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-l-one (Compound 364)

[1494] Compound 364 was synthesîzed similar to compound 187 by replacing 6-methoxypyridin-3amine with 3-azabîcyclo[3.l.l]heptane hydrochloride. LCMS (ES) [M+l] ⁺ m/z: 424. *H NMR. (300 MHz, DMSO-d6) δ 8.45 (d, 7= 5.7 Hz, IH), 8.17 (s, HCOOH), 7.74 (d, 7= 2.7 Hz, IH), 7.04 (dd, J = 6.0,3.0 Hz, IH), 4.50 (s, 2H), 4.14 (t, 7= 5.1 Hz, 2H), 3.84 (d,7=2.4 Hz, 2H), 3.76 (t, 7= 5.1 Hz, 2H), 3.53 (d, 7= 2.4 Hz, 2H), 3.31 (s, 3H), 3.17 (t, 7= 7.2 Hz, 2H), 2.83 (t, 7= 8.1 Hz, 2H), 2.48-2.43 (m, 2H), 2.19-2.10 (m, 2H), 2.03-1.93 (m, 2H), L32 (dt, 7= 6.8, 4.1 Hz, 2H).

Example 1.370

[1495] Synthesis of N-tert-butyl-2-[(2-{furo[2,3-c]pyridin-5-y 1}-5H,6H,7H-cyclopenta[d]pyrimidin-

4-yl)(methyl)amino]acetamide (Compound 365)

[1496] Compound 365 was synthesîzed similar to compound 245 by replacing 2-chloro-4-(oxetan-3yloxy)pyridine with 5-chlorofuro[2,3-c]pyridine. LCMS (ES) [M+l]⁺m/z: 380. *H NMR (300 MHz, DMSO-d6) δ 9.00 (s, IH), 8.73 (s, 1 H), 8.32-8.24 (m, IH), 8.14 (s, 0.5 7/COOH), 7.74 (s, IH), 7.10 (d, 7 = 2.4 Hz, IH), 4.16 (s, 2H), 3.30 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.83 (t, 7= 7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.24 (s, 9H).

Example 1.371

[1497] Synthesis of N-tert-buty l-2-[(2-{4-[(2R)-2-hydroxypropoxy]pyridin-2-y l}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 366)

646

[1498] Compound 366 was synthesized similar to compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-1-ol with (2R)-2-(oxan-2-yloxy)propan-l-ol. Analytical chiral HPLC conditions: Column, Lux-cellulose-2, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase B, CH₃CN; Flow rate: 1 mL/min; Gradient: 20%B in 6min; 254 nm. Rétention time: 2.123 min. LCMS (ES) [M+I] ⁺ m/z: 414. 'HNMR (300 MHz, DMSO-d6) δ 8.47 (dd, 7= 5.7, 1.3 Hz, IH), 7.99-7.78 (m, IH), 7.69 (s, 1 H), 7.05-7.02 (m, IH), 4.94 (d, 7= 3.9 Hz, IH), 4.13 (s, 2H), 4.04-3.93 (m, 3H), 3.26 (s, 3H), 3.13 (t, 7=7.3 Hz, 2H), 2.81 (t,7=7.8 Hz, 2H), 2.03-1.93 (m, 2H), 1.25 (s, 9H), 1.23 (d,7=7.5 Hz, 3H).

Example 1.372

[1499] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(2-methylbutan-2-yl)acetamide (Compound 367)

[ 1500] Compound 367 was synthesized similar to compound 44 by replacing tert-buty lamine with 2methylbutan-2-amine. LCMS (ES) [M+l]⁺ m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 8.46 (d,7= 5.6 Hz, IH), 7.84 (d, 7= 2.5 Hz, 1 H), 7.49 (s, 1 H), 7.04 (dd,7=5.6, 2.6 Hz, 1 H), 4.91 (t,7=5.4 Hz, JH), 4.20-4.10 (m, 4H), 3.76 (q,7= 5.1 Hz, 2H), 3.25 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.15-1.91 (m, 2H), 1.61 (q, 7= 7.5 Hz, 2H), 1.18 (s, 6H), 0.71 (t, 7= 7.4 Hz, 3H).

Example 1.373

[1501] Synthesis of l-(2,2-dimethylpyrrolidin-l -yl)-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-

647

5H,6H,7H-cyciopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-l-one (Compound 368)

[l 502] Compound 368 was synthesized similarto compound 44 by replacing tert-butylamine with 2,2-dimethylpyrrolidine. LCMS (ES) [M+l R m/z; 426. Ή NMR (300 MHz, DMSO-d6) δ 8.46 (d, J= 5 5.5 Hz, lH), 7.77 (d, 7= 2.6 Hz, lH), 7.07-6.99 (m, IH), 4.91 (s, IH), 4.30 (s, 2H), 4.13 (t, 7= 4.9 Hz,

2H), 3.78-3.74 (m, 2H), 3.60 (t, 7= 6.8 Hz, 2H), 3.29(s, 3H), 3.12 (t, 7= 7.1 Hz, 2H), 2.80 (t, 7= 7.8 Hz, 2H), 2.04-1.75 (m, 4H), 1.74-1.69 (m, 2H), 1.31 (s, 6H).

Example L374

[1503] Synthesis of N-tert-butyI-2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H cyciopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 369)

[1504] Compound 369 was synthesized similar to compound 348 by replacing dimethylaminoethanol with N-(2-hydroxyethyl)acetamide. LCMS (ES) [M+l] ⁺ m/z: 441. ^!H NMR (300 MHz, DMSO-d6) Ô 8.48 (d, J = 5.6 Hz, IH), 8.16 (s, 1HCOOH), 8.11 (t, J = 5.5 Hz, IH), 7.85 (d, J = 2.5

Hz, IH), 7.68 (s, 1 H), 7.05 (dd, J = 5.6, 2.6 Hz, 1 H), 4.17-4.13 (m, 4H), 3.45 (q, J = 5.6 Hz, 2H), 3.26 (s, 3H), 3.13 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.03-1.96 (p, J = 7.6 Hz, 2H), 1.84 (s, 3H), 1.24 (s, 9H).

Example 1.375

[1505] Synthesis of N-tert-butyl-2-({2-[4-(2-acetamidoethoxy)pyridin-2-yl]-5H,6H,7H- cyciopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 369)

648

[1506] Compound 369 was synthesized similar to compound 348 by replacing dimethylaminoethanol with N-(2-hydroxyethyl)acetamide. LCMS (ES) [M+l] ⁺ m/z: 441. 'H NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 5.6 Hz, IH), 8.16 (s, IHCOOH), 8.11 (t, J = 5.5 Hz, IH), 7.85 (d, J = 2.5

Hz, IH), 7.68 (s, l H), 7.05 (dd, J = 5.6, 2.6 Hz, IH), 4.17-4.I3 (m, 4H), 3.45 (q, J = 5.6 Hz, 2H), 3.26 (s, 3H), 3.13 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.03-L96 (p, J = 7.6 Hz, 2H), 1.84 (s, 3H), L24 (s, 9H).

Example 1.376

[1507] Synthesis of N-tert-buty l-2-[(2-{4-[(2S)-2-hydroxypropoxy]pyridin-2-y l}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 370)

[1508] Compound 370 was synthesized similar to compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with (2S)-2-(oxan-2-yloxy)propan-l-ol. Analytical chiral HPLC conditions: Column, Lux-cellulose-2, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase 15 B, CH₃CN; Flow rate: 1 mL/min; Gradient: 20%B in 6min; 254 nm. Rétention time: 3.022 min. LCMS (ES) [M+l ]⁺ m/z: 414. ’H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.7 Hz, IH), 7.84 (d,7= 2.4 Hz, IH), 7.68 (s, IH), 7.04 (dd, 7= 5.7, 2.4 Hz, IH), 4.93 (d,7= 3.9 Hz, IH), 4.13 (s, 2H), 4.04-3.93 (m, 3H), 3.26 (s, 3H), 3.14 (t,7= 7.5 Hz, 2H), 2.81 (t,7= 7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.24 (s, 9H), 8.47 (d, 7=5.7 Hz, 3H).

Example 1.377

[1509] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-

649 yl](methyI)amino}-N-[(3S)-oxolan-3-yl]acetamide (Compound 371)

H

[1510] Compound 371 was synthesized similar to Compound 135 by replacing oxo!an-3-amine with (S)-tetrahydrofuran-3-amine. Analytîcal chiral HPLC conditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50%B in 20 min; 270 nm. Rétention time: 7.945 min. LCMS (ES) [M+l]⁺ m/z: 384. Ή NMR (300 MHz, DMSO-d6) δ 8.49 (d, 7= 5.7 Hz, IH), 8.38 (d, 7= 6.9 Hz, IH), 7.81 (d, 7= 2.7 Hz, IH), 7.06 (dd, 7 = 5.4,2.4 Hz, 1 H), 4.31-4.25 (m, 1 H), 4.20 (d, 7= 2.4 Hz, 2H), 3.90 (s, 3H), 3.78-3.60 (m, 3H), 3.46 (dd, 7 = 9.0, 4.2 Hz, ΠΙ), 3.28 (s, 3H), 3.18 (t, 7= 7.2 Hz, 2H), 2.85 (t, 7= 7.8 Hz, 2H), 2.11-1.92 (m, 3H), 1.77-1.67 (m, IH).

Example 1.378

[1511] Synthesis of 2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-N-[(3R)-oxolan-3-yl]acetamide (Compound 372)

H

[1512] Compound 372 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (R)-tetrahydrofuran-3-amine. Analytical chiral HPLC conditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50%B in 20 min; 270 nm. Rétention time: 10.028 min. LCMS (ES) [M+l]⁺ m/z: 384. Ή NMR (300 MHz, DMSO-d6) δ 8.48 (d, 7= 5.7 Hz, IH), 8.38 (d, 7= 6.9 Hz, 1 H), 7.80 (d, 7= 2.7 Hz, IH), 7.04 (dd, 7 = 5.4, 2.7 Hz, 1 H), 4.31-4.25 (m, IH), 4.20 (d, 7= 2.7 Hz, 2H), 3.90 (s, 3H), 3.78-3.60 (m, 3H), 3.46 (dd,

7= 9.0, 4.2 Hz, IH), 3.28 (s, 3H), 3.15 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.10-l.94 (m, 3H),

650

1.77- 1.67 (m, IH).

Example 1.379

[1513] Synthesis of 2-{[2-(4-methoxypyndin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino}-N-(oxetan-3-yl)acetamide (Compound 373)

[1514] Compound 373 was synthesized similar to Compound 135 by replacing oxolan-3-amine with oxetan-3-amine. LCMS (ES) [M+l]⁺m/z: 370. Ή NMR (300 MHz, DMSO-d6) δ 8.96 (d, 7= 6.9 Hz, IH), 8.48 (d, 7= 5.4 Hz, IH), 7.79 (d, 7 = 2.7 Hz, 1 H), 7.03 (dd,7 = 5.7, 2.7 Hz, IH), 4.87-4.78 (m, IH), 4.67 (t,7= 6.9 Hz, 2H), 4.43 (t, J= 6.3 Hz, 2H), 4.20 (s, 2H), 3.89 (s, 3H), 3.29 (s, 3H), 3.16 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.08-1.94 (m, 2H).

Example 1.380

[1515] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(oxetan-3-yl)acetamide (Compound 374)

[1516] Compound 374 was synthesized similar to Compound 44 by replacing tert-butylamine with oxetan-3-amine. LCMS (ES) [M+1]⁴ m/z: 400. ‘H NMR (300 MHz, DMSO-d6) δ 8.94 (d, J = 6.8 Hz, IH), 8.48 (d, J = 5.7 Hz, 1 H), 7.79 (d, J = 2.5 Hz, IH), 7.04 (dd, J = 5.7, 2.6 Hz, IH), 4.93 (t, J = 5.5 Hz, 1 H), 4.90-4.74 (m, 1 H), 4.73 - 4.63 (m, 2H), 4.44 (t, J = 6.3 Hz, 2H), 4.20 (s, 2H), 4.14 (t, J = 4.9 Hz, 2H), 3.80-3.72 (m, 2H), 3.29 (s, 3H), 3.16 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.02-1.97 (m, 2H).

Example l.38l

[1517] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrirmdin-4yl}(methyl)amino)-l-{5-methoxy-lH,2H,3H-pyrrolo[2,3-c]pyridin-I-yl}ethan-l-one (Compound 375)

[1518] Compound 375 was synthesized similar to Compound 44 by replacing tert-butylamine with 5-methoxy-2,3-dihydro-lH-pyrrolo[2,3-c]pyridine. LCMS (ES) [M+l] ⁺ m/z: 477. 'H NMR (300 MHz, DMSO-d6) δ 8.63 (s, IH), 8.43-8.41(m, 1H), 8.13 (s, 1HCOOH), 7.69 (s, IH), 7.02-6.95 (m, IH), 6.77 (m, IH), 4.89-4.87 (m, IH), 4.59 (s, 2H), 4.32-4.26 (m, 2H), 4.01-3.99 (m, 2H), 3.78 (s, 3H), 3.65-3.63 (m, 2H), 3.38 (s, 3H), 3.26-3.20 (m, 4H), 2.86-2.73(m, 2H), 2.07-L95(m, 2H).

Example 1.382

[1519] Synthesis of2-({2-[4-(2-hydroxyethoxy)pyridin-2-yI]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methyl)amino)-N-(l-methylcyclobutyl)acetamide (Compound 376)

[1520] Compound 376 was synthesized similar to Compound 44 by replacing tert-butylamine with 1-methylcyclobutan-1-amine. LCMS (ES) [M+l]⁺ m/z: 412. 'H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J= 5.6 Hz, IH), 8.15 (s, IH), 7.85 (d, 7= 2.6 Hz, 1 H), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 4.92 (t,7=5.4 Hz, lH),4.l9-4.l0(m,4H),3.76(q,7=5.1 Hz, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.2 Hz, 2H), 2.82 (t,7=7.8 Hz, 2H), 2.28-2.18 (m, 2H), 2.04-1.95 (m, 2H), 1.89-1.78 (m, 2H), 1.78-1.65 (m, 2H), 1.33 (s, 3H).

Example 1.383

[1521] Synthesis of 2-[(2-{4-[(2R)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pynmidin-4-yl)(methyl)amino]-N-(l-methylcyclobutyl)acetamide (Compound 377)

652

[1522] Compound 377 was synthesized similar to Compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with (2R)-2-(oxan-2-yloxy)propan-l-ol and by replacing tert-buty lamine with l-methylcyclobutan-l -amine. Analytical chiral HPLC conditions: Column, Lux- cellulose-2, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase B, CH₃CN; Flow rate: I mL/min; Gradient: !0%B in 8min; 254 nm. Rétention time: 2.712 min, LCMS (ES) [M+l]⁺ m/z: 426. Ή NMR (300 MHz, DMSO-d6) δ 8.46 (d, 7= 5.6 Hz, IH), 8,l4(s, l H), 7.84 (d, 7= 2.6 Hz, lH), 7.04 (dd, 7= 5.6, 2.6 Hz, lH), 4.93 (d, 7=4.1 Hz, IH), 4.13 (s, 2H), 4.03-3.92 (m, 3H), 3.27 (s, 3H), 3.15 (t, 7=7.3 Hz, 2H), 2.82 (t, 7= 7.9 Hz, 2H), 2.27-2.21 (m, 2H), 2.05-1.94 (m, 2H), 1.91-1.76 (m, 2H), 1.7610 1.65 (m,2H), 1.34 (s, 3 H), 1.18 (d, 7= 5.8 Hz, 3H).

Example 1.384

[1523] Synthesis of 2-[(2-{4-[(2S)-2-hydroxypropoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(I-methyIcyclobutyl)acetamide (Compound 378)

[1524] Compound 378 was synthesized similar to Compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with (2S)-2-(oxan-2-yloxy)propan-I-ol and by replacing tert-butylamine with 1-methylcyclobutan-l-amine. Analytical chiral HPLC conditions: Column, Luxcel!ulose-2, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase B, CH₃CN; Flow rate: 1 mL/min; Gradient: 10%B in 8min; 254 nm. Rétention time: 4.827 min. LCMS (ES) [M+l]⁺ m/z: 426.

'H NMR (300 MHz, DMSO-d6) δ 8.46 (d,7=5.6 Hz, IH), 8.14 (s, IH), 7.84 (d,7= 2.6 Hz, IH), 7.04 (dd,7= 5.6, 2.6 Hz, IH), 4.93 (d,7=4.1 Hz, lH),4.13(s, 2H), 4.03-3.92 (m,3H),3.27 (s, 3H), 3.15 (t,

653

J = 7.3 Hz, 2H), 2.82 (t, J= 7.9 Hz, 2H), 2.27-2.18 (m, 2H), 2.05-1.94 (m, 2H), 1.91-1.76 (m, 2H), 1.761.65 (m, 2H), 1.34 (s, 3H), 1.18 (d, 7= 5.8 Hz, 3H).

Example 1.385

[1525] Synthesis of N-[(4-benzyl-l,3-oxazol-2-yl)methyl]-2-(4-methoxypyridin-2-y 1)-N-methyl-

5H,6H,7H-cyclopenta[d]pyrimidin-4-aminemide (Compound 379)

Me!

Scheme 126

Step l

[1526] (l,3-Dioxo-l,3-dihydro-2H-isoindol-2-yl)acetic acid (2 g; 9.75 mmol; l eq.) was dissolved in

N.N-dimethylformamide (40 ml) and cooled in an ice bath. 2-Amino-3-phenyl·l-propanol (l .55 g; 10.24 mmol; 1.05 eq.), l'[bis(dimethylamino)methylene]-lH-l,2,3-triazolo[4,5-b]pyridinium 3-oxid

655 hexafluorophosphate (HATU) (5.56 g; 14.62 mmol; l .5 eq.) and Hunig's base (5.1 mL; 29.24 mmol; 3 eq.) were then added. The réaction was stirred to 25 °C over 3.5 h. Ethyl acetate (100 ml), water and sodium bicarbonate solution (50 ml) were added, the phases were separated and the aqueous phase was extracted once (50 ml). The combined organics phases were washed with water, saturated sodium chloride solution and dried over sodium sulfate. After évaporation the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 2-(l,3-dioxo-2,3-dihydro-lH-isoindol-2-yl)-N(l-hydroxy-3-phenylpropan-2-yl)acetamide (1.97 g, 60%) as a white solid. LCMS (ES+): [M+H]⁺ = 339.L

Step 2

[] 527] 2-(l,3-Dioxo-2,3-dihydro-lH-isoindol-2-yl)-N-(l-hydroxy-3-phenylpropan-2-yl)acetamide (1.97 g; 5.82 mmol; l eq.) was dissolved in dichloromethane (150 ml) and cooled in an ice bath. IJ Bis(acetyloxy)-3-oxo-3H-U5,2-benziodaoxol-I-yl acetate (Dess-Martin periodinane) (2.83 g; 6.46 mmol; L11 eq.) was added and the reaction was stirred to 25 °C over 2 h. Sodium bicarbonate solution and sodium thiosulfate solution were added and the mixture was stirred for 10 m. The phases were separated, the aqueous phase was extracted with dichloromethane (2 x 50 ml), the combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. Evaporation of solvent gave 2-(l,3-dioxo-2,3-dihydro-l H-isoindol-2-yl)-N-(l-oxo-3-phenylpropan-2-yl)acetamide as a solid which was used as is. LCMS (ES+): [M+H]* = 337.1.

Step 3

656

[1528] 1,1,1,2,2,2-Hexachloroethane (5.16 g; 21.8 mmol; 2.7 eq.) and triphenylphosphîne (5.76 g;

mmol; 2.7 eq.) were dissolved in tetrahydrofuran (30 ml) and stirred for 10 m. 2-(l,3-Dioxo-2,3dihydro-lH-isoindol-2-yl)-N-(l-oxo-3-phenylpropan-2-yl)acetamide (3.62 g; 8.07 mmol; 1 eq.) suspended in THF (8 ml) was added and the mixture was stirred for 10 m. Pyridine (4.18 mL; 51.7 mmol; 6.4 eq.) in THF ( 1 ml) was then added dropwise over 15 m. The reaction was stirred in heat block at 80 °C for 18 h. After évaporation, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give 2-[(4-benzyl-l,3-oxazol-2-yl)methyl]-2,3-dihydro-lH-isoindole-l,3dione (1.19 g, 46%) as yellow crystals. LCMS (ES+): [M+H]⁺ = 319.0.

Step 4

[1529] 2-[(4-Benzyl-l,3-oxazol-2-yl)methyl]-2,3-dihydro-lH-isoindole-l,3-dione (1.19 g; 3.74 mmol; 1 eq.)was suspended in éthanol (37 ml). Hydrazine (1.7 mL; 18.7 mmol; 5.00 eq.) was added and the reaction was heated in a sand bath at 90 °C for 2 h. The reaction was cooled, diluted with éthanol (20 ml), fïltered and rinsed with more éthanol (20 ml). After évaporation the residue was purified by reverse phase chromatography (acetonitrile/water gradient) to give (4-benzyl-l,3-oxazoI-2-yl)methanamine (0.31 g, 44%) as an oil. LCMS (ES+): [M+H]⁺ = 189. L

Step 5

657

[l 530] 2,4-Dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidine (140 mg; 0.74 mmol; l eq.) was added to an acetonitrile solution (5 ml) of (4-benzyl-l,3-oxazol-2-yl)methanamine (153 mg; 0.81 mmol; 1.1 eq.) Hunig's base (0.39 mL; 2.22 mmol; 3 eq.) was added and the reaction was stirred in 60 °C heat block for 66 h. The solvent was evaporated and the residue was purified by silica gel chromatography (ethyl acetate/dichloromethane gradient) to give N-[(4-benzyl-l,3-oxazol-2-yl)methyl]-2-chloro5H₅6H,7H-cyclopenta[d]pyrimidin4-amine (107 mg, 42%) as a solid. LCMS (ES+): [M+H]⁺ = 341.0. Step 6

[1531] N-[(4-Benzyl-l,3-oxazol-2-yl)methyl]-2-chloro-5H,6H,7H-cyclopenta[d]pyrimidm-4-amine (107 mg; 0.31 mmol; 1 eq.) was dissolved in N,N-dimethylformamide (3 ml) and cooled in an ice bath. lodoinethane (195 pL; 3.14 mmol; 10 eq.) was added followed by sodium hydride (38 mg; 0.94 mmol; 3 eq.) and stirred to 25 °C over 2.5 h. Water (1 ml), ethyl acetate (50 ml) and sodium bicarbonate solution 15 (10 ml) were added, the phases were separated and the aqueous phase was extracted with ethyl acetate (1 x 10 ml). The combined organic phases were washed with water, saturated sodium chloride solution and dried over sodium sulfate. After évaporation of solvent, the residue was purified by silica gel chromatography (ethyl acetate/hexanes gradient) to give N-[(4-benzyl-l,3-oxazol-2-yl)methyl]-2-chloro21052

658

N-methyl-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (92 mg, 83%) as a fdm. LCMS (ES+): [M+H]⁴ = 355.0.

Step 7

[ 1532] N-[(4-Benzyl-l,3-oxazol-2-yl)methyl]-2-chloro-N-methyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine (63 mg; O.l7 mmol; l eq.) was dissolved in toluene (2 ml). 4-Methoxy· 2-(tributylstannyl)pyridine (156 mg; 0.35 mmol; 2 eq.) in l ml toluene was added and the solution was purged with Ar gas. [l,T-Bis(diphenylphosphino)ferrocene]dichloropalladium(n), complex with dichloromethane (I4 mg; 17.5 umol; O.l eq) was added and the reaction vessel was sealed and stirred in 10 a heat block at 110 °C for 17 h. The solvent was evaporated and the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl 8 column, 0-90% acetonitrile/0.1 % aqueous formic acid gradient) to give N-[(4-benzyi-l,3-oxazol-2-yl)methyl]-2-(4-methoxypyridm-2-yl)-N-methyl5H,6H,7H-cyclopenta[d]pyrimidin-4-amme (22 mg, 40%) as a pink solid). LCMS (ES+): [M+H]⁴ = 428.2. ‘H NMR (400 MHz, dmso) δ 8.45 (d,7=5.5 Hz, IH), 7.78 (s, 2H), 7.73 (s, IH), 7.32-7.12 (m, 15 5H), 7.01 (d,7=5.5 Hz, IH), 4.94 (s, 2H), 3.86 (s, 3H), 3.77 (s, 2H), 3.20 - 3.15 (m, 2H), 2.86 - 2.75 (m, 2H), 2.04 - 1.89 (m, 2H).

Example 1.386

[ 1533] Synthesis of 2-(4-methoxypyridin-2-yl)-N-methyl-N-[(4-phenyl-l,3-oxazol-2-yl)methyl]5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (Compound 380)

659

[1534] Compound 380 was synthesized similar to Compound 379 by replacing 2-amino-3-phenyl-lpropanol with 2-amino-2-phenylethanol gave 2-(4-methoxypyridin-2-yl)-N~methyl-N-[(4-pheny 1-1,3oxazol-2-yl)methyl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine as a tan solid. LCMS (ES+): [M+H]^T = 5 414.2. Ή NMR (400 MHz, dmso) δ 8.53 (s, IH), 8.45 (d, 7= 5.6 Hz, 1 H), 7.82 (d, 7= 2.6 Hz, IH), 7.77

-7.71 (m, 214), 7.44 - 7.37 (m, 2H), 7.33 - 7.27 (m, IH), 7.00 (dd, J= 5.6, 2.6 Hz, IH), 5.04 (s, 2H),

3.84 (s, 3H), 3.42 (s, 3H), 3.26-3.22 (m, 2H), 2.87-2.80 (m, 214),2.06- 1.96 (m, 2H).

Example 1.387

[1535] Synthesis ofN-tert-butyl-2-[(2-{4-[(l-hydroxycyclopentyl)methoxy]pyridin-2-y!}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 381)

[1536] Compound 381 was synthesized similar to 174 by replacing 2-methy 1-2-((tetrahydro-2IIpyran-2-yl)oxy)propan-l-ol with [l-(oxan-2-yloxy)cyclopentyl]methanol. LCMS (ES) [M+l]⁺ m/z:

454. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.6 Hz, IH), 7.83 (d, 7= 2.5 Hz, l H), 7.67 (s, IH),

7.05 (dd, 7= 5.7, 2.6 Hz, 1 H), 4.61 (s, 1 H), 4.14 (s, 2H), 4.01 (s, 2H), 3.26 (s, 3H), 3.14 (t, 7= 7.3 Hz,

214), 2.82 (t, 7= 7.8 Hz, 2H), 2.04-1.96 (m, 2H), 1.86-1.51 (m, 8H), 1.25 (s, 9H).

Example 1.388

[1537] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)-l-(piperidin-l-yl)ethan-l-oneide (Compound 382)

660

[1538] Compound 382 was synthesized similar to 174 by replacing tert-butylamine with piperidine.

LCMS (ES) [M+l]⁺ m/z: 440. Ή NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 5.6 Hz, IH), 7.73 (d, J = 2.5 Hz, 1 H), 7.03 (dd, J = 5.7, 2.6 Hz, lH),4.72(s, 1H),4.51 (s, 2H), 3.85 (s, 2H), 3.45 (dt, J = 11.2, 5.1

Hz, 4H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.06-1.92 (m, 2H), 1.61 (s, 4H), 1.47-L39 (m, 2H), 1.23 (s, 6H).

Example 1.389

[1539] Synthesis of N-{bicyclo[l.l ,l]pentan-l-yl}-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 383)

H

[1540] Compound 383 was synthesized similar to 174 by replacing tert-butylamine with bicyclo[l. 1.1 ]pentan-l-amine. LCMS (ES) [M+l]⁺ m/z: 438. 'HNMR (300 MHz, DMSO-d6) δ 8.74 (s, IH), 8.47 (d, J = 5.6 Hz, 11-1),7.79 (d, J = 2.6 Hz, IH), 7.05 (dd, J = 5.7, 2.6 Hz, lH),4.70(s, IH), 4.12 (s, 2H), 3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.7 Hz, 2H), 2.37 (s, IH), 2.03-

1.91 (m, 7H), 1.24 (s, 6H).

Example 1.390

[1541] Synthesis of N-tert-buty 1-2-{[2-(4-{[(2R)-1 -hydroxypropan-2-yl]oxy}pyridin-2-yl)-

5H,6H,7H-cyclopenta[d]pyriniidin-4-yl](methyl)amino}acetamide (Compound 384)

661

[1542] Compound 384 was synthesized similar to 174 by replacing 2-methyl-2-((tetrahydro-2Hpyran-2-yl)oxy)propan-l-ol with (2R)-l-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol. Analytical chiral HPLC conditions: Column, CHIRALCEL OX-3, 50*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, Ethanol; Flow rate: 1 mL/min; Gradient: 50%B in 10 min; 270 nm. Rétention time: 4.949 min. LCMS (ES) [M+l]⁺ m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 8.45 (d,7=5.4 Hz, 1H), 7.83 (d,7= 2.4 Hz, 1H), 7.68 (s, IH), 7.05 (dd, 7= 5.7, 2.4 Hz, IH), 4.93 (t,7= 5.6 Hz, IH), 4.70-4.60 (m, IH), 4.18-4.06 (m, 2H), 3.63-3.48 (m, 2H), 3.26 (s, 3H), 3.14 (t, 7= 7.2 Hz, 2H), 2.81 (t, J= 7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.27 (s, 3H), 1.25 (s, 9H).

Example L391

[1543] Synthesis ofN-tert-butyl-2-{[2-(4-{[(2S)-l-hydroxypropan-2-yl]oxy]pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 385)

H

[1544] Compound 385 was synthesized similar to 174 by replacing 2-methyl-2-((tetrahydro-2Hpyran-2-yl)oxy)propan-l-ol with (2S)-l-((tetrahydro-2H-pyran-2-yl)oxy)propan-2-ol. LCMS (ES) [M+l]⁺m/z: 414. Ή NMR (300 MHz, DMSO-d6) δ 8.45 (d, 7= 5.7 Hz, 1 H), 7.83 (d,7 = 2.6 Hz, IH), 7.69 (s, IH), 7.06 (dd, 7= 5.7, 2.6 Hz, IH), 4.93 (t,7= 5.6 Hz, IH), 4.69-4.60 (m, IH), 4.22-4.02 (m, 2H), 3.56 (tq, 7= 11.5, 6.2, 5.8 Hz, 2H), 3.26 (s, 3H), 3.14 (t, 7 = 7.3 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.04-1.96 (m, 2H), 1.24 (d, J = 6.1 Hz, 3H), 1.21 (s, 9H).

662

Example 1.392

[1545] Synthesis of N-tert-butyI-2-[(2- {4-[(2 S)-2-hydroxy-3-methylbutoxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 386)

[ 1546] Compound 386 was synthesized similar to 174 by replacing 2-methyl-2-((tetrahydro-2Hpyran-2-yl)oxy)propan-l-ol with (2S)-3-methyl-2-(oxan-2-yloxy)butan-l-ol. Analytical chiral HPLC conditions: Column, Lux-ceilulose-2, 100*4.6 mm, 3um; mobile phase A, AcCN; mobile phase B, Methanol; Flow rate: 1 mL/mtn; Gradient: 50%B in 15min; 254 nm. Rétention time: 9.997 min. LCMS (ES) [M+l] ⁺ m/z; 442. Ή NMR (300 MHz, DMSO-d6) S 8.47 (d, 7= 5.6 Hz, IH), 7.83 (d,7=2.5 Hz, 1 H), 7.66 (s, 1 H), 7.06 (dd, 7= 5.7, 2.6 Hz, IH), 4.86 (d, 7= 5.3 Hz, IH), 4.13 (s, 2H), 4.09 (dd, 7 = 10.1,4.5 Hz, IH), 4.00 (dd, 7= 10.1, 6.2 Hz, IH), 3.60 (q, 7= 5.1 Hz, IH), 3.26 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.04-1.96 (p, J= 7.7 Hz, 2H), 1.92-1.76 (m, IH), 1.24 (s, 9H), 0.93 (dd, 7= 6.8, 5.3 Hz, 6H).

Example 1.393

[1547] Synthesis of N-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-3-methyibutoxy]pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 387)

[1548] Compound 387 was synthesized similar to 174 by replacing 2-methyl-2-((tetrahydro-2Hpyran-2-yl)oxy)propan-l-ol with (2R)-3-methyl-2-(oxan-2-yloxy)butan-l-ol. Analytical chiral HPLC conditions: Column, Lux-celluIose-2, 100*4.6 mm, 3um; mobile phase A, AcCN; mobile phase B, Methanol; Flow rate: 1 mL/min; Gradient: 50%B in 15min; 254 nm. Rétention time: 2.582 min. LCMS

(ES) [M+l] ⁺ m/z: 442. Ή NMR (300 MHz, DMSO-d6) δ 8.48 (d, J= 5.6 Hz, IH), 7.84 (d, J= 2.5 Hz, IH), 7.67 (s, IH), 7.08 (dd, J= 5.7, 2.6 Hz, IH), 4.87 (d, J= 5.3 Hz, IH), 4.l4(s, 2H), 4.09 ( J = 10.1, 4.5 Hz, IH), 4.01 (dd, J= 10.1,6.2 Hz, IH), 3.60 (t,J=5.3 Hz, 1 H), 3.27 (s, 3H), 3.14 (t, J= 7.3 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.02-1.97 (m, 2H), 1.83 (dt, J= 13.4, 6.7 Hz, IH), 1.24 (s, 9H), 0.93 (dd, J = 6.8, 5.2 Hz, 6H).

Example 1.394

[1549] Synthesis of N-tert-buty 1-2-[(2-{4-[(l-hydroxycyciobutyl)methoxy]pyridin-2-y 1}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 388)

H

[1550] Compound 388 was synthesized similar to 174 by replacing 2-methyl-2-((tetrahydro-2Hpyran-2-yl)oxy)propan-l-ol with [l-(oxan-2-yloxy)cyclobutyl]methanol. LCMS (ES) [M+1]⁺ m/z: 440. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 7.85 (d, J = 2.5 Hz, IH), 7.67 (s, IH), 7.07 (dd, J = 5.7, 2.6 Hz, IH), 5.29 (s, IH), 4.13 (s, 2H), 4.06 (s, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8 Hz, 2H), 2.17 (d, J = 10.2 Hz, 2H), 2.00 (h, J = 8.7, 7.8 Hz, 4H), 1.62 (dq, J = 19.4, 9.7

Hz, 2H), L24 (s, 9H).

Example 1.395

[1551] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl) (methy l)amino)-N-(propan-2-yl)acetamide (Compound 389)

664

NaOMe/MeOH °C, 40 h

COgMe

Scheme 127

Step 1

[1552] Into a 1 L round-bottom flask were added 4-chloropicolinimidamide hydrochloride (60.0 g,

312 mmol, 1.00 equiv) in MeOH (600 mL), methyl 2-oxocyclopentane-1-carboxy late (66.6 g, 468 mmol, 1.5 equiv), and NaOMe (42.18 g, 781 mmol, 2.5 equiv) in MeOH at room température. The mixture was stirred for 40 hours at 70°C under a nitrogen atmosphère. The precipitated solids were collected by filtration and washed with MeOH (1x1 500 mL). This resulted in 2-(4-chloropyridin-2-yl)10 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (62 g, 80.12%) as a brown solid. LCMS (ES) [M+l]⁺ m/z 248.

Step 2

[1553] into a IL 3-necked round-bottom flask were added 2-(4-chtoropyridin-2-yl)-6,7-dihydro-5H cyclopenta[d]pyrimidin-4-ol (60 g, 242 mmol, 1.00 equiv) in DCM and TEA (123 g, 1211 mmol, 5.0

665 equiv). A stirred mixture of Tf₂O (137 g, 484 mmol, 2.0 equiv) in DCM was added dropwise at 0°C. The resulting mixture was stirred for an additional 2 hours at 0 °C. The reaction was quenched by the addition of NH4CI (aq. 500 mL) at room température. The resulting mixture was extracted with DCM (3 x 600 mL), and the organic layer was separated and dried over anhydrous Na₂SO4. The resulting mixture 5 was filtered and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2-(4-chloropyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimÎdin-4-yl trifiuoromethanesulfonate (63 g, 68.48%) as an off-white solid. LCMS (ES) [M+l]⁴ m/z 380.

Step 3

[1554] Into a 500 mL three-necked round bottom flask were added 2-(4-chloropyrtdin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl trifiuoromethanesulfonate (15.0 g, 39.6 mmol, 1.00 equiv), TEA (16.0 g, 158.4 mmol, 4.00 equiv), and dichloromethane (300 mL). This was followed by the addition ofN-isopropyl-2-(methylamino)acetamide hydrochloride (8.5 g, 51.5 mmol, 1.30 equiv) at room température. The mixture was stirred for 12 h. The reaction was quenched with H₂O (200 mL), and extracted with dichloromethane (2x100 mL). The organic layers were combined, and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was triturated în ethyl acetate/ hexane (1:3). The solid was collected by filtration and dried under an infrared lamp for 3 h. This resulted in 13.0 g (91%) 2-((2-(4-chloropyridin-2-yl)-6,7-dihydro-5H20 cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamide as an off-white solid. LCMS (ES, m/z): [M+H]⁴: 360.

Step 4

666

[1555] Into a 50Û mL three-necked round bottom flask were placed 2-methyl-2-((tetrahydro-2Hpyran-2-yt)oxy)propan-]-ol (12.6 g, 72.4 mmol, 2.00 equiv) and DMSO (150 mL). NaH (60% in minerai oil) (2.9 g, 72.4 mmol, 2.00 equiv) was added at °C and stirred for 1 h. After that, 2-((2-(4chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamide (13.0 g, 36.2 mmol, 1.00 equiv) was added in three portions and the mixture was stirred for an additional 3 h at 40 °C. The reaction mixture was cooled to room température, quenched with HzO (200 mL), and extracted with ethyl acetate (3 xlOO mL). The organic layers were combined, washed with brine (2 xlOO mL), and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: C18-500 g, CH3CN/H2O (NH4HCO3 0. ! %), from 15% to 70% in 30 min, Flow rate, 150 mL/min, Detector, UV 254 nm. This resulted in 15.0 g (83%) N-isopropyl-2-(methyl(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide as a brown solid. LCMS (ES, m/z): [M+H]⁺: 498.

Step 5

[ 1556] Into a 250 mL three-necked round bottom flask were added N-isopropyl-2-(methyl(2-(4-(2methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H- cyclopenta[d]pyrimidin-4-yl)amino)acetamide (15.0 g, 30.2 mmol, L00 equiv), methanol (100 mL), and HCl (c) (5 mL). The mixture was stirred for 0.5 h and diluted with H2O (200 mL). Its pH was adjusted to 9 with K2CO3 solid, and then extracted with dichloromethane (2x 300 mL). The combined organic

667 phases were dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, the residue was triturated in CH3CN (120 mL), and the solid was collected by filtration to give 738 g 2-((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-isopropylacetamide as a white solid. LCMS (ES, m/z): [M+H]⁺: 414. ’H-NMR (300 MHz, DMSO-rfô,ppm): δ 8.48 (d, J= 5.7 Hz, IH), 8.04 (d, J= 7.8 Hz, IH), 7.82 (d, J= 2.4 Hz, IH), 7.05 (dd, 5.7, 2.7 Hz, l H), 4.70 (s, IH), 4.15 (s, 2H), 3.93-3.82 (m, 3H), 3.27 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 2.04-1.94 (m, 21-1), 1.24 (s, 6H), 1.05 (d, 7=6.6 Hz, 6H).

Example 1.396

[1557] Synthesis ofN-ethyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Compound 390)

[1558] Compound 390 was synthesîzed similar to 389 by replacing propane-2-amine with ethylamine. LCMS (ES) [M+l]⁺ m/z: 400. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 8.18 (t, J = 5.1 Hz, IH), 7.81 (d, J = 2.5 Hz, IH), 7.04 (dd, J= 5.7, 2.5 Hz, JH), 4.70 (s, IH), 4.15 (s, 2H), 3.86(s, 2H), 3.27 (s, 3H), 3.18-3.07 (m, 4H), 2.82 (t, J = 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.23 (s,

6H), 1.04 (t, J = 6.6 Hz, 3H).

Example 1.397

[1559] Synthesis of l-(4,4-difluoropiperidin-l-yl)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)ethan-l-one (Compound 391)

668

[l 560] Compound 391 was synthesized similar to 389 by replacing propane-2-amine with ethylamine. LCMS (ES) [M+l]⁺m/z: 476. Ή NMR (300 MHz, DMSO-d6) δ 8.42 (d, 7= 5.6 Hz, IH), 8.I5 (s, ÆCOOH), 7.76 (d,7=2.5 Hz, IH), 7.03 (dd, 7= 5.6, 2.5 Hz, lH),4.7l (s, l H), 4.58 (s, 2H), 3.85 (s, 2H), 3.61-3.54 (m,4H), 3.29 (s, 3H), 3.17 (t, 7= 7.2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.3!-2.09 (m, 2H), 1.99-1.79 (m, 4H), L22 (s, 6H).

Example 1.398

[1561] Synthesis of 2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4y 1} (methy l)am ino)-N-(3 -methy 1 pentan-3 -y l)acetam i de(Compound392)

H

[1562] Compound 392 was synthesized similar to Compound 44 by replacing Intermediate II with 2({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(3-methyipentan-3-yl)acetamide. LCMS (ES) [M+l]⁺ m/z: 428. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, 7= 5.6 Hz, IH), 8.16 (s, HCOOH), 7.83 (d, 7= 2.5 Hz, IH), 7.33 (s, IH), 7.03 (dd, 7= 5.6, 2.6 Hz, IH), 4.20 (s, 2H), 4.14 (t, 7 = 4.9 Hz, 2H), 3.76 (t, 7= 4.9 Hz, 2H), 3.25 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.03-1.96 (m, 2H), 1.71 (dq,7= 14.7, 7.4 Hz, 2H), 1.56-1.38 (m, 2H), 1.09 (s, 3H), 0.70 (t,7=7.4 Hz, 6H).

Example 1.399 and Example 1.400

[ 1563] Synthesis of N-tert-butyl-2-[(2-{4-[(2R)-2-hydroxybutoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 393) and N-tert-butyl-2-[(2-{4[(2R)-2-hydroxybutoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 394)

669

Compound 393

Compound 394

NaH, DMSO. rt, 1 h

TsOH. MeOH rt, 1 ti

[1564] Into a 20-mL vail were placed 2-((tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol (390 mg, 2.24 mmol, 2.00 equiv) and DMSO (4.00 mL). NaH (60% in minerai oil) (90 mg, 2.24 mmol, 2.00 equiv)

670 was added and the mixture was stirred at room température for 0.5 h, and added N-(tert-butyl)-2-((2-(4fluoropyridin-2-yl)-6,7-dihydro-5H-cyciopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (400 mg, l. ] 2 mmol, l .00 equiv). The resulting solution was stirred for l h at room température, and then quenched with cooled water, extracted with 3*30 mL of ethyl acetate. The combined organic phases were washed with brine (20 mL*2), dried over anhydrous sodium sulfate, filtered and the filtrate was concentrated under reduced pressure. This resulted in 841 mg crude of N-(tert-butyl)-2-(methyl(2-(4-(2((tetrahyd ro-2 H-py ran-2-y l)oxy)butoxy )pyrid in-2-y i)-6,7-d i hy dro-5 H-cyc lopenta [d] py rim id in-4yl)amino)acetamide as yellow oil and used to the next step without further purification. LCMS (ES)[M+l]⁺ m/z: 512.

Step 2

[1565] Into a 50-mL round-bottom flask, was placed N-(tert-butyl)-2-(methyl(2-(4-(2-((tetrahydro2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cycIopenta[d]pyrimidin-4-yl)amino)acetainide (841 mg, 1.65 mmol, 1.00 equiv), MeOH (5.0 mL), TsOH (284 mg, 1.65 mmol, 1.00 equiv). The mixture was stirred for 1 h at room température. The reaction mixture was purified by Prep-HPLC with the following conditions: Welch Xtimate Cl 8, 21.2*250 mm, 5 um, Mobile phase, Water (10 mmol/L NH₄HCO₃) and CHaCN (25% Phase B up to 65% in 15 min), Detector, UV 254 nm. 520 mg of N-(tertbutyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide was obtained as white solid. LCMS(ES)[M+1]⁺ m/z: 428.

Step 3

[1566]

Chiral HPLC séparation: 300 mg of N-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)21052

671

6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide was separated by Prep-chiral HPLC with the following conditions: Column, Lux 5um Cellulose-4, 2.12*25 cm, 5 pm, Mobile Phase, MeOH and EtOH (50% Phase B in 23 min), Detector, UV 254 nm. The fraction at 7 min was freezing dried, this resulted in 110 mg of (R)-N-(tert-butyl)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-ylXmethyl)amino)acetamÎde (Compound 393) and The fraction at 16 min, 120 mg (S)-N-(tert-buty 1)-2-((2-(4-(2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (Compound 394) as a white solid.

[1567] Compound 393: Analytical chiral HPLC conditions: Column, Lux-cellulose-4, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase B, Methanol; Flow rate: 1 mL/min; Gradient: 50%B in 6 min; 254 nm. Rétention time: 2.239 min. LCMS (ES)[M+1]^T m/z: 428. 'H NMR (300 MHz, DMSO7_b) S 8.48(0,7=5.7 Hz, IH), 7.84 (d, 7=2.4 Hz, IH), 7.67 (s, IH), 7.07 (dd, 7= 5.7, 2.4 Hz, 1H),4.9O (d,7=5.1 Hz, IH), 4.13 (s, 2H), 4.00 (d, 7= 5.4 Hz, 2H), 3.77-3.71 (m, IH), 3.26 (s, 3H), 3.14 (t, 7 = 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.25 (s, 9H), 0.96 (t, 7= 7.5 Hz, 3H).

[1568] Compound 394: Analytical chiral HPLC conditions: Column, Lux-cellulose-4, 100*4.6 mm, 3um; mobile phase A, Ethanol; mobile phase B, Methanol; Flow rate: 1 mL/min; Gradient: 50%B in 6 min; 254 nm. Rétention time: 4.139 mtn. LCMS (ES)[M+1]⁺ m/z: 428. 'H NMR (300 MHz, DMSOd₆) δ 8.48 (d, 7= 5.7 Hz, 1 H), 7.84 (d, 7= 2.4 Hz, IH), 7.67 (s, IH), 7.07 (dd, 7= 5.7, 2.4 Hz, IH), 4.90 (d, 7= 5.1 Hz, IH), 4.13 (s,2H),4.00 (d,7=5.4 Hz, 2H), 3.77-3.71 (m, 1 H), 3.26 (s, 3H), 3.14 (t, 7 = 7.2 Hz, 2H), 2.84 (t, 7= 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.66-1.40 (m, 2H), 1.25 (s, 9H), 0.96 (t, 7= 7.5 Hz, 3H).

Example 1.401

[1569] Synthesis ofN-tert-butyl-2-({2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl} (methy l)amino)acetamide (Compound 395)

672

[1570] Compound 395 was synthesized similar to Compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with 2-ethyl-2-(oxan-2-yloxy)butan-l-ol. LCMS (ES) [M+l]⁺m/z: 456. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, 7= 5.6 Hz, IH), 7.81 (d,7 = 2.5 Hz, IH), 7.67 (s, IH), 7.06 (dd, 7= 5.7, 2.6 Hz, IH), 4.41 (s, IH), 4.13 (s, 2H), 3.87 (s, 2H), 3.26 (s, 3H), 3.14 (t, 7=7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.07-1.88 (m, 2H), 1.61-1.50 (m, 4H), 1.25 (s, 9H), 0.85 (t,7= 7.4 Hz, 6H).

Example 1.402

[1571] Synthesis of N-tert-buty l-2-[(2-{4-[(l-hydroxycyclohexy l)methoxy]pyridin-2-y l)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 396)

[1572] Compound 396 was synthesized similar to Compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with l-(hydroxymethyl)cyclohexan-l-ol. LCMS (ES) [M+l ] ⁺m/z: 468. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d,7=5.6 Hz, 1H), 7.82 (d,7=2.5 Hz, IH), 7.68 (s, IH), 7.06 (dd, 7= 5.8, 2.5 Hz, IH), 4.43 (s, IH), 4.14 (s, 2H), 3.87 (s, 2H), 3.27 (s, 3H),3.15 (t, 7= 7,2 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.05-1.97 (m, 2H), 1.86-1.33 (m, 9H), 1.25 (s, 9H), 1.25L15(m, IH).

Example 1.403

[1573] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amîno)-N-[(l R,2S)-2-hydroxycyclopentyl]acetamide (Compound 397)

673

[1574] Compound 397 was synthesized similar to 210 by replacing 5-amino-2-methoxypyridîne with (l S,2R)-2-aminocyclopentan-l-ol. Analytical chiral HPLC conditions: Column, (S,S)-WHELKOl, 100*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, éthanol; Flow rate: 1 mL/min; Gradient: 50%B in 10 min; 254 nm. Rétention time: 3.293 min. LCMS (ES) [M+l]⁺m/z: 456.'H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, IH), 7.79 (d, J = 2.5 Hz, IH), 7.69 (d, J = 7.8 Hz, IH), 7.04 (dd, J = 5.6, 2.6 Hz, IH), 4.72 (s, 2H), 4.31 (d, J = 16.6 Hz, IH), 4.20 (d, J = 16.7 Hz, IH), 3.94-3.87 (m, 4H), 3.26 (s, 3H), 3.14 (t, J = 7.6 Hz, 2H), 2.82 (t, J = 7.9 Hz, 2H), 2.01-1.96 (m, 2H), 1.81-1.63 (m, 3H), 1.58-1.39 (m, 3H), 1.23 (s, 6H).

Example 1.404

[1575] Synthesis of N-cyclopropyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl) (methyl)amino)acetamide (Compound 398)

[ 1576] Compound 398 was synthesized similar to 389 by replacing propane-2-amine with cyclopropylamine. LCMS (ES) [M+i]⁺ m/z: 412. Ή NMR (300 MHz, DMSO-d6) Ô 8.47 (d, J = 5.6 Hz, IH), 8.25 (d, J = 4.1 Hz, IH), 7.79 (d, J = 2.5 Hz, IH), 7.04 (dd, J = 5.7, 2.5 Hz, 1H),4.7O (s, IH), 4.14 (s, 2H), 3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.63 (dq, J = 7.4, 3.8 Hz, IH), 2.04-1.95 (m, 2H), 1.24 (s, 6H), 0.69-0.46 (m, 2H), 0.45-0.39 (m, 2H).

Example 1.405

[1577] Synthesis of2-({2-[4-(2-hydroxy-2-methyIpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)-I-(morpholin-4-yl)ethan-l-oneide (Compound 399)

[1578j Compound 399 was synthesized similar to 389 by replacing propane-2-amine with morpholine. LCMS (ES) [M+l] ⁺ m/z: 442. Ή NMR (300 MHz, DMSO-d6) δ 8.46 (d, J= 5.6 Hz, l H), 7.75 (d,7= 2.5 Hz, IH), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 4.70 (s, IH), 4.52 (s, 2H), 3.86 (d, 7= 4.8 Hz, 5 2H), 3.72-3.41 (m, 8H), 3.28 (s, 3H), 3.16 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.1 l-l.9l (m,

2H), L24 (s,6H).

Example 1.406

[1579] Synthesis of N-tert-butyl-2-[(2-{4-[2-(diethylamino)ethoxy]pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 400)

[1580] Compound 400 was synthesized similar to Compound 348 by replacing Dimethylaminoethanol with Diethylaminoethanol. LCMS (ES) [M+l]* m/z: 455. Ή NMR (300 MHz, DMSO-dô) δ 8.47 (d,7=5.6 Hz, 1H),7.83 (d, 7= 2.5 Hz, IH), 7.67 (s, IH), 7.05 (dd, 7= 5.6, 2.6 Hz, IH), 4.16 (t, J = 6.1 Hz, 2H), 4.13 (s, 2H), 3.26 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.87-2.76 (m, 4H),

2.63-2.52 (m, 4H), 2.02-1.99 (m, 2H), 1.25 (s, 9H), 0.98 (t, 7= 7.1 Hz, 6H).

Example 1.407

[1581 ] Synthesis of N-tert-buty l-2-[methyl(2-{4-[2-(pyrrolidin-l-y l)ethoxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 401)

675

H

[l 582] Compound 401 was synthesized similar to Compound 348 by replacing

Dimethylaminoethanol with hydroxyethylpyrrolidine. LCMS (ES) [M+l]⁺ m/z: 454. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 7.84 (d, J= 2.5 Hz, IH), 7.69 (s, IH), 7.05 (dd, J= 5.6, 2.6

Hz, IH), 4.21 (t, J= 5.8 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J= 7.3 Hz, 2H), 2.85-2.78 (m, 4H),

2.62- 2.43 (m, 4H), 2.04-1.94 (m, 2H), 1.77-1.61 (m, 4H), 1.25 (s, 9H).

Example 1.408

[1583] Synthesis of N-tert-buty 1-2-{[2-(4-{[(2S)-1 -(dimethy lamino)propan-2-yl]oxy}pyrid in-2-yl)-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 402)

H

[1584] Compound 402 was synthesized similar to Compound 348 by replacing Dimethylaminoethanol with (S)-l-(dimethylamino)propan-2-ol. LCMS (ES) [M+l]⁺ m/z: 441. *H NMR (300 MHz, DMSO-d6) δ 8.45 (d, J = 5.6 Hz, IH), 7.82 (d, J = 2.5 Hz, IH), 7.68 (s, IH), 7.07 (dd, J = 5.7, 2.6 Hz, IH), 4.83-4.77 (m, IH), 4.11 (s, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.8

Hz, 2H), 2.59-2.52 (m, IH), 2.39 (dd, J = 12.8, 5.5 Hz, 1 H), 2.21 (s, 6H), 2.04-1.97 (m, 2H), L28 (d, J = 6.1 Hz, 3H), 1.25 (s, 9H).

Example 1.409

[1585] Synthesis of 2-{[2-( 4-{[(tert-buty lcarbamoyl)methy]](methyl)amino}-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}-N,N-dimethylacetamide (Compound 403)

676

[l 586] Compound 403 was synthesized similar to Compound 348 by replacing Dimethylaminoethanol with 2-hydroxy-N,N-dimethylacetarnide. LCMS (ES) [M+l] m/z: 441. ’H NMR (300 MHz, DMSO-d6) δ 8.45 (d, 7=5.6 Hz, lH), 7.83 (d,7=2.6 Hz, IH), 7.66 (s, IH), 6.98 (dd, 5 7=5.7, 2.6 Hz, l H), 5.00 (s, 2H), 4.13 (s, 2H), 3.25 (s, 3H), 3.12 (t, 7= 7.3 Hz, 2H),3.0l (s, 3H), 2.85 (s, 3H), 2.81 (t, 7=7.8 Hz, 2H), 2.0I-L96 (m, 2H), 1.24 (s, 9H).

Example L410

[l 587] Synthesis of N-tert-butyl-2-[(2-[4-[2-(dimethylamino)-2-methylpropoxy]pyridin-2-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 404)

[l 588] Compound 404 was synthesized similar to Compound 348 by replacing Dimethylaminoethanol with 2-(dimethylamino)-2-methylpropan-l-ol. LCMS (ES) [M+l] ⁺ m/z: 455. ’H NMR (300 MHz, DMSO-d6) δ 8.49 (d, J = 5.6 Hz, IH), 8.20 (s, 2H), 7.83 (d, J = 2.5 Hz, lH), 7.67 (s, IH), 7.09 (dd, J = 5.6, 2.5 Hz, IH), 4.14 (s, 2H), 4.05 (s, 2H), 3.26 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2,81 (t, J = 7.8 Hz, 2H), 2.36 (s, 6H), 2.04-1.97 (m, 2H), 1.25 (s, 9H), 1.19 (s, 6H).

Example 1.4] 1

[1589] Synthesis of N-tert-butyl-2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 405)

677

[ 1590] Compound 405 was synthesized similar to Compound 174 by replacing 2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol with 4-(hydroxymethyl)tetrahydro-2H-pyran-4-ol. LCMS (ES) [M+l] ⁺ m/z: 470. Ή NMR (300 MHz, DMSO-d6) δ 8.48 (d, J = 5.6 Hz, 1 H), 7.84 (d, J = 2.6 Hz, IH), 7.67 (s, IH), 7.06 (dd, J = 5.6, 2.6 Hz, IH), 4.77 (s, IH), 4.14 (s, 2H), 3.92 (s, 2H), 3.76-3.63 (m, 4H), 3.26 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.02-1.93 (m, 2H), 1.86-1.70 (m, 2H), 1.57-1.43 (m,2H), 1.25 (s, 9H).

Example 1.412

[1591] Synthesis of N-tert-butyl-2-{[2-(4-{[(2R)-l-(dimethylamino)propan-2-yl]oxy}pyridin-2-yl)-

5H,6H,7H-cyclopenta[d]pyrimidin-4-y]](methyl)amino}acetanride (Compound 406)

H

[ 1592] Compound 406 was synthesized similar to Compound 348 by replacing Dimethylaminoethanol with (R)-l-(dimethylamino)propan-2-ol. LCMS (ES) [M+1]⁺ m/z: 441. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J= 5.7 Hz, IH), 7.82 (d, J = 2.4 Hz, IH), 7.67 (s, IH), 7.09 (dd, J= 5.7, 2.7 Hz, IH), 4.84-4.78 (m, 1 H), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, J= 7.2 Hz, 2H), 2.84 (t, J= 7.8 Hz, 2H), 2.61-2.55 (m, IH), 2.46-2.40 (m, IH), 2.23 (s, 6H), 2.04-1.94 (m, 2H), 1.30 (d, J= 6.0 Hz, 3H), 1.26 (s, 9H).

Example 1.413

[1593] Synthesis of N-tert-butyl-2-{[2-(4-{[l-(dimethylamino)-2-methylpropan-2-yl]oxy}pyridin-2yl)-5l·L6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 407)

678

[ 1594] Compound 407 was synthesized similar to Compound 348 by replacing Dimethylaininoethanol with l-(dimethylamino)-2-methylpropan-2-ol. LCMS (ES) [M+l]⁺ m/z: 455. 'H NMR (300 MHz, DMSO-d6) δ 8.44 (d, 7= 5.5 Hz, IH), 7.82 (d, 7= 2.6 Hz, IH), 7.63 (s, IH), 7.09 (dt,

7=5.0,27 Hz, IH), 4.15 (s, 2H), 3.24 (s, 3H), 3.13 (t, 7= 7.4 Hz, 2H), 2.81 (t,7=7.8 Hz, 2H), 2.58 (s,

2H), 2.28 (s, 6H), 2.02-1.96 (m, 2H), l .44 (s, 6H), l .26 (d, 7= l .6 Hz, 9H).

Example 1.414

[ 1595] Synthesis of (2R)-N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H10 cyclopenta[d]pyrimidin-4-yl)(methyl)amino]propanamide (Compound 408)

Scheme 129

Step 1

679

Pd(RPh₃)₄. toluene 120°C,12 h

[1596] Into a 40 mL vial were added (2R)-N-tert-butyl-2-({2-chloro-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amîno)propanamide (330 mg, l.06 mmol, l.OO equiv) and toluene (20 mL), 4-fluoro-2-(tributylstannyl)pyridine (615 mg, 1.59 mmol, 1.50 equiv), Pd(PPh₃)₄ (123 mg, 0.10 5 mmol, 0.10 equiv). The resulting mixture was stirred for 12 h at 120 °C under nitrogen atmosphère. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (10:1) to afford (2R)-N-tert-butyl-2-{[2-(4-fluoropyridin' 2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}propanamide (240 mg, 61%) as a brown solid. LCMS (ES) [M+l]⁺ m/z: 372.

Step 2

[1597] Into a 20 mL vial were added dimethylaminoethanol (115 mg, 1.29 mmol, 2.00 equiv) and DMSO (3 mL), To the above mixture was added NaH (60% in minerai oil) (52 mg, 1.29 mmol, 2.00 equiv) in portions. The resulting mixture was stirred for 0.5 h at room température. To the above mixture 15 was added (2R)-N-tert-butyl-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl](methyl)amino]propanamide (240 mg, 0.64 mmol, 1.00 equiv) in portions. The resulting mixture was stirred for additional 1 h at room température. The reaction was quenched with water ( 1 mL) and purified by Prep-HPLC with the following conditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5 pm, 10 nm, mobile phase, water (0.1% NH4OH) and CH3CN (5% CH3CN up to 25% in 15 min),

Detector, 254 nm UV) to afford (2R)-N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}21052

680

5H,6H,7H-cyclopenta[d]pyrimidin-4-ylXmethyl)amino]propanamide (112.8 mg, 40%) as a white solid. LCMS (ES) [M+l]* m/z: 441. Ή NMR (300 MHz, DMSO-d6) δ 8.49 (d, J =5.6 Hz, IH), 7.89 (d, J = 2.5 Hz, IH), 7.80 (s, IH), 7.06 (dd, J = 5.7, 2.6 Hz, IH), 5.06 (q, J = 7.0 Hz, IH), 4.21 (t, J = 5.7 Hz, 2H), 3.22 (dt, J = 15.6, 7.8 Hz, IH), 3.12 (s, 3H), 3.13-2.99 (m, IH), 2.97-2.72 (m, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 2.06 -1.97 (m, 2H), 1.32 (d, J = 7.0 Hz, 3H), 1.20 (s, 9H).

Example 1.415

[1598] Synthesis of N-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}amino)acetamide (Compound 409)

[1599] Compound 409 was synthesized similar to Compound 174 by replacing N-(tert-butyl)-2(methylamino)acetamîde with tert-butyl 2-aminoacetate. LCMS (ES) [M+l] * m/z: 414. ^lHNMR (300 MHz, DMSO-d6) δ 8.46 (d,7=5.6 Hz, IH), 7.84 (d,7=2.5 Hz, IH), 7.69 (s, IH), 7.14 (t, 7= 5.9 Hz, IH), 7.04 (dd, 7 = 5.6,2.6 Hz, IH), 4.70 (s, IH), 3.94 (d,7=5.8 Hz, 2H), 3.86 (s, 2H), 2.84 (t,7= 7.7 Hz, 2H), 2.74 (t, 7= 7.4 Hz, 2H), 2.09-2.05 (m, 2H), 1.25 (s, 9H), 1.24 (s, 6H).

Example 1.416

[1600] Synthesis of N-(l-cyclopropyl-l H-pyrazol-4-yl)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 410)

[1601] Compound 410 was synthesized similar to Compound 348 by replacing tert-butylamine with 1-cyclopropyl-l H-pyrazol-4-amine. LCMS (ES) [M+l] * m/z: 477. Ή NMR (300 MHz, DMSO-d6) δ

10.24 (s, 1 H), 8.46 (d, J = 5.6 Hz, I H), 7.88 (s, 1 H), 7.76 (d, J = 2.6 Hz, IH), 7.39 (s, 1 H), 7.02 (dd,J=

681

5.7,2.5 Hz, IH), 4.34 (s, 2H),4.ll (t, J = 5.5 Hz, 2H), 3.64 (tt, J = 7.2, 4.0 Hz, IH), 3.32 (s, 3H), 3.19 (t, J = 7.3 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.60 (t, J = 5.5 Hz, 2H),2.2l (s, 6H), 2.05-1.95 (m, 2H), ] .020.83 (m, 4H).

Example 1.417

[1602] Synthesis of N-tert-buty 1-2-{methyl [2-(4-{[(2R)-1-methy Ipyrrolidi n-2-y 1] methoxy }pyrid in-

2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 411)

[1603] Compound 411 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (R)-(l-methylpyrrolidin-2-yl)methanol. LCMS (ES) [M+l] ⁺ m/z: 453. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J= 5.6 Hz, IH), 7.82 (d,7=2.4 Hz, IH), 7.65 (s, IH), 7.05 (dd, 7=5.6,2.4 Hz, 1 H), 4.15-4.11 (m, 3H), 4.01-3.96 (m, IH), 3.26 (s, 3H), 3.16 (t, 7= 7.2 Hz, 2H), 2.992.96 (m, IH), 2.83 (t, 7 =7.6 Hz, 2H), 2.67-2.65 (m, IH), 2.40 (s, 3H), 2.26-2.24 (m, IH), 2.02-1.95 (m, 3H), 1.75-1.63 (m, 3H), 1.24 (s, 9H).

Example 1.418

[1604] Synthesis of N-tert-buty 1-2-{methyl[2-(4-{[(2S)-1-methylpyrrolidin-2-yl]methoxy}pyridin-2- yi)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 412)

[1605] Compound 412 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (S)-(I-methylpyrrolidin-2-yl)methanol. LCMS (ES) [M+l]⁺ m/z: 453. ’H NMR (300 MHz, DMSO-d6) δ 8.47 (d,7=5.4 Hz, IH), 7.82 (d,7=2.4 Hz, IH), 7.67 (s, IH), 7.05 (dd, 7= 5.7, 2.4 Hz, IH), 4.16-4.11 (m, 3H), 4.01-3.97 (m, IH), 3.26 (s, 3H), 3.16 (t, 7= 7.2 Hz, 2H), 2.99-

682

2.96 (m, IH), 2.83 (t, J= 7.5 Hz, 2H), 2.67-2.65 (m, IH), 2.40 (s, 3H), 2.26-2.24 (m, IH), 2.02-1.95 (m, 3H), l .75-1.63 (m, 3H), l .24 (s, 9H).

Example l .419

[1606] Synthesis of N-tert-butyl-2-[(2-{4-[2-(dimethylammo)ethoxy]pyridin-2-yl}-5,5-dimethyl5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 413)

[1607] Compound 413 was synthesized similar to Compound 331 by replacing 2-(methylamino)-N(6-methylpyridin-3-yl)acetamide with N-tert-butyl-2-(methylamino)acetamide hydrochloride and by replacing ethane-l,2-diol with dimethylaminoethanol. LCMS (ES) [M+1 ]⁺ m/z: 455. ’H NMR (300 MHz, DMSO-d6) δ 8.48 (d, 7 = 5.6 Hz, IH), 7.85 (d, J= 2.6 Hz, IH), 7.66 (s, IH), 7.07 (dd, J= 5.6, 2.6 Hz, IH), 4.20 (t, J= 5.7 Hz, 2H), 4.03 (s, 2H), 3.19 (s, 3H), 2.86 (t, 7= 7.3 Hz, 2H), 2.66 (t, 7= 5.7 Hz, 2H), 2.23 (s, 6H), 1.87 (t, 7= 7.3 Hz, 2H), 1.43 (s, 6H), 1.22 (s, 9H).

Example 1.420

[1608] Synthesis of N-tert-buty 1-2-{[2-(4-{[(4R)-2,2-dimethy 1-1,3-dioxolan-4-yi]methoxy}pyridin-

2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide (Compound 414)

[1609] Compound 414 was synthesized similar to Compound 34 by replacing 4-methoxy-2- (trimethylstannyl)pyridine with 4-{[(4S)-2,2-dimethyl-l,3-dioxolan-4-yl]methoxy}-2(tributylstannyl)pyridine. LCMS (ES) [M+l]⁺ m/z: 470.2. Ή NMR (400 MHz, DMSO-d6) δ 8.50 -

8.47 (m, IH), 7.87-7.85 (m, IH), 7.69 (s, IH), 7.08 (dd, 7= 5.6, 2.6 Hz, 1 H), 4.48 -4.40 (m, 1 H), 4.23

- 4.17 (m, 1 H), 4.15 - 4.06 (m, 4H), 3.79 (dd, 7= 8.4, 6.4 Hz, IH), 3.27 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H),

683

2.81 (t, 7= 7.8 Hz, 2H), 2.03 - 1.95 (m, 2H), 1.37- 1.35 (m, 3H), 1.32- 1.30 (m, 3H), 1.24 (s, 9H).

Example 1.421

[1610] Synthesis ofN-tert-butyl-2-[(2-{4-[(2R)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyi)amino]acetamidede (Compound 415)

Scheme 130

[1611 ] To a solution ofN-Tert-butyl-2-{[2-(4-{[(4S)-2,2-dimethyI-l,3-dioxolan-4yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide (44 mg;

0.09 mmol; 1 eq.) in methanol (1 ml) was added HCl (1 ml of 5-6 M HCl in isopropanol). After stirred at 25 °C for 1 h, the mixture was concentrated and the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl8 column, 0-70% acetonitrile/O.1 % aqueous formic acid gradient) to give N-tert-butyl-2-[(2-[4-[(2R)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (32 mg, 80%) as a solid. LCMS (ES+): [M+H]⁺ =470.2. Ή NMR (400 MHz, DMSO-d6) δ 8.47 (d,7=5.6 Hz, IH), 7.86-7.82 (m, IH), 7.69 (s, IH),

7. 04 (dd, 7= 5.7, 2.6 Hz, IH), 5.01 (d, 7= 5.1 Hz, 1H),4.73 (s, IH), 4.17 - 4.11 (m, 3H), 4.01 (dd,7 = 10.0, 6.0 Hz, 1 H), 3.86 - 3.79 (m, IH), 3.49 - 3.44 (m, 2H), 3.26 (s, 3H), 3.16 - 3.10 (m, 2H), 2.84 2.78 (m, 2H), 2.02 - 1.94 (m, 2H), 1.24 (s, 9H).

Example 1.422

684

[1612] Synthesis ofN-tert-butyl·2-[methyl(2-{4-[(1-methylazetidin-3-yl)oxy]pyrldιn-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 416)

[1613] Compound 416 was synthesîzed similar to Compound 348 by replacing dimethylaminoethanol with l-methylazetidin-3-ol. LCMS (ES) [M+l]⁺ m/z: 425. *HNMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, IH), 7.78 (d, J = 2.5 Hz, IH), 7.71 (s, IH), 6.91 (dd, J = 5.6, 2.6 Hz, IH), 4.95 (q, J = 5.6 Hz, IH), 4.12 (s, 2H), 3.83-3.72 (m, 2H), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 3.00 (dd, J = 8.0, 5.5 Hz, 2H), 2.80 (t, J = 7.8 Hz, 2H), 2.30 (s, 3H), 2.03-1.96 (m, 2H), 1.26 (s, 9H).

Example 1.423

[1614] Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidm-4-yl)(methyl)amino]-l-(pyrrolidin-l-yl)ethan-l-one (Compound 417)

[1615] Compound 417 was synthesîzed similar to Compound 348 by replacing tert-butylamine with pyrrolidine. LCMS (ES) [M+l]⁺ m/z: 425. ¹H NMR (300 MHz, DMSO-d6) δ 8.46 (d, J = 5.6 Hz, IH), 8.17 (s, 77COOH), 7.69 (d, J= 2.6 Hz, IH), 7.04 (dd, J= 5.6, 2.6 Hz, IH), 4.39 (s, 2H), 4.19 (t, J= 5.7 Hz, 2H), 3.54 (t, J= 6.8 Hz, 2H), 3.32 (t, J= 6.8 Hz, 2H), 3.29 (s, 3H), 3.15 (t, J = 13 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H), 2.68 (t, 7= 5.6 Hz, 2H), 2.25 (s, 6H), 2.06-1.88 (m, 4H), 1.89-1.82 (m, 2H).

Example 1.424

[1616 ] Synthesis of2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pynmidin-4-yl)(methyl)amino]-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 418)

685

[ 1617] Compound 418 was synthesized similar to Compound 348 by replacing tert-butylamine with l-(trifluoromethyl)cyclopropan-l-amine. LCMS (ES) [M+1]⁺ m/z: 479. 'H NMR (300 MHz, DMSOd6) δ 9.04 (s, IH), 8.46 (d, J = 5.6 Hz, IH), 7.74 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.6, 2.6 Hz, IH), 4.255 4.13 (m, 4H), 3.28 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.9 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H),

2.23 (s, 6H), 2.04-1.97 (m, 2H), L24-L13 (m, 2H), l.00-0.91 (m, 2H).

Example 1.425

[l 618] Synthesis ofN-tert-butyl-2-[methyl(2-{4-[2-(methylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-y])amino]acetamide (Compound 419)

[1619] Compound 419 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with tert-buty 1 N-(2-hydroxyethyI)-N-methyIcarbamate. LCMS (ES) [M+l]⁺m/z: 413. Ή NMR (300 MHz, DMSO-d6) δ 9.36 (br, 2H), 8.76 (d, J = 6.0 Hz, IH), 8.17 (s, IH), 8.11 (br, I H), 7.50 (dd, J = 6.1, 2.6 Hz, IH), 4.62 (t, J = 5.0 Hz, 2H), 4.42 (s, 2H), 3.45 -3.36 (m, 5H), 3.23 15 (t, J = 7.9 Hz, 2H), 3.01 (t, J = 7.9 Hz, 2H), 2.68 - 2.61 (m, 3H), 2.14-2.03 (m, 2H), 1.25 (s, 9H).

Example 1.426

[1620] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-l-(pyrrolidin-l-yl)ethan-I-one (Compound 420)

686

[ 1621] Compound 420 was synthesized similar to Compound 389 by replacing propane-2-amine with pyrrolidine. LCMS (ES) [M+l] ⁺ m/z: 426. 'H NMR (300 MHz, DMSO-d6) § 8.45 (d, 7= 5.6 Hz, IH), 7.71 (s, IH), 7.06-6.99 (m, IH), 4.70 (s, IH), 4.40 (s, 2H), 3.85 (s, 2H), 3.56 (t, J- 6.8 Hz, 2H), 3.33-3.31 (m, 2H), 3.30 (s, 3H),3.l5 (t,7=7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), l.97 (dp,7= 14.0, 7.4 Hz, 4H), ! .79 (p, 7= 6.8 Hz, 2H), l .22 (s, 6H).

Example 1.427

[ ] 622] Synthesis of N-cyclopentyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 421)

[ 1623] Compound 421 was synthesized similar to Compound 389 by replacing propane-2-amine with 1-cyclopenty lamine. LCMS (ES) [M+1]⁺ m/z: 440. ’H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J5.6 Hz, IH), 8.28 (s, IH), 8.09 (d,7=7.5 Hz, IH), 7.80 (d,7= 2.5 Hz, IH), 7.05 (dd,7= 5.7, 2.6 Hz, IH), 4.17 (s, 2H), 4.06-3.95 (m, IH), 3.87 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.02-1.95 (m, 2H), L77 (dq,7= 13.1, 6.8, 6.2 Hz, 2H), 1.57 (tq,7= 5.7,2.8 Hz, 2H), 1.51-1.31 (m, 4H), 1.24 (s, 6H).

Example 1.428 [1624] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl] (methy l)amino)-N-[(3R)-oxolan-3-yl]acetamide (Compound 422)

687

[l 625] Compound 422 was synthesized similar to Compound 389 by replacing propane-2-amine with (R)-tetrahydrofuran-3-amine. LCMS (ES) [M+l]⁺ m/z: 442. ^lH NMR (300 MHz, DMSO-d6) δ 8.49 (d, 7= 5.7 Hz, IH), 8.40 (d, 7= 6.9 Hz, IH), 7.81 (d, 7= 2.4 Hz, IH), 7.09 (dd, 7= 5.7, 2.7 Hz, lH),4.70(s, 1 H), 4.32-4.24 (m, IH), 4.21 (d,7= 1.8 Hz, 2H), 3.88 (s, 2H), 3.78-3.70 (m, 2H), 3.67-3.60 (m, 1 H), 3.46 (dd, 7= 8.7, 3.9 Hz, IH), 3.28 (s, 3H), 3.18 (L 7= 7.2 Hz, 2H), 2.86 (t, 7= 7.8 Hz, 2H), 2.11-1.95 (m, 3H), 1.78-1.68 (m, IH), 1.24(s, 6H).

Example 1.429

[1626] Synthesis of2-[(2-{4-[2~(dimethylamino)-2-methylpropoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 423)

[1627] Compound 423 was synthesized similar to Compound 348 by replacing tert-butylamine with l-(trifluoromethyl)cyclopropan-l-amine and by replacing dimethylaminoethanol with 2(dimethylamino)-2-methylpropan-l-ol. LCMS (ES) [M+l] * m/z: 507. ^!H NMR (300 MHz, DMSO-d6) δ 9.04 (s, IH), 8.46 (d, J = 5.6 Hz, IH), 7.75 (d, J = 2.5 Hz, IH), 7.07 (dd, J = 5.7, 2.5 Hz, 1 H), 4.17 (s, 2H), 3.98 (s, 2H), 3.29 (s, 3H), 3.15 (t, J = 7.4 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.25 (s, 6H), 2.06-1.93 (m,2H), 1.28-1.11 (m, 2H), 1.12(s,6H), 1.01-0.92 (m, 2H).

Example 1.430

[1628] Synthesis of 2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrÎmÎdin-4-yl)(methyl)amino]-N-[(3R)-oxolan-3-yl]acetamide (Compound 424)

688

Step I

[1629] Into a 20 mL vial were added dimethylaminoethanoi (354 mg, 3.97 mmol, 2.00 equiv), DMSO (5 mL). To the above mixture, NaH (60% in minerai oil) (l 59 mg, 3.97 mmol, 2.00 equiv). The resulting mixture was stirred for 30 min at room température, followed by the addition of ethyl 2-{[2-(4fluoropyridin-2-yl)-5,6,7,8-tetrahydroquinazolin-4-yl](methyl)amino}acetate (683 mg, T98 mmol, l.OO equiv). The resulting mixture was stirred for additional 1 h at room température. The reaction was quenched with water (2 mL) at room température. The mixture was acidified to pH 7 with HCOOH. The residue was purified by reverse phase flash chromatography with the following conditions: Cl8-120 g xolumn, FbO (0.05% FA)/MeCN, 10% to 100% gradient in 10 min, detector, UV 254 nm. This resulted in N-(2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro-5U-cyclopenta[d]pyrimidin-4-yl)-N- methylglycine formate (410 mg, 53%) as a white solid. LCMS (ES, m/z): [M-HCOOH+H]⁴·: 372.

Step 2

689

[l 630] Into a 20 mL vial were added N-(2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-yl)-N-methylglycine formate (410 mg, l. 10 mmol, L00 equiv), DMF (5 mL), (3R)-oxolan-3-atnine (125 mg, L43 mmol, L30 equiv), DIEA (428 mg, 3.31 mmol, 3.00 equiv).

HATU (546 mg, l .44 mmol, J .30 equiv) was added at 0°C. The resulting mixture was stirred for 2 h at room température. The crude product was purified by Chiral-Prep-HPLC with the following conditions: XBridge Shield RP 18 OBD Column, 19*150 mm, 5 pm, mobile phase, water (0.05% ΝΗ3Ή2Ο) and CH3CN (16% up to 33% in 8 min). This resulted in (R)-2-((2-(4-(2-(dimethylainino)ethoxy)pyridin-2yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-(tetrahydrofuran-3-yl)acetamide (102.6 mg, 21%) as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 441. ’H NMR (300 MHz, DMSOé) δ 8.47 (d, J = 5.6 Hz, IH), 8.36 (d, J = 6.9 Hz, IH), 7.78 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.32-4.14 (m, 5H), 3.80-3.59 (m, 3H), 3.45 (dd, J = 8.9, 4.1 Hz, IH), 3.28 (s, 3H), 3.16 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 2.15-1.91 (m, 3H), 1.81-1.65 (m, IH).

Example 1.431

[1631] Synthesis of N-tert-butyl-2-[(2-{4-[(l-hydroxy-2-methylpropan-2-yl)oxy]pyridin-2-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyi)amino]acetamide (Compound 425)

[ 1632] Compound 425 was synthesized similar to Compound 44 by replacing 4-[2-(oxan-220 yloxy)ethoxy]-2-(trimethylstannyl)pyridine with 4-{[2-methyl-l-(oxan-2-yloxy)propan-2-yl]oxy}-2(tributylstannyl)pyridine. LCMS (ES+): [M+H]⁺ = 428.1. Ή NMR (400 MHz, DMSO-Λ) δ 8.49 - 8.42

(m, lH), 7,87 - 7.80 (m, lH), 7.69 - 7.62 (m, IH), 7.14-7.03 (m, lH), 5.04 (t, 7= 5.9 Hz, 1H),4.J64.11 (m, 2H), 3.86 (s, IH), 3.50 (d, 7= 5.8 Hz, IH), 3.27 - 3.23 (m, 3H), 3.18 -3.09 (m, 2H), 2.85 2.77 (m, 2H), 2.04 - 1.93 (ni, 2H), 1.39 (s, 3H), 1.24 (s, 9H), 1.23 (s, 3H).

Example 1.432

[1633] Synthesis of N-tert-butyl-2-[nwthyi({2-[4-(3,3,3-trifluoro-2-hydroxypropoxy)pyridin-2-yl]-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 426)

[1634] Compound 426 was synthesized similar to Compound 174 by 2-methyl-2-((tetrahydro-2H- pyran-2-y])oxy)propan-l-ol with 3,3,3-trifluoro-2-(oxan-2-yloxy)propan-l-ol. LCMS (ES+): [M+H]⁺ = 453.1. Ή NMR (400 MHz, DMSO-7_â) δ 8.51 (d,7=5.6 Hz, IH), 7.85 (d, 7= 2.5 Hz, 1 H), 7.65 (s, IH), 7.12 (dd, 7= 5.7, 2.6 Hz, IH), 6.72 (d,7=6.6 Hz, IH), 4.48 - 4.39 (m, IH), 4.36 (dd, 7= 10.7,4.1 Hz, IH), 4.25 (dd, 7= 10.7, 6.1 Hz, IH), 4.14 (s, 2H), 3.25 (s, 3H), 3.16 - 3.09 (m, 2H), 2.86-2.78 (m, 2H), 2.04 - 1.93 (m, 2H), 1.23 (s, 9H).

Example 1.433

[1635] Synthes is of N-tert-buty 1-2-( {2- [4-(2-hyd roxyethoxy)-6-methyIpyrid in-2-y 1 ] -5 H ,6H,7H- cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Compound 427)

H

691

Scheme 132

Step 1

SnBü₃CI_T BuLi.Tol

-78°C~rt

78%

[1636] Into a 100-mL 3-necked round-bottom flask purged and maintained with an inert atmosphère of nitrogen, was placed a mixture of 2-bromo-4-chloro-6-methylpyridine (1.00 g, 4.88 mmol, 1.00 equiv), Toi (30 mL), n-BuLi (2.4 mL, 1.2 equiv) at -78 degrees C, after over 30 mins , was added SnBujCl (1.75 g, 5.37 mmol, 1.1 equiv) was dropwised at -78 degrees C. The resulting solution was stirred for 16 hours at -78 degrees C to rt. The resulting mixture was washed with I x 30 ml of NH₄C1 and I x 30 ml of aq NaHCCh, and I x 30 ml of aq. NaCl. The mixture was dried over anhydrous sodium sulfate and concentrated. This resulted in 1.6 g (78.82%) of 4-chloro-2-methyl-6(tributylstannyl)pyridine as yellow oit. LCMS (ES) [M+1]' m/z 418.

Step 2

[1637] Into a 40-mL vial purged and maintained with an inert atmosphère of nitrogen, was placed a ~ 692 mixture of 2-bromo-4-chloro-6-methylpyridine (1.0 g, 23.98 mmol, 1.00 equiv), Toluene (20.0 mL), N(tert-butyl)-2’((2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (710 mg, 23.98 mmol, 1.0 equiv), Pd(PPh₃)₄ (277 mg, 2.40 mmol, 0.10 equiv). The resulting solution was stirred for 16 hours at 120 degrees C. The resulting mixture was concentrated. The residue was applied onto a silica gel column with MeOH/DCM (13/87). This resulted in 800 mg (86.96%) of 4-chloro-2methyL6-(tributylstannyl)pyridine as a yellow solid. LCMS (ES) [M+l]⁺ m/z 388.

Step 3

[1638] Into a 8-mL vial, was placed a mixture ofNaH(60%) (165 mg, 2.06 mmol, 4.00 equiv),

DMF (4.0 mL), ethane-l,2-diol(320 mg, 2.58 mmol, 5.0 equiv), N-(tert-butyl)-2-((2-(4-chloro-6methylpyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pynmidin-4-yl)(methyl)amino)acetamide (200 mg, 0.516 mmol, 1.00 equiv). The resulting solution was stirred for 16 hours at 80 degrees C. The reaction was then quenched by the addition of 0.5 mL of water. The crude product was purified by Prep-HPLC with the following conditions: SunFire Prep C18 OBD Column, 30*50 mm, 5pm l Onm; Mobile Phase A: Water(Û. 1%FA), Mobile Phase B: AcCN; Flow rate: 90 mL/min; Gradient: 5% B to 35% B in 12 min, 35% B; Wave Length: 220nm nm; RT 1 (min): 12; Number Of Runs: 0. This resulted in 70 mg (32.86%) of N-(tert-buty 1)-2-((2-(4-(2-hydroxyethoxy)-6-methylpyridin-2-yl)-6,7-dihydro-5Hcyc!openta[d]pyrimidin-4-yl)(methyl)amino)acetamide formate as a white solid. LCMS (ES) [M-46+1]* m/z 414. Ή NMR (400 MHz, DMSO-d6, ppm): δ 8.21 (s, 1 H), 7.67 (d, J = 2.4 Hz, IH), 7.65 (s, IH),

6.90 (d, J = 2.3 Hz, IH), 4.15-4.08 (m, 4H), 3.74 (t, J = 4.9 Hz, 2H), 3.25 (s, 3H), 3.13 (t, J = 7.3 Hz, 2H), 2.81 (t, J = 7.9 Hz, 2H), 2.48 (s, 3H), 2.04 - i .92 (m, 1 H), 1.23 (s, 9H).

Example 1.434

[1639] Synthesis of 2-[(2-[4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-

693 cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide (Compound 428)

[] 640] Compound 428 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with dîmethylaminoethanoL LCMS (ES) [M+1 ] * m/z: 413. 'H NMR (300 MHz, DMSO-d6) § 8.47 (dd, J = 5.6, 1.2 Hz, IH), 8.00 (d, J = 7.8 Hz, IH), 7.80 (d, J = 2.5 Hz, IH), 7.10-7.00 (m, IH), 4.20 (t, J = 5.6 Hz, 2H), 4.15 (s, 2H), 3.94-3.80 (m, IH), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.66 (t, J = 5.6 Hz, 2H), 2.23 (s, 6H), 2.04-1.97 (m, 2H), 1.05 (dd, J = 6.6, 1.2 Hz, 6H).

Example 1.435

[1641] Synthesis of 2-[methyl(2-{4-[2-(pyrrolidin-l-yl)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yi)amino]-N-(propan-2-yl)acetamide (Compound 429)

[1642] Compound 429 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with hydroxyethylpyrrolidine. LCMS (ES) [M+l] * m/z: 439. 'H NMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 7.99 (d, J = 7.8 Hz, IH), 7.80 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.6,2.6 Hz, 1 H), 4.22 (t, J = 5.7 Hz, 2H), 4.15 (s, 2H), 3.87 (dq, J = 13.5, 6.7 Hz, IH), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.87-2.76 (m, 4H), 2.59-2.53 (m, 4H), 2.04-1.97 (m, 2H), 1.75-1.61 (m, 4H), 1.04 (d, J = 6.6 Hz, 6H).

Example 1.436

[1643] Synthesis of 2-[methyl(2-{4-[2-(morpholin-4-yl)ethoxy]pyridin-2-yl[-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide (Compound 430)

694

H

[ 1644] Compound 430 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with 4-morpholineethanol. LCMS (ES) [M+l]⁺ m/z: 455. ’H NMR (300 MHz, DMSO-d6) Ô 8.47 (d, J= 5.6 Hz, I H), 7.99 (d, J= 7.8 Hz, IH), 7.81 (d, J= 2.5 Hz, IH), 7.05 (dd, J= 5.6, 2.6 Hz, IH), 4.24 (t, J= 5.6 Hz, 2H), 4.I5 (s, 2H), 3.96-3.78 (m, IH), 3.64-3.53 (m, 4H), 3.27 (s, 3H), 3.15 (t, J= 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.73 (t, J = 5.6 Hz, 2H), 2.50-2.47 (m, 4H), 2.04l .97 (m, 2H), l .04 (d, J = 6.6 Hz, 6H).

Example 1.437

[1645] Synthesis of 2-[(2-{4-[(l-hydroxycyclopropyl)methoxy]pyridin-2-y!}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide (Compound 431 )

H

[1646] Compound 431 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with (1-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropy[)methanol. LCMS (ES) [M+l] ⁺m/z: 412. Ή NMR (300 MHz, DMSO-d6) δ 8.47 (d, J=5.6Hz, IH), 8.00 (d,J=8.0Hz, 1 H), 7.83 (d, J = 2.4 Hz, IH), 7.05 (dd, J= 5.6, 2.8 Hz, 1 H), 5.63 (s, IH), 4.16 (s, 2H), 4.12 (s, 2H), 3.91-3.83 (m, IH), 3.30 (s, 3H), 3.17 (t, J = 7.2 Hz, 2H), 2.84 (t, .1= 7.6 Hz, 2H), 2.03-1.96 (m, 2H), 1.05 (d, J= 6.4 Hz, 6H), 0.74-0.65 (m, 4H).

Example 1.438

[1647] Synthesis of 2-[methyl(2-{4-[2-(4-methylpiperazîn-l-yl)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide (Compound 432)

695

[l 648] Compound 432 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with 2-(4-methylpiperazin-l-yl)ethanol. LCMS (ES) [M+l]⁺ m/z: 468. ΉNMR (300 MHz, DMSO-d6) δ 8.47 (d, J = 5.6 Hz, IH), 7.99 (d, J = 7.7 Hz, IH), 7.80 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.7,2.5 Hz, IH), 4.22 (t, J = 5.7 Hz, 2H), 4.15 (s, 2H), 3.95-3.81 (m, IH), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.72 (t, J = 5.7 Hz, 2H), 2.59-2.50 (m, 4H), 2.40-2.28 (m, 4H), 2.15 (s, 3H), 2.04-1.94 (p, J = 7.6 Hz, 2H), 1.05 (d, J = 6.6 Hz,

6H).

Example 1.439 and Example 1.440

[1649] Synthesis of (2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)propanamide (Compound 433) and (2S)-2[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-(propan-2-yl)propanamide (Compound 434)

Compound 433 Assumed

Compound 434 Assumed

696

Compound 433 Assumed

Compound 434 Assumed

Scheme 133

Step 1

DIEA, NMP, 4 h °C

[1650] Into a 100 mL round-bottom flask were added 2-(4-chloropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl trifiuoromethanesulfonate (2.5 g, 6.58 mmol, 1.00 equiv), N-isopropyl-2(methylamino)propanamide (1.42 g, 9.88 mmol, 1.5 equiv), NMP (20 mL), and DIEA (2.55 g, 19.75 mmol, 3 equiv) at room température. The resulting mixture was stirred for 4 h at 40 °C. The reaction was quenched with water at room température and the resulting mixture was extracted with EtOAc (3 x

200 mL). The combined organic layers were washed with brine (3x200 mL), and dried over anhydrous

Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was recrystallized from EtOAc (100 mL) to afford 2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H21052

697 cyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-isopropylpropanamide (l g, 40.63%) as a light yellow solid. LCMS (ES) [M+lf m/z 374.

Step 2

[1651 ] Into a 40 mL vial were added dimethylaminoethanol (238 mg, 2.67 mmol, 2 equiv) and

DMSO (5 mL) at 0 °C. To the above mixture was added NaH (107 mg, 2.67 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred for an additional 30 min at room température. To the mixture was then added 2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}N-isopropylpropanamide (500 mg, 1.34 mmol, 1.00 equiv) in DMSO dropwise at 0 °C. The resulting solution was stirred for 1 hr at room température. The crude product was purified by Chiral-Prep-HPLC with the following conditions (Prep-HPLC-003): Column, SunFire Prep Cl 8 OBD Column, 19*150 mm, 5pm lOnm; mobile phase, Water (0.05% TFA ) and ACN (35% ACN up to 88% in 8 min). The crude product was purified again by Chiral-Prep-HPLC with the following conditions (ΧΑ-Prep Chiral HPLC-01): Column, CHIRAL ART Cellulose-SB, 3*25 cm, 5 um; mobile phase, Hex(0.5% 2M NH315 MeOH)- and EtOH(0.5% 2M NH3-MeOH)- (hold 30% EtOH(0.5% 2M NH3-MeOH)- in 12 minThis resulted in (2R)-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4yl)(methyl)amino]-N-isopropylpropanamide (111.6 mg, 39.13%) and (2S)-2-[(2-{4-[2(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-Nisopropylpropanamide (114.9 mg, 36.36%) as a white solid.

[1652] Compound 433: Analytical chiral HPLC conditions: Column, YMC-cellulose-SB, 100*4.6 mm, 3mn; mobile phase A, n-Hexane; mobile phase B, éthanol; Flow rate: 1 mL/min; Gradient: 10%B in 10 mîn; 254 nm. Rétention time: 3.067 min. LCMS (ES) [M+l]⁺ m/z 427. ’H NMR (400 MHz, DMSOA) δ 8.49 (d,7= 5.6 Hz, IH), 8.21 (d,7 = 8.0 Hz, IH), 7.87 (d,7=2.5 Hz, IH), 7.10-7.04 (m, IH), 5.07 (q, 7= 7.0 Hz, IH), 4.24 (t,7=5.6 Hz, 2H), 3.95-3.82 (m, IH), 3.28-3.15 (m, IH), 3.11-3.03 (m, 4H), 2.95-2.75 (m, 2H), 2.72 (t, 7= 5.7 Hz, 2H), 2.27 (s, 6H), 2.11-1.88 (m, 2H), 1.34 (d, 7= 7.0

Hz, 3H), 1.08 (d, 7= 6.6 Hz, 3H), 0.91 (d, 7= 6.6 Hz, 3H).

[1653] Compound 434: Analytical chiral HPLC conditions: Column, YMC-cellulose-SB, 100*4.6

698 mm, 3um; mobile phase A, n-Hexane; mobile phase B, éthanol; Flow rate: l mL/min; Gradient: I0%B in 10 min; 254 nm. Rétention time: 4.820 min. LCMS (ES) [M+l]⁺ m/z 427. 'H NMR (400 MHz, DMSOéô) δ 8.49 (d,7= 5.6 Hz, IH), 8.21 (d, 7= 8.0 Hz, IH), 8.17 (s, tfCOOH), 7.87 (d,7=2.5 Hz, IH), 7.10-7.04 (m, 1 H), 5.07 (q, 7= 7.0 Hz, IH), 4.24 (t, 7= 5.6 Hz, 2H), 3.95-3.82 (m, IH), 3.28-3.15 (m, IH), 3.11 (s, 4H), 2.95-2.75 (m, 2H), 2.72 (t, 7= 5.7 Hz, 2H), 2.27 (s, 6H), 2.11-1.88 (m, 2H), 1.34 (d, 7=7.0 Hz, 3H), 1.08 (d,7=6.6 Hz, 3H), 0.91 (d,7= 6.6 Hz, 3H).

Example 1.440

[1654] Synthesis of (2R)-2-[(2-[4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyI)amino]-N-(propan-2-yl)propanamide (Compound 433)

Confirmée!

699

To a stirred mixture of dimethylaminoethanol (2.10g, 24.22 mmol, 3.00 equiv) in DMSO (30 mL) was added NaH (0.97 g, 24.22 mmol, 3.00 equiv) in portions at room température under N₂ atmosphère. The reaction was stirred at room température for 30 min before 2-(4-chloropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-ol (2.0 g, 8.07 mmol, l .00 equiv) was added. The resulting mixture was stirred at 40 °C for l h and quenched with H₂O (5 mL) at 15 °C. The reaction mixture was purified by prep-HPLC (Column, Cl8; mobile phase. Mobile phase : MeCN=5/lB:Water Flow rate: 50mL/min Column: DAICEL CH1RALPAK IC, 250*20mm, 220 nm Gradient: 50%B in 20min; 220nm) to give 2{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol (2.1 g, 86.58%) as an-off white solid. LCMS (ES) [M+l]⁺ m/z: 301.

Step 2

To a stirred solution of 2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-ol (2.00 g, 6.66 mmol, LOÛ equiv) and TEA (2.70 g, 26.63 mmol, 4.00 equiv) in DCM (30 mL) was added (CF₃SO2)₂O (3.76 g, 13.31 mmol, 2.00 equiv) dropwise at 0 °C under

N? atmosphère. After the reaction was stirred at 0-25 °C for 5 h, the reaction was quenched by the addition of water (20 mL) at 0 °C. The resulting solution was extracted with DCM (50 mLX3), the combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated under vacuum. This resulted in 2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl trifiuoromethanesulfonate (2.6 g, 90.30%) as a brown oil, which was used in the next step dîrectly.

Step 3

700

[ 1655] To a stirred solution 2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate (2.50 g, 5.78 mmol, l .00 equiv) and TEA (2.93 g, 28.90 mmol, 5.00 equiv) in DCM (50 mL) was added (2R)-N-isopropyl-2-(methylamino)propanamide hydrochloride (l.57 g, 8.67 mmol, l.50 equiv) in one portion at 25 °C, the resulting reaction was stirred at 25-40 °C for 16 h. The reaction was quenched with water (30 mL) at 0 °C, extracted with DCM (50 mL X5). The combined organic layers were washed with brine (50 mL), dried over anhydrous Na₂SO4. After filtration, the fîltrate was concentrated under reduced pressure. The crude product (2.1 g) was purified by Prep-HPLC with the following conditions (Column, Cl8; mobile phase. Mobile phase: MeCN=5/lB: Water Flow rate: 40mL/min Column: DAICEL CHIRALPAK IC, 250*20mm, 220 nm Gradient: 50%B in 25 min; 220nm)) to afford 750 mg (99.75% purity) of the desired product as a white solid. The 750 mg (99.75% purity) of the desired product was trituration with heptane/ EtOAc (50: l, 50 mL) for I h and fïltered. The fîltrate was concentrated to give (2R)-2-[(2-{4-[2(dimethylamino)ethoxy]pyridin-2-yI}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]-Nisopropylpropanamide (375 mg, 15.2I% yield, 99.903% purity) as a white solid. Analytical chiral HPLC conditions: Column, YMC-cellulose-SB, 100*4.6 mm, 3um; mobile phase A, n-Hexane; mobile phase B, éthanol; Flow rate: 1 mL/min; Gradient: 10%B in 10 min; 254 nm. Rétention time: 3.341 minLCMS (ES) [M+l]⁺ m/z: 427. ‘H NMR (400 MHz, DMSO-A δ 8.49 (d, 7= 5.6 Hz, 1 H), 8.21 (d, 7= 8.0 Hz, 1H), 7.86 (d,7= 2.5 Hz, IH), 7.07 (dd, 7= 5.6, 2.6 Hz, IH), 5.07 (d,7=7.1 Hz, 1H),4.22 (t,7= 5.7 Hz, 2H), 3.89 (dt, 7= Ί.Ί, 6.4 Hz, I H), 3.26 - 3.17 (m, IH), 3.11 (s, 3H), 3.10 - 3.04 (m, I H), 2.94 2.75 (m, 2H), 2.67 (t, 7= 5.7 Hz, 2H), 2.23 (s, 6H), 2.10-1.87 (m, 2H), 1.34 (d, 7= 7.0 Hz, 3H), 1.08 (d, 7= 6.6 Hz, 3H), 0.91 (d,7= 6.5 Hz, 3H).

Example 1.441

[1656] Synthesis of 2-[(2-{4-[2-(dimethylammo)ethoxy]pyridin-2-yl}-5,5-dimetbyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide (Compound 435)

[l 657] Compound 435 was synthesized similar to Compound 331 by replacing 2-(methylamino)-N(6-methylpyridin-3-yl)acetamide with N-isopropyl-2-(methylamino)acetamide hydrochioride and by replacing ethane-l,2-diol with dimethylaminoethanol. LCMS (ES) [M+l] ⁺ m/z: 44L 'HNMR (400 MHz, DMSO-7₆) δ 8.49 (d, J = 5.6 Hz, IH), 8.12 (d, J= 7.8 Hz, IH), 7.81 (d, J = 2.5 Hz, IH), 7.07 (dd, J = 5.6, 2.6 Hz, IH), 4.20 (t, J = 5.7 Hz, 2H), 4.05 (s, 2H), 3.85 (dq, J = 13.5, 6.7 Hz, IH), 3.20 (s, 3H), 2.87 (t, J = 7.3 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 1.87 (t, J = 7.3 Hz, 2H), 1.43 (s, 6H), l .03 (d, J = 6.6 Hz, 6H).

Example L442

[1658] Synthesis of 2-[methyl(2-{4-[2-(3-oxomorpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide (Compound 436)

[1659] Compound 436 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with 4-(2-(benzyloxy)ethyl)morphoIin-3-one. LCMS (ES) [M+l]⁺ m/z: 469. 'H NMR (400 MHz, DMSO-Æ) δ 8.50 (d, 7= 5.6 Hz, IH), 8.00 (d, 7= 8.0 Hz, IH), 7.81 (d, 7= 2.8 Hz, l H), 7.08 (dd, 7= 4.8, 2.8 Hz, IH), 4.32 (t, 7= 5.6 Hz, 2H), 4.15 (s, 2H), 4.05 (s, 2H), 3.92 - 3.85 (m, l H), 3.84 (t, 7= 4.8 Hz, 2H), 3.76 (t, 7= 5.6 Hz, 2H), 3.53 (t, 7= 5.2 Hz, 2H), 3.27 (s, 3H), 3.17 (t, 7 = 7.2 Hz, 2H), 2.84 (t, 7= 7.6 Hz, 2H), 2.03-1.96 (m, 2H), l .05 (d, 7= 6.8 Hz, 6H).

Example L443

[ 1660] Synthesis of N-tert-butyl-2-{methyl[2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy}pyridin-2-yI)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 437)

702

Into a 40 mL vial were added (3R)-l-methylpyrrolidin-3-ol (l 08 mg, L07 mmol, 2 equiv) and DMSO (5 mL) at 0 °C. To the above mixture was added NaH (43 mg, L07 mmol, 2 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 30 min at room température and was added N-tert-butyl-25 {[2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (200 mg,

0.54 mmol, l .00 equiv) in DMSO dropwise at 0 °C. The resulting solution was stirred for l hr at room température and the crude product was purified by Chiral-Prep-HPLC with the foîlowing conditions (Prep-HPLC-003): Column, SunFire Prep CI8 OBD Column, 19*150 mm, 5pm lOnm; mobile phase, Water (0.l%FA) and ACN (l 5% ACN up to 55% in 8 min); This resulted in N-tert-butyl-2-{methyl [210 (4-{[(3R)-l-methylpyrrohdin-3-yl]oxy] pyridin-2-y l)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl]amino}acetamide; (formate) (93.6 mg, 32.98%) as a light brown semi-solid. LCMS (ES) [M+l] ⁺m/z: 439. Ή NMR (400 MHz, DMSO-7₆) δ 8.46 (d, 7= 5.6 Hz, IH), 7.81 (d, 7= 2.5 Hz, IH), 7.69 (s, IH), 6.99 (dd, 7= 5.6, 2.6 Hz, IH), 5.10-5.02 (m, IH), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.93 - 2.85 (m, 1 H), 2.81 (t, 7= 7.8 Hz, 2H), 2.75-2.65 (m, 2H), 2.49-2.33 (m, 2H), 2.31 (s, 3H),

2.05-1.93 (m,2H), 1.88-1.77 (m, IH), 1.25 (s, 9H).

Example 1.444

[1661] Synthesis of N-tert-buty 1-2-{methyl[2-(4-{[(3S)-l -methylpyrrolidin-3-yl]oxy] pyridin-2-y 1)5H,6H,7H-cyclopenta[d]pyrimîdin-4-yl]amino}acetamide (Compound 438)

[1662] Compound 438 was synthesîzed similar to Compound 348 by replacing

703 dimethylaminoethanol with (3S)-l-methylpyrrolidin-3-ol. LCMS (ES) [M+l] m/z: 439. Ή NMR (400 MHz, DMSOés) δ 8.46 (d, 7= 5.6 Hz, lH),7.8i (d,7=2.5 Hz, IH), 7.69 (s, IH), 6.99 (dd,7=5.6, 2.6 Hz, IH), 5.10-5.02 (m, lH),4.12(s, 2H), 3.27 (s, 3H), 3.15 (t, 7 = 7.3 Hz, 2H), 2.93 - 2.85 (m, IH), 2.81 (t, 7= 7.8 Hz, 2H), 2.75-2.65 (m, 2H), 2.49-2.33 (m, 2H), 2.31 (s, 3H), 2.05-1.93 (m, 2H), 1.881.77 (m, IH), 1.25 (s, 9H).

Example 1.445

[1663] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yI]-5,5-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide (Compound 439)

[1664] Compound 439 was synthesized similar to Compound 331 by replacing by replacing 2(methylamino)-N-(6-methylpyridin-3-yî)acetamide with N-isopropy 1-2-(methylamino)acetamide hydrochloride and by replacing ethane-l,2-diol with 2-methyl-2-(oxan-2-yloxy)propan-l-ol. LCMS (ES) [M+l ] ⁺m/z: 442. Ή NMR (400 MHz, DMSOés) δ 8.49 (d, J = 5.6 Hz, IH), 8.18 (d, J = 7.8 Hz, IH), 7.83 (d, J = 2.5 Hz, IH), 7.07 (dd, J = 5.7, 2.6 Hz, IH), 4.70 (s, IH), 4.06 (s, 2H), 3.87 (s, 2H), 3.92 3.79 (m, IH), 3.20 (s, 3H), 2.87 (t, J = 7.2 Hz, 2H), 1.88 (t, J = 7.3 Hz, 2H), 1.43 (s, 6H), 1.24 (s, 6H), 1.02 (d, J = 6.6 Hz, 6H).

Example 1.446

[1665] Synthes i s of N-tert-buty I -2-( {2- [4-(2-hyd roxy-2-methy lpropoxy)-6-methy Ipy rid i n-2-y 1 ]-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 440)

704

[] 666] Compound 440 was synthesized similar to Compound 427 by replacing by replacing ethane1,2-diol with 2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propan-l-ol. LCMS (ES) [M+I] ⁺ m/z: 442. Ή NMR (300 MHz, DMSO-d6, ppm): 7.72-7.59 (m, 2H), 6.98-6.88 (m, IH), 4.67 (br, IH), 4.13 (s, 2H), 3.83 (s, 2H), 3.26 (s, 3H), 3.19-3.02 (m, 2H), 2.91-2.74 (m, 2 H), 2.50 (s, 3H), 2.13-1.86 (m, 2H), 1.451.11 (m, I5H).

Example 1.447

[1667] Synthesis ofN-ethyl-2-[(2-{4-[(l-hydroxycyclopropyl)methoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 441)

[1668] Compound 441 was synthesized similar to Compound 389 by replacing 2-methy 1-2-(oxan-2yloxy)propan-l-ol with (l-((tetrahydro-2H-pyran-2-yl)oxy)cyclopropyl)methanol and by replacing propane-2-amine with ethylamine. LCMS (ES) [M+l]⁺ m/z: 398. *H NMR (400 MHz, DMSO-Λ) δ 8.46 (d, 7= 5.6 Hz, 1H), 8.15 (t, 7= 5.8 Hz, IH), 7.81 (d,7=2.6 Hz, IH), 7.04 (dd,7=5.6, 2.6 Hz, IH), 5.64 (s, IH), 4.17 (s, 2H), 4.12 (s, 2H), 3.31 (s, 3H), 3.20-3.09 (m, 4H), 2.82 (t, J= 7.9 Hz, 2H), 2.03-1.95 (m, 2H), 1.00 (t, 7= 7.2 Hz, 3H), 0.71 (d,7=3.5 Hz, 2H), 0.70-0.63 (m, 2H).

Example 1.448

[1669] Synthesis of N-ethyKZ-t^-^A-ethyl-Z-hydroxybutoxyjpyridin^-yn-SH^HJHcyclopenta^pyrimidinH-yl] (methyl)amino)acetamide (Compound 442)

[1670] Compound 442 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with 2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol and by replacing propane-

705

2-amine with ethylamine. LCMS (ES) [M+l]⁺ m/z: 428. Ή NMR (300 MHz, DMSO-d6) § 8.47 (d, J 5.6 Hz, IH), 8.18 (t, J = 5.7 Hz, IH), 7.80 (d, J = 2.5 Hz, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.43 (s, IH), 4.17 (s, 2H), 3.88 (s, 2H), 3.28 (s, 3H), 3.20-3.07 (m, 4H), 2.82 (t, J = 7.8 Hz, 2H), 2.04-1.94 (m, 2H), i.62-1.46 (m, 4H), 1.00 (t, J = 7.2 Hz, 3H), 0.85 (t, J = 7.5 Hz, 6H).

Example 1.449

[1671] Synthesis of 2-((2-[4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-methylacetamide (Compound 443)

11672] Compound 443 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with 2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-l-ol and by replacing propane2-amine with methylamine. LCMS (ES) [M+l]⁺ m/z: 414. 'H NMR (400 MHz, DMSO-Λ) Ô 8.47 (d, J = 5.6 Hz, lH),8.14(s, 1 HCOOH), 8.12 (d, 7= 4.9 Hz, 1 H), 7.78 (d, 7= 2.5 Hz, IH), 7.08-7.01 (m, IH), 4.42 (s, IH), 4.18 (s, 2H),3.89 (s, 2H), 3.28 (s, 3H),3.I6 (t, 7= 7.3 Hz, 2H), 2.82 (t,7 = 7.8 Hz, 2H), 2.63 (d, 7= 4.5 Hz, 3H), 2.04-1.94 (m, 2H), 1.62-1.48 (m, 4H), 0.86 (t, 7= 7.5 Hz, 6H).

Example 1.450

[1673] Synthesis of 2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyi)amino]-N-(propan-2-yl)acetamide (Compound 444)

[1674] Compound 444 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol w'ith (4-(ethoxymethoxy)tetrahydro-2H-pyran-4-yl)methanol. LCMS (ES) [M+]] ⁺

706 m/z: 456. 'H NMR (300 MHz, DMSO-7_â) δ 8.48 (d, J = 5.6 Hz, IH), 8.15 (s, 1//COOH), 8.02 (d, J = 7.8 Hz, IH), 7.83 (d, J = 2.5 Hz, 1H), 7.06 (dd, J = 5.7, 2.6 Hz, IH), 4.79 (s, IH), 4.16 (s, 2H), 3.93 (s, 2H), 3.92-3.79 (m, IH), 3.67 (dd, J = 7.0, 2.4 Hz, 4H), 3.27 (s, 3 H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.85- 1.67 (m, 2H), 1.50 (d, J = 13.3 Hz, 2H), 1.04 (d, J = 6.6 Hz, 6H)

Example 1.451

[1675] Synthesis of N-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-2-methylbutoxy]pyridin-2-yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 445)

[1676] Compound 445 was synthesized similar to Compound 174 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with (2R)-2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butyl (2S)-2- phenylpropanoate. LCMS (ES) [M+l]⁴ m/z: 442. 'H NMR (300 MHz, DMSO-ifc) δ 8.48 (d, 7= 5.4 Hz, IH), 7.82 (d, 7= 2.7 Hz, IH), 7.67 (s, IH), 7.07 (dd, 7= 5.4, 2.4 Hz, IH), 4.55 (s, lH),4.14(s, 2H), 3.90 (q, 7= 12.0, 9.3 Hz, 2H), 3.27 (s, 3H), 3.14 (d, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.01-1.96 (m, 2H), 1.57 (q, 7= 7.5 Hz, 2H), 1.25 (s, 9H), 1.19 (s, 3H), 0.88 (t, 7= 7.5 Hz, 3H).

Example 1.452

[1677] Synthesis of N-tert-butyl-2-[(2-{4-[(2R)-2-hydroxy-2-methylbutoxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 446)

[1678] Compound 446 was synthesized similar to Compound 174 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with (2R)-2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butyl (2S)-2- phenylpropanoate. LCMS (ES) [M+l]⁴ m/z: 442. Ή NMR (300 MHz, DMSO-7₆) δ 8.48 (d, 7= 5.4 Hz, IH), 7.82 (d, 7= 2.7 Hz, IH), 7.67 (s, IH), 7.07 (dd, 7= 5.4, 2.4 Hz, IH), 4.55 (s, IH), 4.14 (s, 2H), 3.90

707 (q, J= 12.0,9.3 Hz, 2H), 3.27 (s, 3H), 3.17 (s, IH), 3.14 (d, J= 7.3 Hz, 2H), 2.82 (t, J= 7.8 Hz, 2H), 1.99 (p, J= 7.7 Hz, 2H), 1.57 (q, 7= 7.5 Hz, 2H), 1.25 (s, 9H), 1.19 (s, 3H), 0.88 (t, 7= 7.5 Hz, 3H).

Example 1.453

[1679] Synthesis ofN-ethyl-2-[(2-{4-[(4-hydroxyoxan-4-yl)methoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 447)

[1680] Compound 447 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with (4-( ethoxy methoxy)tetrahydro-2H-pyran-4-yl)methanol and by replacing propane-2-amine with ethylamine. LCMS (ES) [M+l]⁺ m/z: 441. Ή NMR (300 MHz, DMSO-7s) δ 8.48 (d, J = 5.6 Hz, IH), 8.18 (t, J = 5.6 Hz, IH), 7.82 (d, J = 2.5 Hz, IH), 7.07 (dd, J = 5.7, 2.6 Hz, IH), 4.80 (s, IH), 4.18 (s, 2H), 3.94 (s, 2H), 3.76 - 3.63 (m, 4H), 3.29 (s, 3H), 3.21 -3.05 (m, 4H), 2.83 (t, J = 7.8 Hz, 2H), 2.05-1.95 (m, 2H), 1.76 (dt, J =13.4, 8.3 Hz, 2H), 1.51 (d, J = 13.3 Hz, 2H), 1.01 (t, J = 7.2 Hz, 3H).

Example 1.454

[1681] Synthesis of2-[(2-{4-[(2R)-2-hydroxy-3-methoxypropoxy]pyridin-2-yl}-5H,6H,7Hcyc lopenta[d] pyrîm i d in-4-y l)(m ethy l)am i no ]-N -(propan-2-y l)acetam ide (Compound 448)

[1682] Compound 448 was synthesized similar to Compound 389 by replacing 2-methyl-2-(oxan-2yloxy)propan-l-ol with (2S)-3-methoxy-2-(oxan-2-yloxy)propan-l-ol. LCMS (ES) [M+l] ⁺ m/z; 430.

Ή NMR (300 MHz, DMSO-7_s) δ 8.47 (d, J = 5.6 Hz, IH), 8.01 (d, J = 7.8 Hz, 1 H), 7.82 (d, J = 2.5 Hz, IH), 7.04 (dd, J = 5.6, 2.6 Hz, 1 H), 5.19 (d, J = 5.0 Hz, IH), 4.16 (s, 2H), 4.13 - 3.92 (m, 3H), 3.86 (dt, J = 13.5,6.8 Hz, IH), 3.48-3.38 (m, 2H), 3.30 (s, 3H), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J =

7.8 Hz, 2H), 2.04-1.96 (m, 2H), 1.05 (d, J = 6.5 Hz, 6H).

Example 1.455

[1683] Synthesis of 2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridÎn-2-yl]-6,6-dimethyl-5H,6H,7H- cyclopenta[d]pyrimidin-4-yl}(methyl)amîno)-N-(propan-2-yl)acetamide (Compound 449)

H

[1684] Compound 449 was synthesized similar to Compound 389 by replacing methyl 2oxocyclopentane-l-carboxylate with 4,4-dimethyl-2-oxocyclopentane-l-carboxylate. LCMS (ES) [M+l]⁺m/z: 442. Ή NMR (400 MHz, DMSO-rf₆) 8 8.47 (d, J=5.5 Hz, IH), 8.00 (d, J=7.8Hz, IH), 7.81 (d, J= 2.6 Hz, IH), 7.04 (dd, J = 5.7, 2.7 Hz, IH), 4.70 (s, 1 H), 4.13 (s, 2H), 3.92-3.82 (m, 3H), 10 3.24 (s, 3H), 2.95 (s, 2H), 2.66 (s, 2H), 1.24 (s, 6H), 1.15 (s, 6H), 1.05 (d, J= 6.6 Hz, 6H).

Example 1.456

[1685] Synthesis of 2-([2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-7,7-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)acetamide (Compound 450)

H

[1686] Compound 450 was synthesized similar to Compound 389 by replacing methyl 2oxocyclopentane-l-carboxylate with 3,3-dimethyl-2-oxocyclopentane-l-carboxylate. LCMS (ES) [M+1]⁺ m/z: 442. Ή NMR (300 MHz, DMSO-rff,) δ 8.50 (d, J= 5.6 Hz, IH), 8.02 (d, J = 7.8 Hz, IH), 7.81 (d, J=2.5 Hz, IH), 7.06 (dd, J= 5.7, 2.6 Hz, 1 H), 4.73 (s, IH), 4.16 (s, 2H), 3.95-3.80 (m, 3H), 3.28 (s, 3H), 3.10 (t, J =7.0 Hz, 2H), 1.87 (t, J= 7.0 Hz, 2H), 1.23 (d, J =5.9 Hz, 12H), 1.05 (d, J =6.6

Hz, 7H).

Example 1.457

709

[1687] Synthesis of N-tert-butyI-2-[(2-{4-[(2S)-2,3-dihydroxypropoxy]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pyrimidin-4-yi)(methy[)amino]acetamide (Compound 451)

[1688] Compound 451 was synthesized similar to Compound 415 by replacing N-Tert-butyl-2-{[2- (4-{[(4S)-2,2-dimethyl-l,3-dioxoian-4-yl] methoxy }pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4y!](methyl)amino]acetamide wit N-Tert-butyl-2-{[2-(4-{[(4R)-2,2-dimethyl-l,3-dioxolan-4yl]methoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide, LCMS (ES) [M+l] ⁺ m/z: 430.2. Ή NMR (400 MHz, DMSOAO δ 8.47 (d, J= 5.6 Hz, IH), 7.85 (d, J= 2.5 Hz, IH), 7.68 (s, lH), 7.05 (dd, 7= 5.7, 2.6 Hz, IH), 5.00 (d, 7= 5.1 Hz, lH), 4.76 - 4.67 (m, lH), 4.]8 —

4.10 (m, 3H), 4.02 (dd, 7= 10.0, 6.0 Hz, IH), 3.86 - 3.79 (m, IH), 3.50 - 3.44 (m, 2H), 3.26 (s, 3H),

3.16-3 .10 (m, 2H), 2.84 - 2.78 (m, 2H), 2.03-1.94 (m, 2H), 1.24 (s, 9H).

Example 1.458

[1689] Synthesis ofN-tert-butyl-2-[(2-{4-[(2S)-3-fluoro-2-hydroxypropoxy]pyridin-2“yl}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 452)

Scheme 134

Step 1

710

[1690] (2S)-2-Oxirany [methanol (28 mg; 0.38 mmol; 1.1 eq.) was dissolved in N,N- di methy Iformamide (1.5 ml), and cooled in an ice bath. Sodium hydride (60%, 30 mg; 0.76 mmol; 2.2 eq.) was added. N-Tert-buty 1-2-{[2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-45 yl](methyl)amino]acetamide (123 mg; 0.34 mmol; 1 eq.) (gcxy02152) dissolved in DMF (2 ml) was added slowly and the reaction was stirred at 25 °C for 18 h. Water (20 ml) was carefully added and the mixture was extracted with ethyl acetate (3 x 25 ml). The combined organic phases were washed with saturated sodium chloride solution and dried over sodium sulfate. After évaporation, 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-tert-butyl-2-[methyl(2-{4-[(2R)-oxiran-2-ylmethoxy]pyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (35 mg, 25%) as an off-white solid. LCMS (ES+): [M+H]⁺ = 412.1.

Step 2

[1691] N-Tert-butyl-2-[methyl(2-{4-[(2R)-oxiran-2-ylmethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pynmidin-4-yl)amino]acetamide (40 mg; 0.1 mmol; 1 eq.) was suspended in toluene (5 ml). Tetrabutylammonium fluoride (0.49 mL; 1 mol/L THF; 0.49 mmol; 5 eq.) was added slowly. The reaction was warmed to 80 °C in a sand bath for 3 h. Solvents were evaporated and the residue was purified by reverse phase chromatography (Waters XSelect CSH Cl8 column, 0-60% acetonitrile/0.1 % aqueous formic acid gradient) to give N-tert-butyl-2-[(2-{4-[(2S)-3-fluoro-2-hydroxypropoxy]pyridin-2 yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (18 mg, 43%) as a white sohd. LCMS (ES+): [M+H]⁺ = 432.I. Ή NMR (400 MHz, DMSO-d6) δ 8.48 (d, J= 5.6 Hz, IH), 7.85 (d, J = 2.5 Hz, IH), 7.68 (s, IH), 7.06 (dd, 7= 5.6, 2.6 Hz, IH), 5.52 (s, IH), 4.62 - 4.53 (m, IH), 4.50 - 4.41 (m, 1H), 4.15 — 4.04 (m, 5H), 3.26 (s, 3H), 3.16-3.11 (m, 3H), 2.84 - 2.77 (m, 2H), 2.03 - 1.94 (m, 2H), 1.24 (s, 9H).

Example 1.459

[1692] Synthesis of (2R)-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(propan-2-yl)propanamide (Compound 453)

[1693] Compound 453 was synthesîzed similar to Compound 389 by replacing N-isopropyl-2(methylamino)acetamide hydrochloride with (2R)-N-isopropyl-2-(methylamino)propenamide. LCMS (ES) [M+l]⁴ m/z: 428. ^lH NMR (400 MHz, DMSO-Æ) δ 8.50 (d,7= 5.6 Hz, IH), 8.27 (d, 7= 8.0 Hz, IH), 7.88 (d, 7= 2.6 Hz, 1 H), 7.07 (dd, 7= 5.7, 2.6 Hz, IH), 5.11 (q, 7= 7.0 Hz, lH),4.70(s, 1 H), 3.89 (s, 2H), 4-3.85 (m, IH), 3.28-3.16 (m, IH), 3.11-3.04 (m, 4H), 2.96-2.77 (m, 2H), 2.10-1.92 (m, 2H), 1.34 (d, 7= 7.0 Hz, 3H), 1.24 (s, 6H), 1.09 (d, 7= 6.6 Hz, 3H), 0.90 (d, 7= 6.5 Hz, 3H).

Example 1.460

[1694] Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyrîdin-2-yl}-6,6-dimethyl-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 454)

[1695] Compound 454 was synthesîzed similar to Compound 348 by replacing methyl 2oxocyclopentane-l-carboxylate with 4,4-dimethyl-2-oxocyclopentane-l-carboxylate. LCMS (ES) [M+l] ⁴ m/z: 455. ¹H NMR (400 MHz, DMSO-A) δ 8.47 (d, 7= 5.7 Hz, IH), 7.83 (d, 7= 2.6 Hz, IH), 7.65 (s, IH), 7.05 (dd, 7= 5.7, 2.7 Hz, IH), 4.20 (t, 7= 5.7 Hz, 2H), 4.10 (s, 2H), 3.24 (s, 3H), 2.95 (s, 2H), 2.70-2.63 (m, 4H), 2.23 (s, 6H), 1.25 (s, 9H), 1.15 (s, 6H).

Example 1.461

[1696] Synthesis of 2-[(2-{4-[2-(dimethy!amino)ethoxy]pyridin-2-yl}-6,6-dimethyl-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide (Compound 455)

H ^Ογ^ΝηΚ

[1697] Compound 455 was synthesized similar to Compound 348 by replacing methyl 2oxocyclopentane-l-carboxylate with 4,4-dimethyl-2-oxocyclopentane-l-carboxylate and by replacing tert-buty lamine with propan-2-amine. LCMS (ES) [M+l]⁴ m/z: 441. 'H NMR (400 MHz, DMSO-7ô) δ 8.47 (d, 7=5.5 Hz, IH), 8.21 (s, 2HCOOH), 7.97 (d, 7= 7.9 Hz, IH), 7.80 (d,7= 2.6 Hz, IH), 7.05 (dd, 7= 5.7, 2.6 Hz, IH), 4.20 (t,7= 5.7 Hz, 2H), 4.12 (s, 2H), 3.92-3.83 (m, IH), 3.24 (s, 3H), 2.95 (s, 2H), 2.72-2.64 (m, 4H), 2.24 (s, 6H), 1.15 (s, 6H), 1.05 (d, 7= 6.6 Hz, 6H).

Example 1.462

[1698] Synthesis of2-[(2-[4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7,7-dimethyl-5H,6H,7Hcyclopenta[d]pynmidin-4-yl)(methyl)amino]-N-(propan-2-yl)acetamide (Compound 456)

H

CK A

[1699] Compound 456 was synthesized similar to Compound 348 by replacing methyl 2oxocyclopentane-i-carboxylate with 3,3-dimethyI-2-oxocyclopentane-1-carboxylate and by replacing tert-butylamine with propan-2-amine. LCMS (ES) [M+l]⁴ m/z: 441. ’H NMR (300 MHz, DMSO-d6, ppm): δ 8.50 (d, J = 5.6 Hz, IH), 8.00 (d, J = 7.8 Hz, IH), 7.81 (d, J = 2.5 Hz, IH), 7.07 (dd, J = 5.7, 2.6

713

Hz, IH), 4.19 (t, J = 5.7 Hz, 2H), 4.14 (s, 2H), 3.87 (dq, J = 13.3, 6.6 Hz, IH), 3.28 (s, 3H),3.10 (l, J = 7.0 Hz, 2H), 2.66 (t, J = 5.7 Hz, 2H), 2.23 (s, 6H), 1.87 (t, J = 7.0 Hz, 2H), l .22 (s, 6H), 1.05 (d, J = 6.6 Hz, 6H).

Example 1.463

[1700] Synthesis ofN-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7,7-dimethyl5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 457)

[1701] Compound 457 was synthesized similar to Compound 348 by replacing methyl 2oxocyclopentane-l-carboxylate with 3,3-dimethyl-2-oxocyclopentane-l-carboxylate. LCMS (ES) [M+l] ⁺ m/z: 441. Ή NMR (300 MHz, DMSO-d6, ppm): 8 8.51 (d, 7= 5.6 Hz, IH), 7.84 (d,7=2.5 Hz, IH), 7.69 (s, IH), 7.08 (dd, 7= 5.7, 2.6 Hz, IH), 4.22 (t, 7= 5.7 Hz, 2H),4.13 (s, 2H), 3.28 (s, 3H), 3.12 (t,7 = 7.0 Hz, 2H), 2.68 (t, 7= 5.7 Hz, 2H), 2.23 (s, 6H), 1.89 (t, 7= 7.0 Hz, 2H), 1.25 (s, 9H), 1.22 (s, 6H).

Exampie 1.464

[1702] Synthesis of N-[(2R)-l-hydroxypropan-2-yl]-2-{[2-(4-methoxypyridin-2-yL)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamidede (Compound 458)

[1703] Compound 458 was synthesized similar to Compound 135 by replacing oxoIan-3-amine with (R)-2-amino-l-propanol. LCMS (ES) [M+lp m/z: 372. Ή NMR (300 MHz, DMSO-d6, ppm): 8 8.48 (d, J = 5.6 Hz, IH), 7.88 (d, J = 8.2 Hz, IH), 7.82 (d, J = 2.6 Hz, IH), 7.04 (dd, J = 5.7, 2.6 Hz, IH), 4.65 (t, J = 5.6 Hz, IH), 4.22 (d, J = 16.4 Hz, IH), 4.15 (d, J = 16.4 Hz, IH), 3.90 (s, 3H), 3.80 (p, J = 6.8 Hz, 1 H), 3.39-3.32 (m, 1 H), 3.27 (s, 3H), 3.21 (q, J = 5.4, 4.6 Hz, 1 H), 3.16 (q, J = 7.4, 5.5 Hz,

714

2H), 2.82 (t, J = 7.9 Hz, 2H), 2.02-1.95 (m, 2H), 1.01 (d, J = 6.7 Hz, 3H).

Example 1.465

[1704] Synthesis of N-[(2S)-l-hydroxypropan-2-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pyrimidin-4-yï](methyl)amino}acetamide (Compound 459)

[1705] Compound 459 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (S)-2-amino-l-propanol. LCMS (ES) [M+l]⁺ m/z: 372. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d,J = 5.6 Hz, IH), 7.88 (d, J = 8.1 Hz, IH), 7.82 (d, J = 2.6 Hz, IH), 7.04 (dd, J = 5.7, 2.6 Hz, IH), 4.65 (t, J = 5.6 Hz, 1 H), 4.22 (d, J = 16.4 Hz, IH), 4.14 (d, J = 16.4 Hz, 1 H), 3.89 (s, 3H), 3.78 (q, J = 6.7 Hz, IH), 3.33 (d, J = 6.0 Hz, IH), 3.26 (s, 3H), 3.25-3.11 (m, 3H), 2.82 (t, J = 7.8 Hz, 2H), 2.04-1.93 (m, 2H), 1.00 (d, J = 6.7 Hz, 3H).

Example 1.466

[1706] Synthesis of N-tert-butyl-2-[methyl(2-{4-[2-(morpholîn-4-yl)ethoxy]pyridin-2-yl}-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)ainino]acetamide (Compound 460)

H

[l 707] Compound 460 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with 4-morpholineethanol. LCMS (ES) [M+l] ⁺ m/z; 469. ’HNMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J = 5.6 Hz, IH), 7.84 (d, J = 2.5 Hz, IH), 7.68 (s, IH), 7.06 (dd, J = 5.7, 2.6 Hz, IH), 4.24 (t, J = 5.6 Hz, 2H), 4.I3 (s, 2H), 3.59 (d, J = 9.3 Hz, 4H), 3.27 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.88-2.67 (m, 4H), 2.48 (d, J = 4.5 Hz, 4H), 2.0I -l .96 (m, 2H), l .25 (s, 9H).

Example 1.467

715

[1708] Synthesis of N-tert-buty 1-2-{methyl[2-(4-{2-[(] S,4S)-2-oxa-5-azabicyclo[2.2.1]heptan-5yl]ethoxy}pyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 461)

[1709] Compound 461 was synthesized similar to Compound 508 by replacing bis(methyl-d3)amine hydrochloride with (lS,4S)-2-oxa-5-azabicyclo[2.2.1]heptane hydrochloride. LCMS (ES) [M+l] ⁺ m/z: 481. ‘H NMR (400 MHz, DMSO-d6, ppm): δ 8.47 (d, J = 5.5 Hz, IH), 8.16 (s, 27/COOH), 7.83 (d, J = 2.6 Hz, IH), 7.66 (s, IH), 7.05 (dd, J = 5.7, 2.6 Hz, IH), 4.34 (s, IH), 4.17 (t, J = 5.7 Hz, 2H), 4.13 (s, 2H), 3.86 (d, J = 7.6 Hz, 1 H), 3.61 - 3.50 (m, 2H), 3.26 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.97 (dq, J = 11.6, 6.6, 6.2 Hz, 2H), 2.92-2.88 (m, IH), 2.81 (t, J = 7.9 Hz, 2H), 2.53 (d, J = 6.8 Hz, IH), 2.00-1.96 (m, 2H), 1.74 (d, J = 9.4 Hz, IH), 1.60 (d, J = 9.6 Hz, IH), 1.25 (s, 9H).

Example 1.468

[1710] Synthesis ofN-tert-butyi-2-{methyl[2-(4-{2-[(lR,4R)-2-oxa-5-azabicycio[2.2.1]heptan-5yl]ethoxy}pyndin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 462)

[1711] Compound 462 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with 2-[(lR,4R)-2-oxa-5-azabicyclo[2.2. l]heptan-5-yl]ethanol. LCMS (ES) [M+l/m/z: 481. ^lH NMR (400 MHz, DMSO-d6, ppm): δ 8.47 (d, .1 = 5.6 Hz, 1 H), 8.16 (s, 2HCOOH), 7.83 (d, J = 2.5 Hz, IH), 7.67 (s, IH), 7.05 (dd, J = 5.7, 2.5 Hz, 1 H), 4.35 (s, 1 H), 4.22 - 4.10 (m, 4H), 3.86 (d, J = 7.6 Hz, IH), 3.59 (s, IH), 3.53 (dd, J = 7.6, 1.8 Hz, IH), 3.26 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 3.07 - 2.86 (m, 3H), 2.81 (t, J = 7.8 Hz, 2H), 2.55-2.50 (m, IH), 2.02-1.96 (m, 2H), 1.75 (dd, J = 9.5, 2.1 Hz, 1 H), 1.60 (d, J = 9.4 Hz, 1 H), l .24 (s, 9H).

716

Example l .469

[ 1712] Synthesis of N-tert-butyl-2-{[2-(4-{2-[(3R)-3-methoxy pyrrolid in-1-y l]ethoxy}py rid in-2-yl)-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide (Compound 463)

[ 1713] Compound 463 was synthesized similar to Compound 508 by replacing bis(methyl-d3)amine hydrochloride with (3R)-3-methoxypyrrolidine hydrochloride. LCMS (ES) [M+l]⁺ m/z: 483. Ή NMR (400 MHz, DMSO-d6, ppm): δ 8.48 (d, 7= 5.6 Hz, IH), 8.l6(s, 2ÆCOOH), 7.84 (d, 7= 2.6 Hz, IH), 7.67 (s, IH), 7.06 (dd,7= 5.7, 2.6 Hz, lH), 4.23 (t,7 = 5.6 Hz, 2H),4.l3 (s, 2H), 3.95-3.85 (m, IH), 3.27 (s, 3H), 3.18(s, 3H), 3.14 (7 7= 7.3 Hz, 2H), 2.90 (t, 7= 5.6 Hz, 2H), 2.89-2.73 (m, 3H), 2.77-2.52 (m, 3H), 2.01-L93 (m, 311), 1.73- 1.53 (m, IH), 1.25 (s, 9H).

Example 1.470

[1714] Synthesis ofN-tert-buty]-2-{[2-(4-{2-[(3S)-3-methoxypyrrolidin-l-yl]ethoxy}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino)acetamide (Compound 464)

[1715] Compound 464 was synthesized similar to Compound 508 by replacing bis(methyl-d3)amine hydrochloride with (3S)-3-methoxypyrrolidme hydrochloride. LCMS (ES) [M+l]⁺ m/z: 483. 'H NMR (400 MHz, DMSO-d6, ppm): δ 8.49 (d, 7= 5.6 Hz, IH), 8.15 (s, 1.5/7COOH), 7.84 (d,7=2.5 Hz, IH), 7.67 (s, IH), 7.07 (dd,7= 5.7, 2.6 Hz, IH), 4.25 (t, 7= 5.6 Hz, 2H), 4.14 (s, 2H), 3.94-3.89 (m, IH), 3.26 (s, 3H), 3.18 (s, 3H), 3.14 (t, 7= 7.3 Hz, 2H), 2.96 (t, 7= 5.6 Hz, 2H), 2.89 (dd,7= 10.5, 6.1 Hz, 1 H), 2.83 -2.77 (m,3H), 2.73 (dd,7= 10.5,3.0 Hz, 1 H), 2.69 - 2.62 (m, 1 H), 2.06 - 1.95 (m, 3H), 1.75

717

- 1.68 (m, IH), 1.24 (s, 9H).

Example 1.471

[1716] Synthesis ofN-tert-butyl-2-[(2-{4-[2-(lH-imidazol-i-yl)ethoxy]pyridin-2-yl}-5H,6I-I,7H- cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 465)

[1717] Compound 465 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with l-(2-hydroxyethy!)imîdazole. LCMS (ES) [M+l | ⁺ m/z: 450. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, 7= 5.6 Hz, 1 H), 7.82 (d, 7= 2.6 Hz, IH), 7.75-7.63 (m, 2H), 7.27 (t, 7= 1.3 Hz, IH), 7.04 (dd, 7 = 5.6, 2.6 Hz, IH), 6.91 (d,7= Ll Hz, IH), 4.42 (s, 4H), 4.14 (s, 2H), 3.26 (s, 3H), 3.14 (t, 7=7.3 Hz, 2H), 2.81 (t, 7= 7.8 Hz, 2H),2.01-L96 (m, 2H), 1.23 (s, 10H).

Example 1.472

[1718] Synthesis of N-tert-butyl-2-[methyl(2-{4-[2-(l H-l,2,3,4-tetrazol-l-yl)ethoxy]pyridin-2-yl}5H,6H,7H-cyclopenta[d]pyrimidm-4-yI)amino]acetamide (Compound 466)

[1719] Compound 466 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with 2-(lH-l,2,3,4-tetrazol-l-yl)ethan-l-ol. LCMS (ES) [M+l]⁺ m/z: 452.2. 'H NMR (400 MHz, DMSO-d6, ppm): δ 9.52 (s, 1H),8.54 (d,7=5.7Hz, IH), 7.84 (d,7=2.6 Hz, IH), 7.71 (s, 1 H), 7.15 (dd, 7= 5.8, 2.6 Hz, IH), 4.96 - 4.91 (m, 2H), 4.68 - 4.63 (m, 2H), 4.17 (s, 2H), 3.29 (s, 3H), 3.17-3.12 (m, 2H), 2.88-2.81 (m,2H), 2.04- 1.96 (m, 2H), LI9 (s, 9H).

Example 1.473

[1720] Synthesis of N-tert-butyl-2-{[2-(4-ethoxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-

718 yl](methy[)amino}acetamide (Compound 467)

[1721] Compound 467 was synthesized similar to Compound 34 by replacing 4-methoxy-2(trimethylstanny[)pyridine with 4-ethoxy-2-(tributylstannyl)pyridine. LCMS (ES+): [M+H]A 384.2. Ή NMR (400 MHz, DMSO-d6) δ 8.48 (d, J= 5.7 Hz, IH), 7.86 (d, J= 2.5 Hz, IH), 7.72 (s, IH), 7.06 (dd, 7= 5.7, 2.6 Hz, 1 H), 4.19 (q, 7= 7.0 Hz, 2H), 4.13 (s, 2H), 3.28 (s, 3H), 3.19-3.11 (m, 2H), 2.86 - 2.79 (m, 2H), 2.04- L94(m,2H), 1.37 (t, J= 7.0 Hz, 3H), 1.24 (s, 9H).

Example 1.474

[1722] Synthesis of N-tert-butyl-2-[methyl(2-{4-[2-(pyridazin-3-yloxy)ethoxy]pyridin-2-yI}5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamîde (Compound 468)

[1723] Compound 468 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with 2-(pyridazin-3-yloxy)ethan-l-ol. LCMS (ES) [M+1]⁺ m/z: 478.2. ’H NMR (400 MHz, DMSO-d6, ppm): δ 8.92 (dd, J= 4.5, 1.3 Hz, IH), 8.50 (d, J= 5.6 Hz, IH), 7.91 (d, 7=2.6 Hz, IH), 7.68 (s, IH), 7.65 (dd,7=8.9, 4.5 Hz, IH), 7.26 (dd, 7= 8.9, 1.3 Hz, IH), 7.12 (dd, 7= 5.7, 2.6 Hz, IH), 4.83 - 4.78 (m, 2H), 4.57 - 4.53 (m, 2H), 4.10 (s, 2H), 3.27 (s, 3H), 3.17 - 3.12 (m, 2H), 2.84-2.78 (m, 2H), 2.03 - 1.94 (m, 2H), 1.18 (s, 9H).

Example 1.475

[1724] Synthesis of2-({2-[4-(2~ethyL2-hydroxybutoxy)pyridin-2-yi]-5H,6H,7Hcyclopenta[d]pyrimidîn-4-yl}(methyl)amino)-N-[(lR,2S)-2-hydroxycycIopentyl]acetamidede

7I9

(Compound 469)

Scheme 135

Step I

[I725] Into a 20-mL vial, was placed NaH (60% in minerai oil) (68 mg, 1.71 mmol, 1.50 equiv), DMSO (4.0 mL), After cooled to 0°C, 2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butan-l-oI (300 mg,

1.71 mmol, 1.50 equiv) was added and stirred at room température and stirred for 0.5 h. This was followed by 2-(4-chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin~4-ol (282 mg, 1.14 mmol, t .00 equiv) was added. The resulting solution was stirred for 12 h at 40 °C, the reaction mixture was cooled to room température and quenched with H₂O (LO mL), the resulting solution was purified by Prep-HPLC with the following conditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5 pm, 10 nm,

Mobile phase A, water (0.05% NH₃ H₂O) and CH₃CN (25% Phase B up to 60% in 12 min), Détecter,

720

220 nm. 305 mg of 2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyndm-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-ol was obtained as a yellow oil. LCMS (ES) [M+l]⁺ m/z: 414.

Step 2

OH

[1726] Into a 50-mL three necked round-bottom flask were placed 2-(4-(2-ethyl-2-((tetrahydro-2Hpyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-ol (305 mg, 0.74 mmol, l .00 equiv), DCM (10.00 mL) and TEA (0.51 mL, 3.69 mmol, 5.00 equiv). This was followed by the addition of trifluoromethanesulfonic anhydride (0.14 ml, 0.96 mmol, 1.30 equiv) at 0 °C. The resulting solution was stirred for 2 h at room température. The reaction was quenched with H₂O (10 mL) and extracted with DCM (20 mL*3). Organic layers were combined, dried over anhydrous sodium sulfate and fîltered. The filtrate was concentrated under reduced pressure, the residue was used to the next step without further purification. This resulted in 763 mg crude of 2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate purple oil. LCMS: (ES) [M+l]⁺ m/z: 546.

Step 3

[1727] Into a 100-mL round-bottom flask were placed 2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pynmidin-4-yl trifluoromethanesulfonate (763 mg, 1.40 mmol, 1.00 equiv) and DCM (10.0 mL). This was followed by the addition of TEA (0.59 mL, 4.20 mmol, 3.00 equiv) and N-((lR,2S)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-2(methylamino)acetamîde hydrochloride (874 mg, 1.96 mmol, l .40 equiv). The resulting solution was stirred for 12 h at 40 °C. The reaction was quenched with H₂O (20 mL), extracted with DCM (20 mL*2). Organic layers were combined, dried over anhydrous sodium sulfate and fîltered. The filtrate was concentrated under reduced pressure, the residue was used to the next step without further

721 purification. This resulted in l.l g crude ofN-((lR,2S)-2-((tert-butyldiphenylsilyl)oxy)cyclopentyl)-2((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide a brown oil. LCMS: (ES) [M+l]⁴ m/z: 806. Step 4

[I728] Into a 100-mL round-bottom flask were placed N-((IR,2S)-2-((tertbutyldiphenylsilyl)oxy)cyclopentyl)-2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyI)amino)acetamide (l JO g, l.37 mmol, 1.00 equiv), THF (10.00 mL) and TBAF (0.37 mL, 1.37 mmol, 1.00 equiv). The reaction solution was stirred for 12 h at room température. The resulting solution was concentrated under reduced pressure, the residue was purified by Prep-HPLC with the following conditions: Welch-XB C18 50*250, 10 um, Mobile phase A, water (0.05% NH3H2O) and CH3CN (30% Phase B up to 80% in 15 min), Detector, 220 nm. 268 mg of2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2-yl)oxy)butoxy)pyridin-2-yl)-6,7dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)-N-((!R,2S)-2-hydroxycyclopentyl)acetamide was obtained as an orange solid. LCMS (ES) [M+l]⁴ m/z: 568.

Step 5

[1729] Into a 8-mL vial were placed 2-((2-(4-(2-ethyl-2-((tetrahydro-2H-pyran-2- yl)oxy)butoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pynmidin-4-yl)(methyl)amino)-N-((lR,2S)2-hydroxycyclopentyl)acetamide (268 mg, 0.47 mmol, 1.00 equiv), MeOH (3.0 mL) and TsOH (81 mg, 0.47 mmol, 1.00 equiv). The mixture was stirred for 1 h at room température. The réaction mixture was purified by Prep-HPLC with the following conditions: Welch-XB Cl 8 50*250, 10 um, Mobile phase,

722 water (0.5% ΝΗ3Ή2Ο) and CHsCN/MeOH l ;l (25% Phase B up to 75% in 15 min), Detector, 220 nm. 130 mg of 2-((2-(4-(2-ethyl-2-hydroxybutoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)-N-((lR,2S)-2-hydroxycyclopenty!)acetamide was obtained as a white solid. LCMS (ES, m/z): [M+H]⁺: 484. Ή-NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J = 5.6 Hz, IH), 7.80 (d, J =

2.5 Hz, IH), 7.68 (d, J = 7.8 Hz, IH), 7.07 (dd, J = 5.6, 2.6 Hz, IH), 4.69 (d, J = 3.8 Hz, IH), 4.44 (s,

IH), 4.31 (d, J = 16.6 Hz, IH), 4.20 (d, J = 16.6 Hz, IH), 3.96-3.81 (m, 4H), 3.26 (s, 3H), 3.19-3.12 (m, 2H), 2.85 (t, J = 7.8 Hz, 2H), 2.04-1.94 (m, 2H), 1.80-1.63 (m, 3H), 1.59-1.35 (m, 7H), 0.88 (t, J = 7.4 Hz, 6H).

Example 1.476

[1730] Synthesis of N-tert-buty l-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5 H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(2,2,2-trifluoroethyl)amino]acetamide (Compound 470)

723

[1731 ] To a stirred mixture of 2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-ol (10 g, 40.375 mmol, l.OO equiv) and TEA (8.17 g, 80.750 mmol, 2 equiv) in DCM (200 mL) was added (trifluoromethane)sulfonyl trifluoromethanesulfonate (22.78 g, 80.750 mmol, 2 equiv) dropwise at 0 °C. The resulting mixture was stirred for 4h at room température under nitrogen atmosphère. The resulting mixture was extracted with CH2CI2 (3 x 300mL). The combined organic layers were dried over anhydrous Na₂SCU· After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA ( l :2) to afford 2-(4chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate (10 g, 65.22%) as off-white solid. LCMS (ES) [M+l] ⁺ m/z: 380.

Step 2

[1732] To a stirred mixture of 2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl trifluoromethanesulfonate (3 g, 7.900 mmol, 1.00 equiv) and 2,2,2-trifluoroethylamine (7.83 g, 79.000 mmol, 10 equiv) in DMF was added K2CO3 (3.28 g, 23.700 mmol, 3 equiv) in portions at room température. The resulting mixture was extracted with CH2CI2 (3 x 50mL). The combined organic layers were dried over anhydrous Na₂SO4· After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by reverse flash chromatography with the following conditions: column, silica gel; mobile phase, MeCN in water(0.1 %NH₃), 10% to 60% gradient in 20 min to afford 2-(4chloropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-amine (500 mg,

19.25%) as a white solid. LCMS (ES) [M+l]⁺ m/z: 329.

Step 3

[1733] To a stirred solution of 2-(4-chloropyridin-2-yl)-N-(2,2,2-trifluoroethyl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-amine (400 mg, 1.217 mmol, 1.00 equiv) in DMF was added NaH (58.40 mg,

724

2.434 mmol, 2 equiv) in portions at 0 °C under nitrogen atmosphère. The resulting mixture was stirred for 30min at 0 °C under nitrogen atmosphère. To the above mixture was added 2-bromo-N-tertbutylacetamide (354.23 mg, 1.826 mmol, l .5 equiv) in portions at °C. The resulting mixture was stirred for additional 4 h at room température. The resulting mixture was extracted with CH₂Cl₂ (3 x 30mL). The combined organic layers were dried over anhydrous Na₂SO₄ and fïltered. The filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH₂Cb/MeOH (10:1) to afford N-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](2,2,2-trifluoroethyl)amino}acetamide (300 mg, 55.79%) as an off-white solid. LCMS (ES) [M+l]⁺ m/z: 442.

Step 4

[l 734] To a stirred solution of N-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](2,2,2-trifîuoroethyl)amîno}acetamide (130 mg, 0.294 mmol, l.OO equiv) and dimethylaminoethanol (10 mL) was added CuCb (3.96 mg, 0.029 mmol, O.l equiv) and K2CO3 (81.32 mg, 0.588 mmol, 2 equiv) in portions at 100 °C. The resulting mixture was extracted with CH₂Cb (3 x 30mL). The combined organic layers were dried over anhydrous Na₂SO₄ and fïltered. The filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the foîlowing conditions (Sunfire Prep Cl 8 XBridge Column, 19*150 mm; mobile phase A, Water(0.0.05%NH3) and mobile phase B, AcCN (25% Phase B up to 72% in 7 min)) to afford N-tertbuty l-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrîmidin-4-yI)(2,2,2trifluoroethyl)amino]acetamide (49.3 mg, 33.88%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 495. ^]H NMR (400 MHz, DMSO-rfô) δ 8.49 (d, 7=5.5 Hz, 1 H), 7.83 (s, IH), 7.68 (s, 1 H), 7.07 (s, IH),4.59(q, 7= 9.2 Hz, 2H), 4.27 - 4.17 (m, 4H), 3.07 (t, 7= 7.3 Hz, 2H), 2.86 (t, 7= 8.0 Hz, 2H), 2.67 (t, 7= 5.7 Hz, 2H), 2.23 (s, 6H), 2.05 - 1.97 (m, 2H), 1.24 (s, 9H).

Example 1.477

[1735] Synthesis of l-[(3R)-3-hydroxypyrrolidin-l-yl]-2-[[2-(4-methoxypyridin-2-yl)-5H,6H,7H-

cyclopenta[d]pyrimidin-4-yl](methyl)amino}ethan-l-one (Compound 471)

[l736] Compound 471 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (3R)-pyrrolidin-3-ol. LCMS (ES) [M+l] ⁺ m/z: 384. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J 5 =5.6 Hz, IH), 7.74 (dd, 7=4.2, 2.6 Hz, lH), 7.02 (dd, J= 5.6, 2.6 Hz, lH), 5.07 (d, 7= 3.4 Hz, IH),

4.94 (d, 7= 3.4 Hz, IH), 4.60-4.19 (m, 3H), 3.88 (s, 3H), 3.77-3.54 (m, 2H), 3.50-3.36 (m, IH), 3.313.23 (m, 4H), 3.14 (t, 7= 7.4 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.05-1.78 (m, 4H).

Example 1.478

[1737] Synthesis of l-[(3S)-3-hydroxypyrrolidin-l-yl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7H- cyclopenta[d]pynmidin-4-yl](methyl)amino}ethan-l-one (Compound 472)

[1738] Compound 472 was synthesized similar to Compound 135 by replacing oxoian-3-amine with (3S)-pyrrolidin-3-oL LCMS (ES) [M+l]⁺ m/z: 384. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, 7 = 5.6 Hz, IH), 7.74 (dd,7 = 4.2, 2.6 Hz, IH), 7.02 (dd,7= 5.6, 2.6 Hz, IH), 5.07 (d,7= 3.5 Hz, 0.5H),’

4.94 (d, 7= 3.5 Hz, 0.5H) 4.60-4.21 (m, 3H), 3.88 (s, 3H), 3.75-3.51 (m, 2H), 3.49-3.35 (m, IH), 3.32-

3.21 (m, 4H), 3.14(1,7=7.3 Hz, 2H), 2.81 (1,7=7.9 Hz, 2H), 2.12-1.67 (m, 4H).

Example 1.479

[1739] Synthesis of N-tert-butyl-2-{[2-(4-{2-[(3R)-3-fluoropyrrolidin-l-yl]ethoxy}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetainide (Compound 473)

726

[l 740] Compound 473 was synthesized similar to Compound 508 by replacing bis(methyl-d3)amine hydrochloride with (3R)-3-fluoropyrrolidine hydrochloride. LCMS (ES) [M+l]⁺ m/z: 471. 'H NMR (400 MHz, DMSO-Λ) δ 8.48 (d, 5.5 Hz, IH), 7.84 (d, J= 2.5 Hz, IH), 7.67 (s, IH), 7.06 (dd, J=

5.7, 2.6 Hz, IH), 5.20 (dt, J= 55.6, 5.8 Hz, 1 H), 4.23 (t, J= 5.6 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3 H), 3.15 (t, J= 13 Hz, 2H), 2.99-2.77 (m, 6H), 2.79-2.63 (m, IH), 2.43 (q, J= 8.0 Hz, IH), 2.23-2.05 (m, IH), 2.04-1.78 (m, 3H), L25 (s, 9H).

Example 1.480

[1741] Synthesis of N-tert-buty l-2-{[2-(4-{2-[(3S)-3-fluoropyrrolidin-l-yl]ethoxy}pyridin-2-y 1)-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino]acetamide (Compound 474)

[1742] Compound 474 was synthesized similar to Compound 508 by replacing bis(methyl-d3)amine hydrochloride with (3S)-3-fluoropyrrolidine hydrochloride. LCMS (ES) [M+l]⁺ m/z: 471. ’H NMR (400 MHz, DMSO-7₆)Ô8.48 (d, 7= 5.4 Hz, IH), 8.16 (s, 1.3 /7COOH)7.84 (d, 7= 2.7 Hz, IH), 7.67 (s,

I H), 7.06 (dd, 7= 5.9, 2.7 Hz, 1 H), 5.20 (dt, 7 = 55.8, 5.8 Hz, IH), 4.23 (t, 7= 5.7 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.4 Hz, 2H), 3.00-2.77 (m, 6H), 2.79-2.63 (m, IH), 2.43 (q,7 = 7.9 Hz, IH), 2.23-2.04 (m, 1 H), 2.04-L79 (m, 3H), 1.25 (s, 9H).

Example 1.481

[1743] Synthesis of N-tert-butyl-2-[(2-{4-[3-(dimethylamino)propyl]pyridin-2-yl}-5H,6H,7H- cyclopenta[d]pynmidin-4-yl)(methyl)amino]acetamide (Compound 475)

727

Scheme 137

Step l

[] 744] Into a 40 mL vial were added N-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7H“ cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (415 mg, LU mmol, 1.00 equiv), dimethy!(prop-2-yn-I-yl)amine (185 mg, 2.23 mmol, 2.00 equiv), DMF (10 mL), Cul (21 mg, 0.11 mmol, 0.10 equiv), Et₃N (337 mg, 3.33 mmol, 3.00 equiv) and Pd(PPh₃)Ch (79 mg, 0.1 ] mmol, 0.10 equiv) at room température. The resulting mixture was stirred for 3 h at 100 °C under nitrogen atmosphère. The reaction was cooled to room température, the residue was purified by reverse flash chromatography with the following conditions: Cl8-120 g column, mobile phase. Phase B, MeCN, Phase A, water, 10% to 50% gradient in 10 min, detector, UV 254 nm. This resulted in N-(tert-butyl)-2((2-(4-(3-(dimethylamino)prop-l-yn-l-yl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4- yl)(methyl)amino)acetamide (140 mg, 30%) as a white solid. LCMS (ES, m/z): [M+H]⁺: 421.

Step 2

728

[1745] To a solution of N-tert-butyl-2-[(2-{4-[3-(dimethylamino)prop-l-yn-l -yl]pyridin-2-yl[5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (140 mg, 0.33 mmol, 1.00 equiv) in 20 mL MeOH was added Pd/C (10%, 50 mg), Pd(OH)2/C (50 mg) under hydrogen atmosphère in a 50 mL pressure tank reactor. The mixture was hydrogenated at room température for 1 h under hydrogen atmosphère, fîltered through a celite pad and the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Sunfire Prep C18 OBD Column, 50*250 mm, 5 pm lOnm, mobile phase, water (0.1% FA) and CH3CN (hold 5% Phase B in 3 min, up to 23% in 12 min), Detector, UV 254 nm. This resulted inN-(tert-butyl)-2-((2-(4-(3(dimethylamino)propyl)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidm-4y!)(methyl)amino)acetamide (74.8 mg, 43%) as a brown solid. LCMS (ES, m/z): [M+H]⁺: 425. 'H-NMR (300 MHz, DMSO-7_e)Ô 8.55 (d, J = 4.9 Hz, IH), 8.23 (s, 2HCOOH), 8.15 (d, J = 1.5 Hz, IH), 7.69 (s, IH), 7.31 (dd, J = 4.9, 1.7 Hz, IH), 4.16 (s, 2H), 3.27 (s, 3H), 3.15 (t, J = 7.2 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.76 - 2.65 (m, 2H), 2.48 - 2.37 (m, 2H), 2.28 (s, 6H), 2.07 -1.91 (m, 2H), 1.82 (p, J = 7.6 Hz, 2H), 1.24 (s, 9H).

Example 1.482

[1746] Synthesis ofN-[2-(dimethylamino)ethyl]-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino[acetamide (Compound 476)

[1747] Compound 476 was synthesized similar to Compound 135 by replacing oxolan-3-amine with (2-aminoethyl)dimethy lamine. LCMS (ES) [M+l]⁺m/z: 385. Ή NMR (300 MHz, DMSO-d6, ppm): δ

729

8.48 (d, 7=5.6 Hz, IH), 8.06 (t, 7= 5.8 Hz, IH), 7.81 (d, 7= 2.6 Hz, IH), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 4.] 8 (s, 2H), 3.90 (s, 3H), 3.27 (s, 3H), 3.17 (dq, 7= 8.2, 5.6, 4.1 Hz, 4H), 2.82 (t, 7= 7.8 Hz, 2H), 2.23 (t,7= 6.8 Hz, 2H), 2.07 (s, 6H), 2.02-1.94 (m, 2H).

S Example 1.483

[1748] Synthesis of 2-{[2-(4-methoxypyridin-2-yI)-5H,6H,7H-cyclopenta[d]pyrimidin-4yl](methyl)amino}-L(morpholm-4-yl)ethan-l-one (Compound 477)

[1749] Compound 477 was synthesized similar to Compound 135 by replacing oxolan-3-amine with 10 morpholine. LCMS (ES) [M+l]⁺ m/z: 384. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.49 (d, J = 5.6 Hz, IH), 7.78 (d, J = 2.6 Hz, IH), 7.06 (dd, J = 5.7,2.6 Hz, 1 H), 4.55 (s, 2H), 3.90 (s, 3H), 3.67 - 3.65 (m, 2H), 3.58 - 3.53 (m, 4H), 3.45 - 3.43 (m, 2H), 3.28 (s, 3H), 3.15 (t, J = 7.4 Hz, 2H), 2.83 (t, J = 7.8 Hz, 2H), 2.00 (p, J = 7.8 Hz, 2H).

Example 1.484

[1750] Synthesis of 2-[(2-{4-[2-(dimethylamino)ethoxy]pyndin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimÎdÎn-4-yl)(methyl)amino]-N-(2,2,2-trifluoroethy[)acetamide (Compound 478)

H

[1751] Compound 478 was synthesized similar to Compound 348 by replacing tert-butylamine with tri fluoroethay lamine. LCMS (ES+): [M+H]⁺ = 453.1. Ή NMR (400 MHz, dmso) δ 8.93 (t, 7= 6.4 Hz,

730

IH), 8.46 (d, J= 5.6 Hz, IH), 7.77 (d, J= 2.5 Hz, IH), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 4.28 (s, 2H), 4.22 (t, 7= 5.6 Hz, 2H), 3.92 (qd, 7= 9.8, 6.3 Hz, 2H), 3.29 (s, 3H), 3.19 - 3.12 (m, 2H), 2.86 - 2.79 (m, 2H), 2.75 (t, 7= 5.6 Hz, 2H), 2.29 (s, 6H), 2.04-1.94 (m, 2H).

Example 1.485

[1752] Synthesis of2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)-N-(2,2,2-triiluoroethyl)acetamide (Compound 479)

H

[1753] Compound 479 was synthesized similar to Compound 389 by replacing tertbutylamine with trifluoroethylamine. LCMS (ES+): [M+H]⁺ = 454.1. Ή NMR (400 MHz, dmso) 5 8.97 (t, 7= 6.4 Hz, IH), 8.45 (d,7= 5.7 Hz, IH), 7.77 (d, 7= 2.5 Hz, IH), 7.04 (dd, 7= 5.6, 2.6 Hz, IH), 4.77-4.62 (m, IH), 4.28 (s, 2H), 3.92 (qd,7= 9.7, 6.3 Hz, 2H), 3.86 (s, 2H), 3.29 (s, 3H), 3.17 -3.10 (m, 2H), 2.86 2.77 (m, 2H), 2.03 - 1.94 (m, 2H), 1.22 (s, 6H).

Example 1.486

[1754] Synthesis of N-tert-butyl-2-[methyl(2-{4-[3-(methylamino)propyl]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 480)

731

Scheme 138

Step l

CBr₄, PPh₃

DCM, 0°C, 1.5 h

[1755] Into a 100 mL round-bottom flask were placed tert-butyl (3hydroxypropyl)(methyl)carbamate (2.00 g, 10.60 mmol, 1.00 equiv), DCM (20.00 mL) and PPh₃ (3.67 g, 13.80 mmol, 1.30 equiv). This was followed by addition of CBr₄ (5.20 g, 13.80 mmol, 1.30 equiv) at 0 °C. The resulting solution was stirred for 1.5 h at 0 °C. The reaction mixture was quenched with H₂O (50.00 mL), extracted with DCM (100 mL*2). The combined organic phase was washed with Na₂CO3 (aq), brine and dried over anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column with petroleum ether/ethyl acetate (93%/7%). This resulted in 2.6 g of tert-butyl (3-bromopropyl)(methyl)carbamate as light yellow oil.

Step 2

[l 756] Into a 40-mL vial purged and maintained with an inert atmosphère of hydrogen were placed DMAC (10 mL), picohnimidamide hydrochloride (14 mg, 0.09 mmol, 0.05 equiv), Nih (28 mg, 0.09 mmol, 0.05 equiv), sodium iodide (71 mg, 0.47 mmol, 0.25 equiv), tert-butyl (35 bromopropyl) (methy l)carbamate (577 mg, 2.30 mmol, 1.20 equiv), N-(tert-buty 1)-2-((2-(4chloropyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-y[)(methyl)amino)acetamide (700 mg, 1.88 mmol, 1.00 equiv), zinc métal powder (246 mg, 3.76 mmol, 2.00 equiv), and trifluoroacetic acid (22 mg, 0.19 mmol, 0.10 equiv). The reaction mixture was heated to 60 °C and stirred for 12 h. The reaction mixture was purified by Prep-HPLC with the following conditions: Welch-XB Cl8 50*250, 10 uni, Mobile phase A, water (0.1% TFA) and CH₃CN (13% Phase B up to 47% in 12 min), Detector, 220 nm. This resulted in 252 mg of tert-butyl (3-(2-(4-((2-(tert-butylamino)-2-oxoethyl)(methyl)amino)-6,7dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl)propyl)(methyl)carbamate as a light yellow oil. LCMS: (ES) [M+l]⁺ m/z: 511.

Step 3

[1757] Into a 20-mL vial were placed tert-butyl (3-(2-(4-((2-(tert-butylamino)-2oxoethyl)(methyl)amino)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-2-yl)pyridin-4 yl)propyl)(methyl)carbamate (252 mg, 0.79 mmol, 1.00 equiv), HCl(g)/MeOH (4 M) (0.78 mL), DCM (3 mL). The mixture was stirred for 12 h at room température. The reaction mixture was purified by

733

Prep-HPLC with the following conditions: Sunfire Prep Cl8 OBD Column, 50*250 mm, 5 pm, 10 nm, Mobile phase, water (0.1% FA) and CPhCN (5% Phase B up to 25% in 12 min), Detector, 220 nm. 169 mg of N-(tert-butyl)-2-(methyl(2-(4-(3-(methylamino)propyl)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)amino)acetamide was obtained as off white solid. LCMS (ES, m/z):

S [M+H]⁺: 4ll. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.58 (d, J = 4.9 Hz, IH), 8.30 (s, L4 77COOH), 8.17 (s, IH), 7.76 (s, lH), 7.33 (dd, J = 4.9, 1.7 Hz, 1H),4.I7 (s, 2H),3.26 (s, 3H), 3.17 (t, J = 7.3 Hz, 2H), 2.84-2.73 (m, 6H), 2.49 (s, 3H), 2.04-1.88 (m, 4H), L24 (s, 9H).

Example L487

[1758] Synthesis of N-tert-buty l-2-({ 2-(4-(3-hydroxy-3-methy lbutyl)pyrid in-2-y l]-5H,6H,7H- cy c lopenta[d ]pyrimidin-4-yl} (methy l)amino)acetamide (Compound 481)

[1759] Compound 481 was synthesized similar to Compound 475 by replacing dimethyl(prop-2-ynl-yl)amine with 2-methyl-3-butyn-2-ol. LCMS (ES) [M+l] ⁺ m/z: 426. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.53 (d, J =4.9 Hz, IH), 8.16(s, 0.7HCOOH), 8.14 (d, 7=1.7 Hz, IH), 7.69 (s, IH), 7.28 (dd, 7 = 5.0, 1.7 Hz, IH), 4.16 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.76-2.67 (m,2H), 2.07-1.91 (m, 2H), 1.75-1.64 (m, 2H), 1.24 (s, 9H), LI7(s,6H).

Example 1.488

[1760] Synthesis of N-tert-buty 1-2-{[2-(4-hydroxypyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-

4-yl](methyl)amino}acetamide (Compound 482)

734

Scheme 139

[1761 ] loto a 20 mL vial were added N-tert-butyl-2-{[2-(4-methoxypyridin-2-yl)-5H,6H,7Hcyc[openta[d]pyrimidin-4-yl](methyl)amino}acetamide (200 mg, 0.54 mmol, 1.00 equiv) and THF (5 mL). To the above mixture was added L-selectride (1.62 mL, 1.62 mmol, 3.00 equiv) dropwise under nitrogen atmosphère. The resulting mixture was stirred for additional 3 h at 60 °C. The mixture was cooled down to room température. The reaction was quenched with water (5 mL), concentrated under vacuum to remove the solvent, the residue was purified by Prep-HPLC with the following conditions; Sunfire Prep Ci 8 OBD Column, 50*250 mm, 5 pm, 10 nm, mobile phase, water (0.05% NH3H2O) and CH3CN (10% up to 70% in 15 min) to afford N-tert-buty 1-2-{[2-(4-hydroxypyrîdin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (49.5 mg, 26%) as an off-white solid. LCMS (ES, m/z): [M+H]⁺: 356. 'H-NMR (300 MHz, DMSO^/^m):δ 7.71 (s, IH), 7.64 (d, 7 = 7.4 Hz, IH), 7.10 (s, IH), 6.14 (d,7= 7.4 Hz, 1 H), 4.13 (s, 2H), 3.30 (s, 3H), 3.16 (1,7= 7.3 Hz, 2H), 2.84 (t,7= 7.8 Hz, 2H), 2.02-1.97 (m, 2H), 1.24 (s, 9H).

Example 1.489

[1762] Synthesis of 2-({2-[4-(2-aminoethoxy)pyridin-2-yl]-5H,6H,7H-cyclopenta[d]pyrimidin-4yl}(methy[)amino)-N-tert-butylacetamide (Compound 483)

[1763] Compound 483 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with ethanolamine. LCMS (ES) [M+1]⁺ m/z: 399. ’H NMR (300 MHz, DMSO21052

735 d6, ppm): δ 8.75 (d, 7= 6.0 Hz, IH), 8.20 (br, 3H), 8.04 (d, 7= 2.6 Hz, IH), 7.88 (s, IH), 7.47 (dd, 7= 6.1,2.6 Hz, 1 H), 4.49 (t, 7= 5.1 Hz, 2H), 4.38 (s, 2H), 3.42 (s,3H), 3.33 (q,7=5.5 Hz, 2H), 3.20 (s, 2H), 3.02 (t, 7= 7.9 Hz, 2H), 2.18-2.00 (m, 2H), 1.26 (s, 9H).

Example 1.490

[1764] Synthesis of N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl[-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 484)

[1765] Compound 484 was synthesized similar to Compound 348 by replacing N-(tert-buty l)-2(methylamino)acetamide hydrochloride with 2-amino-N-tert-butylacetamide hydrochloride. LCMS (ES) [M+l]⁺ m/z; 413. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.46 (d, 7= 5.6 Hz, IH), 7.86 (d, 7= 2.6 Hz, IH), 7.69 (s, IH), 7.14 (t, 7= 5.8 Hz, 1 H), 7.04 (dd, 7= 5.7, 2.6 Hz, IH), 4.19 (t, 7= 5.6 Hz, 2H), 3.93 (d, 7= 5.7 Hz, 2H), 2.83 (t, 7= 7.7 Hz, 2H), 2.78-2.70 (m, 2H), 2.66 (t, 7= 5.6 Hz, 2H), 2.23 (s, 6H), 2.14-1.98 (m, 2H), 1.25 (s, 9H).

Exampie 1.491

[1766] Synthesis of N-tert-butyI-2-[(2-{4-[2-(methylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]acetamide (Compound 485)

[1767] Compound 485 was synthesized similar to Compound 348 by replacing N-(tert-butyl)-2(methylamino)acetamide hydrochloride with 2-amino-N-tert-butylacetamide hydrochloride and by replacing dimethylaminoethanol with methylethanolamine . LCMS (ES) [M+l]⁺ m/z: 399. 'H NMR

736

(300 MHz, DMSO-d6, ppm): δ 9.23 (br, 2H), 8.69 (d, J= 5.9 Hz, IH), 8.41 (br, IH), 8.08 (d, 7=2.6 Hz, IH), 7.95 (s, IH), 7.38 (dd,7=6.2, 2.5 Hz, IH), 4.56 (t, 7=5.0 Hz, 2H), 4.16 (d,7=5.8 Hz, 2H), 2.99 (t, 7= 7.5 Hz, 2H), 2.81 (t, 7= 7.4 Hz, 2H), 2.65 (s, 3H), 2. 19-2.09 (m, 2H), l .25 (s, 9H).

Example l .492

S [1768] Synthesis of2-{[2-(4-{[(2R)-l-(dimethylamino)propan-2-yl]oxy)pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 486)

[ 1769] Compound 486 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (2R)-l-(dimethylamino)propan-2-ol and by replacing tert-butylamine with 1-(trifluoromethyl)cyclopropan-l-amine . LCMS (ES) [M+l]⁺ m/z: 493. 'H NMR (300 MHz, DMSOd6, ppm): δ 9.02 (s, IH), 8.45 (dd, J = 5.7, 1.7 Hz, IH), 8.17 (s, 1.7HCOOH), 7.73 (t, J = 2.2 Hz, IH), 7.13-7.03 (m, IH), 4.86-4.80 (m, J = 7.9 Hz, IH), 4.16 (s, 2H), 3.28 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, .1 = 7.8 Hz, 2H), 2.70-2.59 (m, IH), 2.52-2.49(m, IH), 2.27 (s, 6H), 2.04-1.94 (m, 2H), 1.29 (dd,

1 = 6.1, 1.6Hz,3H), 1.22-1.15 (m, 2H), 1.03-0.95 (m, 2H).

Example 1.493

[1770] Synthesis of2-{methyl[2-(4-{[(3R)-l-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)-5H,6H,7Hcyclopenta[d]pynmidin-4-yl]amino}-N-[l-(trifluoromethyl)cyclopropyl]acetamide (Compound 487)

[1771] Compound 487 was synthesized similar to Compound 348 by replacing dimethylaminoethanol

737 with (3R)-l-methylpyrrolidin-3-ol and by replacing tert-butylamine with l(trifluoromethyl)cyclopropan-l-amine. LCMS (ES) [M+l]⁺ m/z: 491. Ή NMR (300 MHz, DMSO-d6, ppm): δ 9.02 (s, IH), 8.45 (d, J = 5.6 Hz, IH), 8.17 (s, 1HCOOH), 7.68 (d, J = 2.5 Hz, IH), 6.99 (dd, J = 5.6, 2.5 Hz, IH), 5.09-5.00 (m, IH), 4.18 (s, 2H), 3.28 (s, 3H), 3.15 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 8.0 Hz, 3H), 2.76-2.63 (m, 2H), 2.42-2.3l(m, 2H), 2.29 (s, 3H), 2.06- 1.93 (m, 2H), 1.86-1.75 (m, IH), 1.24-1.13 (m, 2H), 1.03-0.94 (m, 2H).

Example 1.494

[1772] Synthesis of N-tert-buty 1-2-{[2-(4-{[(3R,5R)-l,5-dimethylpyrroiidin-3-yl]oxy}pyridtn-2-yl)-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 488)

[1773] Compound 488 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3R,5R)-l,5-dimethylpyrrolidin-3-ol. LCMS (ES) [M+l] ⁺ m/z: 453. ^lH NMR (300 MHz, DMSO-d6, ppm): δ 8.45 (d, J= 5.6 Hz, IH), 7.81 (d,7=2.5 Hz, 1 H), 7.70 (s, IH), 6.99 (dd, 7= 5.7, 2.5 Hz, IH), 5.02-4.96 (m, IH), 4.11 (s, 2H), 3.62 (dd, 7=10.2, 6.6 Hz, 1 H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.81 (t, 7= 7.9 Hz, 2H), 2.41 (dt, 7= 11.4, 6.0 Hz, IH), 2.28-2.24(m, IH), 2.24 (s, 3H), 2.05-1.91 (m, 3H), 1.91-1.78 (m, IH), 1.26 (s, 9H), 1.06 (d,7= 5.9 Hz, 3H).

Example 1.495

[1774 ] Synthesis ofN-tert-buty 1-2-{methyl[2-(4-{[(3R)-l-methylpiperidin-3-yl]oxy}pyridin-2-yI)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 489)

738

[ 1775] Compound 489 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3R)-l-methylpiperidin-3-ol. LCMS (ES) [M+l] ⁺ m/z: 453. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J= 5.7 Hz, IH), 8.18 (s, L7 WCOOH), 7.84 (d, J = 2.5 Hz, IH), 7.71 (s, IH), 7.09 (dd, J = 5.7, 2.6 Hz, IH), 4.66 (dt, J = 8.0, 4.1 Hz, IH), 4.11 (s, 2H), 3.27 (s, 3H), 3.14 (t, J =7.3 Hz, 2H), 2.93 (dd, J = 10.6, 3.4 Hz, IH), 2.81 (t, J = 7.8 Hz, 2H), 2.66-2.51 (m, IH), 2.28 (s, 3H),

2.36- 2.16(m, 2H), 2.05-L92 (m, 3H), L84-I.7l(m, IH), 1.69-1.55 (m, IH), L52-L38(m, IH), I.25 (s, 9H).

Example 1.496

[1776] Synthesis of N-tert-butyl-2-{methyl[2-(4-{[(3S)-l-methylpiperidin-3-yl]oxy}pyridin-2-yl)

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide (Compound 490)

[1777] Compound 490 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3S)-1-methylpiperidin-3-ol. LCMS (ES) [M+l ]⁺ m/z: 453. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J = 5.7 Hz, IH), 8.18 (s, 1.7 HCOOH), 7.84 (d, J = 2.5 Hz, IH), 7.71 (s, JH), 7.09 (dd, J - 5.7, 2.6 Hz, IH), 4.66 (dt, J = 8.0, 4.1 Hz, IH), 4.H (s, 2H), 3.27 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.93 (dd, J = 10.6, 3.4 Hz, I H), 2.81 (t, J = 7.8 Hz, 2H), 2.66-2.51 (m, IH), 2.28 (s, 3H), 2.36-2.16(m, 2H), 2.05-1.92 (m, 3H), 1.84-1.71(m, IH), 1.69-L55 (m, IH), 1.52-1.38 (m, IH), 1.25 (s, 9H).

Example 1.497

[J778] Synthesis of N-tert-butyl-2-{[2-(4-{[(3R)-l-(2,2-difluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-y]](methyl)amino}acetamide (Compound 491)

739

[ 1779] Compound 491 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3R)-l-(2,2-difluoroethyl)pyrrolidin-3-ol. LCMS (ES) [M+l] ⁺ m/z: 489. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.46 (d, J= 5.6 Hz, IH), 7.81 (d, J= 2.5 Hz, IH), 7.69 (s, IH),

7.00 (dd, J= 5.7, 2.6 Hz, lH), 6.12 (tt, 7= 55.8,4.2 Hz, IH), 5.06 (dt, 7= 7.1, 3.3 Hz, IH), 4.12 (s, 2H),

3.27 (s, 3H), 3.l4(t, 7=7.3 Hz, 2H), 3.02 (dd,7= 10.7,6.0 Hz, IH), 2.95-2.74 (m, 6H), 2.65-2.55 (ni, IH), 2.34 (dt, 7= 13.6, 6.9 Hz, IH), 2.02-1.95 (m, 2H), 1.88-1.70 (m, IH), 1.25 (s, 9H).

Example 1.498

[1780] Synthesis of N-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5-oxo-

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 492)

740

[1781] To a stirred solution ofN-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (400 mg, 0.94 mmol, l .00 equiv) in HOAc (l .5 mL) and H2SO4 (0.3 mL) were added CrO₃ (196 mg, 1.96 mmol, 2.0 equiv) in HOAc (2.0 mL) and H₂O (0.4 mL) dropwise below 10 °C under air atmosphère. The resulting mixture was stirred 5 for 16 h at room température. The mixture was basifîed to pH~l3 with (3 N) NaOH in H2O, extracted with CH₂Cl2/MeOH=lO: l (3*30 mL). The combined organic layers were washed with brine (l *30 mL), dried over anhydrous Na2SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by Prep-HPLC with the following conditions: C18 OBD Column, 50*250 mm, 5 pm, lOnm, mobile phase, CH₃CN/H2O (FA: 0.1%), from 5 % to 35% in 12 min, Flow rate, 80 mL/min, 10 Detector, UV 254 nm. This resuit in N-tert-butyl-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5oxo-6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (65 mg, 16%) as a white solid.

LCMS (ES, m/z): [M+H]⁺: 442. Ή-NMR (300 MHz, DMSO-^pm): δ 8.55 (d, J= 5.6 Hz, IH), 7.92 (d, 7=2.5 Hz, IH), 7.74 (s, IH), 7.15 (dd,7=5.6, 2.6 Hz, IH), 4.72 (s, 1H),4.42 (s, 2H), 3.89 (s, 2H), 3.34 (s, 3H), 3.12-2.97 (m, 2H), 2.69-2.58 (m, 2H), 1.25 (s, 6H), 1.23 (s, 9H).

Example 1.499

[ 1782] Synthesis of N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyrÎdin-2-yl}-5-hydroxy5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 493)

Step l

Scheme 140

[1783] To a stirred mixture ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (LO g, 2.67 mmol, l.OO equiv) in i-BuOH (10.0 mL) and H₂O (2.0 mL) was added MgSO₄ (0.97 g, 8.02 mmol, 3.00 equiv) and KMnO₄ (850 mg, 5.35 mmol, 2.00 equiv) in portions at 0°C. The resulting solution was stirred for 16 h at room température, filtered and concentrated, the residue was purified by Prep-HPLC with the following conditions: Sunfire Prep Cl 8 OBD Column, 50*250 mm, 5 pm, 10 nm, mobile phase, water (0.1% FA) and CH3CN (15% up to 50% in 12 min), Detector, UV 220 nm to afford N-tert-butyl-2-{[2-(4-chloropyridin-2-yI)-5-oxo6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (350 mg, 33.7%) as a yellow solid.

LCMS (ES) [M+lf m/z: 388.

Step 2

[1784] To a stirred solution of N-tert-buty l-2-{ [2-(4-chloropyrid in-2-y l)-5-oxo-6H,7H- cyclopenta|d]pyrimidin-4-yl](methyl)amino}acetamide (300 mg, 0.77 mmol, I.00 equiv) in MeOH (10 mL) was added NaBH₄ (58 mg, l .54 mmol, 2.00 equiv) in portions at 0°C under N₂ atmosphère. The resulting solution was stirred for l h at the same température. The reaction was then quenched by the addition of water/ice (10 mL), extracted with EtOAc (30 mL*5). The combined organic layers were washed with brine (l 0 mL), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. This resulted in N-tert-butyi-2-{[2-(4-chloropyridin-2-yl)-5-hydroxy5H,6H,7H-cyclopenta[d]pyrimidin-4-yl] (methyl)amino} acetamide (286 mg, 95%) as a yellow solid used to the next step directly without further purification. LCMS (ES) [M+l]⁺ m/z: 390.

Step 3

[1785] To a stirred solution ofN-tert-butyl-2-{[2-(4-chloropyridin-2-yl)-5-hydroxy-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl](methyl)amino} acetamide (300 mg, 0.76 mmol, 1.00 equiv) in DMF (8 mL) was added imidazole (157 mg, 2.31 mmol, 3.00 equiv) and TBSCI (232 mg, 1.53 mmol, 2.00 equiv) in portions at room température. The reaction was stirred at 60 °C for 16 h. The reaction was quenched with water (10 mL) at room température, extracted with EtOAc (3* 30 mL). The combined organic layers were washed with brine (20 mL* 1), dried over anhydrous Na₂SO₄. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with THF/ΡΕ (I ;100 to 1:1) to afford N-tert-btityl-2-({5-[(tert21052

743

butyldimethylsilyl)oxy]-2-(4-chloropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrîmidin-4yl](methyl)amino)acetamide (370 mg, 95%) as an off-white solid. LCMS (ES) [M+l]⁺ m/z: 504.

Step 4

[1786] To a solution of dimethylaminoethanol (I24 mg, 1.39 mmol, 2.00 equiv) in DMSO (5.0 mL) was added sodium hydride (60% in minerai oil, 55 mg, 1.39 mmol, 2.00 equiv) at 15°C. After the reaction was stirred at 15-25 °C for I h, N-tert-butyl-2-({5-[(tert-butyldimethylsilyl)oxy]-2-(4chloropyridin-2-y!)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl}(methyl)amîno)acetamide (350 mg, 0.69 mmol, l .00 equiv) was added in one portion. Then the resulting mixture was stirred for another 2 h at

40 °C. The reaction was cooled to room température and purified by Prep-HPLC with conditions:

Kinetex EVO C18 Column, 21.2* 150, 5 um, mobile phase A, water (0.1% FA) and mobile phase B, CHjCN (10% Phase B up to 50% in 15 min), Detector, UV 254 nm, to give N-tert-butyl-2-[(2-{4-[2(dimethylamino)ethoxy]pyridin-2-yl]-5-hydroxy-5H,6H,7H-cyclopenta[d]pyrimidin-4yl)(methyl)amino]acetamide (72 mg, 23.43%) as an off white solid. LCMS (ES) [M+l]⁺ m/z: 443. 'H

NMR (400 MHz, DMSO-Æ) δ 8.48 (d, J= 5.6 Hz, 1 H), 7.84 (d, 7= 2.5 Hz, IH), 7.68 (s, IH), 7.07 (dd, 7=5.7,2.5 Hz, IH), 5.32 (d, 7 =7.1 Hz, 1 H), 5.27-5.20 (m, 11-1),4.34-4.09 (m, 4H), 3.36 (s, 3H), 3.04 (dt, 7= 16.9, 8.4 Hz, JH), 2.66 (t, 7= 5.6 Hz, 3H), 2.23(s, 6H), 2.25-2.15 (m, IH), 1.93 (dd,7= 13.6, 8.2 Hz, IH), 1.25 (s, 9H).

Example 1.500

[1787] Synthesis of N-tert-butyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-7-hydroxy5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 494)

744

Scheme I4l

Step I

Cl

Pb(OAc)₄, HOAc 120°C,32 h

Si ., < 745

[l 788] Into a 250 mL round-bottom flask were added 2,4-dichloro-5H,6H,7Hcyclopenta[d]pyrimidine (6.0 g, 31.74 mmol, l.OO equiv), HOAc (60 mL) and Pb(OAc)₄ (28.2 g, 63.60 mmol, 2.00 equiv) at room température. The mixture was heated to 120 °C and stirred for 16 h. Another batch Pb(OAc)₄ (28.2 g, 63.60 mmol, 2.00 equiv) was added at room température and stirred for I6 h at 5 120 °C. The reaction was cooled to room température and concentrated under reduced pressure to remove the solvent. The residue was purified by reverse flash chromatography with the following conditions: column, C18-120 g, mobile phase, MeCN in water, 10% to 50% gradient in 10 min, detector, UV 254 nm. The fraction of the target was freezing dried, this resulted in 2,4-dihydroxy-6,7-dihydro5H-cyclopenta[d]pyrimidin-7-yl acetate ( l .4 g, 21%) as a brown solid. LCMS (ES) [M+1 ]⁺ m/z: 211.

Step 2

[1789] Into a 250 mL round-bottom flask were added 2,4-dihydroxy-6,7-dihydro-5Hcyclopenta[d]pyrimidin-7-yl acetate (1.4 g, 6.66 mmol, 1.00 equiv), DCE (20 mL), TEA (1.35 g, 13.34 mmol, 2.00 equiv) and POCh (20.4 g, 133.04 mmol, 20.00 equiv) at room température. The resulting mixture was stirred for 2 h at 90 °C. The resulting mixture was concentrated under reduced pressure. The residue was diluted with DCM (100 mL), quenched with water (50 mL), extracted with CH2CI2 (50 mL* 1 ), dried over anhydrous sodium sulfate. After filtration, the fîltrate was concentrated under reduced pressure, the residue was purified by silica gel column chromatography, eluted with PE / EA (3:1) to afford 2,4-dichloro-6,7-dihydro-5H-cydopenta[d]pyrimidin-7-yl acetate (1.3 g, 79%) as a yellow oil.

LCMS (ES) [M+1 ]⁺ m/z: 247.

Step 3

746

[ 1790] Into a 40 mL vial were added 2,4-dichloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.3 g, 5.26 mmol, l.OO equiv), NMP (15 mL), DIEA (2.04 g, 15.78 mmol, 3.00 equiv) audNtert-butyl-2-(methylamino)acetamide hydrochloride (1.43 g, 7.92 mmol, 1.50 equiv) at room température. The resulting mixture was stirred for 2 h at 60 °C. The reaction was cooled to room température, quenched with water (20 mL), the aqueous layer was extracted with EtOAc (30 mL*3). The combined organic phase was washed with brine (20 mL*3), dried over anhydrous sodium sulfate. After filtration, the fïltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:1) to afford 4-((2-(tert-butylamino)-210 oxoethyl)(methyl)amino)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.5 g, 80%) as a yellow solid. LCMS (ES) [M+l ]⁺ m/z: 355.

Step 4

[1791] Into a 50 mL round-bottom flask were added 4-((2-(tert-butylamino)-2- oxoethyl)(methyl)amino)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl acetate (1.5 g, 4.23 mmol, 1.00 equiv), THF (18 mL), LiOH (0.20 g, 8.45 mmol, 2.00 equiv) and H₂O (9 mL) at room température. The resulting mixture was stirred for 1 h at room température. The reaction was diluted with water (30 mL), extracted with EtOAc (30 mL*2). The combined organic phase was dried over anhydrous sodium, filtered and the fïltrate was concentrated under reduced pressure. The crude product

747

was used to the next step directly without further purification. LCMS (ES) [M+l]⁺ m/z: 313.

Step 5

[1792] Into a 50 mL round-bottom flask were added N-(tert-butyI)-2-((2-chloro-7-hydroxy-6,7- dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (L2 g, 3.84 mmol, l .00 equiv), DCM (15 mL), imidazole (0.52 g, 7.67 mmol, 2.00 equiv) and TBSCl (0.69 g, 4.60 mmol, 1.20 equiv) at room température. The resulting mixture was stirred for 12 h at room température. The reaction was quenched with water (30 mL), the aqueous layer was extracted with EtOAc (50 mL*2). The residue was purified by silica gel column chromatography, eluted wîth PE / EA (10: l) to afford N-(tert-buty 1)-2-((710 ((tert-butyldimethyisilyl)oxy)-2-chloro-6,7-dihydro-5H-cyclopenta[d]pynmidin-4yl)(methyl)amino)acetamide (1.3 g, 79%) as a white solid. LCMS (ES) [M+1]⁺ m/z: 427.

Step 6

[ 1793] Into a 40 mL vial were added N-(tert-butyl)-2-((7-((tert-butyldimethylsily[)oxy)-2-chloro15 6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(niethyi)amino)acetamide (L3 g, 3.05 mmol, 1.00 equiv), toluene (20 mL) ,4-fluoro-2-(tributylstannyl)pyridine (1.88 g, 4.87 mmol, 1.60 equiv) and Pd(PPh₃)4 (350 mg, 0.30 mmol, 0.10 equiv) at room température. The resulting mixture was stirred for 12 h at 120°C under nitrogen atmosphère. The réaction was cooled to room température, concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with ethyl acetate to afford N-(tert-butyl)-2-((7-((tert-butyldÎmethylsilyl)oxy)-2-(4-fluoropyridin-2-yl)-6,7-dihydro21052

748

5H-cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (900 mg, 61%) as a yellow solid. LCMS (ES) [M+l]* m/z: 488.

Step 7

[1794] Into a 20 mL vial were added dimethylaminoethanol (158 mg, 1.77 mmol, 2.00 equiv), DMSO (7 mL), NaH (60% in minerai oil) (71 mg, l .78 mmol, 2.00 equiv). The resulting mixture was stirred for 30 min at room température. To the above mixture was added N-tert-butyl-2-({7-[(tertbutyldimethylsilyl)oxy]-2-(4-fluoropyridin-2-yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4- yl}(methyl)amino)acetamide (432 mg, 0.89 mmol, 1.00 equiv) at room température. The resulting mixture was stirred for additional 4 h at room température. The reaction was quenched with water (0.5 mL) and purified by Prep-HPLC with the following conditions: XBridge Shield RP 18 OBD Column, 19* 150 mm, 5 pm, mobile phase, waier (0.05% NH₃ H2O) and CH3CN (16% up to 33% in 8 min). This resulted in N-(tert-butyl)-2-((2-(4-(2-(dimethylamino)ethoxy)pyridin-2-yl)-7-hydroxy-6,7-dihydro-5H15 cyclopenta[d]pyrimidin-4-yl)(methyl)amino)acetamide (57 mg, 14.54%) as an off-white solid. LCMS (ES, m/z): [M+H]*: 443. 'H-NMR (300 MHz, DMSO-O δ 8.48 (d, J = 5.6 Hz, 1 H), 7.87 (d, J = 2.6 Hz, IH), 7.70 (s, IH), 7.07 (dd, J = 5.7, 2.6 Hz, IH), 5.44 (s, IH), 4.82 (t, J = 6.5 Hz, IH), 4.20 (t, J = 5.7 Hz, 2H), 4.14 (s, 2H), 3.29 (s, 3H), 3.18 (ddd, J = 13.8, 8.4,4.4 Hz, 1 H), 2.99 (dt, J = ! 5.1, 7.1 Hz, IH), 2.67 (t, J = 5.6 Hz, 2H), 2.28 (dt, J = 7.5, 4.9 Hz, 1 H), 2.23 (s, 6H), 1.77 (dt, J = 13.6, 6.8 Hz, IH), 1.25 (S, 9H).

Example 1.501

[1795] Synthesis of N-tert-butyl-2-[(2-{4-[2-(dimethylammo)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[b]pyridin-4-yl)(methyl)amino]acetamide (Compound 495)

749

[1796] Into a 50 mL round-bottom flask were added 2,4-dichloro-5H,6H,7H-cyclopenta[b]pyridine (500.00 mg, 2.66 mmol, L00 equiv), 4-fluoro-2-(tributylstannyl)pyridine (l 129.37 mg, 2.93 mmol, L10 equiv), DMF (25.00 mL), CsF (807.78 mg, 5.32 mmol, 2.00 equiv). Cul (50.64 mg, 0.27 mmol, 0.10 equiv) and Pd(PPh3)4 (307.25 mg, 0.27 mmol, 0.10 equiv). The resulting mixture was stirred for ovemight at 110 °C under nitrogen atmosphère. The mixture was allow'ed to cool down to room température. The reaction was quenched with Water/Ice. The resulting mixture was extracted with EA (3 x 30 mL). The combined organic layers were washed with brine (3x100 mL), dried over anhydrous Na₂SÛ4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified

750 by silica gel column chromatography, eluted with THF/PE (5%) to afford 2-{4-chloro-5H,6H,7Hcyclopenta[b]pyridin-2-yl}-4-fluoropyridine (i 85.00 mg, 27.98%) as white solid. LCMS (ES) [M+l]⁺m/z: 249.

Step 2

NaH, DMF

63.03%

[1797] Into a 40 mL vial were added dimethylaminoethanol (1290.35 mg, 14.48 mmol, 20.00 equiv) and DMF (20.00 mL). To the above solution was added NaH (60%) (86.85 mg, 2.172 mmol, 3.00 equiv) in portions at 0 °C. The resulting mixture was stirred for additional 30 min at room température. To the above mixture was added 2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}-4-fluoropyridine (180.00 mg, 0.72 mmol, l .00 equiv) in portions at room température. The resulting mixture was stirred for additional l h at 50 °C. The mixture was allowed to cool down to room température and quenched with sat. NH4CI (aq.). The aqueous layer was extracted with DCM:MeOH (10:1) (3x30 mL). The combined organic layers were dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with DCM/MeOH (10%) to afford {2-[(2-{4-chloro-5H,6H,7H-cyclopenta[b]pyridin-2-yl}pyridin-4yl)oxy]ethyl]dimethylamine (145.00 mg, 63.03%) as a yellow solid. LCMS (ES) [M+l]⁺ m/z: 318. Step 3

Cl

[1798] Info a 40 mL vial were added {2-[(2-{4-chloro-5H,6H,7H-cydopenta[b]pyridin-2-yl}pyridin4-yl)oxy]ethyl}dimethylamine (140.00 mg, 0.44 mmol, 1.00 equiv), N-tert-buty 1-2(methylamino)acetamide hydrochloride (79.59 mg, 0.44 mmol, 1.00 equiv), B1NAP (54.86 mg, 0.09 mmol, 0.20 equiv), Cs₂CO3 (287.05 mg, 0.88 mmol, 2.00 equiv), 1,4-dioxane (14.00 mL) and Pd(OAc)₂(9.89 mg, 0.04 mmol, 0.10 equiv). The resulting mixture was stirred for 1 h at 100 °C under nitrogen

751 atmosphère. The mixture was allowed to cool down to room température and quenched with Water/Ice. The aqueous layer was extracted with DCM:MeOH(lO:l) (3x30 mL). The combined organic layers were dried over anhydrous Na₂SÛ4. After filtration, the filtrate was concentrated under reduced pressure. The crude product was purified by Prep-HPLC with the following conditions: Column, Sunfire Prep Cl8 OBD Column, 50^!k250mm 5um lOnm; mobile phase, Water (0.1% FA) and ACN (5% Phase B up to 20% in 13 min); Detector, 254. This resulted in N-tert-butyl-2-[(2-{4-[2(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[b]pyridin-4-y[)(methyl)amino]acetamide; bis(formic acid) (132.50 mg, 58.11%) as yellow gum. LCMS (ES, m/z): [M+H]: 426. 'H-NMR (300 MHz, DMSO-A^™): δ 8.43 (d, J= 5.6 Hz, IH), 8.18 (s, 2/7COOH), 7.86 (d, J= 2.5 Hz, IH), 7.57 (s, IH), 7.54 (s, IH), 6.97 (dd,7 = 5.9, 2.6 Hz, 1 H), 4.24 (t, 7= 5.5 Hz, 2H), 3.94 (s, 2H), 3.06 (s, 3H), 3.01 (t, 7= 7.3 Hz, 2H), 2.85 (t, 7= 7.6 Hz, 2H), 2.79 (t, 7= 5.8 Hz, 2H), 2.32 (s, 6H), 2.02-1.97 (m, 2H), 1.27 (s, 9H).

Example 1.502 [1799] Synthesis of N-tert-buty 1-2-{[2-(4-{ [(3 R)-1-ethylpyrrol idin-3-y l]oxy}py ridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-y]](methyl)amino}acetamide (Compound 496)

[1800] Compound 496 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3R)-l-ethylpyrrolidin-3-oL LCMS (ES) [M+l] ⁺ m/z: 453. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d,7= 5.7 Hz, IH), 8.28 (br, HCOOH), 7.82 (d, 7= 2.4 Hz, IH), 7.72 (s, IH), 7.02 (dd,7= 5.7, 2.7 Hz, IH), 5.14-5.08 (m, IH), 4.12 (s, 2H),3.27 (s, 3H), 3.14 (t, 7= 2.4 Hz, 2H), 3.06 (dd, 7 = 1 1.1, 5.7 Hz, IH), 2.92-2.78 (m, 4H), 2.67-2.60 (m, 3H), 2.42-2.30 (m, IH), 2.04-1.82 (m, 3H), 1.25 (s, 9H), 1.08 (t, 7= 7.2 Hz, 3H).

Example 1.503

[1801] Synthesis of N-tert-butyl-2-{[2-(4-{[(3R)-l-(2-fluoroethyl)pyrrolidin-3-yl]oxy}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 497)

752

[1802] Compound 497 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with (3R)-l-(2-fluoroethyl)pyrrolidin-3-ol. LCMS (ES) [M+l]⁴ m/z: 47]. 'H NMR (300 MHz. DMSO-d6, ppm): δ 8.47 (d, J= 5.6 Hz, IH), 8.17(1.60 HCOOH), 7.83 (d,7=2.5 Hz, IH), 7.72 (s, I H), 7.01 (dd, 7= 5.7, 2.6 Hz, I H), 5.11-5.01 (m, 1 H), 4.61 (t, 7= 4.9 Hz, 1 H), 4.46 (t, 7 = 4.9 Hz, IH), 4.12 (s, 2H), 3.27 (s, 3H), 3.15 (t,7= 7.3 Hz, 2H), 2.97 (dd,7= 10.7, 6.0 Hz, 1H), 2.882.73 (m,5H), 2.71 (t, 7=4.9 Hz, IH), 2.60-2.46 (m, IH), 2.43-2.25 (m, IH), 2.01-1.96 (m, 2H), 1.891.74 (m, IH), 1.25 (s, 9H).

Example 1.504

[1803] Synthesis of N-tert-butyl-2-[methyl({2-[4-(methylsulfanyl)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl})amino]acetamide (Compound 498)

H

[1804] Compound 498 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with MeSNa. LCMS (ES) [M+l]⁺ m/z: 386. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d,7=5.2 Hz, IH), 8.15 (d,7= 1.8 Hz, IH), 7.68 (s, IH), 7.30 (dd, 7= 5.3, 2.0 Hz, IH), 4.14 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.82 (t, 7= 7.8 Hz, 2H), 2.58 (s, 3H), 2.08 - 1.86 (m, 2H), 1.25 (s, 9H).

Example 1.505

[1805] Synthesis ofN-tert-butyl-2-{[2-(4-{[2-(dimethylamino)ethyl]sulfany[}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (Compound 499)

[ 1806] Compound 499 was synthesized similar to Compound 348 by replacing dimethylaminoethanol with 2-(Dimethy!amino)ethanethioL LCMS (ES) [M+l] m/z: 443. ’H NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J= 5.2 Hz, 1H), 8.16 (s, 0.5HCOOH), 8.15 (d, J= 2.5 Hz 1 H),

7.67 (s, LH), 7.33 (dd, J= 5.3, 2.0 Hz, IH), 4.14 (s, 2H), 3.26 (s, 3H), 3.25-3.20 (m, 2H), 3.13 (t,J= 7.3

Hz, 2H), 2.81 (t, J= 7.8 Hz, 2H), 2.58 (t, J= 7.0 Hz, 2H), 2.23 (s, 6H), 2.01-1.96 (m, 2H), 1.25 (s, 9H).

Example 1.506

[1807] Synthesis ofN-cyclopropyl-2-[(2-{4-[2-(dimethylamino)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)(methyl)amino]acetamide (Compound 500)

[ 1808] Compound 500 was synthesized similar- to Compound 348 by replacing tert-butylamine with 1-cyclopropy lamine. LCMS (ES) [M+l] m/z: 411. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J = 5.6 Hz, JH), 8.24 (d, J = 4.1 Hz, IH), 7.80 (d, J = 2.5 Hz, lH), 7.05 (dd, J = 5.7, 2.6 Hz, 1H), 4.26 (t, J = 5.5 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.14 (t, J = 7.3 Hz, 2H), 2.89-2.76 (m, 4H), 2.63 (tq, J = 8.3, 15 4.8 Hz, 1 H), 2.36 (s, 6H), 2.04- i .94 (m, 2H), 0.67-0.50 (m, 2H),0.47-0.36 (m, 2H).

Example 1.507

[1809] Synthesis of N-tert-buty 1-2-({2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-7-oxo5H,6H,7H-cyclopenta[d]pyrimjdin-4-yl}(methyl)amino)acetamide (Compound 501)

754

[1810] Into a 40 mL vial were added 2-methyl-2-(oxan-2-yloxy)propan-l-ol (643 mg, 3.69 mmol, 2.00 equiv), DMSO (16 mL) and NaH (60% in minerai oil) (148 mg, 3.70 mmol, 2.00 equiv) at room température. The resulting mixture was stirred for 30 min at room température. To the above mixture was added N-(tert-butyl)-2-((7-((tert-butyldimethylsilyl)oxy)-2-(4-fluoropyridin-2-yl)-6,7-dihydro-5H10 cyclopenta[d]pyrimidin-4-yl)(methy[)amino)acetamide (900 mg, 1.84 mmol, 1.00 equiv) at room température. The resulting mixture was stirred for additional 2 h at room température. The reaction was

755 quenched with water (2 mL) and purified by reverse flash chromatography with the following conditions: C18-I20 g, column, mobile phase, MeCN in water, I0%to 80% gradient in 10 min, detector, UV 254 nm, Flow rate, 70 mL/min. This resulted in N-(tert-butyl)-2-((7-hydroxy-2-(4-(2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yi)-6,7-dihydro-5H-cyclopenta[d]pyrimÎdin-4yl)(methyl)amino)acetamide (500 mg, 51%) as a yellow solid. LCMS (ES) [M+l]* m/z: 528.

Step 2

[l811] Into a 50 mL round-bottom flask were added N-(tert-butyl)-2-((7-hydroxy-2-(4-(2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide (500 mg, 0.95 mmol, l.OO equiv), DCM (30 mL) and MnO₂ (824 mg, 9.48 mmol, 10.00 equiv) at room température. The resulting mixture was stirred for 36 h at room température. The resulting mixture was filtered, the filter cake was washed with MeOH. The filtrate was concentrated under reduced pressure. This resulted in N-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)amino)acetamide (300 mg, 60%) as a brown solid. LCMS (ES) [M+l]⁺ m/z: 526.

[1812] Into a 50 mL round-bottom flask were added N-(tert-butyl)-2-(methyl(2-(4-(2-methyl-2((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin4-yl)amino)acetamide (300 mg, 0.57 mmol, l.OO equiv), dioxane (I0 mL) and HCl (gas) (2 M) in 1,4dioxane (0.1 mL) at room température. The resulting mixture was stirred for 1 h at room température and concentrated to remove the solvent. The residue was dissolved in CH₃CN (5 mL) and purified by

756

Prep-HPLC with the foilowing conditions: SunFire Prep Cl 8 OBD Column, 19*150 mm, 5 um, mobile phase, water (0.1% TFA) and CH₃CN (36% up to 68% in 7 min). This resulted in N-(tert-butyl )-2-((2(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl)-7-oxo-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4yl)(methyl)amino)acetamide as a yellow solid. LCMS (ES) [M-TFA+1]⁺ m/z: 442. 'H NMR (300 MHz,

DMSO-ife) δ 8.76 (d, J = 6.9 Hz, IH), 8.21 (d, J = 2.7 Hz, 1 H), 7.90 (s, 1 H), 7.73 (dd, J = 7.0, 2.8 Hz, IH), 4.37 (s, 2H), 4.22 (s, 2H), 3.60-3.33 (m, 5H), 2.77 - 2.68 (m, 2H), 1.27 (s, 6H), 1.24(s, 9H).

Example 1.508

[1813] Synthesis of N-tert-butyl-2-{[2-(4-{[(3R,5S)-l,5-dimethylpyrrolidin-3-yl]oxy}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino} acetamide (Compound 502)

[1814] Compound 502 was synthesîzed similar to Compound 348 by replacing dimethylaminoethanol with (3R,5S)-l,5-dimethylpynrolidin-3-ol. LCMS (ES) [M+l]⁺ m/z: 453. ’H NMR (300 MHz, DMSO-d6, ppm): δ 8.45 (d, J = 5.6 Hz, 1 H), 8.17 (s, 1 i/COOH), 7.80 (d, J = 2.5 Hz, IH), 7.71 (s, IH), 6.96 (dd, J = 5.6, 2.6 Hz, IH), 4.99-4.89 (m, IH), 4.12 (d, J = 2.4 Hz, 2H), 3.27 (s, 3H), 3.20-3.08 (m, 3H), 2.81 (t, J = 7.9 Hz, 2H), 2.60 (dt, J = 15.0, 7.8 Hz, IH), 2.53-2.50 (m, IH), 2.22 (s, 3H), 2.27-2.13(m, 1 H), 2.06-1.94 (m, 2H), 1.54 - 1.39 (m, IH), 1.25 (s, 9H), 1.09 (d, J = 6.0 Hz, 3H).

Example 1.509

[1815] Synthesis of (2R)-N-tert-butyl-2-{methy 1(2-(4-{[(3R)-1-methylpyrrolidin-3-yl]oxy jpyridin-

2-yl)-5H,6l·l,7H-cyclopenta[d]pyrimidin-4-yl]amino}propanamide (Compound 503)

757

[1816] Compound 503 was synthesized similar to Compound 101 by replacing 4-methoxy-2(tributy I stan ny l)py rid i ne with (R)-4-(( 1 -methy Ipyrrol id i n-3 -y l)oxy)-2-(trimethy Istanny l)pyridine. LC MS (ES) [M+l] ⁺ m/z: 453. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.48 (d, J = 5.7 Hz, 1 H), 8.19 (s, 2H), 7.85 (d, J = 2.5 Hz, IH), 7.79 (s, IH), 7.01 (dd, J = 5.6, 2.6 Hz, 1 H), 5.10 (t, J = 4.6 Hz, IH), 5.04 (q, J = 7.2 Hz, IH), 3.29-2.99 (m, 2H), 3.13 (s, 3H), 2.95 (dd, J = 10.9, 5.8 Hz, IH), 2.87 - 2.71 (m, 4H), 2.58-2.50 (m, IH), 2.44-2.37(m, IH), 2.36 (s, 3H), 2.14-1.76 (m, 3H), 1.33 (d, J = 7.0 Hz, 3H), 1.21 (s, 9H).

Example 1.510

[1817] Synthesis of (2R)-2-{methyl[2-(4-{[(3R)-l-methylpyrrolidin-3-yl]oxy}pyridin-2-yl)5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}-N-(propan-2-yl)propanamide (Compound 504)

[1818] Compound 504 was synthesized similar to Compound 101 by replacing 4-methoxy-2(tributy Istanny l)pyrid ine with (R)-4-(( 1 -methyIpyrrolidin-3-yl)oxy)-2-(trimethyIstannyl)pyridine and by replacing tert-butylamine with isopropylamine. LCMS (ES) [M+1]⁺ m/z: 439. 'H NMR (300 MHz, DMSO-d6, ppm): δ 8.49 (d, J = 5.6 Hz, IH), 8.18 (s, HCOOH), 8.17 (d, J = 9.1 Hz, IH), 7.81 (d, J = 2.5 Hz, IH), 7.01 (dd, J = 5.6, 2.6 Hz, IH), 5.17 - 5.08 (m, 1 H), 5.06 (q, J = 6.9 Hz, IH ), 3.98 - 3.80 (m, IH), 3.31 - 3.02 (m, 2H), 3.11 (s, 3H), 2.99 - 2.71 (m, 5H), 2.56-2.51 (m, tH), 2.46-2.36 (m, IH), 2.36 (s, 3H), 2.10 — 1.78 (m, 3H), 1.34 (d, J = 7.0 Hz, 3H), 1.08 (d, J = 6.6 Hz, 3H), 0.92 (d, J = 6.6 Hz, 3H).

Example 1.511

[1819] Synthesis of 2-[methyl(2-{4-[2-(thiomorpholin-4-yl)ethoxy]pyridin-2-yl}-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl)amino]-N-(propan-2-yl)acetamide (Compound 505)

758

[l820] Compound 505 was synthesized similar to Compound 389 by replacing dimethylaminoethanol with 2-thiomorpholinoacetate and by replacing tert-butylamine with isopropyl amine. LCMS (ES) [M+l]⁺ m/z: 471. Ή NMR (300 MHz, DMSO-d6, ppm): δ 8.47 (d, J = 5.6 Hz, IH),

7.99 (d, J = 7.8 Hz, IH), 7.80 (d, J = 2.6 Hz, IH), 7.05 (dd, J = 5.6, 2.6 Hz, IH), 4.22 (t, J = 5.7 Hz, 2H), .15 (s,2H), 3.87 (dq, J= 13.4, 6.7 Hz, lH), 3.27 (s,3H),3.l5 (t, J = 7.3 Hz, 2H), 2.82 (t, J = 7.8 Hz, 2H), 2.78 (dd, J = 6.1,4.0 Hz, 6H), 2.64 - 2.57 (m, 4H), 2.05 - 1.93 (m, 2H), 1.04 (d, J = 6.6 Hz, 6H).

Example 1.512

[1821] Synthesis of N-tert-buty l-2-[methyl(2-{4-[2-(methylsulfanyl)ethoxy]pyridin-2-y I}-

5H,6H,7H-cyclopcnta[d]pyrimidin-4-yl)amino]acetainide (Compound 506)

H

N

Scheme 144

[1822] Into a 50 mL round-bottom flask were added 2-{[2-(4-{[(tert- butylcarbamoyl)methyl](methyl)amino}-5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethyl methanesulfonate (500 mg, 1.05 mmol, 1.00 equiv), DMF (5.0 mL) and (methylsulfanyl)sodium (220 mg, 3.14 mmol, 3.00 equiv) at room température. The resulting mixture was stirred for 2 h at 60 °C. The

759 reaction was cooled to room température and quenched with water (l .0 mL), purified by reverse flash chromatography with the following conditions: Cl8 silica gel, mobile phase, water (0.05% ΝΗ3Ή2Ο), 10% to 80% gradient in 10 min, detector, UV 254 nm. This resulted in N-tert-butyl-2-[methyl(2-{4-[2(methylsulfanyl)ethoxy]pyridin-2-yl}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (400 mg, 89%) as a yellow semi-solid. LCMS (ES) [M+l]⁺ m/z: 430. *H NMR (400 MHz, DMSO-d6, ppm);

δ 8.48 (d, J = 5.6 Hz, IH), 7.84 (d, J = 2.4 Hz, IH), 7.67 (s, IH), 7.05 (dd, J = 5.6, 2.8 Hz, IH), 4.30 (t, J = 6.4 Hz, 2H), 4.12 (s, 2H), 3.32 (s, 3H), 3.14 (t, J = 6.8 Hz, 2H), 2.88 (t, J = 6.8 Hz, 2H), 2.50 (t, J =1.6 Hz, 2H), 2.17 (s, 3H), 2.0 (m, 2H), 1.24 (s, 9H).

Example 1.513

[1823] Synthesis of N-terNbutyl-2-({2-[4-(2-methanesulfonylethoxy)pyridin-2-yi]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (Compound 507)

Scheme 145

[1824] Into a 40 mL vial were added N-tert-butyl-2-[methyl(2-{4-[2- (methylsulfanyl)ethoxy]pyridin-2-yi}-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl)amino]acetamide (200 mg, 0.47 mmol, 1.00 equiv), THF (4.0 mL), H₂O (0.5 mL) and potassium peroxymonosulfate (1.14 g, l .86 mmol, 4.00 equiv) at 0 °C. The resulting mixture was stirred for 2 h at room température. The residue was dissolved in MeOH (10 mL). The resulting mixture was filtered, the fïlter cake was washed with MeOH (2*5 mL). The filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH (5 mL) and purified by Prep-HPLC with the following conditions: Sunfire Prep C18 OBD

760

Column, 50*250 mm, 5 pm,l0 nm, mobile phase, water (0.1% FA) and CHsCN (5% up to 35% in 12 min) to afford N-tert-butyl-2-({2-[4-(2-methanesulfonylethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide formate (124.8 mg, 53%) as a white solid.

LCMS (ES) [M+l]⁺ m/z 462. 'H NMR (400 MHz, DMSO-7&) δ 8.52 (d,7= 5.6 Hz, IH), 8.15 (s, IH), 5 7.85 (d,7=2.5 Hz, IH), 7.64 (s, IH), 7.12 (dd, 7= 5.6,2.6 Hz, 1 H), 4.53 (t, 7= 5.7 Hz, 2H), 4.15 (s,

2H), 3.68 (t,7= 5.7 Hz, 2H), 3.25 (s, 3H), 3.14 (t,7= 7.28 Hz, 2H), 3.11 (s, 3H), 2.82 (t,7= 7.8 Hz,

2H), 2.00-1.96 (m, 2H), 1.24 (s, 9H).

Example 1.513

[1825] Synthesis of N-tert-buty 1-2-( {2-[4-(2-hydroxy-2-methylpropoxy)pyridin-2-yl]-5H,6H,7H10 cyclopenta[d]pyrimidin-4-yl}((2H3)methyl)amino)acetamide (Compound 509)

CD₃I, NaH, DMF

761

Scheme 146

Step l

(B0C)₂O, TEA, DMAP

[I826] A mixture of N-tert-butyl-2-({2-chloro-5H,6H,7H-cyclopenta[d]pyrimidin-4y!}amino)acetamide (2 g, 7.073 mmol, l.OO equiv), (Boc^O (3.09 g, 14.146 mmol, 2 equiv), TEA (1.43 g, 14.146 mmol, 2 equiv) and DMAP (0. i 7 g, i .415 mmol, 0.2 equiv) in DCM (30 mL) was stirred for 24h at room température. The resulting mixture was extracted with CH2CI2 (3 x lOOmL). The combined organic layers were dried over anhydrous NasSCq. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / THF (2:1) to afford tert-butyl (2-(tert-butylamino)-2-oxoethyl)(2-chloro-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)carbamate (L6 g, 59.08%) as a white solid. LCMS (ES) [M+l |⁺ m/z: 383. Step 2

H

[1827] A mixture of tert-butyl (2-(tert-butylamino)-2-oxoethyl)(2-chloro-6,7-dîhydro-5Hcyclopenta[d]pyrimidin-4-yl)carbamate (I g, 2.612 mmol, 1.00 equiv) ,4-fluoro-2(tributylstannyl)pyridine (1.51 g, 3.918 mmol, 1.5 equiv) and Pd(PPhs)₄ (0.60 g, 0.522 mmol, 0.2 equiv) in Toluene (20 mL) was stirred for 16h at 100 degrees C under nitrogen atmosphère. The resulting mixture was concentrated under vacuum. The residue was purified by silica gel column chromatography, eluted with PE / THF ( 1:1 ) to afford tert-butyl N-[(tert-butylcarbamoyl)methyl]-N-[2-(4-fluoropyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]carbamate L0 g ( 86.33%) as an off-white solid. LCMS (ES) [M+l]* m/z: 444.

762

Step 3

[1828] To a stirred solution of tert-butyl N-[(tert-butylcarbamoyl)methyl]-N-[2-(4-fluoropyridin-2yl)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]carbamate (500 mg, l. 127 mmol, l.OO equiv) in EA (20 mL, 204.301 mmol, 181.22 equiv)was added HCl in ether(2M) (1.69 mL, 3.381 mmol, 3equiv) in portions at room température. The resulting mixture was concentrated under reduced pressure to afford N-tertbuty 1-2-{[2-(4-fIuoropyridin-2-y l)-5H,6H,7H-cyclopenta[d]pyrimidin-4-yl]amino}acetamide hydrochloride(360 mg, 92.99%) as a white solid. LCMS (ES) [M-HC1+1] + m/z: 344.

Step 4

[1829] To a stirred solution of N-tert-buty 1-2-{[2-(4-fluoropyridîn-2-y 1)-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl]amino}acetamide (360 mg, 1.048 mmol, 1.00 equiv) in DMF was added NaH (50.31 mg, 2.096 mmol, 2 equiv) in portions at 0 degrees C under nitrogen atmosphère. The resulting mixture was stirred for 20min at 0 degrees C under nitrogen atmosphère. To the above mixture was added CDal (227.94 mg, 1.572 mmol, 1.50 equiv) dropwise at 0 degrees C. The resulting mixture was stirred for additional 6h at room température. The resulting mixture was extracted with CH2CI2 (3 x 50mL). The combined organic layers were dried over anhydrous Na₂SO4. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA (1:4) to afford N-(tert-butyl)-2-((2-(4-fIuoropyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimîdin-4-yl)(meÎhyl-d3)amino)acetamide (300 mg, 79.39%) as a white solid. LCMS (ES) [M+l]⁺m/z: 361.

763

Step 5

[1830] To a stirred solution of 2-methyl-2-(oxan-2-yloxy)propan-l-ol (435.05 mg, 2.496 mmol, 3 equiv) in DMF (30 mL) was added NaH (39.95 mg, 1.664 mmol, 2 equiv) in portions at 0 degrees C under nitrogen atmosphère. The resulting mixture was stirred for 20 min at 0 degrees C under nitrogen atmosphère. To the above mixture was added N-(tert-butyl)-2-((2-(4-fluoropyridin-2-yl)-6,7-dihydro5H-cyclopenta[d]pyrimidin-4-yl)(methyi-d3)amino)acetamide (300 mg, 0.832 mmol, l .00 equiv) in portions at 0 degrees C. The resulting mixture was stirred for additional 4h at room température. The resulting mixture was extracted with CH2CI2 (3 x 30mL). The combined organic layers were dried over anhydrous Na2SÛ4. After filtration, the fïltrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with PE / EA ( l :4) to afford N-(tert-butyl)-2((methyl-d3)(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2-yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5Hcyclopenta[d]pyrimidin-4-yl)amino)acetamide (300 mg, 70.03%) as a white solid. LCMS (ES) [M+l] m/z: 515.

Step 6

[l 831] A mixture of N-(tert-butyl)-2-((methyl-d3)(2-(4-(2-methyl-2-((tetrahydro-2H-pyran-2yl)oxy)propoxy)pyridin-2-yl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)acetamide (300 mg, 0.583 mmol, l .00 equiv) in EtOAc (5mL) and HCI(g) in ether(2M) (0.58 mL, L166 mmol, 2 equiv) was stirred for 3h at room température . The crude product was purified by Prep-HPLC with the foilowing conditions (Prep-HPLC-OOl): Column, Sunfire Prep C18 OBD Column, 50*250 mm, 5pm lOnm;

mobile phase, Water(O.l%FA) and ACN (5% PhaseB up to 25% in 15 min) to afford N-(tert-butyl)-2((2-(4-(2-hydroxy-2-methylpropoxy)pyridin-2-yI)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)(methyld3)amino)acetamide (175,9 mg, 70,09%) as a yellow green solid. LCMS (ES) [M+l] ⁺ m/z: 431. 'H NMR (300 MHz, DMSO-Λ) δ 8.47 (d, 7= 5.6 Hz, IH), 7.83 (d,7=2.5 Hz, IH), 7.68 (s, IH), 7.05 (dd,

7= 5.9, 2.6 Hz, IH), 4.13 (s, 2H), 3.86 (s, 2H), 3.14 (t, 7= 7.2 Hz, 2H), 2.81 (t,7=7.7 Hz, 2H), 2.04 -

1.93 (m, 2H), 1.25 (s, 9H), 1.24 (s, 6H).

Example 1.513

[1832] Synthesis of N-tert-buty 1-2-{[2-(4-{2-[di(2H3)methylamino]ethoxy}pyridin-2-y 1)5H,6H,7H-cyclopenta[djpyrimidin-4-yl](methyl)ammo}acetamide (Compound 508)

n ^XN^ZxtS Va V ^N vf ^N CD₃ H H O^, N../ O^N^/ J । MsCI, TEA, DCM J ¹ ï 0^oC-rt, 2 h ï C'Y ' Z'V N VL x - o - VL N Τι OH N ||J OMs ^N V ^N V H ν' /Vn W Λ../Χ /X ,CD₃ N 01 Y N N^V CD₃ Scheme 147

ÇD₃ HCl ^CDs Cs₂CO₃, ACN, 60°C, 3 h

Step 1

765

[1833] To a stirred solution of N-tert-butyl-2-({2-[4-(2-hydroxyethoxy)pyridin-2-yl]-5H,6H,7Hcyclopenta[d]pyrimidin-4-yl}(methyl)amino)acetamide (L4 g, 3.50 mmol, l.OO equiv) in DCM (20 mL) at 0 °C were added TEA (709 mg, 7.00 mmol, 2.0 equiv) and methanesulfonyl chloride (482 mg, 4.20 mmol, I.2 equiv) dropwise. The resulting mixture was stirred for 2 h at room température and was diluted with 30 mL H₂O. The mixture was extracted with CH2CI2 (3 x 20 mL). The combined organic layers were washed with brine (50 mL), dried over anhydrous NajSCh. After filtration, the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography, eluted with CH2CI2 / MeOH (l 0: l ) to afford 2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-

5H,6H,7H-cyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethyl methanesulfonate (1.3 g, 77.6%) as a white solid. LCMS (ES) [M+l]⁺ m/z: 478.

Step

[1834] To a stirred mixture of 2-{[2-(4-{[(tert-butylcarbamoyl)methyl](methyl)amino}-5H,6H,7Hcyclopenta[d]pyrimidin-2-yl)pyridin-4-yl]oxy}ethyl methanesulfonate (300 mg, 0.62 mmol, 1.00 equiv) and bis(methyl-d3)amine hydrochloride (64 mg, 1.25 mmol, 2.00 equiv) in CH3CN (5 mL) was added CS2CO3 (818 mg, 2.51 mmol, 4.00 equiv). The resulting mixture was stirred for 3 h at 60 °C. The mixture was cooled down to room température and filtered. The filtrate was purified by Prep-HPLC with the following conditions: XBridge Prep Cl 8 OBD Column, 19*150 mm, 5 um, mobile phase, water (10 mmol/L NH4HCO3) and CH3CN (30% Phase B up to 40% in 7 min), Detector, UV 254 nm. The desired fraction was freeze-dried to afford N-tert-butyl-2-{[2-(4-{2-[di(2H3)methylamino]ethoxy}pyridin-2-yl)21052

766

5H,6H,7H-cyclopenta[d]pyrimidin-4-yl](methyl)amino}acetamide (l 14.7 mg, 42.2%) as a white solid. LCMS (ES) [M+l]⁺ m/z: 433. Ή NMR (300 MHz, DMSO-Æ) δ 8.47 (d, 7= 5.6 Hz, IH), 7.84 (d,7 = 2.6 Hz, IH), 7.68 (s, l H), 7.05 (dd, 7= 5.7, 2.6 Hz, IH), 4.19 (t, 7= 5.7 Hz, 2H), 4.13 (s, 2H), 3.27 (s, 3H), 3.15 (t, 7= 7.3 Hz, 2H), 2.81 (t,7= 7.8 Hz, 2H), 2.66 (t,7= 5.7 Hz, 2H), 2.01-1.96 (m, 2H), 1.25 5 (s, 9H).

2. BIOLOGICAL EXAMPLES

Example 2.1

Biological In-Vitro Ferroportin Internalization Assay

[ 1835] The protocol for this assay is generally as described in WO2018/128828, incorporated herein by reference in its entirety. Functîonal internalization of ferroportin protein was measured using a stably-transfected CHO cell line expressing the human ferroportin tagged to a lucîferase reporter. Cells were plated for 24h in the presence of ferrie ammonium citrate (FAC). Ferroportin protein expression was induced with doxycycline for 24 h. The next day, the compounds were added. Test compounds were dissolved in DMSO. Cells were incubated with the test compounds for 6 h, and subsequently lucîferase activity was measured using the Nano-Glo Lucîferase Assay System and Glomax (Promega, Madison, WI).

[1836] The average pECso was determined for the test compounds. The data is provided in Table 2 below.

Table 2

Ctnpd No. from Table 1	pECso
1	6.9
2	6.6
3	6.8
4	6.4
5	6.2
6	6.5

Ctnpd No. from Table 1	pECso
7	6.6
8	5
9	6.2
10	6.6
11	6.3
12	5.8

Ctnpd No. from Table 1	pECso
13	6.4
14	6.8
15	6.9
16	6.6
17	6.6
18	7.1

767

Cmpd No. from Table 1	pECso
19	5.4
20	6.7
21	6.9
22	7
23	6.9
24	7.6
25	7.1
26	6.6
27	6.8
28	5.9
29	5.9
30	5.7
31	6.2
32	7.2
3	5.7
34	7.9
35	7
36	7.3
37	6.6
38	6.6
39	6.3
40	7.1
41	7.3
42	7.3
43	7
44	7.9

Cmpd No. from Table 1	pECso
45	7.2
46	5.1
47	5.7
48	6.8
49	7.1
50	5.6
51	7.5
52	6.8
53	6.6
54	6.9
55	6.3
56	6.7
57	7.5
58	6.7
59	6.8
60	7.6
61	7.1
62	7.6
63	7.2
64	7.8
65	7.6
66	7.7
67	6.6
68	7.2
69	7
70	7.4
71	5.9
72	5.5

Cmpd No. from Table 1	pECso
73	6.8
74	7.5
75	7.5
76	6
77	7
78	7.4
79	6.5
80	6.8
81	6.8
82	6.8
83	6.9
84	6.6
85	5.5
86	6.8
87	6.6
88	7.1
89	7.3
90	7.4
91	7.3
92	6.5
93	6.1
94	6.3
95	7.3
96	6.6
97	7.1
98	7
99	7.3
100	7.5
101	8.2
102	7.1

768

Cmpd No. from Table 1	pECso
103	6.4
104	7.2
105	7.7
106	5.4
107	5.7
108	7.6
109	7
110	7.9
111	7.2
112	8
113	7.7
114	7.6
115	7.1
116	7.4
117	6.9
118	7.8
119	7.7
120	7.2
121	7.9
122	7.8
123	7.2
124	7
125	7.5
126	7.9
127	7.1
128	7.4
129	7.2
130	6.9
131	7.1
132	7.3

Cmpd No. from Table 1	pECso
133	7
134	6.9
135	7.4
136	7.7
137	7.8
138	7.8
139	7.5
140	7
141	7.1
142	7.4
143	7.2
144	7.5
145	6.9
146	6.8
147	6.7
148	7.6
149	7.2
150	7.3
151	8.1
152	7.9
153	7.6
154	7.4
155	7.5
156	7.9
157	7.3
158	6.2
159	8.0
160	5.2
161	7.4
162	5.7

Cmpd No. from Table l	pECso
163	5.4
164	5.0
165	7.4
166	6.7
167	7.9
168	7.3
169	7.3
170	7.8
171	7.2
172	7.5
173	6.8
174	8.2
175	<5.0
176	7.8
177	6.9
178	7.2
179	7.7
180	5.2
181	6.5
182	7.6
183	8
184	7.7
185	7.2
186	7
187	7.9
188	6.7
189	7.7
190	7.8
191	7
192	6.5

769

Cmpd No. from Table 1	pECso
193	6.8
194	5.4
195	6.9
196	5.6
197	7.4
198	8.1
199	7.9
200	7.6
201	7.4
202	7.5
203	6.3
204	6.9
205	7.5
206	6.9
207	7.2
208	5.7
209	8
210	7.9
211	7.9
212	7.1
213	6.4
214	7.8
215	7.5
216	6.6
217	6.9
218	7
219	7.1
220	7
221	7
222	7.2

Cmpd No. from Table 1	pECso
223	7.8
224	7.9
225	6.8
226	7.1
227	7.2
228	7.1
229	7.9
230	6.6
231	6.2
232	7
233	7.4
234	6.4
235	7.5
236	7.4
237	7.1
238	7.5
239	7.8
240	7.1
241	8
242	7.7
243	7.4
244	6.4
245	7.7
246	7.3
247	7.2
248	7.1
249	7.2
250	7.4
251	8.3
252	7.9

Cmpd No. from Table 1	pECsû
253	7.6
254	7
255	6.9
256	6.6
257	7
258	6.3
259	7.1
260	7.6
261	7.6
262	7.1
263	8
264	6.5
265	7.5
266	7.3
267	7.1
268	6
269	8.4
270	7.5
271	7.4
272	7.8
273	7.8
274	6.8
275	7
276	7.7
277	8.2
278	7.8
279	8.2
280	8.3
281	7.3
282	7.5

770

Cmpd No. from Table 1	pECso
283	6.6
284	7.7
285	7.8
286	7.5
287	7.2
288	7.1
289	7.5
290	7.6
291	7.3
292	8.1
293	7.9
294	7.9
295	7
296	7.6
297	7.5
298	6.1
299	6.1
300	6.2
301	6.9
302	7.9
303	6.4
304	6.8
305	7.8
306	6.6
307	7.4
308	8.1
309	8.1
310	7.4
311	8.4
312	7.7

Cmpd No. from Table 1	pECso
313	7.3
314	7.6
315	6.8
316	7.8
317	7.9
318	7.9
319	6.4
320	7.1
321	7.1
322	7.7
323	7.5
324	7.4
325	7.9
326	7.9
327	7.9
328	6.8
329	6.8
330	7.8
331	8.3
332	7.8
333	7.8
334	7.2
335	8.4
336	7.8
337	7.4
338	7.1
339	8.2
340	7.7
341	7.6
342	7.6

Cmpd No. from Table 1	pECso
343	Ί.Ί
344	7.6
345	6.7
346	7.6
347	7.6
348	8.0
349	7.8
350	7.7
351	7.6
352	7.6
353	7.8
354	7.7
355	7.7
356	8.3
357	7.7
358	7.7
359	7.5
360	7.8
361	8.1
362	8
363	8.3
364	8.1
365	7.4
366	7.7
367	8
368	7.8
369	7.7
370	8.2
371	7.5
372	7.5

771

Cmpd No. from Table l	pECso
373	7.3
374	7.2
375	8
376	8
377	7.8
378	8
379	7.2
380	6.6
381	8.3
382	7.8
383	7.8
384	8.1
385	8.2
386	8.4
387	8.2
388	8.2
389	7.9
390	7.8
391	7.7
392	8.3
393	8.1
394	8.3
395	8.4
396	8.5
397	7.6
398	8.1
399	7.5
400	8.2
40]	8.3
402	7.8

Cmpd No. from Table 1	pECso
403	7.6
404	8
405	8.3
406	Ί.Ί
407	6.6
408	8.5
409	7.6
410	7.3
411	8.2
412	8.1
413	8
414	8.3
415	7.7
416	8
417	7.1
418	7.5
419	7.6
420	8
421	8.2
422	7.4
423	7.7
424	7
425	8.3
426	8.4
427	7.6
428	7.5
429	8
430	8
431	7.4
432	7.5

Cmpd No. from Table 1	pECso
433	8.0
434	7.4
435	7.8
436	7.3
437	8.0
438	7.7
439	7.8
440	8
441	7.5
442	8
443	7.8
444	7.9
445	8.3
446	8.2
447	7.6
448	7.4
449	7.2
450	6.4
451	7.8
452	8.4
453	8.1
454	7.9
455	7.7
456	6.2
457	6.3
458	7.3
459	7.3
460	8.2
461	8.3
462	8.4

Cmpd No. from Table 1	pECso
463	8.1
464	8.0
465	8.3
466	7.9
467	8.3
468	8.5
469	8.3
470	7.2
471	7.4
472	7.4
473	8.3
474	8.3
475	7.6
476	6.7
477	6.9
478	7.6

772

Cmpd No. from Table 1	pECso
479	7.9
480	7.3
481	7.7
482	6.1
483	7.2
484	7
485	7.1
486	7.4
487	7.5
488	7.8
489	8.2
490	7.9
491	8.2
492	6.6
493	6.9
494	6.3

Cmpd No. from Table 1	pECso
495	7.4
496	8.0
497	8.2
498	7.5
499	8.2
500	7.3
501	6.4
502	8.2
503	8.5
504	7.9
505	8.8
506	8.0
507	7.9
508	7.6
509	8.2

[l 837] Efforts hâve been made to ensure accuracy with respect to numbers used (e.g., amounts, température, etc.) but some experimental errors and déviations should be accounted for.

[l 838] One skilled in the art will recognize many methods and materials similar or équivalent to those described herein, which could be used in the practicing the subject matter described herein. The present disclosure is in no way limited to just the methods and materials described.

[ 1839] Unless defined otherwise, technical and scientific terms used herein hâve the same meaning as commonly understood by one of ordinary skill in the art to which this subject matter belongs, and are consistent with: Singleton et al (1994) Dictionary of Micro biology and Molecular Biology, 2nd Ed., J. Wiley & Sons, New York, NY; and Janeway, C., Travers, P., Walport, M., Shlomchik (2001 ) Immunobiology, 5th Ed., Garland Publishing, New York.

[1840] Throughout this spécification and the claims, the words “comprise,” “comprises,” and

773 “comprising” are used in a non-exclusive sense, except where the context requires otherwise. It is understood that embodiments described herein include “consisting of ’ and/or “consisting essentially of ’ embodiments.

[1841] Where a range of values is provided, it is understood that each intervening value, to the tenth of the unit of the lower limit, unless the context clearly dictâtes otherwise, between the upper and lower limit ofthe range and any other stated or intervening value in that stated range, is encompassed. The upper and lower limits of these small ranges which may independently be included in the smaller rangers is also encompassed, subject to any specifically excluded limit in the stated range. Where the stated range includes one or both ofthe limits, ranges excluding either or both of those included limits are also included.

[1842] Many modifications and other embodiments set forth herein will corne to mind to one skilled in the art to which this subject matter pertains having the benefit of the teachings presented in the foregoing descriptions and the associated drawings. Therefore, it is to be understood that the subject matter is not to be limited to the spécifie embodiments disclosed and 15 that modifications and other embodiments are intended to be included within the scope of the appended claims. Although spécifie terms are employed herein, they are used in a generic and descriptive sense only and not for purposes of limitation.

Claims

I. A compound of Formula (Γ):

or a pharmaceutically acceptable sait thereof; wherein,

Z is N or CH;

Ring B is

indicates the point of attachment to the remainder ofthe molécule;

R⁶, in each instance, is selected from the group consisting of halogen, hydroxy, C|-C3 alkoxy, C|-C3 alkyl, C|-Cj aIkoxy-C]-C3alkyl, hydroxy-Ci-Cio alkoxy, hydiOxy-CrC|o-alkyl, cyano, -NR^GR^H, halo-Cf-C₃ alkoxy, -O-(Ci-C₆alkyl)-R^bb, -O-R^bb, -(C|-C6 alkyl)-NR^olR^Hl,-S-C|-Cî alkyl,-S-C_rC₃ alkyl-NR^GIR^HI, halo-C,.C3 alkyl, -O-RMQ-rY 5- to 7-membered monocyclic heteroaryl, and C3-Cô cycloalkyl; wherein, the alkyl moiety in hydroxy-Ci-C|0 alkoxy or -O-(CrC6 alkyl)-R^bb is optionally substituted with cyano, hydroxy, hydroxy-C|-C3-alkyl, halogen, orC|-C₃ alkoxy;

R^bb is 4- to 7-membered monocyclic or bridged heterocyclyl, C3-C7 cycloalkyl, 5- or 6-inembered monocyclic heteroaryl, -SO2-C|-C₃ alkyl, -S-C]-C₃ alkyl, -C(0)NR^G1R^H1, or -NR^GR^H;

R^ct is C]-C₃ alkyl; and

R^dd is Ci-C₃ alkyl or a 6-membered heteroaryl;

wherein, said cycloalkyl, heterocyclyl, or heteroaryl of R⁶, R^bb, or

R^dd is optionally substituted with one or two substituents, each

775 independently selected from the group consisting of hydroxy, halogen, halo-Ci-Cj alkyl, oxo, C|-C₃ alkoxy, and C|-C₃ alkyl;

R^gi and R^Hl are each independently hydrogen or C |-C₃ alkyl;

and,

R^g and R¹¹ are each independently hydrogen, -C(O)R^Ga, or optionally deuterated C|-C₃ alkyl; wherein,

R^Ga is Ci-C₃ alkyl or hydrogen;

or, two R⁶ groups, taken together with the atom to which each is attached, form a 5or 6-membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- to 6-membered monocyclic heteroaryl fused with Ring B; wherein, said heterocyclyl, phenyl, cycloalkyl, or heteroaryl fused with ring B îs optionally substituted with one or two substituents, each independently selected from the group consisting of C । -C₃ alkoxy, hydroxy, hydroxy-C । -C ₃-alkyl, C । -C₃alkyl, C3-C7 cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl;

n is 0, 1,2, or 3;

Y¹, Y², Y³, and Y⁴ are each independently selected from the group consisting of CH, N, NH, O, S, SH, S-R⁶, N-R⁶, and C-R⁶, provided that 1 or 2 of Y¹, Y², Y³, and Y⁴can be N, N-R⁶, NH, O, SH or S-R⁶;

fisOor 1;

p is 1 or 2;

R^x, in each instance, îs halogen, C|-C₆ alkyl, C|-C₃ alkoxy, hydroxy, oxo, or cyano;

m is 0, 1, or 2;

R³ is selected from the group consisting of hydrogen, optionally deuterated C₍-C₃ alkyl, hydroxy-Ci-C₃ alkyl, halo-C|-C₃ alkyl, cyclopropyl, and phenyl;

R^4a _R4g

wherein,

776

R^4a and R^4g are each independently selected from the group consisting of hydrogen, Ci-Cio alkyl, hydroxy-C ]-C&alkyl, halo-Ci-C3 alkyl, C1-C3 alkoxy-CiC6alkyl, -Ci-Cô alkyl-NR^JIR^J2, C3-C7 cycloalkyl, 4- to 10-membered monocyclic, fused bicyclic, bridged bicyclic, or spiro heterocyclyl, Cô-Cio monocyclic or fused bicyclic aryl, 5- to 10-membered monocyclic or fused bicyclic heteroaryl, (Cô-Cio monocyclic or fused bicyclic aryl)-C|-C3 alkyl, and (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C|-C₃ alkyl;

R^JI and R^J2 are independently hydrogen or Cj-C₃ alkyl;

wherein the cycloalkyl, heterocyclyl, aryl, heteroaryl, aryl-alkyl, or heteroaryl-alkyl of R^4aor R^4s is optionally substituted with one, two, or three substituents, each independently selected from the group consisting of halogen, Ci-C& alkyl, halo-C|-C₃ alkyl, hydroxy, Cj-C₃ alkoxy, halo-C|C₃ alkoxy, oxo, C₃-C₇ cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;

R^4b is hydrogen or C₍-C6 alkyl; or

R^4a and R^4b taken together with the atom to which each is attached form a 5- to 10-membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C|-C₆ alkyl, halo-C|-C₃ alkyl, hydroxy, and Cj-C₃ alkoxy; or

R^4b and R^4l taken together with the atom to which each is attached form a 5- to 7- membered monocyclic heterocyclyl optionally substituted with one, two, or three substituents, each independently selected from the group consisting of hydroxy, halogen, and C_t-C₃ alkyl; or

R^4c and R^4d are each independently selected from the group consisting of hydrogen, Cj-Cj alkoxy, hydroxy, Ci~C₃ alkyl-thio-Cj-C₃ alkyl, hydroxy-Cj-C₆alkyl, Ci-C₆ alkoxy-Cj-C₃ alkyl, C₃-C₇ cycloalkyl, and C1-C3 alkyl; or

R^4c and R^4d taken together with the atom to which each is attached form a C3-C7 cycloalkyl.
2. The compound of claim 1, or a pharmaceutically acceptable sait thereof, wherein p is l.

777
3. The compound of claim l or 2, or a pharmaceutically acceptable sait thereof, wherein Z is N.
4 - to 10-membered monocyclic or fused bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen. Ci-C₆15 alkyl, halo-C|-C₃ alkyl, hydroxy, C|-C₃ alkoxy, oxo, C3-C7 cycloalkyl, and 5- to 10-membered

785 monocyclic or fused bicyclic heterocyclyl (Co-Cjû monocyclic or fused bicyclic aryl)-C|-C₃ alkyl or (5- to 10-membered monocyclic or fused bicyclic heteroaryl)-C|-C₃ alkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, CT-C& alkyl,

4. The compound of any one of claim l-3, or a pharmaceutically acceptable sait thereof, wherein:

Y¹, Y², Y³, and Y⁴ are each CH or C-R⁶

Y¹ is CH, Y² is C-R⁶, Y³ is CH, and Y⁴ is CH;

Y³ is N and Y¹, Y², and Y⁴ are each CH or C-R⁶;

Y² is N and Y¹, Y³, Y⁴ are each CH or C-R⁶;

or

Y¹ is N and Y², Y³, and Y⁴ are each CH or C-R⁶.
5 halo-C|-C₃ alkyl, hydroxy, CT-C₃ alkoxy, Cj-C₇ cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic heterocyclyl, or, hydroxy-Ci-Cé alkyl, halo-C|-C₃ alkyl, Ci-C₃ alkoxy-Ci-C^ alkyl, and -C_rC6 alkylNR^JlR^J2, wherein R^Jl and R^J2 are each independently hydrogen or C|-C₃ alkyl.

5. The compound of any one of claims 1 -4, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consistîng of halogen, hydroxy, Ct-C3 alkoxy, C]-C3alkyl, C|-C3 alkoxy-C|-C3alkyl, hydroxy-Ci-Cmalkoxy, hydroxy-Ct-Cio-alkyl, -O-(Ci-C6alkyl)-R^bb, halo-CrC₃ alkoxy, -O-R^cc-O-R^dd, halo-C(-C3 alkyl, -(CrC6 alkyl)NR^GIR^HI, -S-CHj, -S(CH2)₂N(CH₃)₂, and -NR^GR^H; wherein,

R^bbis -NR^GR, -C(O)N(CH₃)₂, -S(O)₂CH₃, or -SCH₃;

R^g and R^h are each independently hydrogen, optionally deuterated CrC3 alkyl, or -C(O)R^Ga, wherein R^Ga is CrC₃ alkyl;

R^gi and R^ri are each independently hydrogen or C|-C₃ alkyl;

R^cc and R^dd are each independently C₍-C₃ alkyl; and, wherein the alkyl moiety in hydroxy-C|-Cioalkoxy is optionally substituted with hydroxy, halogen, or C_rC₃ alkoxy.
6. The compound of claim 5, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consistîng of methoxy, ethoxy, methyl, fluoro, chloro, ethyl, -N(CH₃)₂, hydroxy, -OCH₂CH₂OH, -CH₂OH, -CH₂OCH₃, -OCH₂CH₂NH₂, -OCH₂CH₂N(CH₃)₂, -OCH₂C(CH₃)₂OH, -OCH₂CF₃, -OCHF₂,

-OCFj, -OCH₂CH₂OCH₃, -OCH₂CH₂F, -OC(CH₃)₂CH₂OH, -OCH₂CH(CH₃)OH,

778

-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.
7. The compound of any one of claims 1-6, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of -O-(Ci-C6alkyl)-R^bb, -O-R^bb, -O-R^cc-O-R^dd, 5- to 7-membered monocyclic heteroaryl, and C₃-C& cycloalkyl; wherein,

R^cc is Ci-C₃ alkyl and R^dd is 6-membered heteroaryl;

R^bb is 4- to 7-membered monocyclic or bridged heterocyclyl, 5- or 6-membered monocyclic heteroaryl. or C₃-C₂ cycloalkyl; and wherein said cycloalkyl, heteroaryl, or heterocyclyl of R⁶, R^bb, or R^dd is optionally substituted with one or two substituents, each independently selected from the group consisting of hydroxy, halogen, C_t-C₃ alkoxy, oxo, halo-Ci-C₃ alkyl, and C_t-C₃ alkyl.
8 ίΟ

8ll

812

813

Compound No. Structure

234 Q .. Z QZ O Çz \ zj ZI H o w r V¹ ΤΊ “Π

235 zA o Zz \-Ç z=Z ZI kk / — \ ’ X\

236 H YQ A \ /A N Vk i ^N ΎΎΊ nQQ

237 H Οχ,ΝχA j ~N·' vk Λ ⁿ va J

238 H PY vk A 0 x N Z Z ⁰ N-X

814

8I5

Compound No. Structure

252 Αγγχ n γ a/ ?

253 A. Y A Z=< ZI H g d ° cA

254 R-. \=z ζγ ZI w \ Z. / cA

255 k = z ^x)—z O R^zο θ

256 b b z kz b

816

817

818

819

Compound No. Structure

291 H V TA. /T~'N ΑΧ A^ yOH ^νΆ i

292 Jx p T^Z —\ zV HZ M o I

293 CM T z b b IZ 2—z A\ pb ij

294 H 'Ά A+ yy+T nR ¹

295 H °_γν /γΑ_Ν TA A/^ o N T| A OH N^T i

820

821

Compound No. Structure

3U x O O a b IZ / >=z Vf /=< b

312 0 o v yq * 2ΓΧ M d O [—z o Γ \ \ cV

313 V / Τ 'Ν VL Λ ^N vXY ^NV_N \ 4

314 LL 0 0 IZ χ—z y~\ pA o Z—L Z / y0

315 T o Ll. 0 0 ^îbd

S22

Compound No. Structure

321 /y _od r o o z

322 . ! 7 o a h —z Az Va d=\

323 d o Z γζ o Çl \ q O o

324 z^Ç—z o a Z=/ ZI Va —* a d o A^z Z

823

824

Compound No. Structure

340 Y o O Z—(\ z / O

341 H °ïY /mka < I II

342 o V /V °

343 R-. z y—z o q o o Q

344 ri . z M z p \=z \/ ZT ri q ( O \ \ —z \

825

826

Compound No. Structure

361 H A- /A-An \A X/. o N Y A _0H N^J 5

362 _o î z A—z o fl M d o o o X

363 H T X. X/A_n XL x o N γΥ OH ^N-J

364 I o o b—z V f=\ flj

365 H °y“x Ά c(X fl~o 7

827

Compound No. Structure

373 MX Z Λ x-Va j

374 }=( / E >Z Q A λ 4 b T

375 r Y A ⁰ '00

376 °TX γΑΛ⁰ Ά^οη

377 H 0.-., N. 'Ύ CiS i OH 60,J

378 y>o N iAr'°'^'^OH

379 3 cA o 5

828

Compound No. Structure

387 H ,/γ\ Aa* T

388 < a b> I z /⁵¾ H. p=C

389 ο<2νη Ν' V N N. A î

390 O NH 'n' ^UnZYAh 1

391 F γγ-F ΗΤ \/ ^Άι '·γγ° ΐ

392 H cy_:A J 2 cÇa<>^_oh

393 H °γ^Νγ; I ΥΎ^Ν '1 A. JL N YY ON N.

394 H °ηα^ν-α· J Τ' /Ύ^ν ύ ' ^γ^γ°^^ΌΗ

829

Compound No. Structure

402 O NH ΎΓ yiiS WAy/Y V ¹ ‘ ?

403 Ο^,ΝΗ ,Ύ'Ν ° A ίΧγγ⁰ .Α_ν ' (U ' t

404 z— । y- H ΣΖ >=Z A fri 'ri

405 V ï λ, f J ALy/ri

406 ri' nS k-V Vyyyri¹ _N O * ^fί

407 oÇth /Άι ^N <Λ N rirA > N Μ ^{Λ 1} i

408 O^^NH Af V edi o M ¹7

409 nrr Vl V Vri ..--- o X N Y y -^ Oh 7

Compound No. Structure

410 H ΟχΛ^Λ । r N-K! ^βΝ Aï ^riA+v⁰'^''^'' M ¹

411 yy N ⁿ Ay * 1

412 a s IZ o z—C z '0

413 H VS M ¹

414 °v .a-^Aw __o ï

415 yy N /Vi^^N r^Oh ^λ J! A o A ^N Wr 7

416 p y- b rz >z f ri O z—ç z A

830

Compound No. Structure

417 °v^NY •ir ΥνΥ M ¹ 7

418 A fl. Q 0; o — Z \

419 Ά ^N C 9

420 aO A^J <Ύι v ?

421 H O^fA <Ή v +--X⁰ '0⁷ΌΗ

422 H °ν^Μ,<·ζ\ flS v Ν'^ίγγΑ^Ο H 7

423 H AA^C|0 j Δ ^N' yyS V nU ¹ 7

83 l

Compound No. Structure

428 oTnh orS nJ ¹

429 }γ _zR Ab B Y^H Hg Çr o

430 0' O Y AR 17 \=Z ]—\ ^zA

431 z: y- 2 o \— ζγ Q T o $<l o x

432 Ÿr 'N <xTï nR R_s

Compound No. Structure

433 u Yi n 'Ά Ο ¹ ?

434 Y z s— z o V/ γ Z0 '' zi Cy v o —z

435 z— o ÎZ^ V /H O Z—V z. / A/ X

436 _o<y o V <Λ iz y=^ o zA V

437 3γ° zk ZI : R % o 4 1

832

833

Compound No. Structure

449 H TT N νΛ v 'V. _N ⁰ - Voh N V 9

450 H o. n Jï N ΥΑθ'θ-ΧΗ 9

451 T I o Ύ X rz >=z --χ Z-J O Z X Z

452 H ΛΎ N OfS r^F ⁿV

453 H bd /Ίΐ ⁿ x/· t

834

Compound No.

Structure

464

465

466

467

468

835

Compound No. Structu re

H OH

469 \ k il

Z^ûH

Y Y 1

O.V

470 FjC^N^ /yS \ VL V

N_s 1 t

O. 17 •OH

471 Y

Oi '''Τι Q ,0^ ï

O.. O ΌΗ

472

Vj

YZ Q

473 H W Y ζγΥ Ύ

836

Compound No. Structure

479 F °yA_F ^F''TU v

480 H A ^N' ΠΠ h, M ^H *

481 H ΎΎ ΊΓ /Άΐ H \ , < I ^μξ \/ \ XL ^·_ c ÙZ — ^N 1'7 ''-' Ou >

482 1 1 T C ¹ x^~~ A

483 H AV N χΛι —nh₇ nX i

837

Compound No. Structure

489 Z=/ ZI Y. o 0

490 W N N Y A/

491 H Ύ <Ύι ^NÇ/ü> F 1

492 z o A—z \=z J A o z—e z / y=/ oA/

493 S z— o y„ Vq IZ Y X

838

Compound No. Structure

499 A ZI x w — Z X

500 z— o y 0 J—X

501 H ?

502 I o % b x z /² ‘Ά

503 H frh¹ vA Jk ^njiTT Ύ Jj— ^L—^f

839

840 or a pharmaceutically acceptable sait thereof.

8. The compound of claim 7, or a pharmaceutically acceptable sait thereof, wherein R⁶, in each instance, is selected from the group consisting of cyclopropyl, -O-R^bb, -0-(CH2)-R^bb, -O-(CH2)2-R^bb, -O-(CH2)₂~O-pyrîdazinyl, and optionally C_rC₃ alkyl-substituted imidazolyl; wherein,

R^bbis selected from the group consisting of cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, tetrahydrofuranyl, tetrahydropyranol, oxetanyl, dioxolanyl, azetidinyl, morpholinyl, piperazinyl, 2-oxa-5-azabicyclo[2.2.1]heptane, imidazolyl, tetrazolyl, pyridazïnyl, piperidinyl, thiomorpholinyl, and pyrrolidinyl, each optionally substituted with hydroxy, oxo, fluoro, -CF₃, -CH₂CF₃, -CH₂CHF₂, -CH₂CH₂F, methoxy, ethyl, or methyl.
9. The compound of claim 8, or a pharmaceutically acceptable sait thereof, wherein R⁶, in

779

780
10 C₃-C₇ cycloalkyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-C₆ alkyl, halo-C]-C₃ alkyl, hydroxy, C|-C₃alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl;

10 membered monocyclic heterocyclyl fused with Ring B, a C4-C7 cycloalkyl fused with Ring B, a phenyl fused with Ring B, or a 5- or 6- membered monocyclic heteroaryl fused with Ring B, each optionally substituted with one or two substituents, each independently selected from the group consisting of C1-C3 alkoxy, hydroxy, hydroxy-C i-C3-alkyl, C]-C₃ alkyl, C₃-C₇ cycloalkyl, and 5- or 6-membered monocyclic heterocyclyl.

10. The compound of any one of claims l -4, or a pharmaceutically acceptable sait thereof, wherein two R⁶ groups, taken together with the atom to which each is attached, form a 5- or 6-
11. The compound of claim 10, or a pharmaceutically acceptable sait thereof, wherein two R⁶

781 groups, taken together with the atom to which each is attached, form a pyrazolyl, dioxanyl, pyridinyl, pyrimidinyl, thiazolyl, furanyl, dioxolanyl, or phenyl ring fused with Ring B, wherein said ring is optionally substituted with one substituent selected from the group consisting of hydroxy, methoxy, tetrahydropyranyl, -CHEOH, and methyl.
12. The compound of claim 11, or a pharmaceutically acceptable sait thereof, wherein two R⁶ groups, taken together with the atom to which each is attached, form a ring selected from the

782 wherein the pair of represent the attachment of the ring with Ring B.
13. The compound of any one of claims l -12, or a pharmaceutically acceptable sait thereof, wherein f is l.
14. The compound of any one of claims l-3, or a pharmaceutically acceptable sait thereof, wherein f is 0 and Ring B is

; wherein, n is 0 or l ; and

Y“ and Y³ are each independently selected from the group consisting of CH, N, NH, NR⁶, S, O, and CR⁶, provided that only one of Y² and Y³ can be N, NH, NR⁶, S, or O.
15. The compound of any one of claims l-14, or a pharmaceutically acceptable sait thereof, wherein n is l,
16. The compound of any one of claims 1-15, or a pharmaceutically acceptable sait thereof, wherein R³ is selected from the group consisting of hydrogen, methyl, -CD₃, ethyl, phenyl, -CH₂CF₃, and -CH₂CH₂OH.
17. The compound of claim 16, or a pharmaceutically acceptable sait thereof, wherein R³ is methyl.
18. The compound of any one of claims l -17, or a pharmaceutically acceptable sait thereof,

783 wherein R⁴ is
19. The compound of claim 18, or a pharmaceutically acceptable sait thereof, wherein R^4e îs selected from the group consisting of hydrogen, methyl, isopropyl, -CHiOH, -CH2OC(CH₃)₃, and -CH2CH7SCH3; and R^4d is selected from the group consisting of hydrogen and methyl; or, R^4c and R^4d taken together with the atom to which each is attached form a cyclopropyl ring.
20. The compound of claim 19, or a pharmaceutically acceptable sait thereof, wherein R^4cand R^4d are each hydrogen.
21. The compound of any one of claims 18-20, or a pharmaceutically acceptable sait thereof, wherein R^4b is hydrogen.
22. The compound of any one of claims 18-21, or a pharmaceutically acceptable sait thereof, wherein R^4a is C|-Cô alkyl.
23. The compound of claim 22, or a pharmaceutically acceptable sait thereof, wherein R^4a is methyl, ethyl, isopropyl, tert-butyl, or 3-methylpentan-3-yl.
24. The compound of any one of claims 18-21, or a pharmaceutically acceptable sait thereof, wherein R⁴¹' is phenyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Ci-C& alkyl, halo-Ci-C₃ alkyl, hydroxy, C_rC₃alkoxy, C₃-C₇ cycloalkyl, and 5- to 10-membered monocyclic or fused bicyclic heterocyclyl.
25. The compound of claim 24, or a pharmaceutically acceptable sait thereof, wherein R^4a îs

5
26. The compound of any one of claims 18-21, or a pharmaceutically acceptable sait thereof, wherein R^4a is 5- to 10-membered monocyclic or fused bicyclic heteroaryl optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, C|-C₆ alkyl, halo-CJ-Cj alkyl, hydroxy, Ci-C₃ alkoxy, C3-C7 cycloalkyl, and 5- to 10-membered monocyclic, fused bicyclic, or spiro heterocyclyl;
27 . The compound of claim 26, or a pharmaceutically acceptable sait thereof, wherein R^4a is

786

787
28. The compound of claim 26, or a pharmaceutically acceptable sait thereof, wherein R.^4ais
29. The compound of claim 26, or a pharmaceutically acceptable sait thereof, wherein R.^4a is

788
30. The compound of claim 26, or a pharmaceutically acceptable sait thereof, wherein R^4j is

5
31. The compound of claim 26, or a pharmaceutically acceptable sait 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.
32. The compound of any one of claims 18-20, or a pharmaceutically acceptable sait thereof, 10 wherein R^4a and R^4h taken together with the atom to which each is attached form a 5- to 10membered monocyclic, fused bicyclic, or bridged bicyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from the group consisting of halogen, Cj-Cô alkyl, halo-Ci-C₃ alkyl, hydroxy, and Cj-C₃ alkoxy.

15
33. The compound of claim 32, or a pharmaceutically acceptable sait thereof, wherein R^4a

and R^4b taken together with the atom to which each is attached form a I , I

789
34. The compound of any one of claims 18 or 22-31, or a pharmaceutically acceptable sait thereof, wherein R^4b and R^4l taken together with the atom to which each is attached form a 5- to 7-membered monocyclic heterocyclyl, optionally substituted with one or two substituents, each independently selected from C1-C3 alkyl.
35. The compound of any one of claims 1-17, or a pharmaceutically acceptable sait thereof, R⁴⁹

I .0 wherein R⁴ îs , wherein R^4g is selected from the group consisting of C&-Cio monocyclic or fused bicyclic aryl and C1-C3 alkyl.
36. The compound of claim 35, or a pharmaceutically acceptable sait thereof, wherein R^4g is selected from the group consisting of phenyl and methyl.
37. The compound of claim 1, wherein the compound is selected from the group consisting of:

790

791

792

793

794

Compound No. Structure
38. A compound of formula:

or a pharmaceutically acceptable sait thereof.
39.

A compound of formula:

or a pharmaceutically acceptable sait thereof.
40.

A compound of formula:
41, and a pharmaceutically acceptable excipient.

41. A compound of formula:

841
42. A pharmaceutical composition comprising a compound according to any one of claims l-39 or a pharmaceutically acceptable sait thereof, and a pharmaceutically acceptable excipient.
43. A compound of any one of claims l -39 or the pharmaceutical composition of claim 42 for use in a method of inhibiting iron transport mediated by ferroportin in a subject.

43 Q z/— Z O q ^x zA Va o I
44. A pharmaceutical composition comprising a compound according to claim 40 or

44 T O o

51 % Z A—Z o AM / ^Z=Ç * ^z—A

52 # A y-z o G <

55 fZ Mz o r t

795

796

797

798

799

Compound No. Structure

103 H vv N aV , < L if 1 ^N ?

104 K f iz M —γ o zV 'U

Mb

105 /aV'N Vk A / / ^N ïTV

N V

NH

106 z A P/ ^N r il

N V i

107 O^NH V 1 τ o x / ^zi

Compound No.

108

109

HO

111

Structure

800

801

802

Compound No. Structure

129 H W Y A VL ^N Y%- NU 9

130 Λα (0

131 Ο °yN /ΥΥ VL X/^ ⁿyA N. 7

132 Λα v? JJ o /

133 ΞΕ / O O IZ Xz ° ^ZA Y ' b

803

Compound No. Structure

143 T p ' IZ Ή /0 °

144 H °A^NyA ΛΑ™ ^N II V ^OH t

145 I / \ o o z H iz O zA Z ' b

146 R-. M Z0 ZT

147 H l 7 T ° 'Ά /A^N VX A ^N t^n- N==/

804

Compound No. Structure

148 H °Y^N/V^0H Ύ λΎν η ^OH ⁿV

149 H O^N^-. ] T o Ύ L-V 'Χγγ'⁰ ^OH

150 H Y^Nn N /V'N VL Λ ^NW- N=/ 5

I5l ^—^~Z O Y^z \ z=l ZT 0 0 ⁷ Q \

152 H Y^NV'% Y U,. /Ύ^ν vX Y.o ^N Wr ^N V î

805

Compound No. Structure

158 z ° Z—( ZI Q fl O Z

159 Z Vz O M z0 zz q fl O

160 Q z γζ O Y Z S^z~ fl

I6l O N \ J. T N==/ *

162 H °ΤΎ N cL ' AA nA

806

807

Compound No. Structure

177 H 1 T 1

178 A o ^zv/ Vq° , ,^z=\ A / q o—

179 CJ J^z va o o z

180 0.^ .NH HH| ^N θ' ⁿ n N^q

808

809
45. A compound according to claim 40 or 41, or the pharmaceutical composition of claim 44 for use in a method of inhibiting iron transport mediated by ferroportin în a subject, comprising administering to the subject an effective amount of a.