POLQ inhibitors

Abstract

This specification generally refers to compounds of formula (I): (I) (wherein G, G a , G b , X, Y, R 1 , R 2 , Q 1 , Q 2 , and Q 3 has any of the meanings defined herein), or a stereoisomer or pharmaceutical salt thereof, as well as compositions containing them and their use in therapy. The compounds are inhibitors of the polymerase, DNA polymerase theta (Polθ or POLQ), and are thereby useful, particularly in the treatment of cancer. [Formula 1] JPEG2025540239000397.jpg36128

Description

[Technical Field]

[0001] This application claims the benefit of priority to U.S. Provisional Application Nos. 63 / 386,263, filed December 6, 2022, and 63 / 497,847, filed April 24, 2023, each of which is incorporated by reference in its entirety for all purposes. [Background technology]

[0002] DNA polymerase theta (Polθ) is a specialized polymerase encoded in the human genome by the POLQ gene and is therefore also known simply as POLQ. It belongs to the A family, a group of DNA polymerases considered error-prone due to the lack of proofreading activity. It is the only human DNA polymerase that also contains an active DNA helicase domain (Loeb and Monnat, 2008; Ramsden et al., 2022). POLQ is involved in genome maintenance processes through its role in translesion synthesis (TLS), a DNA damage tolerance mechanism, and alternative DNA-end joining (alt-EJ), a DNA repair mechanism involved in the resolution of DNA double-strand breaks (DSBs) (Ramsden et al., 2022; Yoon et al., 2019).

[0003] DNA DSBs are the most cytotoxic lesions cells face, and several DNA damage signaling and repair mechanisms have evolved to address them. In human cells, DSB repair is primarily carried out by the non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways, with a third pathway, termed alt-EJ, generally considered a less frequently used alternative. The HRR and alt-EJ pathways share a first step in which the ends of DNA DSBs are processed (resected) to generate regions of single-stranded DNA (ssDNA). During HRR, resection is relatively extensive, whereas during alt-EJ, resection is maintained at a shorter extent through an elusive mechanism. Furthermore, alt-EJ is associated with the use of sequence microhomology (2–6 base pairs) surrounding the DSB site for repair by direct annealing, DNA flap processing, and ligation, which explains its error-prone nature. Therefore, alt-EJ is also referred to as microhomology-mediated end joining (MMEJ) (Ciccia and Elledge, 2010).

[0004] HRR is a form of DNA repair that uses the sister chromatid as a template for repair when a DSB occurs on a chromosomal chromatid. Therefore, HRR is considered error-free and can occur only when the sister chromatid is available, i.e., during the DNA replication (synthesis) phase (S phase) and gap phase 2 (G2 phase) of the cell cycle. HRR deficiency (HRD) has been well described in tumors and is genetically associated with mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 (BRCA genes), among others (Pellegrino et al., 2019). HRD is also associated with increased levels of genomic instability, highlighted by the presence of specific mutational signatures, including single-base substitutions (SBS), insertion-deletions (INDELs), and rearrangements (Nik-Zainal et al., 2016). Interestingly, the SBS signature associated with HRD (SBS3) also associates with the INDEL signature (ID6), characterized by extensive microhomology usage at breakpoints (Alexandrov et al., 2020), suggesting that MMEJ may be an important DNA repair pathway in the absence of HRR. Consistent with this, signatures of MMEJ-mediated repair events have been identified in secondary (reversion) mutations that repair open reading frames of BRCA and other HRR-related genes in tumors from patients progressing through treatment, strongly suggesting that these reversion events are mediated by MMEJ repair and drive treatment resistance in these clinical cases (Pettitt et al., 2020, Tobalina et al., 2021).

[0005] Recently, POLQ has become the only known MMEJ-specific protein to be involved in MMEJ repair but not in HRR (Wyatt et al., 2016; Yousefzadeh et al., 2014). Interestingly, reports have highlighted the genetic dependency of synthetic lethality between inactivating mutations in genes involved in HRR (BRCA1, BRCA2, FANCD2, ATM) and the absence of POLQ activity (Ceccaldi et al., 2015; Mateos-Gomez et al., 2015; Shima et al., 2004), either as a polymerase or helicase (Mateos-Gomez et al., 2017). Therefore, there is growing interest in developing POLQ inhibitors for the treatment of HRD tumors, either as single agents or in combination with poly(ADP-ribose) polymerase (PARP) inhibitors (Zatreanu et al., 2021, Zhou et al., 2021). Importantly, POLQ-deficient cells have also been shown to be sensitive to DNA-damaging agents, including ionizing radiation (Higgins et al., 2010, Yousefzadeh et al., 2014), potentially opening up the possibility of combining POLQ inhibitors with chemotherapy or radiation therapy (Higgins and Boulton, 2018).

[0006] Therefore, there is a need for POLQ inhibitors that are selective, exhibit good bioavailability, and are suitable for dosing. Summary of the Invention

[0007] One embodiment disclosed herein is a compound of formula (I):

[0008] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, During the ceremony, R1 and R 2 are each independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, —CN, C2-C4 alkyne, or C2-C6 alkoxyalkyl; Q 1 , Q 2 , and Q 3 may be independently N, CLR, or CR x and Q 1 , Q 2 , and Q 3 Not more than one of the following is a CLR: L is a bond, -O-, -C(O)-, or -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -O(CH2) p NR y , -NR y -, -(CH2) p -, -(CH2) p NR y -, -(CH2) p O-, -(CH2) p C(O)-, -(CH2) p C(O)O- or -O(CH2) p - and p is independently 1, 2, or 3; R, H, R a , R b , R c , or R d and R a is a 3-10 membered heterocycle optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R b is a C1-C7 alkyl, and one or two methylene groups from the C1-C7 alkyl are NR e or O, one or two single bonds in the C2-C7 alkyl chain are optionally and independently replaced with a double or triple bond, and the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amido, C1-C4 sulfonyl, C1-C4 sulfonamido, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3- to 10-membered heterocycle; the C3-C6 carbocyclic ring is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; the 3- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4- to 6-membered heterocycle, and C1-C7 alkyl, and the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R c is a C3-C6 carbocycle optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; R d is C1-C4 sulfonyl or C1-C4 sulfonamide, R y is H, C1-C3 alkyl, or C1-3 haloalkyl; R x is H, halo, hydroxy, -CN, -NH2, C1-C3 alkoxy, C1-C3 alkyl, or C1-3 haloalkyl; R e is H, halo, C1-C8 alkyl, or C1-C8 haloalkyl; X is C1-C4 alkylene, Y is phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; G is N or CH; G a and G b is N, CH, or CR 5 and G a and G b and only one of G is N or CH; a and G b Only one of the CR 5 and R 5 but,

[0009] [ka] and Z a and Z b are independently C1-C3 alkyl or C1-C3 haloalkyl, or Z a and Z b form a 3- to 6-membered carbocyclic or heterocyclic ring, Z c is H, —CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkyne. DETAILED DESCRIPTION OF THE INVENTION

[0010] This detailed description and its specific examples illustrate embodiments and are for purposes of illustration only. Accordingly, it is not intended to be limiting of the exemplary embodiments set forth herein. Furthermore, it should be understood that various features that are, for clarity, described in the context of separate embodiments, may also be combined to form a single embodiment. Conversely, various features that are, for brevity, described in the context of a single embodiment, may also be combined to form subcombinations thereof.

[0011] Listed below are definitions of various terms used in the specification and claims.

[0012] The term "alkoxy" refers to an alkyl group attached to the remainder of the molecule through an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0013] The term "alkoxyalkyl" refers to an alkyl group attached to an alkoxy group, where the group is attached to the remainder of the molecule through a carbon on the alkyl group, i.e., having the structure -RO-R', where R and R' are the same or different alkyl groups.

[0014] The term "alkyl" or "alkane" refers to a straight-chain or branched non-aromatic hydrocarbon that is completely saturated. Examples of straight-chain and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl, and octyl.

[0015] The term "alkylamino" refers to an amino group substituted with at least one alkyl group, i.e., -NRR', NHR, NRR'H + , or NH2R + where R and R' are the same or different alkyl groups.

[0016] The term "alkyne" or "alkynyl" refers to a non-aromatic hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkyne groups include acetylene, propyne, and butyne.

[0017] The term "amide" refers to a group having the general formula RC(=O)NR 1 R 2 or

[0018] [ka] where R 1 , R 2 , and R 3 are either hydrogen or the same or different alkyl groups, provided that at least one is an alkyl group.

[0019] The term "carbamate" refers to a compound of the general formula ROC(O)NRR or

[0020] [ka] where R 1 , R 2 , and R 3 are either hydrogen or the same or different alkyl groups, provided that at least one is an alkyl group. The carbamate is attached to the rest of the molecule through a carbon of one of the alkyl groups.

[0021] The term "carbocycle" refers to a partially or fully saturated non-aromatic hydrocarbon ring system, including cycloalkyl, cycloalkenyl, and cycloalkynyl. Cycloalkyl includes cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, and cyclohexene.

[0022] The term "ester" refers to a compound having the structure R 1 -C(O)-OR 2 , or

[0023] [ka] where R 1 and R 2 are the same or different alkyl groups. The ester is attached to the rest of the molecule through a carbon in one of the alkyl groups.

[0024] The term "halo" refers to fluoro, chloro, bromo, and iodo. In some embodiments, halo is fluoro or chloro. In other embodiments, halo is fluoro. In yet other embodiments, halo is chloro.

[0025] The term "haloalkyl" means an alkyl group in which one or more hydrogens have been replaced with halo.

[0026] The term "hydroxyalkyl" means an alkyl group in which one or more hydrogens have been replaced with hydroxy.

[0027] The terms "heterocycle," "heterocyclic," or "heterocyclyl" refer to a partially or fully saturated hydrocarbon ring system in which at least one ring carbon atom is replaced with a heteroatom independently selected from nitrogen, oxygen, and sulfur. Heterocycle groups can be attached to the remainder of the molecule through a carbon or nitrogen ring atom. Heterocycles include monocyclic heterocycles as well as spiro, fused, and / or bridged polycyclic heterocycles, such as bicyclic heterocycles. Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, azetidine, pyrrolidine, piperidine, piperazine, azepane, diazepane, oxetane, and isoxazolidine. Examples of polycyclic heterocycles include 2-azaspiro[3.3]heptane, 2,6-diazaspiro[3.3]heptane, 1,6-diazaspiro[3.3]heptane, 2-thia-6-azaspiro[3.3]heptane, 3,6-diazabicyclo[3.1.1]heptane, 2,6-diazaspiro[3.4]octane, 3,8-diazabicyclo[3.2.1]octane, and 4,7-diazaspiro[2.5]octane.

[0028] The term "sulfonyl" refers to a group of the general formula R 1 S(O)2R 2 or

[0029] [ka] where R 1 and R 2 are either hydrogen or the same or different alkyl groups, provided that at least one is an alkyl group. The sulfonyl is attached to the rest of the molecule through a carbon of either alkyl group.

[0030] As used herein, "C" refers to a compound in which x and y are integers. x~y The prefix C used in terms such as "alkyl" x~y indicates the range of the number of carbon atoms present in the group. 1~3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl. 1~4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i-propyl, n-butyl, i-butyl, s-butyl, and t-butyl. In some cases, the group has two sections containing carbons, in which case the prefix indicates the numerical range of the total carbons in the group, e.g., C 2~6 Alkoxyalkyl refers to an alkoxyalkyl group in which the alkyl and alkoxy groups together have 2 to 6 carbons.

[0031] "Patient" refers to an animal for which one or more of the active agents described herein have a therapeutic effect. In some embodiments, the patient is a human.

[0032] As used herein, and unless otherwise indicated, the term "pharmaceutically acceptable" is used herein to refer to compounds, materials, compositions, and / or dosage forms that are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication, commensurate with a reasonable benefit / risk ratio.

[0033] As used herein, unless otherwise specified, the phrase "effective amount" means an amount of a compound or composition sufficient to significantly and positively modify the symptoms and / or condition being treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary depending on the particular condition being treated, the severity of the condition, the duration of treatment, the nature of any concurrent therapy, the particular active ingredient used, the particular pharmaceutically acceptable excipients / carriers employed, and similar factors within the knowledge and expertise of the attending physician.

[0034] The term "treating," as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progression of, or slowing or delaying the progression of, the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment," as used herein, unless otherwise indicated, refers to the act of treating, as "treating" is defined immediately above. The term "treating" also includes adjuvant and neoadjuvant therapy of a subject. The term "treating" also includes reducing or inhibiting tumor growth or the proliferation of cancer cells in a subject.

[0035] The term "pharmaceutically acceptable salts" includes acid or base addition salts that retain the biological effectiveness and properties of the compounds disclosed herein. In many cases, the compounds disclosed herein are capable of forming acid and / or base salts by virtue of the presence of basic and / or carboxyl groups or groups similar thereto.

[0036] compound One embodiment disclosed herein is a compound of formula (I):

[0037] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, During the ceremony, R 1 and R 2are each independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, —CN, C2-C4 alkyne, or C2-C6 alkoxyalkyl; Q 1 , Q 2 , and Q 3 may be independently N, CLR, or CR x and Q 1 , Q 2 , and Q 3 Not more than one of the following is a CLR: L is a bond, -O-, -C(O)-, or -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -O(CH2) p NR y , -NR y -, -(CH2) p -, -(CH2) p NR y -, -(CH2) p O-, -(CH2) p C(O)-, -(CH2) p C(O)O-, -O(CH2) p - and p is independently 1, 2, or 3; R, H, R a , R b , R c , or R d and R a is a 3-10 membered heterocycle optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R bis a C1-C7 alkyl, and one or two methylene groups from the C1-C7 alkyl are NR e or O, one or two single bonds in the C2-C7 alkyl chain are optionally and independently replaced with a double or triple bond, and the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amido, C1-C4 sulfonyl, C1-C4 sulfonamido, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3- to 10-membered heterocycle; the C3-C6 carbocyclic ring is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; the 3- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4- to 6-membered heterocycle, and C1-C7 alkyl, and the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R c is a C3-C6 carbocycle optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; R d is C1-C4 sulfonyl or C1-C4 sulfonamide, R y is H, C1-C3 alkyl, or C1-3 haloalkyl; R x is H, halo, hydroxy, -CN, -NH2, C1-C3 alkoxy, C1-C3 alkyl, or C1-3 haloalkyl; R e is H, halo, C1-C8 alkyl, or C1-C8 haloalkyl; X is C1-C4 alkylene, Y is phenyl or 5-6 membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with 1-3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; G is N or CH; G a and G b is N, CH, or CR 5 and G a and G b and only one of G is N or CH; a and G b Only one of the CR 5 and R 5 but,

[0038] [ka] and Z a and Z b are independently C1-C3 alkyl or C1-C3 haloalkyl, or Z a and Z b form a 3- to 6-membered carbocyclic or heterocyclic ring, Z c is H, —CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkyne.

[0039] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N.

[0040] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is CH.

[0041] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a But it's CR5.

[0042] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b But it's CR5.

[0043] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b But it is N.

[0044] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b But it is CH.

[0045] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b But it is N.

[0046] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: b But it is CH.

[0047] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1 to C3 alkyl.

[0048] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Zb is -CH3.

[0049] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a or G b is CR5 and R 5 but,

[0050] [ka] wherein p is 1 to 4.

[0051] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a or G b is CR5 and R 5 but,

[0052] [ka] where p is 2.

[0053] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: a or G b is CR5 and R 5 but,

[0054] [ka] where p is 1.

[0055] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z c is -CH3.

[0056] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z c But it is -CN.

[0057] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0058] [ka] wherein p is 1 to 4.

[0059] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0060] [ka] where p is 1.

[0061] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0062] [ka] where p is 2.

[0063] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0064] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl

[0065] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0066] [ka] wherein p is 1 to 4, and Z c is -CH3.

[0067] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0068] [ka] wherein p is 1 and Z c is a C1-C3 alkyl.

[0069] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0070] [ka] wherein p is 1 and Z c is -CH3.

[0071] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0072] [ka] wherein p is 2 and Z c is -CH3.

[0073] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0074] [ka] wherein p is 1 to 4, and Z c But it is -CN.

[0075] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and Gb is N and G a is CR5 and R 5 but,

[0076] [ka] wherein p is 1 and Z c But it is -CN.

[0077] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0078] [ka] wherein p is 2 and Z c But it is -CN.

[0079] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0080] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is N-heteroaryl.

[0081] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is pyridine.

[0082] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is substituted.

[0083] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3, and haloalkyl.

[0084] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is substituted with —Cl.

[0085] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is substituted with —CH 3 .

[0086] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is substituted with cyclopropyl.

[0087] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is unsubstituted.

[0088] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0089] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is pyridine substituted with one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0090] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one substituent selected from halo and C1-C3 alkyl.

[0091] Some embodiments disclosed herein provide a compound of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is pyridine substituted with one substituent selected from halo and C1-C3 alkyl.

[0092] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one substituent selected from -Cl and -CH.

[0093] Some embodiments disclosed herein provide compounds of Formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is pyridine substituted with one substituent selected from -Cl and -CH.

[0094] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, —CN, or C2-C4 alkyne.

[0095] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, halo, —CH 3 , —OCH 3 , CH 2 OH, —CN, or —C—CH.

[0096] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, halo, or C1-C3 alkyl.

[0097] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, halo, or -CH 3. is.

[0098] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 are each independently H, —Cl, —F, or —CH 3 .

[0099] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 and R 2 But it is -H.

[0100] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 But it's a halo.

[0101] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -Cl.

[0102] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 But it is -F.

[0103] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 But it is -H.

[0104] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is a halo, R 2 But it is -H.

[0105] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -Cl, and R 2 But it is -H.

[0106] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -F and R 2 But it is -H.

[0107] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 and R 2 But it is -H.

[0108] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 But it's a halo.

[0109] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is -Cl.

[0110] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 But it is -F.

[0111] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 2 is -CH3.

[0112] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 But it is -H.

[0113] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -H and R 2 But it's a halo.

[0114] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -H and R 2 is -Cl.

[0115] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -H and R 2 But it is -F.

[0116] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein R 1 is -H and R 2 is -CH3.

[0117] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But it's the CLR.

[0118] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 But it's the CLR.

[0119] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 But it's the CLR.

[0120] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 But it's the CLR.

[0121] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR, and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -is 。

[0122] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR, and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -is 。

[0123] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR, and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -is 。

[0124] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR, and L is a bond, -O-, -(CH2) p O- or -O(CH2) p - である。

[0125] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is a CLR and L is a bond.

[0126] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is a CLR and L is a bond 。

[0127] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2is a CLR and L is a bond.

[0128] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is a CLR and L is a bond.

[0129] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR and L is -O-.

[0130] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O- 。

[0131] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O- 。

[0132] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O- 。

[0133] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR and L is -(CH2) p It is O-.

[0134] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -(CH2) p It is O-.

[0135] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -(CH2) p It is O-.

[0136] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -(CH2) p It is O-.

[0137] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR and L is -O(CH2) p -It is.

[0138] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O(CH2) p -It is.

[0139] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O(CH2) p -It is.

[0140] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O(CH2) p -It is.

[0141] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: 1 , Q 2 , or Q 3 is CLR and L is -O(CH2)2-.

[0142] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O(CH2)2-.

[0143] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O(CH2)2-.

[0144] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O(CH2)2-.

[0145] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR, and L is -C(O)-, -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -(CH2)p C(O)- or -(CH2) p C(O)O-.

[0146] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR, and L is -C(O)-, -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -(CH2) p C(O)- or -(CH2) p C(O)O-.

[0147] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR, and L is -C(O)-, -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -(CH2) p C(O)- or -(CH2) p C(O)O-.

[0148] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR, and L is -C(O)-, -O(CH2) p C(O)-, -C(O)NR y -, -O(CH2) p C(O)NR y -, -(CH2) p C(O)- or -(CH2) p C(O)O-.

[0149] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR, R is H, R a or R b is.

[0150] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 is CLR, R is H, R a or R a is.

[0151] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 2 is CLR, R is H, R a or R b is.

[0152] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 3 is CLR, R is H, R a or R b is.

[0153] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR and R is R a is.

[0154] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3But CLR a and R a is a 3- to 10-membered N-heterocycle.

[0155] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is a 4- to 7-membered N-heterocycle.

[0156] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is a six-membered N-heterocycle.

[0157] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is piperidine, 1,2-diazinane, 1,3-diazinane, 1,4-diazinane, 1,2-oxazinane, 1,3-oxazinane, or 1,4-oxazinane.

[0158] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R ais substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4- to 6-membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

[0159] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is substituted with C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, —CN, C2-C8 ester, and C1-C5 alkoxy.

[0160] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is substituted with C1-C7 alkyl substituted with oxo.

[0161] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is substituted with C1-C7 alkyl substituted with C1-C5 alkoxy.

[0162] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and R a is substituted with methyl.

[0163] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and L is -O(CH2) p - and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0164] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a and L is -O(CH2) p - and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0165] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)2-, and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0166] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1, Q 2 , or Q 3 But CLR a L is -O(CH2)2-, and R a is an optionally substituted 4- to 7-membered N-heterocycle.

[0167] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)2-, and R a is an unsubstituted 4- to 7-membered N-heterocycle.

[0168] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)2-, and R a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

[0169] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)3-, and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0170] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)3-, and Ra is a 4- to 7-membered N-heterocycle.

[0171] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)3-, and R a is an unsubstituted 4- to 7-membered N-heterocycle.

[0172] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O(CH2)3-, and R a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

[0173] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a where L is a bond and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0174] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a where L is a bond and R a is a 4- to 7-membered N-heterocycle.

[0175] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a where L is a bond and R a is an unsubstituted 4- to 7-membered N-heterocycle.

[0176] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a where L is a bond and R a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

[0177] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O- and R a is an optionally substituted 3- to 10-membered N-heterocycle.

[0178] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O- and R a is a 4- to 7-membered N-heterocycle.

[0179] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3But CLR a L is -O- and R a is an unsubstituted 4- to 7-membered N-heterocycle.

[0180] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR a L is -O- and R a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

[0181] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 is CLR and R is R b is.

[0182] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R bis substituted with 1 to 4 substituents independently selected from halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amido, C1-C4 sulfonyl, C1-C4 sulfonamido, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxyl, and the 3-10 membered heterocycle The ring is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4- to 6-membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

[0183] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with at least one C3-C6 carbocyclic ring, and the C3-C6 carbocyclic ring is substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy.

[0184] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with at least one C3-C6 carbocyclic ring, and the C3-C6 carbocyclic ring is substituted with 1 to 4 substituents independently selected from hydroxy and halo.

[0185] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with hydroxy.

[0186] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with a 3- to 10-membered heterocycle.

[0187] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with an N-heterocycle.

[0188] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with a 4- to 7-membered N-heterocycle.

[0189] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R bis substituted with a 3-10 membered heterocycle, for example, but not limited to, an N-heterocycle such as, but not limited to, a 4-7 membered N-heterocycle, wherein the heterocycle is substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

[0190] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with a 3-10 membered heterocycle, for example, but not limited to, a 4-7 membered N-heterocycle, wherein the heterocycle is substituted with C1-C7 alkyl, oxo, and / or halo.

[0191] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with amino, C1-C8 amido, and / or C1-C4 alkylamino.

[0192] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and R b is substituted with oxo, hydroxy, and / or carboxy.

[0193] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an optionally substituted C1-C5 alkyl.

[0194] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an optionally substituted C1-C3 alkyl.

[0195] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is C1-C5 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy.

[0196] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is C1-C3 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy.

[0197] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is a C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amido.

[0198] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b and L is -O- and R b is a C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amido.

[0199] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an unsubstituted C1-C5 alkyl.

[0200] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an unsubstituted C1-C3 alkyl.

[0201] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an optionally substituted C1-C7 alkyl, and one or two methylene groups from the C1-C7 alkyl are independently selected from NR e or substituted with O.

[0202] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an optionally substituted C1-C7 alkyl, and one methylene group from the C1-C7 alkyl is replaced with NH.

[0203] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b L is -O- and R b is an optionally substituted C1-C7 alkyl, and one methylene group from the C1-C7 alkyl is replaced with NCH3.

[0204] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an optionally substituted C1-C5 alkyl.

[0205] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an optionally substituted C1-C3 alkyl.

[0206] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is C1-C5 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy.

[0207] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is C1-C3 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy.

[0208] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R bis a C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amido.

[0209] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is a C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amido.

[0210] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an unsubstituted C1-C5 alkyl.

[0211] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an unsubstituted C1-C3 alkyl.

[0212] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R bis an optionally substituted C1-C7 alkyl, and one or two methylene groups from the C1-C7 alkyl are independently selected from NR e or substituted with O.

[0213] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an optionally substituted C1-C7 alkyl, and one methylene group from the C1-C7 alkyl is replaced with NH.

[0214] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR b where L is a bond and R b is an optionally substituted C1-C7 alkyl, and one methylene group from the C1-C7 alkyl is replaced with NCH3.

[0215] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR c is.

[0216] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR c and R cis substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy.

[0217] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 , or Q 3 But CLR c and R c is substituted with 1 to 4 substituents independently selected from hydroxy and halo.

[0218] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0219] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl, and R 1 and R 2 are each independently H, —Cl, —F, or —CH 3 .

[0220] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0221] [ka] wherein p is 1 or 2, and Z c is -CH3, Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl, and R 1 and R 2 are each independently H, —Cl, —F, or —CH 3 .

[0222] Some embodiments disclosed herein provide compounds of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein G is N and G b is N and G a is CR5 and R 5 but,

[0223] [ka] where p is 1 or 2, and Z c is —CH3, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl, and R 1 and R 2 are each independently H, —Cl, —F, or —CH 3 .

[0224] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0225] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0226] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0227] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0228] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0229] [ka] wherein p is 1 or 2, and Z c is -CH3, Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0230] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G ais CR5 and R 5 but,

[0231] [ka] wherein p is 1 or 2, and Z c is -CH3, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0232] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0233] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is phenyl having one substituent selected from halo and C1-C3 alkyl; R 1 and R 2are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0234] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0235] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is N-heteroaryl having one substituent selected from halo and C1-C3 alkyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a or R b is.

[0236] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0237] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a is.

[0238] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0239] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R a is.

[0240] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0241] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R b is.

[0242] Some embodiments disclosed herein provide a compound of formula (I), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein: G is N and G b is N and G a is CR5 and R 5 but,

[0243] [ka] wherein p is 1 to 4, and Z c is C1-C3 alkyl, Y is N-heteroaryl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or C1-C3 alkyl; Q 1 , Q 2 , and Q 3 is CLR or CH, and Q 1 , Q 2 , and Q 3 and only one of the groups is CLR, and L is a bond, —O—, —(CH) p O- or -O(CH2) p - and R is R b is.

[0244] Some embodiments disclosed herein include a compound of formula (I) having the structure of formula (IA):

[0245] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 5 , Q 1 , Q 2 , Q 3 and X and Y are as defined in formula (I).

[0246] Other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0247] Still other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0248] Still other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0249] Still other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0250] Other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0251] Other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0252] Other embodiments disclosed herein provide compounds of formula (IA), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl; and Z a and Z b are independently C1-C3 alkyl, and Z c But it's H.

[0253] In still other embodiments, X is -CH2-, Y is phenyl substituted with 1 or 2 substituents independently selected from halo and C1-C3 alkyl, and Z a and Z b is -CH3 and Z c is H. In a further embodiment, Y is phenyl and Z a and Z b is -CH3 and Z c is H.

[0254] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IB):

[0255] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 5 , Q 1 , Q 2 , Q 3 and X and Y are as defined in formula (I).

[0256] Other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0257] Still other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0258] Still other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0259] Yet other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0260] Other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0261] Other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0262] Other embodiments disclosed herein provide compounds of formula (IB), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN. a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0263] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IC):

[0264] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: R 1 , R 2 , R 5 , Q 1 , Q 2 , Q 3 and X and Y are as defined in formula (I).

[0265] Other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0266] Still other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0267] Still other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0268] Still other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl. In yet a further embodiment of the invention, Y is phenyl substituted with halo. In yet a further embodiment of the invention, Y is phenyl substituted with Cl.

[0269] Yet other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is 5-6 membered heteroaryl. In further embodiments, Y is pyridine.

[0270] Still other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is a 5-6 membered heteroaryl optionally substituted with 1-3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0271] Other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0272] Yet other embodiments disclosed herein provide compounds of formula (IC), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C-C alkyl.

[0273] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (ID):

[0274] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: G, G a , G b , X, Y, R 1 , R 2, L and R are as defined in formula (I).

[0275] Other embodiments herein provide compounds of formula (ID), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0276] Still other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0277] Yet other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0278] Other embodiments herein provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0279] Yet other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0280] Still other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0281] Other embodiments herein provide compounds of formula (ID), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0282] Other embodiments herein provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0283] Yet other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0284] Still other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0285] Other embodiments herein provide compounds of formula (ID), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0286] Other embodiments herein provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0287] Yet other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0288] Still other embodiments provide compounds of formula (ID), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0289] Other embodiments herein provide compounds of formula (ID), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0290] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IE):

[0291] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: G, G a , G b , X, Y, R 1 , R 2 , L and R are as defined in formula (I).

[0292] Other embodiments herein are compounds of formula (IE), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p or any stereoisomer or pharmaceutically acceptable salt thereof.

[0293] Still other embodiments provide compounds of formula (IE), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or Rb is.

[0294] Yet other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0295] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0296] Yet other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0297] Still other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0298] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0299] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0300] Yet other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0301] Still other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0302] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0303] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0304] Yet other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0305] Still other embodiments provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0306] Other embodiments herein provide compounds of formula (IE), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0307] Some embodiments disclosed herein provide a compound of Formula (I) having the structure of Formula (IF):

[0308] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: G, G a , G b , X, Y, R 1 , R 2 , L and R are as defined in formula (I).

[0309] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0310] Still other embodiments provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0311] Yet other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0312] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0313] Yet other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0314] Still other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0315] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0316] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0317] Yet other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0318] Still other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0319] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is Ra is.

[0320] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0321] Yet other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0322] Still other embodiments provide compounds of formula (IF), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0323] Other embodiments herein provide compounds of formula (IF), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0324] Some embodiments disclosed herein provide a compound of Formula (I) having the structure of Formula (IG):

[0325] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: G, G a , G b , X, Y, R 1 , R 2 , L and R are as defined in formula (I).

[0326] Other embodiments herein provide compounds of formula (IG), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0327] Still other embodiments provide compounds of formula (IG), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0328] Yet other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0329] Other embodiments herein provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0330] Yet other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0331] Still other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0332] Other embodiments herein provide compounds of formula (IG), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0333] Other embodiments herein provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0334] Yet other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0335] Still other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0336] Other embodiments herein provide compounds of formula (IG), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0337] Other embodiments herein provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0338] Yet other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0339] Still other embodiments provide compounds of formula (IG), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0340] Other embodiments herein provide compounds of formula (IG), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0341] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IH):

[0342] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: G, G a , G b , X, Y, R 1 , R 2 , L and R are as defined in formula (I).

[0343] Other embodiments herein provide compounds of formula (IH), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0344] Still other embodiments provide compounds of formula (IH), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0345] Yet other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0346] Other embodiments herein provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0347] Yet other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0348] Still other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0349] Other embodiments herein provide compounds of formula (IH), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0350] Other embodiments herein provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0351] Yet other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is Ra is.

[0352] Still other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0353] Other embodiments herein provide compounds of formula (IH), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0354] Other embodiments herein provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0355] Yet other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0356] Still other embodiments provide compounds of formula (IH), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0357] Other embodiments herein provide compounds of formula (IH), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0358] Some embodiments disclosed herein provide a compound of formula (I) having the structure of formula (II):

[0359] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: X, Y, R 1 , R 2 , R 5 , L and R are as defined in formula (I).

[0360] Other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0361] Still other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0362] Still other embodiments disclosed herein provide compounds of Formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0363] Still other embodiments disclosed herein provide compounds of Formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0364] Other embodiments disclosed herein provide compounds of Formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0365] Other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0366] Other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN. a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0367] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0368] Still other embodiments provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0369] Yet other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0370] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0371] Yet other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0372] Still other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0373] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0374] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0375] Yet other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0376] Still other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0377] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0378] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0379] Yet other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0380] Still other embodiments provide compounds of formula (II), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0381] Other embodiments herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0382] Other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0383] Other embodiments disclosed herein provide compounds of formula (II), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or —CH3, and L is a bond, —O—, —(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0384] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IJ):

[0385] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: X, Y, R 1 , R 2 , R 5 , L and R are as defined in formula (I).

[0386] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0387] Still other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0388] Still other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0389] Still other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0390] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0391] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0392] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN. a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0393] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0394] Still other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0395] Yet other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0396] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0397] Yet other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0398] Still other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0399] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0400] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0401] Yet other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0402] Still other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0403] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0404] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0405] Yet other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0406] Still other embodiments provide compounds of formula (IJ), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0407] Other embodiments herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0408] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0409] Other embodiments disclosed herein provide compounds of formula (IJ), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or —CH3, and L is a bond, —O—, —(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0410] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IK):

[0411] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: X, Y, R 1 , R 2 , R 5 , L and R are as defined in formula (I).

[0412] Other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0413] Still other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0414] Still other embodiments disclosed herein provide compounds of Formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0415] Yet other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0416] Other embodiments disclosed herein provide compounds of Formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0417] Other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0418] Other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN. a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0419] Other embodiments herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0420] Still other embodiments provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0421] Yet other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0422] Other embodiments herein provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0423] Yet other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0424] Still other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0425] Other embodiments herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0426] Other embodiments herein provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0427] Yet other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0428] Still other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0429] Other embodiments herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0430] Other embodiments herein provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0431] Yet other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0432] Still other embodiments provide compounds of formula (IK), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0433] Other embodiments herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0434] Other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0435] Other embodiments disclosed herein provide compounds of formula (IK), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or —CH3, and L is a bond, —O—, —(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0436] Some embodiments disclosed herein include a compound of Formula (I) having the structure of Formula (IL):

[0437] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, wherein: X, Y, R 1 , R 2 , R 5 , L and R are as defined in formula (I).

[0438] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is —CH 2 —.

[0439] Still other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0440] Still other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0441] Still other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0442] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0443] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0444] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN, and in a further embodiment, Z a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0445] Other embodiments herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0446] Still other embodiments provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0447] Yet other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0448] Other embodiments herein provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0449] Yet other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0450] Still other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0451] Other embodiments herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0452] Other embodiments herein provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0453] Yet other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0454] Still other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0455] Other embodiments herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0456] Other embodiments herein provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0457] Yet other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0458] Still other embodiments provide compounds of formula (IL), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0459] Other embodiments herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0460] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0461] Other embodiments disclosed herein provide compounds of formula (IL), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or —CH3, and L is a bond, —O—, —(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0462] Some embodiments disclosed herein include a compound of formula (I) having the structure of formula (IM):

[0463] [ka] or any stereoisomer thereof or a pharmaceutically acceptable salt thereof, During the ceremony, X, Y, R 1 , R 2 , R 5 , L and R are as defined in formula (I).

[0464] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0465] Still other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0466] Still other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, —CN, C1-C3 haloalkyl, and cyclopropyl.

[0467] Yet other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In a further embodiment of the invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0468] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein X is -CH- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C-C alkyl, C-C alkoxy, -CN, C-C haloalkyl, and cyclopropyl.

[0469] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl, and Z c is H. In still further embodiments, Z a and Z b is -CH3 and Z c But it's H.

[0470] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN. a and Z b forms a three-membered carbocyclic ring, and Z c is H or C1-C3 alkyl. a and Z b forms a four-membered carbocyclic ring, and Z c is H or C1-C3 alkyl.

[0471] Other embodiments herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p -It is.

[0472] Still other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond, —O—, —(CH) p O- or O(CH2) p - and R is R a or R b is.

[0473] Yet other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0474] Other embodiments herein provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b is.

[0475] Yet other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b is.

[0476] Still other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a or R b is.

[0477] Other embodiments herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a or R b is.

[0478] Other embodiments herein provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a is.

[0479] Yet other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a is.

[0480] Still other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R a is.

[0481] Other embodiments herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R a is.

[0482] Other embodiments herein provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b is.

[0483] Yet other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b is.

[0484] Still other embodiments provide compounds of formula (IM), or any stereoisomer or pharmaceutically acceptable salt thereof, wherein L is -(CH) p O- and R is R b is.

[0485] Other embodiments herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein L is O(CH) p - and R is R b is.

[0486] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2-; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0487] Other embodiments disclosed herein provide compounds of formula (IM), or any stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein Z a and Z b forms a 3- to 6-membered carbocyclic ring, and Z c is H, C1-C3 alkyl, or CN; X is -CH2; Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl; R 1 and R 2 are each independently H, halo, or —CH3, and L is a bond, —O—, —(CH2) p O- or O(CH2) p - and R is R a or R b is.

[0488] Some embodiments disclosed herein include: 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol, tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate, N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)acetamide, N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)heptanamide, 1-(4-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole, 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(2-chloro-6-fluoro-3-methylbenzyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-(3-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 1), 1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 2), (R)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, (S)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 1), 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 2), (R)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, (S)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-methoxyphenyl)-5-isopropoxy-1H-benzo[d]imidazole, 9-benzyl-6-isopropoxy-8-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine, 9-benzyl-6-isopropoxy-8-(2-methyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purine, tert-butyl 4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazine-1-carboxylate, 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)ethan-1-one, 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)hexan-1-one, 9-benzyl-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)-N,N-dimethylpyrrolidin-3-amine, 9-benzyl-8-(4-methyl-6-(piperazin-1-yl)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxyphenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one, 1-(4-((4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)methyl)piperidin-1-yl)ethan-1-one, 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), (R)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one, 3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propan-1-amine, N-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)acetamide, 1-(4-(2-(3-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-2-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(2-chloro-3-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), (R)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, (R)-8-(4-(azetidin-2-ylmethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(pyrrolidin-3-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(3-(piperazin-1-yl)propoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((3-fluoroazetidin-3-yl)methoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N,N-dimethylacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-methylacetamide, 1-(4-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethan-1-amine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)acetic acid, (R)-9-benzyl-8-(2-chloro-4-(pyrrolidin-2-ylmethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-hydroxyacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)acetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-(2-hydroxyethyl)acetamide, (2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)glycine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-N-methylglycine, 9-benzyl-8-(2-chloro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(piperidin-3-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-((2-azaspiro[3.3]heptan-6-yl)oxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-(azetidin-3-yloxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2,3-difluorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyrimidin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperidin-4-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylazetidin-3-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylpiperidin-4-amine, 9-benzyl-8-(4-methyl-6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine, 1-(4-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)piperazin-1-yl)ethan-1-one, 1-(4-(2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(4-methyl-6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 4-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)morpholine, 2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethan-1-amine, 3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propan-1-amine, 1-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)azetidin-1-yl)ethan-1-one, (S)-9-benzyl-8-(4-methyl-6-(pyrrolidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylethan-1-amine, (S)-9-benzyl-8-(4-methyl-6-(piperidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(3-methyl-2-(2-(piperazin-1-yl)ethoxy)pyridin-4-yl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-2-(((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine, (R)-3-(((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine, 8-{6-[(azetidin-3-yl)oxy]-4-methylpyridin-3-yl}-9-benzyl-6-[(1-methylcyclopropyl)oxy]-9H-purine, 9-benzyl-8-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,6-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,3-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-bromo-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-3-ylmethyl)-9H-purine, 2-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzonitrile, 9-benzyl-8-(2-ethynyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (2-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)methanol, 3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propanoic acid, (2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-L-proline, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)pyrrolidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)azetidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-4-ol, 2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)azetidin-3-ol, 8-(4-(2-(1,6-diazaspiro[3.3]heptan-6-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-5-one, (R)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane, 9-benzyl-8-(2,3-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-5-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,5-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-(2-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-(3-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-3-yl)ethyl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-phenylpropyl)-9H-purine, (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-phenylpropyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-2-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-4-ylmethyl)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((5-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-2-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((6-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((4-(trifluoromethyl)pyridin-2-yl)methyl)-9H-purine, 6-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)picolinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((6-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)nicotinonitrile, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-4-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)isonicotinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 5-chloro-2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 2-chloro-4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((5-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((3-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)azetidin-3-amine, 1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)piperidin-4-amine, 4-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)piperazin-2-one, (E)-3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)acrylic acid, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chloro-N,N-dimethylbenzamide, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chloro-N-methylbenzamide, (4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)(piperazin-1-yl)methanone, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorobenzamide, 9-benzyl-8-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-ylmethyl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)methanamine, 9-benzyl-8-(2-chloro-4-methoxyphenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-methoxypyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutoxy)-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutoxy)-1H-benzo[d]imidazole, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutoxy)-3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridine, 3-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutoxy)-3H-imidazo[4,5-b]pyridine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclobutoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-cyclopropoxy-9H-purine, 1-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile, 2-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol, (R)-1-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)pyrrolidin-3-ol, (S)-9-Benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine 8-(4-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 3-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane, (R)-9-benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-3-ol, 2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,6-diazaspiro[3.4]octan-7-one, (cis)-9-benzyl-8-(2-chloro-4-(2-(3,5-dimethylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-2-one, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 1), 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 2), (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, (S)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,3-dimethylpiperazin-2-one, 8-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (R)-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)methanol, 8-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (1S,4S)-2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octane, 8-(4-(2-(4,7-diazaspiro[2.5]octan-4-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-2-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)acetonitrile, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one, 4-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-cyclopropylpyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-ethylpyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 1), (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, 2-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenyl)acetamide, (E)-3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenyl)acrylic acid, 3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2,2-dimethylpropanoic acid, 2-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethan-1-ol, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 1), 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 2), (R)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, (R)-1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol 1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, 2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenyl)acetamide, 1-(3-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)azetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)azetidin-1-yl)ethan-1-one, (S)-5-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)piperidin-2-one, 5-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)tetrahydropyrimidin-2(1H)-one, 5-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)pentanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)butanoic acid, 1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)-2-methylpropan-2-ol, 2-(2-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethoxy)acetic acid, (R)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)propanoic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (1s,3s)-3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)cyclobutane-1-carboxylic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, and pharmaceutically acceptable salts thereof.

[0489] It is understood that any of the formula variable group definitions, claims, aspects or embodiments disclosed herein may be combined (where context allows) with any other definition, claim, aspect or embodiment herein to provide further embodiments of the present invention.

[0490] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, such as acetate, aspartate, benzoate, besylate, bromide / hydrobromide, bicarbonate / carbonate, hydrogensulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, ethanedisulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate, etc. The salts are: tobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methylsulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate / hydrogenphosphate / dihydrogenphosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, sulfate / bisulfate, tartrate, tosylate, and trifluoroacetate. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, and phosphoric acid. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, and sulfosalicylic acid.

[0491] Pharmaceutically acceptable base addition salts can be formed using inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonia, ammonium, and salts of metals from columns I to XII of the periodic table. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper, with particularly preferred salts including ammonium, potassium, sodium, calcium, and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, and basic ion exchange resins. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0492] Pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from a basic or acidic moiety by conventional chemical methods. Generally, such salts are prepared by reacting the free acid form of these compounds with a stoichiometric amount of an appropriate base (e.g., NaCl). + , Ca 2+ , Mg 2 + or K +The salts may be prepared by reacting the salts with a suitable base (e.g., hydroxide, carbonate, bicarbonate, etc.) or by reacting the free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or an organic solvent, or a mixture of the two. Generally, the use of non-aqueous media such as ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable where feasible. Additional lists of suitable salts can be found, for example, in "Remington's Pharmaceutical Sciences," 20th ed., Mack Publishing Company, Easton, Pa., (1985); Berge et al., "J. Pharm. Sci.," 1977, 66, 1-19; and Stahl and Wermuth, "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" (Wiley-VCH, Weinheim, Germany, 2002).

[0493] It should also be understood that certain compounds disclosed herein, and pharmaceutical salts thereof, can exist in both solvated and unsolvated forms (e.g., hydrated and anhydrous forms, etc.). The compounds herein should be understood to encompass all such solvated forms. For clarity, this includes both solvated (e.g., hydrated) forms of the free forms of the compounds, as well as solvated (e.g., hydrated) forms of salts of the compounds.

[0494] Any formula set forth herein is also intended to represent unlabeled and isotopically labeled forms of the compounds disclosed herein. Isotopically labeled compounds have the structure shown by the formula set forth herein, except that one or more atoms are replaced with atoms of the same element but with different mass numbers. Examples of isotopes that can be incorporated into the compounds disclosed herein and their pharmaceutically acceptable salts include isotopes of hydrogen, carbon, nitrogen, oxygen, phosphorus, sulfur, fluorine, chlorine, and iodine, such as: 2 H, 3 H, 11 C.13 C. 14 C. 15 N, 35 S, 36 Cl, and 125 Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art, or by processes similar to those described in the accompanying Examples, using an appropriate isotopically labeled reagent in place of the previously used non-labeled reagent.

[0495] The compounds disclosed herein may have different isomeric forms. The terms "optical isomer," "stereoisomer," "enantiomer," or "diastereoisomer" refer to any of the various stereoisomeric configurations that may exist for a given compound disclosed herein. Substituents may be attached to chiral carbon centers; therefore, the disclosed compounds are understood to include enantiomers, diastereomers, and racemates. The term "enantiomer" includes pairs of stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. The term (+ / -) is used to indicate a racemic mixture when appropriate. The terms "diastereomer" or "diastereoisomer" include stereoisomers that have at least two asymmetric atoms but are not mirror images of each other. Absolute stereochemistry is defined according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry at each chiral center can be defined as either R or S. Resolved compounds of unknown absolute configuration can be designated (+) or (-) depending on the direction (dextrorotatory or levorotatory) they rotate plane-polarized light within the wavelength of the sodium D line. Certain compounds disclosed herein have been isolated or prepared as single enantiomers, but the absolute configuration is unknown. In some cases, these compounds are labeled as (Isomer 1) or (Isomer 2). In the case of a single enantiomer so labeled, it should be understood that it can be either the R or S enantiomer.For example, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 1) (Example S8) can be R-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine or S-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine. , 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 2) (Example S7) can be (S-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine or (R-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine.

[0496] It is understood that one skilled in the art can determine the optical rotation and / or absolute stereochemistry. It is understood that such disclosure includes other stereoisomeric forms of the same compound, as well as stereoisomeric mixtures. Some of the compounds disclosed herein contain one or more asymmetric centers or axes and can therefore give rise to enantiomers, diastereomers, or other stereoisomeric forms, which can be defined as R- or S- in terms of absolute stereochemistry. The present disclosure is meant to include all such possible isomers, including racemic mixtures, optically pure forms, and intermediate mixtures. Optically active R- and S-isomers can be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques well known in the art, such as chiral HPLC.

[0497] Pharmaceutical Composition In some embodiments, pharmaceutical compositions are disclosed that include a compound disclosed herein and a pharmaceutically acceptable carrier.

[0498] The term "pharmaceutically acceptable carrier" includes compounds, materials, compositions, and / or dosage forms that are recognized by one of skill in the art, within the scope of sound medical judgment, as being suitable for use in contact with the tissues of human beings and animals without undue toxicity, irritation, allergic response, or other problem or complication.

[0499] The disclosed compositions can be in a form suitable for oral use (e.g., as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (e.g., as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), for administration by insufflation (e.g., as a finely divided powder), or for parenteral administration (e.g., as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular or intramuscular administration, or as a suppository for rectal administration).

[0500] The amount of active ingredient that is combined with one or more pharmaceutically acceptable carriers to produce a single dosage form will necessarily vary depending on the host treated and the particular route of administration. Further information regarding routes of administration and dosage regimens can be found in Chapter 25.3 of Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of the Editorial Board), Pergamon Press 1990.

[0501] Pharmaceutical formulations of the compounds disclosed herein may conveniently be administered in unit dosage form and may be prepared by any of the methods well known in the art of pharmacy, e.g., as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., 1985).

[0502] Pharmaceutical formulations suitable for oral administration may contain one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules can be prepared using binders, fillers, lubricants, and / or surfactants, such as sodium lauryl sulfate. Liquid compositions may contain conventional additives such as suspending agents, emulsifiers, and / or preservatives. Liquid compositions can be encapsulated, for example, in gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard-shell capsules, and soft elastic gelatin (SEG) capsules. Such two-piece hard-shell capsules can be prepared, for example, by filling a compound of Formula (I) into a gelatin or hydroxypropyl methylcellulose (HPMC) shell.

[0503] Therapeutic utility The term "subject" includes warm-blooded mammals, e.g., primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, e.g., a human. In some embodiments, the subject is suffering from cancer. In some embodiments, the subject is in need of treatment (e.g., the subject will benefit biologically or medically from treatment). In some embodiments, the subject is suffering from cancer.

[0504] Terms such as "treat," "treating," and "treatment," as well as "palliative" or "alleviating," refer to both (1) therapeutic measures that cure, delay, relieve symptoms, and / or halt progression of a diagnosed pathological condition or disorder, and (2) prophylactic or preventative measures that prevent and / or delay the onset of the targeted pathological condition or disorder. Thus, those in need of treatment include those already with the disorder; patients prone to having the disorder; and patients in whom the disorder is to be prevented. In certain aspects, this includes amelioration of one or more symptoms of cancer, or slowing or delaying the progression of cancer in a subject. The terms "treat," "treating," "treatment," "palliative," and "alleviating" also include reducing or inhibiting tumor growth or cancer cell proliferation in a subject. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure if the patient exhibits, for example, complete, partial, or transient remission of a particular type of cancer.

[0505] In some embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. In certain embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

[0506] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is a solid cancer such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In certain embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA1 and / or BRCA2 mutation. In other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA1 mutation. In yet other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA2 mutation.

[0507] In some embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is breast cancer. In further embodiments, the cancer is BRCA1- and / or BRCA2-positive breast cancer. In other embodiments, the cancer is BRCA1-positive breast cancer. In yet other embodiments, the cancer is BRCA2-positive breast cancer.

[0508] In some embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is ovarian cancer. In further embodiments, the cancer is BRCA1- and / or BRCA2-positive ovarian cancer. In other embodiments, the cancer is BRCA1-positive ovarian cancer. In yet other embodiments, the cancer is BRCA2-positive ovarian cancer.

[0509] In some embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is pancreatic cancer. In further embodiments, the cancer is BRCA1- and / or BRCA2-positive pancreatic cancer. In other embodiments, the cancer is BRCA1-positive pancreatic cancer. In yet other embodiments, the cancer is BRCA2-positive pancreatic cancer.

[0510] In some embodiments, methods are provided for treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is prostate cancer. In further embodiments, the cancer is BRCA1- and / or BRCA2-positive prostate cancer. In other embodiments, the cancer is BRCA1-positive prostate cancer. In yet other embodiments, the cancer is BRCA2-positive prostate cancer.

[0511] In some embodiments, provided is a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is PARP inhibitor (PARPi) resistant. In some embodiments, the PARPi resistant cancer is PARPi resistant ovarian cancer. In some embodiments, the PARPi resistant cancer is PARPi resistant breast cancer. In some embodiments, the PARPi resistant cancer is PARPi resistant prostate cancer. In some embodiments, the PARPi resistant cancer is PARPi resistant pancreatic cancer.

[0512] In some embodiments, provided are methods of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the method comprises treating a subject with a primary and a secondary solid tumor. In yet other embodiments, the method comprises treating a subject with a primary solid tumor. In yet other embodiments, the method comprises treating a subject with a secondary solid tumor.

[0513] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is Ataxia Telangiectasia Mutated (ATM) mutation-positive. In certain embodiments, the ATM mutation-positive cancer is a hematological cancer such as leukemia or lymphoma. In certain embodiments, the ATM mutation-positive cancer is acute leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). In other embodiments, the ATM mutation-positive cancer is a solid cancer. In certain embodiments, the ATM mutation-positive cancer is lung cancer, gastric cancer, stomach cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or sarcoma.

[0514] In some embodiments, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is positive for a mutation in a gene encoding a Fanconi anemia (FA) protein or an FA-like gene, including FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCP (SLX4), and FANCS (BRCA1).

[0515] In some embodiments, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is positive for mutations in genes encoding DNA repair proteins, including RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP-interacting protein), PALB2 (partner and localizer of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ recQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (nibrin), and EMSY.

[0516] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, wherein the cancer is selected from the group consisting of AICDA, ALKBH3, APOBEC2, APOBEC4, APTX, ATF2, ATM, AURKA, BARD1, BRCA2, BRIP1, CBX3, CCNH, CDC16, CDC25A, CDC25B, CDC45, CDKN1A, CDKN2A, CHEK2, CLK2, CLSPN, CUL4A, CUL5, DCLRE1A, DCLRE1C, DDB1, DKC1, DNMT3A, DNMT3B, DUT, EME2, ENDOV, EP300, ERCC4, ERCC5, FAN1, FANCG, FANCL, FBXO18, FEN1, GADD45A, GINS1, GTF2 H2, GTF2H3, GTF2H4, HDAC2, HDAC3, HDAC4, HELQ, INIP, INO80C, KDM4B, LIG3, LMO4, MAD2L2, MBD4, MGMT, MLH1, MNAT1, MPG, MRE11A, MSH2, MSH6, MTBP, MUT YH, NABP1, NBN, NEIL1, NEIL2, NEIL3, NEK1, NHEJ1, NTHL1, ORC6, PALB2, PARP2, PARP3, PAXIP1, PIF1, PMS2, POLB, POLE, POLK, POLL, POLM, POLN, PPP1CA, PRKDC, PRMT2, PROKR1, RAD21, RAD23B, RAD51, RAD51AP1, RAD52, RAD9A, RAD9B, RB1, RECQL4, RECQL5, REV1, RIF1, RINT1, RMI1, RNASEH1, RNASEH2A, RPA1 , RPA2, RTEL1, SHPRH, SIRT6, SLX4, SMC5, SMG1, SMUG1, SPO11, SUMO1, SUMO2, SUV39H1, SUV420H2, SWI5, TDG, TELO2, THOC1, TICRR, TNKS, TNKS2, TOP1, TOP2A, TOP3A, TOP3B, TREX2, TRP53BP1, UBE2N, UNG, UVSSA, WRN, XAB2, XRCC2, XRCC3, and / or XRCC5.

[0517] In some embodiments, provided is a compound of formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof. In some embodiments, provided is a compound of formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

[0518] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof, wherein the cancer is a solid cancer such as breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In certain embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA1 and / or BRCA2 mutation. In other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA1 mutation. In yet other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer that contains a BRCA2 mutation.

[0519] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is breast cancer. In further embodiments, the cancer is BRCA1 and / or BRCA2 positive breast cancer. In other embodiments, the cancer is BRCA1 positive breast cancer. In yet other embodiments, the cancer is BRCA2 positive breast cancer.

[0520] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is ovarian cancer. In further embodiments, the cancer is BRCA1 and / or BRCA2 positive ovarian cancer. In other embodiments, the cancer is BRCA1 positive ovarian cancer. In yet other embodiments, the cancer is BRCA2 positive ovarian cancer.

[0521] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is pancreatic cancer. In further embodiments, the cancer is BRCA1 and / or BRCA2-positive pancreatic cancer. In other embodiments, the cancer is BRCA1-positive pancreatic cancer. In yet other embodiments, the cancer is BRCA2-positive pancreatic cancer.

[0522] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is prostate cancer. In further embodiments, the cancer is BRCA1 and / or BRCA2 positive prostate cancer. In other embodiments, the cancer is BRCA1 positive prostate cancer. In yet other embodiments, the cancer is BRCA2 positive prostate cancer.

[0523] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is a PARP inhibitor (PARPi)-resistant cancer. In some embodiments, the PARPi-resistant cancer is a PARPi-resistant ovarian cancer. In some embodiments, the PARPi-resistant cancer is a PARPi-resistant breast cancer. In some embodiments, the PARPi-resistant cancer is a PARPi-resistant prostate cancer. In some embodiments, the PARPi-resistant cancer is a PARPi-resistant pancreatic cancer.

[0524] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof for use in treating cancer in a subject in need thereof, wherein the method comprises treating a subject with a primary and a secondary solid tumor. In yet other embodiments, the method comprises treating a subject with a primary solid tumor. In yet other embodiments, the method comprises treating a subject with a secondary solid tumor.

[0525] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof, wherein the cancer is ataxia telangiectasia mutated (ATM) mutation-positive. In certain embodiments, the ATM mutation-positive cancer is a hematological cancer such as leukemia or lymphoma. In certain embodiments, the ATM mutation-positive cancer is acute leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML), or myelodysplastic syndrome (MDS). In other embodiments, the ATM mutation-positive cancer is a solid cancer. In certain embodiments, the ATM mutation-positive cancer is lung cancer, gastric cancer, stomach cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or sarcoma.

[0526] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is positive for a mutation in a gene encoding a Fanconi anemia (FA) protein or an FA-like gene, including FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (RALB2), FANCP (SLX4), and FANCS (BRCA1).

[0527] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is positive for mutations in genes encoding DNA repair proteins, including RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP-interacting protein), PALB2 (partner and localizer of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (nibrin), and EMSY.

[0528] In some embodiments, provided is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof, wherein the cancer is selected from the group consisting of AICDA, ALKBH3, APOBEC2, APOBEC4, APTX, ATF2, ATM, AURKA, BARD1, BRCA2, BRIP1, CBX3, CCNH, CDC16, CDC25A, CDC25B, CDC45, CDKN1A, CDKN2A, CHEK2, CLK2, CLSPN, CUL4A, CUL5, DCLRE 1A, DCLRE1C, DDB1, DKC1, DNMT3A, DNMT3B, DUT, EME2, ENDOV, EP300, ERCC4, ERCC5, FAN1, FANCG, FANCL, FBXO18, FEN1, GADD45A, GINS1, GTF2H2, GTF2H 3, GTF2H4, HDAC2, HDAC3, HDAC4, HELQ, INIP, INO80C, KDM4B, LIG3, LMO4, MAD2L2, MBD4, MGMT, MLH1, MNAT1, MPG, MRE11A, MSH2, MSH6, MTBP, MUTYH, NABP 1, NBN, NEIL1, NEIL2, NEIL3, NEK1, NHEJ1, NTHL1, ORC6, PALB2, PARP2, PARP3, PAXIP1, PIF1, PMS2, POLB, POLE, POLK, POLL, POLM, POLN, PPP1CA, PRKDC , PRMT2, PROKR1, RAD21, RAD23B, RAD51, RAD51AP1, RAD52, RAD9A, RAD9B, RB1, RECQL4, RECQL5, REV1, RIF1, RINT1, RMI1, RNASEH1, RNASEH2A, RPA1, RPA 2, positive for mutations in one or more genes associated with the double-strand break (DSB) repair pathway, including RTEL1, SHPRH, SIRT6, SLX4, SMC5, SMG1, SMUG1, SPO11, SUMO1, SUMO2, SUV39H1, SUV420H2, SWI5, TDG, TELO2, THOC1, TICRR, TNKS, TNKS2, TOP1, TOP2A, TOP3A, TOP3B, TREX2, TRP53BP1, UBE2N, UNG, UVSSA, WRN, XAB2, XRCC2, XRCC3, and / or XRCC5.

[0529] Combination therapy The compounds of formula (I), the compounds disclosed herein, their stereoisomers, or pharmaceutically acceptable salts thereof may also be administered in conjunction with other compounds used for the treatment of the above conditions.

[0530] In some embodiments, there is provided a method of treating cancer in a subject in need thereof, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a second active ingredient, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture.

[0531] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a PARP inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the PARP inhibitor is olaparib, AZD9574 (WO 2021 / 260092), AZD5305 (WO 2021 / 013735), talazoparib, niraparib, or rucaparib. In other embodiments, the PARP inhibitor is olaparib, AZD9674, or AZD5305. In certain embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In certain embodiments, the PARP inhibitor is olaparib, and the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In another embodiment, the PARP inhibitor is niraparib and the cancer is ovarian cancer. In another embodiment, the PARP inhibitor is rucaparib and the cancer is ovarian cancer or prostate cancer. In another embodiment, the PARP inhibitor is talazoparib and the cancer is breast cancer or prostate cancer.

[0532] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with an ATR inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the ATR inhibitor is AZD6738 (WO 2011 / 154737).

[0533] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a DNA-PK inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the DNA-PK inhibitor is AZD7648 (WO 2018 / 114999).

[0534] In some embodiments, a method for treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with an antibody-drug conjugate, wherein the compound and the antibody-drug conjugate are administered simultaneously, sequentially, or in admixture. In certain embodiments, the antibody-drug conjugate is trastuzumab deruxtecan (T-DXd). In certain embodiments, the antibody-drug conjugate is a topoisomerase-activated antibody-drug conjugate. In certain embodiments, the cancer is breast cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

[0535] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a platinum-based anticancer agent, wherein the compound and the platinum-based anticancer agent are administered simultaneously, sequentially, or in admixture. In certain embodiments, the platinum-based anticancer agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, triplatin tetranitrate, picoplatin, or satraplatin.

[0536] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with a taxane, wherein the compound and the platinum-based anticancer agent are administered simultaneously, sequentially, or in admixture. In certain embodiments, the taxane is docetaxel.

[0537] In some embodiments, a method of treating cancer in a subject in need thereof is provided, comprising administering a therapeutically effective amount of a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof in combination with immunotherapy, wherein the compound and immunotherapy are administered simultaneously, sequentially, or in admixture. In certain embodiments, the immunotherapy is an antibody, such as durvalumab. In certain embodiments, the immunotherapy is durvalumab and the cancer is non-small cell lung cancer (NSCLC).

[0538] In some embodiments, there is provided a compound of formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof in combination with a second active ingredient, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture.

[0539] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with a PARP inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the PARP inhibitor is olaparib, AZD9574 (WO 2021 / 260092), AZD5305 (WO 2021 / 013735), talazoparib, niraparib, or rucaparib. In other embodiments, the PARP inhibitor is olaparib, AZD9674, or AZD5305. In certain embodiments, the PARP inhibitor is olaparib and the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer. In other embodiments, the PARP inhibitor is niraparib and the cancer is ovarian cancer. In another embodiment, the PARP inhibitor is rucaparib and the cancer is ovarian cancer or prostate cancer, hi another embodiment, the PARP inhibitor is talazoparib and the cancer is breast cancer or prostate cancer.

[0540] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with an ATR inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the ATR inhibitor is AZD6738 (WO 2011 / 154737).

[0541] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with a DNA-PK inhibitor, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture. In certain embodiments, the DNA-PK inhibitor is AZD7648 (WO 2018 / 114999).

[0542] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with an antibody-drug conjugate, wherein the compound and the antibody-drug conjugate are administered simultaneously, sequentially, or in admixture. In certain embodiments, the antibody-drug conjugate is trastuzumab deruxtecan (T-DXd). In certain embodiments, the antibody-drug conjugate is a topoisomerase-activated antibody-drug conjugate. In certain embodiments, the cancer is breast cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

[0543] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with a platinum-based anticancer agent, wherein the compound and the platinum-based anticancer agent are administered simultaneously, sequentially, or in admixture. In certain embodiments, the platinum-based anticancer agent is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, triplatin tetranitrate, picoplatin, or satraplatin. In certain embodiments, the platinum-based anticancer agent is carboplatin.

[0544] In some embodiments, a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof is provided for use in treating cancer in a subject in need thereof in combination with a taxane, wherein the compound and the platinum-based anticancer drug are administered simultaneously, sequentially, or in admixture. In certain embodiments, the taxane is docetaxel.

[0545] In some embodiments, provided herein is a compound of Formula (I), a compound disclosed herein, a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, for use in treating cancer in a subject in need thereof in combination with immunotherapy, wherein the compound and immunotherapy are administered simultaneously, sequentially, or in admixture. In certain embodiments, the immunotherapy is an antibody such as durvalumab. In certain embodiments, the immunotherapy is durvalumab and the cancer is non-small cell lung cancer (NSCLC).

[0546] Another aspect of the present disclosure provides processes for preparing compounds of formula (I), or pharmaceutically acceptable salts thereof. Suitable processes are exemplified by the following representative process variations, and unless otherwise indicated, G, G a , G b , Q1, Q2, Q3 and R 1 , R 2 , R a , R b , R c , R d , X, YZ a / Z aa , Z b / Z bb , Z c / Z cc has any of the meanings defined above. Necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials, along with variants of the following representative processes, is described within the accompanying Examples. Alternatively, necessary starting materials can be obtained by analogous procedures to those exemplified, which are within the ordinary skill of an organic chemist.

[0547] [ka]

[0548] Compounds of formula (I) can be made, for example, by: a)1.Q 1 , Q 2 or Q 3is C—OH with a primary or secondary alcohol under conditions known in the art to be suitable for the Mitsunobu reaction (e.g., Example 1), Alternatively, by reaction with a primary or secondary halide under typical conditions for nucleophilic substitution, for example, in a suitable solvent such as DMA or DMF, in the presence of a suitable base such as potassium carbonate or cesium carbonate, at a suitable temperature (0-120°C), with or without protecting groups for other functional groups.

[0549] 2.Q 1 , Q 2 or Q 3 by reaction of another compound of formula (I), wherein C-LG, where LG is a leaving group such as a halogen, with a suitable amine under conditions known in the art (e.g., Example 19), optionally catalyzed by a metal complex, such as a palladium catalyst suitable for the Buchwald-Hartwig amination reaction.

[0550] 3.Q 1 , Q 2 or Q 3 is C-LG, where LG is a leaving group such as a halogen, with a suitable alcohol (e.g., Example 20), under conditions known in the art (e.g., reaction in the presence of a strong base such as sodium hydride to form an alkoxide), optionally catalyzed by a metal complex such as a palladium catalyst (e.g., RockPhos Pd G3) suitable for ether-forming reactions.

[0551] More generally, compounds of formula (I) can be prepared from compounds of formula (I) (eg, amide coupling in Example N1, reductive amination in Example N6).

[0552] Q 1 , Q 2 or Q 3 is C-OH or Q 1 , Q 2 or Q 3The compound of formula (I), wherein is C-LG, can be prepared by the following method: b) G a But, CR 5 and R 5 but,

[0553] [ka] by reacting another compound of formula (II) with a compound of formula (III), where LG is a leaving group known in the art, for example, a halide such as F, Cl, or Br, or trifluoromethanesulfonic acid (triflate). The reaction conditions can be in the presence of a suitable base (e.g., sodium hydride or LHMDS), with or without protecting groups for other functional groups, in a suitable solvent (e.g., THF), and at a suitable temperature (e.g., 0°C to ambient temperature).

[0554] [ka]

[0555] The compound of formula (II) can be prepared by reacting a compound of formula (IV) with a compound of formula (V). The reaction conditions involved a one-step procedure as described in section (d). The reaction can be converted into a two-step procedure involving isolation of an intermediate compound of formula (VI). The reaction conditions are described in section (d).

[0556] Alternatively, compounds of formula (II) can be prepared by reacting compounds of formula (IVa) with compounds of formula (V). The reaction conditions are described in section (d).

[0557] [ka]

[0558] Alternatively, compounds of formula (IV) can be prepared by reaction of formula (IVa) by reduction of the nitro group to an amino group, as described in section (d).

[0559] [ka]

[0560] When X=CH2, compounds of formula (IVa) can be prepared from the reaction between compounds of formula (VII) and compounds of formula (VIIIa) under conditions known in the art to be suitable for reductive amination.

[0561] Alternatively, the compound of formula (IVa) can be prepared from the reaction between the compound of formula (VIIa) and the compound of formula (VIII). The reaction conditions can be an inert solvent (e.g., DMF) in the presence of a base (e.g., triethylamine) at a suitable temperature (e.g., room temperature).

[0562] [ka]

[0563] Alternatively, compound (II) can be obtained from the reaction between compounds of formula (IIa) and formula (VIIIb) under conditions known in the art to be suitable for nucleophilic substitution, or from the reaction between compounds of formula (IIa) and formula (VIIIc) under conditions known in the art to be suitable for a Mitsunobu reaction.

[0564] [ka]

[0565] c) G b But, CR 5 and R 5 but

[0566] [ka] by reaction of another compound of formula (IX) with a compound of formula (X) under conditions known in the art to be suitable for a Mitsunobu reaction, or by a nucleophilic substitution reaction between another compound of formula (IX) and a compound of formula (Xa), where LG is a leaving group known in the art, e.g., a halide such as Cl, Br, or I. The nucleophilic substitution reaction conditions can be in the presence of a suitable base (e.g., potassium carbonate), with or without protecting groups for other functional groups, in a suitable solvent (e.g., acetonitrile, DMF, or DMA), and at a suitable temperature (0-120°C).

[0567] [ka]

[0568] Compounds of formula (IX) can be prepared by reaction of compounds of formula (XI) with compounds of formula (V), with or without a protecting group for the hydroxy group.

[0569] Compounds of formula (IX) can also be prepared by reaction of compounds of formula (XIa) with compounds of formula (V), with or without a protecting group for the hydroxy group.

[0570] Alternatively, compounds of formula (XI) can be prepared from compounds of formula (XIa) by reduction of the nitro group to an amino group.

[0571] The conditions for the above reaction are exemplified in section (d).

[0572] [ka]

[0573] Compounds of formula (XIa) can be prepared by reaction of compounds of formula (XII) with compounds of formula (VIII), with or without a protecting group for the hydroxy group, where LG is a leaving group known in the art, for example, a halide (such as F or Cl) or trifluoromethanesulfonic acid (triflate).

[0574] [ka]

[0575] d) by reacting a compound of formula (XIII) with a compound of formula (V). The reaction conditions include a one-step procedure using a suitable solvent (e.g., EtOH, isopropanol, dioxane, or DMSO) and a suitable temperature (60-120°C), optionally in the presence of a mild oxidant (such as iron(III) chloride and / or atmospheric oxygen) and / or an acid (e.g., p-toluenesulfonic acid, acetic acid) and / or a catalyst (e.g., copper(II) acetate, see Example 8). The reaction can be converted into a two-step procedure involving isolation of the intermediate compound of formula (XIV), followed by the addition of a mild oxidant (e.g., iron(III) chloride and / or oxygen) for the second step.

[0576] Alternatively, by reacting a compound of formula (XIIIa) with a compound of formula (V), which can be carried out using a suitable solvent (e.g., NMP and water) in the presence of a mild reducing agent such as sodium dithionite (also known as sodium hydrosulfite) at a suitable temperature (e.g., 80-120°C).

[0577] Alternatively, compounds of formula (XIII) can be prepared from compounds of formula (XIIIa) by reduction of the nitro group to an amino group (e.g., in the presence of iron using a suitable solvent such as ethanol).

[0578] [ka]

[0579] Compounds of formula (XIIIa) can be made by reacting a compound of formula (XV) with another compound of formula (VIII), where LG is a leaving group known in the art, for example, a halide (such as F or Cl) or trifluoromethanesulfonic acid (triflate) or methanesulfonyl.

[0580] [ka]

[0581] G a But, CR 5 and R 5 but,

[0582] [ka] In the case where the compound of formula (XIIIa) is a compound of formula (IVa), the compound of formula (XIIIa) can be prepared by reacting the compound of formula (IVa) with the compound of formula (III). The reaction conditions can be in the presence of a suitable base (e.g., sodium hydride or LHMDS), in a suitable solvent (e.g., THF), and at a suitable temperature (e.g., near ambient temperature), with or without protecting groups for other functional groups.

[0583] [ka] G a But, CR 5 and R 5 but,

[0584] [ka] wherein the compound of formula (XIIIa) can also be prepared by reaction of another compound of formula (XVI) with a compound of formula (III) under conditions known in the art to be suitable for a Mitsunobu reaction: Alternatively, it can be prepared by the reaction (nucleophilic substitution) of another compound of formula (XVI) with a compound of formula (IIIa), where LG is a leaving group known in the art, e.g., a halide such as Cl, Br, or I. The nucleophilic substitution reaction conditions can be used in the presence of a suitable base (e.g., potassium carbonate), with or without protecting groups for other functional groups, in a suitable solvent (e.g., acetonitrile, DMF, or DMA), and at a suitable temperature (0-120°C).

[0585] [ka]

[0586] Compounds of formula (XVI) can be made by the reaction of another compound of formula (XVII) with another compound of formula (VIII), with or without protecting groups for hydroxyl and other functional groups.

[0587] [ka]

[0588] (e) By reacting a compound of formula (XVIII) (where LG is an art-known leaving group, e.g., a halide such as Cl, Br, or I) with a compound of formula (XIX) (where FG is a functional group suitable for cross-coupling reactions (e.g., Suzuki reactions) such as a boronic ester or a boronic acid). Reaction conditions are exemplified in Example 5.

[0589] [ka]

[0590] Compounds of formula (XVIII) can be prepared from compounds of formula (XX) by, for example, bromination (when LG is Br) as described in Example 5.

[0591] [ka]

[0592] (f) From the reaction between a compound of formula (XXI) and a compound of formula (VIIIb) (e.g., Example 23) under conditions known in the art to be suitable for nucleophilic substitution.

[0593] or from the reaction between a compound of formula (XXI) and a compound of formula (VIIIc) under conditions known in the art to be suitable for a Mitsunobu reaction.

[0594] [ka]

[0595] It will be understood that the compound of formula (XXI) can be prepared by the reactions already exemplified in sections (a) to (e) in the same manner as the compound of formula (I). [Example]

[0596] The compounds described herein are further illustrated in the following examples, which are given by way of illustration only and are not limiting. In general:

[0597] General Experimental Conditions and Abbreviations The compounds described herein are further illustrated in the following examples. Compounds were named using Chemdraw version 20.0.2.51. These examples are given for illustrative purposes only and are non-limiting. In general: Reagents and solvents (all anhydrous HPLC grade) were obtained from commercial suppliers and used without further purification unless otherwise noted. All reagents were weighed and handled in air unless otherwise noted. Brine refers to a saturated solution of NaCl. Concentration under reduced pressure refers to the use of a rotary evaporator.

[0598] Unless otherwise stated, operations were carried out at ambient temperature, i.e., in the range of 17-25°C, under an atmosphere of an inert gas such as nitrogen.

[0599] Evaporation was performed by rotary evaporation under reduced pressure using a warm or hot water bath, or using a Genevac apparatus or Biotage v10 evaporator in vacuo, and residual solids were removed by filtration prior to the work-up procedure.

[0600] Flash chromatography purification was performed on an automated Teledyne Isco CombiFlash® Rf, Teledyne Isco CombiFlash® Companion®, or CHEETAH® MP200 system with integrated UV detection using prepacked silica gel columns (40–60 μm) or C18 spheres (20–35 μm) using the chromatographic conditions detailed in the corresponding experimental data.

[0601] Preparative reversed-phase HPLC was performed on an Agilent 1290 Infinity II preparative system equipped with a Waters CSH C18 OBD column (5 micron silica, 30 mm diameter, 100 mm length) and an SQ MS detector (multimode ESI / APCI source); a Waters MassLynx system equipped with an XBridge or Xselect CSH Prep C18 OBD column (5 μm silica, 30 mm diameter, 150 mm length) and MS detection; and a Gilson GX-281 equipped with an XBridge (10 μm, 19 mm diameter, 150 mm length) or Sunfire C18 column (10 μm, 19 mm diameter, 250 mm length) and UV detection. The HPLC was performed on a 1000 sachets eluted with water (containing 0.1–0.3% aqueous ammonia), water (0.05% aqueous ammonia, and 10 mmol / L). The separations were carried out using decreasingly polar mixtures of water (containing 0.1% NH4HCO3), water (containing 0.1% formic acid), or water (containing 0.05% TFA) with acetonitrile or methanol as eluents.

[0602] Preparative SFC purification was performed on either a Sepiatec P100 SFC system or a Waters Prep 100 SFC system equipped with a QDa MS detector, using the chromatographic conditions detailed in the corresponding experimental data.

[0603] Preparative chiral HPLC was performed using a Gilson GX-281 system equipped with UV detection and one of the following columns: Chiralpak AS, AD, Chiralcel OD, OJ, Chiralpak IA, IB, IC, ID, IE, IF, IG, IH columns (Daicel Chemical Industries, Ltd.), (R,R)-Whelk-O1, (S,S)-Whelk-O1 columns (Regis technologies, Inc.), and CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.). Different column sizes (250 × 20 mm, 250 × 30 mm) were used with the isocratic solvent system: either ethanol in hexane (%Et / Hex) or isopropanol in hexane (%IPA / Hex) at the indicated percentages.

[0604] Yields, if any, are not necessarily the maximum achievable.

[0605] Generally, the structure of the final product of Formula I is confirmed by nuclear magnetic resonance (NMR) spectroscopy; 1H-NMR chemical shift values ​​are measured on the delta scale and quoted in ppm relative to TMS or residual solvent peaks as an internal standard; proton magnetic resonance spectra were measured on a Bruker Avance 500 spectrometer at a proton frequency of 500 MHz, a Bruker Avance 400, Bruker Avance III HD, or Bruker Avance Neo spectrometer at a proton frequency of 400 MHz, or a Bruker Avance III, Avance III HD, or Avance III NEO spectrometer at a proton frequency of 300 MHz; measurements were performed at ambient temperature unless otherwise noted. The following abbreviations were used: s: singlet; d: doublet; t: triplet; q: quartet; m: multiplet; dd: doublet of doublets; ddd: doublet of doublets of doublets; dt: doublet of triplets; br s: broad signal; hept: septet.

[0606] In general, the final product of Formula I was characterized by liquid chromatography (LCMS or UPLC) followed by mass spectrometry; reverse-phase C18 silica was used at a flow rate of 1 mL / min, and detection was performed by electrospray mass spectrometry and UV / vis absorbance recording in the wavelength range of 220-320 nm. Analytical UPLC was performed using a Waters Acquity UPLC CSH C18 column with dimensions of 2.1 x 50 mm and a particle size of 1.7 microns. Gradient analysis was employed using a mixture of decreasing polarity as the eluent, e.g., water (containing 0.1% v / v formic acid or 0.3% ammonia v / v) as solvent A and acetonitrile as solvent B. A typical 1.7-minute analytical UPLC method employed a solvent gradient from a 97:3 mixture of solvents A and B, respectively, to a 3:97 mixture of solvents A and B over 1.3 minutes at 1 mL / min. LCMS was also performed using a Shimadzu LCMS-2020 equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS 2020 MS detector, performing electrospray ionization in positive ion detection mode. LC was performed with two setups: 1) a Halo C18 column (2.0 μm 3.0 × 30 mm) coupled with a gradient of water and formic acid-FA (0.1%) (A) and CH3CN and FA (0.1%) (B) (5 to 100% B in 1.2 min) at a flow rate of 1.5 mL / min; 2) a Poroshell HPH C18 column (2.7 μm 3.0 × 50 mm) coupled with a gradient of 46 mM aqueous ammonium carbonate / ammonia buffer, pH 10 (A) and MeCN (B) (5 to 95% B in 2 min) at a flow rate of 1.2 mL / min; 3) a Halo C18 column (2.0 μm A 3.0 x 30 mm column was loaded onto a column containing a gradient (5 to 95% B in 2 min) of water and TFA (0.05%) (A) combined with CHCN and TFA (0.05%) (B) (flow rate 1.5 mL / min). The column oven temperature (CTO-20AC) was 40.0 °C. The injection volume was 1 µL. PDA (SPD-M20A) detection was in the range of 190-400 nm.MS detector configured with electrospray ionization as the ionization source; acquisition mode: scan; nebulization gas flow rate: 1.5 L / min; drying gas flow rate: 15 L / min; detector voltage: tuning voltage ±0.2 kV; DL temperature: 250 °C; heat block temperature: 250 °C; scan range: 90.00 - 900.00 m / z. Unless otherwise stated, reported molecular ions correspond to [M+H]+ and are understood to be rounded to the nearest unit. Typically, molecules with multiple isotopic patterns (e.g., 100 kJ / 200 kcal) are reported unless otherwise specified. 35 Cl, 79 Br, 12 For C), only the most common lower isotopes are reported.

[0607] Ion exchange purification was typically performed using SCX-2 (Biotage, propylsulfonic acid functionalized silica, prepared with trifunctional silane, non-endcapped) cartridges.

[0608] The purity of the intermediates was assessed by thin layer chromatography, mass spectrometry, HPLC (high performance liquid chromatography) and / or NMR analysis.

[0609] The following abbreviations were used:

[0610] [Table 1]

[0611] Example 1 9-benzyl-6-isopropoxy-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine

[0612] [ka]

[0613] DIAD (0.260 mL, 1.34 mmol) was added dropwise to a solution of 4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol (200 mg, 0.53 mmol), 2-(4-methylpiperazin-1-yl)ethan-1-ol (116 mg, 0.80 mmol), and PPh3 (392 mg, 1.50 mmol) in THF (20 mL) at 0 °C under nitrogen. The resulting mixture was stirred at room temperature for 16 h. The residue was purified by preparative TLC (EtOAc) and then further purified by preparative HPLC (XBridge Shield RP18 OBD column, 5 μm silica, 30 mm diameter, 150 mm length) using mixtures of decreasing polarity of water (containing 0.05% aqueous NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 9-benzyl-6-isopropoxy-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine (76 mg, 28%) as a yellow oil. 1 H NMR(300MHz,DMSO-d6):1.42(6H,d),1.95(3H,s),2.16(3H,s),2.33(8H,m),2.70(2H,t), 4.13(2H,t),5.26(2H,s),5.62(1H,p),6.84-6.94(4H,m),7.18-7.31(4H,m),8.55(1H,s). m / z:ES+[M+H]+501.

[0614] The starting material, 4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol, was prepared as follows.

[0615] N4-benzyl-6-chloropyrimidine-4,5-diamine

[0616] [ka]

[0617] A mixture of phenylmethanamine (47.0 g, 439 mmol) and triethylamine (74.0 g, 732 mmol) was added dropwise to 4,6-dichloropyrimidin-5-amine (60 g, 366 mmol) in DMA (400 mL) over 20 minutes at 100° C. under air. The resulting solution was stirred at 100° C. for 8 hours. The reaction mixture was then poured into water (1000 mL) with stirring. The resulting precipitate was collected by filtration, washed with water (500 mL), and dried at 60° C. to give N4-benzyl-6-chloropyrimidine-4,5-diamine (60.0 g, 70%) as a pale yellow solid.

[0618] 1 H NMR (300MHz, DMSO-d6): 4.65 (2H, d), 5.11 (2H, s), 7.19-7.29 (1H, m), 7.29-7.45 (5H, m), 7.76 (1H, s). m / z:ES+[M+H]+235.

[0619] 4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-methylphenol

[0620] [ka]

[0621] 4-Hydroxy-2-methylbenzaldehyde (580 mg, 4.26 mmol) was added to a solution of N4-benzyl-6-chloropyrimidine-4,5-diamine (500 mg, 2.13 mmol) and silica gel-supported iron(III) chloride (6.91 g, 6.39 mmol) in 1,4-dioxane (40 mL). The resulting mixture was stirred at 100 °C for 3 days. The solvent was removed under reduced pressure. The filtrate was collected by filtration, and the precipitate was washed with EtOAc (100 mL) and dried under vacuum to give the crude product. The crude product was purified by flash C18-flash chromatography with an elution gradient of 5 to 80% MeCN in water (containing 0.05% NH4HCO3). Pure fractions were evaporated to dryness to afford 4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-methylphenol (230 mg, 31%) as a yellow solid. 1 H NMR (400MHz, DMSO-d6): 1.94 (3H, s), 5.34 (2H, s), 6.70-6.75 (2H, m), 6.87-6.92 (2H, m), 7.19-7.26 (4H, m), 8.81 (1H, s), 9.94 (1H, s). m / z:ES+[M+H]+351.

[0622] 4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol

[0623] [ka]

[0624] NaH (50.2 mg, 1.25 mmol) was added portionwise to a solution of 4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-methylphenol (220 mg, 0.63 mmol) and IPA (0.097 mL, 1.25 mmol) in THF (10 mL). The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was quenched with saturated NaHCO (50 mL) and extracted with EtOAc (3 × 20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give 4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol (210 mg, 89%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):1.41(6H,d),1.90(3H,s),5.26(2H,s),5.61(1H,p),6.6 8-6.75(2H,m),6.84-6.90(2H,m),7.13-7.25(4H,m),8.54(1H,s),9.85(1H,s). m / z:ES+[M+H]+375.

[0625] Example 2 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-isopropoxy-1H-benzo[d]imidazole

[0626] [ka]

[0627] 2-(2-Chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol (125 mg, 0.24 mmol), 2-bromopropane (0.046 mL, 0.49 mmol), and potassium carbonate (169 mg, 1.22 mmol) were suspended in acetonitrile (5 mL) and sealed in a microwave tube. The reaction was heated to 100° C. in a microwave reactor for 12 h and cooled to room temperature. The solids were removed by filtration, and the filtrate was evaporated to dryness. The crude product was purified by preparative HPLC (Waters CSH C18 OBD column, 5 μm silica, 30 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% aqueous ammonia) and MeCN as eluent. Fractions containing the desired compound were evaporated to dryness to give 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-isopropoxy-1H-benzo[d]imidazole (14 mg, 10%). 1 H NMR(500MHz,CD3OD):1.32(3H,s),1.33(3H,s),2.27(3H,s),2.43-2.72(6H,m),2.84(2H,t),3.30(2H,p),4.19(2H,d), 4.55-4.64(1H,m),5.26(2H,s),6.86(1H,dt),6.93(2H,dd),7.01(1H,dd),7.15-7.23(4H,m),7.31(1H,d),7.35(1H,d). m / z:ES+[M+H]+553.

[0628] The starting material, 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol, was prepared as follows.

[0629] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole

[0630] [ka]

[0631] A solution of crude 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde (578 mg, 1.02 mmol) in NMP (3 mL) was added in one portion to a stirred suspension of N-(3-chlorobenzyl)-4-methoxy-2-nitroaniline (299 mg, 1.02 mmol, commercially available from Princeton Biol Molecular Research Inc., ACD identifier: MFCD12564576) and sodium dithionite (628 mg, 3.07 mmol) in water (1 mL). The resulting solution was stirred at reflux for 18 h. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with NaHCO (50 mL), water (50 mL), and saturated brine (5 mL). The organic layer was dried over MgSO, filtered, and evaporated onto silica gel (1 g). The resulting powder was purified by flash silica chromatography using an elution gradient of 0 to 20% MeOH in DCM with ammonia as a modifier. Pure fractions were evaporated to dryness to give 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole (213 mg, 40%) as a white solid. Impure fractions were combined, concentrated in vacuo, and repurified by preparative HPLC (Waters CSH C18 OBD column, 5 μm silica, 30 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% aqueous NH3) and MeCN as eluent. Fractions containing the desired compound were evaporated to dryness to give 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole (92 mg, 17%) as a white solid. 1H NMR(500MHz,CDCl3):2.30(3H,s),2.48(4H,s),2.63(4H,s),2.84(2H,t),3.87(3H,s),4.14(2H,t),5.17(2H,s),6. 82(1H,d),6.88(1H,dd),6.91(1H,dd),6.95(1H,s),7.04-7.1(2H,m),7.15(1H,t),7.18-7.22(1H,m),7.35(2H,s). m / z:ES+525[M+H]+525.

[0632] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol

[0633] [ka]

[0634] A solution of boron tribromide in dichloromethane (1.52 mL, 1.52 mmol) was added dropwise over 2 min to a stirred solution of 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole (0.20 g, 0.38 mmol) in anhydrous dichloromethane (1 mL) under nitrogen at 0 °C. The resulting suspension was stirred at room temperature for 35 min. The reaction mixture was quenched with 2 M HCl (5 mL) and evaporated to remove DCM. DMSO (2 mL) was added, and the resulting solution was purified by flash reverse-phase silica chromatography (elution gradient 5–95% MeCN in water with 0.1% formic acid as a modifier). Pure fractions were evaporated to dryness to afford 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol (150 mg, 77%) as a white solid. 1H NMR(500MHz,CDCl3):2.64(3H,s),2.81-2.96(6H,m),3.06(4H,s),4.11(2H,t),5.15(2H,s),6.83(2H,td),6.8 7(1H,dd),6.93(1H,s),7-7.06(2H,m),7.12-7.22(2H,m),7.29-7.35(2H,m),8.38(1H,s).m / z:ES+[M+H]+511.

[0635] The 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde used as starting material is described in Example 4.

[0636] Example 3 3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propan-1-amine

[0637] [ka]

[0638] TFA (2 mL, 25.96 mmol) was added to a solution of tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate (100 mg, 0.18 mmol) in DCM (5 mL) at 0° C. The resulting mixture was stirred at room temperature for 2 h. The reaction mixture was evaporated to give a crude oil. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 5 μm silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% aqueous NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propan-1-amine (27 mg, 33%) as a yellow oil that solidified on standing. 1H NMR (400 MHz, CDCl): 1.39 (6H, d), 1.97-2.07 (2H, m), 2.99 (2H, t), 4.13 (2H, t), 4.58 (1H, p), 5.23 (2H, s), 6.88 (2H, dt), 6.97-7.03 (2H, m), 7.06-7.13 (2H, m), 7.25 (3H, dd), 7.33-7.41 (2H, m). No 2H observed. m / z: ES+ [M+H]+ 450.

[0639] The tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate used as a starting material was prepared as follows.

[0640] N-benzyl-4-isopropoxy-2-nitroaniline

[0641] [ka]

[0642] Phenylmethanamine (2.37 g, 22.1 mmol) was slowly added to a solution of DIEA (7.02 mL, 40.2 mmol) and 1-fluoro-4-isopropoxy-2-nitrobenzene (4 g, 20.1 mmol, commercially available) in DMA (10 mL) at room temperature. The resulting mixture was stirred at 100 °C for 18 hours and cooled to room temperature. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was washed sequentially with saturated NH Cl (20 mL × 1), saturated NaHCO (20 mL × 1), and saturated brine (20 mL × 1). The organic layer was dried over Na SO , filtered, and evaporated to give the crude material. The residue was purified by preparative TLC (petroleum ether: EtOAc = 1:6) to give N-benzyl-4-isopropoxy-2-nitroaniline (4.50 g, 78%) as a red oil that solidified upon standing. 1H NMR(400MHz,DMSO-d6):1.22(6H,d),4.47(1H,hept),4.60(2H,d),6.88(1H,d ),7.18(1H,dd),7.25(1H,ddd),7.29-7.39(4H,m),7.51(1H,d),8.51(1H,t). m / z(ES+),[M+H]+=287.

[0643] 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol - Example A1

[0644] [ka]

[0645] A solution of sodium dithionite (7.30 g, 41.9 mmol) in water (5.00 mL) was added dropwise to a stirred mixture of N-benzyl-4-isopropoxy-2-nitroaniline (3 g, 10.5 mmol) and 2-chloro-4-hydroxybenzaldehyde (1.80 g, 11.5 mmol) in NMP (20 mL) at room temperature. The resulting mixture was stirred at 100 °C for 18 h. The reaction mixture was poured into saturated brine (75 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a yellow gum. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 100% petroleum ether in EtOAc. Pure fractions were evaporated to dryness to give 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol (2.30 g, 56%) as a yellow oil that solidified on standing. 1 H NMR(300MHz,DMSO-d6):1.27(6H,d),4.60(1H,p),5.25(2H,s),6.85(2H,td), 6.93-7.04(3H,m),7.15-7.30(4H,m),7.30(1H,t),7.37(1H,d),10.41(1H,s). m / z:ES+[M+H]+393.

[0646] Tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate - Example A2

[0647] [ka]

[0648] DIAD (1.00 g, 4.96 mmol) was added dropwise to 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol (1.5 g, 3.82 mmol), tert-butyl (3-hydroxypropyl)carbamate (0.803 g, 4.58 mmol), and Ph3P (1.50 g, 5.73 mmol) in THF (20 mL) under nitrogen at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc:petroleum ether (200 mL, 1:5). The solid was filtered off, and the organic layer was washed successively with saturated NH4Cl (30 mL), saturated NaHCO3 (30 mL), and saturated brine (30 mL × 2). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate (900 mg, 43%) as a yellow gum. 1 H NMR(400MHz,CDCl3):1.38(6H,d),1.46(9H,s),2.03(2H,q),3.35(2H,q),4.07(2H,t),4.58(1H,hept),4.74(1H,s) ,5.22(2H,s),6.87(2H,ddd),6.95-7.02(2H,m),7.06(1H,d),7.09(1H,d),7.25(3H,dd),7.35(1H,d),7.39(1H,d). m / z:ES+[M+H]+550.

[0649] Example 4 9-benzyl-8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine

[0650] [ka]

[0651] To a solution of (E)-N-benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropoxy)pyrimidin-4-amine (82 g crude, calculated as 129 mmol, 1.00 equivalents) in IPA (820 mL) was added FeCl (32 g, 193 mmol, 1.50 equivalents) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 1.5 hours. The resulting mixture was concentrated in vacuo. The reaction mixture was diluted with 500 mL of HO, and the aqueous layer was adjusted to pH = 10 with NaOH and extracted with DCM / IPA (6:1). The combined organic layers were washed with saturated NaHCO and brine (1000 mL × 5), dried over NaSO, and concentrated. The residue was applied to a silica gel column eluted with DCM / ammonia solution (3.5 M in MeOH) (1:0 to 1:20). The resulting mixture was further purified by SFC (OptiChiral-C9-5 column, 5 μm silica, 30 mm diameter, 250 mm length) eluted with 50% scCO and MeOH (containing 0.1% 2 M NH3-MeOH) and concentrated under vacuum below 40 °C to give a yellow solid, which was slurried in Et2O (10 V) for 2 h. The resulting mixture was filtered, and the filtrate cake was dried under vacuum to give 9-benzyl-8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (32.4 g, 45%) as a pale yellow solid. 1H NMR(400MHz,CDCl3):0.76-0.88(2H,m),1.01-1.26(2H,m),1.80(3H,s),2.31(3H,s),2.37-2.57(4H,m),2.64(4H,brs),2.85( 2H,t),4.15(2H,t),5.34(2H,s),6.82(1H,dd),6.93(2H,dd),7.06(1H,d),7.13-7.21(2H,m),7.14-7.19(2H,m),8.67(1H,s). m / z:ES+[M+H]+533.

[0652] The (E)-N-benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropoxy)pyrimidin-4-amine used as the starting material was prepared as follows.

[0653] N-Benzyl-6-chloro-5-nitropyrimidin-4-amine

[0654] [ka]

[0655] To a stirred solution of 4,6-dichloro-5-nitropyrimidine (400 g, 2.01 mol, 1.00 equiv.) in DCM (4000 mL) was added TEA (228 g, 2.26 mol, 1.1 equiv.) at room temperature under a nitrogen atmosphere. Phenylmethanamine (243.1 g, 2.26 mol, 1.1 equiv.) was charged at 0 °C. The reaction mixture was stirred at room temperature for 30 min. The resulting mixture was washed with brine (1000 mL × 5), dried over anhydrous Na2SO4, and concentrated. The residue was applied to a silica gel column using petroleum ether / ethyl acetate (2:1 to 1:1). This afforded N-benzyl-6-chloro-5-nitropyrimidin-4-amine (327 g, 60%) as a yellow solid. 1 H NMR (300MHz, CDCl3):4.82(2H,d),7.28-7.47(5H,m),7.82(1H,s),8.43(1H,s).m / z:ES+[M+H]+265.

[0656] N-Benzyl-6-(1-methylcyclopropoxy)-5-nitropyrimidin-4-amine

[0657] [ka]

[0658] To a stirred solution of N-benzyl-6-chloro-5-nitropyrimidin-4-amine (210 g, 0.79 mol, 1.00 equiv.) in THF (2100 mL) was added 1-methylcyclopropan-1-ol (114.3 g, 1.59 mmol, 2.00 equiv.) under a nitrogen atmosphere at room temperature. LHMDS (1980 mL, 1.98 mol, 2.50 equiv.) was added at 0 °C. The reaction mixture was stirred at room temperature for 18 h. The reaction mixture was diluted with 1000 mL of NH4Cl and extracted with ethyl acetate (1500 mL × 3). The combined organic layers were washed with brine (2000 mL × 2), dried over Na2SO4, and concentrated. The residue was applied to a silica gel column with petroleum ether / ethyl acetate (1:50 to 1:20). This gave N-benzyl-6-(1-methylcyclopropoxy)-5-nitropyrimidin-4-amine (108 g, 45%) as a yellow oil. 1 H NMR(400MHz,DMSO-d6):0.76(2H,t),0.92(2H,t),1.62(3H,s),4.70(2H,d),7.17-7.26(1H,m),7.26-7.39(4H,m),8.33(1H,s),8.86(1H,t). m / z:ES+[M+H]+301.

[0659] N4-benzyl-6-(1-methylcyclopropoxy)pyrimidine-4,5-diamine

[0660] [ka]

[0661] To a stirred solution of N-benzyl-6-(1-methylcyclopropoxy)-5-nitropyrimidin-4-amine (108 g, 360 mmol, 1.00 equiv.) in EtOH (1080 mL) was added iron powder (201 g, 3.60 mol, 10 equiv.) and NH4Cl (23.2 g, 432 mmol, 1.2 equiv.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 18 h. The resulting mixture was filtered through Celite and eluted with EtOH. The filtrate was concentrated to give the crude material. The crude product was purified by flash silica chromatography eluting with petroleum ether:ethyl acetate 10:1 to 1:3 to give N4-benzyl-6-(1-methylcyclopropoxy)pyrimidine-4,5-diamine (77 g, 79%) as an off-white solid. 1 H NMR(300MHz,DMSO-d6):0.68(2H,t),0.85(2H,t),1.60(3H,s),4.12(2H,s),4 .59(2H,d),6.69(1H,t),7.05-7.41(5H,m),7.72(1H,s).m / z:ES+[M+H]+271.

[0662] (E)-N-Benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropoxy)pyrimidin-4-amine

[0663] [ka]

[0664] To a stirred solution of N4-benzyl-6-(1-methylcyclopropoxy)pyrimidine-4,5-diamine (35 g, 129 mmol, 1.00 equiv.) in MeOH / AcOH (20 V / 1 V) was added 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde (47.6 g, 168 mmol, 1.30 equiv.) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at room temperature for 15 hours. The resulting mixture was concentrated in vacuo to give (E)-N-benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropoxy)pyrimidin-4-amine (82 g, crude) as a yellow oil, which was used directly without further purification. 1 H NMR(300MHz,CDCl3):0.69-0.81(2H,m),0.98-1.10(2H,m),1.70(3H,s),2.55(3H,s),2.73-3.10(10H,m),4.08-4.20(2H,m),4 .75(2H,d),6.38-6.49(1H,m),6.77-6.88(1H,m),6.88-6.97(1H,m),7.24-7.38(5H,m),8.00(1H,d),8.23(1H,s),9.40(1H,s). m / z:ES+[M+H]+535.

[0665] The 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde used as the starting material was prepared as follows.

[0666] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate

[0667] [ka]

[0668] To a stirred solution of 2-chloro-4-hydroxybenzaldehyde (300 g, 1.92 mol, 1.00 equiv.) in DMF (3000 mL) was added tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (643.4 g, 2.59 mol, 1.35 equiv.), KCO (528.8 g, 3.84 mol, 2.00 equiv.), and KI (63.6 g, 0.38 mol, 0.20 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred at 80 °C for 14 h. The resulting mixture was diluted with 2 L of water. The resulting mixture was filtered, and the filtrate cake was washed with HO. The filtrate cake was then dried under vacuum to give tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (390 g, 55%) as a yellow solid, which was used in the next step without further purification. 1 H NMR (400MHz, DMSO-d6): 1.39 (9H, s), 2.43 (4H, t), 2.73 (2H, t), 3.30 (4H, m), 4.23 (2H, t), 7.08 (1H, dd), 7.20 (1H, d), 7.81 (1H, d), 10.19 (1H, s). m / z:ES+[M+H]+369.

[0669] 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde

[0670] [ka]

[0671] To a stirred solution of tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (390 g, 1.06 mol, 1.00 equiv.) in formic acid (1850 mL) was added formaldehyde (48.5 g, 1.28 mol, 1.20 equiv.) under a nitrogen atmosphere. The reaction mixture was stirred at 70 °C for 14 h. The reaction mixture was diluted with 1000 mL of HO and extracted with MTBE (1500 mL × 3). The aqueous layer was adjusted to pH = 10 with NaOH and extracted with DCM (1000 mL × 3). The combined organic layers were washed with saturated and brine (1000 mL × 5), dried over NaSO, and concentrated. The residue was purified by flash silica chromatography eluting with DCM / ammonia solution (3.5 M in MeOH) (1:100 to 1:30). This gave 176 g (42%) of 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde as a yellow oil. 1 H NMR (300MHz, DMSO-d6): 2.14 (3H, s), 2.39 (8H, d), 2.70 (2H, t), 4.22 (2H, t), 7.10 (1H, dd), 7.22 (1H, d), 7.82 (1H, d), 10.20 (1H, d). m / z:ES+[M+H]+283.

[0672] Example 5 9-benzyl-8-(2-chloro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine

[0673] [ka]

[0674] DIAD (143 μL, 0.74 mmol) was added dropwise to a solution of 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenol (150 mg, 0.37 mmol), (1-methylpiperidin-4-yl)methanol (95 mg, 0.74 mmol), and Ph3P (193 mg, 0.74 mmol) in THF (5 mL) at 0 °C under nitrogen. The resulting mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated, diluted with EtOAc (50 mL), and washed sequentially with saturated NH4Cl (2 × 15 mL) and saturated brine (2 × 15 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The residue was purified by preparative TLC (EtOAc) to give the crude product as a yellow gum. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 5 μm silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.05% aqueous NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 9-benzyl-8-(2-chloro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (5.0 mg, 2.6%) as a white solid. 1 H NMR(400MHz,DMSO-d6):0.80-0.88(2H,m),0.98-1.06(2H,m),1.21-1.37(2H,m),1.64-1.78(6H,m),1.80-1.95(2H,m),2.17(3H ,s),2.79(2H,dd),3.94(2H,d),5.29(2H,s),6.86-6.95(2H,m),7.00-7.06(1H,m),7.16-7.25(4H,m),7.40(1H,d),8.61(1H,s). m / z:ES+[M+H]+518.

[0675] The starting material, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenol, was prepared as follows.

[0676] 9-benzyl-6-chloro-9H-purine

[0677] [ka]

[0678] (Bromomethyl)benzene (12.2 g, 71.2 mmol) was added dropwise over 10 min at 25 °C to a solution of 6-chloro-9H-purine (10 g, 64.70 mmol) and potassium carbonate (10.73 g, 77.64 mmol) in acetonitrile (300 mL). The resulting suspension was stirred at 25 °C for 16 h. The reaction mixture was filtered through Celite, and the filtrate was concentrated. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 9-benzyl-6-chloro-9H-purine (9.00 g, 57%) as a white solid. 1 H NMR(400MHz, CDCl3):5.48(2H,s),7.29-7.47(5H,m),8.13(1H,s),8.81(1H,s).m / z:ES+[M+H]+245.

[0679] 9-benzyl-6-(1-methylcyclopropoxy)-9H-purine

[0680] [ka]

[0681] 1-Methylcyclopropan-1-ol (6.52 g, 90.4 mmol) was added to 9-benzyl-6-chloro-9H-purine (8.81 g, 36.0 mmol) in THF (72 mL). The reaction mixture was stirred at 0 °C, and then sodium hydride (60% in mineral oil, 3.62 g, 90.5 mmol) was slowly added to the mixture. The reaction was stirred at room temperature for 17 h. Water (50 mL) was slowly added, and the reaction mixture was extracted with DCM (3 × 50 mL). The organics were combined and concentrated in vacuo. The crude material was purified by column chromatography on silica gel (330 g, 0–50% EtOAc in heptane) to afford 9-benzyl-6-(1-methylcyclopropoxy)-9H-purine (7.18 g, 71%) as a yellow gum. 1 H NMR (500MHz, CDCl3):0.8-0.86(2H,m),1.1-1.17(2H,m),1.78(3H,s),5.41(2H,s),7.26-7.39(5H,m),7.88(1H,s),8.64(1H,s).

[0682] m / z: ES+[M+H]+281.

[0683] 9-benzyl-8-bromo-6-(1-methylcyclopropoxy)-9H-purine

[0684] [ka]

[0685] Lithium bis(trimethylsilyl)amide (28.6 mL, 28.6 mmol) was added to a solution of 9-benzyl-6-(1-methylcyclopropoxy)-9H-purine (5 g, 17.84 mmol) and 1,2-dibromotetrachloroethane (8.72 g, 26.8 mmol) in THF (29 mL) at 0 °C under nitrogen. The resulting mixture was stirred at 25 °C for 16 h. The reaction mixture was quenched with water (50 mL) and extracted with EtOAc (3 × 100 mL) and saturated brine (1 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 9-benzyl-8-bromo-6-(1-methylcyclopropoxy)-9H-purine (5.70 g, 89%) as a yellow gum. 1 H NMR (300MHz, CDCl3):0.76-0.87(2H,m),1.06-1.16(2H,m),1.76(3H,s),5.44(2H,s),7.27-7.37(5H,m),8.60(1H,s);m / z:ES+[M+H]+359.

[0686] 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenol

[0687] [ka]

[0688] Dichloro[1,1'-bis(diphenylphosphino)ferrocene]palladium(II) (907 mg, 1.39 mmol) was added to a solution of 9-benzyl-8-bromo-6-(1-methylcyclopropoxy)-9H-purine (5 g, 13.9 mmol), 3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (7.09 g, 27.8 mmol) and cesium carbonate (9.07 g, 27.8 mmol) in 1,4-dioxane (20 mL) and water (2 mL) under nitrogen at 25°C. The resulting mixture was stirred at 90°C for 3 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with water (3 x 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenol (5.60 g, 99%) as a yellow solid. 1 H NMR (400 MHz, DMSO-d6): 0.83 (2H, t), 1.02 (2H, t), 1.73 (3H, s), 5.29 (2H, s), 6.83 (1H, dd), 6.88-6.92 (2H, m), 6.99 (1H, d), 7.18-7.22 (3H, m), 7.29 (1H, d), 8.61 (1H, s) - one H not observed. m / z: ES-[MH]-405.

[0689] Example 6 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine

[0690] [ka]

[0691] tert-Butyldimethylsilyl trifluoromethanesulfonate (12.05 mL, 52.5 mmol) was added to a solution of tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (6.5 g, 10.50 mmol) in DCM (130 mL). The resulting solution was stirred at room temperature for 10 min. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 30 to 90% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (3.10 g, 57%) as a white foam. 1 H NMR (400 MHz, DMSO-d6): 0.72-0.9 (2H, m), 0.95-1.12 (2H, m), 1.73 (3H, s), 2.25-2.49 (4H, m), 2.59-2.92 (6H, m), 4.19 (2H, t), 5.30 (2H, s), 6.91 (2H, dd), 7.04 (1H, dd), 7.13-7.29 (4H, m), 7.41 (1H, d), 8.63 (1H, s) - one proton not observed. m / z: ES+ [M+H]+ 519.

[0692] The tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as the starting material was made as follows.

[0693] tert-Butyl 4-(2-(4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0694] [ka]

[0695] Iron(III) chloride solution (20.73 g, 128 mmol) was added to N4-benzyl-6-chloropyrimidine-4,5-diamine (30 g, 128 mmol, Example 1) and tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (51.9 g, 141 mmol) in EtOH (500 mL). The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc (100 mL), and washed with water (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash C18 chromatography with an elution gradient of 40–70% MeCN in water. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (12.00 g, 16%) as a yellow solid.

[0696] 1 H NMR(300MHz,DMSO-d6):1.17(2H,t),1.40(9H,s),1.99(2H,s),2.45(4H,t),2.74(2H,t),4.22(2H,t),5 .38(2H,s),6.89-6.99(2H,m),7.09(1H,dd),7.17-7.25(3H,m),7.29(1H,d),7.51(1H,d),8.86(1H,s). m / z:ES+[M+H]+583.

[0697] tert-Butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0698] [ka]

[0699] Sodium hydride (6.17 g, 257 mmol) was added to 1-methylcyclopropan-1-ol (5.56 g, 77.12 mmol) and tert-butyl 4-(2-(4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (30 g, 51.4 mmol) in THF (200 mL) at 0 °C under nitrogen. The resulting mixture was stirred at room temperature for 1 h. The reaction mixture was poured into ice water. The reaction mixture was evaporated, diluted with EtOAc (250 mL), and washed successively with water (3 × 200 mL) and saturated brine (2 × 200 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash C18-flash chromatography with an elution gradient of 30–80% MeCN in water (containing 0.1% NHHCO). Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (13.00 g, 41%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):0.8-0.88(2H,m),0.98-1.06(2H,m),1.40(9H,s),1.74(3H,s),2.39-2.48(4H,m),2.69-2.82(2H ,m),3.33(4H,s),4.20(2H,t),5.30(2H,s),6.85-6.96(2H,m),7.05(1H,d),7.14-7.29(4H,m),7.42(1H,d),8.62(1H,s). m / z:ES+[M+H]+619.

[0700] The tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate used as the starting material was prepared as described in Example 4.

[0701] Example 7 4-((8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-2-methylthiazole

[0702] [ka]

[0703] A solution of sodium hydrosulfite (282 mg, 1.62 mmol) in water (1 mL) was added to a stirred mixture of 6-(1-methylcyclopropoxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine (130 mg, 0.40 mmol) and 2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde (137 mg, 0.49 mmol, starting material from Example 4) in NMP (3 mL). The resulting mixture was stirred at 100° C. for 16 h and then at 110° C. for an additional 16 h. The crude product was purified by flash C18-flash chromatography with an elution gradient of 5 to 40% MeCN in water (containing 5% TFA). Fractions were evaporated to dryness to give the crude product. The crude product was further purified by preparative HPLC (XBridge Prep OBD C18 column, 5 μm silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.1% NH3 in water and 10 mmol / L NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 4-((8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-2-methylthiazole (55 mg, 24%) as a white solid. 1 H NMR(400MHz,DMSO-d6):0.81-0.88(2H,m),1.01(2H,d),1.73(3H,s),2.15(3H,s),2.33(4H,s),2.49(3H,s),2.52 (4H,s),2.69(2H,t),4.17(2H,t),5.30(2H,s),6.96(1H,s),7.02(1H,dd),7.22(1H,d),7.43(1H,d),8.60(1H,s). m / z:ES+[M+H]+554.

[0704] The 6-(1-methylcyclopropoxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine used as the starting material was made as follows.

[0705] 6-chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine

[0706] [ka]

[0707] A solution of (2-methylthiazol-4-yl)methanamine (330 mg, 2.58 mmol) in DCM (10 mL) was added to a mixture of 4,6-dichloro-5-nitropyrimidine (500 mg, 2.58 mmol) and N,N-diisopropylethylamine (1.35 mL, 7.73 mmol) in DCM (10 mL) at 0° C. The resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with water (25 mL) and extracted with DCM (3 × 20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give 6-chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine (0.4 g) as a yellow gum. The product was used directly in the next step without further purification.

[0708] 6-(1-methylcyclopropoxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine

[0709] [ka]

[0710] LHMDS (2.66 mL, 2.66 mmol) was added to 6-chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine (0.38 g, 1.33 mmol) and 1-methylcyclopropan-1-ol (0.192 g, 2.66 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at room temperature for 16 h. The reaction mixture was quenched with saturated NH4Cl (25 mL), and then the THF solvent was removed under reduced pressure. The reaction mixture was extracted with EtOAc (3 × 20 mL), and the organic layer was dried over Na2SO4, filtered, and evaporated to give a yellow gum. The crude product was purified by flash C18-flash chromatography with an elution gradient of 5 to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 6-(1-methylcyclopropoxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine (0.150 g, 35%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):0.76(2H,dd),0.88-0.96(2H,m),1.61(3H,s),2.61(3H,s),4.71(2H,dd),7.18(1H,d),8.33(1H,s),8.80(1H,t). m / z:ES+[M+H]+322.

[0711] Example 8 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-5-isopropoxy-1H-imidazo[4,5-b]pyridine

[0712] [ka]

[0713] tert-Butyl 4-(2-(4-(1-benzyl-5-isopropoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (44 mg, 0.07 mmol) was added to trifluoroacetic acid (0.5 mL, 6.49 mmol) in dichloromethane (2 mL). The resulting solution was stirred at room temperature for 1 h, after which the solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 30–80% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-5-isopropoxy-1H-imidazo[4,5-b]pyridine (0.026 g, 71%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): 1.32 (6H, d), 2.40 (4H, t), 2.64-2.72 (6H, m), 4.18 (2H, t), 5.24-5.34 (3H, m), 6.63 (1H, d), 6.94-6.99 (2H, m), 7.07 (1H, dd), 7.21-7.29 (4H, m), 7.49 (1H, d), 7.80 (1H, d) - one proton not observed. m / z: ES+ [M+H]+ 506.

[0714] The tert-butyl 4-(2-(4-(1-benzyl-5-isopropoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as the starting material was prepared as follows.

[0715] 6-amino-5-nitropyridin-2(1H)-one

[0716] [ka]

[0717] 6-Chloro-3-nitropyridin-2-amine (10 g, 57.62 mmol) was added to NaOH (23.1 g, 57.6 mmol) in EtOH (50 mL) and water (16.6 mL). The resulting solution was stirred at 80° C. for 30 minutes. The reaction mixture was acidified with concentrated HCl, and the precipitate formed was filtered to give 6-amino-5-nitropyridin-2(1H)-one (8.00 g, 90%) as a yellow solid. The product was used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6): 11.51 (s, 1H), 8.53 (s, 2H), 7.98 (d, 1H), 5.66 (d, 1H). m / z:ES-[MH]-154.

[0718] 6-Isopropoxy-3-nitropyridin-2-amine

[0719] [ka]

[0720] 6-Amino-5-nitropyridin-2(1H)-one (4 g, 25.8 mmol) was added to potassium carbonate (10.7 g, 77.4 mmol) and 2-iodopropane (13.1 g, 77.4 mmol) in DMF (80 mL) at 80 °C. The resulting solution was stirred at 80 °C overnight. After cooling the reaction mixture, the solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 6-isopropoxy-3-nitropyridin-2-amine (3.20 g, 63%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 1.18 (6H, d), 5.12-5.24 (1H, m), 5.95 (1H, d), 7.97 (2H, s), 8.10 (1H, d). m / z:ES+[M+H]+198.

[0721] 6-Isopropoxypyridine-2,3-diamine

[0722] [ka]

[0723] 6-Isopropoxy-3-nitropyridin-2-amine (3.1 g, 15.72 mmol) and palladium on carbon (310 mg, 0.29 mmol) in MeOH (60 mL) were stirred at room temperature under a hydrogen atmosphere for 2 hours. The reaction mixture was filtered through filter paper to give 6-isopropoxypyridine-2,3-diamine (2.60 g, 99%) as a purple oil. The product was used directly in the next step without further purification. 1 H NMR (300MHz, DMSO-d6): 1.18 (6H, d), 3.92-4.69 (2H, m), 4.9-4.97 (1H, m), 4.97-5.51 (2H, m), 5.73 (1H, d), 6.73 (1H, d). m / z:ES+[M+H]+168.

[0724] N3-benzyl-6-isopropoxypyridine-2,3-diamine

[0725] [ka]

[0726] 6-Isopropoxypyridine-2,3-diamine (1.5 g, 8.97 mmol) was added to a solution of benzaldehyde (0.909 mL, 8.97 mmol) and acetic acid (0.051 mL, 0.90 mmol) in dichloromethane (30 mL). The reaction was stirred at room temperature for 5 hours. Sodium triacetoxyborohydride (5.70 g, 26.91 mmol) was then added to the reaction mixture. The resulting solution was stirred at room temperature for an additional 16 hours. The reaction mixture was concentrated under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give N3-benzyl-6-isopropoxypyridine-2,3-diamine (1.10 g, 48%) as a purple oil. 1H NMR (300 MHz, DMSO-d6): 1.17 (6H, d), 4.20 (2H, s), 4.94 (1H, p), 5.45 (2H, s), 5.73 (1H, d), 6.57 (1H, d), 7.12-7.25 (1H, m), 7.25-7.46 (4H, m) - one proton not observed. m / z: ES+ [M+H]+ 258.

[0727] tert-Butyl 4-(2-(4-(1-benzyl-5-isopropoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0728] [ka]

[0729] N3-Benzyl-6-isopropoxypyridine-2,3-diamine (50 mg, 0.19 mmol) was added to tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (86 mg, 0.23 mmol, starting material from Example 6) and copper(II) acetate monohydrate (7.76 mg, 0.04 mmol) in acetic acid (2 mL). The resulting solution was stirred at 100° C. for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 10% MeOH in dichloromethane. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(1-benzyl-5-isopropoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (118 mg, 100%) as a yellow solid. 1H NMR(300MHz,DMSO-d6):1.2-1.35(6H,m),1.39(9H,d),2.44(4H,s),2.73(2H,s),3.17(8H,d),4.08(3H,q),4.1 9(1H,d),5.30(1H,d),6.82(1H,t),6.97(1H,d),7.07(1H,d),7.2-7.25(1H,m),7.27(1H,d),7.46-7.56(1H,m). m / z:ES+[M+H]+606.

[0730] Example 9 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol

[0731] [ka]

[0732] tert-Butyl 4-(2-(4-(1-benzyl-4-isopropoxy-1H-imidazo[4,5-c]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (90 mg, 0.15 mmol) was added to trifluoroacetic acid (1 mL, 12.98 mmol) in dichloromethane (4 mL). The resulting solution was stirred at room temperature for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 30 to 80% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-isopropoxy-1H-imidazo[4,5-c]pyridine (0.029 g, 38%) as a white solid. 1H NMR (400 MHz, DMSO-d6): 1.37 (6H, d), 2.36-2.44 (4H, m), 2.64-2.72 (6H, m), 4.18 (2H, t), 5.28 (2H, s), 5.44-5.55 (1H, m), 6.92-6.96 (2H, m), 7.05 (1H, dd), 7.12 (1H, d), 7.21-7.28 (4H, m), 7.47 (1H, d), 7.85 (1H, d) - one proton not observed. m / z: ES+ [M+H]+ 506.

[0733] The tert-butyl 4-(2-(4-(1-benzyl-4-isopropoxy-1H-imidazo[4,5-c]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as the starting material was prepared as follows.

[0734] 4-Chloro-2-isopropoxy-3-nitropyridine

[0735] [ka]

[0736] 4-Chloro-3-nitropyridin-2(1H)-one (5.0 g, 28.6 mmol) was added to sodium hydride (2.06 g, 85.9 mmol) in DMF (100 mL) at 0 °C. The reaction was allowed to warm to room temperature over 30 min, and then 2-iodopropane (24.3 g, 143.2 mmol) was added. The resulting solution was stirred at room temperature for an additional 12 h. The reaction mixture was quenched with saturated NH4Cl (50 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash C18-flash chromatography with an elution gradient of 5–80% MeOH in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to give 4-chloro-2-isopropoxy-3-nitropyridine (2.10 g, 34%) as a yellow oil. 1H NMR (300MHz, DMSO-d6): 1.30 (6H, d), 5.29-5.44 (1H, m), 7.43 (1H, d), 8.37 (1H, d).

[0737] N-Benzyl-2-isopropoxy-3-nitropyridin-4-amine

[0738] [ka]

[0739] 4-Chloro-2-isopropoxy-3-nitropyridine (1.0 g, 4.62 mmol) was added to benzylamine (0.504 mL, 4.62 mmol) and TEA (6.43 mL, 46.2 mmol) in DMSO (20 mL). The resulting solution was stirred at 90 °C for 5 h. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give N-benzyl-2-isopropoxy-3-nitropyridin-4-amine (1.20 g, 90%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 1.25 (6H, d), 4.49 (2H, d), 5.21-5.35 (1H, m), 6.39 (1H, d), 7.21-7.28 (1H, m), 7.3-7.35 (4H, m), 7.75 (1H, d), 7.87 (1H, t). m / z:ES-[MH]- 286.

[0740] N4-benzyl-2-isopropoxypyridine-3,4-diamine

[0741] [ka]

[0742] N-Benzyl-2-isopropoxy-3-nitropyridin-4-amine (1 g, 3.48 mmol) was added to iron (0.972 g, 17.40 mmol) and ammonium chloride (1.862 g, 34.80 mmol) in EtOH (16 mL) and water (1.6 mL). The resulting solution was stirred at 80 °C for 12 h. The reaction mixture was filtered through filter paper, and the solvent was then removed under reduced pressure. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give N4-benzyl-2-isopropoxypyridine-3,4-diamine (0.518 g, 58%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):1.25(6H,d),4.04(2H,s),4.35(2H,d),5.09-5.19(1H,m),5.91( 1H,t),6.10(1H,d),7.18(1H,d),7.2-7.25(1H,m),7.28-7.32(1H,m),7.32-7.37(3H,m). m / z:ES+[M+H]+258.

[0743] tert-Butyl 4-(2-(4-(1-benzyl-4-isopropoxy-1H-imidazo[4,5-c]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0744] [ka]

[0745] N4-Benzyl-2-isopropoxypyridine-3,4-diamine (50 mg, 0.19 mmol) was added to tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (86 mg, 0.23 mmol) and copper(II) acetate monohydrate (7.8 mg, 0.04 mmol) in AcOH (2 mL). The resulting solution was stirred at 100 °C for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 10 to 80% MeOH in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(1-benzyl-4-isopropoxy-1H-imidazo[4,5-c]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (95 mg, 81%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):1.37(6H,d),1.39(9H,s),2.44(4H,t),2.74(2H,t),3.28-3.3(2H,m),3.32-3.34(2H,m),4.20(2H,t),5.28 (2H,s),5.47-5.53(1H,m),6.92-6.96(2H,m),7.05(1H,dd),7.12(1H,d),7.21-7.24(3H,m),7.27(1H,d),7.47(1H,d),7.85(1H,d). m / z:ES+[M+H]+606.

[0746] Example 10 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine

[0747] [ka]

[0748] A solution of tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (2.07 g, 3.16 mmol) in acetonitrile was cooled to 0° C. in an ice / water bath. 4.0 M hydrogen chloride in dioxane (8.0 mL, 32.0 mmol) was added and the ice bath was removed. Stirring was continued at room temperature for 1 hour, after which additional 4.0 M hydrogen chloride in dioxane (8.0 mL, 32.0 mmol) was added and stirring was continued for an additional 30 minutes. The reaction mixture was evaporated to give the crude product as a yellow solid. The crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column using 1 M NH3 / MeOH and dried to give the crude free base. The crude free base was purified by flash deactivated alumina chromatography with an elution gradient of 0 to 10% MeOH in DCM to give 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine (1.50 g, 86%) as a yellow foam.

[0749] 1 H NMR (500 MHz, CDCl): 0.8-0.87 (2H, m), 1.14-1.2 (2H, m), 1.81 (3H, s), 2.55 (4H, s), 2.80 (2H, t), 2.92 (4H, t), 4.12 (2H, t), 5.44 (2H, s), 6.80 (1H, dd), 6.88 (1H, dd), 7.02 (1H, d), 7.12 (1H, dd), 7.25 (1H, d), 8.30 (1H, dd), 8.64 (1H, s). No 1H observed. m / z: ES+ [M+H]+ 554.

[0750] The tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate used as the starting material was made as follows.

[0751] tert-Butyl 4-(2-(3-chloro-4-(6-chloro-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0752] [ka]

[0753] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (1 g, 2.71 mmol) and 6-chloropyrimidine-4,5-diamine (0.431 g, 2.98 mmol) were dissolved in IPA (38.7 mL). Iron(III) chloride (0.088 g, 0.54 mmol) was added, and the reaction was stirred under air at 80 °C for 2.5 days. The reaction was cooled to room temperature, diluted with DCM (50 mL), and water (50 mL) was added. The mixture was filtered through a small plug of Celite to aid separation, and the Celite was washed with DCM (50 mL). The mixture was then extracted with DCM (50 mL × 3), and the combined organics were washed with saturated NaHCO (20 mL), separated, dried over MgSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 100% EtOAc in heptane, then 3:1 EtOAc / EtOH in EtOAc to elute the product. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(3-chloro-4-(6-chloro-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (1.050 g, 78%) as a pale yellow solid. 1 H NMR (500 MHz, DMSO-d6): 1.40 (9H, s), 2.44-2.48 (4H, m), 2.76 (2H, t), 3.26-3.38 (4H, m), 4.23 (2H, t), 7.15 (1H, dd), 7.30 (1H, d), 7.81 (1H, d), 8.75 (1H, s). No 1H observed. m / z: ES+ [M+H]+ 493.

[0754] The tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate used as the starting material was prepared as described in Example 4.

[0755] tert-Butyl 4-(2-(3-chloro-4-(6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0756] [ka]

[0757] To a solution of tert-butyl 4-(2-(3-chloro-4-(6-chloro-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (1.62 g, 3.28 mmol) and 4-chloro-2-(chloromethyl)pyridine hydrochloride (0.977 g, 4.93 mmol) in anhydrous DMF (16.4 mL) was added cesium carbonate (3.21 g, 9.85 mmol). The reaction was inactivated by applying three cycles of vacuum and nitrogen backfill, and then the reaction was stirred under nitrogen at 60 °C for 19 h. The reaction was quenched with ice water (20 mL) and ethyl acetate (20 mL) was added. The organic layer was removed and the aqueous layer was further extracted with ethyl acetate (10 mL × 6). The combined organic layers were washed with saturated aqueous LiCl (10 mL × 3), filtered through an isolute phase separation cartridge, and evaporated to give the crude product as a brown foam. The crude product was purified by flash silica chromatography in n-heptane with an elution gradient of 0 to 35%, then to 70%, of 3:1 EtOAc:EtOH. Pure fractions were evaporated to dryness to give tert-butyl 4-(2-(3-chloro-4-(6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (1.13 g, 56%) as a light brown foam. 1H NMR(500MHz,CDCl3):1.47(9H,s),2.5-2.54(4H,m),2.83(2H,t),3.44-3.48(4H,m),4.14(2H,t),5.47 (2H,s),6.84(1H,dd),6.98(1H,d),7.05(1H,d),7.14(1H,dd),7.31(1H,d),8.28(1H,d),8.77(1H,s). m / z:ES+[M+H]+618.

[0758] tert-Butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0759] [ka]

[0760] To a suspension of sodium hydride (0.889 g, 22.2 mmol) in tetrahydrofuran (15 mL) cooled to 0° C. under nitrogen was added a steady stream of 1-methylcyclopropan-1-ol (0.802 g, 11.1 mmol) and a solution of tert-butyl 4-(2-(3-chloro-4-(6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (3.44 g, 5.56 mmol) in tetrahydrofuran (30 mL). The reaction mixture was stirred at 0° C. for 20 minutes, then the ice bath was removed and the reaction was stirred at room temperature under nitrogen for 19 hours. The reaction mixture was cooled in an ice / water bath and carefully quenched with saturated ammonium chloride solution (15 mL). After gas evolution subsided, the mixture was diluted with water (150 mL) and EtOAc (150 mL). The aqueous phase was extracted with EtOAc (150 mL). The combined organic phases were washed with brine, dried, and evaporated. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 100% 3:1 EtOAc / EtOH in heptane to afford tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (2.07 g, 57%) as a pale yellow foam. 1 H NMR(500MHz,CDCl3):0.8-0.87(2H,m),1.14-1.2(2H,m),1.47(9H,s),1.81(3H,s),2.45-2.59(4H,m),2.82(2H,t),3.38-3.53(4H ,m),4.12(2H,t),5.44(2H,s),6.80(1H,dd),6.89(1H,d),7.01(1H,d),7.12(1H,dd),7.24-7.28(1H,m),8.30(1H,d),8.64(1H,s). m / z:ES+[M+H]+654.

[0761] Example 11 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purine

[0762] [ka]

[0763] tert-Butyl 4-(2-(4-(9-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (120 mg, 0.18 mmol) was added to trifluoroacetic acid (0.2 mL, 2.60 mmol) in dichloromethane (2 mL). The resulting solution was stirred at room temperature for 2 hours. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 50 to 100% MeOH in water (0.1% NH4HCO3), followed by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purine (30.0 mg, 29%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): 1.95 (6H, s), 2.3-2.45 (4H, m), 2.58-2.79 (6H, m), 4.18 (2H, t), 5.30 (2H, s), 6.91 (2H, dd), 7.04 (1H, dd), 7.15-7.23 (3H, m), 7.27 (1H, d), 7.43 (1H, d), 8.61 (1H, s) - 1H not observed. m / z: ES+ [M+H]+ 575.

[0764] The tert-butyl 4-(2-(4-(9-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as the starting material was made as follows.

[0765] N-benzyl-5-nitro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidin-4-amine

[0766] [ka]

[0767] LHMDS (11.3 mL, 11.3 mmol) was added to N-benzyl-6-chloro-5-nitropyrimidin-4-amine (1 g, 3.78 mmol) and 1,1,1-trifluoro-2-methylpropan-2-ol (1.24 mL, 11.3 mmol) in THF (20 mL) at 0 °C. The resulting mixture was stirred at 60 °C for 12 h. The reaction mixture was diluted with EtOAc (100 mL) and washed sequentially with saturated brine (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 5% EtOAc in petroleum ether. Fractions were evaporated to dryness to give N-benzyl-5-nitro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidin-4-amine (800 mg, 59%) as a pale yellow oil. 1 H NMR (300MHz, DMSO-d6): 1.81 (6H, s), 4.69 (2H, d), 7.07-7.47 (5H, m), 8.31 (1H, s), 8.90 (1H, t). m / z:ES+[M+H]+357.

[0768] N4-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidine-4,5-diamine

[0769] [ka]

[0770] Iron (549 mg, 9.82 mmol) was added to a mixture of N-benzyl-5-nitro-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidin-4-amine (700 mg, 1.96 mmol) and ammonium chloride (1.05 g, 19.6 mmol) in ethanol (15 mL). The resulting mixture was stirred at 80 °C for 4 h. The solvent was then removed under reduced pressure and the crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give N4-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidine-4,5-diamine (400 mg, 63%) as a white solid. 1 H NMR (300MHz, DMSO-d6): 1.72 (6H, s), 4.16 (2H, s), 4.61 (2H, d), 6.95 (1H, t), 7.11-7.46 (5H, m), 7.72 (1H, s). m / z:ES+[M+H]+327.

[0771] tert-Butyl 4-(2-(4-(9-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0772] [ka]

[0773] Iron(III) chloride (49.7 mg, 0.31 mmol) was added to N4-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)pyrimidine-4,5-diamine (100 mg, 0.31 mmol), tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (124 mg, 0.34 mmol), and AcOH (1.7 μL, 0.03 mmol) in IPA (2 mL). The resulting mixture was stirred at 80 °C for 4 h. The solvent was then removed under reduced pressure, and the crude residue was purified by flash C18-flash chromatography with an elution gradient of 40 to 90% MeOH in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(9-benzyl-6-((1,1,1-trifluoro-2-methylpropan-2-yl)oxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (140 mg, 68%) as a white foam. 1 H NMR(300MHz,DMSO-d6):1.38(9H,s),1.94(6H,s),2.43(4H,t),2.72(2H,t),3.24-3.32(4H,m),4.19(2H ,t),5.29(2H,s),6.90(2H,dd),7.03(1H,dd),7.12-7.24(3H,m),7.26(1H,d),7.43(1H,d),8.60(1H,s). m / z:ES+[M+H]+675.

[0774] Example 12 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutoxy)-9H-purine

[0775] [ka]

[0776] Pd(PPh) (31.0 mg, 0.03 mmol) was added to 9-benzyl-8-bromo-6-(1-methylcyclobutoxy)-9H-purine (100 mg, 0.27 mmol), 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine (196 mg, 0.54 mmol), and CsCO (262 mg, 0.80 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL) under nitrogen. The resulting solution was stirred at 100 °C for 1 h. The solvent was removed under reduced pressure. The crude product was purified by flash C18-flash chromatography with an elution gradient of 50 to 100% MeOH in water (0.1% NH4HCO3), followed by preparative HPLC (Phenomenex Gemini-NX axia Prep C18 OBD column, 5 μm silica, 19 mm diameter, 100 mm length) using decreasingly polar mixtures of water (0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutoxy)-9H-purine (16 mg, 11%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): 1.62-1.96 (5H, m), 2.26-2.49 (8H, m), 2.61-2.78 (6H, m), 4.18 (2H, t), 5.28 (2H, s), 6.85-6.95 (2H, m), 6.98-7.11 (1H, m), 7.15-7.25 (3H, m), 7.26 (1H, d), 7.41 (1H, d), 8.51 (1H, s) - one hydrogen not observed. m / z: ES+ [M+H]+ 533.

[0777] The starting material, 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine, was prepared as follows.

[0778] tert-Butyl 4-(2-(4-bromo-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0779] [ka]

[0780] Potassium carbonate (6.66 g, 48.2 mmol) was added to 4-bromo-3-chlorophenol (5 g, 24.1 mmol), tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (7.19 g, 28.92 mmol) in DMF (100 mL) at 25 °C under nitrogen. The resulting suspension was stirred at 80 °C for 3 h. The reaction mixture was diluted with water (300 mL), and the aqueous layer was extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na SO , filtered, and evaporated to give the crude product. The crude product was purified by crystallization from EtOAc / petroleum ether to give tert-butyl 4-(2-(4-bromo-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (5.50 g, 54%) as a white solid. 1 H NMR (300MHz, CDCl3): 1.46 (9H, s), 2.51 (4H, s), 2.81 (2H, t), 3.45 (4H, t), 4.07 (2H, t), 6.70 (1H, dd), 7.02 (1H, d), 7.47 (1H, d). m / z:ES+[M+H]+419.

[0781] tert-Butyl 4-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0782] [ka]

[0783] PdCl(dppf) (0.523 g, 0.71 mmol) was added to tert-butyl 4-(2-(4-bromo-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (3 g, 7.15 mmol), bis(pinacolato)diboron (3.63 g, 14.29 mmol), and potassium acetate (2.10 g, 21.4 mmol) in 1,4-dioxane (60 mL) under nitrogen. The resulting solution was stirred at 100 °C for 2 h. The reaction mixture was diluted with EtOAc (250 mL) and washed sequentially with water (3 × 250 mL) and saturated brine (3 × 250 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give tert-butyl 4-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (3.00 g, 90%) as a pale yellow gum. 1 H NMR(300MHz,DMSO-d6):1.16(9H,s),1.27(12H,s),2.42(4H,m),2.58(2H,t ),3.17-3.20(4H,m),4.01(2H,t),6.79(1H,dd),6.88(1H,d),7.46(1H,d). m / z:ES+[M+H]+467.

[0784] 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine

[0785] [ka]

[0786] Trifluoroacetic acid (20 mL) was added to tert-butyl 4-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (2 g, 4.28 mmol) in dichloromethane (20 mL). The resulting solution was stirred at 25 °C for 2 h, and then the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XBridge Prep C18 OBD column, 30 × 150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3 and 0.1% aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine (1.05 g, 67%) as a white solid. 1 H NMR (300 MHz, DMSO-d6): 1.29 (12H, s), 3.20 (4H, t), 3.30 (6H, t), 4.30 (2H, t), 6.95 (1H, dd), 7.05 (1H, d), 7.62 (1H, d) - one proton not observed. m / z: ES+ [M+H]+ 367.

[0787] The starting material, 9-benzyl-8-bromo-6-(1-methylcyclobutoxy)-9H-purine, was prepared as follows.

[0788] 9-benzyl-6-(1-methylcyclobutoxy)-9H-purine

[0789] [ka]

[0790] Sodium hydride (265 mg, 11.03 mmol) was added portionwise over 2 min to a mixture of 9-benzyl-6-chloro-9H-purine (900 mg, 3.68 mmol, starting material from Example 5), 1-methylcyclobutan-1-ol (634 mg, 7.36 mmol) in THF (30 mL) under nitrogen at 0 °C. The resulting suspension was stirred at 25 °C for 4 h. The reaction mixture was diluted with aqueous NH4Cl (3 mL) and water (50 mL). The aqueous layer was extracted with EtOAc (3 × 25 mL). The combined organic layers were dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 9-benzyl-6-(1-methylcyclobutoxy)-9H-purine (900 mg, 83%) as a colorless solid. 1 H NMR (300MHz, CDCl3): 1.64-1.94(5H,m),2.29-2.42(2H,m),2.52-2.67(2H,m),5.41(2H,s),7.24-7.38(5H,m),7.90(1H,s),8.51(1H,s). m / z:ES+[M+H]+295.

[0791] 9-benzyl-8-bromo-6-(1-methylcyclobutoxy)-9H-purine

[0792] [ka]

[0793] Lithium bis(trimethylsilyl)amide (6.79 mL, 6.79 mmol) was added to a solution of 9-benzyl-6-(1-methylcyclobutoxy)-9H-purine (500 mg, 1.70 mmol) and 1,2-dibromo-1,1,2,2-tetrachloroethane (2.21 g, 6.79 mmol) in THF (30 mL) under nitrogen at 25 °C. The resulting solution was stirred at 25 °C for 5 h. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 9-benzyl-8-bromo-6-(1-methylcyclobutoxy)-9H-purine (400 mg, 63%) as a yellow gum. 1 H NMR(300MHz,DMSO-d6):1.63(3H,s),1.67-1.87(2H,m),2.16-2.35(2H,m),2.3 7-2.40(2H,m),5.32(2H,s),7.11-7.16(2H,m),7.12-7.36(3H,m),8.37(1H,s). m / z:ES+[M+H]+373.

[0794] Example 13 1-((9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile

[0795] [ka]

[0796] Hydrogen chloride (4 M in dioxane) (7.93 μL, 0.03 mmol) was added to a stirred solution of tert-butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (10 mg, 0.02 mmol) in anhydrous acetonitrile (0.5 mL) cooled to 0 °C. After 20 min, additional hydrogen chloride (4 M in dioxane, 7.9 μL, 0.03 mmol) was added and the reaction was allowed to warm to room temperature. The reaction mixture was then diluted with methanol and the crude product was purified by ion exchange chromatography using an SCX column. The desired product was eluted from the column with 1 M NH3 / MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters CSH C18 OBD column, 5 μm silica, 30 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% concentrated aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 1-((9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile (2.6 mg, 31%) as a white solid. 1 H NMR (500 MHz, CDCl): 1.52-1.63 (2H, m), 1.63-1.74 (2H, m), 2.68-2.75 (4H, m), 2.87 (2H, t), 3.02-3.1 (4H, m), 4.15 (2H, t), 5.36 (2H, s), 6.82 (1H, dd), 6.93 (2H, dd), 7.06 (1H, d), 7.14-7.23 (4H, m), 8.74 (1H, s) - one H not observed. m / z: ES+ [M+H]+ 530.

[0797] The tert-butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as the starting material was made as follows.

[0798] tert-Butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[0799] [ka]

[0800] Sodium hydride (206 mg, 5.14 mmol) was added to tert-butyl 4-(2-(4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (150 mg, 0.26 mmol, Example 6 starting material) in THF (6 mL) at 0° C. under nitrogen. The reaction was stirred for 15 minutes before adding 1-hydroxycyclopropane-1-carbonitrile (107 mg, 1.29 mmol). The resulting solution was stirred at room temperature for a further 2 hours. The reaction mixture was poured into saturated NH4Cl (75 mL) and extracted with EtOAc (3×100 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give a brown oil. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate (73.0 mg, 45%) as a green oil. 1 H NMR(300MHz,DMSO-d6):1.40(13H,s),1.64(2H,t),1.73-1.82(2H,m),2.45(4H,t),2.72-2.77(2H,m),4.21( 2H,t),5.35(2H,s),6.89-6.94(2H,m),7.02-7.11(1H,m),7.17-7.24(4H,m),7.39-7.46(1H,m),8.78(1H,s). m / z:ES+[M+H]+630.

[0801] Example 14 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-3-((4-chloropyridin-2-yl)methyl)-7-(1-methylcyclopropoxy)-3H-imidazo[4,5-b]pyridine

[0802] [ka]

[0803] p-Toluenesulfonic acid monohydrate (94 mg, 0.49 mmol) was added to N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)pyridine-2,3-diamine (100 mg, 0.33 mmol) and 2-chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde (106 mg, 0.39 mmol) in EtOH (5.5 mL) at 25 °C. The resulting mixture was stirred at 60 °C for 2 h. The reaction mixture was quenched with water (15 mL) and extracted with EtOAc (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give a brown oil. Twenty-one fractions containing the desired compound were evaporated to dryness to give 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-3-((4-chloropyridin-2-yl)methyl)-7-(1-methylcyclopropoxy)-3H-imidazo[4,5-b]pyridine (25 mg, 14%) as a white solid. 1 H NMR (400 MHz, CDCl): 0.84 (2H, t), 1.23 (2H, t), 1.72 (3H, s), 2.56-2.61 (4H, m), 2.81 (2H, t), 2.96 (4H, t), 4.12 (2H, t), 5.49 (2H, s), 6.76-6.85 (2H, m), 7.01 (1H, d), 7.06-7.13 (2H, m), 7.30 (1H, d), 8.31 (2H, t) - one proton not observed. m / z: ES+ [M+H]+ 553.

[0804] The 2-chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde used as the starting material was prepared as follows.

[0805] 2-chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde

[0806] [ka]

[0807] 2,2,2-Trifluoroacetic acid (3 mL, 2.71 mmol) was added to tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (1.0 g, 2.71 mmol, Example 6 starting material) in DCM (5 mL) at 25° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with EtOAc (25 mL) and washed sequentially with water (3×25 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 50% pentane in EtOAc. Pure fractions were evaporated to dryness to give 2-chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde (0.700 g, 96%) as a yellow gum. 1 H NMR (300 MHz, DMSO-d6): 3.22-3.39 (10H, m), 4.41 (2H, t), 7.11 (1H, dd), 7.23 (1H, d), 7.86 (1H, d), 10.20 (1H, d). One H not observed. m / z: ES+ [M+H]+ 269.

[0808] The starting material, N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)pyridine-2,3-diamine, was prepared as follows.

[0809] 2-chloro-4-(1-methylcyclopropoxy)-3-nitropyridine

[0810] [ka]

[0811] Sodium hydride (0.415 g, 10.4 mmol) was added in one portion to a solution of 2,4-dichloro-3-nitropyridine (2 g, 10.4 mmol) and 1-methylcyclopropan-1-ol (0.747 g, 10.4 mmol) in THF (20 mL) at 0 °C under nitrogen. The resulting suspension was stirred at 25 °C for 1 h. The reaction mixture was quenched with water (20 mL) and extracted with EtOAc (3 × 50 mL). The upper layer was dried over NaSO, filtered, and evaporated to give a yellow solid, which was purified by preparative TLC (petroleum ether / EtOAc 3:1) to give 2-chloro-4-(1-methylcyclopropoxy)-3-nitropyridine (0.900 g, 38%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 0.85-0.92 (2H, m), 0.98-1.05 (2H, m), 1.57 (3H, s), 7.66 (1H, d), 8.51 (1H, d). m / z:ES+[M+H]+229.

[0812] N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-3-nitropyridin-2-amine

[0813] [ka]

[0814] BINAP (82 mg, 0.13 mmol) was added to 2-chloro-4-(1-methylcyclopropoxy)-3-nitropyridine (300 mg, 1.31 mmol), (4-chloropyridin-2-yl)methanamine (281 mg, 1.97 mmol), CsCO (1283 mg, 3.94 mmol), and Pd(dba) (120 mg, 0.13 mmol) in dioxane (7 mL) at 25 °C. The resulting mixture was stirred at 100 °C for 2 h. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3 × 100 mL), and washed sequentially with water (2 × 50 mL) and saturated brine (2 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a yellow oil. This oil was purified by preparative TLC (petroleum ether / EtOAc 2:1) to afford N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-3-nitropyridin-2-amine (275 mg, 63%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):0.79-0.93(2H,m),0.93-1(2H,m),1.54(3H,s),4.69(2H, d),6.74(1H,d),7.36(1H,d),7.40(1H,m),7.87(1H,t),8.07(1H,d),8.49(1H,d). m / z:ES+[M+H]+335.

[0815] N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)pyridine-2,3-diamine

[0816] [ka]

[0817] Iron (307 mg, 5.50 mmol) was added to N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-3-nitropyridin-2-amine (230 mg, 0.69 mmol) and ammonium chloride (294 mg, 5.50 mmol) in EtOH:HO (4:1) (8 mL) at 25 °C. The resulting mixture was stirred at 80 °C for 2 h. The mixture was filtered through a Celite pad and the solvent was removed. The reaction mixture was quenched with water (15 mL), extracted with EtOAc (3 × 50 mL), and washed successively with water (2 × 20 mL) and saturated brine (2 × 20 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a yellow oil. This oil was purified by preparative TLC (EtOAc) to give N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)pyridine-2,3-diamine (110 mg, 52%) as a yellow oil. 1 H NMR(300MHz,DMSO-d6):0.76(2H,t),0.81-0.96(2H,m),1.50(3H,s),4.14(2 H,s),4.63(2H,d),6.25(1H,t),6.53(1H,d),7.29-7.42(3H,m),8.48(1H,d). m / z:ES+[M+H]+305.

[0818] Example 15 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazole

[0819] [ka]

[0820] 2,2,2-Trifluoroacetic acid (0.3 mL, 3.9 mmol) was added to tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (80 mg, 0.12 mmol) in DCM (1 mL) at 25° C. The resulting mixture was stirred at 25° C. for 1 h. The reaction mixture was diluted with EtOAc (10 mL) and washed successively with water (3×10 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 15 × 150 mm, 10 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3 and 0.1% aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazole (28 mg, 41%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 0.82 (2H, t), 0.98 (2H, t), 1.59 (3H, s), 2.31-2.45 (4H, m), 2.6-2.76 (6H, m), 4.15 (2H, t), 5.34 (2H, s), 6.95-7.02 (2H, m), 7.06 (1H, d), 7.13-7.19 (2H, m), 7.21 (1H, d), 7.37-7.43 (2H, m), 8.36 (1H, d) - one hydrogen not observed. m / z: ES+ [M+H]+ 552.

[0821] The starting material, tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate, was prepared as follows:

[0822] 1-Fluoro-3-(1-methylcyclopropoxy)-2-nitrobenzene

[0823] [ka]

[0824] Sodium hydride (78 mg, 3.27 mmol) was added to 1,3-difluoro-2-nitrobenzene (400 mg, 2.51 mmol) and 1-methylcyclopropan-1-ol (181 mg, 2.51 mmol) in THF (3 mL) at 0 °C. The resulting mixture was stirred at 25 °C for 2 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), and washed sequentially with water (3 × 5 mL) followed by saturated brine (3 × 5 mL). The upper layer was dried over Na SO , filtered, and evaporated to give the crude product. The crude product was purified by preparative TLC (petroleum ether / EtOAc 2:1) to give 1-fluoro-3-(1-methylcyclopropoxy)-2-nitrobenzene (440 mg, 83%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 0.79-1.01 (4H, m), 1.54 (3H, s), 7.15-7.19 (1H, m), 7.35-7.39 (1H, m), 7.63-7.65 (1H, m). m / z:ES+[M+H]+212.

[0825] N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropoxy)-2-nitroaniline

[0826] [ka]

[0827] N,N-Diisopropylethylamine (826 mg, 6.39 mmol) was added to 1-fluoro-3-(1-methylcyclopropoxy)-2-nitrobenzene (270 mg, 1.28 mmol) and (4-chloropyridin-2-yl)methanamine (219 mg, 1.53 mmol) in DMSO (5 mL) at 25 °C. The resulting mixture was stirred at 130 °C for 2 h. The reaction mixture was concentrated, diluted with EtOAc (20 mL), and washed sequentially with water (3 × 5 mL) and saturated brine (3 × 5 mL). The upper layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 5% MeOH in DCM. Pure fractions were evaporated to dryness to afford N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropoxy)-2-nitroaniline (237 mg, 55%) as a yellow solid. 1 H NMR(300MHz,CDCl3):0.73(2H,t),1.06(2H,t),1.58(3H,s),4.56(2H,s),6.24(1H,dd),6 .68(1H,dd),7.18(1H,t),7.23-7.26(1H,m),7.27-7.29(1H,m),7.36(1H,d),8.50(1H,d). m / z:ES+[M+H]+334.

[0828] tert-Butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0829] [ka]

[0830] Sodium hydrosulfite (730 mg, 4.19 mmol) was added to N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropoxy)-2-nitroaniline (140 mg, 0.42 mmol) in MeOH (2 mL) and water (2 mL) at 25° C. The mixture was stirred for 16 h. Then, tert-butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (201 mg, 0.55 mmol) and 4-methylbenzenesulfonic acid (87 mg, 0.50 mmol) were added. The reaction mixture was stirred at 25° C. for an additional 3 h. The reaction mixture was concentrated and then diluted with EtOAc (15 mL). The crude mixture was then washed sequentially with water (3×15 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in DCM. Pure fractions were evaporated to dryness to give tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (90 mg, 33%) as a yellow gum. 1 H NMR(300MHz,DMSO-d6):0.80(2H,t),0.97(2H,t),1.38(9H,s),1.57(3H,s),2.38-2.47(4H,m),2.72(2H,t),3.2 5-3.31(4H,m),4.16(2H,t),5.33(2H,s),6.93-7.08(3H,m),7.11-7.22(3H,m),7.35-7.42(2H,m),8.35(1H,d). m / z:ES+[M+H]+652.

[0831] Example 16 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridine

[0832] [ka]

[0833] HCl (4 M in dioxane, 123 mg, 3.37 mmol) was added to tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (220 mg, 0.34 mmol) in dichloromethane (1 mL) at room temperature. The reaction mixture was stirred at room temperature for 1 h, then evaporated to dryness, redissolved in DMF (2 mL), and filtered through Celite. The residue was purified by preparative HPLC (YMC-Actus Triart C18 ExRS column, 30 × 150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3 and 0.1% aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridine (67 mg, 36%) as a white solid. 1 H NMR (400 MHz, DMSO-d6): 0.78 (2H, t), 0.93 (2H, t), 1.69 (3H, s), 2.34-2.44 (4H, m), 2.59-2.76 (6H, m), 4.15 (2H, t), 5.38 (2H, s), 6.95-7.02 (1H, m), 7.19-7.24 (3H, m), 7.34-7.42 (2H, m), 7.92 (1H, d), 8.34 (1H, d) - one proton not observed. m / z: ES+ [M+H]+ 553

[0834] The starting material, tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate, was prepared as follows:

[0835] 2-Chloro-4-(methylthio)-3-nitropyridine

[0836] [ka]

[0837] Sodium thiomethoxide (0.872 g, 12.4 mmol) was added to 2,4-dichloro-3-nitropyridine (2 g, 10.4 mmol) in MeOH (10 mL), and the reaction mixture was stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc (50 mL), and washed sequentially with water (2 × 15 mL) and saturated brine (2 × 15 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 2-chloro-4-(methylthio)-3-nitropyridine (1.40 g, 66%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 2.40 (3H, s), 7.54 (1H, d), 8.37 (1H, d). m / z:ES+[M+H]+205.

[0838] 2-(1-methylcyclopropoxy)-4-(methylthio)-3-nitropyridine

[0839] [ka]

[0840] Sodium hydride (2.06 g, 86.0 mmol) was added in one portion to 2-chloro-4-(methylthio)-3-nitropyridine (2.2 g, 10.7 mmol) and 1-methylcyclopropan-1-ol (1.16 g, 16.1 mmol) in THF (200 mL) at 0 °C under nitrogen. The resulting suspension was stirred at room temperature for 6 h. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (2 × 50 mL). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 10–40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 2-(1-methylcyclopropoxy)-4-(methylthio)-3-nitropyridine (1.30 g, 50%) as a brown solid. 1 H NMR (300MHz, DMSO-d6): 0.76 (2H, t), 0.88 (2H, t), 1.62 (3H, s), 2.59 (3H, s), 7.21 (1H, d), 8.29 (1H, d). m / z:ES+[M+H]+241.

[0841] 2-(1-methylcyclopropoxy)-4-(methylsulfonyl)-3-nitropyridine

[0842] [ka]

[0843] m-Chloroperbenzoic acid (2.05 g, 11.9 mmol) was added to 2-(1-methylcyclopropoxy)-4-(methylthio)-3-nitropyridine (1.30 g, 5.41 mmol) in dichloromethane (100 mL), and the reaction was stirred at room temperature for 6 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc (100 mL), and washed sequentially with water (3 × 50 mL) and saturated brine (3 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 25–50% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 2-(1-methylcyclopropoxy)-4-(methylsulfonyl)-3-nitropyridine (720 mg, 49%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 0.80 (2H, t), 0.93 (2H, t), 1.64 (3H, s), 3.46 (3H, s), 7.69 (1H, d), 8.78 (1H, d). m / z:ES+[M+H]+273.

[0844] N-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)-3-nitropyridin-4-amine

[0845] [ka]

[0846] Triethylamine (0.530 mL, 3.80 mmol) was added to a solution of 4-chloro-2-pyridinemethanamine (542 mg, 3.80 mmol) and 2-(1-methylcyclopropoxy)-4-(methylsulfonyl)-3-nitropyridine (690 mg, 2.53 mmol) in DMF (110 mL). The reaction mixture was stirred at 60 °C for 16 h. The reaction mixture was then cooled, concentrated, and further diluted with EtOAc (100 mL). The organic layer was washed sequentially with water (2 × 75 mL) and saturated brine (2 × 75 mL), dried over NaSO, filtered, and evaporated. The crude product was purified by flash silica chromatography with an elution gradient of 30 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford N-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)-3-nitropyridin-4-amine (260 mg, 31%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):0.72(2H,t),0.84(2H,t),1.60(3H,s),4.60(2H,d) ,6.46(1H,d),7.4-7.6(2H,m),7.86(1H,d),7.98(1H,t),8.44-8.61(1H,m). m / z:ES+[M+H]+335.

[0847] N4-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)pyridine-3,4-diamine

[0848] [ka]

[0849] Iron (417 mg, 7.47 mmol) was added to ammonium chloride (40 mg, 0.75 mmol) and N-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)-3-nitropyridin-4-amine (250 mg, 0.75 mmol) in ethanol / water (10:1, 1 mL). The reaction mixture was stirred at 60 °C for 3 h. The reaction mixture was then cooled, evaporated to dryness, and redissolved in EtOAc (200 mL). The organic layer was washed sequentially with water (2 × 100 mL) and saturated brine (2 × 100 mL), dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 30 to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford N4-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)pyridine-3,4-diamine (170 mg, 75%) as a yellow solid. 1 H NMR(300MHz,DMSO-d6):0.64(2H,t),0.82(2H,t),1.58(3H,s),3.88-4.16(2H,m ),4.45(2H,d),6.07(2H,d),7.23(1H,d),7.38-7.53(2H,m),8.42-8.66(1H,m). m / z:ES+[M+H]+305.

[0850] tert-Butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[0851] [ka]

[0852] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate (203 mg, 0.55 mmol) was added to N4-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropoxy)pyridine-3,4-diamine (140 mg, 0.46 mmol) in MeOH (20 mL) and acetic acid (1 mL) and stirred at room temperature for 16 h. The reaction mixture was evaporated to dryness, redissolved in EtOAc (100 mL), and washed sequentially with water (2 × 50 mL) and saturated brine (2 × 50 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 30–70% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropoxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate acid (230 mg, 77%) as a brown solid. 1 H NMR(300MHz,DMSO-d6):0.78(2H,t),0.94(2H,t),1.40(9H,s),1.70(3H,s),2.41-2.47(4H,m),2.74(2H,t),3.25-3. 4(4H,m),4.18(2H,t),5.39(2H,s),6.97-7.04(1H,m),7.2-7.25(3H,m),7.35-7.43(2H,m),7.93(1H,d),8.35(1H,d). m / z:ES+[M+H]+653.

[0853] Example 17 3-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-N,N-dimethylpropan-1-amine

[0854] [ka]

[0855] K2CO3 (56 mg, 0.41 mmol) was added to 3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenol (60 mg, 0.14 mmol) and 3-bromo-N,N-dimethylpropan-1-amine (45 mg, 0.27 mmol) in DMF (1 mL). The resulting mixture was stirred at 60 °C for 4 h. The reaction mixture was filtered through Celite. The crude filtrate was purified by preparative HPLC (XBridge Shield RP18 OBD column, 30 × 150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3 and 0.1% aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 3-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-N,N-dimethylpropan-1-amine (8.0 mg, 11%) as a yellow solid. 1 H NMR(400MHz,DMSO-d6):0.85(2H,t),1.02(2H,t),1.73(3H,s),1.79-1.91(2H,m),2.13(6H,s),2.34(2H,t),4 .07(2H,t),5.40(2H,s),6.96(1H,dd),7.17(1H,d),7.26(1H,d),7.32-7.44(2H,m),8.30(1H,d),8.57(1H,s). m / z:ES+[M+H]+527.

[0856] The starting material, 3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenol, was prepared as follows.

[0857] 4-((tert-butyldiphenylsilyl)oxy)-2-chlorobenzaldehyde

[0858] [ka]

[0859] tert-Butylchlorodiphenylsilane (26.3 g, 95.8 mmol) was added to a mixture of 1H-imidazole (4.87 g, 71.5 mmol) and 2-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol) in DMF (200 mL) at room temperature. The mixture was stirred at this temperature for 3 h. The reaction mixture was diluted with EtOAc (500 mL) and washed successively with water (3 × 400 mL) and saturated brine (2 × 400 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 4-((tert-butyldiphenylsilyl)oxy)-2-chlorobenzaldehyde (13.0 g, 51%) as a white solid. 1 H NMR (300MHz, DMSO-d6): 1.01 (9H, dd), 6.89-6.95 (1H, m), 7.33-7.56 (7H, m), 7.64-7.72 (5H, m), 10.14 (1H, dd). m / z:ES+[M+H]+395.

[0860] 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9H-purine

[0861] [ka]

[0862] Iron(III) chloride solution (51.3 g, 316 mmol) was added to 6-chloropyrimidine-4,5-diamine (21.96 g, 151.9 mmol) and 4-((tert-butyldiphenylsilyl)oxy)-2-chlorobenzaldehyde (50 g, 126.6 mmol) in IPA (500 mL). The reaction mixture was stirred at 60 °C for 4 h. The reaction mixture was adjusted to pH 7 with 1 M NaOH. The reaction mixture was poured into water (1.5 L) and extracted with EtOAc (3 × 1.5 L). The organic layer was dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 20% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9H-purine (29.0 g, 44%) as a yellow solid. 1 H NMR (300MHz, DMSO-d6): 1.08 (9H, s), 6.86 (1H, dd), 7.03 (1H, d), 7.44-7.55 (7H, m), 7.69-7.75 (4H, m), 8.74 (1H, s), 14.06 (1H, s). m / z:ES+[M+H]+519.

[0863] 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purine

[0864] [ka]

[0865] DIAD (9.36 mL, 48.1 mmol) was added over 5 minutes to (4-chloropyridin-2-yl)methanol (3.32 g, 23.1 mmol), 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9H-purine (10 g, 19.2 mmol), and triphenylphosphine (12.62 g, 48.1 mmol) in THF (125 mL) under nitrogen at 0°C. The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was poured into water (750 mL) and extracted with EtOAc (3 x 750 mL). The organic layer was dried over NaSO, filtered, and evaporated to give a brown oil. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purine (12.00 g, 97%) as a beige waxy solid. 1 H NMR(300MHz,DMSO-d6):1.05(9H,s),5.45(2H,s),6.69(1H,dd),6.94(1H,d),7. 27-7.33(2H,m),7.41-7.55(7H,m),7.63-7.69(4H,m),8.23(1H,d),8.79(1H,s). m / z:ES+[M+H]+644.

[0866] 3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenol

[0867] [ka]

[0868] Sodium hydride (2.60 g, 65.1 mmol) was added to a solution of 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purine (12 g, 18.6 mmol) in DMF (12 mL) at 0 °C under nitrogen. The reaction mixture was stirred for 15 min, and then 1-methylcyclopropan-1-ol (4.19 g, 46.5 mmol) was added at 0 °C. The resulting solution was allowed to warm to room temperature and stirred for 2 h. The reaction mixture was then poured into saturated aqueous NH4Cl (500 mL) and extracted with EtOAc (3 × 500 mL). The organic layer was dried over Na2SO4, filtered, and evaporated to give the crude product as a brown oil. The crude product was purified by flash silica chromatography with an elution gradient of 50–70% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenol (3.00 g, 36%) as a white solid. 1 H NMR(300MHz,DMSO-d6):0.84(2H,t),1.02(2H,t),1.73(3H,s),5.41(2H,s),6.78(1H,dd ),6.94(1H,d),7.21-7.32(2H,m),7.37(1H,dd),8.31(1H,d),8.56(1H,s),10.43(1H,s). m / z:ES+[M+H]+442.

[0869] Example 18 8-(4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine

[0870] [ka]

[0871] To tert-butyl 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (150 mg, 0.24 mmol) was added TFA (3 mL) at room temperature. The resulting mixture was stirred at 25 °C for 30 h. The reaction mixture was diluted with DCM (50 mL) and neutralized with saturated aqueous NaHCO. The organic layer was further washed with saturated brine (3 × 10 mL), dried over NaSO, filtered, and evaporated to give the crude product. The crude product was purified by preparative HPLC (XBridge Prep OBD C18 column, 30 × 150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NHHCO and 0.1% aqueous ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to give 8-(4-(2-(2,6-diazaspiro[3.3]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine (29.3 mg, 23%) as a yellow solid. 1 H NMR (400 MHz, CDCl): 0.84 (2H, t), 1.16 (2H, t), 1.81 (3H, s), 2.83 (2H, t), 3.36-3.48 (4H, m), 3.83 (4H, s), 4.01 (2H, t), 5.35 (2H, s), 6.80 (1H, dd), 6.91-6.96 (2H, m), 7.04 (1H, d), 7.14-7.21 (4H, m), 8.68 (1H, s) - one hydrogen not observed. m / z: ES+ [M+H]+ 531.

[0872] The starting material, tert-butyl 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate, was prepared as follows.

[0873] 4-(2-Bromoethoxy)-2-chlorobenzaldehyde

[0874] [ka]

[0875] 1,2-Dibromoethane (120 g, 639 mmol) was added to 2-chloro-4-hydroxybenzaldehyde (10 g, 63.9 mmol) and K2CO3 (22.07 g, 160 mmol) in MeCN (50 mL) at 25 °C. The resulting mixture was stirred at 60 °C for 8 h. The reaction mixture was filtered through filter paper and concentrated in vacuo. The crude product was purified by flash silica chromatography with an elution gradient of 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to give 4-(2-bromoethoxy)-2-chlorobenzaldehyde (13.00 g, 77%) as a white solid. 1 H NMR (300MHz, DMSO-d6): 3.82 (2H, t), 4.48 (2H, t), 7.11 (1H, dd), 7.23 (1H, d), 7.83 (1H, d), 10.19 (1H, s). m / z:ES+[M+H]+265( 35 Cl 81 Br / 37 Cl 79 Br peak).

[0876] tert-Butyl 6-(2-(3-chloro-4-formylphenoxy)ethyl)-2,6-diazaspiro[3.3]heptane-2-carboxylate

[0877] [ka]

[0878] 4-(2-Bromoethoxy)-2-chlorobenzaldehyde (200 mg, 0.76 mmol) was added to tert-butyl 2,6-diazaspiro[3.3]heptane-2-carboxylate (451 mg, 2.28 mmol), potassium carbonate (210 mg, 1.52 mmol), and sodium iodide (11.4 mg, 0.08 mmol) in DMF (5 mL) at room temperature. The resulting mixture was stirred at 80 °C for 2 h. The reaction m...

Claims

1. Compounds of formula (I): 【Chemistry 1】 (I) or a stereoisomer or pharmaceutical salt thereof, During the ceremony, R １ and R ２ each independently represents H, halo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, C １ ~C ３ Haloalkyl, C １ ~C ３ Hydroxyalkyl, -CN, C ２ ~C ４ Alkyne, or C ２ ~C ６ is an alkoxyalkyl; Q １ , Q ２ , and Q ３ are independently N, CLR, or CR ｘ and Q １ , Q ２ , and Q ３ at most one of is C-L-R; L is a bond, —O—, —C(O)—, —O(CH ２ ) ｐ C(O)-, -C(O)NR ｙ -, -O(CH ２ ) ｐ C(O)NR ｙ -, -O(CH ２ ) ｐ NR ｙ , -NR ｙ -, -(CH ２ ) ｐ－ , -(CH ２ ) ｐ NR ｙ -, -(CH ２ ) ｐ O-, -(CH ２ ) ｐ C(O)-,-(CH ２ ) ｐ C(O)O- or -O(CH ２ ) ｐ - and p is independently 1, 2, or 3; R is H, R ａ , R ｂ , R ｃ , or R ｄ and R ａ is amino, carboxy, halo, hydroxy, oxo, -CN, -S(O) ２ OH, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ２ ~C ５ Alkoxyalkyl, 4- to 6-membered heterocycle, and C １ ~C ７ a 3- to 10-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ optionally substituted with 1 to 4 substituents independently selected from alkoxy; R ｂ But C １ ~C ７ alkyl, １ ~C ７ One or two methylene groups from the alkyl group are ｅ or O, and C ２ ~C ７ one or two single bonds in the alkyl chain are optionally independently replaced with a double or triple bond; Said C １ ~C ７ Alkyl is halo, oxo, hydroxy, carboxyl, amino, -CN, C ２ ~C ４ Alkynyl, C ２ ~C ６ Carbamate, C １ ~C ８ Amide, C １ ~C ４ Sulfonyl, C １ ~C ４ Sulfonamides, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ３ ~C ６ optionally substituted with 1 to 4 substituents independently selected from carbocycle, and 3- to 10-membered heterocycle; Said C ３ ~C ６ the carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; The 3- to 10-membered heterocycle is selected from the group consisting of amino, carboxy, halo, hydroxy, oxo, —CN, —S(O) ２ OH, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ２ ~C ５ Alkoxyalkyl, 4- to 6-membered heterocycle, and C １ ~C ７ and optionally substituted with 1 to 4 substituents independently selected from alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ optionally substituted with 1 to 4 substituents independently selected from alkoxy; R ｃ C optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy ３ ~C ６ is a carbocyclic ring, R ｄ But C １ ~C ４ Sulfonyl or C １ ~C ４ is a sulfonamide, R ｙ But H, C １ ~C ３ alkyl, or C1-3 haloalkyl; R ｘ is H, halo, hydroxy, -CN, -NH ２ , C １ ~C ３ Alkoxy, C １ ~C ３ Alkyl, or C １ - ３ is haloalkyl, R ｅ But, H, halo, C １ ~C ８ Alkyl, or C １ ~C ８ is haloalkyl, X is C １ ~C ４ is alkylene, Y is phenyl or 5-6 membered heteroaryl, and said phenyl or heteroaryl is selected from halo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -CN, C １ ~C ３ optionally substituted with 1 to 3 substituents independently selected from haloalkyl, and cyclopropyl; G is N or CH; G ａ and G ｂ is N, CH, or CR ５ and G ａ and G ｂ and only one of G is N or CH; ａ and G ｂ Only one of the CR ５ and R ５ but, 【Chemistry 2】 and Z ａ and Z ｂ But independently, C １ ~C ３ Alkyl or C １ ~C ３ haloalkyl or Z ａ and Z ｂ form a 3- to 6-membered carbocyclic or heterocyclic ring, Z ｃ H, -CN, C １ ~C ３ Alkyl, C １ ~C ３ haloalkyl, or C ２ ~C ４ A compound or a stereoisomer or pharmaceutical salt thereof, which is an alkyne.

2. The compound of claim 1 , wherein G is N.

3. 2. The compound of claim 1, wherein G is CH.

4. G ａ But, CR ５ The compound according to any one of claims 1 to 3,

5. G ｂ But, CR ５ The compound according to any one of claims 1 to 3,

6. G ｂ The compound according to any one of claims 1 to 4, wherein is N.

7. G ｂ The compound according to any one of claims 1 to 4, wherein is CH.

8. G ａ The compound of any one of claims 1 to 3 or 5, wherein is N.

9. G ａ The compound of any one of claims 1 to 3 or 5, wherein is CH.

10. Z ａ and Z ｂ But independently, C １ ~C ３ The compound of any one of claims 1 to 9, which is alkyl.

11. Z ａ and Z ｂ But -CH ３ 11. The compound of claim 10, wherein:

12. R ５ but, 【Transformation 3】 10. The compound according to any one of claims 1 to 9, wherein p is 1 to 4.

13. 13. The compound of claim 12, wherein p is 2.

14. 13. The compound of claim 12, wherein p is 1.

15. Z ｃ But -CH ３ The compound according to any one of claims 1 to 14, wherein

16. Z ｃ The compound according to any one of claims 1 to 14, wherein is -CN.

17. The compound of any one of claims 1 to 16, wherein Y is phenyl.

18. The compound of any one of claims 1 to 16, wherein Y is N-heteroaryl.

19. 19. The compound of claim 18, wherein Y is pyridine.

20. The compound of any one of claims 1 to 19, wherein Y is substituted.

21. Y is halo, C １ ~C ３ Alkyl, C １ ~C ３ Alkoxy, -CN, and C １ ~C ３ 21. The compound of claim 20, substituted with 1 to 3 substituents independently selected from haloalkyl.

22. 21. The compound of claim 20, wherein Y is substituted with -Cl.

23. Y is -CH ３ 21. The compound of claim 20 substituted with:

24. The compound of any one of claims 1 to 19, wherein Y is unsubstituted.

25. R １ The compound of any one of claims 1 to 24, wherein is halo.

26. R １ The compound of any one of claims 1 to 24, wherein is -Cl.

27. R １ But -CH ３ The compound according to any one of claims 1 to 24,

28. R ２ The compound of any one of claims 1 to 27, wherein is -H.

29. Q １ , Q ２ , or Q ３ The compound of any one of claims 1 to 28, wherein is C-L-R.

30. Q １ is C-L-R.

31. Q ２ is C-L-R.

32. Q ３ is C-L-R.

33. L is a bond, —O—, —(CH ２ ) ｐ O- or -O(CH ２ ) ｐ The compound according to any one of claims 29 to 32, wherein

34. 34. The compound of claim 33, wherein L is a bond.

35. 34. The compound of claim 33, wherein L is -O-.

36. L is -(CH ２ ) ｐ The compound of claim 33, wherein the compound is O-.

37. L is -O(CH ２ ) ｐ The compound of claim 33, wherein

38. L is -C(O)-, -O(CH ２ ) ｐ C(O)-, -C(O)NR ｙ -, -O(CH ２ ) ｐ C(O)NR ｙ -, -(CH ２ ) ｐ C(O)- or -(CH ２ ) ｐ The compound according to any one of claims 29 to 32, which is C(O)O-.

39. R is H, R ａ or R ｂ The compound according to any one of claims 29 to 38, wherein

40. R is R ａ 40. The compound of claim 39, wherein:

41. R ａ is a 3- to 10-membered N-heterocycle.

42. R ａ is a 4- to 7-membered N-heterocycle.

43. R ａ is a 6-membered N-heterocycle.

44. R ａ is piperidine, 1,2-diazinane, 1,3-diazinane, 1,4-diazinane, 1,2-oxazinane, 1,3-oxazinane, or 1,4-oxazinane.

45. R ａ is amino, carboxy, halo, hydroxy, oxo, CN, S(O) ２ OH, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ２ ~C ５ Alkoxyalkyl, 4- to 6-membered heterocycle, and C １ ~C ７ substituted with 1 to 4 substituents independently selected from alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ 45. The compound of any one of claims 40 to 44, optionally substituted with 1 to 4 substituents independently selected from alkoxy.

46. R ａ But C １ ~C ７ is substituted with alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ 46. ​​The compound of claim 45, optionally substituted with 1 to 4 substituents independently selected from alkoxy.

47. Said C １ ~C ７ 47. The compound of claim 46, wherein the alkyl is substituted with oxo.

48. C １ ~C ７ The alkyl is C １ ~C ５ 49. The compound of claim 48, which is substituted with alkoxy.

49. Said C １ ~C ７ The compound of any one of claims 46 to 48, wherein the alkyl is methyl.

50. R is R ｂ 40. The compound of claim 39, wherein:

51. R ｂ halo, oxo, hydroxy, carboxyl, amino, -CN, C ２ ~C ４ Alkynyl, C ２ ~C ６ Carbamate, C １ ~C ８ Amide, C １ ~C ４ Sulfonyl, C １ ~C ４ Sulfonamides, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ３ ~C ６ substituted with 1 to 4 substituents independently selected from a carbocycle and a 3- to 10-membered heterocycle; ３ ~C ６ The carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxyhalo, carboxy, and the 3- to 10-membered heterocycle is optionally substituted with amino, carboxy, halo, hydroxy, oxo, —CN, S(O) ２ OH, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ２ ~C ５ Alkoxyalkyl, 4- to 6-membered heterocycle, and C １ ~C ７ and optionally substituted with 1 to 4 substituents independently selected from alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ 51. The compound of claim 50, optionally substituted with 1 to 4 substituents independently selected from alkoxy.

52. R ｂ is substituted with a 3- to 10-membered heterocycle.

53. 53. The compound of claim 52, wherein the heterocycle is an N-heterocycle.

54. 54. The compound of claim 53, wherein the N-heterocycle is a 4- to 7-membered N-heterocycle.

55. The heterocycle may be selected from the group consisting of amino, carboxy, halo, hydroxy, oxo, -CN, S(O) ２ OH, C １ ~C ４ Alkylamino, C １ ~C ５ Alkoxy, C ２ ~C ５ Alkoxyalkyl, 4- to 6-membered heterocycle, and C １ ~C ７ substituted with 1 to 4 substituents independently selected from alkyl, １ ~C ７ Alkyl is amino, carboxy, halo, hydroxy, oxo, -CN, C ２ ~C ８ Esters, and C １ ~C ５ 55. The compound of any one of claims 52 to 54, optionally substituted with 1 to 4 substituents independently selected from alkoxy.

56. The heterocycle is C １ ~C ７ 56. The compound of claim 55, substituted with alkyl, oxo, and / or halo.

57. R ｂ But Amino, C １ ~C ８ Amide, and / or C １ ~C ４ 52. The compound of claim 51 , substituted with alkylamino.

58. R ｂ is substituted with oxo, hydroxy, and / or carboxy.

59. 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol, tert-butyl(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate, N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)acetamide, N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)heptanamide, 1-(4-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole, 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(2-chloro-6-fluoro-3-methylbenzyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-(3-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 1), 1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 2), (R)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, (S)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 1), 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (isomer 2), (R)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, (S)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-methoxyphenyl)-5-isopropoxy-1H-benzo[d]imidazole, 9-benzyl-6-isopropoxy-8-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine, 9-benzyl-6-isopropoxy-8-(2-methyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purine, tert-butyl 4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazine-1-carboxylate, 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)ethan-1-one, 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)hexan-1-one, 9-benzyl-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)-N,N-dimethylpyrrolidin-3-amine, 9-benzyl-8-(4-methyl-6-(piperazin-1-yl)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxyphenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one, 1-(4-((4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)methyl)piperidin-1-yl)ethan-1-one, 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), (R)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one, 3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propan-1-amine, N-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)acetamide, 1-(4-(2-(3-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-2-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(2-chloro-3-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), (R)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, (R)-8-(4-(azetidin-2-ylmethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(pyrrolidin-3-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(3-(piperazin-1-yl)propoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((3-fluoroazetidin-3-yl)methoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N,N-dimethylacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-methylacetamide, 1-(4-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethan-1-amine, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)acetic acid, (R)-9-benzyl-8-(2-chloro-4-(pyrrolidin-2-ylmethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-hydroxyacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)acetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-(2-hydroxyethyl)acetamide, (2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)glycine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-N-methylglycine, 9-benzyl-8-(2-chloro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(piperidin-3-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-((2-azaspiro[3.3)heptan-6-yl)oxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-(azetidin-3-yloxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2,3-difluorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyrimidin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperidin-4-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylazetidin-3-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylpiperidin-4-amine, 9-benzyl-8-(4-methyl-6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine, 1-(4-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)piperazin-1-yl)ethan-1-one, 1-(4-(2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)ethan-1-one, 9-benzyl-8-(4-methyl-6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 4-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)morpholine, 2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethan-1-amine, 3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propan-1-amine, 1-(3-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)azetidin-1-yl)ethan-1-one, (S)-9-benzyl-8-(4-methyl-6-(pyrrolidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylethan-1-amine, (S)-9-benzyl-8-(4-methyl-6-(piperidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(3-methyl-2-(2-(piperazin-1-yl)ethoxy)pyridin-4-yl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-2-(((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine, (R)-3-(((5-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine, 8-{6-[(azetidin-3-yl)oxy]-4-methylpyridin-3-yl}-9-benzyl-6-[(1-methylcyclopropyl)oxy]-9H-purine, 9-benzyl-8-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,6-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,3-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-bromo-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-3-ylmethyl)-9H-purine, 2-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzonitrile, 9-benzyl-8-(2-ethynyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (2-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)methanol, 3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propanoic acid, (2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-L-proline, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)pyrrolidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)azetidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-4-ol, 2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)azetidin-3-ol, 8-(4-(2-(1,6-diazaspiro[3.3)heptan-6-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-5-one, (R)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane, 9-benzyl-8-(2,3-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-5-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2,5-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-(2-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 9-(3-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutoxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-3-yl)ethyl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-phenylpropyl)-9H-purine, (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-phenylpropyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-2-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(pyridin-4-ylmethyl)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((5-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-2-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((6-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((4-(trifluoromethyl)pyridin-2-yl)methyl)-9H-purine, 6-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)picolinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((6-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)nicotinonitrile, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(2-(pyridin-4-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)isonicotinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 5-chloro-2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 2-chloro-4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((5-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-((3-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)azetidin-3-amine, 1-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)piperidin-4-amine, 4-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)piperazin-2-one, (E)-3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)acrylic acid, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chloro-N,N-dimethylbenzamide, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chloro-N-methylbenzamide, (4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)(piperazin-1-yl)methanone, 4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorobenzamide, 9-benzyl-8-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-ylmethyl)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenyl)methanamine, 9-benzyl-8-(2-chloro-4-methoxyphenyl)-6-(1-methylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-methoxypyridin-3-yl)-6-(1-methylcyclopropoxy)-9H-purine, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutoxy)-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutoxy)-1H-benzo[d]imidazole, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutoxy)-3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridine, 3-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutoxy)-3H-imidazo[4,5-b]pyridine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethylcyclopropoxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclobutoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-cyclopropoxy-9H-purine, 1-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile, 2-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol, (R)-1-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethyl)pyrrolidin-3-ol, (S)-9-benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-(2-(3,8-diazabicyclo[3.2.1]octan-3-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 3-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane, (R)-9-benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-3-ol, 2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,6-diazaspiro[3.4]octan-7-one, (cis)-9-benzyl-8-(2-chloro-4-(2-(3,5-dimethylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9H-purine, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-2-one, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 1), 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 2), 6-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,3-dimethylpiperazin-2-one, 8-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (R)-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)methanol, 8-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, 8-(4-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (1S,4S)-2-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octane, 8-(4-(2-(4,7-diazaspiro[2.5]octan-4-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropoxy)-9H-purine, (S)-2-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)acetonitrile, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one, 4-(3-(4-(9-benzyl-6-(1-methylcyclopropoxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-cyclopropylpyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-ethylpyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine (isomer 1), (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropoxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 1), (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropoxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, and 10. The compound of claim 1 selected from pharmaceutically acceptable salts thereof.

60. 2-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenyl)acetamide, E-3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenyl)acrylic acid, 3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2,2-dimethylpropanoic acid, 2-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethan-1-ol, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 1), 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 2), (R)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, (R)-1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol 1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, 2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenyl)acetamide, 1-(3-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)zetidin-1-yl)-2-hydroxyethan-1-one, 1-(3-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)zetidin-1-yl)ethan-1-one, (S)-5-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)piperidin-2-one, 5-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)tetrahydropyrimidin-2(1H)-one, 5-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)pentanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)butanoic acid, 1-(3-chloro-4-(6-(1-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)-2-methylpropan-2-ol, 2-(2-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)ethoxy)acetic acid, and 10. The compound of claim 1 selected from pharmaceutically acceptable salts thereof.

61. (R)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)propanoic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (1s,3s)-3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)cyclobutane-1-carboxylic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, and pharmaceutically acceptable salts thereof.

62. 10. The compound of claim 1 selected from the compounds of Table T and Table U, and pharmaceutically acceptable salts thereof.

63. A compound according to any one of claims 1 to 62 for use in the treatment of cancer.

64. 64. The compound for use according to claim 63, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

65. 65. The compound for use according to claim 63 or 64, wherein the cancer is a solid cancer.

66. 66. The compound for use according to any one of claims 63 to 65, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

67. 67. The compound for use according to any one of claims 63 to 66, wherein the cancer comprises a BRCA1 and / or BRCA2 mutation.

68. 68. The compound for use according to any one of claims 63 to 67, wherein the cancer is PARP inhibitor (PARPi) resistant.

69. 64. The compound for use according to claim 63, wherein the cancer is ataxia telangiectasia mutated (ATM) mutation positive.

70. 64. The compound for use according to claim 63, wherein the cancer is a blood cancer.

71. 64. The compound for use according to claim 63, wherein the cancer is a solid cancer.

72. 64. The compound for use according to claim 63, wherein the cancer is positive for a mutation in the gene encoding the Fanconi Anemia (FA) protein or an FA-like gene.

73. 64. The compound for use according to claim 63, wherein the cancer is positive for a mutation in a gene encoding a DNA repair protein.

74. 74. The compound of claim 73, wherein the mutation is in one or more genes selected from RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP-interacting protein), PALB2 (partner and localizer of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQRecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (nibrin), and EMSY.

75. 63. A method of treating cancer, comprising administering to a patient in need thereof a therapeutically effective amount of a compound of any one of claims 1-62.

76. 76. The method of claim 75, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

77. 77. The method of claim 75 or 76, wherein the cancer is a solid cancer.

78. 78. The method of any one of claims 75 to 77, wherein the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer.

79. 79. The method of any one of claims 75 to 78, wherein the cancer comprises a BRCA1 and / or BRCA2 mutation.

80. 80. The method of any one of claims 75 to 79, wherein the cancer is PARP inhibitor (PARPi) resistant.

81. 76. The method of claim 75, wherein the cancer is ataxia telangiectasia mutated (ATM) mutation positive.

82. 76. The method of claim 75, wherein the cancer is a hematological cancer.

83. 76. The method of claim 75, wherein the cancer is a solid cancer.

84. 76. The method of claim 75, wherein the cancer is positive for a mutation in the gene encoding the Fanconi Anemia (FA) protein or an FA-like gene.

85. 76. The method of claim 75, wherein the cancer is positive for a mutation in a gene encoding a DNA repair protein.

86. 86. The method of claim 85, wherein the mutation is in one or more genes selected from RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP-interacting protein), PALB2 (partner and localizer of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQRecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (nibrin), and EMSY.

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