POLQ inhibitors

Abstract

The present specification relates generally to compounds of formula (I): # imgabs0 # or a stereoisomer or a pharmaceutical salt thereof wherein G, Ga, Gb, X, Y, R1, R2, Q1, Q2 and Q3 have any of the meanings defined herein, compositions containing them and their use in therapy. These compounds are inhibitors of the polymerase, i.e. DNA polymerase theta (Pol theta or POLQ), and are therefore particularly useful in the treatment of cancer.

Description

[0001] This application claims priority to U.S. Provisional Application No. 63 / 386,263, filed December 6, 2022, and U.S. Provisional Application No. 63 / 497,847, filed April 24, 2023, each of which is incorporated herein by reference in its entirety for all purposes. Background Art

[0002] DNA polymerase θ (Polθ) is a specialized polymerase encoded by the POLQ gene in the human genome and is therefore also referred to as POLQ. It belongs to family A, a group of DNA polymerases considered error-prone due to their 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 participates in genome maintenance processes through its role in translesion synthesis (TLS), a mechanism of DNA damage tolerance, and alternative DNA end joining (alt-EJ), a DNA repair mechanism involved in resolving double-strand breaks (DSBs) (Ramsden et al., 2022; Yoon et al., 2019).

[0003] DNA DSBs are among the most cytotoxic lesions faced by cells, and several DNA damage signaling and repair mechanisms have evolved to cope with them. In human cells, DSB repair primarily occurs through the nonhomologous end joining (NHEJ) and homologous recombination repair (HRR) pathways, with a third pathway, known as alt-EJ, generally considered a less commonly used option. The first step of both the HRR and alt-EJ pathways is shared, in which the ends of the DNA DSB are processed (resected) to generate a region of single-stranded DNA (ssDNA). While resection is relatively extensive during HRR, it is maintained at a shorter stretch during alt-EJ through a mechanism that remains elusive. Furthermore, alt-EJ is associated with repair using sequence microhomologies (2 to 6 base pairs) surrounding the DSB site through direct annealing, processing of the DNA flap, and ligation, explaining its error-prone nature. Consequently, alt-EJ is also known as microhomology-mediated end joining (MMEJ) (Ciccia and Elledge, 2010).

[0004] HRR is a form of DNA repair that, once a DSB occurs on a chromosome, is repaired using the sister chromatid as a template. Therefore, HRR is considered error-free and occurs only when sister chromatids are available, i.e., during the DNA replication (synthesis) phase (S phase) and the interstitial phase (G2 phase) of the cell cycle. HRR deficiency (HRD) is 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 involving single-base substitutions (SBSs), insertions and deletions (INDELs), and rearrangements (Nik-Zainal et al., 2016). Interestingly, the SBS signature associated with HRD (SBS3) is also associated with an INDEL signature (ID6), characterized by extensive use of microhomologies 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 were identified in secondary (reversion) mutations that restore open reading frames of BRCA and other HRR-related genes in tumors from patients at treatment progression, strongly suggesting that these reversion events are mediated by MMEJ repair and drive therapy resistance in these clinical cases (Pettitt et al., 2020; Tobalina et al., 2021).

[0005] Recently, POLQ has been implicated in MMEJ repair, but not in HRR, making it the only MMEJ-specific protein known to date (Wyatt et al., 2016; Yousefzadeh et al., 2014). Interestingly, reports have highlighted synthetic lethal genetic dependencies between inactivating mutations in genes involved in HRR (BRCA1, BRCA2, FANCD2, ATM) and the absence of POLQ activity, either as a polymerase or helicase (Mateos-Gomez et al., 2017). Consequently, 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, studies have also shown that POLQ-deficient cells are sensitive to DNA-damaging agents, including ionizing radiation (Higgins et al., 2010; Yousefzadeh et al., 2014), which may open the possibility of combining POLQ inhibitors with chemotherapy or radiotherapy (Higgins and Boulton, 2018).

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

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

[0008]

[0009] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof;

[0010] in,

[0011] R 1 and R 2 Each is independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CN, C2-C4 alkyne or C2-C6 alkoxyalkyl;

[0012] Q 1 , Q 2 and Q 3 independently N, CLR or CR x , where Q 1 , Q 2 and Q 3 No more than one of them is CLR;

[0013] L is a bond, -O-; -C(O)-; -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 -;

[0014] p is independently 1, 2 or 3

[0015] R is H, R a 、R b 、R c or R d ;

[0016] R a is a 3- to 10-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 4- to 6-membered heterocyclic ring, and C1-C7 alkyl, wherein C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

[0017] R b is C1-C7 alkyl, wherein one or two methylene groups from C1-C7 alkyl are optionally independently replaced by NR e or O and one or two single bonds in the C2-C7 alkyl chain are optionally independently replaced by a double bond or a triple bond, wherein the C1-C7 alkyl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle and 3- to 10-membered heterocycle,

[0018] wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo and carboxyl;

[0019] wherein the 3- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxyl, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

[0020] R c is a C3-C6 carbocycle optionally substituted by 1 to 4 substituents independently selected from hydroxy, halo and carboxyl;

[0021] R d is C1-C4 sulfonyl or C1-C4 sulfonamide;

[0022] R y is H, C1-C3 alkyl or C 1-3 alkyl halide;

[0023] R x is H, halo, hydroxy, -CN, -NH2, C1-C3 alkoxy, C1-C3 alkyl or C 1-3 alkyl halide;

[0024] R e is H, halo, C1-C8 alkyl or C1-C8 haloalkyl;

[0025] X is C1-C4 alkylene;

[0026] Y is phenyl or 5- to 6-membered heteroaryl, wherein phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0027] G is N or CH;

[0028] G a and G b is N, CH or CR 5 , where G a and G b One and only one of is N or CH, and G a and G b One and only one of them is CR 5 ;

[0029] R 5 yes

[0030] Za and Z b is independently C1-C3 alkyl or C1-C3 haloalkyl, or Z a and Z b forming a 3- to 6-membered carbocyclic or heterocyclic ring; and

[0031] Z c It is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl or C2-C4 alkyne. DETAILED DESCRIPTION

[0032] This detailed description and its specific examples, while indicating embodiments, are intended for illustrative purposes only. Therefore, there is no limitation on the exemplary embodiments described in this specification. Furthermore, it should be understood that, for the sake of clarity, various features described in the context of separate embodiments may also be combined to form a single embodiment. Conversely, for the sake of brevity, various features described in the context of individual embodiments may also be combined to form subcombinations thereof.

[0033] Listed below are definitions of various terms used in the specification and claims.

[0034] The term "alkoxy" refers to an alkyl group attached to the rest of the molecule via an oxygen atom. Representative alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy, tert-butoxy, and the like.

[0035] The term "alkoxyalkyl" refers to an alkyl group attached to an alkoxy group, wherein the group is attached to the rest of the molecule through a carbon on the alkyl group, i.e., a group having the structure -RO-R', where R and R' are the same or different alkyl groups.

[0036] The term "alkyl" or "alkane" refers to a fully saturated straight or branched chain non-aromatic hydrocarbon. Examples of straight and branched chain alkyl groups include methyl, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, amyl, and octyl.

[0037] The term "alkylamino" refers to an amino group substituted with at least one alkyl group, ie, a group having -NRR', NHR, NRR'H + or NH2R + A group of the structure wherein R and R' are the same or different alkyl groups.

[0038] The term "alkyne" or "alkynyl" is a non-aromatic hydrocarbon containing at least one carbon-carbon triple bond. Examples of alkyne groups include acetylene, propyne, and butyne.

[0039] The term "amide" refers to an amide having the general formula RC(=O)NR 1 R 2 or A group in which R 1 、R 2 and R 3 are hydrogen or the same or different alkyl groups, provided that at least one is an alkyl group.

[0040] The term "carbamate" refers to a carbamate having the general formula R1OC(O)NR2R3 or A group in which R 1 、R 2 and R 3 is 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 on any alkyl group.

[0041] The term "carbocycle" refers to a partially or fully saturated non-aromatic hydrocarbon ring system, including cycloalkyl, cycloalkenyl and cycloalkynyl. Cycloalkyl groups include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene and cyclohexene.

[0042] The term "ester" refers to a 1 -C(O)-OR 2 or A group in which R 1 and R 2 The ester is attached to the rest of the molecule through a carbon on any of the alkyl groups.

[0043] The term "halo" refers to fluorine, chlorine, bromine, and iodine. In some embodiments, halo is fluorine or chlorine. In other embodiments, halo is fluorine. In yet other embodiments, halo is chlorine.

[0044] The term "haloalkyl" refers to an alkyl group in which one or more hydrogens are replaced by a halo group.

[0045] The term "hydroxyalkyl" means an alkyl group in which one or more hydrogens are replaced by a hydroxy group.

[0046] The term "heterocycle", "heterocyclic" or "heterocyclyl" refers to a partially or fully saturated hydrocarbon ring system in which at least one ring carbon atom is replaced by a heteroatom independently selected from nitrogen, oxygen and sulfur. The heterocyclic group can be attached to the rest of the molecule via a carbon or nitrogen ring member atom. Heterocycles include monocyclic heterocycles and 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.

[0047] The term "sulfonyl" refers to a group having the general formula R 1 S(O)2R 2 or A group in which R 1 and R 2 is hydrogen or the same or different alkyl groups, provided that at least one is an alkyl group. The sulfonyl group is attached to the rest of the molecule through a carbon on either alkyl group.

[0048] In this specification, when a term such as "C x-y The prefix C used in "alkyl" etc. (wherein x and y are integers) x-y The numerical range of carbon atoms present in the indicated group. Suitable C 1-3 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and isopropyl. Suitable C 1-4 Examples of alkyl groups include, but are not limited to, methyl, ethyl, n- and isopropyl, n-, isobutyl, sec-, and tert-butyl. In some cases, a group will have two carbon-containing moieties, 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 group and the alkoxy group together have 2 to 6 carbons.

[0049] "Patient" refers to an animal in which one or more active agents as described herein will have a therapeutic effect. In some embodiments, the subject is a human.

[0050] As used herein, and unless otherwise indicated, the term "pharmaceutically acceptable" refers to those compounds, materials, compositions and / or dosage forms which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and animals without excessive toxicity, irritation, allergic response, or other problems or complications, commensurate with a reasonable benefit / risk ratio.

[0051] As used herein, unless otherwise indicated, the phrase "effective amount" as used herein refers to an amount of a compound or composition sufficient to significantly and positively alter the symptoms and / or condition to be treated (e.g., to provide a positive clinical response). The effective amount of the active ingredient used in the pharmaceutical composition will vary with the specific condition being treated, the severity of the condition, the duration of treatment, the nature of concurrent therapy, the specific active ingredient employed, the specific pharmaceutically acceptable excipient / carrier utilized, and similar factors within the knowledge and expertise of the attending physician.

[0052] As used herein, unless otherwise indicated, the terms "treat" and "treating" mean reversing, alleviating, inhibiting the progression of, or slowing or delaying the progression of the disorder or condition to which such terms apply, or one or more symptoms of such disorder or condition. As used herein, the terms "treat" and "treatment" refer to the act of treating, as "treating" is defined immediately above, unless otherwise indicated. The term "treat" also includes adjuvant and neoadjuvant treatment of a subject. The term "treat" also includes reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject.

[0053] The term "pharmaceutically acceptable salt" includes acid addition salts 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 due to the presence of basic and / or carboxyl groups or groups similar thereto.

[0054] Compound

[0055] One embodiment disclosed herein provides a compound of formula (I):

[0056]

[0057] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof;

[0058] in,

[0059] R 1 and R 2 Each is independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CN, C2-C4 alkyne or C2-C6 alkoxyalkyl;

[0060] Q1 , Q 2 and Q 3 independently N, CLR or CR x , where Q 1 , Q 2 and Q 3 No more than one of them is CLR;

[0061] L is a bond, -O-; -C(O)-; -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 -;

[0062] p is independently 1, 2 or 3

[0063] R is H, R a 、R b 、R c or R d ;

[0064] R a is a 3- to 10-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 4- to 6-membered heterocyclic ring, and C1-C7 alkyl, wherein C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

[0065] R b is C1-C7 alkyl, wherein one or two methylene groups from C1-C7 alkyl are optionally independently replaced by NR eor O and one or two single bonds in the C2-C7 alkyl chain are optionally independently replaced by a double bond or a triple bond, wherein the C1-C7 alkyl is optionally substituted by 1 to 4 substituents independently selected from the group consisting of halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle and 3- to 10-membered heterocycle,

[0066] wherein the C3-C6 carbocyclic ring is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo and carboxyl,

[0067] wherein the 3- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxyl, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

[0068] R c is a C3-C6 carbocycle optionally substituted by 1 to 4 substituents independently selected from hydroxy, halo and carboxyl;

[0069] R d is C1-C4 sulfonyl or C1-C4 sulfonamide;

[0070] R y is H, C1-C3 alkyl or C1-3 haloalkyl;

[0071] R x is H, halo, hydroxy, -CN, -NH2, C1-C3 alkoxy, C1-C3 alkyl or C 1-3 alkyl halide;

[0072] R e is H, halo, C1-C8 alkyl or C1-C8 haloalkyl;

[0073] X is C1-C4 alkylene;

[0074] Y is phenyl or 5- to 6-membered heteroaryl, wherein phenyl or heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0075] G is N or CH;

[0076] Ga and G b is N, CH or CR 5 , where G a and G b One and only one of is N or CH, and G a and G b One and only one of them is CR 5 ;

[0077] R 5 yes

[0078] Z a and Z b is independently C1-C3 alkyl or C1-C3 haloalkyl, or Z a and Z b forming a 3- to 6-membered carbocyclic or heterocyclic ring; and

[0079] Z c It is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl or C2-C4 alkyne.

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

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

[0082] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G a It's CR5.

[0083] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G b It's CR5.

[0084] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G b It's N.

[0085] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G b It is CH.

[0086] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G bIt's N.

[0087] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G b It is CH.

[0088] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl.

[0089] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b It is -CH3.

[0090] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G a or G b Is CR5 and R 5 yes where p is 1-4.

[0091] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G a or G b Is CR5 and R 5 yes where p is 2.

[0092] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G a or G b Is CR5 and R 5 yes where p is 1.

[0093] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z c It is -CH3.

[0094] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z c It is -CN.

[0095] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, Gb It's N, G a Is CR5 and R 5 yes where p is 1-4.

[0096] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a Is CR5 and R 5 yes where p is 1.

[0097] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a Is CR5 and R 5 yes where p is 2.

[0098] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 1-4, and Z c It is a C1-C3 alkyl group.

[0099] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 1-4, and Z c It is -CH3.

[0100] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 1 and Z c It is a C1-C3 alkyl group.

[0101] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R5 yes where p is 1 and Z c It is -CH3.

[0102] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 2 and Z c It is -CH3.

[0103] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 1-4, and Z c It is -CN.

[0104] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 1 and Z c It is -CN.

[0105] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes where p is 2 and Z c It is -CN.

[0106] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0107] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is N-heteroaryl.

[0108] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is pyridine.

[0109] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is substituted.

[0110] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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.

[0111] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is substituted with -Cl.

[0112] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is substituted with -CH3.

[0113] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is substituted with cyclopropyl.

[0114] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is unsubstituted.

[0115] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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.

[0116] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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.

[0117] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one substituent selected from halo and C1-C3 alkyl.

[0118] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is pyridine substituted with one substituent selected from halo and C1-C3 alkyl.

[0119] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted with one substituent selected from -Cl and -CH3.

[0120] Some embodiments disclosed herein provide a compound of Formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is pyridine substituted with one substituent selected from -Cl and -CH3.

[0121] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CN or C2-C4 alkyne.

[0122] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently H, halo, -CH3, -OCH3, CH2OH, -CN or -C-CH.

[0123] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently H, halo or C1-C3 alkyl.

[0124] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently H, halo or -CH3.

[0125] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Each is independently H, -Cl, -F or -CH3.

[0126] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 and R 2 Yes -H.

[0127] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R1 It is a halo group.

[0128] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 It is -Cl.

[0129] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -F.

[0130] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 Yes -H.

[0131] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 is a halo group and R 2 Yes -H.

[0132] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 is -Cl and R 2 Yes -H.

[0133] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -F and R 2 Yes -H.

[0134] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 is -CH3 and R 2 Yes -H.

[0135] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 It is a halo group.

[0136] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 It is -Cl.

[0137] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 Yes -F.

[0138] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 2 It is -CH3.

[0139] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -H.

[0140] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -H and R 2 It is a halo group.

[0141] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -H and R 2 It is -Cl.

[0142] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -H and R 2 Yes -F.

[0143] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein R 1 Yes -H and R 2 It is -CH3.

[0144] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's CLR.

[0145] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 It's CLR.

[0146] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 It's CLR.

[0147] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 It's CLR.

[0148] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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 -.

[0149] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -.

[0150] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -.

[0151] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is a bond, -O-, -(CH2) p O- or -O(CH2) p -.

[0152] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and L is the key.

[0153] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is the key.

[0154] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is the key.

[0155] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is the key.

[0156] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and L is -O-.

[0157] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O-.

[0158] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O-.

[0159] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O-.

[0160] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and L is -(CH2) p O.

[0161] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -(CH2) p O.

[0162] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -(CH2) p O.

[0163] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -(CH2) p O.

[0164] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and L is -O(CH2) p -.

[0165] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O(CH2) p -.

[0166] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O(CH2) p -.

[0167] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O(CH2) p -.

[0168] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and L is -O(CH2)2-.

[0169] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and L is -O(CH2)2-.

[0170] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and L is -O(CH2)2-.

[0171] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and L is -O(CH2)2-.

[0172] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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-.

[0173] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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-.

[0174] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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-.

[0175] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any 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-.

[0176] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and R is H, R a or R b .

[0177] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 is CLR and R is H, R a or R b .

[0178] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 2 is CLR and R is H, R a or R b .

[0179] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 3 is CLR and R is H, R a or R b .

[0180] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and R is R a .

[0181] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a It is a 3- to 10-membered N-heterocyclic ring.

[0182] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a It is a 4- to 7-membered N-heterocyclic ring.

[0183] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a It is a 6-membered N-heterocyclic ring.

[0184] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the 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.

[0185] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a Optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, 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 C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester and C1-C5 alkoxy.

[0186] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R aSubstituted with C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester and C1-C5 alkoxy.

[0187] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a It is substituted by a C1-C7 alkyl group, and the alkyl group is substituted by an oxo group.

[0188] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a is substituted by a C1-C7 alkyl group, and the alkyl group is substituted by a C1-C5 alkoxy group.

[0189] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a And R a Substituted with methyl.

[0190] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2) p - and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0191] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2) p - and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0192] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)2- and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0193] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)2- and R a is an optionally substituted 4- to 7-membered N-heterocyclic ring.

[0194] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)2- and R a It is an unsubstituted 4- to 7-membered N-heterocyclic ring.

[0195] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)2- and R a It is a 4- to 7-membered N-heterocyclic ring substituted by a hydroxyl group, a methyl group or an amino group.

[0196] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)3- and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0197] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3It's the CLR a and L is -O(CH2)3- and R a It is a 4- to 7-membered N-heterocyclic ring.

[0198] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)3- and R a It is an unsubstituted 4- to 7-membered N-heterocyclic ring.

[0199] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O(CH2)3- and R a It is a 4- to 7-membered N-heterocyclic ring substituted by a hydroxyl group, a methyl group or an amino group.

[0200] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is a bond and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0201] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is a bond and R a It is a 4- to 7-membered N-heterocyclic ring.

[0202] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is a bond and R a It is an unsubstituted 4- to 7-membered N-heterocyclic ring.

[0203] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is a bond and R a It is a 4- to 7-membered N-heterocyclic ring substituted by a hydroxyl group, a methyl group or an amino group.

[0204] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O- and R a is an optionally substituted 3- to 10-membered N-heterocyclic ring.

[0205] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O- and R a It is a 4- to 7-membered N-heterocyclic ring.

[0206] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O- and R a It is an unsubstituted 4- to 7-membered N-heterocyclic ring.

[0207] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR a and L is -O- and R a It is a 4- to 7-membered N-heterocyclic ring substituted by a hydroxyl group, a methyl group or an amino group.

[0208] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 is CLR and R is R b .

[0209] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b is substituted with 1 to 4 substituents independently selected from the group consisting of halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, halo, and carboxyl, and wherein the 3-membered The 4- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester and C1-C5 alkoxy.

[0210] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b is substituted with at least one C3-C6 carbocyclic ring, wherein the C3-C6 carbocyclic ring is substituted with 1 to 4 substituents independently selected from hydroxy, halo and carboxyl.

[0211] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b is substituted with at least one C3-C6 carbocyclic ring, wherein the C3-C6 carbocyclic ring is substituted with 1 to 4 substituents independently selected from hydroxy and halo.

[0212] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLRb And R b Substituted with hydroxyl groups.

[0213] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b is substituted with a 3- to 10-membered heterocyclic ring.

[0214] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b Substituted with an N-heterocycle.

[0215] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b Substituted with a 4- to 7-membered N-heterocycle.

[0216] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b substituted with a 3- to 10-membered heterocycle, such as, but not limited to, an N-heterocycle, such as, but not limited to, a 4- to 7-membered N-heterocycle, wherein the heterocycle is substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxyl, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

[0217] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLRb And R b Substituted with a 3- to 10-membered heterocycle, such as, but not limited to, an N-heterocycle, such as, but not limited to, a 4- to 7-membered N-heterocycle, wherein the heterocycle is substituted with C1-C7 alkyl, oxo, and / or halo.

[0218] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b Substituted with amino, C1-C8 amide and / or C1-C4 alkylamino.

[0219] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b And R b Substituted with oxo, hydroxy and / or carboxyl groups.

[0220] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is an optionally substituted C1-C5 alkyl group.

[0221] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is an optionally substituted C1-C3 alkyl group.

[0222] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is a C1-C5 alkyl group substituted by 1 to 4 substituents independently selected from amino, carboxyl, oxy and hydroxy.

[0223] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is a C1-C3 alkyl group substituted by 1 to 4 substituents independently selected from amino, carboxyl, oxy and hydroxy.

[0224] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amide.

[0225] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amide.

[0226] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b It is an unsubstituted C1-C5 alkyl group.

[0227] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b It is an unsubstituted C1-C3 alkyl group.

[0228] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is an optionally substituted C1-C7 alkyl group, wherein one or two methylene groups from the C1-C7 alkyl group are independently replaced by NR e Or O instead.

[0229] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is an optionally substituted C1-C7 alkyl group, wherein one methylene group from the C1-C7 alkyl group is replaced by NH.

[0230] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is -O-, and R b is an optionally substituted C1-C7 alkyl group, wherein one methylene group from the C1-C7 alkyl group is replaced by NCH3.

[0231] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is an optionally substituted C1-C5 alkyl group.

[0232] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is an optionally substituted C1-C3 alkyl group.

[0233] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is a C1-C5 alkyl group substituted by 1 to 4 substituents independently selected from amino, carboxyl, oxy and hydroxy.

[0234] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is a C1-C3 alkyl group substituted by 1 to 4 substituents independently selected from amino, carboxyl, oxy and hydroxy.

[0235] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amide.

[0236] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and C1-C8 amide.

[0237] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b It is an unsubstituted C1-C5 alkyl group.

[0238] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q2 or Q 3 It's the CLR b , L is a bond, and R b It is an unsubstituted C1-C3 alkyl group.

[0239] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is an optionally substituted C1-C7 alkyl group, wherein one or two methylene groups from the C1-C7 alkyl group are independently replaced by NR e Or O instead.

[0240] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is an optionally substituted C1-C7 alkyl group, wherein one methylene group from the C1-C7 alkyl group is replaced by NH.

[0241] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR b , L is a bond, and R b is an optionally substituted C1-C7 alkyl group, wherein one methylene group from the C1-C7 alkyl group is replaced by NCH3.

[0242] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR c .

[0243] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR c And R c Substituted with 1 to 4 substituents independently selected from hydroxy, halo and carboxyl.

[0244] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Q 1 , Q 2 or Q 3 It's the CLR c And R c Substituted with 1 to 4 substituents independently selected from hydroxy and halo.

[0245] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes Where p is 1-4, Z c is a C1-C3 alkyl group, Y is an N-heteroaryl group having one substituent selected from the group consisting of a halo group, a C1-C3 alkyl group, a C1-C3 alkoxy group, -CN, a C1-C3 haloalkyl group, and a cyclopropyl group, R 1 and R 2 Each is independently H, -Cl, -F or -CH3.

[0246] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes Where p is 1 or 2, 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 Each is independently H, -Cl, -F or -CH3.

[0247] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein G is N, G b It's N, G a It is CR5, R 5 yes Where p is 1 or 2, Z c is -CH3, Y is an N-heteroaryl group having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl, R 1 and R 2 Each is independently H, -Cl, -F or -CH3.

[0248] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0249] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0250] Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0251] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0252] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0253] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0254] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0255] Y is an N-heteroaryl group having one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0256] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0257] Q 1 , Q 2 and Q 3is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0258] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0259] G is N, G b It's N, G a It is CR5, R 5 yes p is 1 or 2, and Z c is -CH3;

[0260] Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0261] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0262] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0263] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0264] G is N, G b It's N, G a It is CR5, R 5 yes p is 1 or 2, and Z c is -CH3;

[0265] Y is an N-heteroaryl group having one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0266] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0267] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0268] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0269] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0270] Y is a phenyl group having one substituent selected from a halo group and a C1-C3 alkyl group;

[0271] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0272] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0273] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0274] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0275] Y is an N-heteroaryl group having one substituent selected from halo and C1-C3 alkyl;

[0276] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0277] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a or R b .

[0278] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0279] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0280] Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0281] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0282] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2)p -, and R is R a .

[0283] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0284] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0285] Y is an N-heteroaryl group having one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0286] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0287] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R a .

[0288] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0289] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0290] Y is phenyl having one substituent selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0291] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0292] Q 1 , Q2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R b .

[0293] Some embodiments disclosed herein provide a compound of formula (I) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein

[0294] G is N, G b It's N, G a It is CR5, R 5 yes p is 1-4, and Z c is a C1-C3 alkyl group;

[0295] Y is an N-heteroaryl group having one substituent selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl;

[0296] R 1 and R 2 Each is independently H, halo or C1-C3 alkyl;

[0297] Q 1 , Q 2 and Q 3 is CLR or CH, where Q 1 , Q 2 and Q 3 One and only one of them is CLR, L is a bond, -O-, -(CH2) p O- or -O(CH2) p -, and R is R b .

[0298] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IA):

[0299]

[0300] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0301] R 1 、R 2 、R 5 , Q 1 , Q 2 , Q 3and X and Y are as defined in formula (I).

[0302] Other embodiments disclosed herein provide a compound of formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0303] Still other embodiments disclosed herein provide a compound of Formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0304] Yet other embodiments disclosed herein provide a compound of formula (IA) or any stereoisomer thereof or any 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.

[0305] Still other embodiments disclosed herein provide a compound of formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

[0306] Other embodiments disclosed herein provide a compound of formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0307] Other embodiments disclosed herein provide compounds of formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0308] Other embodiments disclosed herein provide a compound of formula (IA) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein 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, Z aand Z b are independently C1-C3 alkyl and Z c It’s H.

[0309] In yet other embodiments, X is -CH2-, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl, and Z a and Z b is -CH3 and Z c is H. In another embodiment, Y is phenyl, Z a and Z b is -CH3 and Z c It’s H.

[0310] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IB):

[0311]

[0312] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0313] R 1 、R 2 、R 5 , Q 1 , Q 2 , Q 3 and X and Y are as defined in formula (I).

[0314] Other embodiments disclosed herein provide a compound of formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0315] Still other embodiments disclosed herein provide a compound of Formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0316] Yet other embodiments disclosed herein provide a compound of formula (IB) or any stereoisomer thereof or any 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.

[0317] Still other embodiments disclosed herein provide a compound of formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

[0318] Other embodiments disclosed herein provide a compound of formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0319] Other embodiments disclosed herein provide compounds of formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0320] Other embodiments disclosed herein provide compounds of formula (IB) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b Is H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0321] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IC):

[0322]

[0323] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0324] R 1 、R 2 、R 5 , Q1 , Q 2 , Q 3 and X and Y are as defined in formula (I).

[0325] Other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0326] Still other embodiments disclosed herein provide a compound of Formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0327] Yet other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any 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.

[0328] Still other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl. In another embodiment of the present invention, Y is phenyl substituted by halo. In another embodiment of the present invention, Y is phenyl substituted by Cl.

[0329] Still other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is a 5- to 6-membered heteroaryl. In further embodiments, Y is pyridine.

[0330] Yet other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is a 5- to 6-membered heteroaryl optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, and cyclopropyl.

[0331] Other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0332] Still other embodiments disclosed herein provide a compound of formula (IC) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and Y is phenyl optionally substituted with 1 to 3 substituents independently selected from halo and C1-C3 alkyl.

[0333] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (ID):

[0334]

[0335] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0336] G, G a , G b , X, Y, R 1 、R 2 , L and R are as defined in formula (I).

[0337] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0338] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0339] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0340] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0341] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0342] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0343] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0344] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0345] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0346] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0347] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0348] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0349] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0350] Still other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0351] Other embodiments herein provide a compound of formula (ID) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0352] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IE):

[0353]

[0354] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0355] G, G a , G b , X, Y, R 1 、R 2 , L and R are as defined in formula (I).

[0356] Other embodiments herein provide compounds of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0357] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0358] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0359] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0360] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0361] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0362] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0363] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0364] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0365] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0366] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0367] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0368] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0369] Still other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0370] Other embodiments herein provide a compound of formula (IE) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0371] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IF):

[0372]

[0373] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0374] G, G a , G b , X, Y, R 1 、R 2 , L and R are as defined in formula (I).

[0375] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0376] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0377] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

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

[0379] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0380] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0381] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0382] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0383] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0384] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0385] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0386] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0387] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0388] Still other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0389] Other embodiments herein provide a compound of formula (IF) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0390] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IG):

[0391]

[0392] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0393] G, G a , G b , X, Y, R 1 、R 2 , L and R are as defined in formula (I).

[0394] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0395] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0396] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0397] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

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

[0399] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0400] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0401] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

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

[0403] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0404] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0405] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0406] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0407] Still other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0408] Other embodiments herein provide a compound of formula (IG) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0409] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IH):

[0410]

[0411] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0412] G, G a , G b , X, Y, R 1 、R 2 , L and R are as defined in formula (I).

[0413] Other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0414] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0415] Still other embodiments herein provide compounds of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0416] Other embodiments herein provide compounds of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0417] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0418] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0419] Other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0420] Other embodiments herein provide compounds of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0421] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0422] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0423] Other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0424] Other embodiments herein provide compounds of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0425] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0426] Still other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0427] Other embodiments herein provide a compound of formula (IH) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0428] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (II):

[0429]

[0430] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0431] X, Y, R 1 、R 2 、R 5 , L and R are as defined in formula (I).

[0432] Other embodiments disclosed herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0433] Still other embodiments disclosed herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0434] Yet other embodiments disclosed herein provide a compound of formula (II) or any stereoisomer thereof or any 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.

[0435] Still other embodiments disclosed herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

[0436] Other embodiments disclosed herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0437] Other embodiments disclosed herein provide compounds of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0438] Other embodiments disclosed herein provide compounds of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b Is H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0439] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0440] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0441] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0442] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0443] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0444] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0445] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0446] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0447] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0448] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0449] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0450] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0451] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0452] Still other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0453] Other embodiments herein provide a compound of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0454] Other embodiments disclosed herein provide compounds of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl, or CN; X is -CH2- and 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, and L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0455] Other embodiments disclosed herein provide compounds of formula (II) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl or CN; X is -CH2- and Y is phenyl optionally substituted by 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 .

[0456] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IJ):

[0457]

[0458] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0459] X, Y, R1 、R 2 、R 5 , L and R are as defined in formula (I).

[0460] Other embodiments disclosed herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0461] Still other embodiments disclosed herein provide a compound of Formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0462] Yet other embodiments disclosed herein provide a compound of formula (IJ) or any stereoisomer thereof or any 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.

[0463] Still other embodiments disclosed herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

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

[0465] Other embodiments disclosed herein provide compounds of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0466] Other embodiments disclosed herein provide compounds of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z bIs H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0467] Other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0468] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0469] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0470] Other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0471] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0472] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0473] Other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p- and R is R a or R b .

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

[0475] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0476] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0477] Other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

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

[0479] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0480] Still other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0481] Other embodiments herein provide a compound of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0482] Other embodiments disclosed herein provide compounds of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z bis H, C1-C3 alkyl, or CN; X is -CH2- and 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, and L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0483] Other embodiments disclosed herein provide compounds of formula (IJ) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl or CN; X is -CH2- and Y is phenyl optionally substituted by 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 .

[0484] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IK):

[0485]

[0486] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0487] X, Y, R 1 、R 2 、R 5 , L and R are as defined in formula (I).

[0488] Other embodiments disclosed herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0489] Still other embodiments disclosed herein provide a compound of Formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0490] Still other embodiments disclosed herein provide a compound of formula (IK) or any stereoisomer thereof or any 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.

[0491] Still other embodiments disclosed herein provide a compound of formula (IK) or any stereoisomer thereof or any 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 another embodiment of the present invention, Y is phenyl substituted with one or two substituents independently selected from halo and C1-C3 alkyl.

[0492] Other embodiments disclosed herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0493] Other embodiments disclosed herein provide compounds of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0494] Other embodiments disclosed herein provide compounds of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b Is H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0495] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2)p O- or O(CH2) p -.

[0496] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0497] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0498] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0499] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0500] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0501] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0502] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0503] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0504] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0505] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0506] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0507] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0508] Still other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0509] Other embodiments herein provide a compound of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0510] Other embodiments disclosed herein provide compounds of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl, or CN; X is -CH2- and 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, and L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0511] Other embodiments disclosed herein provide compounds of formula (IK) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ringa and Z b is H, C1-C3 alkyl or CN; X is -CH2- and Y is phenyl optionally substituted by 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 .

[0512] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IL):

[0513]

[0514] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof; wherein,

[0515] X, Y, R 1 、R 2 、R 5 , L and R are as defined in formula (I).

[0516] Other embodiments disclosed herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0517] Still other embodiments disclosed herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0518] Yet other embodiments disclosed herein provide a compound of formula (IL) or any stereoisomer thereof or any 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.

[0519] Still other embodiments disclosed herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

[0520] Other embodiments disclosed herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0521] Other embodiments disclosed herein provide compounds of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z c It’s H.

[0522] Other embodiments disclosed herein provide compounds of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b Is H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0523] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0524] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0525] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0526] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0527] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0528] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a or R b .

[0529] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0530] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0531] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0532] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0533] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0534] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0535] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0536] Still other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0537] Other embodiments herein provide a compound of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0538] Other embodiments disclosed herein provide compounds of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl, or CN; X is -CH2- and 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, and L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0539] Other embodiments disclosed herein provide compounds of formula (IL) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl or CN; X is -CH2- and Y is phenyl optionally substituted by 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 .

[0540] Some embodiments disclosed herein provide compounds of Formula (I) having the structure of Formula (IM):

[0541]

[0542] or any stereoisomer thereof or any pharmaceutically acceptable salt thereof;

[0543] in,

[0544] X, Y, R 1 、R 2 、R 5 , L and R are as defined in formula (I).

[0545] Other embodiments disclosed herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2-.

[0546] Still other embodiments disclosed herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl.

[0547] Yet other embodiments disclosed herein provide a compound of formula (IM) or any stereoisomer thereof or any 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.

[0548] Still other embodiments disclosed herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Y is phenyl substituted by one or two substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl and cyclopropyl. In another embodiment of the present invention, Y is phenyl substituted by one or two substituents independently selected from halo and C1-C3 alkyl.

[0549] Other embodiments disclosed herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein X is -CH2- and 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.

[0550] Other embodiments disclosed herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z a and Z b are independently C1-C3 alkyl and Z c is H. In another embodiment, Z a and Z b is -CH3 and Z cIt’s H.

[0551] Other embodiments disclosed herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b Is H, C1-C3 alkyl or CN. In another embodiment, Z is from a 3-membered carbocyclic ring. a and Z b , and Z c Is H or C1-C3 alkyl. In other embodiments, Z from a 4-membered carbocyclic ring a and Z b , and Z c is H or C1-C3 alkyl.

[0552] Other embodiments herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p -.

[0553] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0554] Still other embodiments herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0555] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a or R b .

[0556] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a or R b .

[0557] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is Ra or R b .

[0558] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a or R b .

[0559] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R a .

[0560] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R a .

[0561] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R a .

[0562] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R a .

[0563] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is a bond and R is R b .

[0564] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -O- and R is R b .

[0565] Still other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is -(CH2) p O- and R is R b .

[0566] Other embodiments herein provide a compound of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein L is O(CH2) p - and R is R b .

[0567] Other embodiments disclosed herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl, or CN; X is -CH2- and 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, and L is a bond, -O-, -(CH2) p O- or O(CH2) p - and R is R a or R b .

[0568] Other embodiments disclosed herein provide compounds of formula (IM) or any stereoisomer thereof or any pharmaceutically acceptable salt thereof, wherein Z is from a 3- to 6-membered carbocyclic ring a and Z b is H, C1-C3 alkyl or CN; X is -CH2- and Y is phenyl optionally substituted by 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 .

[0569] Some embodiments disclosed herein provide a compound selected from the group consisting of:

[0570] 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol,

[0571] tert-Butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate,

[0572] N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)acetamide,

[0573] N-(3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)heptylamide,

[0574] 1-(4-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole,

[0575] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(2-chloro-6-fluoro-3-methylbenzyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0576] 1-(3-chlorobenzyl)-5-isopropoxy-2-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-1H-benzo[d]imidazole,

[0577] 1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (Isomer 1),

[0578] 1-Benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (Isomer 2),

[0579] (R)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0580] (S)-1-benzyl-2-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0581] 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (Isomer 1),

[0582] 1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole (Isomer 2),

[0583] (R)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0584] (S)-1-benzyl-2-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0585] 1-benzyl-2-(2-chloro-4-methoxyphenyl)-5-isopropoxy-1H-benzo[d]imidazole,

[0586] 9-Benzyl-6-isopropoxy-8-(4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine,

[0587] 9-Benzyl-6-isopropoxy-8-(2-methyl-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purine,

[0588] tert-Butyl 4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazine-1-carboxylate,

[0589] 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)ethan-1-one,

[0590] 1-(4-(2-(4-(9-benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenoxy)ethyl)piperazin-1-yl)hexan-1-one,

[0591] 9-benzyl-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0592] 1-(4-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperazin-1-yl)ethan-1-one,

[0593] 9-benzyl-8-(4-methyl-6-(2-(4-methylpiperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0594] (R)-1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)-N,N-dimethylpyrrolidin-3-amine,

[0595] 9-benzyl-8-(4-methyl-6-(piperazin-1-yl)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0596] 9-benzyl-8-(2-chloro-3-methoxyphenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0597] 9-benzyl-8-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0598] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(piperazin-1-yl)ethan-1-one,

[0599] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one,

[0600] 1-(4-((4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)methyl)piperidin-1-yl)ethan-1-one,

[0601] 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0602] 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2),

[0603] 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 1),

[0604] (R)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0605] (S)-9-Benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0606] 1-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one,

[0607] 3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propan-1-amine,

[0608] N-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)acetamide,

[0609] 1-(4-(2-(3-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-2-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one,

[0610] 9-benzyl-8-(2-chloro-3-((1-methylpiperidin-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0611] 9-benzyl-8-(2-chloro-3-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0612] 9-benzyl-8-(2-chloro-3-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0613] 9-benzyl-8-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0614] 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 1),

[0615] 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2),

[0616] (R)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0617] (S)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0618] 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one,

[0619] (R)-8-(4-(azetidin-2-ylmethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0620] (S)-9-Benzyl-8-(2-chloro-4-(pyrrolidin-3-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine

[0621] 9-benzyl-8-(2-chloro-4-(3-(piperazin-1-yl)propyloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0622] 9-benzyl-8-(2-chloro-4-((3-fluoroazetidin-3-yl)methoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0623] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N,N-dimethylacetamide,

[0624] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-methylacetamide,

[0625] 1-(4-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-1-yl)ethan-1-one,

[0626] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethan-1-amine,

[0627] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)acetic acid,

[0628] (R)-9-benzyl-8-(2-chloro-4-(pyrrolidin-2-ylmethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0629] N-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-hydroxyacetamide,

[0630] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)acetamide,

[0631] 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-(2-hydroxyethyl)acetamide,

[0632] (2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)glycine,

[0633] N-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-N-methylglycine,

[0634] 9-benzyl-8-(2-chloro-4-(((3S,4R)-4-fluoropyrrolidin-3-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0635] (R)-9-benzyl-8-(2-chloro-4-(piperidin-3-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0636] 9-benzyl-8-(2-chloro-4-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0637] 8-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0638] 8-(4-(azetidin-3-yloxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0639] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0640] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0641] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2,3-difluorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0642] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-phenethyl-9H-purine,

[0643] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-2-ylmethyl)-9H-purine,

[0644] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyrimidin-2-ylmethyl)-9H-purine,

[0645] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-2-ylmethyl)-9H-purine,

[0646] 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperidin-4-amine,

[0647] 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylazetidin-3-amine,

[0648] 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylpiperidin-4-amine,

[0649] 9-benzyl-8-(4-methyl-6-(3-(piperazin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0650] 3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine,

[0651] 1-(4-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)piperazin-1-yl)ethan-1-one,

[0652] 1-(4-(2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethyl)piperazin-1-yl)ethan-1-one,

[0653] 9-benzyl-8-(4-methyl-6-(3-(pyrrolidin-1-yl)propoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0654] 9-benzyl-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0655] 4-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)morpholine,

[0656] 2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethan-1-amine,

[0657] 3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propan-1-amine,

[0658] 1-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)azetidin-1-yl)ethan-1-one,

[0659] (S)-9-Benzyl-8-(4-methyl-6-(pyrrolidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0660] 2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylethan-1-amine,

[0661] (S)-9-Benzyl-8-(4-methyl-6-(piperidin-3-yloxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0662] 9-benzyl-8-(3-methyl-2-(2-(piperazin-1-yl)ethoxy)pyridin-4-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0663] (R)-2-(((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine,

[0664] (R)-3-(((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine,

[0665] 8-{6-[(azetidin-3-yl)oxy]-4-methylpyridin-3-yl}-9-benzyl-6-[(1-methylcyclopropyl)oxy]-9H-purine,

[0666] 9-benzyl-8-(2,6-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0667] 9-benzyl-8-(2-fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0668] 9-benzyl-8-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0669] 9-benzyl-8-(2,6-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0670] 9-benzyl-8-(2,3-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0671] 9-benzyl-8-(2-bromo-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0672] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-3-ylmethyl)-9H-purine,

[0673] 2-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)benzonitrile,

[0674] 9-benzyl-8-(2-ethynyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0675] (2-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)methanol,

[0676] 3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propanoic acid,

[0677] (2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-L-proline,

[0678] (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)pyrrolidin-3-ol,

[0679] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)azetidin-3-ol,

[0680] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-4-ol,

[0681] 2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol,

[0682] 1-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)azetidin-3-ol,

[0683] 8-(4-(2-(1,6-diazaspiro[3.3]hept-6-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0684] (S)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one,

[0685] 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide,

[0686] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-5-one,

[0687] (R)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one,

[0688] 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane,

[0689] 9-benzyl-8-(2,3-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0690] 9-benzyl-8-(2-chloro-5-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0691] 9-benzyl-8-(2-chloro-3-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0692] 9-Benzyl-8-(2,5-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0693] 9-(2-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0694] 9-(3-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0695] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutyloxy)-9-(pyridin-2-ylmethyl)-9H-purine,

[0696] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-3-yl)ethyl)-9H-purine,

[0697] (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-phenylpropyl)-9H-purine,

[0698] (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-phenylpropyl)-9H-purine,

[0699] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-2-yl)ethyl)-9H-purine,

[0700] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-phenethyl-9H-purine,

[0701] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0702] 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-4-ylmethyl)-9H-purine,

[0703] 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole,

[0704] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((5-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0705] 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole,

[0706] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0707] 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-2-methylthiazole,

[0708] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((6-methylpyridin-2-yl)methyl)-9H-purine,

[0709] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((4-(trifluoromethyl)pyridin-2-yl)methyl)-9H-purine,

[0710] 6-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)picolinonitrile,

[0711] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((6-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0712] 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)nicotinonitrile,

[0713] 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-5-methylthiazole,

[0714] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-4-yl)ethyl)-9H-purine,

[0715] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purine,

[0716] 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-5-methylthiazole,

[0717] 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)isonicotinonitrile,

[0718] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0719] 5-chloro-2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole,

[0720] 2-chloro-4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole,

[0721] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((5-methylpyridin-2-yl)methyl)-9H-purine,

[0722] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((3-methylpyridin-2-yl)methyl)-9H-purine,

[0723] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0724] 1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)azetidin-3-amine,

[0725] 1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)piperidin-4-amine,

[0726] 4-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)piperazin-2-one,

[0727] (E)-3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)acrylic acid,

[0728] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one,

[0729] 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chloro-N,N-dimethylbenzamide,

[0730] 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chloro-N-methylbenzamide,

[0731] (4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)(piperazin-1-yl)methanone,

[0732] 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorobenzamide,

[0733] 9-benzyl-8-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0734] 9-benzyl-8-(2-chloro-4-(piperazin-1-ylmethyl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0735] (4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)methanamine,

[0736] 9-benzyl-8-(2-chloro-4-methoxyphenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0737] 9-benzyl-8-(2-methoxypyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0738] 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutyloxy)-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole,

[0739] 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutyloxy)-1H-benzo[d]imidazole,

[0740] 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutyloxy)-3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridine,

[0741] 3-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutyloxy)-3H-imidazo[4,5-b]pyridine,

[0742] 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclopropyloxy)-9H-purine,

[0743] 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethylcyclopropyloxy)-9H-purine,

[0744] 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclobutyloxy)-9H-purine,

[0745] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-cyclopropyloxy-9H-purine,

[0746] 1-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile,

[0747] 2-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol,

[0748] (R)-1-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethyl)pyrrolidin-3-ol,

[0749] (S)-9-Benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0750] 8-(4-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0751] 3-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane,

[0752] (R)-9-benzyl-8-(2-chloro-4-(2-(3-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0753] (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-3-ol,

[0754] 2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,6-diazaspiro[3.4]octan-7-one,

[0755] (cis)-9-benzyl-8-(2-chloro-4-(2-(3,5-dimethylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0756] (S)-9-Benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0757] (R)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0758] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-2-one,

[0759] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 1),

[0760] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 2),

[0761] (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one,

[0762] (S)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one,

[0763] 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane,

[0764] 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,3-dimethylpiperazin-2-one,

[0765] 8-(4-(2-(4,7-diazaspiro[2.5]octan-7-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0766] (R)-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)methanol,

[0767] 8-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0768] 8-(4-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0769] (1S,4S)-2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2,5-diazabicyclo[2.2.2]octane,

[0770] 8-(4-(2-(4,7-diazaspiro[2.5]octan-4-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine,

[0771] (S)-2-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)acetonitrile,

[0772] 1-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one,

[0773] 4-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one,

[0774] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-cyclopropylpyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0775] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-ethylpyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0776] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2),

[0777] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine (Isomer 1),

[0778] (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0779] (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine,

[0780] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 2),

[0781] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 1),

[0782] (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine,

[0783] (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine,

[0784] 2-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenyl)acetamide,

[0785] (E)-3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenyl)acrylic acid,

[0786] 3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2,2-dimethylpropanoic acid,

[0787] 2-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethan-1-ol,

[0788] 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0789] 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (Isomer 1),

[0790] 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 2),

[0791] (R)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0792] (S)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0793] (S)-1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol,

[0794] (R)-1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol,

[0795] 1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol,

[0796] 2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenyl)acetamide,

[0797] 1-(3-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)azetidin-1-yl)-2-hydroxyethan-1-one,

[0798] 1-(3-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)azetidin-1-yl)ethan-1-one,

[0799] (S)-5-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)piperidin-2-one,

[0800] 5-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)tetrahydropyrimidin-2(1H)-one,

[0801] 5-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)pentanoic acid,

[0802] 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)butanoic acid,

[0803] 1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)-2-methylpropan-2-ol,

[0804] 2-(2-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethoxy)acetic acid.

[0805] (R)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0806] (S)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0807] 3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)propanoic acid,

[0808] (R)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid,

[0809] (S)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid,

[0810] (1s,3s)-3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)cyclobutane-1-carboxylic acid,

[0811] (R)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0812] (S)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid,

[0813] and pharmaceutically acceptable salts thereof.

[0814] It is to be understood that any definition, claim, aspect or embodiment disclosed herein for a variable group in a formula may be combined with any other definition, claim, aspect or embodiment herein (unless the context does not permit) to provide further embodiments of the present description.

[0815] Pharmaceutically acceptable acid addition salts can be formed with inorganic and organic acids, for example, acetate, aspartate, benzoate, benzenesulfonate, bromide / hydrobromide, bicarbonate / carbonate, bisulfate / sulfate, camphorsulfonate, chloride / hydrochloride, chlortheophyllonate, citrate, edisylate, fumarate, glucoheptonate, gluconate, glucuronate, hippurate, hydroiodide / iodide, isethionate, lactate, lactate, The esters of the present invention include hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate, hydroxybenzoate,

[0816] Pharmaceutically acceptable base addition salts can be formed with inorganic and organic bases. Inorganic bases from which salts can be derived include, for example, ammonia and salts of ammonium and metals from Groups I to XII of the Periodic Table of the Elements. In certain embodiments, salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium salts, potassium salts, sodium salts, calcium salts, 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, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine penicillin, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine, and tromethamine.

[0817] The pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from alkaline or acidic moieties by conventional chemical methods. Typically, such salts can be prepared by reacting the free acid forms of these compounds with a stoichiometric amount of a suitable base (such as Na + , Ca 2+ Mg 2 + or K +The present invention relates to a kind of pharmaceutical composition comprising the following: a) a hydroxyl group of ...

[0818] It should also be understood that certain compounds disclosed herein and their pharmaceutical salts can exist in solvated as well as unsolvated forms, such as, for example, hydrated forms and anhydrous forms. It should be understood that the compounds herein encompass all such solvated forms. For the sake of clarity, this includes solvated (e.g., hydrated) forms of the free form of the compound, as well as solvated (e.g., hydrated) forms of the salt of the compound.

[0819] Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms of the compounds disclosed herein. Isotopically labeled compounds have structures depicted by the formulas given herein, except that one or more atoms are replaced by atoms of the same element but with a different mass number. 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 I. Isotopically labeled compounds disclosed herein can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying examples, using an appropriate isotopically labeled reagent in place of the non-labeled reagent previously employed.

[0820] Compounds disclosed herein can have different isomeric forms. The terms "optical isomers," "stereoisomers," "enantiomers," or "diastereoisomers" refer to any of the various stereoisomeric configurations that may exist for a given compound disclosed herein. It should be understood that substituents may be attached to the chiral center of a carbon atom, and therefore, the disclosed compounds include enantiomers, diastereomers, and racemates. The term "enantiomer" includes paired stereoisomers that are non-superimposable mirror images of each other. A 1:1 mixture of a pair of enantiomers is a racemic mixture. Where appropriate, the (+ / -) term is used to represent a racemic mixture. The term "diastereomer" includes stereoisomers that have at least two asymmetric atoms but that are not mirror images of each other. Absolute stereochemistry is specified according to the Cahn-Ingold-Prelog RS system. When a compound is a pure enantiomer, the stereochemistry of each chiral center can be specified by R or S. The unknown splitting compound of absolute configuration can be designated as (+) or (-) according to the direction (right-handed or left-handed) of rotating plane polarized light at the wavelength of the sodium D line. Certain compounds disclosed herein have been separated or prepared as single enantiomers, but have unknown absolute configuration. 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 an R or S enantiomer. For example, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine or (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine , and 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine or (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine.

[0821] It will be understood that one skilled in the art can determine optical rotation and / or absolute stereochemistry. It will be understood that such disclosures include other stereoisomeric forms of the same compound, as well as stereoisomeric mixtures. Certain compounds disclosed herein contain one or more asymmetric centers or axes and, therefore, can produce enantiomers, diastereomers, or other stereoisomeric forms that can be defined as (R)- or (S)- based on absolute stereochemistry. This disclosure is intended 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).

[0822] Pharmaceutical composition

[0823] In some embodiments, disclosed are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable carrier.

[0824] The term "pharmaceutically acceptable carrier" includes compounds, materials, compositions and / or dosage forms that are recognized by those skilled in the art to be suitable for use in contact with the tissues of humans and animals without excessive toxicity, irritation, allergic response, or other problems or complications within the scope of sound medical judgment.

[0825] 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), in a form suitable for topical use (e.g., as a cream, ointment, gel, or aqueous or oily solution or suspension), in a form suitable for administration by inhalation (e.g., as a finely divided powder or liquid aerosol), in a form suitable for administration by insufflation (e.g., as a finely divided powder), or in a form suitable 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).

[0826] 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 being treated and the particular route of administration. For further information on routes of administration and dosage regimens, the reader is referred to Volume 5, Chapter 25.3 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

[0827] 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, for example, as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).

[0828] Pharmaceutical preparations suitable for oral administration may include one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules can be prepared with adhesives, 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 may be encapsulated in, for example, 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 made, for example, by filling a compound of formula (I) into a gelatin or hydroxypropyl methylcellulose (HPMC) shell.

[0829] Therapeutic uses

[0830] The term "subject" includes warm-blooded mammals, such as primates, dogs, cats, rabbits, rats, and mice. In some embodiments, the subject is a primate, such as a human. In some embodiments, the subject has 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 has cancer.

[0831] The terms "treat" and "relieve" refer to (1) therapeutic measures that cure, slow, alleviate the symptoms of, and / or halt the development of a diagnosed pathological condition or disorder, and (2) prophylactic measures that prevent and / or slow the development of a targeted pathological condition or disorder. Thus, those in need of treatment include those already suffering from the disorder; those susceptible to the disorder; and those in need of prevention of the disorder. In certain aspects, this includes improving one or more symptoms of cancer, or slowing or delaying the progression of cancer in a subject. The terms "treat" and "relieve" also include reducing or inhibiting the growth of a tumor or the proliferation of cancer cells in a subject. In certain aspects, a subject's cancer is successfully "treated" according to the methods of the present disclosure if the patient shows, for example, complete, partial, or transient remission of a certain type of cancer.

[0832] 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 certain 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 exhibits homologous recombination repair deficiency (HRD).

[0833] 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 comprising a BRCA1 and / or BRCA2 mutation. In other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer comprising a BRCA1 mutation. In yet other embodiments, the cancer is breast cancer, ovarian cancer, pancreatic cancer, or prostate cancer comprising a BRCA2 mutation.

[0834] 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 breast cancer. In other 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.

[0835] 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 ovarian cancer. In other 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.

[0836] 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 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.

[0837] 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 prostate cancer. In other 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.

[0838] 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 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.

[0839] In some embodiments, there is provided a method for treating cancer in a subject in need thereof, the method 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 primary and secondary solid tumors. In 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.

[0840] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method 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 mutation (ATM) mutation-positive. In certain embodiments, the ATM mutation-positive cancer is a hematological cancer, such as a leukemia or lymphoma. In certain embodiments, the ATM mutation-positive cancer is an 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.

[0841] 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 positive for a mutation in a gene encoding a Fanconi anemia (FA) protein or a 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).

[0842] 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 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 (chaperone and localization protein of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (Nibrin), and EMSY.

[0843] 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 positive for mutations in one or more genes associated with the double-strand break (DSB) repair pathway, including 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, FB XO18, FEN1, GADD45A, GINS1, GTF2H2, GTF2H3, GTF2H4, HDAC2, HDAC3, HDAC4, HELQ, INIP, INO80C, KDM4B, LIG3, LMO4, MAD2L2, MBD4, MGMT, MLH1, MNA T1, MPG, MRE11A, MSH2, MSH6, MTBP, MUTYH, 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, R EV1, 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.

[0844] 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 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 exhibits homologous recombination repair deficiency (HRD).

[0845] 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.

[0846] 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 breast cancer. In other 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.

[0847] 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 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.

[0848] 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 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.

[0849] 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 prostate cancer. In other 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.

[0850] 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 a 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.

[0851] 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 a cancer in a subject in need thereof, wherein the method includes treating a subject with primary and secondary solid tumors. In other embodiments, the method includes treating a subject with a primary solid tumor. In yet other embodiments, the method includes treating a subject with a secondary solid tumor.

[0852] 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 a cancer in a subject in need thereof, wherein the cancer is ataxia telangiectasia mutation (ATM) mutation-positive. In certain embodiments, the ATM mutation-positive cancer is a hematological cancer, such as a leukemia or lymphoma. In certain embodiments, the ATM mutation-positive cancer is an 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.

[0853] In some embodiments, provided are compounds of formula (I), compounds disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts 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 a 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).

[0854] 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 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 (chaperone and localization protein of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (Nibrin), and EMSY.

[0855] 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 positive for a mutation in one or more genes associated with the double-strand break (DSB) repair pathway, including AICDA, ALKBH3, APOBEC2, APOBEC4, APTX, ATF2, ATM, AURKA, BARD1, BRCA2, BRIP1, CBX3, CCNH, CDC16, CDC25A, CDC25B, CDC45, CDKN1A, CDKN2A, CHEK2, CL K2, CLSPN, CUL4A, CUL5, DCLRE1A, DCLRE1C, DDB1, DKC1, DNMT3A, DNMT3B, DUT, EME2, ENDOV, EP300, ERCC4, ERCC5, FAN1, FANCG, FANCL, FBXO18, FE N1, GADD45A, GINS1, GTF2H2, GTF2H3, GTF2H4, HDAC2, HDAC3, HDAC4, HELQ, INIP, INO80C, KDM4B, LIG3, LMO4, MAD2L2, MBD4, MGMT, MLH1, MNAT1, MPG , MRE11A, MSH2, MSH6, MTBP, MUTYH, 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, S WI5, TDG, TELO2, THOC1, TICRR, TNKS, TNKS2, TOP1, TOP2A, TOP3A, TOP3B, TREX2, TRP53BP1, UBE2N, UNG, UVSSA, WRN, XAB2, XRCC2, XRCC3 and / or XRCC5.

[0856] Combination therapy

[0857] The compounds of formula (I), compounds disclosed herein, stereoisomers thereof, or pharmaceutically acceptable salts thereof may also be administered in combination with other compounds useful in treating the above-mentioned conditions.

[0858] 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 second active ingredient, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture.

[0859] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method 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 specific 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 other embodiments, the PARP inhibitor is niraparib, and the cancer is ovarian cancer. In other embodiments, the PARP inhibitor is rucaparib and the cancer is ovarian cancer or prostate cancer. In other embodiments, the PARP inhibitor is talazoparib and the cancer is breast cancer or prostate cancer.

[0860] 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).

[0861] 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).

[0862] In some embodiments, there is provided a method for treating cancer in a subject in need thereof, the method 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 and an antibody drug conjugate, wherein the compound and the antibody drug conjugate are administered simultaneously, sequentially, or in combination. In certain embodiments, the antibody drug conjugate is trastuzumab (T-DXd). In certain embodiments, the antibody drug conjugate is a topoisomerase antibody drug conjugate. In specific embodiments, the cancer is breast cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

[0863] In some embodiments, a method of treating cancer in a subject in need thereof is provided, the method 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 anticancer drug, wherein the compound and the platinum anticancer drug are administered simultaneously, sequentially, or in admixture. In certain embodiments, the platinum anticancer drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, triplatin tetranitrate, picoplatin, or satraplatin.

[0864] 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 anticancer drug are administered simultaneously, sequentially, or in combination. In certain embodiments, the taxane is docetaxel.

[0865] 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 immunotherapy, wherein the compound and the immunotherapy are administered simultaneously, sequentially, or in admixture. In certain embodiments, the immunotherapy is an antibody, such as durvalumab. In specific embodiments, the immunotherapy is durvalumab, and the cancer is non-small cell lung cancer (NSCLC).

[0866] 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 combination with a second active ingredient in treating cancer in a subject in need thereof, wherein the compound and the second active ingredient are administered simultaneously, sequentially, or in admixture.

[0867] 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 combination with a PARP inhibitor in treating cancer in a subject in need thereof, 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 other embodiments, the PARP inhibitor is rucaparib, and the cancer is ovarian cancer or prostate cancer. In other embodiments, the PARP inhibitor is talazoparib and the cancer is breast cancer or prostate cancer.

[0868] 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 combination with an ATR inhibitor in treating cancer in a subject in need thereof, 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).

[0869] 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 combination with a DNA-PK inhibitor in treating cancer in a subject in need thereof, 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).

[0870] 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 combination with an antibody drug conjugate for treating a cancer in a subject in need thereof, wherein the compound and the antibody drug conjugate are administered simultaneously, sequentially, or in combination. In certain embodiments, the antibody drug conjugate is trastuzumab (T-DXd). In certain embodiments, the antibody drug conjugate is a topoisomerase antibody drug conjugate. In specific embodiments, the cancer is breast cancer, gastric cancer, or non-small cell lung cancer (NSCLC).

[0871] 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 combination with a platinum anticancer drug in treating a cancer in a subject in need thereof, wherein the compound and the platinum anticancer drug are administered simultaneously, sequentially, or in combination. In certain embodiments, the platinum anticancer drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, triplatin tetranitrate, picoplatin, or satraplatin. In specific embodiments, the platinum anticancer drug is carboplatin.

[0872] 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 combination with a taxane in treating cancer in a subject in need thereof, wherein the compound and the platinum anticancer drug are administered simultaneously, sequentially, or in admixture. In certain embodiments, the taxane is docetaxel.

[0873] 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 combination with an immunotherapy in treating cancer in a subject in need thereof, wherein the compound and the immunotherapy are administered simultaneously, sequentially, or in admixture. In certain embodiments, the immunotherapy is an antibody, such as durvalumab. In specific embodiments, the immunotherapy is durvalumab, and the cancer is non-small cell lung cancer (NSCLC).

[0874] Another aspect of the present disclosure provides a method for preparing a compound of formula (I) or a pharmaceutically acceptable salt thereof. Suitable methods are illustrated by the following representative method variations, wherein, unless otherwise stated, G, 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 meaning defined herein before. The necessary starting materials can be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative method variations and in the accompanying examples. Alternatively, the necessary starting materials can be obtained by procedures similar to those described, which are within the ordinary skill of organic chemists.

[0875]

[0876] The compound of formula (I) can be prepared, for example, by the following method:

[0877] a) 1. by making another compound of formula (I) (wherein Q 1 , Q 2 or Q 3 is C-OH) with a primary or secondary alcohol under conditions known in the art for a Mitsunobu reaction (e.g., Example 1);

[0878] Or by reaction with a primary or secondary halide under typical nucleophilic substitution conditions (e.g., a suitable solvent such as DMA or DMF) in the presence of a suitable base (e.g., potassium carbonate or cesium carbonate) at a suitable temperature (0°C to 120°C) with or without protecting groups for other functional groups.

[0879] 2. by making another compound of formula (I) (wherein Q 1 , Q 2 or Q 3 is C-LG, LG is a leaving group such as a halogen) is reacted with a suitable amine (e.g., Example 19) under conditions known in the art, optionally catalyzed by a metal complex (such as a palladium catalyst suitable for Buchwald-Hartwig amination reactions).

[0880] 3. by making another compound of formula (I) (wherein Q 1 , Q 2 or Q 3 is C-LG, LG is a leaving group such as a halogen) is reacted with a suitable alcohol (e.g., Example 20) under conditions known in the art (e.g., in the presence of a strong base such as sodium hydride to form an alkoxide), optionally catalyzed by a metal complex suitable for ether-forming reactions such as a palladium catalyst (e.g., RockPhos PdG3).

[0881] More generally, compounds of formula (I) can be prepared from compounds of formula (I) (eg, amide coupling as in Example N1, reductive amination as in Example N6).

[0882] where Q 1 , Q 2 or Q 3 is C-OH or where Q 1 , Q 2 or Q 3 The compound of formula (I) C-LG can be prepared by the method described below

[0883] b) When G a It's CR 5 And R 5 yes When, by reacting another compound of formula (II) with a compound of formula (III), wherein LG is a leaving group known in the art, for example, a halide such as F, Cl or Br, or trifluoromethanesulfonate (triflate). The reaction conditions are in the presence of a suitable base (for example, sodium hydride or LHMDS) and a suitable temperature (such as 0° C. to ambient temperature), with or without protecting groups for other functional groups, and a suitable solvent (for example, THF) can be used.

[0884]

[0885] The compound of formula (II) can be prepared by reacting a compound of formula (IV) with a compound of formula (V). The reaction conditions relate to the one-step procedure described in paragraph (d). This reaction can be converted into a two-step procedure to isolate the intermediate compound of formula (VI). The reaction conditions are described in paragraph (d).

[0886] 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 paragraph (d).

[0887]

[0888] Alternatively, compounds of formula (IV) can be prepared by reaction of formula (IVa) by reducing the nitro group to an amino group as described in paragraph (d)

[0889]

[0890] When X = CH2, compounds of formula (IVa) can be prepared by reaction between compounds of formula (VII) and compounds of formula (VIIIa) under conditions known in the art to be suitable for reductive amination.

[0891] Alternatively, the compound of formula (IVa) can be prepared by the reaction between a compound of formula (VIIa) and a compound of formula (VIII). The reaction conditions are in the presence of a base (such as triethylamine) and a suitable temperature (e.g. room temperature), and an inert solvent (e.g. DMF) can be used.

[0892]

[0893] Alternatively, compound (II) can be obtained by reacting a compound of formula (IIa) with a compound of formula (VIIIb) under conditions known in the art to be suitable for nucleophilic substitution, or by reacting a compound of formula (IIa) with a compound of formula (VIIIc) under conditions known in the art to be suitable for Mitsunobu reaction.

[0894]

[0895] c) When G b It's CR 5 And R 5 yes by reacting another compound of formula (IX) with a compound of formula (X) under conditions known in the art to be suitable for Mitsunobu reactions,

[0896] Or by reacting another compound of formula (IX) with a compound of formula (Xa) to undergo a nucleophilic substitution reaction, wherein LG is a leaving group known in the art, for example, a halide (such as Cl, Br or I). The conditions for the nucleophilic substitution reaction are in the presence of a suitable base (e.g., potassium carbonate) and a suitable temperature (between 0° C. and 120° C.), with or without protecting groups for other functional groups, and a suitable solvent (e.g., acetonitrile, DMF or DMA) can be used.

[0897]

[0898] Compounds of formula (IX) can be prepared by reacting compounds of formula (XI) with compounds of formula (V) with or without protecting groups for the hydroxyl groups.

[0899] Compounds of formula (IX) can also be prepared by reacting compounds of formula (XIa) with compounds of formula (V) with or without protecting groups for the hydroxyl groups.

[0900] Alternatively, compounds of formula (XI) can be prepared from compounds of formula (XIa) by reducing the nitro group to an amino group.

[0901] The conditions for the above reaction are described in paragraph (d).

[0902]

[0903] Compounds of formula (XIa) can be prepared by reacting a compound of formula (XII) with a compound of formula (VIII), wherein LG is a leaving group known in the art, for example a halide (such as F or Cl) or trifluoromethanesulfonate (triflate); with or without a protecting group for the hydroxy group.

[0904]

[0905] d) by reacting a compound of formula (XIII) with a compound of formula (V). The reaction conditions relate to a one-step procedure and can use a suitable solvent (e.g., EtOH, isopropanol, dioxane, or DMSO) and a suitable temperature (60° C. to 120° C.), optionally in the presence of a mild oxidant (e.g., 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 in Example 8). The reaction can be converted in a two-step procedure to isolate an intermediate compound of formula (XIV), wherein a mild oxidant (e.g., iron (III) chloride and / or oxygen) is added in the second step.

[0906] Alternatively, by reacting a compound of formula (XIIIa) with a compound of formula (V) in the presence of a mild reducing agent such as sodium dithionite (also known as sodium dithionite) at a suitable temperature (e.g., 80° C. to 120° C.), a suitable solvent (e.g., NMP and water) may be used.

[0907] Alternatively, compounds of formula (XIII) can be prepared from compounds of formula (XIIIa) by reducing the nitro group to the amino group (for example in the presence of iron with a suitable solvent such as ethanol)

[0908]

[0909] Compounds of formula (XIIIa) can be prepared by reacting a compound of formula (XV) with another compound of formula (VIII), wherein LG is a leaving group known in the art, for example, a halide (such as F or Cl) or trifluoromethanesulfonate (triflate) or mesyl.

[0910]

[0911] When G a It's CR 5 And R 5 yes When the compound of formula (XIIIa) is substituted with the compound of formula (IVa), the compound of formula (III) can be prepared by reacting the compound of formula (XIIIa) with the compound of formula (III). The reaction conditions are in the presence of a suitable base (e.g., sodium hydride or LHMDS) and a suitable temperature (e.g., around ambient temperature), with or without protecting groups for other functional groups, and a suitable solvent (e.g., THF) can be used.

[0912]

[0913] When G a It's CR 5 And R 5 yes When the compound of formula (XIIIa) is prepared, the compound of formula (XIIIa) can also be prepared by reacting another compound of formula (XVI) with a compound of formula (III) under conditions known in the art to be suitable for Mitsunobu reaction.

[0914] Or by reacting another compound of formula (XVI) with a compound of formula (IIIa) (nucleophilic substitution), wherein LG is a leaving group known in the art, for example, a halide (such as Cl, Br or I). The conditions for the nucleophilic substitution reaction are in the presence of a suitable base (such as potassium carbonate) and a suitable temperature (between 0° C. and 120° C.), with or without protecting groups for other functional groups, and using a suitable solvent (such as acetonitrile, DMF or DMA).

[0915]

[0916] A compound of formula (XVI) can be prepared by reacting another compound of formula (XVII) with another compound of formula (VIII) with or without protecting groups for hydroxyl and other functional groups.

[0917]

[0918] (e) by reacting a compound of formula (XVIII) (when LG is a leaving group known in the art, such as a halide (such as Cl, Br or I)) with a compound of formula (XIX) (when FG is a functional group suitable for a cross-coupling reaction (such as a Suzuki reaction), such as a borate ester or a boronic acid). The reaction conditions are described in Example 5.

[0919]

[0920] Compounds of formula (XVIII) can be prepared, for example, from compounds of formula (XX) by bromination as described in Example 5 (when LG is Br).

[0921]

[0922] (f) is prepared by reaction between a compound of formula (XXI) and a compound of formula (VIIIb) under conditions known in the art to be suitable for nucleophilic substitution (eg, Example 23).

[0923] Or prepared by the reaction between a compound of formula (XXI) and a compound of formula (VIIIc) under conditions known in the art to be suitable for Mitsunobu reaction.

[0924]

[0925] It will be appreciated that compounds of formula (XXI), similarly to compounds of formula (I), can be prepared by the reactions already described in paragraphs (a) to (e).

[0926] Example

[0927] The compounds described in this specification are further illustrated in the following examples. These examples are given by way of illustration only and are non-limiting. In general:

[0928] General experimental conditions and abbreviations

[0929] The compounds described in this specification are further illustrated in the following examples. Compounds were named using Chemdraw 20.0.2.51. These examples are provided by way of illustration only and are non-limiting. In general:

[0930] Reagents and solvents (all anhydrous HPLC grade) were obtained from commercial suppliers and used without any further purification unless otherwise stated. Unless otherwise stated, all reagents were weighed and handled in air. Brine refers to a saturated solution of NaCl. Concentration under reduced pressure refers to the use of a rotary evaporator.

[0931] Unless otherwise stated, operations were performed at ambient temperature, ie in the range of 17°C to 25°C, and under an atmosphere of inert gas, such as nitrogen.

[0932] The work-up procedure was carried out by rotary evaporation under reduced pressure, using a warm or hot water bath or in vacuo using a Genevac apparatus or a Biotage v10 evaporator and after removal of the residual solid by filtration.

[0933] In automated Teledyne Isco with integrated UV detection Rf, Teledyne Isco or Flash chromatography purifications were performed on an MP200 system using pre-packed silica gel columns (40 μm to 60 μm) or C18 spherical columns (20 μm to 35 μm) using chromatographic conditions as detailed in the corresponding experimental data.

[0934] Preparative reversed-phase HPLC was performed on the following systems: an Agilent 1290 Infinity II preparative system equipped with an SQ MS detector (multimodal ESI / APCI source) with a Waters CSH C18 OBD column (5 μm silica, 30 mm diameter, 100 mm length); a Waters MassLynx system with integrated MS detection with an XBridge or Xselect CSH Prep C18 OBD column (5 μm silica, 30 mm diameter, 150 mm length); a Gilson GX-281 system with integrated UV detection with an XBridge (10 μm, 19 mm diameter, 150 mm length) or Sunfire C18 column (10 μm, 19 mm diameter, 250 mm length) using water (containing 0.1%-0.3% ammonia), water (containing 0.05% ammonia and 10 mmol NH4HCO3), water (containing 0.1% formic acid), or water (containing 0.05% TFA) and decreasingly polar mixtures of acetonitrile or methanol were used as eluents.

[0935] Preparative SFC purifications were performed on a Sepiatec P100 SFC system equipped with a QDa MS detector or a Waters Prep 100 SFC system using chromatographic conditions as detailed in the corresponding experimental data.

[0936] Preparative chiral HPLC was performed using a Gilson GX-281 system with integrated UV detection and equipped with one of the following columns of different column dimensions (250×20 mm, 250×30 mm): 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.), CHIRAL Cellulose-SB, SC, SA columns (YMC Co., Ltd.), with the specified percentage of ethanol in hexane (% Et / Hex) or isopropanol in hexane (% IPA / Hex) as the isocratic solvent system.

[0937] The yield, if any, is not necessarily the maximum achievable.

[0938] In general, the structure of the final product of Formula I was confirmed by nuclear magnetic resonance (NMR) spectroscopy; 1 H-NMR chemical shift values are measured on the δ scale and are expressed in ppm relative to TMS or the residual solvent peak as an internal standard. Proton magnetic resonance spectra were determined using a Bruker Avance 500 spectrometer at a proton frequency of 500 MHz, using a Bruker Avance 400, Bruker Avance III HD, or Bruker Avance Neo spectrometer at a proton frequency of 400 MHz, or using 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 indicated. The following abbreviations are used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublets; dt, doublet of triplets; br s, broad signal; hept, septet.

[0939] In general, the final product of Formula I is also characterized by liquid chromatography (LCMS or UPLC) followed by mass spectrometry; using reversed-phase C18 silica at a flow rate of 1 mL / min, and detecting by electrospray mass spectrometry and recording UV / vis absorbance in the wavelength range of 220 nm to 320 nm. Analytical UPLC is performed using a Waters Acquity UPLC CSH C18 column with dimensions of 2.1×50 mm and a particle size of 1.7 microns. Gradient analysis is performed using a mixture of decreasing polarity as the eluent, such as a gradient using water (containing 0.1% v / v formic acid or 0.3% v / v ammonia) as solvent A and acetonitrile as solvent B. A typical 1.7-minute analytical UPLC method would employ the following solvent gradient: from a 97:3 mixture of solvents A and B to a 3:97 mixture of solvents A and B, respectively, over 1.3 min at 1 mL / min. Additionally, LCMS was performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode, equipped with a 20ADXR pump, a SIL-20ACXR autosampler, a CTO-20AC column oven, an M20A PDA detector, and an LCMS2020MS detector. LC was run in two setups: 1) a Halo C18 column (2.0 μm 3.0×30 mm) in combination 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 minutes) at a flow rate of 1.5 mL / min; 2) a Poroshell HPH C18 column (2.7 μm 3.0×50 mm) in combination with a gradient of 46 mM aqueous ammonium carbonate / ammonia buffer at pH 10 (A) and MeCN (B) (5% to 95% B in 2 minutes) at a flow rate of 1.2 mL / min; 3) a Halo C18 column (2.0 μm 3.0×30 mm) in combination with water and TFA (0.05%) (A) and a gradient of CH3CN and TFA (0.05%) (5% to 95% B in 2 minutes) at a flow rate of 1.2 mL / min. B, in 2 minutes) at a flow rate of 1.5 mL / min (B). The column oven (CTO-20AC) temperature was 40.0°C. The injection volume was 1 μL. The PDA (SPD-M20A) detection range was 190 nm to 400 nm. MS detector, which was configured with electrospray ionization as the ionizable source; acquisition mode: scan; nebulizing gas flow: 1.5 L / min; drying gas flow: 15 L / min; detector voltage: tuning voltage ± 0.2 kV; DL temperature: 250°C; heating block temperature: 250°C; scanning range: 90.00 m / z-900.00 m / z. It should be understood that, unless otherwise stated, the reported molecular ions correspond to [M+H]+, rounded to the lower unit. Unless otherwise stated, in general: for molecules with multiple isotopic patterns (e.g.35 Cl, 79 Br, 12 C), only the lowest common isotope is reported.

[0940] Ion exchange purification was typically performed using an SCX-2 (Biotage, propanesulfonic acid functionalized silica. Made using trifunctional silane. Non-endcapped) column.

[0941] The purity of the intermediates was assessed by thin layer chromatography, mass spectrometry, HPLC (high performance liquid chromatography) and / or NMR analysis.

[0942] The following abbreviations are used

[0943] Ac2O acetic anhydride

[0944] AcOH acetic acid

[0945] aq. aqueous solution

[0946] BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl

[0947] BOC tert-Butoxycarbonyl

[0948] Cbz benzyloxycarbonyl

[0949] DCM dichloromethane

[0950] DEA Diethylamine

[0951] DIAD Diisopropyl azodicarboxylate

[0952] DIEA Diisopropylethylamine

[0953] DMA N,N-dimethylacetamide

[0954] DMF N,N-dimethylformamide

[0955] DMSO dimethyl sulfoxide

[0956] Et2O ether

[0957] EtOAc

[0958] EtOH

[0959] h hour

[0960] HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate

[0961] HOBt 1-Hydroxybenzotriazole

[0962] HPLC high-performance liquid chromatography

[0963] IPA or iPrOH Isopropyl alcohol

[0964] LCMS liquid chromatography-mass spectrometry

[0965] LHMDS Lithium bis(trimethylsilyl)amide

[0966] MeCN Acetonitrile

[0967] MeI methyl iodide

[0968] MeOH methanol

[0969] min

[0970] Ms2O Methanesulfonic anhydride

[0971] MTBE methyl tert-butyl ether

[0972] NMP 1-Methyl-2-pyrrolidone

[0973] m / z mass-to-charge ratio

[0974] NMR Nuclear Magnetic Resonance

[0975] PDA Photodiode Array

[0976] Pd2(dba)3 tris(dibenzylideneacetone)dipalladium(0)

[0977] PdCl2(dppf) [1,1'-bis(diphenylphosphino)ferrocene]palladium(II) dichloride

[0978] PdCl2(PPh3)2 Bis(triphenylphosphine)palladium(II) dichloride

[0979] Pd(PPh3)4 Palladium-tetrakis(triphenylphosphine)

[0980] PPh3 triphenylphosphine

[0981] RockPhos Pd G3 [(2-di-tert-butylphosphino-3-methoxy-6-methyl-2',4',6'-triisopropyl-1,1'-biphenyl)-2-(2-aminobiphenyl)]methanesulfonate Palladium(II)

[0982] rac racemic

[0983] rac-BINAP Pd G3 See CAS number: 2151915-22-7

[0984] rt / RT room temperature

[0985] scCO2 supercritical carbon dioxide

[0986] SCX Strong Cation Exchanger

[0987] SFC Supercritical Fluid Chromatography

[0988] T3P Propylphosphonic Anhydride

[0989] TBAF Tetra-n-butylammonium fluoride

[0990] TBDPS tert-Butyldiphenylsilyl

[0991] TEA triethylamine

[0992] tert uncle

[0993] TFA trifluoroacetic acid

[0994] THF Tetrahydrofuran

[0995] TLC thin layer chromatography

[0996] TMS Tetramethylsilane

[0997] UPLC ultra-performance liquid chromatography

[0998] UV

[0999] Example 1

[1000] 9-Benzyl-6-isopropoxy-8-(2-methyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9H-purine

[1001]

[1002] Under nitrogen, DIAD (0.260 mL, 1.34 mmol) was added dropwise to 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 PPh (392 mg, 1.50 mmol) in THF (20 mL) at 0° C. The resulting mixture was stirred at rt for 16 hours. 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 decreasingly polar mixtures of water (containing 0.05% aqueous NH) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 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 HNMR(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.

[1003] 4-(9-Benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol used as a starting material was prepared as follows:

[1004] N4-Benzyl-6-chloropyrimidine-4,5-diamine

[1005]

[1006] A mixture of benzylamine (47.0 g, 439 mmol) and triethylamine (74.0 g, 732 mmol) was added dropwise to 4,6-dichloropyrimidine-5-amine (60 g, 366 mmol) in DMA (400 mL) at 100 ° C over a period of 20 minutes 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 light yellow solid.

[1007] 1H 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.

[1008] 4-(9-Benzyl-6-chloro-9H-purin-8-yl)-3-methylphenol

[1009]

[1010] 4-hydroxy-2-methylbenzaldehyde (580mg, 4.26mmol) is added to N4-benzyl-6-chloropyrimidine-4,5-diamine (500mg, 2.13mmol) in 1,4-dioxane (40mL) and iron (III) chloride (6.91g, 6.39mmol) supported on silica gel. The resulting mixture is stirred at 100 ° C for 3 days. The solvent is removed under reduced pressure. The filtrate is collected by filtration, the precipitate is washed with EtOAc (100mL), and dried under vacuum to obtain a crude product. The crude product is purified by fast C18 flash chromatography, and the elution gradient is 5% to 80% MeCN in water (containing 0.05% NH4HCO3). The pure fraction is evaporated to dryness to obtain 4- (9-benzyl-6-chloro-9H-purine-8-yl) -3-methylphenol (230mg, 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.

[1011] 4-(9-Benzyl-6-isopropoxy-9H-purin-8-yl)-3-methylphenol

[1012]

[1013] NaH (50.2 mg, 1.25 mmol) was added in batches to 4- (9-benzyl-6-chloro-9H-purine-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 rt for 2 hours. 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-purine-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.

[1014] Example 2

[1015] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-isopropoxy-1H-benzo[d]imidazole

[1016]

[1017] By 2-(2-chloro-4-(2-(4-methylpiperazine-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo [d] imidazole-5-ol (125mg, 0.24mmol), 2-bromopropane (0.046mL, 0.49mmol) and potassium carbonate (169mg, 1.22mmol) are suspended in acetonitrile (5mL) and sealed in microwave tube.The reaction is heated to 100 ℃ for 12 hours in a microwave reactor and cooled to room temperature.Solids are removed by filtration and the filtrate is evaporated to dryness.The crude product is passed through preparative HPLC (Waters CSH C18 OBD column, 5 μm silica, 30mm diameter, 100mm length) using a decreasing polarity mixture of water (containing 1% ammonia) and MeCN as eluent. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-isopropoxy-1H-benzo[d]imidazole (14 mg, 10%). 1H 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.

[1018] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol used as starting material was prepared as follows:

[1019] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole

[1020]

[1021] A solution of crude 2-chloro-4-(2-(4-methylpiperazine-1-yl)ethoxy)benzaldehyde (578 mg, 1.02 mmol) in NMP (3 mL) was added once to a stirred suspension of N-(3-chlorobenzyl)-4-methoxy-2-nitroaniline (299 mg, 1.02 mmol, purchased 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 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed successively with saturated 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 gel chromatography with a gradient of 0% to 20% MeOH in DCM and ammonia as the modifier. Pure fractions were evaporated to dryness to afford 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 purified by preparative HPLC (Waters CSHC18 OBD column, 5 μm silica, 30 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% aqueous NH 3 ) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-5-methoxy-1H-benzo[d]imidazole as a white solid (92 mg, 17%). 1 H 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.

[1022] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol

[1023]

[1024] 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) was added dropwise under nitrogen over a period of 2 minutes at 0°C. The resulting suspension was stirred at room temperature for 35 minutes. The reaction mixture was quenched with 2M HCl (5 mL) and evaporated to remove DCM. DMSO (2 mL) was added, and the resulting solution was purified by flash reverse-phase silica gel chromatography with an elution gradient of 5% to 95% MeCN in water and 0.1% formic acid as the 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. 1 HNMR(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(2 H,td),6.87(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.

[1025] 2-Chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde used as starting material is described in Example 4.

[1026] Example 3

[1027] 3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propan-1-amine

[1028]

[1029] At 0 ° C, TFA (2mL, 25.96mmol) was slowly added to tert-butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate (100mg, 0.18mmol) in DCM (5mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was evaporated to a crude oil. The crude product was purified by preparative HPLC (XBridge Shield RP18 OBD column, 5μm silica, 30mm diameter, 150mm length) using a decreasing polarity mixture of (containing 0.05% aqueous NH3) and MeCN as eluent. Fractions containing the desired compound were evaporated to dryness to afford 3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propan-1-amine (27 mg, 33%) as a yellow oil which solidified upon standing. 1 HNMR (400 MHz, CDCl3): 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). 2H was not observed. m / z: ES+[M+H]+450.

[1030] 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:

[1031] N-Benzyl-4-isopropoxy-2-nitroaniline

[1032]

[1033] At rt, benzylamine (2.37g, 22.1mmol) is slowly added to DIEA (7.02mL, 40.2mmol) and 1-fluoro-4-isopropoxy-2-nitrobenzene (4g, 20.1mmol, commercially available) in DMA (10mL). The resulting mixture is stirred at 100°C for 18 hours and cooled to rt. The reaction mixture is poured into water (50mL) and extracted with EtOAc (3×50mL). The organic layer is washed with saturated NH4Cl (20mL×1), saturated NaHCO3 (20mL×1) and saturated brine (20mL×1) successively. The organic layer is dried over Na2SO4, filtered and evaporated to obtain crude material. The residue is purified by preparative TLC (petroleum ether: EtOAc=1:6) to obtain N-benzyl-4-isopropoxy-2-nitroaniline (4.50g, 78%) as a red oil, which solidifies when standing. 1 HNMR(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.

[1034] 4-(1-Benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol-Example A1

[1035]

[1036] At rt, 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). The resulting mixture was stirred at 100 ° C for 18 hours. The reaction mixture was poured into saturated brine (75 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na SO , filtered and evaporated to give a yellow gum. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 100% petroleum ether in EtOAc. Pure fractions were evaporated to dryness to afford 4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenol (2.30 g, 56%) as a yellow oil which solidified on standing. 1H 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.

[1037] tert-Butyl (3-(4-(1-benzyl-5-isopropoxy-1H-benzo[d]imidazol-2-yl)-3-chlorophenoxy)propyl)carbamate - Example A2

[1038]

[1039] Under nitrogen, at 0 ° C, DIAD (1.00 g, 4.96 mmol) was added dropwise to 4- (1-benzyl-5-isopropoxy-1H-benzo [d] imidazole-2-yl) -3-chlorophenol (1.5 g, 3.82 mmol), tert-butyl (3-hydroxypropyl) carbamate (0.803 g, 4.58 mmol) and Ph P (1.50 g, 5.73 mmol) in THF (20 mL). The resulting mixture was stirred at rt for 16 hours. The solvent was removed under reduced pressure. The reaction mixture was diluted with EtOAc: petroleum ether (200 mL, 1: 5). The solid was filtered out, and the organic layer was washed with saturated NH Cl (30 mL), saturated NaHCO (30 mL) and saturated brine (30 mL × 2) in sequence. The organic layer was dried over Na SO, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with a gradient of elution from 0% to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 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.

[1040] Example 4

[1041] 9-Benzyl-8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine

[1042]

[1043] To a stirred solution of (E)-N-benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropyloxy)pyrimidin-4-amine (82 g crude, calculated as 129 mmol, 1.00 equiv) in IPA (820 mL) was added FeCl3 (32 g, 193 mmol, 1.50 equiv) at room temperature under a nitrogen atmosphere. The reaction mixture was stirred at 80 ° C for 1.5 h. The resulting mixture was concentrated under vacuum. The reaction mixture was diluted with 500 ml of H2O, 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 NaHCO3 and brine (1000 mL×5), dried over Na2SO4, and concentrated. The residue was applied to a silica gel column and eluted with DCM / ammonia solution (3.5 M in MeOH) (1:0-1:20). 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% 2M NH3-MeOH) and concentrated under vacuum at less than 40°C to give a yellow solid that was slurried in Et2O (10 V) for 2 h. The resulting mixture was filtered and the filter cake was dried under vacuum to give 9-benzyl-8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (32.4 g, 45%) as a light yellow solid. 1 H 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,br s),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.

[1044] (E)-N-Benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropyloxy)pyrimidin-4-amine used as a starting material was prepared as follows:

[1045] N-Benzyl-6-chloro-5-nitropyrimidin-4-amine

[1046]

[1047] At room temperature, under a nitrogen atmosphere, TEA (228 g, 2.26 mol, 1.1 equivalents) was added to a stirred solution of 4,6-dichloro-5-nitropyrimidine (400 g, 2.01 mol, 1.00 equivalents) in DCM (4000 mL). Benzylamine (243.1 g, 2.26 mol, 1.1 equivalents) was loaded 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 with petroleum ether / ethyl acetate (2: 1-1: 1). This gave N-benzyl-6-chloro-5-nitropyrimidine-4-amine (327 g, 60%) as a yellow solid. 1 HNMR(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.

[1048] N-Benzyl-6-(1-methylcyclopropyloxy)-5-nitropyrimidin-4-amine

[1049]

[1050] At room temperature, under nitrogen atmosphere, 1-methylcyclopropane-1-ol (114.3g, 1.59mmol, 2.00 equivalents) was added to a stirred solution of N-benzyl-6-chloro-5-nitropyrimidine-4-amine (210g, 0.79mol, 1.00 equivalents) in THF (2100mL). LHMDS (1980mL, 1.98mol, 2.50 equivalents) was loaded at 0°C. The reaction mixture was stirred for 18h at rt. The reaction mixture was diluted with 1000ml NH4Cl and extracted with ethyl acetate (1500mL×3). The combined organic layers were washed with brine (2000mL×2), dried over Na2SO4, and concentrated. The residue was applied to a silica gel column with petroleum ether / ethyl acetate (1:50-1:20). This afforded N-benzyl-6-(1-methylcyclopropyloxy)-5-nitropyrimidin-4-amine (108 g, 45%) as a yellow oil. 1H 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.

[1051] N4-Benzyl-6-(1-methylcyclopropyloxy)pyrimidine-4,5-diamine

[1052]

[1053] At room temperature, under a nitrogen atmosphere, iron powder (201g, 3.60mol, 10 equivalents) and NHCl (23.2g, 432mmol, 1.2 equivalents) were added to a stirred solution of N-benzyl-6-(1-methylcyclopropyloxy)-5-nitropyrimidine-4-amine (108g, 360mmol, 1.00 equivalents) in EtOH (1080mL). The reaction mixture was stirred at 80 ° C for 18h. The resulting mixture was filtered through celite and eluted with EtOH. The filtrate was concentrated to give a crude material. The crude product was purified by flash silica gel chromatography, eluting with petroleum ether: ethyl acetate 10: 1 to 1: 3 to give N4-benzyl-6-(1-methylcyclopropyloxy)pyrimidine-4,5-diamine (77g, 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.

[1054] (E)-N-Benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropyloxy)pyrimidin-4-amine

[1055]

[1056] To a stirred solution of N4-benzyl-6-(1-methylcyclopropyloxy)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 rt for 15 h. The resulting mixture was concentrated under vacuum to afford (E)-N-benzyl-5-((2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzylidene)amino)-6-(1-methylcyclopropyloxy)pyrimidine-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.

[1057] 2-Chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde used as starting material was prepared as follows:

[1058] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate

[1059]

[1060] Under nitrogen atmosphere, 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). 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 filter cake was washed with H O. The filter 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. 1HNMR(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.

[1061] 2-Chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)benzaldehyde

[1062]

[1063] Under a nitrogen atmosphere, formaldehyde (48.5 g, 1.28 mol, 1.20 equiv) was added 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). The reaction mixture was stirred at 70 ° C for 14 h. The reaction mixture was diluted with 1000 ml of H2O 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 Na2SO4, and concentrated. The residue was purified by flash silica gel chromatography, eluting with DCM / ammonia solution (3.5 M in MeOH) (1:100-1:30). 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.

[1064] Example 5

[1065] 9-Benzyl-8-(2-chloro-4-((1-methylpiperidin-4-yl)methoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine

[1066]

[1067] Under nitrogen, at 0 ° C, DIAD (143 μ L, 0.74 mmol) was added dropwise to 4- (9- benzyl -6- (1- methylcyclopropyloxy) -9H- purine -8- bases) -3- chlorophenol (150 mg, 0.37 mmol), (1- methylpiperidin-4-yl) methanol (95 mg, 0.74 mmol) and Ph P (193 mg, 0.74 mmol) in THF (5 mL). The resulting mixture was stirred at rt for 18 hours. The reaction mixture was concentrated and diluted with EtOAc (50 mL) and washed successively with saturated NH Cl (2 × 15 mL) and saturated brine (2 × 15 mL). The organic layer was dried over Na SO dried, filtered and evaporated to give a crude product. The residue was purified by preparative TLC (EtOAc) to give the title compound 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 (containing 0.05% aqueous NH 3 ) 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-methylcyclopropyloxy)-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.

[1068] 4-(9-Benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenol used as a starting material was prepared as follows:

[1069] 9-Benzyl-6-chloro-9H-purine

[1070]

[1071] At 25 ° C, over a period of 10 minutes, (bromomethyl) benzene (12.2g, 71.2mmol) was added dropwise to 6-chloro-9H-purine (10g, 64.70mmol) and potassium carbonate (10.73g, 77.64mmol) in acetonitrile (300mL). The resulting suspension was stirred at 25 ° C for 16 hours. The reaction mixture was filtered through celite and the filtrate was concentrated. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 50% EtOAc in petroleum ether. The pure fraction was evaporated to dryness to give 9-benzyl-6-chloro-9H-purine (9.00g, 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.

[1072] 9-Benzyl-6-(1-methylcyclopropyloxy)-9H-purine

[1073]

[1074] 1-Methylcyclopropane-1-ol (6.52 g, 90.4 mmol) is added to 9-benzyl-6-chloro-9H-purine (8.81 g, 36.0 mmol) in THF (72 mL). The reaction mixture is stirred at 0 ° C, and then sodium hydride (60% in mineral oil, 3.62 g, 90.5 mmol) is slowly added to the mixture. The reactant is stirred at room temperature for 17 hours. Water (50 mL) is slowly added, and the reaction mixture is extracted with DCM (3 × 50 mL). The organic matter is combined and concentrated in vacuo. The crude material is purified by silica gel column chromatography (330 g, 0%-50% EtOAc in heptane) to give 9-benzyl-6-(1-methylcyclopropyloxy)-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).

[1075] m / z:ES+[M+H]+281.

[1076] 9-Benzyl-8-bromo-6-(1-methylcyclopropyloxy)-9H-purine

[1077]

[1078] Under nitrogen, at 0 ° C, bis(trimethylsilyl) lithium amide (28.6 mL, 28.6 mmol) was added to 9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine (5 g, 17.84 mmol) and 1,2-dibromotetrachloroethane (8.72 g, 26.8 mmol) in THF (29 mL). The resulting mixture was stirred at 25 ° C for 16 hours. 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 Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 9-benzyl-8-bromo-6-(1-methylcyclopropyloxy)-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.

[1079] 4-(9-Benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenol

[1080]

[1081] Under nitrogen, at 25 ° C, dichloro [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) (907 mg, 1.39 mmol) was added to 9-benzyl-8-bromo-6- (1-methylcyclopropyloxy) -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). The resulting mixture was stirred at 90 ° C for 3 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 × 50 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenol (5.60 g, 99%) as a yellow solid. 1H 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) - no H observed. m / z: ES-[MH]-405.

[1082] Example 6

[1083] 9-Benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine

[1084]

[1085] Tert-Butyldimethylsilyl trifluoromethanesulfonate (12.05 mL, 52.5 mmol) was added to tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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 rt for 10 minutes. 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 give 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-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) - No proton observed. m / z: ES+[M+H]+519.

[1086] Tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as a starting material was prepared as follows:

[1087] tert-Butyl 4-(2-(4-(9-benzyl-6-chloro-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1088]

[1089] 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 days. 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% to 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.

[1090] 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.

[1091] tert-Butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1092]

[1093] Under nitrogen, 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. The resulting mixture was stirred at rt for 1 hour. The reaction mixture was poured into ice water. The reaction mixture was evaporated, diluted with EtOAc (250 mL) and washed sequentially with water (3×200 mL) and saturated brine (2×200 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 30% to 80% MeCN in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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.

[1094] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate used as starting material was prepared as described in Example 4.

[1095] Example 7

[1096] 4-((8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-2-methylthiazole

[1097]

[1098] A solution of sodium dithionite (282 mg, 1.62 mmol) in water (1 mL) was added to a stirred mixture of 6-(1-methylcyclopropyloxy)-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, Example 4 starting material) in NMP (3 mL). The resulting mixture was stirred at 100 ° C for 16 hours and then at 110 ° C for another 16 hours. The crude product was purified by flash C18 flash chromatography with an elution gradient of 5% to 40% MeCN (containing 5% TFA) in water. The 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% aqueous NH3 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-methylcyclopropyloxy)-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.

[1099] 6-(1-Methylcyclopropyloxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine used as a starting material was prepared as follows:

[1100] 6-Chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine

[1101]

[1102] At 0 ° C, a solution of (2-methylthiazol-4-yl)methylamine (330 mg, 2.58 mmol) in DCM (10 mL) was added to a stirred 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). The resulting mixture was stirred at rt 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 Na2SO4, filtered and evaporated to give 6-chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidine-4-amine (0.4 g) as a yellow gum. The product was used directly in the next step without further purification.

[1103] 6-(1-methylcyclopropyloxy)-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidin-4-amine

[1104]

[1105] At 0 ° C, LHMDS (2.66 mL, 2.66 mmol) was added to 6-chloro-N-((2-methylthiazol-4-yl)methyl)-5-nitropyrimidine-4-amine (0.38 g, 1.33 mmol) and 1-methylcyclopropane-1-ol (0.192 g, 2.66 mmol) in THF (20 mL). The resulting mixture was stirred at rt for 16 hours. The reaction mixture was quenched with saturated NH4Cl (25 mL), and the THF solvent was then 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 fast C18 flash chromatography with an elution gradient of 5% to 100% MeCN in water. Pure fractions were evaporated to dryness to afford 6-(1-methylcyclopropyloxy)-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.

[1106] Example 8

[1107] 1-Benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-5-isopropoxy-1H-imidazo[4,5-b]pyridine

[1108]

[1109] 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 rt for 1 hour, and then the solvent was removed under reduced pressure. The crude product was purified by fast C18 flash chromatography with an elution gradient of 30% to 80% MeOH in water (0.1% NH4HCO3). The pure fractions were evaporated to dryness to give 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) - No proton observed. m / z: ES+[M+H]+506.

[1110] 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 a starting material was prepared as follows:

[1111] 6-Amino-5-nitropyridin-2(1H)-one

[1112]

[1113] 6- chloro-3-nitropyridine -2- amine (10g, 57.62mmol) is added to NaOH (23.1g, 57.6mmol) in EtOH (50mL) and water (16.6mL). The resulting solution is stirred at 80 DEG C for 30 minutes. The reaction mixture is acidified with concentrated HCl, and the formed precipitate is filtered to obtain 6- amino -5- nitropyridine -2 (1H) -one (8.00g, 90%) as a yellow solid. The product is used directly in the next step without further purification. 1H NMR (300MHz, DMSO-d6): 11.51 (s, 1H), 8.53 (s, 2H), 7.98 (d, 1H), 5.66 (d, 1H). m / z:ES–[M–H]–154.

[1114] 6-Isopropoxy-3-nitropyridin-2-amine

[1115]

[1116] At 80 DEG C, 6-amino-5-nitropyridine-2 (1H) -one (4g, 25.8mmol) is added to potassium carbonate (10.7g, 77.4mmol) and 2-iodopropane (13.1g, 77.4mmol) in DMF (80mL). The resulting solution is stirred at 80 DEG C overnight. After cooling the reaction mixture, the solvent is removed under reduced pressure. The crude product is purified by flash silica gel chromatography, and the elution gradient is 0% to 20% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to obtain 6-isopropoxy-3-nitropyridine-2-amine (3.20g, 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.

[1117] 6-Isopropoxypyridine-2,3-diamine

[1118]

[1119] 6-isopropoxy-3-nitropyridine-2-amine (3.1 g, 15.72 mmol) and palladium / carbon (310 mg, 0.29 mmol) in MeOH (60 mL) were stirred at rt for 2 hours under a hydrogen atmosphere. The reaction mixture was filtered through filter paper to obtain 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.

[1120] N3-Benzyl-6-isopropoxypyridine-2,3-diamine

[1121]

[1122] 6-isopropoxypyridine-2,3-diamine (1.5g, 8.97mmol) is added to benzaldehyde (0.909ml, 8.97mmol) and acetic acid (0.051ml, 0.90mmol) in dichloromethane (30mL). The reaction is stirred at rt for 5 hours. Then sodium triacetoxyborohydride (5.70g, 26.91mmol) is added to the reaction mixture. The resulting solution is stirred for another 16 hours at rt. The reaction mixture is concentrated under reduced pressure. The crude product is purified by flash silica gel chromatography with an elution gradient of 0% to 20% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to obtain N3-benzyl-6-isopropoxypyridine-2,3-diamine (1.10g, 48%) as a purple oil. 1 H 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) - No proton observed. m / z: ES+[M+H]+258.

[1123] tert-Butyl 4-(2-(4-(1-benzyl-5-isopropoxy-1H-imidazo[4,5-b]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1124]

[1125] 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, Example 6 starting materials) 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 hour. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 10% MeOH in dichloromethane. The pure fractions were evaporated to dryness to give 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.

[1126] Example 9

[1127] 2-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-1-(3-chlorobenzyl)-1H-benzo[d]imidazol-5-ol

[1128]

[1129] 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 rt for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by fast C18 flash chromatography with an elution gradient of 30% to 80% MeOH in water (0.1% NH4HCO3). The pure fractions were evaporated to dryness to give 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. 1 H 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) - No proton observed. m / z: ES+[M+H]+506.

[1130] 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 a starting material was prepared as follows:

[1131] 4-Chloro-2-isopropoxy-3-nitropyridine

[1132]

[1133] At 0 ° C, 4- chloro-3-nitropyridine-2 (1H) -one (5.0g, 28.6mmol) is added to the sodium hydride (2.06g, 85.9mmol) in DMF (100mL). The reaction is warmed to rt over 30 minutes, and 2- iodopropane (24.3g, 143.2mmol) is then added. The resulting solution is stirred for another 12 hours at rt. The reaction mixture is quenched with saturated NH4Cl (50mL), extracted with EtOAc (3 × 100mL), and the organic layer is dried over Na2SO4, filtered and evaporated to give a crude product. The crude product is purified by fast C18 flash chromatography, and the elution gradient is 5% to 80% MeOH in water (0.1% NH4HCO3). The pure fraction is evaporated to dryness to give 4- chloro-2-isopropoxy-3-nitropyridine (2.10g, 34%) as a yellow oil. 1 H NMR(300MHz, DMSO-d6):1.30(6H,d),5.29–5.44(1H,m),7.43(1H,d),8.37(1H,d).

[1134] N-Benzyl-2-isopropoxy-3-nitropyridin-4-amine

[1135]

[1136] 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 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 10% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to give N-benzyl-2-isopropoxy-3-nitropyridine-4-amine (1.20 g, 90%) as a yellow solid. 1 HNMR(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–[M–H]–286.

[1137] N4-Benzyl-2-isopropoxypyridine-3,4-diamine

[1138]

[1139] N-benzyl-2-isopropoxy-3-nitropyridine-4-amine (1g, 3.48mmol) is added to iron (0.972g, 17.40mmol) and ammonium chloride (1.862g, 34.80mmol) in EtOH (16mL) and water (1.6mL). The resulting solution is stirred at 80 ° C for 12 hours. The reaction mixture is filtered through filter paper, and the solvent is then removed under reduced pressure. The crude product is purified by flash silica gel chromatography with an elution gradient of 0% to 20% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to obtain N4-benzyl-2-isopropoxypyridine-3,4-diamine (0.518g, 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.

[1140] tert-Butyl 4-(2-(4-(1-benzyl-4-isopropoxy-1H-imidazo[4,5-c]pyridin-2-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1141]

[1142] 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 hour. The solvent was removed under reduced pressure. The crude product was purified by fast C18 flash chromatography with an elution gradient of 10% to 80% MeOH in water (0.1% NH4HCO3). The pure fractions were evaporated to dryness to give 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. 1HNMR(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.

[1143] Example 10

[1144] 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine

[1145]

[1146] A solution of tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (2.07 g, 3.16 mmol) in acetonitrile was cooled to 0 ° C. with an ice / water bath. Hydrogen chloride (4.0 M in dioxane) (8.0 mL, 32.0 mmol) was added and the ice bath was removed. Stirring was continued at rt for 1 h, then additional hydrogen chloride (4.0 M in dioxane) (8.0 mL, 32.0 mmol) was added and stirring was continued for another 30 min. 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 to dryness using 1 M NH / MeOH 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 afford 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine as a yellow foam (1.50 g, 86%).

[1147] 1H NMR (500 MHz, CDCl3): 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). 1H was not observed. m / z: ES+[M+H]+554.

[1148] Tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate used as a starting material was prepared as follows:

[1149] tert-Butyl 4-(2-(3-chloro-4-(6-chloro-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1150]

[1151] 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 at 80 ° C under air for 2.5 days. The reaction was cooled to rt, 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 3 (20 mL), separated, dried over MgSO 4 , filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography (elution gradient 0% to 100% EtOAc in heptane, then 3:1 EtOAc / EtOH in EtOAc) to elute the product. Pure fractions were evaporated to dryness to give tert-butyl 4-(2-(3-chloro-4-(6-chloro-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (1.050 g, 78%) as a light yellow solid. 1H 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). 1H was not observed. m / z: ES+[M+H]+493.

[1152] tert-Butyl 4-(2-(3-chloro-4-formylphenoxy)ethyl)piperazine-1-carboxylate used as starting material was prepared as described in Example 4.

[1153] tert-Butyl 4-(2-(3-chloro-4-(6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1154]

[1155] To a solution of tert-butyl 4-(2-(3-chloro-4-(6-chloro-9H-purine-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (1.62g, 3.28mmol) and 4-chloro-2-(chloromethyl)pyridine hydrochloride (0.977g, 4.93mmol) in anhydrous DMF (16.4mL) was added cesium carbonate (3.21g, 9.85mmol). The reaction was inertized by applying three vacuum and nitrogen backfill cycles, and the reaction was then stirred at 60°C under nitrogen for 19h. The reaction was quenched with ice water (20mL) and ethyl acetate (20mL) was added. The organic layer was removed and the aqueous layer was further extracted with ethyl acetate (10mL×6). The combined organic layer was washed with a saturated aqueous solution of LiCl (10mL×3), filtered through an isolute phase separation column, and evaporated to give a crude product as brown foam. The crude product was purified by flash silica gel chromatography, elution gradient 0% to 35% then to 70% 3:1 EtOAc:EtOH in n-heptane. Pure fractions were evaporated to dryness to afford 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.

[1156] tert-Butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1157]

[1158] To a suspension of sodium hydride (0.889 g, 22.2 mmol) in tetrahydrofuran (15 mL) cooled to 0 ° C under nitrogen was added 1-methylcyclopropan-1-ol (0.802 g, 11.1 mmol) and 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) as a steady stream. The reaction mixture was stirred at 0 ° C for 20 min, then the ice bath was removed and the reaction was stirred at room temperature under nitrogen for 19 h. The reaction mixture was cooled with 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 is extracted with EtOAc (150mL).The combined organic phase is washed with brine, dried and evaporated.The crude product is purified by flash silica gel chromatography (elution gradient is 0% to 100% 3: 1 EtOAc / EtOH in heptane) to give tert-butyl 4-(2-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine-8-yl)phenoxy)ethyl)piperazine-1-carboxylate (2.07g, 57%) as light yellow foam. 1H 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.

[1159] Example 11

[1160] 9-Benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)-9H-purine

[1161]

[1162] tert-Butyl 4-(2-(4-(9-benzyl-6-((1,1,1-trifluoro-2-methylprop-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 rt 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 (XBridgePrep 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 afford 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. 1H 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) - not observed for 1H. m / z: ES+[M+H]+575.

[1163] 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 a starting material was prepared as follows:

[1164] N-Benzyl-5-nitro-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyrimidin-4-amine

[1165]

[1166] At 0 ° C, LHMDS (11.3 mL, 11.3 mmol) was added to N-benzyl-6-chloro-5-nitropyrimidine-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). The resulting mixture was stirred at 60 ° C for 12 hours. The reaction mixture was diluted with EtOAc (100 mL) and washed with saturated brine (3×100 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 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 HNMR(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.

[1167] N4-Benzyl-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyrimidine-4,5-diamine

[1168]

[1169] Iron (549 mg, 9.82 mmol) was added to a mixture of N-benzyl-5-nitro-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyrimidine-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 hours. The solvent was then removed under reduced pressure, and the crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to give N4-benzyl-6-((1,1,1-trifluoro-2-methylprop-2-yl)oxy)pyrimidine-4,5-diamine (400 mg, 63%) as a white solid. 1 HNMR(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.

[1170] 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

[1171]

[1172] 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 hours. The solvent was then removed under reduced pressure, and the crude residue was purified by 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. 1H 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.

[1173] Example 12

[1174] 9-Benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutyloxy)-9H-purine

[1175]

[1176] Under nitrogen, Pd(PPh3)4 (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 Cs2CO3 (262 mg, 0.80 mmol) in 1,4-dioxane (2 mL) and water (0.4 mL). The resulting solution was stirred at 100°C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash C18 flash chromatography using a 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 (containing 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-methylcyclobutyloxy)-9H-purine (16 mg, 11%) as a white solid. 1H 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) - no H observed. m / z: ES+[M+H]+533.

[1177] 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine used as a starting material was prepared as follows:

[1178] tert-Butyl 4-(2-(4-bromo-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1179]

[1180] Under nitrogen, potassium carbonate (6.66 g, 48.2 mmol) was added to 4-bromo-3-chlorophenol (5 g, 24.1 mmol) and tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (7.19 g, 28.92 mmol) in DMF (100 mL) at 25 ° C. The resulting suspension was stirred at 80 ° C for 3 hours. 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 Na2SO4, filtered and evaporated to give a 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.

[1181] tert-Butyl 4-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1182]

[1183] Under nitrogen, PdCl2(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(pinacol)diboronate (3.63 g, 14.29 mmol) and potassium acetate (2.10 g, 21.4 mmol) in 1,4-dioxane (60 mL). The resulting solution was stirred at 100 ° C for 2 hours. 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 Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 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.

[1184] 1-(2-(3-chloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenoxy)ethyl)piperazine

[1185]

[1186] 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 hours, and then the solvent was removed under reduced pressure. The crude product was purified by preparative HPLC (XBridgePrep C18 OBD column, 30*150 mm, 5 μm) using decreasingly polar mixtures of water (containing 10 mmol / L NH4HCO3 and 0.1% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 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) - no proton observed. m / z: ES+[M+H]+367.

[1187] 9-Benzyl-8-bromo-6-(1-methylcyclobutyloxy)-9H-purine used as starting material was prepared as follows:

[1188] 9-Benzyl-6-(1-methylcyclobutyloxy)-9H-purine

[1189]

[1190] Under nitrogen, at 0 ° C, over a period of 2 minutes, sodium hydride (265 mg, 11.03 mmol) was added in batches to a mixture of 9-benzyl-6-chloro-9H-purine (900 mg, 3.68 mmol, Example 5 starting material), 1-methylcyclobutan-1-ol (634 mg, 7.36 mmol) in THF (30 mL). The resulting suspension was stirred at 25 ° C for 4 hours. The reaction mixture was diluted with NH4Cl aqueous solution (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 a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 40% EtOAc in petroleum ether. The 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.

[1191] 9-Benzyl-8-bromo-6-(1-methylcyclobutyloxy)-9H-purine

[1192]

[1193] Under nitrogen, at 25 ° C, bis (trimethylsilyl) lithium amide (6.79 mL, 6.79 mmol) was added to a solution of 9-benzyl-6- (1-methylcyclobutyloxy) -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). The resulting solution was stirred at 25 ° C for 5 hours. The reaction mixture was poured into water (150 mL) and extracted with EtOAc (3 × 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 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.

[1194] Example 13

[1195] 1-((9-Benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9H-purin-6-yl)oxy)cyclopropane-1-carbonitrile

[1196]

[1197] Hydrogen chloride (4M in dioxane) (7.93 μl, 0.03 mmol) was added to a stirred solution of tert-butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropyl)-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 minutes, additional hydrogen chloride (4M 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 using 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 ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 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, CDCl3): 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) - no H observed. m / z: ES+[M+H]+530.

[1198] Tert-butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate used as a starting material was prepared as follows:

[1199] tert-Butyl 4-(2-(4-(9-benzyl-6-(1-cyanocyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazine-1-carboxylate

[1200]

[1201] Under nitrogen at 0 ° C, 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). After the reaction had been stirred for 15 minutes, 1-hydroxycyclopropane-1-carbonitrile (107 mg, 1.29 mmol) was added. The resulting solution was stirred for another 2 hours at rt. 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 gel 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-cyanocyclopropyloxy)-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.

[1202] Example 14

[1203] 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-3-((4-chloropyridin-2-yl)methyl)-7-(1-methylcyclopropyloxy)-3H-imidazo[4,5-b]pyridine

[1204]

[1205] At 25 ° C, p-toluenesulfonic acid monohydrate (94 mg, 0.49 mmol) was added to N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)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). The resulting mixture was stirred at 60 ° C for 2 hours. 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. 21 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-methylcyclopropyloxy)-3H-imidazo[4,5-b]pyridine (25 mg, 14%) as a white solid. 1 H NMR (400 MHz, CDCl3): 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) - No proton observed. m / z: ES+[M+H]+553.

[1206] 2-Chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde used as starting material was prepared as follows:

[1207] 2-Chloro-4-(2-(piperazin-1-yl)ethoxy)benzaldehyde

[1208]

[1209] 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 hour. The reaction mixture was diluted with EtOAc (25 mL) and washed successively with water (3 × 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 50% pentane in EtOAc. The 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). No H was observed. m / z: ES+[M+H]+269.

[1210] N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)pyridine-2,3-diamine used as a starting material was prepared as follows:

[1211] 2-Chloro-4-(1-methylcyclopropyloxy)-3-nitropyridine

[1212]

[1213] Under nitrogen, at 0 ° C, sodium hydride (0.415g, 10.4mmol) was added once to 2,4-dichloro-3-nitropyridine (2g, 10.4mmol) and 1-methylcyclopropane-1-ol (0.747g, 10.4mmol) in THF (20mL). The resulting suspension was stirred at 25 ° C for 1 hour. The reaction mixture was quenched with water (20mL) and extracted with EtOAc (3 × 50mL). The top layer was dried over Na2SO4, 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-methylcyclopropyloxy)-3-nitropyridine (0.900g, 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.

[1214] N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-3-nitropyridin-2-amine

[1215]

[1216] BINAP (82 mg, 0.13 mmol) was added to 2-chloro-4-(1-methylcyclopropyloxy)-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 hours. The reaction mixture was quenched with water (20 mL), extracted with EtOAc (3 x 100 mL) and washed with water (2 x 50 mL) followed by saturated brine (2 x 50 mL). The organic layer was dried over NaSO, filtered and evaporated to give a yellow oil. The oil was purified by preparative TLC (petroleum ether / EtOAc 2:1) to give N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-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.

[1217] N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)pyridine-2,3-diamine

[1218]

[1219] At 25 ° C, iron (307 mg, 5.50 mmol) is added to N-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-3-nitropyridine-2-amine (230 mg, 0.69 mmol) and ammonium chloride (294 mg, 5.50 mmol) in EtOH:HO(4:1) (8 mL). The resulting mixture is stirred at 80 ° C for 2 hours. The mixture is filtered through a celite pad and the solvent is removed. The reaction mixture is quenched with water (15 mL), extracted with EtOAc (3 × 50 mL) and washed with water (2 × 20 mL) and saturated brine (2 × 20 mL) in sequence. The organic layer is dried over NaSO, filtered and evaporated to give a yellow oil. The oil was purified by preparative TLC (EtOAc) to give N2-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)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.

[1220] Example 15

[1221] 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-benzo[d]imidazole

[1222]

[1223] 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-methylcyclopropyloxy)-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 hour. The reaction mixture was diluted with EtOAc (10 mL) and washed sequentially with water (3 x 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. The 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-methylcyclopropyloxy)-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) - no H observed. m / z: ES+[M+H]+552.

[1224] Tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate used as starting material was prepared as follows:

[1225] 1-Fluoro-3-(1-methylcyclopropyloxy)-2-nitrobenzene

[1226]

[1227] At 0 ° C, sodium hydride (78 mg, 3.27 mmol) was added to 1,3-difluoro-2-nitrobenzene (400 mg, 2.51 mmol) and 1-methylcyclopropane-1-ol (181 mg, 2.51 mmol) in THF (3 mL). The resulting mixture was stirred at 25 ° C for 2 hours. The reaction mixture was concentrated, diluted with EtOAc (20 mL) and washed with water (3 × 5 mL) and then with saturated brine (3 × 5 mL). The top layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by preparative TLC (petroleum ether / EtOAc 2: 1) to give 1-fluoro-3- (1-methylcyclopropyloxy) -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.

[1228] N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropyloxy)-2-nitroaniline

[1229]

[1230] At 25 ° C, N, N-diisopropylethylamine (826 mg, 6.39 mmol) was added to 1-fluoro-3-(1-methylcyclopropyloxy)-2-nitrobenzene (270 mg, 1.28 mmol) and (4-chloropyridin-2-yl)methylamine (219 mg, 1.53 mmol) in DMSO (5 mL). The resulting mixture was stirred at 130 ° C for 2 hours. The reaction mixture was concentrated, diluted with EtOAc (20 mL) and washed with water (3 × 5 mL) and saturated brine (3 × 5 mL) in sequence. The top layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 5% MeOH in DCM. The pure fraction was evaporated to dryness to give N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropyloxy)-2-nitroaniline (237 mg, 55%) as a yellow solid. 1H 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.

[1231] tert-Butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-benzo[d]imidazol-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1232]

[1233] At 25 ° C, sodium dithionite (730 mg, 4.19 mmol) was added to N-((4-chloropyridin-2-yl)methyl)-3-(1-methylcyclopropyloxy)-2-nitroaniline (140 mg, 0.42 mmol) in MeOH (2 mL) and water (2 mL). The mixture was stirred for 16 hours. 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 for another 3 hours at 25 ° C. The reaction mixture was concentrated and then diluted with EtOAc (15 mL). The crude mixture was then washed with water (3×15 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 10% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-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.

[1234] Example 16

[1235] 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-imidazo[4,5-c]pyridine

[1236]

[1237] To tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (220 mg, 0.34 mmol) in dichloromethane (1 mL) was added HCl (4 M in dioxane, 123 mg, 3.37 mmol) at rt. The reaction mixture was stirred at rt for 1 hour, 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% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-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) - No proton observed. m / z: ES+[M+H]+553

[1238] Tert-butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate used as a starting material was prepared as follows:

[1239] 2-Chloro-4-(methylthio)-3-nitropyridine

[1240]

[1241] Sodium methanethiolate (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 rt for 16 hours. The reaction mixture was evaporated to dryness, redissolved in EtOAc (50 mL), and washed with water (2 × 15 mL) and saturated brine (2 × 15 mL) in sequence. The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography with an elution gradient of 0% to 30% EtOAc in petroleum ether. The pure fraction was 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.

[1242] 2-(1-Methylcyclopropyloxy)-4-(methylthio)-3-nitropyridine

[1243]

[1244] Under nitrogen, at 0 ° C, sodium hydride (2.06g, 86.0mmol) was added once to 2-chloro-4-(methylthio)-3-nitropyridine (2.2g, 10.7mmol) and 1-methylcyclopropane-1-ol (1.16g, 16.1mmol) in THF (200mL). The resulting suspension was stirred at rt for 6 hours. The reaction mixture was then diluted with EtOAc (100mL) and washed with saturated brine (2 × 50mL). The organic layer was dried over Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel chromatography, with an elution gradient of 10% to 40% EtOAc in petroleum ether. The pure fraction was evaporated to dryness to give 2-(1-methylcyclopropyloxy)-4-(methylthio)-3-nitropyridine (1.30g, 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.

[1245] 2-(1-methylcyclopropyloxy)-4-(methylsulfonyl)-3-nitropyridine

[1246]

[1247] Meta-chloroperbenzoic acid (2.05 g, 11.9 mmol) is added to 2- (1- methylcyclopropyloxy) -4- (methylthio) -3- nitropyridine (1.30 g, 5.41 mmol) in dichloromethane (100 mL), and the reaction is stirred at rt for 6 hours. The reaction mixture is then evaporated to dryness and redissolved in EtOAc (100 mL) and washed with water (3 × 50 mL) and saturated brine (3 × 50 mL) in sequence. The organic layer is dried over Na2SO4, filtered and evaporated to give a crude product. The crude product is purified by flash silica gel chromatography with an elution gradient of 25% to 50% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to give 2- (1- methylcyclopropyloxy) -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.

[1248] N-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropyloxy)-3-nitropyridin-4-amine

[1249]

[1250] Triethylamine (0.530mL, 3.80mmol) is added to 4-chloro-2-pyridinemethylamine (542mg, 3.80mmol) and 2-(1-methylcyclopropyloxy)-4-(methylsulfonyl)-3-nitropyridine (690mg, 2.53mmol) in DMF (110mL).The reaction mixture is stirred at 60 ℃ for 16 hours.Then the reaction mixture is cooled, concentrated and further diluted with EtOAc (100mL).The organic layer is washed with water (2 × 75mL) and saturated brine (2 × 75mL) successively, through Na2SO4 drying, filtered and evaporated.The crude product is purified by flash silica gel chromatography, and the elution gradient is 30% to 60% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford N-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropyloxy)-3-nitropyridin-4-amine (260 mg, 31%) as a yellow solid. 1H 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.

[1251] N4-((4-chloropyridin-2-yl)methyl)-2-(1-methylcyclopropyloxy)pyridine-3,4-diamine

[1252]

[1253] 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-methylcyclopropyloxy)-3-nitropyridine-4-amine (250 mg, 0.75 mmol) in ethanol / water (10: 1; 1 mL). The reaction mixture was stirred at 60 ° C for 3 hours. The reaction mixture was then cooled, evaporated to dryness, and redissolved in EtOAc (200 mL). The organic layer was washed with water (2×100 mL) and saturated brine (2×100 mL), dried over Na2SO4, filtered and evaporated to give the crude product. The crude product was purified by flash silica gel 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-methylcyclopropyloxy)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.

[1254] tert-Butyl 4-(2-(3-chloro-4-(1-((4-chloropyridin-2-yl)methyl)-4-(1-methylcyclopropyloxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate

[1255]

[1256] 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-methylcyclopropyloxy)pyridine-3,4-diamine (140 mg, 0.46 mmol) in MeOH (20 mL) and acetic acid (1 mL) and stirred at rt for 16 hours. 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 gel chromatography with an elution gradient of 30% to 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-methylcyclopropyloxy)-1H-imidazo[4,5-c]pyridin-2-yl)phenoxy)ethyl)piperazine-1-carboxylate (230 mg, 77%) as a brown solid. 1 HNMR(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.

[1257] Example 17

[1258] 3-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-N,N-dimethyl-1-propylamine

[1259]

[1260] KCO (56 mg, 0.41 mmol) was added to 3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-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 hours. 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% ammonia) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 3-(3-chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-N,N-dimethyl-1-propylamine as a yellow solid (8.0 mg, 11%). 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.

[1261] 3-Chloro-4-(9-((4-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenol used as a starting material was prepared as follows:

[1262] 4-((tert-Butyldiphenylsilyl)oxy)-2-chlorobenzaldehyde

[1263]

[1264] At rt, tert-butyldiphenylchlorosilane (26.3g, 95.8mmol) is added to a mixture of 1H-imidazole (4.87g, 71.5mmol) and 2-chloro-4-hydroxybenzaldehyde (10g, 63.9mmol) in DMF (200mL). The mixture is stirred at this temperature for 3 hours. The reaction mixture is then diluted with EtOAc (500mL) and washed with water (3×400mL) and saturated brine (2×400mL) in sequence. The organic layer is dried over Na2SO4, filtered and evaporated to obtain a crude product. The crude product is purified by flash silica gel chromatography, and the elution gradient is 0% to 30% EtOAc in petroleum ether. The pure fraction is evaporated to dryness to obtain 4-((tert-butyldiphenylsilyl)oxy)-2-chlorobenzaldehyde (13.0g, 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.

[1265] 8-(4-((tert-Butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9H-purine

[1266]

[1267] 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 hours. The reaction mixture was adjusted to pH 7 with 1M 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 Na2SO4, filtered and evaporated to give a crude product. The crude product was purified by flash silica gel 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.

[1268] 8-(4-((tert-Butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9-((4-chloropyridin-2-yl)methyl)-9H-purine

[1269]

[1270] Under nitrogen, at 0 ℃, over a period of 5 minutes, DIAD (9.36mL, 48.1mmol) was added to (4-chloropyridin-2-yl)methanol (3.32g, 23.1mmol), 8-(4-((tert-butyldiphenylsilyl)oxy)-2-chlorophenyl)-6-chloro-9H-purine (10g, 19.2mmol) and triphenylphosphine (12.62g, 48.1mmol) in THF (125mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was poured into water (750mL) and extracted with EtOAc (3×750mL). The organic layer was dried over Na SO , filtered and evaporated to give a brown oil. The crude product was purified by flash silica gel 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-c...

Claims

1. A compound of formula (I): or a stereoisomer or a pharmaceutical salt thereof; in, R 1 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 independently N, CLR or CR x , where Q 1 , Q 2 and Q 3 No more than one of them is CLR; L is a bond, -O-; -C(O)-; -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 -; p is independently 1, 2 or 3 R is H, R a 、R b 、R c or R d ; R a is a 3- to 10-membered heterocyclic ring optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 4- to 6-membered heterocyclic ring, and C1-C7 alkyl, wherein said C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R b is a C1-C7 alkyl group, wherein one or two methylene groups from said C1-C7 alkyl group are optionally independently replaced by NR e or O and one or two single bonds in the C2-C7 alkyl chain are optionally independently replaced by a double bond or a triple bond, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from the group consisting of halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-C6 carbocyclic ring is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo and carboxyl; wherein the 3- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo, -CN, -S(O)OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxyl, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R c is a C3-C6 carbocycle optionally substituted by 1 to 4 substituents independently selected from hydroxy, halo and carboxyl; 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 C 1-3 alkyl halide; R e is H, halo, C1-C8 alkyl or C1-C8 haloalkyl; X is C1-C4 alkylene; Y is phenyl or 5- to 6-membered heteroaryl, wherein the phenyl or heteroaryl is optionally substituted with 1 to 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 , where G a and G b One and only one of is N or CH, and G a and G b One and only one of them is CR 5 ; R 5 yes Z a and Z b are independently C1-C3 alkyl or C1-C3 haloalkyl, or Z a and Z b forming a 3- to 6-membered carbocyclic or heterocyclic ring; and Z c It is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl or C2-C4 alkyne.

2. The compound according to claim 1, wherein G is H.

3. The compound according to claim 1, wherein G is CH.

4. The compound according to any one of claims 1 to 3, wherein G a It's CR5.

5. The compound according to any one of claims 1 to 3, wherein G b It's CR5.

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

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

8. A compound according to any one of claims 1 to 3 or 5, wherein G a It's N.

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

10. The compound according to any one of claims 1 to 9, wherein Z a and Z b are independently C1-C3 alkyl.

11. The compound according to claim 10, wherein Z a and Z b It is -CH3.

12. A compound according to any one of claims 1 to 9, wherein R 5 yes And where p is 1-4.

13. The compound according to claim 12, wherein p is 2. The compound according to claim 12 , wherein p is 1.

15. A compound according to any one of claims 1 to 14, wherein Z c It is -CH3.

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

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

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

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. The compound of claim 20, wherein Y is substituted with 1 to 3 substituents independently selected from the group consisting of halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, and C1-C3 haloalkyl.

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

23. The compound of claim 20, wherein Y is substituted with -CH3.

24. A compound according to any one of claims 1 to 19, wherein Y is unsubstituted.

25. A compound according to any one of claims 1 to 24, wherein R 1 It is a halo group.

26. A compound according to any one of claims 1 to 24, wherein R 1 It is -Cl.

27. A compound according to any one of claims 1 to 24, wherein R 1 It is -CH3.

28. A compound according to any one of claims 1 to 27, wherein R 2 Yes -H.

29. A compound according to any one of claims 1 to 28, wherein Q 1 , Q 2 or Q 3 It's CLR.

30. The compound according to claim 29, wherein Q 1 It's CLR.

31. The compound according to claim 29, wherein Q 2 It's CLR.

32. The compound according to claim 29, wherein Q 3 It's CLR.

33. A compound according to any one of claims 29 to 32, wherein L is a bond, -O-; -(CH2) p O- or -O(CH2) p -.

34. The compound of claim 33, wherein L is a bond.

35. The compound of claim 33, wherein L is -O-.

36. The compound of claim 33, wherein L is -(CH2) p O-.

37. The compound of claim 33, wherein L is -O(CH2) p -.

38. A compound according to any one of claims 29 to 32, wherein 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-.

39. A compound according to any one of claims 29 to 38, wherein R is H, R a or R b .

40. The compound of claim 39, wherein R is R a .

41. The compound according to claim 40, wherein R a It is a 3- to 10-membered N-heterocyclic ring.

42. The compound according to claim 41, wherein R a It is a 4- to 7-membered N-heterocyclic ring.

43. The compound according to claim 42, wherein R a It is a 6-membered N-heterocyclic ring.

44. The compound according to claim 43, wherein R a is piperidine, 1,2-diazinane, 1,3-diazinane, 1,4-diazinane, 1,2-oxazinane, 1,3-oxazinane or 1,4-oxazinane.

45. A compound according to any one of claims 40 to 44, wherein R a is substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, CN, S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

46. The compound according to claim 45, wherein R a Substituted with C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester and C1-C5 alkoxy.

47. The compound of claim 46, wherein the C1-C7 is substituted with oxo.

48. The compound of claim 48, wherein the C1-C7 alkyl group is substituted with a C1-C5 alkoxy group.

49. The compound of any one of claims 46 to 48, wherein the C1-C7 alkyl group is methyl.

50. The compound of claim 39, wherein R is R b .

51. The compound according to claim 50, wherein R b is substituted with 1 to 4 substituents independently selected from the group consisting of halo, oxo, hydroxy, carboxyl, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, C1-C8 amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3- to 10-membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from the group consisting of hydroxy, halo, and carboxyl, and wherein the 3-membered The 4- to 10-membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxy, oxo, -CN, S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, a 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, carboxyl, halo, hydroxy, oxo, -CN, C2-C8 ester and C1-C5 alkoxy.

52. The compound according to claim 51, wherein R b is substituted with a 3- to 10-membered heterocyclic ring.

53. The compound of claim 52, wherein the heterocycle is an N-heterocycle.

54. The compound of claim 53, wherein the N-heterocycle is a 4- to 7-membered N-heterocycle.

55. according to the compound described in any one of claim 52 to 54, wherein said heterocycle is replaced by 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo, CN, S (O) OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4 yuan to 6 yuan of heterocycle and C1-C7 alkyl, wherein said C1-C7 alkyl is optionally replaced by 1 to 4 substituents independently selected from amino, carboxyl, halo, hydroxyl, oxo ,-CN, C2-C8 ester and C1-C5 alkoxy.

56. The compound of claim 55, wherein the heterocycle is substituted with C1-C7 alkyl, oxo and / or halo.

57. The compound according to claim 51, wherein R b Substituted with amino, C1-C8 amide and / or C1-C4 alkylamino.

58. The compound according to claim 51, wherein R b Substituted with oxo, hydroxy and / or carboxyl groups.

59. The compound of claim 1 , selected from the group consisting of: 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)heptylamide, 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-methylcyclopropyloxy)-9H-purine, 1-(4-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (R)-1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxyphenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-yl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-1-(4-methylpiperazin-1-yl)ethan-1-one, 1-(4-((4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2), 9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 1), (R)-9-benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, (S)-9-Benzyl-8-(2-chloro-4-(2-(1-methylpyrrolidin-2-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 1-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-1-yl)ethan-1-one, 3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propan-1-amine, N-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)acetamide, 1-(4-(2-(3-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-3-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 1), 9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2), (R)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, (S)-9-benzyl-8-(2-chloro-4-((1-methylazepan-4-yl)oxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, (R)-8-(4-(azetidin-2-ylmethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, (S)-9-Benzyl-8-(2-chloro-4-(pyrrolidin-3-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine 9-benzyl-8-(2-chloro-4-(3-(piperazin-1-yl)propyloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-((3-fluoroazetidin-3-yl)methoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N,N-dimethylacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-methylacetamide, 1-(4-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-1-yl)ethan-1-one, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethan-1-amine, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)acetic acid, (R)-9-benzyl-8-(2-chloro-4-(pyrrolidin-2-ylmethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-hydroxyacetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)acetamide, 2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)-N-(2-hydroxyethyl)acetamide, (2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)glycine, N-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(piperidin-3-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperidin-4-yloxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(4-((2-azaspiro[3.3]hept-6-yl)oxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, 8-(4-(azetidin-3-yloxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-9-(2,3-difluorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyrimidin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-2-ylmethyl)-9H-purine, 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)piperidin-4-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)-N,N-dimethylazetidin-3-amine, 1-(5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)-N,N-dimethylpropan-1-amine, 1-(4-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)piperazin-1-yl)ethan-1-one, 1-(4-(2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine, 4-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propyl)morpholine, 2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)ethan-1-amine, 3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)propan-1-amine, 1-(3-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 2-((5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(3-methyl-2-(2-(piperazin-1-yl)ethoxy)pyridin-4-yl)-6-(1-methylcyclopropyloxy)-9H-purine, (R)-2-(((5-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-4-methylpyridin-2-yl)oxy)methyl)morpholine, (R)-3-(((5-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-fluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-methoxy-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2,6-dimethyl-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2,3-difluoro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-bromo-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-3-ylmethyl)-9H-purine, 2-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (2-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-5-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)methanol, 3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propanoic acid, (2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-L-proline, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)pyrrolidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)azetidin-3-ol, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-4-ol 2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-azaspiro[3.3]heptan-6-ol, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)azetidin-3-ol, 8-(4-(2-(1,6-diazaspiro[3.3]hept-6-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, (S)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-2-thia-6-azaspiro[3.3]heptane 2,2-dioxide, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-5-one, (R)-4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one, 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-5-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-3-methoxy-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2,5-dichloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-(2-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-(3-chlorobenzyl)-8-(4-methyl-6-(2-(piperazin-1-yl)ethoxy)pyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclobutyloxy)-9-(pyridin-2-ylmethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-3-yl)ethyl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-phenylpropyl)-9H-purine, (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-phenylpropyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-2-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-phenethyl-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(4-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(pyridin-4-ylmethyl)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((5-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((3-chloropyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-2-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((6-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((4-(trifluoromethyl)pyridin-2-yl)methyl)-9H-purine, 6-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)picolinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((6-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)nicotinonitrile, 4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(2-(pyridin-4-yl)ethyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purine, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)-5-methylthiazole, 2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)isonicotinonitrile, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-methoxypyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine, 5-chloro-2-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole, 2-chloro-4-((8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purin-9-yl)methyl)thiazole, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-((5-methylpyridin-2-yl)methyl)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)azetidin-3-amine, 1-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)piperidin-4-amine, 4-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)piperazin-2-one, (E)-3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)acrylic acid, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-one, 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chloro-N,N-dimethylbenzamide, 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chloro-N-methylbenzamide, (4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)(piperazin-1-yl)methanone, 4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorobenzamide, 9-benzyl-8-(2-chloro-4-(pyrrolidin-1-ylmethyl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(piperazin-1-ylmethyl)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, (4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenyl)methanamine, 9-benzyl-8-(2-chloro-4-methoxyphenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-methoxypyridin-3-yl)-6-(1-methylcyclopropyloxy)-9H-purine, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutyloxy)-1-(pyridin-2-ylmethyl)-1H-benzo[d]imidazole, 1-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-4-(1-methylcyclobutyloxy)-1H-benzo[d]imidazole, 2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutyloxy)-3-(pyridin-2-ylmethyl)-3H-imidazo[4,5-b]pyridine, 3-benzyl-2-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-7-(1-methylcyclobutyloxy)-3H-imidazo[4,5-b]pyridine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethylcyclopropyloxy)-9H-purine, 9-benzyl-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-ethynylcyclobutyloxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(3-chlorobenzyl)-6-cyclopropyloxy-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-methylcyclopropyloxy)-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-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 8-(4-(2-(3,8-diazabicyclo[3.2.1]oct-3-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, 3-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (R)-1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperidin-3-ol, 2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (S)-9-Benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, (R)-9-benzyl-8-(2-chloro-4-(2-(2-methylpiperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9H-purine, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-1,4-diazepan-2-one, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 1), 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3-methylpiperazin-2-one (isomer 2), 6-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)-3,6-diazabicyclo[3.1.1]heptane, 1-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (R)-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)methanol, 8-(4-(2-((1S,4S)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, 8-(4-(2-((1R,4R)-2,5-diazabicyclo[2.2.1]hept-2-yl)ethoxy)-2-chlorophenyl)-9-benzyl-6-(1-methylcyclopropyloxy)-9H-purine, (1S,4S)-2-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, (S)-2-(4-(2-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)ethyl)piperazin-2-yl)acetonitrile, 1-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)-3-chlorophenoxy)propyl)piperazin-2-one, 4-(3-(4-(9-benzyl-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-((4-ethylpyridin-2-yl)methyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine (Isomer 1), (R)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-9-(1-(4-chloropyridin-2-yl)ethyl)-6-(1-methylcyclopropyloxy)-9H-purine, 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine (isomer 2), 8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, (S)-8-(2-chloro-4-(2-(piperazin-1-yl)ethoxy)phenyl)-6-(1-methylcyclopropyloxy)-9-(1-(pyridin-2-yl)propan-2-yl)-9H-purine, and their pharmaceutically acceptable salts.

60. The compound of claim 1 , selected from the group consisting of: 2-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenyl)acetamide, E-3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenyl)acrylic acid, 3-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2,2-dimethylpropanoic acid, 2-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)ethan-1-ol, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (Isomer 1), 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid (isomer 2), (R)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, (R)-1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)propan-2-ol, 1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purin-8-yl)phenyl)acetamide, 1-(3-(3-chloro-4-(6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)azetidin-1-yl)ethan-1-one, (S)-5-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)piperidin-2-one, 5-(3-chloro-4-(6-(1-methylcyclopropyloxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8-yl)phenoxy)tetrahydropyrimidin-2(1H)-one, 5-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)pentanoic acid, 4-(3-chloro-4-(9-(3-chlorobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)butanoic acid, 1-(3-chloro-4-(6-(1-methylcyclopropyloxy)-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-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)ethoxy)acetic acid, and their pharmaceutically acceptable salts.

61. The compound of claim 1 , selected from the group consisting of: (R)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(3-chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, 3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)propanoic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-3-methylbutanoic acid, (1s,3s)-3-(2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)cyclobutane-1-carboxylic acid, (R)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, (S)-4-(2-chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(1-methylcyclopropyloxy)-9H-purin-8-yl)phenoxy)-2-methylbutanoic acid, and pharmaceutically acceptable salts thereof.

62. 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. The compound for use according to claim 63, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

65. The compound for use according to claim 63 or 64, wherein the cancer is a solid cancer.

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. The compound for use according to any one of claims 63 to 66, wherein the cancer comprises a BRCA1 and / or BRCA2 mutation.

68. The compound for use according to any one of claims 63 to 67, wherein the cancer is PARP inhibitor (PARPi) resistant.

69. The compound for use according to claim 63, wherein the cancer is ataxia telangiectasia mutated (ATM) mutation positive.

70. The compound for use according to claim 63, wherein the cancer is a hematological cancer.

71. The compound for use according to claim 63, wherein the cancer is a solid cancer.

72. The compound for use according to claim 63, wherein the cancer is positive for a mutation in a gene encoding a Fanconi anemia (FA) protein or a FA-like gene.

73. 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. The compound of claim 73, wherein the mutation is in one or more genes selected from the group consisting of RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP interacting protein), PALB2 (chaperone and localization protein of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom's syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (Nibrin), and EMSY.

75. A method of treating cancer comprising administering to a patient in need thereof a therapeutically effective amount of a compound according to any one of claims 1 to 62.

76. The method of claim 75, wherein the cancer exhibits homologous recombination repair deficiency (HRD).

77. The method of claim 75 or 76, wherein the cancer is a solid cancer.

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. The method of any one of claims 75 to 78, wherein the cancer comprises a BRCA1 and / or BRCA2 mutation.

80. The method of any one of claims 75 to 79, wherein the cancer is PARP inhibitor (PARPi)-resistant.

81. The method of claim 75, wherein the cancer is ataxia telangiectasia mutated (ATM) mutation positive.

82. The method of claim 75, wherein the cancer is a hematological cancer.

83. The method of claim 75, wherein the cancer is a solid cancer.

84. The method of claim 75, wherein the cancer is positive for a mutation in a gene encoding a Fanconi anemia (FA) protein or a FA-like gene.

85. The method of claim 75, wherein the cancer is positive for a mutation in a gene encoding a DNA repair protein.

86. The method of claim 85, wherein the mutation is in one or more genes selected from the group consisting of RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP interacting protein), PALB2 (chaperone and localization protein of BRCA2), RECQL4 (RecQ protein-like 4), BLM (Bloom's syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (Nibrin), and EMSY.

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