WO2025248119A1

WO2025248119A1 - 6-(cyclo)alkoxypurine derivatives useful as polq inhibitors

Info

Publication number: WO2025248119A1
Application number: PCT/EP2025/065051
Authority: WO
Inventors: Jason Shields; Ariamala Gopalsamy; Bernard Barlaam; Michael BODNARCHUK; Gail WRIGLEY; Oliver Turner; Helen Elizabeth Jones; Sofia FERRER CABRERA
Original assignee: AstraZeneca AB
Current assignee: AstraZeneca AB
Priority date: 2024-05-31
Filing date: 2025-05-30
Publication date: 2025-12-04
Anticipated expiration: 2026-11-30

Abstract

The specification generally relates to compounds of Formula (I) or a stereoisomer or pharmaceutically acceptable salt thereof, wherein G, G_a, G_b, X, Y, R¹, R², Q¹, Q², and Q³ have any of the meanings defined herein, together with compositions containing them and their use in therapy. The compounds are inhibitors of the polymerase, DNA polymerase theta (Polθ or POLQ), and are thereby particularly useful in the treatment of cancer.

Description

6-(CYCL0)ALK0XYPURINE DERIVATIVES USEFUL AS POLQ INHIBITORS

BACKGROUND

DNA polymerase theta (Pol0) is a specialized polymerase encoded in the human genome by the POLQ gene and hence it is also simply known as POLQ. It belongs to the A family, a group of DNA polymerases regarded as 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 has been involved in genome maintenance processes through its roles in translesion synthesis (TLS), a DNA-damage tolerance mechanism, and alternative DNA-end joining (alt-EJ), a DNA repair mechanism involved in the resolution of DNA double-strand breaks (DSBs) (Ramsden et al., 2022; Yoon et al., 2019).

DNA DSBs are the most cytotoxic lesion faced by cells and several DNA-damage signalling and repair mechanisms have evolved to deal with them. In human cells, DSB repair is mostly performed by the non-homologous end joining (NHEJ) and homologous recombination repair (HRR) pathways, with a third pathway, named alt-EJ, generally regarded as a less frequently used option. The first steps of the HRR and alt-EJ pathways are shared, where the ends of the DNA DSB will be processed (resected) to generate regions of single-stranded DNA (ssDNA). While during HRR resection is relatively extensive, it is kept to shorter stretches during alt-EJ through a mechanism that remained elusive. In addition, alt-EJ has been linked to the use of sequence microhomologies (2-6 base pairs) surrounding the DSB site for repair by direct annealing, processing of the DNA flaps and ligation, which explains its error-prone nature. As such, alt-EJ is also referred to as microhomology-mediated end joining (MMEJ) (Ciccia and Elledge, 2010).

HRR is a form of DNA repair that, once a DSB has occurred on a chromosome’s chromatid, uses the sister chromatid as template for repair. As such, HRR is regarded as error-free and can only take place once a sister chromatid is available, namely during the DNA replication (synthesis) phase (S phase) and gap phase 2 (G2 phase) of the cell cycle. HRR deficiency (HRD) is well described in tumours 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 increasing levels of genomic instability, highlighted by the presence of specific mutational signatures involving single-base substitutions (SBS), insertions-deletions (INDEL) and rearrangements (Nik-Zainal et al., 2016). Interestingly, the SBS signature associated with HRD (SBS3), is also associated with an INDEL signature (ID6) that is characterised by extensive microhomology usage at the break point (Alexandrov et al., 2020), suggesting that MMEJ could be an important DNA repair pathway in the absence of HRR. In agreement with this, signatures of MMEJ-mediated repair events have been identified in secondary (reversion) mutations restoring the open-reading frame of BRCA and other HRR-related genes in tumours from patients progressing on treatment, strongly suggesting that these reversion events are mediated by MMEJ repair and driving therapy resistance in these clinical cases (Pettitt et al., 2020; Tobalina et al., 2021).

Recently, POLQ has been involved in MMEJ repair while not playing a significant role in HRR, making it the only MMEJ-specific protein known to date (Wyatt et al., 2016; Yousefzadeh et al., 2014). Interestingly, reports have highlighted a synthetic lethal genetic dependency between inactivating mutations in genes involved in HRR (BRCA1, BRCA2, FANCD2, A TM) and lack of POLQ activity (Ceccaldi et al., 2015; Mateos-Gomez et al., 2015; Shima et al., 2004), being that activity either polymerase or helicase (Mateos-Gomez et al., 2017). As such, there is an increasing interest in developing POLQ inhibitors for the treatment of HRD tumours, both as single agents or in combination with poly(ADP-ribose) polymerase (PARP) inhibitors (Zatreanu et al., 2021; Zhou et al., 2021). Importantly, it has also been shown that POLQ-deficient cells are sensitive to DNA damaging agents including ionising radiation (Higgins et al., 2010; Yousefzadeh et al., 2014), which could open the possibility of combinations of POLQ inhibitors with chemo- or radiotherapy (Higgins and Boulton, 2018).

Accordingly, there is a need for POLQ inhibitors that are selective, demonstrate good bioavailability and are suitable for dosing.

SUMMARY

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

or any stereoisomer thereof or pharmaceutically acceptable salt thereof; wherein,

R¹ and R² are each, independently, H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 haloalkyl, C1-C3 hydroxyalkyl, -CN, C2-C4 alkynyl, or C2-C6 alkoxyalkyl;

Q¹, Q², and Q³ are, independently N, C-L-R, or CR^X, wherein no more than one of Q¹, Q², and Q³ is C-L-R;

R^xis H, halo, hydroxy, -CN, -NH2, C1-C3 alkoxy, C1-C3 alkyl, or C1-C3 haloalkyl;

L is a bond, -O-; -C(O)-; -O(CH₂)_PC(O)-; -C(O)NR^y-; -O(CH₂)_PC(O)NR^y-; -O(CH₂)_PNR^y; -NR^y-; -(CH₂)_P-; -(CH₂)_PNR^y-; -(CH₂)_PO-; -(CH₂)_PC(O)-; -(CH₂)_PC(O)O-; or -O(CH₂)_P-; p is, independently, 1, 2, or 3

R is H, R^a, R^b, R^c, R^d, R^f, R^g, or R^h;

R^a is a 3-10 membered heterocycle optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, C1-C7 alkyl, -S(O)2Ci-C3 alkyl and -C(O)- C3-C6 carbocycle, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

R^b is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with S, S(O), NR^e, O or CW^XW² wherein W¹ and W² together form a C3- Ce carbocycle, and one or two single bonds in a C2-C7 alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

R^c is a C3-C6 carbocycle optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN;

R^d is C1-C4 sulfonyl or C1-C4 sulfonamide;

R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and/or wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle, wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with NR^e or O and one or two single bonds in a C2-C7 alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

R^g is a 3-10 membered heterocycle substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, C1-C7 alkyl, -S(O)2Ci-C3 alkyl and -C(O)C3-Ce carbocycle, wherein at least one of the substituents is -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle, and wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

R^h is a C3-C6 carbocycle substituted with 1 to 4 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN;

R^y is H, C1-C3 alkyl, or C1-C3 haloalkyl;

R^e is H, halo, Ci-Cs alkyl, or Ci-Cs haloalkyl;

X is a C1-C4 alkylene;

Y is a phenyl or 5-6 membered heteroaryl wherein when Q¹, Q², and Q³ are, independently N or CR^X, or when one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, the phenyl or 5-6 membered heteroaryl is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, - CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl; wherein when one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, the phenyl or 5-6 membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O- (C1-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

G is N or CH;

G_a and Gb are N, CH, or CR⁵ wherein one, and only one, of G_a and Gb is N or CH and one, and only one, of G_a and Gb is CR⁵; y ;

R⁵ is ;

Z_a and Zb are, independently, C1-C3 alkyl or C1-C3 haloalkyl, or Z_a and Zb together form a C3-C6 carbocycle or a 3-6 membered heterocycle; and

Z_c is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkynyl.

In some embodiments, the present disclosure provides a compound of formula (I), wherein: R¹ and R² are each, independently, H or halo;

Q¹, Q², and Q³ are, independently, CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R;

L is -O-;

R is R^b, wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl;

Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and Ci- C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O- (C1-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

In some embodiments, the present disclosure provides a compound of formula (I), wherein:

R¹ and R² are each, independently, H or halo;

Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R;

L is -O-;

R is R^f, R^g, or R^h;

R^f is a C1-C7 alkyl, wherein; one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and optionally wherein the C1-C7 alkyl is substituted with a carboxy; or one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle, and wherein the C1-C7 alkyl is substituted with a carboxy;

R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle; R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C 1- C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN;

Y is a phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

The present disclosure also provides a pharmaceutical composition which comprises a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as described anywhere herein, and at least one pharmaceutically acceptable excipient.

The present disclosure also provides a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as described anywhere herein, or a pharmaceutical composition thereof, for use in the treatment cancer. In some embodiments, the cancer is breast, ovarian, pancreatic, or prostate cancer.

The present disclosure also provides a method of treating cancer which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as described anywhere herein or of a pharmaceutical composition thereof. In some embodiments, the cancer is breast, ovarian, pancreatic, or prostate cancer. The present disclosure also provides the use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as described anywhere, or a pharmaceutical composition thereof, in the manufacture of a medicament for the treatment of cancer in a subject. In some embodiments, the cancer is breast, ovarian, pancreatic, or prostate cancer.

DETAILED DESCRIPTION

This detailed description and its specific examples, while indicating embodiments, are intended for purposes of illustration only. Therefore, there is no limitation to the illustrative embodiments described in this specification. In addition, it is to be appreciated that various features that are, for clarity reasons, described in the context of separate embodiments, also may be combined to form a single embodiment. Conversely, various features that are, for brevity reasons, described in the context of a single embodiment, also may be combined to form sub-combinations thereof.

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

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.

The term “alkoxy alkyl” refers to an alkyl group attached to an alkoxy group, where in the group is attached to the rest of the molecule via a carbon on the alkyl group, i.e. a group having a structure of -R-O-R’ wherein R and R’ are the same or different alkyl groups.

The term “alkyl” refers to a straight chained or branched non-aromatic hydrocarbon which is completely saturated. The term “alkylene” refers to a saturated hydrocarbon group with two points of attachment to adjacent atoms/groups. Alkyls and alkylenes may include straight chain(s) and/or branched chain(s). Examples of straight chained and branched alkyl groups include methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, pentyl, hexyl, pentyl and octyl.

The term “alkylamino” refers to an amino group substituted with at least one alkyl group, i.e. a group having a structure of -NRR’, NHR, NRR’H⁺, or NEER wherein R and R’ are the same or different alkyl groups. The term “alkynyl” is a non-aromatic hydrocarbon comprising at least one carbon-carbon triple bond. Examples of alkynyl groups include acetylenyl, propynyl, and butynyl.

The term “amide” refers to a group with the general formula of R'C(=O)NR"R"', or , where R', R", and R'" are either hydrogen or the same or different alkyl groups, provided at least one is an alkyl group. The amide is connected to the rest of the molecule via either the carbon or the nitrogen.

The term “amino” refers to a group with the formula -NR'R" wherein R' and R" are independently selected from, for example, hydrogen or a hydrocarbon group, or, in the case of a “cyclic” amino group, R' and R", taken together with the nitrogen atom to which they are attached, form a heterocyclic ring. Amino groups may be primary (-NH2), secondary (-NHR' where R' is a hydrocarbon group), or tertiary (-NR'R" where R' and R"). In cationic form, amino groups may be quaternary.

The term “carbamate” refers to a group with the general formula of R'OC(O)NR"R"' or wherein R', R", and R'" are either hydrogen or the same or different alkyl groups, provided at least one is an alkyl group. The carbamate is connected to the rest of the molecule via the oxygen or the nitrogen or a carbon on any of the alkyl groups.

The term “carbocycle” refers to a partially or completely saturated non-aromatic hydrocarbon ring system, including cycloalkyls, cycloalkenyls, and cycloalkynyls. Cycloalkyls include cyclopropane, cyclobutane, cyclopentane, cyclohexane, cyclopropene, cyclobutene, cyclopentene, and cyclohexene. Carbocycles include monocyclic carbocycles as well as spiro, fused and/or bridged polycyclic carbocycles such as bicyclic carbocycles.

The term “carboxy” refers to a group with the formula -C(=O)OH. The term “ester” refers to a group having the structure R'-C(O)-OR", or wherein R' and R" are the same or different alkyl groups. The ester is connected to the rest of the molecule via a carbon on either alkyl group.

The term “halo” means fluoro, chloro, bromo, and iodo. In some embodiments, halo is fluoro or chloro. In other embodiments, halo is fluoro. In still other embodiments, halo is chloro.

The term “haloalkyl” means an alkyl group in which one or more hydrogens has been substituted with a halo.

The term “heteroaryl” refers to a substituted or unsubstituted monocyclic aromatic ring system, whose ring structures include at least one heteroatom. Examples of monocyclic heteroaryls or heteroarylenes include, but are not limited to, pyrrole, pyridine, pyrazine, pyridazine, pyrimidine, furan, triazole, thiophene, imidazole, isoxazole, oxazole, oxadiazole, thiazole and pyrazole. Examples of bicyclic heteroaryls, include, but are not limited to purine, indole, indazole, quinoline, quinazoline, benzofuran, benzoxazole, and benzodioxole.

The term “hydroxy alkyl” means an alkyl group in which one or more hydrogens has been substituted with a hydroxy group.

The term “heterocycle” refers to a partially or completely saturated hydrocarbon ring system wherein at least one of the ring carbon atoms is replaced with a heteroatom independently selected from nitrogen, oxygen and sulphur. Heterocyclic groups can be attached to the rest of the molecule via a carbon or nitrogen ring-member atoms. Heterocycles include monocyclic heterocycles as well as spiro, fused and/or bridged polycyclic heterocycles such as bicyclic heterocycles. Examples of monocyclic heterocycles include, but are not limited to, tetrahydropyran, tetrahydrofuran, morpholine, azetidine, pyrrolidine, piperidine, piperazine, pyridine, azepane, diazepane, oxetane, tetrahydropyran, thietane, and isoxazolidine.

The term “sulfonamide” refers to a group with the formula -S(=0)2NR'R", wherein R' and R" are independently amino substituents, as defined for amino groups. o, o

X

The term “sulfonyl” refers to a group having the general formula R'S(0)2R", or R’ ^R" wherein R' and R" are either hydrogen or the same or different alkyl groups, provided at least one is an alkyl group. The sulfonyl is connected to the rest of the molecule via a carbon on either alkyl group.

In this specification the prefix C_{x y} as used in terms such as “Cx-_y alkyl” and the like where x and y are integers, indicates the numerical range of carbon atoms that are present in the group. Examples of suitable C1-3 alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, and i -propyl. Examples of suitable C1-4 alkyl groups include, but are not limited to, methyl, ethyl, n- propyl, and i-propyl, n-butyl, i-butyl, s-butyl and t-butyl. In some cases, a group will have two sections comprising carbon, which case the prefix indicates the numerical range of total carbons in the group, e.g., C2-6 alkoxyalkyl, refers to an alkoxyalkyl group wherein the alkyl group and the alkoxy group together have 2 to 6 carbons.

A “patient” or “subject” refers to an animal in which the one or more active agents as described herein will have a therapeutic effect. In some embodiments, the patient is a human being.

As used herein, unless otherwise stated, the term “pharmaceutically acceptable” as used herein 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 problem or complication, commensurate with a reasonable benefit/risk ratio.

As used herein, unless otherwise stated, the phrase "effective amount" means an amount of a compound or composition which is sufficient to significantly and positively modify the symptoms and/or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically-acceptable excipient(s)/carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. The term "treating", as used herein, unless otherwise indicated, means reversing, alleviating, inhibiting the progress of, or slowing or delaying the progression of, the disorder or condition to which such term applies, or one or more symptoms of such disorder or condition. The term "treatment", as used herein, unless otherwise indicated, refers to the act of treating as "treating" is defined immediately above. The term "treating" also includes adjuvant and neoadjuvant treatment of a subject. The term "treating" also includes the reduction or inhibition of the growth of a tumor or proliferation of cancerous cells in a subject.

The language “pharmaceutically acceptable salt” includes acid addition or base addition salts that retain the biological effectiveness and properties of the compounds disclosed herein. In many cases, the compounds disclosed herein capable of forming acid and/or base salts by virtue of the presence of basic and/or carboxyl groups or groups similar thereto.

Compounds

The present disclosure provides a compound of formula (I): or a stereoisomer or pharmaceutically salt thereof; wherein,

Q¹, Q², and Q³ are, independently N, C-L-R, or CR^X, wherein no more than one of Q¹, Q², and Q³ is C-L-R; R^xis H, halo, hydroxy, -CN, -NH₂, C1-C3 alkoxy, C1-C3 alkyl, or C1-C3 haloalkyl;

L is a bond, -O-; -C(O)-; -O(CH₂)_PC(O)-; -C(O)NR^y-; -O(CH₂)_pC(O)NR^y-; -O(CH₂)_pNR^y; -NR^y-; -(CH₂)_P.; -(CH₂)_pNR^y-; -(CH₂)_PO-; -(CH₂)_PC(O)-; -(CH₂)_PC(O)O-; or -O(CH₂)_p-; p is, independently, 1, 2, or 3

R is H, R^a, R^b, R^c, R^d, R^f, R^g, or R^h;

R^a is a 3-10 membered heterocycle optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)₂OH, C1-C4 alkylamino, C1-C5 alkoxy, C₂-Cs alkoxyalkyl, 4-6 membered heterocycle, C1-C7 alkyl, -S(O)₂Ci-C3 alkyl and -C(O)- C3-C6 carbocycle, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C₂-Cs ester, and C1-C5 alkoxy;

R^b is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with S, S(O), NR^e, O or CW^XW² wherein W¹ and W² together form a C3- Ce carbocycle, and one or two single bonds in a C₂-C? alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C₂-C4 alkynyl, C₂-Ce carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)₂OH, C1-C4 alkylamino, C1-C5 alkoxy, C₂-Cs alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C₂-Cs ester, and C1-C5 alkoxy; R^c is a C3-C6 carbocycle optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN;

R^d is C1-C4 sulfonyl or C1-C4 sulfonamide;

R^g is a 3-10 membered heterocycle substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, C1-C7 alkyl, -S(O)2Ci-C3 alkyl and -C(O)C3-Ce carbocycle, wherein at least one of the substituents is -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle, and wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy; R^h is a C3-C6 carbocycle substituted with 1 to 4 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN;

R^y is H, C1-C3 alkyl, or C1-C3 haloalkyl;

R^e is H, halo, Ci-Cs alkyl, or Ci-Cs haloalkyl;

X is a C1-C4 alkylene;

Y is a phenyl or 5-6 membered heteroaryl wherein when Q¹, Q², and Q³ are, independently N or CR^X, or when one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, the phenyl or 5-6 membered heteroaryl is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, - CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl; wherein when one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, the phenyl or 5-6 membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O- (C1-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

G is N or CH;

G_a and Gb are N, CH, or CR⁵ wherein one, and only one, of G_a and Gb is N or CH and one, and only one, of G_a and Gb is CR⁵; Z_a and Zb are, independently, C1-C3 alkyl or C1-C3 haloalkyl, or Z_a and Zb together form a C3-C6 carbocycle or a 3-6 membered heterocycle; and

Z_c is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkynyl.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein G is N. In some embodiments G is CH.

In some embodiments G_a is CR⁵. In some embodiments Gb is CR⁵. In some embodiments Gb is N. In some embodiments Gb is CH. In some embodiments G_a is N. In some embodiments G_a is CH. In some embodiments G is N, Gb is N and G_a is CR⁵.

In some embodiments Z_a and Zb, are independently, C1-C3 alkyl. In some embodiments Z_a and Zb are -CH3.

In some embodiments , wherein p is 1-4. In some embodiments, p is 2. In other embodiments, p is 1.

In some embodiments , wherein p is 1.

In some embodiments Z_c is -CH3. In some embodiments Z_c is -CN.

In some embodiments , wherein p is

1-4. In some embodiments, p is 1. In other embodiments, p is 2. In some embodiments and Z_c is C1-C3 alkyl. In certain embodiments, Z_c is -CH3.

In some embodiments and Z_c is C1-C3 alkyl. In certain embodiments, Z_c is -CH3.

In some embodiments and Z_c is -CH₃.

In some embodiments and Z_c is -CN. In some embodiments, p is 1. In other embodiments, p is 2. In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein X is CH2.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Y is phenyl. In some embodiments Y is a 5-6 membered N-heteroaryl. In some embodiments Y is a pyridinyl.

In some embodiments Y is substituted. In some embodiments Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, hydroxy, -O-(Ci- C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl. In some embodiments Y is substituted with hydroxy. In some embodiments Y is substituted with -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), optionally - O(CH₂)₂OCH₃. In some embodiments Y is substituted with 1 or 2 halo selected from -Cl and -F. In some embodiments Y is substituted with -OCF3. In some embodiments Y is substituted with - OCH3. In some embodiments Y is substituted with -CH3. In some embodiments Y is substituted with -CN. In some embodiments Y is substituted with halo and hydroxy. In some embodiments Y is substituted with 1 or 2 substituents selected from halo and C1-C3 alkoxy. In some embodiments Y is substituted with 1 or 2 substituents selected from halo and CN. In some embodiments Y is substituted with 1 or 2 substituents selected from halo and with -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), optionally -O(CH₂)₂OCH3. In some embodiments Y is substituted with 1 or 2 substituents selected from C1-C3 alkyl and C1-C3 alkoxy.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, and wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d, and wherein Y is substituted with 1 to 3 substituents independently selected from halo, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O- (C1-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is substituted with 1 to 3 substituents independently selected from halo, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d, and wherein Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d, and wherein Y is phenyl substituted with halo and hydroxy.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with halo and hydroxy. In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, and wherein Y is phenyl substituted with - Cl and hydroxy.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with -Cl and hydroxy.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d, and wherein Y is phenyl substituted with halo and -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl).

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with halo and -O-(Ci- C3 alkylene)-O-(Ci-C3 alkyl).

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, and wherein Y is phenyl substituted with - Cl and -O-(CH₂)2-O-(CH₃).

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with -Cl and -O-(CH2)2- O-(CH₃).

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d, and wherein Y is phenyl substituted with OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is H, R^a, R^b, R^c, or R^d, and wherein Y is phenyl substituted with - OCF3.

In some embodiments Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^b, and wherein Y is phenyl substituted with -OCF3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is optionally substituted with 1 to 3 substituents independently selected from halo, Ci- C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci- C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, Ci- C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, Ci- C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, Ci- C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and Ci- C3 alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with 1 or 2 halo. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with 1 or 2 halo. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl and -F. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl and -F. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with - Cl.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with halo and C1-C3 alkoxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, Y is a phenyl substituted with halo and C1-C3 alkoxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with -Cl and -OCH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with -Cl and -OCH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with -F and -OCH3.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with halo and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with halo and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with -Cl and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with -Cl and CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with C1-C3 alkyl and C1-C3 alkoxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with C1-C3 alkyl and C1-C3 alkoxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a phenyl substituted with -CH3 and -OCH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a phenyl substituted with - CH₃ and -OCH₃.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a pyridinyl substituted with 1 or 2 substituents independently selected from halo, Ci- C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C- L-R and R is R^f, wherein Y is a pyridinyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is a pyridinyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is a pyridinyl substituted with 1 or 2 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, and -CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a pyridinyl substituted with C1-C3 alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a pyridinyl substituted with C1-C3 alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is a pyridinyl substituted with C1-C3 alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is a pyridinyl substituted with C1-C3 alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is a pyridinyl substituted with -CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, wherein Y is a pyridinyl substituted with -CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g, wherein Y is a pyridinyl substituted with -CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h, wherein Y is a pyridinyl substituted with -CH3.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h, wherein Y is not substituted.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R¹ and R² are each, independently, H, halo, C1-C3 alkyl, C1-C3 alkoxy, C1-C3 hydroxyalkyl, -CN, or C2-C4 alkynyl.

In some embodiments R¹ and R² are each, independently, H, halo, -CH3, -OCH3, CH2OH, -CN, or -C-CH. In some embodiments R¹ and R² are each, independently, H, halo, or C1-C3 alkyl. In some embodiments R¹ and R² are each, independently, H, halo, or -CH3. In some embodiments R¹ and R² are each, independently, H, -Cl, -F, or -CH3. In some embodiments R¹ and R² are -H.

In some embodiments R¹ is -H. In some embodiments R¹ is -CH3. In some embodiments R¹ is halo. In some embodiments R¹ is -Cl. In some embodiments R¹ is -F.

In some embodiments R² is -H. In some embodiments R² is -CH3. In some embodiments R² is halo. In some embodiments R² is -Cl. In some embodiments R² is -F.

In some embodiments R¹ is -CH3 and R² is -H. In some embodiments R¹ is - H and R² is - CH3. In some embodiments R¹ and R² are each, independently, H or halo. In some embodiments R¹ and R² are each, independently, H, Cl, or F.

In some embodiments R¹ or R² is halo and the other is H. In some embodiments R¹ or R² is Cl or F, and the other is H. In some embodiments R¹ and R² are each, independently, H or -Cl, wherein when R¹ is H, R² is -Cl, and when R¹ is -Cl, R² is H. In some embodiments R¹ is -H and R² is halo. In some embodiments R¹ is -H and R² is - Cl. In some embodiments R¹ is -H and R² is -F. In some embodiments R¹ is halo and R² is -H. In some embodiments R¹ is -Cl and R² is -H. In some embodiments R¹ is -F and R² is -H.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², or Q³ is C-L-R. In some embodiments Q¹ is C-L-R. In some embodiments Q² is C-L-R. In some embodiments Q³ is C-L-R.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is a bond, -O-, -(CH2)_PO- or -O(CH2)_P- . In some embodiments Q¹ is C-L-R and L is a bond, -O-, -(CH2)_PO- or -0(CH2)_P- In some embodiments Q² is C-L-R and L is a bond, -O-, -(CH2)_PO- or -O(CH2)_P- In some embodiments Q³ is C-L-R and L is a bond, -O-, -(CH2)_P0- or -0(CH2)_P-

In some embodiments Q¹, Q², or Q³ is C-L-R and L is a bond. In some embodiments Q¹ is C-L-R and L is a bond. In some embodiments Q² is C-L-R and L is a bond. In some embodiments Q³ is C-L-R and L is a bond.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is -O-. In some embodiments Q¹ is C- L-R and L is -O-. In some embodiments Q² is C-L-R and L is -O-. In some embodiments Q³ is C- L-R and L is -O-.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is -(CH2)_PO. In some embodiments Q¹ is C-L-R and L is -(CH2)_PO. In some embodiments Q² is C-L-R and L is -(CH2)_PO. In some embodiments Q³ is C-L-R and L is -(CH2)_PO.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is -O(CH2)_P-. In some embodiments Q¹ is C-L-R and L is -O(CH2)_P-. In some embodiments Q² is C-L-R and L is -O(CH2)_P-. In some embodiments Q³ is C-L-R and L is -O(CH2)_P-.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is -O(CH2)2-. In some embodiments Q¹ is C-L-R and L is -O(CH2)2-. In some embodiments Q² is C-L-R and L is -O(CH2)2-. In some embodiments Q³ is C-L-R and L is -O(CH2)2-.

In some embodiments Q¹, Q², or Q³ is C-L-R and L is -C(O)-; -O(CH2)_PC(O)-; -C(O)NR^y- ; -O(CH2)_PC(O)NR^y-; -(CH2)_PC(O)-; or -(CH2)_PC(O)O-. In some embodiments Q¹ is C-L-R and L is -C(0)-; -O(CH₂)_PC(O)-; -C(O)NR^y-; -O(CH₂)_pC(O)NR^y-; -(CH₂)_PC(O)-; or -(CH₂)_PC(O)O-. In some embodiments Q² is C-L-R and L is -C(O)-; -O(CH₂)_PC(O)-; -C(O)NR^y-; -O(CH₂)_pC(O)NR^y- ; -(CH₂)_PC(O)-; or -(CH₂)_PC(O)O-. In some embodiments Q³ is C-L-R and L is -C(O)-; - O(CH₂)_PC(O)-; -C(O)NR^y-; -O(CH₂)_pC(O)NR^y-; -(CH₂)_PC(O)-; or -(CH₂)_PC(O)O-.

In some embodiments Q¹, Q², and Q³ are, independently N, C-L-R, or CR^X, wherein no more than one of Q¹, Q², and Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q¹ is C-L-R and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q² is C-L-R and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q³ is C-L-R and R is H, R^a, R^b, R^c, orR^d.

In some embodiments Q¹, Q², or Q³ is C-L-R, L is -O- and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q¹ is C-L-R, L is -O- and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q² is C-L- R, L is -O- and R is H, R^a, R^b, R^c, orR^d. In some embodiments Q³ is C-L-R, L is -O- and R is H, R^a, R^b, R^c, orR^d.

In some embodiments Q¹, Q², or Q³ is C-L-R and R is R^a. In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is a 3-10 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C- L-R^a and R^a is a 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is a 6 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^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.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)₂OH, C1-C4 alkylamino, C1-C5 alkoxy, C₂-Cs alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C₂-Cs ester, and C1-C5 alkoxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is substituted with C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C₂-Cs ester, and C1-C5 alkoxy. In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^ais substituted with C1-C7 alkyl substituted with oxo. In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is substituted with C1-C7 alkyl substituted with a C1-C5 alkoxy. In some embodiments Q¹, Q², or Q³ is C-L-R^a and R^a is substituted with methyl. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)_P- and R^a is an optionally substituted 3-10 membered N-heterocycle.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)2- and R^a is an optionally substituted 3-10 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)2- and R^a is an optionally substituted 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)2- and R^a is an unsubstituted 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)2- and R^a is a 4-7 membered N- heterocycle substituted with hydroxy, methyl, or amino.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)3- and R^a is an optionally substituted 3-10 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)3- and R^a is a 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L- R^a and L is -O(CH2)3- and R^a is an unsubstituted 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O(CH2)3- and R^a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is a bond and R^a is an optionally substituted 3-10 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is a bond and R^a is a 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is a bond and R^a is an unsubstituted 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is a bond and R^a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino.

In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O- and R^a is an optionally substituted 3-10 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O- and R^a is a 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O- and R^a is an unsubstituted 4-7 membered N-heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^a and L is -O- and R^a is a 4-7 membered N-heterocycle substituted with hydroxy, methyl, or amino. In some embodiments Q¹, Q², or Q³ is C-L-R and R is R^b. In some embodiments Q¹ is C- L-R and R is R^b. In some embodiments Q² is C-L-R and R is R^b. In some embodiments Q³ is C- L-R and R is R^b.

In some embodiments Q¹, Q², or Q³ is C-L-R, L is -O- and R is R^b. In some embodiments Q¹ is C-L-R, L is -O- and R is R^b. In some embodiments Q² is C-L-R, L is -O- and R is R^b. In some embodiments Q³ is C-L-R, L is -O- and R is R^b.

In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3- Ce carbocycle, and 3-10 membered heterocycle; wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy, and wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, and C1-C5 alkoxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with amino, Ci-Cs amide, and/or C1-C4 alkylamino. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with oxo, hydroxy, and/or carboxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with hydroxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with carboxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is C4 alkyl substituted with carboxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with at least one C3-C6 carbocycle, wherein the C3-C6 carbocycle is substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with at least one C3-C6 carbocycle, wherein the C3-C6 carbocycle is substituted with 1 to 4 substituents independently selected from hydroxy and halo. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with a 3-10 membered heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with a N- heterocycle. In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with a 4-7 membered N-heterocycle.

In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with a 3-10 membered heterocycle, such as, but not limited to a N-heterocycle, such as, but not limited to a 4-7 membered N-heterocycle, wherein the heterocycle is substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b and R^b is substituted with a 3-10 membered heterocycle, such as, but not limited to a N-heterocycle, such as, but not limited to a 4-7 membered N-heterocycle, wherein the heterocycle is substituted with C1-C7 alkyl, oxo, and/or halo.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an optionally substituted C1-C5 alkyl. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an optionally substituted C1-C3 alkyl. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is a C1-C5 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is a C1-C3 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O- and R^b is substituted with carboxy. In some embodiments Q¹ is C-L-R^b, L is -O- and R^b is substituted with carboxy. In some embodiments Q² is C-L-R^b, L is -O- and R^b is substituted with carboxy. In some embodiments Q³ is C-L-R^b, L is - O- and R^b is substituted with carboxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O- and R^b is a C4 alkyl substituted with carboxy. In some embodiments Q¹ is C-L-R^b, L is -O- and R^b is a C4 alkyl substituted with carboxy. In some embodiments Q² is C-L-R^b, L is -O- and R^b is a C4 alkyl substituted with carboxy. In some embodiments Q³ is C-L-R^b, L is -O- and R^b is a C4 alkyl substituted with carboxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and Ci-C₈ amide. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and Ci-Cs amide. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an unsubstituted C1-C5 alkyl. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an unsubstituted C1-C3 alkyl.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an optionally substituted C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl is independently replaced with NR^e or O. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an optionally substituted C1-C7 alkyl, wherein one methylene group from the C1-C7 alkyl is replaced with NH. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is an optionally substituted C1-C7 alkyl, wherein one methylene group from the C1-C7 alkyl is replaced with NCH3.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an optionally substituted C1-C5 alkyl. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an optionally substituted C1-C3 alkyl.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an C1-C5 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an C1-C3 alkyl substituted with 1 to 4 substituents independently selected from amino, carboxy, oxy, and hydroxy.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an C1-C5 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and Ci-Cs amide. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an C1-C3 alkyl substituted with 1 to 4 substituents independently selected from -CN, C2-C4 alkynyl, C2-C6 carbamate, and Ci-Cs amide.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an unsubstituted Ci- C5 alkyl. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an unsubstituted C1-C3 alkyl.

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an optionally substituted C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl is independently replaced with NR^e or O. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an optionally substituted C1-C7 alkyl, wherein one methylene group from the C1-C7 alkyl is replaced with NH. In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is a bond, and R^b is an optionally substituted C1-C7 alkyl, wherein one methylene group from the C1-C7 alkyl is replaced with NCH3.

In some embodiments Q¹, Q², or Q³ is C-L-R^c. In some embodiments Q¹, Q², or Q³ is C-L- R^c and R^c is substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy. In some embodiments Q¹, Q², or Q³ is C-L-R^c and R^c is substituted with 1 to 4 substituents independently selected from hydroxy and halo.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f, R^g, or R^h. In some embodiments Q¹ is C-L-R and R is R^f, R^g, or R^h. In some embodiments Q² is C-L-R and R is R^f, R^g, or R^h. In some embodiments Q³ is C-L-R and R is R^f, R^g, or R^h.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R, L is -O- and R is R^f, R^g, or R^h. In some embodiments Q¹ is C-L-R, L is -O- and R is R^f, R^g, or R^h. In some embodiments Q² is C-L-R, L is -O- and R is R^f, R^g, or R^h. In some embodiments Q³ is C-L-R, L is -O- and R is R^f, R^g, or R^h.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^f. In some embodiments Q¹ is C-L-R and R is R^f. In some embodiments Q² is C-L-R and R is R^f. In some embodiments Q³ is C-L-R and R is R^f.

In some embodiments Q¹ is C-L-R, L is -O- and R is R^f. In some embodiments Q² is C-L- R, L is -O- and R is R^f. In some embodiments Q³ is C-L-R, L is -O- and R is R^f.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with NR^e or O and one or two single bonds in a C2-C7 alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, - S(O)₂OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O). In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O).

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O), wherein the C3-C4 alkyl is optionally substituted with a carboxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S, and wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S, and wherein the C1-C7 alkyl is substituted with carboxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3- C4 alkyl are independently replaced with S, and wherein the C3-C4 alkyl is substituted with carboxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S(O), and wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S(O). In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O).

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW¹ W² wherein W¹ and W² together form a C3-C6 carbocycle, wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with NR^e or O and one or two single bonds in a C2-C7 alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-Cs amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and

3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl,

4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f and R^f is a C3-C4 alkyl, wherein one methylene group from the C3-C4 alkyl is replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O). In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O).

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S, and wherein the C1-C7 alkyl is substituted with carboxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S, and wherein the C3-C4 alkyl is substituted with carboxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S(O). In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O).

In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O). In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O).

In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S, and wherein the C1-C7 alkyl is substituted with carboxy. In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S, and wherein the C3-C4 alkyl is substituted with carboxy. In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S(O). In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O).

In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O). In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O).

In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S, and wherein the C1-C7 alkyl is substituted with carboxy. In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S, and wherein the C3-C4 alkyl is substituted with carboxy.

In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with S(O). In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O).

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^f, L is -O-, and R^f is a C3-C4 alkyl, wherein one methylene group from the C3-C4 alkyl is replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle.

In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C3- C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments Q¹ is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl, wherein one methylene group from the C3-C4 alkyl is replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle.

In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C3- C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle. In some embodiments Q² is C-L-R^f, L is -O- and R^f is a C3-C4 alkyl, wherein one methylene group from the C3-C4 alkyl is replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^g. In some embodiments Q¹ is C-L-R and R is R^g. In some embodiments Q² is C-L-R and R is R^g. In some embodiments Q³ is C-L-R and R is R^g.

In some embodiments Q¹ is C-L-R, L is -O- and R is R^g. In some embodiments Q² is C-L- R, L is -O- and R is R^g. In some embodiments Q³ is C-L-R, L is -O- and R is R^g.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is substituted with -S(O)₂CH₃. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a 4-6 membered N-heterocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a 4-6 membered N-heterocycle substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a 4-6 membered N-heterocycle substituted with - C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is an azetidinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is an azetidinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is an azetidinyl substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyrrolidinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyrrolidinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyrrolidinyl substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyridinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyridinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g and R^g is a pyridinyl substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a 4-6 membered N-heterocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L- Rg, L is -O-, and R^g is a 4-6 membered N-heterocycle substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a 4-6 membered N-heterocycle substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is an azetidinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is an azetidinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is an azetidinyl substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a pyrrolidinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a pyrrolidinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a pyrrolidinyl substituted with -C(O)-C3 carbocycle.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a pyridinyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^g, L is -O-, and R^g is a pyridinyl substituted with -S(O)2CH3. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-Rg, L is -O-, and R^g is a pyridinyl substituted with -C(O)-C3 carbocycle.

In some embodiments Q¹ is C-L-R^g, L is -O- and R^g is a 4-6 membered N-heterocycle. In some embodiments Q¹ is C-L-R^g, L is -O- and R^g is a 4-6 membered N-heterocycle substituted with -S(O)₂CH₃. In some embodiments Q¹ is C-L-R^g, L is -O- and R^g is a 4-6 membered N- heterocycle substituted with -C(O)-C3 carbocycle.

In some embodiments Q² is C-L-R^g, L is -O- and R^g is a 4-6 membered N-heterocycle. In some embodiments Q² is C-L-R^g, L is -O- and R^g is a 4-6 membered N-heterocycle substituted with -S(O)₂CH₃. In some embodiments Q² is C-L-R^g, L is -O- and R^g is a 4-6 membered N- heterocycle substituted with -C(O)-C₃ carbocycle.

In some embodiments Q² is C-L-R^g, L is -O- and R^g is an azetidinyl substituted with - S(O)₂CH₃. In some embodiments Q² is C-L-R^g, L is -O- and R^g is an azetidinyl substituted with - C(O)-C₃ carbocycle. In some embodiments Q² is C-L-R^g, L is -O- and R^g is a pyrrolidinyl substituted with -S(O)₂CH₃. In some embodiments Q² is C-L-R^g, L is -O- and R^g is a pyridinyl substituted with -S(O)₂CH₃.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R and R is R^h. In some embodiments Q¹ is C-L-R and R is R^h. In some embodiments Q² is C-L-R and R is R^h. In some embodiments Q³ is C-L-R and R is R^h.

In some embodiments Q¹ is C-L-R, L is -O- and R is R^h. In some embodiments Q² is C-L- R, L is -O- and R is R^h. In some embodiments Q³ is C-L-R, L is -O- and R is R^h.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with CN, and optionally wherein R^h is additionally substituted with 1 to 3 substituents independently selected from hydroxy, halo, carboxy, Ci-C₃ alkyl, and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with Ci-C₃ alkyl, and optionally wherein R^h is additionally substituted with 1 to 3 substituents independently selected from hydroxy, halo, carboxy, Ci-C₃ alkyl, and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with Ci-C₃ alkyl. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with CH₃.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with hydroxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is substituted with C1-C3 alkyl and hydroxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L- R^h and R^h is substituted with CH3 and hydroxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is a C4 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is a C4 carbocycle substituted with CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is a C4 carbocycle substituted with C1-C3 alkyl and hydroxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h and R^h is a C4 carbocycle substituted with CH3 and hydroxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is substituted with CN.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is substituted with C1-C3 alkyl, and optionally wherein R^h is additionally substituted with 1 to 3 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is substituted with C1-C3 alkyl and hydroxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is substituted with CH3 and hydroxy.

In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is a C4 carbocycle. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is a C4 carbocycle substituted with CN. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O- , and R^h is a C4 carbocycle substituted with C1-C3 alkyl and hydroxy. In some embodiments one, and only one, of Q¹, Q², or Q³ is C-L-R^h, L is -O-, and R^h is a C4 carbocycle substituted with CH3 and hydroxy. In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is substituted with CN. In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is substituted with C1-C3 alkyl and hydroxy.

In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is a C4 carbocycle. In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with CN. In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with C1-C3 alkyl and hydroxy. In some embodiments Q¹ is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with CH3 and hydroxy.

In some embodiments Q² is C-L-R^h, L is -O- and R^h is substituted with CN.

In some embodiments Q² is C-L-R^h, L is -O- and R^h is substituted with C1-C3 alkyl, and optionally wherein R^h is additionally substituted with 1 to 3 substituents independently selected from hydroxy, halo, carboxy, C1-C3 alkyl, and CN. In some embodiments Q² is C-L-R^h, L is -O- and R^h is substituted with C1-C3 alkyl and hydroxy. In some embodiments Q² is C-L-R^h, L is -O- and R^h is substituted with CH3 and hydroxy.

In some embodiments Q² is C-L-R^h, L is -O- and R^h is a C4 carbocycle. In some embodiments Q² is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN. In some embodiments Q² is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with CN. In some embodiments Q² is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with C1-C3 alkyl and hydroxy. In some embodiments Q² is C-L-R^h, L is -O- and R^h is a C4 carbocycle substituted with CH3 and hydroxy.

In some embodiments disclosed herein is provided a compound of formula (I): (I) or a stereoisomer or pharmaceutically salt thereof; wherein,

Q¹, Q², and Q³ are, independently N or CR^X, or one, and only one, of Q¹, Q², or Q³ is C-L-R;

R is H, R^a, R^b, R^c, orR^d;

R^b is a C1-C7 alkyl, wherein one or two methylene groups from the C1-C7 alkyl are optionally independently replaced with S, S(O), NR^e, O or CW^XW² wherein W¹ and W² together form a C3- Ce carbocycle, and one or two single bonds in a C2-C7 alkyl chain are optionally independently replaced with a double or triple bond(s), wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from: halo, oxo, hydroxy, carboxy, amino, -CN, C2-C4 alkynyl, C2-C6 carbamate, Ci-C₈ amide, C1-C4 sulfonyl, C1-C4 sulfonamide, C1-C4 alkylamino, C1-C5 alkoxy, C3-C6 carbocycle, and 3-10 membered heterocycle, wherein the C3-C6 carbocycle is optionally substituted with 1 to 4 substituents independently selected from hydroxy, halo, and carboxy; wherein the 3-10 membered heterocycle is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, -S(O)2OH, C1-C4 alkylamino, C1-C5 alkoxy, C2-C5 alkoxyalkyl, 4-6 membered heterocycle, and C1-C7 alkyl, wherein the C1-C7 alkyl is optionally substituted with 1 to 4 substituents independently selected from amino, carboxy, halo, hydroxy, oxo, -CN, C2-C8 ester, and C1-C5 alkoxy;

R^d is C1-C4 sulfonyl or C1-C4 sulfonamide;

R^y is H, C1-C3 alkyl, or C1-C3 haloalkyl;

R^e is H, halo, Ci-Cs alkyl, or Ci-Cs haloalkyl;

X is a C1-C4 alkylene;

Y is a phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, - CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

G is N or CH;

G_a and Gb are N, CH, or CR⁵ wherein one, and only one, of G_a and Gb is N or CH and one, and only one, of G_a and Gb is CR⁵;

Z_c is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkynyl.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein,

R¹ and R² are each, independently, H or halo;

L is -O-;

Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and Ci- C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O- (C1-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R¹ and R² are each, independently, H or halo;

L is -O-;

R is R^b, wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl; Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O- (CH₂)2-O-CH₃, and -OCF₃.

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

In some embodiments disclosed herein is provided a compound of formula (I): or a stereoisomer or pharmaceutically salt thereof; wherein,

Q¹, Q², and Q³ are, independently N, C-L-R, or CR^X, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R;

R is R^f, R^g, or R^h;

R^y is H, C1-C3 alkyl, or C1-C3 haloalkyl;

R^e is H, halo, Ci-Cs alkyl, or Ci-Cs haloalkyl;

X is a C1-C4 alkylene;

Y is a phenyl or 5-6 membered heteroaryl, wherein the phenyl or 5-6 membered heteroaryl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, Ci- C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

G is N or CH;

Z_c is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkynyl.

R¹ and R² are each, independently, H or halo;

Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R;

L is -O-;

R is R^f, R^g, or R^h;

R^f is a C1-C7 alkyl, wherein; one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and optionally wherein the C1-C7 alkyl is substituted with a carboxy; or one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle, and wherein the C1-C7 alkyl is substituted with a carboxy; R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle;

R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

In some embodiments disclosed herein is provided a compound of formula (I), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R is R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle, and wherein the C3-C4 alkyl is substituted with a carboxy.

In some embodiments R is R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O), and optionally wherein the C3-C4 alkyl is substituted with a carboxy.

In some embodiments R is R^g and R^g is a 4-6 membered N-heterocycle selected from azetidinyl, pyrrolidinyl and pyridinyl, wherein the N-heterocycle is substituted at the N position with -S(O)₂Ci-C₃ alkyl or -C(O)-C3-Ce carbocycle. In some embodiments R is R^h and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN.

In some embodiments Y is a pyridinyl substituted with -CH3. In some embodiments Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, -CH3, and -CN.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-A): or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein,

R¹ and R² are each, independently, H or halo, and

Y, Q¹, Q² and Q³ are as defined in formula (I).

In some embodiments Q¹, Q², or Q³ is C-L-R, wherein L and R are as defined in formula (I).

In some embodiments Q¹, Q², or Q³ is C-L-R, L is -O-, and R is R^b, wherein R^b is as defined in formula (I).

In some embodiments Q¹, Q², or Q³ is C-L-R^b, L is -O-, and R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl.

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein: Q¹, Q², and Q³ are, independently, CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R;

L is -O-;

R is R^b, wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl; and

Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and Ci- C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O- (C1-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein:

L is -O-;

Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O- (CH₂)2-O-CH₃, and -OCF₃.

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², and Q³ are, independently, CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R;

L is -O-;

Y is a phenyl substituted with -Cl and hydroxy. In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², and Q³ are, independently, CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R;

L is -O-;

Y is a phenyl substituted with -Cl and -O-(CH2)2-O-CH3.

L is -O-;

Y is a phenyl substituted with -OCF3.

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², or Q³ is C-L-R, L is -O-, and R is R^f, R^g, or R^h, wherein R^f, R^g, or R^h are as defined in formula (I).

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein Q¹, Q², or Q³ is C-L-R, L is -O-, and R is R^f, R^g, or R^h, wherein:

R^f is a C1-C7 alkyl, wherein; one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and optionally wherein the C1-C7 alkyl is substituted with a carboxy; or one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle, and wherein the Ci- C7 alkyl is substituted with a carboxy;

R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle; and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN.

L is -O-;

R is R^f, R^g, or R^h;

R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle;

R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C 1- C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN; and

Y is a phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl.

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein: Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R;

L is -O-;

R is R^f, R^g, or R^h;

Y is a pyridinyl substituted with -CH3.

L is -O-;

R is R^f, R^g, or R^h;

Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, - CH₃, and -CN.

Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R, wherein L is -O- and R is R^f;

R^f is a C1-C7 alkyl, wherein; one or two methylene groups from the C1-C7 alkyl are independently replaced with S or S(O), and optionally wherein the C1-C7 alkyl is substituted with a carboxy; or one or two methylene groups from the C1-C7 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3-C6 carbocycle, and wherein the C1-C7 alkyl is substituted with a carboxy; and

In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein: Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R, wherein L is -O- and R is R^f;

R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle, and wherein the C3-C4 alkyl is substituted with a carboxy; and

Y is a pyridinyl substituted with -CH3.

Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, - CH₃, and -CN. In some embodiments disclosed herein is provided a compound of formula (I-A), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein:

R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O), and optionally wherein the C3-C4 alkyl is substituted with a carboxy; and

Y is a pyridinyl substituted with -CH3.

Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R, wherein L is -O- and R is R^g;

R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle; and

Y is a pyridinyl substituted with -CH3.

R^g is a 4-6 membered N-heterocycle selected from azetidinyl, pyrrolidinyl and pyridinyl, wherein the N-heterocycle is substituted at the N position with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle; and

Y is a pyridinyl substituted with -CH3.

R^g is a 4-6 membered N-heterocycle selected from azetidinyl, pyrrolidinyl and pyridinyl, wherein the N-heterocycle is substituted at the N position with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle; and Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, - CH₃, and -CN.

Q¹, Q², and Q³ are, independently CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C- L-R, wherein L is -O- and R is R^h;

Y is a pyridinyl substituted with -CH3.

R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C 1- C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN; and Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, - CH₃, and -CN.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-B): or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein,

R¹ and R² are each, independently, H or halo, and

Y and R^b are as defined in formula (I).

In some embodiments disclosed herein is provided a compound of formula (I-B), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl. In some embodiments R^b is a C4 alkyl substituted with a carboxy.

In some embodiments Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O-(CH2)2-O-CH3, and -OCF3.

In some embodiments Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O-(CH2)2-O-CH3, and -OCF3, and wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl.

In some embodiments Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O-(CH2)2-O-CH3, and -OCF3, and wherein R^b is a C4 alkyl substituted with a carboxy. In some embodiments Y is a phenyl substituted with -Cl and hydroxy, and wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl.

In some embodiments Y is a phenyl substituted with -Cl and -O-(CH2)2-O-CH3, and wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl. In some embodiments Y is a phenyl substituted with -OCF3, and wherein R^b is substituted with a carboxy, optionally wherein R^b is C4 alkyl.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-C): or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein,

R¹ and R² are each, independently, H or halo, and

Y and R^f are as defined in formula (I).

In some embodiments disclosed herein is provided a compound of formula (I-C), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein:

Y is a pyridinyl substituted with -CH3.

R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle, and wherein the C3-C4 alkyl is substituted with a carboxy; and Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, - CH₃, and -CN.

R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S, and wherein the C3-C4 alkyl is substituted with a carboxy; and

R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O); and

Y is a phenyl or pyridinyl, wherein the phenyl or pyridinyl is optionally substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and 0CR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl. In some embodiments disclosed herein is provided a compound of formula (I-C), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein:

Y is a pyridinyl substituted with -CH3.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-D): or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein,

R¹ and R² are each, independently, H or halo, and

Y and R^f are as defined in formula (I).

In some embodiments disclosed herein is provided a compound of formula (I-D), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein:

In some embodiments disclosed herein is provided a compound of formula (I-D), or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein: R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S(O); and

Y is a pyridinyl substituted with -CH3.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-E):

or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R¹ and R² are each, independently, H or halo, and wherein R^g is as defined in formula (I).

In some embodiments R^g is a 4-6 membered N-heterocycle substituted with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle. In some embodiments R^g is a 4-6 membered N-heterocycle selected from azetidinyl, pyrrolidinyl and pyridinyl, wherein the N-heterocycle is substituted at the N position with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle.

In some embodiments R^g is an azetidinyl substituted with -S(O)2CH3. In some embodiments R^g is an azetidinyl substituted with -C(O)-C3 carbocycle. In some embodiments R^g is a pyrrolidinyl substituted with -S(O)2CH3. In some embodiments R^g is a pyrrolidinyl substituted with -C(O)-C3 carbocycle.

In some embodiments R^g is a pyridinyl substituted with -S(O)2CH3. In some embodiments R^g is a pyridinyl substituted with -C(O)-C3 carbocycle.

In some embodiments disclosed herein is provided a compound of formula (I) having the structure of formula (I-F):

or any stereoisomer thereof or pharmaceutically acceptable salt thereof, wherein R¹ and R² are each, independently, H or halo, and wherein R^h is as defined in formula (I).

In some embodiments R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN. In some embodiments R^h is a C4 carbocycle substituted with CN. In some embodiments R^h is a C4 carbocycle substituted with C1-C3 alkyl and hydroxy. In some embodiments R^h is a C4 carbocycle substituted with CH3 and hydroxy. Some embodiments disclosed herein provide a compound selected from:

2-(l-((2-Chl oro-3 -(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid_x

8-(2-Chloro-4-(2-(methylsulfinyl)ethoxy)phenyl)-6-(l-methylcyclopropoxy)-9-((4- methylpyri din-2 -yl)methyl)-9H-purine; 2-((2-(3-Chloro-4-(9-(3-chlorobenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- y l)phenoxy )ethy 1 )thi o)aceti c aci d ;

8-(2-Chloro-4-((l-(methylsulfonyl)azetidin-3-yl)oxy)phenyl)-6-(l-methylcyclopropoxy)-9- ((4-methylpyridin-2-yl)methyl)-9H-purine; 3-(3-Chloro-4-(6-(l-rnethylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8- yl)phenoxy)cy clobutane- 1 -carbonitrile;

(ls,3s)-3-(3-Chloro-4-(6-(l-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H- purin-8-yl)phenoxy)-l-methylcyclobutan-l-ol;

(lr,3r)-3-(3-Chloro-4-(6-(l-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H- purin-8-yl)phenoxy)-l-methylcyclobutan-l-ol;

(S)-8-(2-Chloro-4-((l-(methylsulfonyl)pyrrolidin-3-yl)oxy)phenyl)-6-(l- methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purine;

4-(3 -Chi oro-4-(6-(l-methylcy cl opropoxy)-9-(3-(trifluorom ethoxy )benzyl)-9H-purin-8- yl)phenoxy)-2 -methylbutanoic acid;

2-(l-((3-Chloro-4-(9-(3-chlorobenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

2-(l-((2-Chl oro-3 -(9-(3-chlorobenzyl)-6-(l -methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

8-(2-Chloro-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)-6-(l-methylcyclopropoxy)- 9-((4-methylpyridin-2-yl)methyl)-9H-purine;

(3-(3-Chloro-4-(6-(l-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8- yl)phenoxy)azetidin-l-yl)(cyclopropyl)methanone;

2-(l-((2-Chl oro-3 -(9-(5-chloro-2-fluorobenzyl)-6-(l -methylcy cl opropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

2-(l-(2-(2-Chloro-3-(9-(3-chlorobenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)ethyl)cyclopropyl)acetic acid;

2-(l-((3-Chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid; 4-(3-Chloro-4-(9-(5-chloro-2-(2-methoxyethoxy)benzyl)-6-(l-methylcyclopropoxy)-9H- purin-8-yl)phenoxy)-2 -methylbutanoic acid;

2-(l-((3-Chloro-4-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

2-(l-((2-Chloro-3-(9-(5-chloro-2-cyanobenzyl)-6-(l -methylcy cl opropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

(S)-4-(3-Chloro-4-(9-(5-chloro-2-hydroxybenzyl)-6-(l -methylcy clopropoxy)-9H-purin-8- yl)phenoxy)-2 -methylbutanoic acid;

(R)-4-(3-Chloro-4-(9-(5-chloro-2-hydroxybenzyl)-6-(l -methylcy cl opropoxy)-9H-purin-8- yl)phenoxy)-2 -methylbutanoic acid; and pharmaceutically acceptable salts thereof.

It is to be understood that any of definitions, claims, aspects or embodiments of the variable groups of the formulae disclosed herein, may be combined with any other definitions, claims, aspects or embodiments herein (unless the context does not permit) to provide further embodiments of the specification.

Pharmaceutically acceptable acid addition salts can be formed with inorganic acids and organic acids, e.g., acetate, aspartate, benzoate, besylate, bromide/hydrobromide, bicarbonate/carbonate, bisulfate/sulfate, camphorsulfonate, chloride/hydrochloride, chlortheophyllonate, citrate, ethanedi sulfonate, fumarate, gluceptate, gluconate, glucuronate, hippurate, hydroiodide/iodide, isethionate, lactate, lactobionate, lauryl sulfate, malate, maleate, malonate, mandelate, mesylate, methyl sulfate, naphthoate, napsylate, nicotinate, nitrate, octadecanoate, oleate, oxalate, palmitate, palmoate, phosphate/hydrogen phosphate/dihydrogen phosphate, polygalacturonate, propionate, stearate, succinate, subsalicylate, sulfate/hydrogensulfate, tartrate, tosylate and trifluoroacetate salts. Inorganic acids from which salts can be derived include, for example, hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like. Organic acids from which salts can be derived include, for example, acetic acid, propionic acid, glycolic acid, oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, toluenesulfonic acid, trifluoroacetic acid, sulfosalicylic acid, and the like.

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 columns I to XII of the periodic table. In certain embodiments, the salts are derived from sodium, potassium, ammonium, calcium, magnesium, iron, silver, zinc, and copper; particularly suitable salts include ammonium, potassium, sodium, calcium and magnesium salts. Organic bases from which salts can be derived include, for example, primary, secondary, and tertiary amines, substituted amines including naturally occurring substituted amines, cyclic amines, basic ion exchange resins, and the like. Certain organic amines include isopropylamine, benzathine, cholinate, diethanolamine, diethylamine, lysine, meglumine, piperazine and tromethamine.

The pharmaceutically acceptable salts of the compounds disclosed herein can be synthesized from a basic or acidic moiety, by conventional chemical methods. Generally, such salts can be prepared by reacting free acid forms of these compounds with a stoichiometric amount of the appropriate base (such as Na⁺, Ca²⁺, Mg²+, or K⁺ hydroxide, carbonate, bicarbonate or the like), or by reacting free base forms of these compounds with a stoichiometric amount of the appropriate acid. Such reactions are typically carried out in water or in an organic solvent, or in a mixture of the two. Generally, use of non-aqueous media like ether, ethyl acetate, ethanol, isopropanol, or acetonitrile is desirable, where practicable. Lists of additional suitable salts can be found, e.g., in “Remington's Pharmaceutical Sciences,” 20th ed., Mack Publishing Company, Easton, Pa., (1985); Berge et al., "J. Pharm. Sci., 1977, 66, 1-19 and in “Handbook of Pharmaceutical Salts: Properties, Selection, and Use” by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

It is also to be understood that certain compounds disclosed herein, and pharmaceutically salts thereof, can exist in solvated as well as unsolvated forms such as, for example, hydrated and anhydrous forms. It is to be understood that the compounds herein encompass all such solvated forms. For the sake of clarity, this includes both 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.

Any formula given herein is also intended to represent unlabeled forms as well as isotopically labeled forms for the compounds disclosed herein. Isotopically labeled compounds have structures depicted by the formulas given herein except that one or more atoms are replaced by an atom of the same element but with differing 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, phosphorous, sulfur, fluorine, chlorine and iodine, such as ²H, ³H, ⁿC, ¹³C, ¹⁴C, ¹⁵N, ³⁵S, ³⁶C1 and ¹²⁵I. 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 appropriate isotopically labeled reagents in place of the non-labeled reagents previously employed.

The compounds disclosed herein may have different isomeric forms. The language “optical isomer,” “stereoisomer” “enantiomer” or “diastereoisomer” refers to any of the various stereoisomeric configurations which may exist for a given compound disclosed herein. Likewise, it is understood that the compounds disclosed herein may exist in tautomeric forms other than that shown in the formula and these are also included within the scope of the present specification. It is understood that a substituent may be attached at a chiral center of a carbon atom and, therefore, the disclosed compounds include enantiomers, diastereomers and racemates. The term “enantiomer” includes pairs of stereoisomers that are non-superimposable mirror images of each other. A 1 : 1 mixture of a pair of enantiomers is a racemic mixture. The (+/-) term is used to designate a racemic mixture where appropriate. The terms “diastereomers” or “diastereoisomers” include stereoisomers that have at least two asymmetric atoms, but which are not mirror images of each other. The absolute stereochemistry is specified according to the Cahn-Ingold-Prelog R-S system. When a compound is a pure enantiomer, the stereochemistry at each chiral center may be specified by either R or S.

It is understood that one of skill in the art could determine optical rotation and/or absolute stereochemistry. It is understood that such a disclosure includes other stereoisomeric forms of the same compound, as well as stereoisomeric mixtures. Certain of the compounds disclosed herein contain one or more asymmetric centers or axes and may thus give rise to enantiomers, diastereomers or other stereoisomeric forms that may be defined, in terms of absolute stereochemistry, as (R)- or (5)-. The present disclosure is meant to include all such possible isomers, including racemic mixtures, optically pure forms and intermediate mixtures. Optically active (R)- and (5)-isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques well known in the art, such as chiral HPLC.

Pharmaceutical Compositions

In some embodiments, disclosed are pharmaceutical compositions comprising a compound disclosed herein and a pharmaceutically acceptable excipient.

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

The language “pharmaceutically acceptable carrier” and “pharmaceutically acceptable excipient” includes 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 problem or complication, as ascertained by one of skill in the art. For example, "pharmaceutically acceptable" as used herein includes compounds approved by a regulatory agency of the Federal or a state government, or listed in the U.S. Pharmacopeia, European Pharmacopeia or other generally recognized pharmacopeia for use in animals, and more particularly in humans.

The disclosed compositions may be in a form suitable for oral use, for topical use, for administration by inhalation, for administration by insufflation or for parenteral administration.

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 upon the host treated and the particular route of administration. For further information on Routes of Administration and Dosage Regimes the reader is referred to Chapter 25. 3 in Volume 5 of Comprehensive Medicinal Chemistry (Corwin Hansch; Chairman of Editorial Board), Pergamon Press 1990.

The 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 pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed. , Mack Publishing Company, Easton, PA., (1985).

Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and/or excipients and may be in solid or liquid form.

Therapeutic Utilities

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof.

In certain embodiments, the cancer exhibits homologous recombination repair deficiency (HRD).

In some embodiments, the cancer is a breast, ovarian, pancreatic, or prostate cancer comprising a BRCA1 and/or BRCA2 mutation. In other embodiments, the cancer is a breast, ovarian, pancreatic, or prostate cancer comprising a BRCAl mutation. In still other embodiments, the cancer is a breast, ovarian, pancreatic, or prostate cancer comprising a BRCA2 mutation.

In some embodiments, the cancer is BRCA1 and/or BRCA2-positive breast cancer. In other embodiments, the cancer is BRCA1 -positive breast cancer. In still other embodiments, the cancer is BRCA2-positive breast cancer. In some embodiments, the cancer is BRCA1 and/or BRCA2 -positive ovarian cancer. In other embodiments, the cancer is BRCA1 -positive ovarian cancer. In still other embodiments, the cancer is BRCA2 -positive ovarian cancer.

In some embodiments, 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 still other embodiments, the cancer is BRCA2 -positive pancreatic cancer.

In some embodiments, the cancer is prostate cancer. In further embodiments, the cancer is BRCA1 and/or BRCA2-positive prostate cancer. In other embodiments, the cancer is BRCA1- positive prostate cancer. In still other embodiments, the cancer is BRCA2 -positive prostate cancer.

In some embodiments, 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.

In some embodiments, the method comprises treating a subject with primary and secondary solid tumors. In still other embodiments, the method comprises treating subjects with primary solid tumors. In yet other embodiments, the method comprises treating subjects with secondary solid tumors.

In some embodiments, the cancer is Ataxia Telangiectasia Mutated (ATM) mutationpositive. In certain embodiments, the ATM mutation-positive cancer is a hematological cancer, such as leukemia or lymphoma. In certain embodiments, the ATM mutation-positive cancer is acute leukemia, chronic lymphocytic leukemia (CLL), acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). In other embodiments, the ATM mutation-positive cancer is a solid cancer. In certain embodiments, the ATM mutation-positive cancer is lung cancer, gastric cancer, stomach cancer, breast cancer, ovarian cancer, colorectal cancer, melanoma, or sarcoma.

In some embodiments, the cancer is positive for a mutation in genes coding for Fanconi anemia (FA) proteins or FA-like genes, including FANCA, FANCB, FANCC, FANCD1 (BRCA2), FANCD2, FANCE, FANCF, FANCG, FANCI, FANJ (BRIP1), FANCL, FANCM, FANCN (PALB2), FANCP (SLX4), and FANCS (BRCA1).

In some embodiments, the cancer is positive for a mutation in genes coding for DNA repair proteins, including RAD50, RAD51, RAD51B, RAD51C, RAD51D, RAD51L1, RAD51L2, RAD51L3, XRCC2, XRCC3, RAD52, RAD54, RAD54L, RAD54B, MRE11, NBS1, DMC1, CTIP (CTBP-interacting Protein), PALB2 (Partner and Localizer of BRCA2), RECQL4 (RecQ Protein-like 4), BLM (Bloom syndrome, RecQ helicase-like), WRN (Werner syndrome, RecQ helicase-like), NBS1 (Nibrin), and EMSY.

In some embodiments, 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, CLK2, CLSPN, CUL4A, CUL5, DCLRE1A, DCLRE1C, DDB1, DKC1, DNMT3A, DNMT3B, DUT, EME2, ENDOV, EP300, ERCC4, ERCC5, FAN1, FANCG, FANCL, FBXO18, FEN1, GADD45A, GINS1, GTF2H2, GTF2H3, GTF2H4, HDAC2, HDAC3, HDAC4, HELQ, INIP, INO80C, KDM4B, LIG3, LM04, MAD2L2, MBD4, MGMT, MLH1, MNAT1, MPG, MRE11 A, MSH2, MSH6, MTBP, MUTYH, NABP1, NBN, NEIL1, NEIL2, NEIL3, NEK1, NHEJ1, NTHL1, 0RC6, PALB2, PARP2, PARP3, PAXIP1, PIF1, PMS2, POLB, POLE, POLK, POLL, POLM, POLN, PPP1CA, PRKDC, PRMT2, PR0KR1, RAD21, RAD23B, RAD51, RAD51 API, RAD52, RAD9A, RAD9B, RBI, RECQL4, RECQL5, REV1, RIF1, RINT1, RMI1, RNASEH1, RNASEH2A, RPA1, RPA2, RTEL1, SHPRH, SIRT6, SLX4, SMC5, SMG1, SMUG1, SPO11, SUM01, SUM02, SUV39H1, SUV420H2, SWI5, TDG, TELO2, THOC1, TICRR, TNKS, TNKS2, TOPI, TOP2A, TOP3A, TOP3B, TREX2, TRP53BP1, UBE2N, UNG, UVSSA, WRN, XAB2, XRCC2, XRCC3, and/or, XRCC5.

Combination Therapy

The compounds of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof, may also be administered in conjunction with other compounds used for the treatment of the above conditions. In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and a second active ingredient, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof in combination with a second active ingredient, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with a second active ingredient, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and a PARP inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subj ect in need thereof in combination with a PARP inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with a PARP inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In certain embodiments, the PARP inhibitor is olaparib, AZD9574 (WO 2021/260092), saruparib (AZD5305) (WO 2021/013735), talazoparib, niraparib, or rucaparib. In other embodiments, the PARP inhibitor is olaparib, AZD9574, or saruparib (AZD5305). In particular embodiments, the cancer is breast, ovarian, pancreatic, or prostate cancer. In certain embodiments, the PARP inhibitor is olaparib and the cancer is breast, ovarian, pancreatic, 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.

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an ATR inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subj ect in need thereof in combination with an ATR inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture. In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with an ATR inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In certain embodiments, the ATR inhibitor is AZD6738 (WO 2011/154737).

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and a DNA-PK inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof in combination with a DNA-PK inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with an DNA-PK inhibitor, wherein the compound and second active ingredient are administered concurrently, sequentially or in admixture.

In certain embodiments, the DNA-PK inhibitor is AZD7648 (WO 2018/114999).

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and an antibody drug conjugate, wherein the compound and antibody drug conjugate are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subject in need thereof in combination with an antibody drug conjugate, wherein the compound and antibody drug conjugate are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with an antibody drug conjugate, wherein the compound and antibody drug conjugate are administered concurrently, sequentially or in admixture.

In certain embodiments, the antibody drug conjugate is trastuzumab deruxtecan (T-DXd). In certain embodiments, the antibody drug conjugate is a TOPOisomerase antibody drug conjugate. In particular embodiments, the cancer is breast cancer, gastric cancer or non-small cell lung cancer (NSCLC).

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and a platinum-based anti-cancer drug, wherein the compound and platinum-based anti-cancer drug are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subj ect in need thereof in combination with a platinum-based anti-cancer drug, wherein the compound and platinum-based anti-cancer drug are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with a platinum-based anti-cancer drug, wherein the compound and platinum-based anti-cancer drug are administered concurrently, sequentially or in admixture.

In certain embodiments, the platinum-based anti-cancer drug is cisplatin, carboplatin, oxaliplatin, nedaplatin, lobaplatin, triplatin tetranitrate, triplatin tetranitrate, picoplatin, or satraplatin.

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof and a taxane, wherein the compound and taxane are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in treating cancer in a subj ect in need thereof in combination with a taxane, wherein the compound and taxane are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with a taxane, wherein the compound and taxane are administered concurrently, sequentially or in admixture. In certain embodiments, the taxane is docetaxel.

In some embodiments, there is provided a method of treating cancer in a subject in need thereof comprising administering a combination of a therapeutically effective amount of a compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in combination with immunotherapy, wherein the compound and immunotherapy are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof for use in of treating cancer in a subject in need thereof in combination with immunotherapy, wherein the compound and immunotherapy are administered concurrently, sequentially or in admixture.

In some embodiments, there is provided use of compound of Formula (I) optionally wherein the compound of formula (I) has the structure of formula (I-A), a compound disclosed herein, a stereoisomer thereof, a pharmaceutically acceptable salt thereof, or a pharmaceutical composition thereof in the manufacture of a medicament for the treatment of cancer in a subject in need thereof in combination with immunotherapy, wherein the compound and immunotherapy are administered concurrently, sequentially or in admixture.

In certain embodiments, the immunotherapy is an antibody, such as durvalumab. In particular embodiments, the immunotherapy is durvalumab and the cancer is non-small cell lung cancer (NSCLC).

Process

Another aspect of the present specification provides a process for preparing a compound of the Formula (I), or a pharmaceutically acceptable salt thereof. A suitable process is illustrated by the following representative process variants in which, unless otherwise stated, G, G_a, Gb, Qi, Q2, Q3 and R¹, R², X, Y Z_a, Zb, Z_c have any of the meanings defined hereinbefore. Necessary starting materials may be obtained by standard procedures of organic chemistry. The preparation of such starting materials is described in conjunction with the following representative process variants and within the accompanying Examples. Alternatively, necessary starting materials are obtainable by analogous procedures to those illustrated which are within the ordinary skill of an organic chemist.

Compounds of Formula (I) may be made by, for example:

1. by reaction of another compound of formula (I) where Q¹, Q² or Q³ is C-OH with a primary or secondary alcohol under conditions known in the art as suitable for Mitsunobu reaction; or by reaction with a primary or secondary halide under typical conditions for nucleophilic substitution, e. g. a suitable solvent such as DMA or DMF in the presence of a suitable base, for example potassium carbonate or cesium carbonate at a suitable temperature (0-120 °C) with or without a protecting group for other functionalities (e.g. Example 1).

2. by reaction of another compound of formula (I) where Q¹, Q² or Q³ is C-LG, LG being a leaving group such as halogen, with a suitable amine under conditions known in the art, optionally catalysed by metal complexes such as palladium catalysts suitable for Buchwald- Hartwig amination reactions.

3. by reaction of another compound of formula (I) where Q¹, Q² or Q³ is C-LG, LG being a leaving group such as halogen, with a suitable alcohol under conditions known in the art (e. g. reaction in the presence of a strong base such sodium hydride to form the alkoxide), optionally catalysed by metal complexes such as palladium catalysts (e. g. RockPhos Pd G3) suitable for ether formation reactions.

More generally, a compound of Formula (I) can be made from a compound of Formula (I) (e. g. amide coupling, reductive amination). Compounds of formula (I) where Q¹, Q² or Q³ is C-OH or where Q¹, Q² or Q³ is C-LG can be made by methods illustrated thereafter. a) Compound of formula (I) where Q¹, Q² or Q³ is C-OH may be made by reaction of another compound of formula (I) where Q¹, Q² or Q³ is C-LG, LG being a leaving group such as halogen under conditions known in the art (e. g. reaction in the presence of a strong base such sodium hydride), optionally catalysed by metal complexes such as palladium catalysts (e.g. Pd2(dba)s) in a suitable solvent (e.g. 1,4-di oxane: water (1 : 1)) and a suitable temperature (such as from ambient temperature to 100 °C), with or without a protecting group for other functionalities (e.g. Example 1). b) When reaction of another compound of formula (II) with a compound of formula (III), where LG is a leaving group known to the art, for example halide such as F, Cl or Br, or trifluoromethanesulfonate (triflate) (e.g. Example 1). Conditions for the reaction may use a suitable solvent (for example THF) in the presence of a suitable base (for example sodium hydride or LHMDS) and a suitable temperature (such as from 0 °C to ambient temperature), with or without a protecting group for other functionalities.

Compound of formula (II) can be made by reaction of compound of formula (IV) with compound of formula (V). Conditions for the reaction involved a one-step procedure as described in paragraph (d). The reaction can be converted in a two-step procedure with the isolation of intermediate compound of formula (VI). Conditions for the reaction are described in paragraph (d).

Alternatively, compound of formula (II) can be made by reaction of compound of formula (IVa) with compound of formula (V). Conditions for the reaction are described in paragraph (d).

Alternatively, compound of formula (IV) can be made by reaction of formulae (IVa) by reduction of the nitro group to the amino group, as described in paragraph (d) When X= CH2, compound of formula (IVa) can be made from reaction between compound of formula (VII) and compound of formula (Villa) under conditions known in the art as suitable for reductive amination.

Alternatively compound of formula (IVa) can be made from reaction between compound of formula (Vila) and compound of formula (VIII). Conditions for the reaction may use an inert solvent (for example DMF) in the presence of a base (such as tri ethylamine) and a suitable temperature (e. g. room temperature).

(VII) (Vila) (Vlll) (Villa)

Alternatively compounds of formula (II) can be obtained from reaction between compound of formula (Ila) and compound of formula (Vlllb) under conditions known in the art as suitable for nucleophilic substitution (e.g. in the presence of a base such as DIPEA in a suitable solvent such as acetonitrile at a suitable temperature such as 60-120 °C, as in Example 1) or from reaction between compound of formula (Ila) and compound of formula (VIIIc) under conditions known in the art as suitable for Mitsunobu reactions.

Compounds of formula (Ila) can be made by reaction of a compound of formula (IVb) with a compound of formula (V) (e.g. Example 1). Conditions for the reaction may use a Lewis acid (for example ferric chloride) in a suitable solvent (for example isopropanol or methanol) and a suitable temperature (60-120 °C). c) When reaction of another compound of formula (IX) with a compound of formula (X) under conditions known in the art as suitable for Mitsunobu reaction, or by reaction nucleophilic substitution reaction of another compound of formula (IX) with a compound of formula (Xa), where LG is a leaving group known to the art, for example halide such as Cl, Br or I). Conditions for the nucleophilic substitution reaction may use a suitable solvent (for example acetonitrile, DMF or DMA) in the presence of a suitable base (for example potassium carbonate) and a suitable temperature (0-120 °C) with or without a protecting group for other functionalities.

Compound of formula (IX) can be made by reaction of compound of formula (XI) with compound of formula (V), with or without a protecting group for the hydroxy group.

Compound of formula (IX) can also be made by reaction of compound of formula (Xia) with compound of formula (V), with or without a protecting group for the hydroxy group.

Alternatively compound of formula (XI) can be made from compound of formula (Xia) by reduction of the nitro group to the amino group.

Conditions for the above reactions are illustrated in paragraph (d). Compound of formula (Xia) can be made by reaction of compound of formula (XII) with compound of formula (VIII) where LG is a leaving group known to the art, for example halide (such as F or Cl) or trifluoromethanesulfonate (triflate); with or without a protecting group for the hydroxy group. d) by reaction of compound of formula (XIII) with compound of formula (V). Conditions for the reaction involved one step procedure and may use a suitable solvent (for example EtOH, isopropanol, dioxane or DMSO) and a suitable temperature (60-120 °C), optionally in the presence of a mild oxidant (such as iron(III) chloride and/or atmospheric oxygen) and/or an acid (e. g. p- toluenesulfonic acid, acetic acid) and/or a catalyst (e. g. copper(II) acetate). The reaction can be converted in a two-step procedure with the isolation of intermediate compound of formula (XIV), where a mild oxidant (e. g. iron(III) chloride and/or oxygen) is added for the second step.

Alternatively by reaction of compound of formula (Xllla) with compound of formula (V) for the reaction may use a suitable solvent (for example NMP and water) in the presence of a mild reducing agent such as sodium dithionate (also known as sodium hydrosulfite) at a suitable temperature (e. g. 80-120 °C).

Alternatively compound of formula (XIII) can be made from compound of formula (Xllla) by reduction of the nitro group to the amino group (e. g. in the presence of iron with a suitable solvent such as ethanol) Compound of formula (Xllla) can be made by reaction of compound of formula (XV) and another compound of formula (VIII) where LG is a leaving group known to the art, for example halide (such as F or Cl) or trifluoromethanesulfonate (triflate) or methanesulfonyl.

When compound of formula (Xllla) can be made by reaction of compound of formula (IVa) with compound of formula (III). Conditions for the reaction may use a suitable solvent (for example THF) in the presence of a suitable base (for example sodium hydride or LHMDS) and a suitable temperature (such around ambient temperature) with or without a protecting group for other functionalities.

When compound of formula (Xllla) can also be made by reaction of another compound of formula (XVI) with a compound of formula (III) under conditions known in the art as suitable for Mitsunobu reaction, or by reaction (nucleophilic substitution) of another compound of formula (XVI) with a compound of formula (Illa), where LG is a leaving group known to the art, for example halide such as Cl, Br or I). Conditions for the nucleophilic substitution reaction may use a suitable solvent (for example acetonitrile, DMF or DMA) in the presence of a suitable base (for example potassium carbonate) and a suitable temperature (0-120 °C) with or without a protecting group for other functionalities.

Compound of formula (XVI) can be made by reaction of another compound of formula (XVII) and another compound of formula (VIII) with or without a protecting group for the hydroxyl and other functionalities.

(e) by reaction of compound of formula (XVIII), when LG is a leaving group known to the art for example halide such as Cl, Br or I, with compound of formula (XIX) when FG is a functional group suitable for cross-couplings reactions (e. g. Suzuki reaction) such as a boronate ester or boronic acid.

(XVIII) (XIX)

Compound of formula (XVIII) can be made from compound of formula (XX), for example by bromination (when LG is Br).

(f) from reaction between compound of formula (XXI) and compound of formula (Vlllb) under conditions known in the art as suitable for nucleophilic substitution. or from reaction between compound of formula (XXI) and compound of formula (VIIIc) under conditions known in the art as suitable for Mitsunobu reactions.

It is understood that compound of formula (XXI), by analogy with compound of formula (I), may be made by reaction already illustrated above.

EXAMPLES

General Experimental Conditions and Abbreviations

The compounds described in this specification are further illustrated in the following Examples. The compounds were named using Chemdraw version 20. 0. 2. 51. These Examples are given by way of illustration only and are non-limiting. In general:

Reagents and solvents (all anhydrous HPLC-grade) were obtained from commercial suppliers and used without any further purification unless otherwise stated. All reagents were weighed and handled in air unless otherwise stated. Brine refers to a saturated solution of NaCl. Concentration under reduced pressure refers to the use of a rotary evaporator. Operations were carried out at ambient temperature, i. e. in the range 17 to 25 °C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated.

Evaporations were carried out by rotary evaporation under reduced pressure utilising a warm or hot water bath or utilising Genevac equipment or Biotage vlO evaporator in vacuo and work up procedures were carried out after removal of residual solids by filtration.

Flash chromatographic purifications were performed on an automated Teledyne Isco CombiFlash® Rf, Teledyne Isco CombiFlash® Companion® or CHEETAH® MP200 system with integrated UV detection using prepacked silica gel columns (40-60 pm) or Cl 8 spherical (20-35 pm) using the chromatographic conditions as detailed in corresponding experimental data.

Preparative reverse phase HPLC was performed on an Agilent 1290 Infinity II Preparative system equipped with a SQ MS detector (Multimode ESVAPCI source), with a Waters CSH C18 OBD column (5 microns silica, 30 mm diameter, 100 mm length); Waters MassLynx system with integrated MS detection, with a XBridge or Xselect CSH Prep Cl 8 OBD column (5pm silica, 30 mm diameter, 150 mm length); Gilson GX-281 with integrated UV detection, with either XBridge (10pm, 19 mm diameter, 150 mm length) or Sunfire C18 columns (10pm, 19 mm diameter, 250 mm length) using decreasingly polar mixtures of water (containing 0. 1 — 0. 3% aqueous ammonium), water (containing 0. 05% aqueous ammonia and 10 mmol NH4HCO3), water (containing 0. 1% formic acid) or water (containing 0. 05% TFA) and acetonitrile or methanol as eluents.

Preparative SFC purification was performed on either a Sepiatec Pl 00 SFC system or Waters Prep 100 SFC system equipped with QDa MS detector, using the chromatographic conditions as detailed in corresponding experimental data.

Preparative chiral HPLC was performed with a Gilson GX-281 system with integrated UV detection and equipped with one of Chiralpak AS, AD, Chiralcel OD,OJ Chiralpak IA,IB,IC,ID,IE,IF,IG,IH columns (Daicel Chemical Industries, Ltd. ) (R,R)-Whelk-01, (S,S)- Whelk-Ol columns (Regis technologies, Inc. ) CHIRAL Cellulose-SB, SC, SA columns (YMC Co. , Ltd. ) at different column size (250x20mm, 250x30mm) with noted percentage of either ethanol in hexane (%Et/Hex) or isopropanol in hexane (%IPA/Hex) as isocratic solvent systems.

Yields, where present, are not necessarily the maximum attainable. In general, the structures of end-products of the Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; 'H-NMR chemical shift values were measured on the delta scale and are quoted in ppm with measurement against TMS or residual solvent peaks as internal standards; proton magnetic resonance spectra were determined using a Bruker Avance 500 spectrometer at a proton frequency of 500 MHz, Bruker Avance 400, Bruker Avance III HD or Bruker Avance Neo spectrometers at a proton frequency of 400 MHz or Bruker Avance III, Avance III HD or Avance III NEO spectrometers at a proton frequency of 300 MHz ; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; br s, broad signal; hept, heptet.

In general, end products of the Formula I were also characterized by mass spectrometry following liquid chromatography (LCMS or UPLC); reverse-phase Cl 8 silica was used with a flow rate of 1 mL/min and detection was by Electrospray Mass Spectrometry and by UV/vis absorbance recording a wavelength range of 220-320 nm. Analytical UPLC was performed using a Waters Acquity UPLC CSH C18 column with dimensions 2. 1 x 50 mm and particle size 1. 7 micron) Gradient analysis was employed using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 0. 1% v/v formic acid or 0. 3% ammonia v/v) as solvent A and acetonitrile as solvent B. A typical 1. 7 minute analytical UPLC method would employ a solvent gradient over 1. 3 min, at 1 mL/min, from a 97:3 mixture of solvents A and B respectively to a 3:97 mixture of solvents A and B. Also, LCMS was performed using a Shimadzu LCMS-2020 with electrospray ionization in positive ion detection mode with 20ADXR pump, SIL-20ACXR autosampler, CTO-20AC column oven, M20A PDA Detector and LCMS 2020 MS detector. LC was run in two set ups: 1) Halo C18 column (2. 0 pm 3. 0 x 30 mm) in combination with a gradient (5-100% B in 1. 2 minutes) of water and formic acid - FA (0. 1%) (A) and CH3CN and FA (0. 1%) (B) at a flow rate of 1. 5 mL/min; 2) Poroshell HPH Cl 8 column (2. 7 pm 3. 0 x 50 mm) in combination with a gradient (5-95% B in 2 minutes) of aqueous 46 mM ammonium carbonate/ammonia buffer at pH 10 (A) and MeCN (B) at a flow rate of 1. 2 mL/min ; 3) Halo C18 column (2. 0 pm 3. 0x30 mm) in combination with a gradient (5-95% B in 2 minutes) of water and TFA (0. 05%) (A) and CH3CN and TFA (0. 05%) 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 pL. PDA (SPD- M20A) detection was in the range 190-400 nm. The MS detector, which was configured with electrospray ionization as ionizable source; Acquisition mode: Scan; Nebulizing Gas Flow:l.

5 L/min; Drying Gas Flow: 15 L/min; Detector Voltage: Tuning Voltage ± 0. 2 kv; DL Temperature: 250 oC; Heat Block Temperature: 250 oC; Scan Range: 90. 00 - 900. 00 m/z. It is understood that, unless otherwise specified, the reported molecular ion corresponds to the [M+H]+, rounded to the lower unit. Typically, unless otherwise specified; for molecules with multiple isotopic patterns (e. g. ³⁵C1, ⁷⁹Br, ¹²C) only the lower most common isotope is reported.

Ion exchange purification was generally performed using a SCX-2 (Biotage, Propylsulfonic acid functionalized silica. Manufactured using a trifunctional silane. Non endcapped) cartridge. Intermediate purity was assessed by thin layer chromatographic, mass spectral, HPLC

(high performance liquid chromatography) and/or NMR analysis.

The following abbreviations have been used: abs Absolute stereochemistry according to the Cahn-Ingold-Prelog R-S system aq. Aqueous

DIPEA Diisopropylethylamine DMF N,N-dimethylformamide DMSO dimethyl sulphoxide EtOAc ethyl acetate EtOH Ethanol HPLC high performance liquid chromatography IPA or iPrOH Isopropanol LCMS liquid chromatography-mass spectrometry LHMDS lithium bis(trimethylsilyl)amide MeCN Acetonitrile min minute(s) m/z mass to charge ratio NMR nuclear magnetic resonance PDA photo-diode array

Pd2(dba)s tris(dibenzylideneacetone)dipalladium(0) rt / RT room temperature SCX strong cation exchanger SFC supercritical fluid chromatography tert Tertiary TFA trifluoroacetic acid THF Tetrahydrofuran TMS Tetramethylsilane UPLC ultra performance liquid chromatography uv Ultraviolet

Example 1

2-(l-((2-Chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid

Lithium hydroxide (12.02 mg, 0.50 mmol) was added to methyl 2-(l-((2-chloro-3-(9-(5-chloro-2- methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)methyl)cyclopropyl)acetate (100 mg, 0.17 mmol) in THF : H2O (1 : 1, 3 mL). The resulting mixture was stirred at 60 °C for 1 hour. The reaction mixture was adjusted to pH 5 with 2M HC1, poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford a yellow solid, which was purified by preparative HPLC (Column: XBridge Prep OBD C18 Column, 30*150 mm, 5 pm) using decreasingly polar mixtures of water (containing 0.1% aq. NH3 and 10 mmol/L NH4HCO3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-(l-((2-chloro-3-(9-(5-chloro-2- methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8-yl)phenoxy)methyl)cyclopropyl)acetic acid (34.0 mg, 35 %) as a white solid. 'H NMR (400 MHz, DMSO-t/e): 0.58 (2H, d), 0.62 (2H, s), 0.85 (2H, d), 1.03 (2H, d), 1.74 (3H, s), 2.39 (2H, s), 3.49 (3H, s), 4.05 (2H, s), 5.24 (2H, s), 6.80 (1H, d), 6.87 (1H, d), 7.01 (1H, dd), 7.23 (1H, dd), 7.27 (1H, d), 7.37 (1H, t), 8.64 (1H, s). One proton not observed. m/r. ES+ [M+H]+ 583.

Methyl 2-(l-((2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetate used as a starting material was prepared as follows.

8-(3-Bromo-2-chlorophenyl)-6-chloro-9H-purine

Ferric chloride (50. 5 g, 311 mmol) was added slowly to 6-chloropyrimidine-4,5-diamine (15 g, 104 mmol) and 3-bromo-2-chlorobenzaldehyde (22. 77 g, 104 mmol) in IPA (300 mL). The resulting mixture was stirred at 75 °C for 12 hours. The solvent was removed under reduced pressure. The reaction mixture was washed with water (750 mL), filtered and the resulting solid was collected and poured into THF (1 L). The solution was filtered and the filtrate was collected. The solvent was removed under reduced pressure to afford 8-(3-bromo-2-chlorophenyl)-6-chloro- 9H-purine (15. 0 g, 42%) as a yellow solid used without further purification. 'H NMR (500 MHz, CDC1₃): 7. 19 (1H, s), 7. 47-7. 64 (2H, m), 7. 89 (1H, s), 8. 98 (1H, d). m/z ES+ [M+H]+ 343.

8-(3-Bromo-2-chlorophenyl)-6-chloro-9-(5-chloro-2-methoxybenzyl)-9H-purine

8-(3-Bromo-2-chlorophenyl)-6-chloro-9H-purine (8. 0 g, 23. 3 mmol) was added to 4-chloro-2- (chlorom ethyl)- 1 -methoxybenzene (4. 44 g, 23. 3 mmol) and DIPEA (12. 2 mL, 69. 8 mmol) in MeCN (200 mL). The resulting mixture was stirred at 80 °C for 3 hours. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (3 x 400 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 8-(3-bromo-2-chlorophenyl)-6-chloro-9-(5-chloro-2- methoxybenzyl)-9H-purine (9. 00 g, 78 %) as a yellow solid. ^JH NMR (500 MHz, DMSO-t/e): 3. 45 (3H, s), 5. 34 (2H, s), 6. 79-6. 89 (2H, m), 7. 24 (1H, dd), 7. 44 (1H, t), 7. 62 (1H, dd), 8. 01 (1H, dd), 8. 91 (1H, s). m/z ES+ [M+H]+ 497. 8-(3-bromo-2-chlorophenyl)-9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H- purine

NaH (3. 21 g, 80. 23 mmol) was added to 15-crown-5 (0. 353 g, 1. 60 mmol), 1- methylcyclopropan-l-ol (2. 314 g, 32. 09 mmol) and 8-(3-bromo-2-chlorophenyl)-6-chloro-9-(5- chloro-2-methoxybenzyl)-9H-purine (8 g, 16. 05 mmol) in THF (200 mL). The resulting mixture was stirred at rt for 2 hours. The reaction mixture was poured into water (500 mL) and extracted with EtOAc (3 x 400 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 8-(3-bromo- 2-chlorophenyl)-9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purine (8. 00 g, 93 %) as a yellow solid. 'H NMR (500 MHz, DMSO-t/e): 0. 81-0. 85 (2H, m), 0. 98-1. 04 (2H, m), 1. 73 (3H, s), 3. 48 (3H, s), 5. 27 (2H, s), 6. 84-6. 89 (2H, m), 7. 22 (1H, dd), 7. 40 (1H, t), 7. 54 (1H, dd), 7. 96 (1H, dd), 8. 67 (1H, s). m/z ES+ [M+H]+ 533.

2-Chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8-yl)phenol

8-(3-Bromo-2-chlorophenyl)-9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H- purine (2 g, 3. 74 mmol) was added to KOH (0. 420 g, 7. 49 mmol), Pd2(dba)s (0. 343 g, 0. 37 mmol), 2-di-tert-butylphosphino-2', 4', 6'-triisopropyl- 1,1 '-biphenyl (0. 159 g, 0. 37 mmol) in 1,4- dioxane: water (1 : 1, 40 mL). The resulting mixture was stirred at 80 °C for 2 hours under nitrogen. The reaction mixture was poured into water (400 mL) and extracted with EtOAc (3 x 250 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the crude product, which was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-chloro-3-(9-(5-chloro-2- methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8-yl)phenol (1. 50 g, 85%) as a yellow solid. 'HNMR (500 MHz, DMSO-t/e): 0. 81-0. 91 (2H, m), 1. 03 (2H, d), 1. 74 (3H, s), 3. 54 (3H, s), 5. 24 (2H, s), 6. 77 (1H, d), 6. 86-6. 92 (2H, m), 7. 15 (1H, dd), 7. 21-7. 28 (2H, m), 8. 62 (1H, s), 10. 57 (1H, s). m/z ES+ [M+H]+ 471.

Methyl 2-(l-((2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H- purin-8-yl)phenoxy)methyl)cyclopropyl)acetate

2-Chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8-yl)phenol (300 mg, 0.64 mmol) was added to methyl 2-(l-(bromomethyl)cyclopropyl)acetate (264 mg, 1.27 mmol) and CS2CO3 (1037 mg, 3.18 mmol) in DMF (5 mL). The resulting mixture was stirred at 80°C for 2 hours. The reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 25 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford a yellow oil which solidified on standing. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford methyl 2-(l-((2-chloro-3-(9-(5-chloro-2-methoxybenzyl)-6-(l-methylcyclopropoxy)- 9H-purin-8-yl)phenoxy)methyl)cyclopropyl)acetate (300 mg, 79%) as a yellow oil which solidified on standing. 'H NMR (300 MHz, DMSO-^): 0.63 (2H, s), 0.66 (2H, s), 0.84 (2H, d), 1.04 (2H, s), 1.74 (3H, s), 2.53 (2H, s), 3.50 (3H, s), 3.59 (3H, s), 4.01 (2H, s), 5.24 (2H, s), 6.77 (1H, d), 6.87 (1H, d), 7.03 (1H, dd), 7.22 (1H, dd), 7.27 (1H, d), 7.34-7.41 (1H, m), 8.64 (1H, s). m/z ES+ [M+H]+ 597. The following examples in Table A were synthesised using a similar method to Example 1.

Table A

Table B: Assay Results for Examples

Example 2 Pol0 polymerase domain enzyme inhibition

The following assay was used to identify compounds that inhibit PolO polymerase domain. The ability of compounds to inhibit the isolated polymerase domain (I1780-V2590) of DNA polymerase theta (PolO) was assessed in a PPiLight inorganic pyrophosphate assay (Lonza, product code LT07-610) with the luminescent end point detection of the formation of the product inorganic pyrophosphate (PPi). The PPiLight inorganic pyrophosphate assay provides a high-throughput screening method to monitoring polymerase activity by quantifying the amount of PPi released during the polymerisation reaction using luciferase.

17 nt

T T

₅-_ AAAAAAAAAAAAAAAAACGTACAGTCAGTG KS2 ONA

3'- GCATGTCAGTCAC _{T T}

DNA template

In the assay, PolO interacts with the substrates (deoxy thymidine triphosphate (dTTP) (Sigma, product code T0251) and a DNA template with a 17-nucleotide overhang (Eurogentec, custom creates order), and PPi is formed due to the polymerase reaction. This free PPi interacts with AMP, to generate the ATP used in the luciferase reaction in the production of light. The test compound competitive binding inhibits the polymerase reaction, resulting in the loss of luminescence.

The assay was performed as follows with all reagent additions carried out using a CERTUS FLEX liquid dispenser workstation:

Test compound (15 nL) was acoustically dispensed into Greiner 1536 well white small volume medium bind assay plates.

IX assay screening buffer (50 mM Tris pH7. 5, 5 mM MgCh, 0. 01% v/v Pluronic F127, 2 mM DTT, 0. 05 mg/ml BSA) is prepared dTTP/DNA (1. 5 pL) was dispensed of into each of the wells followed by 1. 5 pL of PolO, the plates are covered and the reaction is allowed to progress for 20 minutes at room temperature.

To quench, TFA (0. 5 pL) was dispensed into the wells, then 2. 0 pL of PPiLight reagent was dispensed into each well and incubated at room temperature for 1 hour.

Plates were then read on an EnVision plate reader for luminescence 400-700 nm.

Compounds were dosed directly from a compound source plate containing serially diluted compounds (4 wells containing 10 mM, 0. 1 mM, 1 pM and 10 nM respectively) to an assay microplate using a labcyte ECHO 550 liquid handler. The ECHO 550 using acoustic technology to transfer between microplates of DMSO compound solutions, with the system being able to be programmed to transfer small nL volumes of compounds from different source plate wells to give serial dilutions for the compounds to be tested and backfilled to normalise the DMSO concentration across the dilution range. In total 15 nL of compound plus DMSO were added to each wells and compounds tested over 12 concentrations points. The final concentration range was 10, 3. 33333, 1. 66667, 0. 3, 0. 1, 0. 025, 0. 009, 0. 003, 0. 0015, 0. 00027, 0. 0001125 and 0. 0000225 mM. The luminescence response measured on the EnVision for each compound was exported into Genedata to perform curve fitting analysis and expressed as an IC50 value. This was determined by calculation of the compound required to give a 50% reduction in control compound binding to PolO.

Results are shown in Table B.

Example 3

Homologous Recombination Synthetic Lethal Inhibition of Proliferation.

This assay identifies anti-proliferative effects of POLQ compounds in the homologous recombination deficient colorectal cell line DLD-1 BRCA2-/- over 8-9 population doublings (7 days for DLD-1 and 12 days for DLD-1 BRCA2-/-). DLD1 BRCA2 wt are used as a control to detect cell toxic effects not specific to homologous recombination deficiency.

DLD-1 BRCA2-/- and DLD-1 cells were kept in continuous culture in Assay Medium (RPMI 1640 phenol red free (Sigma R7509) containing 1% GlutaMAX (Gibco 35050) and 10% Foetal Bovine Serum (Gibco 10270-106)). On the day of the assay cells in culture of ~80 -90% confluent were used. Cell monolayers were washed with 10 mL PBS, then removed and added 2 mL TrypLE Express (Gibco 12604). The cells with TrypLE Express were incubated for 5 minutes in cell culture incubator and then the detached cells resuspend in 15 mL Assay Medium. Cells were counted using a ViCell and the cell images were monitored for clumps of cells, ideally they should be single or < 3 cell clusters. The cells were diluted to 3,000 cells/mL of DLD-1 BRCA2- /- and 1,500 cells/mL of DLD-1 in Assay Medium and 100 pL added per well of transparent bottomed, black, tissue culture-treated 96-well plates (CoStar, No. 3904) Assay Ready Plates. The Assay Ready Plates contain a 10 point 10 pM to 0. 51 nM dose range with three-fold dilutions in DMSO with a final volume of 100 nL. The plates were incubated at 37°C with 5% CO2 for 6 days. On day 6, 100 pL/well of Assay Medium was added to duplicate Assay Ready Plates. 90 pL of culture medium was removed from the cell plates and replenished with the Assay Media and compounds from the duplicate Assay Ready Plates using the Bravo. The plates were further incubated at 37°C with 5% CO2. On day 7 the plates containing DLD-1 and Cell Titre Gio 3D (Promega G9683) were equilibrated to room temperature, then 60 pL of Cell Titre Gio 3D was added per well and incubated on a shaking platform for 30 min. Plates were read on the Envision measuring luminescence for 1 second per well. On day 12 the plates containing DLD-1 BRCA2- /- cells and Cell Titre Gio 3D (Promega G9683) were equilibrated to room temperature, then 60 pL Cell Titre Gio 3D added per well and incubated on a shaking platform for 30 min. Plates were read on the Envision measuring luminescence for 1 second per well. The data was exported into a suitable software package (such as Genedata) to perform curve fitting analysis. Inhibition of cell proliferation was expressed as an IC50 value and was determined by calculation of the concentration of compound that was required to give a 50% reduction of the average maximum Total Intensity signal.

Results are shown in Table B.

REFERENCES

All references cited herein, including patents, patent applications, papers, text books, and the like, and the references cited therein, to the extent that they are not already, are hereby incorporated herein by reference in their entirety for all purposes.

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Claims

1. A compound of formula (I): or a stereoisomer or pharmaceutically salt thereof; wherein,

R is H, R^a, R^b, R^c, R^d, R^f, R^g, or R^h;

R^d is C1-C4 sulfonyl or C1-C4 sulfonamide;

R^y is H, C1-C3 alkyl, or C1-C3 haloalkyl;

R^e is H, halo, Ci-Cs alkyl, or Ci-Cs haloalkyl;

X is a C1-C4 alkylene;

G is N or CH;

R⁵ is ;

Z_c is H, -CN, C1-C3 alkyl, C1-C3 haloalkyl, or C2-C4 alkynyl.

2. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein Q¹, Q², or Q³ is C-L-R.

3. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1 or claim 2 wherein Q¹ is C-L-R.

4. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1 or claim 2 wherein Q² is C-L-R.

5. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 4 wherein L is -O-.

6. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5 wherein R is H, R^a, R^b, R^c, orR^d.

7. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 6 wherein R is R^b, optionally wherein R^b is C4 alkyl.

8. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 7 wherein R^b is substituted with a carboxy.

9. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 5 wherein R is R^f, R^g, or R^h.

10. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 9 wherein R is R^f.

11. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 10 wherein R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW¹ W² wherein W¹ and W² together form a C3-C6 carbocycle.

12. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 11 wherein one methylene group from the C3-C4 alkyl is replaced with CW^XW² wherein W¹ and W² together form a C3 carbocycle.

13. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 10 to 12 wherein R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O).

14. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 10 to 13 wherein R^f is a C3-C4 alkyl, wherein the C3-C4 alkyl is substituted with a carboxy.

15. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 9 wherein R is R^g.

16. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 15 wherein R^g is a 4-6 membered N-heterocycle.

17. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 16 wherein R^g is an azetidinyl.

18. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 16 wherein R^g is a pyrrolidinyl.

19. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 16 wherein R^g is a pyridinyl.

20. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 19 wherein R^gis substituted with -S(O)2CH3.

21. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 15 to 20 wherein R^g is substituted with -C(O)-C3 carbocycle.

22. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 9 wherein R is R^h.

23. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 22 wherein R^h is a C4 carbocycle.

24. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 23 wherein R^h is substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN.

25. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 22 to 24 wherein R^h is substituted with hydroxy.

26. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 22 to 25 wherein R^h is substituted with CH3.

27. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 22 to 26 wherein R^h is substituted with CN.

28. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 27 wherein Y is phenyl.

29. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 27 wherein Y is a pyridinyl.

30. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 29 wherein Y is substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, hydroxy, - O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl.

31. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 30 wherein Y is substituted with hydroxy.

32. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 30 or claim 31 wherein Y is substituted with -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), optionally -O(CH2)2OCH3.

33. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 30 to 32 wherein Y is substituted with halo selected from -Cl and -F.

34. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 30 to 33 wherein Y is substituted with -OCF3.

35. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 30 to 34 wherein Y is substituted with -OCH3.

36. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 30 to 35 wherein Y is substituted with -CH3.

37. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 30 to 36 wherein Y is substituted with -CN.

38. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 37 wherein X is CH2.

39. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 38 wherein R¹ and R² are each, independently, H or halo.

40. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 39 wherein R¹ and R² are each, independently, H or -Cl, wherein when R¹ is H, R² is -Cl, and when R¹ is -Cl, R² is H.

41. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 40 wherein G is N.

42. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 41 wherein G_a is CR⁵.

43. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 42 wherein wherein p is 1.

44. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 43 wherein Z_c is -CH3.

45. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 44 wherein Gb is N.

46. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein,

R¹ and R² are each, independently, H or halo;

Q¹, Q², and Q³ are, independently, CH or C-L-R, wherein one, and only one, of Q¹, Q², or Q³ is C-L-R;

L is -O-;

Y is a phenyl substituted with 1 to 3 substituents independently selected from halo, C1-C3 alkyl, C1-C3 alkoxy, -CN, C1-C3 haloalkyl, cyclopropyl, hydroxy, -O-(Ci-C3 alkylene)-O- (C1-C3 alkyl), and OCR^Z3 wherein at least one R^z is halo and the remaining R^z are selected from halo, H and C1-C3 alkyl; wherein at least one of the substituents is selected from hydroxy, -O-(Ci-C3 alkylene)-O-(Ci-C3 alkyl), and OCR^k3 wherein at least one R^k is halo and the remaining R^k are selected from halo, H and C1-C3 alkyl;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

47. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 46 wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, hydroxy, -O-(CH2)2-O-CH3, and -OCF3.

48. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1 wherein,

R¹ and R² are each, independently, H or halo;

L is -O-;

R is R^f, R^g, or R^h;

X is CH₂;

Gis N;

Ga is CR⁵; wherein p is 1 and Z_c is -CH3; and

Gb is N.

49. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 48 wherein R is R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with CW'W² wherein W¹ and W² together form a C3 carbocycle, and wherein the C3-C4 alkyl is substituted with a carboxy.

50. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 48 wherein R is R^f and R^f is a C3-C4 alkyl, wherein one or two methylene groups from the C3-C4 alkyl are independently replaced with S or S(O), and optionally wherein the C3-C4 alkyl is substituted with a carboxy.

51. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 48 wherein R is R^g and R^g is a 4-6 membered N-heterocycle selected from azetidinyl, pyrrolidinyl and pyridinyl, wherein the N-heterocycle is substituted at the N position with -S(O)2Ci-C3 alkyl or -C(O)-C3-Ce carbocycle.

52. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 48 wherein R is R^h and R^h is a C4 carbocycle substituted with 1 or 2 substituents independently selected from hydroxy, C1-C3 alkyl, and CN, wherein at least one of the substituents is C1-C3 alkyl or CN.

53. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 48 to 52 wherein Y is a pyridinyl substituted with -CH₃.

54. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 48 to 52, wherein Y is a phenyl substituted with 1 or 2 substituents independently selected from -Cl, -F, -OCH3, -CH3, and -CN.

55. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in claim 1, selected from:

8-(2-Chloro-4-(2-(methylsulfinyl)ethoxy)phenyl)-6-(l-methylcyclopropoxy)-9-((4- methylpyri din-2 -yl)methyl)-9H-purine;

2-((2-(3-Chloro-4-(9-(3-chlorobenzyl)-6-(l-methylcyclopropoxy)-9H-purin-8- y l)phenoxy )ethy 1 )thi o)aceti c aci d ;

8-(2-Chloro-4-((l-(methylsulfonyl)azetidin-3-yl)oxy)phenyl)-6-(l-methylcyclopropoxy)-9- ((4-methylpyridin-2-yl)methyl)-9H-purine;

3-(3-Chloro-4-(6-(l-methylcyclopropoxy)-9-((4-methylpyridin-2-yl)methyl)-9H-purin-8- yl)phenoxy)cy clobutane- 1 -carbonitrile;

2-(l-((2-Chl oro-3 -(9-(3-chlorobenzyl)-6-(l -methylcyclopropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid; 8-(2-Chloro-4-((l-(methylsulfonyl)piperidin-4-yl)oxy)phenyl)-6-(l-methylcyclopropoxy)- 9-((4-methylpyridin-2-yl)methyl)-9H-purine;

4-(3-Chloro-4-(9-(5-chloro-2-(2-methoxyethoxy)benzyl)-6-(l -methylcy clopropoxy)-9H- purin-8-yl)phenoxy)-2 -methylbutanoic acid;

2-(l -((2-Chl oro-3 -(9-(5-chloro-2-cyanobenzyl)-6-(l -methylcy cl opropoxy)-9H-purin-8- yl)phenoxy)methyl)cyclopropyl)acetic acid;

56. A pharmaceutical composition which comprises a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1 to 55, and at least one pharmaceutically acceptable excipient.

57. A compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, or a pharmaceutical composition as claimed in claim

56, for use in the treatment cancer.

58. A method of treating cancer which comprises administering to a patient in need thereof, a therapeutically effective amount of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, or a pharmaceutical composition as claimed in claim 56.

59. Use of a compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, as claimed in any one of claims 1-55, or a pharmaceutical composition as claimed in claim 56, in the manufacture of a medicament for the treatment of cancer in a subject.

60. The compound of formula (I), or a stereoisomer or pharmaceutically acceptable salt thereof, or a pharmaceutical composition for use as claimed in claim 57, the method as claimed in claim 58 or the use as claimed in claim 59, wherein the cancer is breast, ovarian, pancreatic, or prostate cancer.