Benzoxazol derivatives as mtor inhibitors and their use in therapy

Abstract

The present disclosure relates to benzoxazol compounds suitable as kinase inhibitors, in particular mTOR kinase inhibitors. Kinase inhibitors are useful in the treatment of various conditions, including cancer. The present disclosure concerns compounds as described herein, and such compounds for use in therapy.

Description

[0001] Inhibitor Compounds

[0002] FIELD

[0003] The present disclosure relates to compounds suitable as kinase inhibitors, in particular mTOR kinase inhibitors. Kinase inhibitors are useful in the treatment of various conditions, including cancer. The present disclosure concerns compounds as described herein, and such compounds for use in therapy.

[0004] BACKGROUND

[0005] Mechanistic Target Of Rapamycin (referred to as mTOR herein), a Serine / Threonine kinase, is a central master regulator of key oncogenic processes central to neoplasms, regulating pathways ranging from cell migration responsible for metastases, to its main function of protein synthesis and cell proliferation, responsible for initial tumour colonisation. mTOR exerts its effects through its dimeric complexes, mTORCI and mTORC2, mTORCI being central to protein translation and mTORC2 central to survival and migration.

[0006] mTOR is implicated in both liquid and solid cancers. Upstream regulators of mTOR are significantly dysregulated in colorectal cancer, with key oncogenic drivers such as PI3K and KRAS being mutated in 24.7% and 40.49% of patient samples, respectively. Additionally, key colorectal cancer tumour suppressors such as APC and P53 are inactivated by mutation in 76.65% and 59.7% of patient samples, respectively. On the other hand, mTOR itself is rarely mutated, only being mutated in 7.53% of colorectal cancer samples (Zhuang et al., ‘Multi gene mutation signatures in colorectal cancer patients: predict for the diagnosis, pathological classification, staging and prognosis’, Bmc Cancer, 2021, 21, (1)). mTOR dysregulation is highest in one of the major colorectal cancer immune subtypes, the IFN-y dominant C2 immune subtype, associated with a poor 5-year overall survival rate of 49% (Soldevilla et al., ‘The correlation between immune subtypes and consensus molecular subtypes in colorectal cancer identifies novel tumour microenvironment profiles, with prognostic and therapeutic implications’, Eur. J. Cancer, 2019, 123, pp. 118-129). As such, the mTOR axis is an attractive therapeutic target for the treatment of colorectal cancer, among other cancers, targeting both upstream regulators and mTOR itself to suppress tumorigenesis.

[0007] Further to this, in hypoxic microenvironments, mTOR can both be activated by HIF-1a, and sustain HIF-1a activity in a reciprocal fashion (Dodd, etal. ‘mTORCI drives HIF-1alpha and VEGF-A signalling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3’, Oncogene, 2015, 34, (17), pp. 2239-2250). This is mediated through the

[0008] 55718966-2 crosstalk between the mTOR complexes, and HIF-1a / VEGF-A signalling to establish a reciprocal activation loop of mTOR and hypoxic signalling, and is correlated with worse patient prognoses in cancers such as glioblastoma (Wei et al. ‘Hypoxia-Induced Autophagy Is Involved in Radioresistance via HIF1A-Associated Beclin-1 in Glioblastoma Multiforme’, Heliyon, 2023, 9, (1), pp. e12820)( Liu et al. ‘Phosphorylated mTOR and YAP serve as prognostic markers and therapeutic targets in gliomas’, Lab Invest, 2017, 97, (11), pp. 1354-1363).

[0009] Rapamycin was the first mTOR inhibitor, discovered in 1975, and associates with FKBP12 to form a ternary complex, and binds to the FRB domain, blocking substrate recruitment and entry into the active site, halting protein translation and inducing growth arrest. In its original form, rapamycin was found to have poor water solubility and bioavailability, limiting its clinical efficacy; derivatives (knows as ‘rapalogs’) aimed to solve this, such as everolimus and temsirolimus. As a result of the crosstalk between mTORCI and mTORC2, first generation inhibitors can only transiently inhibit mTOR signalling and therefore are often ineffective in aggressive cancers such as colorectal cancer, in both in vitro and in vivo settings.

[0010] Following the lack of success of first generation mTOR inhibitors, second generation ATP-competitive inhibitors were created to address the previous limitations of rapamycin and its rapalog derivatives. Some of these second-generation inhibitors share a pyrazolo[3,4-d]pyrimidine core, allowing these inhibitors to mimic and bind to the highly conserved ATP binding pocket that exists in kinases, thus inhibiting the kinase’s activity. A well characterised second generation mTOR inhibitor that currently exists in clinical trials is sapanisertib (also known as INK128). Sapanisertib is promiscuous in nature, also inhibiting up to 27 other kinases including lipid and tyrosine kinases. Without being bound by theory, this promiscuous nature is thought to be the main reason that sapanisertib has had limited success in clinical trials (due to high treatment-emergent serious adverse events and all-cause mortality rates). Other second generation mTOR inhibitors include PP242 and AZD8055 which suffer from promiscuity and low potency, respectively.

[0011] To date, there are no clinically effective FDA approved mTOR kinase inhibitors that can be used as a monotherapy or in combination, across multiple cancer types without issues of toxicity and low clinical efficacy, mainly due to their promiscuous nature. Due to the toxicities seen from clinical trials, existing mTOR inhibitors also cannot be used for combination therapy, i.e., to enhance other therapeutic strategies.

[0012] 55718966-2 The present invention seeks to provide (preferably selective (optionally super-selective) and potent) novel mTOR inhibitors, such as second-generation ATP-competitive inhibitors. The inventors hope to address the main limitations of existing mTOR inhibitors. It is thought that an increment of the complexity of the chemical structure of sapanisertib could produce novel derivatives with high potency against mTOR and high kinome selectivity. Without being bound by theory, these properties could lead to more promising drug candidates for the treatment of mTOR-driven disorders, including cancer.

[0013] SUMMARY

[0014] The present invention provides a cohort of novel compounds that have been found to act as inhibitors of kinases. In particular, the compounds disclosed herein have been found to show good levels of inhibition against mTOR and / or improved selectivity for mTOR over other kinases in comparison to other mTOR inhibitors known in the art.

[0015] Viewed from a first aspect, the invention provides a compound for use in a method of treatment or prophylaxis of a disease, wherein the compound is of formula (I), or a pharmaceutically acceptable salt, or solvate thereof:

[0016]

[0017] wherein:

[0018] W1, W2, and W3are each independently selected from H, halo, and ORW;

[0019] W4is selected from H, R11, C(O)R12, and C(O)OR13; wherein R11is selected from Ci-6alkyl, Cs-scycloalkyl, C2-6alkenyl, Cs-scycloalkenyl, and C2-6alkynyl; R12is selected from C1-5alkyl, C3-7cycloalkyl, C2-5alkenyl, C3-7cycloalkenyl, and C2-5alkynyl; and R13is selected from C1-4alkyl, C3-6cycloalkyl, C2-4alkenyl, C3-6cycloalkenyl, C2-4alkynyl, and benzyl; wherein R11, R12, and R13are each optionally substituted one or more times with halo, such as fluoro;

[0020] 55718966-2 each RWis independently selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl;

[0021] G1and G2are each independently selected from H, halo, and amino;

[0022] X1is N or CH;

[0023] X2is N; and

[0024] G3is:

[0025] Y-( )n1

[0026] /

[0027] Z

[0028]

[0029] wherein:

[0030] n1 is an integer selected from 0, 1, and 2;

[0031] Y is selected from (Ila) to (lie):

[0032] (Ha)

[0033]

[0034] wherein ring A is a 3- to 12-membered N-heterocycloalkylene;

[0035] *1

[0036] (Hb) wherein ring B is a 3- to 12-membered cycloalkylene;

[0037] R3

[0038]

[0039] wherein n2 is an integer selected from 1 to 6;

[0040] wherein each R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl,

[0041] 55718966-2 C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0042] ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and

[0043] *1 indicates a bond to Z and *2 indicates a bond to Y-( )n1of G3.

[0044] Z is selected from (IIIa) to (I lie):

[0045] « / vvv

[0046] (IIIa)

[0047]

[0048] v;

[0049] wherein:

[0050] V is selected from OR4, CFHR4, CF2R4, CF3, and C3-6heterocyclyl; wherein the C3-6heterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, phenylC1-2alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0051] R4is selected from C1-6alkyl, C1-6haloalkyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C3-6heterocycloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, wherein the C1-6alkyl, C1-6haloalkyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C3-6heterocycloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl are each optionally substituted one or more times with any one or a combination

[0052] 55718966-2 selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0053] I

[0054] R

[0055]

[0056] 5 / ^O

[0057] R" N

[0058] (lllb) R6;

[0059] wherein:

[0060] R5and R6are each independently selected from C1-6alkyl, C1-6haloalkyl, C6-10aryl, C5-10heteroaryl, C3-10heterocycloalkyl, N(R10)2, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, wherein the C1-6alkyl, C1-6haloalkyl, C6-10aryl, C5-10heteroaryl, C3-10heterocycloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; or

[0061] R5and R6combine with the nitrogen atom to form a 3- to 12-membered N-heterocycle, wherein the 3- to 12-membered N-heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, phenylC1-2alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and

[0062] (IIIc) C5-10heteroaryl;

[0063] wherein:

[0064] the C5-10heteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the C1-6alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl and C3-6cycloalkenyl are optionally

[0065] 55718966-2 substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0066] and further wherein:

[0067] each R9is independently selected from R10, OR10, and N(R10)2; and

[0068] each R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, C5-10heteroaryl, C3-10heterocycloalkyl, C2-6alkenyl, C3-6alkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino.

[0069] In particular, the present inventors have unexpectedly identified that increasing the structural complexity around position G3(as shown in formula (I) above) may facilitate the provision of kinase inhibitor compounds (specifically mTOR inhibitor compounds) with increased potency and / or selectivity.

[0070] Viewed from a second aspect, the invention provides a method of treatment or prophylaxis of a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof.

[0071] Viewed from a third aspect, the invention provides a use of compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for the treatment of a disease.

[0072] Viewed from a fourth aspect, the invention provides a compound of formula (I) (as defined in the first aspect) with the proviso that when:

[0073] (a) W1, W2, W3, and W4are each H;

[0074] (b) X1and X2are each N;

[0075] (c) G1is amino; and

[0076] (d) G2is H;

[0077] then G3is not one of the following groups:

[0078] 55718966-2

[0079]

[0080] Viewed from a fifth aspect, the invention provides a pharmaceutical composition comprising the compound of formula (I) (as defined in either the first or fourth aspects), or a pharmaceutically acceptable salt, or solvate thereof, and further comprising one or more pharmaceutically acceptable carriers and / or excipients.

[0081] Viewed from a sixth aspect, the invention provides a method of manufacture of a compound of formula (I), or any one of the compounds disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof.

[0082] BRIEF DESCRIPTION OF FIGURES

[0083] Fig. 1: Extended kinase screening panels of: (1A) known inhibitor sapanisertib;

[0084] (1B) compound 1137; (1C) compound 1177; (1D) compound 1328; (1E) compound 1346; (1F) compound 1396; each with 350 wild-type protein kinases and 14 lipid kinases. Hits (filled circles on the branches) are defined as <50% remaining kinase activity after 1 pM treatment.

[0085] Fig. 2: Tabular comparison between the kinome inhibition profiles of compounds 1137, 1177, 1328, 1346, and 1396 with known inhibitor sapanisertib. All kinases with

[0086] 55718966-2 less than 50% activity remaining after compound addition are shown. Compounds were screened at 1 pM.

[0087] Fig. 3: Western blots in: (3A) MCF7 cells with compound 1396 demonstrating that the compounds disclosed herein inhibit both mTORCI and mTORC2 downstream substrates, with intrafamily selectivity; * = (Phospho-(Ser / Thr) ATM / ATR Substrate); (3B) SW48 cells with compound 1396 demonstrating mTORCI and mTORC2 inhibition down to the lowest concentration tested.

[0088] Fig. 4: EC50curves of novel compound 1458 vs FDA approved ADC payload MMAE in: (4A) HKH2; (4B) SW48; and (4C) MCF7 cells with a concentration range of 100 nM – 0.01 nM.

[0089] Fig. 5: EC50curves displaying a significant reduction in activity of novel compound 1478, a proxy for a conjugated compound with respect to its parent compound 1396 in: (5A) HKH2; (5B) SW48; and (5C) MCF7 cancer cells in a concentration range of 300 – 0.03 nM.

[0090] DETAILED DESCRIPTION

[0091] In the discussion that follows, reference is made to a number of terms, which are to be understood to have the meanings provided below, unless a context indicates to the contrary. The nomenclature used herein for defining compounds, in particular the compounds described herein, is intended to be in accordance with the rules of the International Union of Pure and Applied Chemistry (IUPAC) for chemical compounds, specifically the “IUPAC Compendium of Chemical Terminology (Gold Book)” (see A. D. Jenkins et al., Pure & Appl. Chem., 68, 2287-2311 (1996)). For the avoidance of doubt, if an IUPAC rule is contrary to a definition provided herein, the definition herein is to prevail.

[0092] Each and every patent and non-patent reference referred to herein is hereby incorporated by reference in its entirety, as if the entire contents of each reference were set forth herein in their entirety.

[0093] The term “comprising” or variants thereof will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, but not the exclusion of any other element, integer or step, or group of elements, integers or steps.

[0094] The term “consisting” or variants thereof will be understood to imply the inclusion of a stated element, integer or step, or group of elements, integers or steps, and the exclusion of any other element, integer or step or group of elements, integers or steps.

[0095] 55718966-2 Throughout this specification, the terms “comprise”, “comprising” and / or “comprises” is / are used to denote aspects, embodiments and examples of the disclosure that “comprise” a particular feature or features. It should be understood that this / these terms may also encompass aspects, embodiments and examples which “consist essentially of’ or “consist of’ the relevant feature or features.

[0096] The term “about” herein, when qualifying a number or value, is used to refer to values that lie within ± 5% of the value specified. For example, if a suitable daily dose is indicated to be about 0.1 to about 100 mg / kg, doses of 0.095 to 105 mg / kg are included.

[0097] As used herein, “alkyl” defines a univalent group derived from an alkane by removal of a hydrogen atom from any carbon atom, wherein the term “alkane” is intended to define acyclic branched or unbranched hydrocarbons having the general formula CnH2n+2, wherein n is an integer >1. As used herein, C1-nalkyl refers to an alkyl group having 1 to n carbon atoms. By way of example, an alkyl group may be a C1-6alkyl (having 1 to 6 carbon atoms. In some cases, alkyl groups may be a Ci-4alkyl (having 1 to 4 carbon atoms). In some cases, an alkyl group may be a Ci-salkyl (having 1 to 3 carbon atoms. Representative examples of alkyl group include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyl, tert-butyl, and the like.

[0098] As used herein, “alkenyl” defines a univalent group derived from an alkene by removal of a hydrogen atom from any carbon atom, wherein the term “alkene” is intended to define acyclic branched or unbranched hydrocarbons having one carbon-carbon double bond and the general formula CnH2n, where n is an integer >2. As used herein, C2-nalkenyl refers to an alkenyl group having 2 to n carbon atoms. By way of example, an alkenyl group may be a C2-6alkenyl (having 2 to 6 carbon atoms). Representative examples of alkenyl group include, but are not limited to, ethenyl, prop-1-enyl, prop-2-enyl, 1-methyl-ethenyl, but-1-enyl, but-2-enyl, but-3-enyl, 1-methyl-prop-1-enyl, 1-methyl-prop-2-enyl, 2-methyl-prop-1-enyl, and 2-methyl-prop-2-enyl.

[0099] As used herein, “alkynyl” defines a monovalent radical derived from an alkyne by removal of a hydrogen atom from any carbon atom, wherein the term “alkyne” is intended to define acyclic branched or unbranched hydrocarbons having one carbon-carbon triple bond and the general formula CnH2n-2, where n is an integer >2. As used herein, C2-nalkynyl refers to an alkynyl group having 2 to n carbon atoms, and C3-nalkynyl refers to an alkynyl group having 3 to n carbon atoms. By way of example, an alkynyl group may be a C3-6alkynyl (having 3 to 6 carbon atoms). Representative examples of alkynyl groups include, but are not limited to, ethynyl, prop-1-ynyl, prop-2-ynyl, but-1-ynyl, but-2-ynyl, but-3-ynyl, and 1-methyl-prop-2-ynyl.

[0100] 55718966-2 As used herein, “carbocyclyl” refers to a monovalent radical derived from a carbocycle or cyclic hydrocarbon by the removal of a hydrogen atom from the carbocycle or cyclic hydrocarbon. A hydrocarbon is any molecule comprising only the elements carbon and hydrogen. The carbocyclic ring may be a monocyclic or polycyclic ring. In some cases, the carbocyclyl is a monocyclic or bicyclic ring, such as a monocyclic ring. In other examples, the carbocyclyl may be a bicyclic ring, which may, in some cases be a fused ring. Carbocyclyl groups may comprise 3 to 12 carbon atoms in the ring system. As used herein, the term carbocyclyl includes both aromatic and aliphatic compounds and so encompasses the cycloalkyl, cycloalkenyl and aryl groups as defined herein.

[0101] As used herein, “cycloalkyl” refers to a monovalent radical derived from a cycloalkane. A cycloalkane is a cyclic compound having carbon ring atoms, wherein the ring is saturated. The cycloalkyl ring may be a monocyclic or polycyclic ring. In some examples, the cycloalkyl may be a cycloalkyl containing 3 to 12 carbon ring atoms. In some examples, the cycloalkyl may be a C3-10cycloalkyl, a cycloalkyl containing 3 to 10 carbon atoms in the ring. In some examples, the cycloalkyl may be a C3-6cycloalkyl, a cycloalkyl containing 3 to 6 carbon atoms in the ring. Representative examples of cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc.

[0102] As used herein, “cycloalkenyl” refers to a monovalent radical derived from a cycloalkene. A cycloalkene is a cyclic compound having carbon ring atoms, wherein the ring comprises at least one carbon-carbon double bond (but is not aromatic). The cycloalkenyl ring may be a monocyclic or polycyclic ring. In some examples, the cycloalkenyl may be a cycloalkenyl containing 3 to 12 carbon ring atoms. In some examples, the cycloalkenyl may be a C3-10cycloalkenyl, a cycloalkenyl containing 3 to 10 carbon atoms in the ring. In some examples, the cycloalkenyl may be a C3-6cycloalkenyl, a cycloalkenyl containing 3 to 6 carbon atoms in the ring. Representative examples of cycloalkenyl groups include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, etc.

[0103] As used herein, the term "aryl" refers to a monocyclic or polycyclic aromatic hydrocarbon system having 6 to 14 carbon atoms, in some cases having 6 to 10 carbon atoms. An “aryl” group may be made up of two or more fused rings (rings that share two adjacent carbon atoms). When an aryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. In some examples, the aryl may be a C6-10aryl (an aryl comprising 6 to 10 carbon atoms in the ring). Representative examples

[0104] 55718966-2 of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl, 1 -naphthyl, 2-naphthyl and anthracenyl.

[0105] As used herein, the term “heterocyclyl” refers to a monovalent radical derived from a heterocycle by the removal of a hydrogen atom from the heterocycle. The heterocyclic ring may be a monocyclic or polycyclic ring. Where the heterocyclic ring is polycyclic, at least one ring contains at least one ring heteroatom as defined further herein, the other ring may optionally contain ring heteroatom(s). In some cases, the heterocyclyl is a monocyclic or bicyclic ring, such as a monocyclic ring. In other examples, the heterocyclyl may be a bicyclic ring, which may, in some cases be a fused ring. Heterocyclyl groups may comprise 3 to 12 atoms in the ring system. As used herein, the term heterocyclyl includes both aromatic and aliphatic compounds and so encompasses heterocycloalkyl, heterocycloalkenyl, and heteroaryl groups.

[0106] A heterocycle is a cyclic compound having as ring members atoms of at least two different elements (such as carbon and nitrogen). A heterocyclyl may comprise at least 1 heteroatom selected from nitrogen, oxygen and sulfur. Any N heteroatom present in the heterocyclic group may be C1-6alkyl-substituted. As used herein, a heterocyclyl may refer to a ring consisting of carbon atoms and from 1 to 5 ring heteroatoms, each independently selected from nitrogen, oxygen and sulfur.

[0107] As used herein, the term “N-heterocycle” refers to a heterocyclic group containing at least ring N atom.

[0108] As used herein, the term “heterocycloalkyl” refers to a monovalent radical derived from a heterocycloalkane. The heterocycloalkyl may be a monocyclic or polycyclic ring. In some examples, the heterocycloalkyl may be a heterocycloalkyl containing 3 to 12 ring atoms. In some examples, the heterocycloalkyl may be C3-7heterocycloalkyl, a heterocycloalkyl comprising 3 to 7 ring atoms. In some examples, the heterocycloalkyl may be C3-6heterocycloalkyl, a heterocycloalkyl comprising 3 to 6 ring atoms.

[0109] Representative examples of suitable heterocycloalkyl groups include azetidinyl, pyrrolidinyl tetrahydrofuranyl, thiolanyl, dioxolanyl, dithiolanyl, thiazolidinyl, isothiazolidinyl, oxazolidinyl, isoxazolidinyl, pyrazolidinyl, imidazolidinyl, piperidinyl, N-alkylpiperazinyl, piperazinyl, morpholinyl, dioxanyl, oxazolidinyl, hexahydropyrimidinyl, hexahydropyridazinyl, tetrahydropyranyl, thianyl, dithianyl, triazinanyl, azabicyclo[3.1.0]hexane, aza-bicyclo[3.2.1]octane, and azaspiro[3.3]heptane.

[0110] As used herein, “heteroaryl” may be a monocyclic or polycyclic ring system having one or more aromatic rings containing 1 or more heteroatom(s). As used herein, C5-10heteroaryl may refer to a heteroaromatic system having 5 to 10 ring atoms. The

[0111] 55718966-2 heteroaryl may comprise from 1 to 5 (e.g. from 1 to 4) ring heteroatoms, each independently selected from nitrogen, oxygen and sulphur. When a heteroaryl group is a fused ring system, then the ring that is connected to the rest of the molecule is fully aromatized. The other ring(s) in the fused ring system may or may not be fully aromatized. Representative examples of heteroaryl groups may include, but are not limited to, pyrrolyl, thiazolyl, isothiazolyl, pyrazolyl, imidazolyl, triazolyl (1,2,4- or 1,2,3-triazolyl), tetrazolyl, furanyl, thiophenyl, oxazolyl, isoxazolyl, oxadiazolyl (1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl or 1,2,3-oxadiazolyl), thiadiazolyl (1,3,4- or 1,2,5-thiadiazolyl), pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl (1,2,4- or 1,3,5-triazinyl), indolyl, isoindolyl, indolizinyl, indazolyl, benzimidazolyl, azaindolyl (4-, 5-, 6- or 7-azaindolyl), purinyl, benzofuranyl, isobenzofuranyl, benzothiophenyl, benzisoxazolyl, benzisothiazolyl, benzoxazolyl, benzthiazolyl, benzthiadiazolyl, quinolinyl, isoquinolinyl, quinolizinyl, quinoxalinyl, phthalazinyl, quinazolinyl, cinnolinyl, naphthyridinyl, pyridopyrimidinyl, pyridopyrazinyl, benzoxazinyl, benzodioxole (e.g. 1,3-benzodioxole), and the like.

[0112] Where any of the groups above (e.g. carbocyclic, cycloalkyl, cycloalkenyl, aryl, heterocyclic, heterocycloalkyl, heterocycloalkenyl, heteroaryl) are defined as being monocyclic, the group comprises a single ring. Where any of these are defined as being polycyclic, the group comprises two or more rings in the ring system. In some examples, the polycyclic group may be bicyclic, and so comprise two rings in the ring system. Where two or more rings are present (and unless otherwise indicated), the ring system may be a bridged, fused, or spirocyclic ring system.

[0113] As used herein, the term “bridged” refers to a ring system comprising two or more rings, where at least two rings share three or more atoms. Bridged ring systems comprise two bridgeheads, which correspond to the outer of the shared atoms, and a bridge separating the two bridgehead atoms, which corresponds to the remaining shared atoms. As used herein, a “C1-nalkylene bridge” may be used to refer to the bridging group and defines the number of carbon atoms present in the bridge. For example, a C1-3alkylene bridge refers to a bridging group comprising from 1 to 3 carbon atoms in the bridge.

[0114] As used herein, where a ring system is “fused”, the ring system comprises two or more rings, where at least two rings share two adjacent atoms.

[0115] As used herein, where a ring system is “spirocyclic”, the ring system comprising two or more rings, where at least two rings share only a single atom.

[0116] As used herein, halo represents a halogen radical. Typically, halo refers to any selected from fluoro, bromo, chloro and iodo. In some cases, halo refers to fluoro.

[0117] 55718966-2 As used herein, “haloalkyl” represents a monovalent group derived from an alkyl group, as defined above, by replacement of one or more hydrogen atoms from one or more carbon atoms with a halo group. The haloalkyl may be a “Ci-ehaloalkyl”, an alkyl group containing 1 to 6 carbon atoms, in which one or more hydrogens thereon has been replaced with a halogen atom. In some examples, the haloalkyl may be a “Ci-shaloalkyl”, an alkyl group containing 1 to 3 carbon atoms, in which one or more hydrogens thereon has been replaced with a halogen atom. Haloalkyl groups may comprise one or more different types of halo. For example, one or more independently selected from fluoro, chloro, bromo and iodo. In some cases, the haloalkyl is a fluoroalkyl.

[0118] As used herein, “hydroxyl” refers to an -OH group.

[0119] As used herein, “alkoxy” refers to a monovalent group derived from an alkyl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-. As used herein, a C1-6 alkoxy represents an alkoxy group containing 1 to 6 carbon atoms and a C1-C3 alkoxy represents an alkoxy group containing 1 to 3 carbon atoms. Representative examples of alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, hexyloxy etc.

[0120] As used herein, “aryloxy” refers to a monovalent group derived from an aryl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-.

[0121] As used herein, “heteroaryloxy” refers to a monovalent group derived from an heteroaryl group, as defined above, appended to the parent molecular moiety through an oxy group, -O-.

[0122] As used herein, “oxo” refers to a double bond to an oxygen (=O). Where a group is said to be substituted, or optionally substituted, with an oxo group, two hydrogen atoms on a carbon are replaced with a double bond to the oxygen to form a carbonyl group. As used herein, “cyano” refers to a -C=N group.

[0123] As used herein, “nitro” refers to -NO2 group.

[0124] As used herein, “amino” refers to an -NH2group.

[0125] As used herein, “phenylC1-nalkyl” refers to monovalent group in which the phenyl contains a C1-nalkyl substituent directly appended to the aromatic ring. The phenylC1-nalkyl group is appended to the parent molecular moiety through the C1-nalkyl group. In some examples, the phenylC1-nalkyl may be a phenylCi-4alkyl. A representative example is benzyl.

[0126] Where any of the groups are defined as being substituted, or “optionally substituted”, any hydrogen atom(s) may be replaced with the substituent(s), providing

[0127] 55718966-2 valencies are satisfied. By way of example, when an alkyl group is substituted, any hydrogen atom(s) may be replaced with the substituent(s), providing valencies are satisfied.

[0128] The groups above are defined in relation to the monovalent radical. In some cases, the groups may be present in the compounds of the invention as a divalent radical (which is derived from the parent structure by removal of two hydrogen atoms). In those cases, the suffix -ene may be used to designate the presence of the divalent moiety. By way of example, where the alkyl comprises a divalent hydrocarbon radical, this moiety may sometimes be referred to herein as an alkylene.

[0129] For the avoidance of doubt, a wavy line in a chemical structure bisects the bond linking the moiety shown to the rest of the compound.

[0130] The term “solvate” is used herein to refer to a complex comprising a solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc., depending on the number of water molecules present per molecule of substrate.

[0131] As used herein, the term "pharmaceutically acceptable salt" refers to those salts, which are generally considered suitable for use in medicine (including in a veterinary context). For example, pharmaceutically acceptable salts may be those which can be contacted with the tissues of a mammalian subject (e.g. humans) without undue toxicity, irritation, allergic response or the like. By way of further example of suitable pharmaceutically acceptable salts, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19, the entire contents of which are incorporated herein by reference.

[0132] As used herein, "treatment" defines the therapeutic treatment of a subject that may be a mammalian subject, such as human or non-human animal (e.g. a domesticated animal such as a farmed animal), in order to impede or reduce or halt the rate of progress of a condition, or to ameliorate or cure the condition. In certain instances, the term "treatment" is used to define the therapeutic treatment of a subject in order to impede or reduce or halt the rate of progress of a condition, or to ameliorate or cure the condition. In those instances, the subject has the condition and so may considered as a subject in need of treatment.

[0133] As used herein, references to prophylaxis are intended herein not to require complete prevention of a condition: its development may instead be hindered through treatment in accordance with the invention. In those instances, the subject may be at risk of developing the condition.

[0134] 55718966-2 As used herein, a "therapeutically effective amount" defines an amount of any one or a combination of the compounds or compositions described herein that is sufficient to impede a condition and thus produces the desired therapeutic or inhibitory effect.

[0135] As stated above, according to a first aspect, a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, is for use in a method of treatment or prophylaxis of a disease.

[0136] According to a second aspect, the invention provides a method of treatment or prophylaxis of a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof.

[0137] According to a third aspect, the invention provides a use of compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for the treatment of a disease.

[0138] According to a fourth aspect, the invention provides a compound of formula (I) or a pharmaceutically acceptable salt, or solvate thereof, with the proviso that when: (a) W1, W2, W3, and W4are each H;

[0139] (b) X1and X2are each N;

[0140] (c) G1is amino; and

[0141] (d) G2is H;

[0142] then G3is not one of the following groups:

[0143]

[0144] 55718966-2

[0145]

[0146] In some embodiments of the fourth aspect, the compound is according to formula (la):

[0147]

[0148] wherein W1, W2, W3, X1, X2, G1, G2, and G3are as defined in respect of formula (I), with the proviso that when:

[0149] (a) W1, W2, and W3are each H;

[0150] (b) X1and X2are each N;

[0151] (c) G1is amino; and

[0152] (d) G2is H;

[0153] then G3is not one of the following groups:

[0154]

[0155] 55718966-2

[0156]

[0157] o According to a fifth aspect, the invention provides a pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, and further comprising one or more pharmaceutically acceptable carriers and / or excipients.

[0158] According to a sixth aspect, the invention provides a method of manufacture of a compound of formula (I), or any one of the compounds disclosed herein, or a pharmaceutically acceptable salt, or solvate thereof.

[0159] Compounds of formula (I)

[0160] The compounds of formula (I) are described in further detail below and it will be appreciated that the embodiments of formula (I) are equally applicable to each of the first, second, third, fourth, fifth, and sixth aspects as disclosed herein.

[0161] The general structure of formula (I) is set out below:

[0162]

[0163] 55718966-2 wherein:

[0164] W1, W2, and W3are each independently selected from H, halo, and ORW;

[0165] W4is selected from H, R11, C(O)R12, and C(O)OR13; wherein R11is selected from Ci-ealkyl, Cs-scycloalkyl, C2-6alkenyl, Cs-scycloalkenyl, and C2-6alkynyl; R12is selected from C1-5alkyl, C3-7cycloalkyl, C2-5alkenyl, C3-7cycloalkenyl, and C2-5alkynyl; and R13is selected from C1-4alkyl, C3-6cycloalkyl, C2-4alkenyl, C3-6cycloalkenyl, C2-4alkynyl, and benzyl; wherein R11, R12, and R13are each optionally substituted one or more times with halo, such as fluoro;

[0166] each RWis independently selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl;

[0167] G1and G2are each independently selected from H, halo, and amino;

[0168] X1is N or CH;

[0169] X2is N; and

[0170] G3is:

[0171] Z

[0172]

[0173] wherein:

[0174] n1 is an integer selected from 0, 1, and 2;

[0175] Y is selected from (Ila) to (lie):

[0176] *1-;

[0177] (Ha)

[0178]

[0179] wherein ring A is a 3- to 12-membered N-heterocycloalkylene;

[0180]

[0181] *1

[0182] (Hb)

[0183] wherein ring B is a 3- to 12-membered cycloalkylene;

[0184] 55718966-2 R3

[0185] (lie)

[0186]

[0187] n2

[0188] wherein n2 is an integer selected from 1 to 6;

[0189] wherein each R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci_6alkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Cs-wheteroaryl, Ce-waryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0190] ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-6alkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and

[0191] *1 indicates a bond to Z and *2 indicates a bond to Y-( )n1of G3.

[0192] Z is selected from (IIIa) to (I I Ic):

[0193] (IIIa)

[0194]

[0195] V °;

[0196] wherein:

[0197] V is selected from OR4, CFHR4, CF2R4, CF3, and C3-6heterocyclyl;

[0198] 55718966-2 wherein the Cs-eheterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, C5-10heteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2;

[0199] R4is selected from Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, Ce-wheteroaryl, Cs-eheterocycloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce- aryl, Cs-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Cs-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2;

[0200] (lllb)

[0201]

[0202] R6;

[0203] wherein:

[0204] R5and R6are each independently selected from Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, N(R10)2, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; or

[0205] R5and R6combine with the nitrogen atom to form a 3- to 12-membered A / -heterocycle, wherein the 3- to 12-membered A / -heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-ealkenyl,

[0206] 55718966-2 Cs-ealkynyl, Cs-ecycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and

[0207] (IIIc) C5-10heteroaryl;

[0208] wherein:

[0209] the Cs-wheteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl and Cs-ecycloalkenyl are optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0210] and further wherein:

[0211] each R9is independently selected from R10, OR10, and N(R10)2; and

[0212] each R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino.

[0213] As noted above, W4is selected from H, R11, C(O)R12, and C(O)OR13. As indicated in formula (I), R11, R12, and R13may be optionally substituted one or more times with halo, such as fluoro. Byway of example, where W4is R11, and is selected from Ci-ealkyl, Cs-ecycloalkyl, C2-ealkenyl, Cs-scycloalkenyl, and C2-ealkynyl; each of the Ci-ealkyl, C3-8cycloalkyl, C2-ealkenyl, Cs-scycloalkenyl, and C2-ealkynyl may be optionally substituted one or more times (e.g. from 1 to 5 times) with fluoro. By way of further example, where W4is C(O)R12, and R12is selected from Ci-salkyl, Cs-zcycloalkyl, C2-salkenyl, C3-7cycloalkenyl, and C2-salkynyl; each of the Ci-salkyl, Cs-zcycloalkyl, C2-salkenyl, C3-7cycloalkenyl, and C2-salkynyl may be optionally substituted one or more times (e.g. from 1 to 5 times) with fluoro. By way of yet further example, where W4is C(O)OR13and R13is selected from Ci-4alkyl, Cs-ecycloalkyl, C2-4alkenyl, Cs-ecycloalkenyl, C2-4alkynyl, and benzyl; each of the Ci-4alkyl, Cs-ecycloalkyl, C2-4alkenyl, Cs-ecycloalkenyl, C2-4alkynyl, and

[0214] 55718966-2 benzyl may be optionally substituted one or more times (e.g. from 1 to 5 times) with fluoro.

[0215] In some embodiments, W4is selected from H, R11, C(O)R12, and C(O)OR13; wherein R11is selected from Ci-ealkyl, Cs-scycloalkyl, C2-6alkenyl, Cs-scycloalkenyl, and C2-6alkynyl; R12is selected from Ci-salkyl, Cs-zcycloalkyl, C2-5alkenyl, Cs-zcycloalkenyl, and C2-5alkynyl; and R13is selected from Ci-4alkyl, Cs-ecycloalkyl, C2-4alkenyl, C3-6cycloalkenyl, and C2-4alkynyl; wherein R11, R12, and R13are each optionally substituted one or more times with halo, such as fluoro.

[0216] In some embodiments, W4is selected from H, C(O)R12, and C(O)OR13. In some embodiments, R12is selected from Ci-salkyl, and Cs-zcycloalkyl; and R13is selected from Ci^alkyl, Cs-ecycloalkyl, and benzyl; wherein R12and R13are each optionally substituted one or more times with halo, such as fluoro. In some embodiments, R12is selected from Ci-5alkyl, and Cs-zcycloalkyl; and R13is selected from Ci^alkyl, and Cs-ecycloalkyl; wherein R12and R13are each optionally substituted one or more times with halo, such as fluoro. In some embodiments, W4is selected from H, C(O)Ci-5alkyl, and C(O)OCi-4alkyl. In some embodiments, W4is selected from H, C(O)Ci-4alkyl, and C(O)OCi-4alkyl. In some embodiments, W4is selected from H, C(O)CH3, and C(O)O-(tert-butyl). In some embodiments, W4is H.

[0217] In some embodiments, the compound is of formula (la), or a pharmaceutically acceptable salt, or solvate thereof:

[0218]

[0219] wherein:

[0220] W1, W2, and W3are each independently selected from H, halo, and ORW; each RWis independently selected from C1-6alkyl, C1-6haloalkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl;

[0221] G1and G2are each independently selected from H, halo, and amino;

[0222] X1is N or CH;

[0223] 55718966-2 X2is N; and

[0224] G3is:

[0225]

[0226] wherein:

[0227] n1 is an integer selected from 0, 1, and 2;

[0228] Y is selected from (Ila) to (lie):

[0229] (Ha)

[0230]

[0231] wherein ring A is a 3- to 12-membered N-heterocycloalkylene;

[0232] (Hb) wherein ring B is a 3- to 12-membered cycloalkylene;

[0233] R3

[0234]

[0235] wherein n2 is an integer selected from 1 to 6;

[0236] wherein each R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-ioheteroaryl, Ce-waryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;

[0237] ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (lie) are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo,

[0238] 55718966-2 hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and

[0239] *1 indicates a bond to Z and *2 indicates a bond to Y-( )n1of G3.

[0240] Z is selected from (IIIa) to (I I Ic):

[0241] z^o

[0242] (IIIa)

[0243]

[0244] V;

[0245] wherein:

[0246] V is selected from OR4, CFHR4, CF2R4, CF3, and C3-eheterocyclyl; wherein the C3-eheterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci -ealkoxy, phenylCi-2alkyl, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0247] R4is selected from Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, C3-eheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, and C3-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, C3-eheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, and C3-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0248] 55718966-2 (lllb)

[0249]

[0250] R6;

[0251] wherein:

[0252] R5and R6are each independently selected from Ci-ealkyl, Ci-ehaloalkyl, Ce- aryl, Ce-wheteroaryl, C3-10heterocycloalkyl, N(R10)2, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Ce-wheteroaryl, C3-10heterocycloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-6haloalkyl, Ci-6alkoxy, C2-6alkenyl, C3-6alkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Ce-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2; or

[0253] R5and R6combine with the nitrogen atom to form a 3- to 12-membered A / -heterocycle, wherein the 3- to 12-membered A / -heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Ce-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2; and

[0254] (lllc) Ce-wheteroaryl;

[0255] wherein:

[0256] the Ce-wheteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-6alkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Ce-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl and Cs-ecycloalkenyl are optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, amino, Ci-ealkyl, Ci-ealkoxy, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2;

[0257] and further wherein:

[0258] 55718966-2 each R9is independently selected from R10, OR10, and N(R10)2; and

[0259] each R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce- aryl, C5-10heteroaryl, C3-10heterocycloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino.

[0260] For the avoidance of doubt, all embodiments described herein apply to both formula (I) and formula (la), formula (la) being a sub-group of formula (I). As stated above, G1is selected from H, halo, and amino. In some embodiments, G1is amino.

[0261] As stated above, G2is selected from H, halo, and amino. In some embodiments, G2is H.

[0262] As stated above, W1, W2, and W3are each independently H or fluoro. In some embodiments, W1is H or fluoro. In some embodiments, W2and W3are each H. In some embodiments, W1is H or fluoro, and W2and W3are each H. In some embodiments, W1is fluoro, and W2and W3are each H. In some embodiments, W1, W2and W3are each H.

[0263] As stated above, X1is selected from N and CH. In some embodiments, X1is N. In some embodiments, X1is CH.

[0264] As stated above, X2is N.

[0265] In some embodiments, X1is selected from N and CH, and X2is N.

[0266] As stated above, G3is:

[0267] Y-( )n1

[0268] /

[0269] Z

[0270]

[0271] As stated above, n1 is an integer selected from 0, 1 and 2. In some embodiments, n1 is 1.

[0272] As stated above, each R9is independently selected from R10, OR10, and N(R10)2; and

[0273] each R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Ce-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, C3-6alkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino.

[0274] In some embodiments, R9is selected from R10, OR10, and N(R10)2; and each R10is independently selected from H, and C1-6alkyl.

[0275] 55718966-2 In some embodiments, R9is selected from R10, OR10, and N(R10)2; and each R10is independently selected from H, and Ci-salkyl.

[0276] As stated above, Y is any one selected from formulae (Ila), (lib) and (He) as described herein.

[0277] In some embodiments, Y is of formula (Ila):

[0278] *1-1

[0279] (Ha)

[0280]

[0281] wherein ring A is a 3- to 12-membered A / -heterocycloalkylene.

[0282] For the avoidance of any doubt, and as described herein, the 3- to 12-membered A / -heterocycloalkylene of ring A of formula (Ila) may be monocyclic or polycyclic. Where ring A is polycyclic at least one of the rings in the ring system comprises an N ring atom, the other of the ring(s) may not comprise any heteroatoms in the ring system. In some embodiments ring A contains 1 ring N atom.

[0283] In some embodiments, ring A is monocyclic and may preferably be a C3-yheterocycloalkyl. Representative examples for ring A include, but are not limited to, azetidinyl, pyrrolidinyl, piperidinyl, and the like.

[0284] In some embodiments, ring A of formula (Ila) is bicyclic and comprises two rings in the ring system. Where ring A is bicyclic, the two rings may be a fused ring system, a bridged ring system, or a spirocyclic ring system.

[0285] By way of example, in some embodiments, ring A may comprise two rings in a fused ring system, such as a first Cs-yheterocycloalkyl fused to a second Cs-ycycloalkyl or Cs-yheterocycloalkyl. In some embodiments, ring A may comprise a pyrrolidine fused to a cyclopropyl group, such as azabicyclo[3.1.0]hexane (e.g. 3-azabicyclo[3.1.0]hexane).

[0286] By way of further example, in some embodiments, ring A may comprise two rings in a bridged ring system. In some embodiments, ring A may comprise a C3-yheterocycloalkyl which further comprises a Ci-salkylene group bridging two ring carbon atoms of the Cs-yheterocycloalkyl. Representative examples include, but are not limited to, azabicyclo[3.2.1]octane (e.g. 8-azabicyclo[3.2.1]octane).

[0287] By way of further example, in some embodiments, ring A may comprise two rings in a spirocyclic ring system, such as a first Cs-yheterocycloalkyl joined to a second C3-ycycloalkyl or Cs-yheterocycloalkyl by way of a spiro centre. In some embodiments, ring A may comprise a Cs-sheterocycloalkyl (such as azetidinyl) joined to a Cs-scycloalkyl

[0288] 55718966-2 (such as cyclobutyl). Representative examples include, but are not limited to, azaspiro[3.3]heptane (e.g. 2-azaspiro[3.3]heptane).

[0289] In some embodiments, Y is of formula (lib):

[0290]

[0291] (Hb)

[0292] wherein ring B is a 3- to 12-membered cycloalkylene.

[0293] For the avoidance of any doubt, and as described herein, the 3- to 12-membered cycloalkylene of ring B may be monocyclic or polycyclic.

[0294] In some embodiments, ring B is monocyclic and may preferably be a C3-ycycloalkyl. Representative examples for ring B include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, and cycloheptyl. In some embodiments ring B is cyclohexyl.

[0295] In some embodiments, ring B of formula (lib) is bicyclic and comprises two rings in the ring system. Where ring B is bicyclic, the two rings may be a fused ring system, a bridged ring system, or a spirocyclic ring system.

[0296] In some embodiments, Y is of formula (lie):

[0297] R3

[0298]

[0299] wherein n2 is an integer selected from 1 to 6.

[0300] In each of formula (Ila), (lib), and (lie), the position designated as “*1” indicates " S'

[0301] a bond to Z and the position designated as *2 indicates a bond to

[0302]

[0303] n1of G3.

[0304] In other words, in each of formula (Ila), (lib), and (lie), at *1, the N atom forms a covalent bond with an atom forming part of a Z group (as defined herein).

[0305] In formula (Ila) and (lib), at *2, a covalent bond is formed between a ring atom on ring A (of formula Ila), or a ring atom on ring B (of formula B) with a carbon atom in the

[0306] alkylene group '

[0307]

[0308] V^ni por examp|ewhere n1 is 1 and 'V^ni jS a methyiene group, a bond is formed between a ring atom on ring A or ring B and the carbon of the methylene

[0309] group. Where n1 is 0 and '

[0310]

[0311] V^ni js absent,rjng A or ring B are directly appended to the

[0312] 55718966-2 parent structural moiety as shown on formula (I) (by way of the N ring atom shown appended to group G3on formula (I)).

[0313] In formula (lie), a covalent bond is formed between a carbon atom in the alkylene

[0314] chain with a carbon atom in

[0315]

[0316] *n1(where n1 is 1 or 2). Where n1 is 0, the alkylene chain shown in formula (lie) is directly appended to the parent structural moiety as shown on formula (I) (by way of the N ring atom shown appended to group G3on formula (I)).

[0317] Where Y is of formula (lib) or (He), the N atom is substituted with group R3as shown above. As stated herein, in each case, R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination (e.g. from 1 to 6, or from 1 to 4 times) selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, C5-10heteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2.

[0318] In some embodiments, R3is independently selected from Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C(O)R9, and N(R10)2. In some embodiments, R3is Ci-ealkyl. In some embodiments, R3is Ci-salkyl, such as methyl, or ethyl.

[0319] As stated above, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 6, or from 1 to 4) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, Ce- aryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, C3-6alkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2.

[0320] In some embodiments, ring A of formula (Ha), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 6, or from 1 to 4) times with any one or a combination selected from: halo, hydroxy,

[0321] 55718966-2 oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-6alkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cswcycloalkenyl, phenylCi-4alkyl, Ce- aryl, Cs-wheteroaryl, Ce-waryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-6alkenyl, C3-6alkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2.

[0322] In some embodiments, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (lie) are each optionally substituted one or more (e.g., from 1 to 6, or from 1 to 4) times with any one or a combination selected from: halo, hydroxy, C1-6 alkyl, Ci-ehaloalkyl, Ci-ealkoxy, and cyano. In some embodiments, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 3) times with any one or a combination selected from: halo, hydroxy, Ciwalkyl, Ci-salkoxy, and cyano. In some embodiments, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (lie) are each optionally substituted with a group selected from: fluoro, methyl, hydroxy, methoxy, and cyano. In some embodiments, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted with a group selected from: fluoro, methyl, and cyano. In some embodiments, ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted with a group selected from: fluoro, and cyano. In some embodiments, ring A of formula (Ha), ring B of formula (I lb), and the alkylene group of formula (He) are each optionally substituted with a group selected from: fluoro, and methyl.

[0323] In some embodiments Y is of formula (He), and n2 is selected from 2, 3, and 4, optionally 3.

[0324] In some embodiments, Y is selected from formulae (Hd-i):

[0325]

[0326] 55718966-2

[0327]

[0328] In formula (He), an optional C salkylene group bridges carbon 1 or 2 to carbon 3 or 4.

[0329] In formula (llh), the NR3group is covalently bonded to a carbon atom on the cycloalkyl ring at any suitable position (e.g. by the replacement of a hydrogen atom).

[0330] In each of formula (lld-i), the wavy line intersecting the bond to the N atom indicates the covalent bond that forms between the N atom and an atom forming part of a Z group (as defined herein). The wavy line intersecting the bond to the carbon atom on each of formula (lld-i) indicates the covalent bond that forms between the carbon

[0331] atom and a carbon atom in the alkylene group '

[0332]

[0333] of G3 (where n1 is >0). Where n1

[0334] is 0 and is absent, the carbon atom directly appended to the parent structural moiety as shown on formula (I) (by way of the N ring atom shown appended to group G3 on formula (I)).

[0335] In each of formulae (lld-i):

[0336] each R1is independently selected from H, halo (e.g. fluoro), Ci-salkyl, Ci_3alkoxy (e.g. Ci-2alkoxy), cyano, hydroxy and Ci-shaloalkyl (e.g. CiJIuoroalkyl);

[0337] each R2is independently selected from halo, oxo, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Csecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one ora combination selected from: halo, hydroxy, amino, Ci-ealkyl, Ci-ealkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0338] each n' is an integer selected from 0 to 6;

[0339] each n" is an integer selected from 0 to 5;

[0340] n’” is an integer selected from 0 to 3;

[0341] n”” is an integer selected from 0 to 1; and

[0342] each R3, R9, and R10are as defined above and herein.

[0343] In some embodiments of formulae (lld-i), each R1is independently selected from H, halo (e.g. fluoro), Ci^alkyl, Ci-salkoxy (e.g. Ci-2alkoxy), cyano, hydroxy and Ci- shaloalkyl (e.g. Ci-2fluoroalkyl). In some embodiments, each R1is independently selected

[0344] 55718966-2 from H, fluoro, methyl, hydroxy, methoxy, and cyano. In some embodiments, each R1is independently selected from H, fluoro, methyl, and cyano (such as fluoro, methyl, and cyano). In some embodiments, each R1is independently selected from fluoro and cyano. In some embodiments, each R1is independently selected from H, fluoro and methyl.

[0345] In some embodiments of formulae (lld-i), each R2is independently selected from halo, oxo, Ci-salkyl, Ci-shaloalkyl, Ci-salkoxy. In some embodiments, each R2is independently selected from fluoro, and methyl. In some embodiments, each R2is independently selected from Ci-salkyl (such as methyl).

[0346] In some embodiments, each n' is an integer selected from 0 to 3. In some embodiments, n' is 0 or 1.

[0347] In formulae (lid), (Ilf), and (llg), in some embodiments, each n” is an integer selected from 1 to 2, preferably 1.

[0348] In formulae (Uh), in some embodiments, n” is an integer selected from 1 to 2, preferably 2.

[0349] In formula (III), in some embodiments, n” is an integer selected from 1 to 3, preferably 2. In particular, in some embodiments where n1 is 1; n” of formula (III) is 2.

[0350] In formula (llg), in some embodiments, n’” is an integer selected from 1 to 2, preferably 1.

[0351] In formula (III), in some embodiments, n”” is 0 and the alkylene group is unsubstituted. In other words a hydrogen atom is bonded to the carbon at the indicated position. In formula (III), where n” is greater than 1, each alkylene repeat unit may independently be optionally substituted with groups R2. If multiple R2groups are present, these may be the same or different.

[0352] In some embodiments, Y is selected from formulae (I Ij-r):

[0353]

[0354] 55718966-2 In each of formulae (llj-r):

[0355] R1is as defined above for formula (lld-i);

[0356] R2is H or as defined above for formula (lld-i);

[0357] R3, R9, and R10are as defined above and herein;

[0358] n3 is an integer selected from 0 to 3; and

[0359] n4 is an integer selected from 0 to 2.

[0360] In some embodiments, n3 is 0 or 2. In some embodiments, n4 is selected from 2, 3, and 4, optionally 1 or 3.

[0361] In some preferred embodiments, Y is selected from one of the following structures:

[0362]

[0363] wherein:

[0364] R1is selected from H, fluoro, methyl, hydroxy, methoxy and cyano (e.g. H, fluoro and methyl); and

[0365] R3is Ci-salkyl. As stated above, Z is any one selected from formulae (IIIa), (lllb) and (I He) as described herein.

[0366] In some embodiments, Z is of formula (IIIa):

[0367]

[0368] v ° (IIIa);

[0369] wherein:

[0370] V is selected from OR4, CFHR4, CF2R4, CF3, and C3-6heterocyclyl; wherein the Cs-eheterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Ce-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2;

[0371] R4is selected from Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, C5-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce- aryl, C5-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl,

[0372] 55718966-2 Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and R9and R10as defined above in formula (I), and also as defined herein.

[0373] As stated above, V is selected from OR4, CFHR4, CF2R4, CF3, and C3-6heterocyclyl. In some embodiments, V is OR4. In some embodiments, V is Cs-eheterocyclyl. In some embodiments, V is selected from CFHR4, CF2R4, and CF3. In some particular embodiments V is selected from OR4, and Cs-eheterocyclyl.

[0374] In some embodiments, R4is selected from Ci-ealkyl, phenylCi-4alkyl, Ce- aryl, C2-ealkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, wherein the Ci-ealkyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, C2-ealkenyl, C3-ealkynyl, C3-ecycloalkyl, and C3-6cycloalkenyl, are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, nitro, amino, cyano, Ci-Cealkyl, Ci-Cealkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2.

[0375] In some embodiments, R4is selected from Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, C3-6cycloalkyl, C3-ecycloalkenyl, Ce-waryl, and Ce-wheteroaryl; wherein the Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, Ce-waryl, and Cs-wheteroaryl are each optionally substituted one or more times (e.g. 1 or 2 times) with halo, hydroxy, nitro, amino, cyano, Ci-C3alkyl, Ci-C3alkoxy (e.g. optionally substituted one or more times with any selected from fluoro, nitro, and methoxy).

[0376] In some embodiments, R4is selected from Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, C3-6cycloalkyl, C3-ecycloalkenyl, Ce-waryl, and Ce-wheteroaryl; wherein the Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, C3-ecycloalkyl, C3-ecycloalkenyl, Ce-waryl, and Cs-wheteroaryl are each optionally substituted one or more times (e.g. 1 or 2 times) with any selected from fluoro, nitro, and methoxy (e.g. with fluoro).

[0377] In some embodiments, R4is selected from Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, C3-6cycloalkyl, and C3-ecycloalkenyl. In some embodiments, R4is selected from Ci-4alkyl, C2-5alkenyl, C3-ealkynyl, and C3-ecycloalkyl.

[0378] In some embodiments, R4is selected from phenyl, and Cs-wheteroaryl (such as a C5-10heteroaryl selected from benzodioxole, pyridine, pyridazine, and pyrimidines). In such embodiments, the phenyl, and Cs-wheteroaryl may be each optionally substituted one or more times (e.g. 1 or 2 times) with any selected from fluoro, nitro, and methoxy (e.g. with fluoro).

[0379] As stated above, in some embodiments V is C3-6heterocyclyl which may be optionally substituted one or more times (e.g. from 1 to 3 times) with any one or a combination selected from: halo, hydroxy, amino, cyano, Ci-Cealkyl, Ci-Cealkoxy, Ce-

[0380] 55718966-2 waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2. In some embodiments, the Cs-eheterocyclyl is optionally substituted one or more times (e.g. 1 or 2 times) with any selected from fluoro, hydroxy, amino, cyano, Ci-Csalkyl, and Ci-Csalkoxy. In some embodiments, the Cs-eheterocyclyl is tetrahydrofuranyl.

[0381] In some embodiments, Z is any one selected from the following structures:

[0382]

[0383] In some embodiments, Z is of formula (I lib):

[0384] < / w I v

[0385]

[0386] R6(lllb);

[0387] wherein:

[0388] R5and R6are each independently selected from Ci-6alkyl, Ci-6haloalkyl, C6-ioaryl, C5-10heteroaryl, Cs-ioheterocycloalkyl, N(R10)2, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Ce- heteroaryl, C3-loheterocycloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl,

[0389] 55718966-2 Cs-ealkynyl, Cswcycloalkyl, Cswcycloalkenyl, Ce- aryl, Ce-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; or

[0390] R5and R6combine with the nitrogen atom to form a 3- to 12-membered A / -heterocycle, wherein the 3- to 12-membered A / -heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ciwalkyl, Ciwhaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-6alkenyl, Cs-ealkynyl, Cswcycloalkyl, Cswcycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2.

[0391] In some embodiments, R5and R6are each independently selected from Ci-ealkyl and phenyl, wherein the Ci-ealkyl and phenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, Ci-ealkyl, and Ci-ealkoxy. In some embodiments, R5and R6are each independently selected from Ciwalkyl and phenyl.

[0392] In some embodiments, R5and R6combine with the nitrogen atom to form a 5- to 6-membered A / -heterocycle, wherein the 5- to 6-membered A / -heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, Ciwalkyl, and Ci-ealkoxy. Representative examples of suitable 5- to 6-membered N-heterocycles include (but are not limited to) pyrrolidinyl, piperidinyl, morpholinyl, and piperazinyl, each of which may be optionally substituted with a Ciwalkyl.

[0393] In some embodiments, Z is selected from one of the following structures:

[0394]

[0395] In some embodiments, Z is of formula (Hie) and is a Cs-wheteroaryl. As stated above, the Cs-wheteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ciwalkyl, Ciwhaloalkyl, Ci-ealkoxy, C2walkenyl, C3-6alkynyl, Cswcycloalkyl, Cswcycloalkenyl, Ce-waryl, Ce-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl and Cs-ecycloalkenyl are optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected

[0396] 55718966-2 from: halo, hydroxy, amino, Ci-ealkyl, Ci-6alkoxy, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2.

[0397] In some embodiments, the Cewheteroaryl is a heteroaryl containing from two to three ring heteroatoms each independently selected from N, O, and S. In some embodiments, the Ce-wheteroaryl is a heteroaryl containing two ring heteroatoms selected from N, O, and S, with the proviso that at least one ring heteroatom is N.

[0398] In some embodiments, the Cewheteroaryl is optionally substituted one or more (e.g., from 1 to 2) times with any one or a combination selected from: halo, hydroxy, amino, Ci-ealkyl, Ci-6alkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2. In some embodiments, the Cs-wheteroaryl is optionally substituted one or two times with Ci-ealkyl (such as methyl).

[0399] In some embodiments, Z is any one selected from formulae (llld-f):

[0400]

[0401] wherein:

[0402] ring C is 5- or 6-membered carbocycle or heterocycle;

[0403] X3is selected from O, and S;

[0404] each X is independently selected from CR7, N, O, and S;

[0405] each X' is independently selected from C, and N;

[0406] each R7is independently selected from H, halo, hydroxy, amino, Ci-ealkyl, Ci-6alkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0407] each R8is independently selected halo, hydroxy, amino, Ci-ealkyl, Ci-6alkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0408] R9is selected from R10, OR10, and N(R10)2;

[0409] each R10is independently selected from H, and C1-6alkyl; and

[0410] n5 is an integer selected from 0 to 4.

[0411] In some embodiments, Z is selected from formulae (lllg-k):

[0412] 55718966-2

[0413]

[0414] In each of formulae (Illg) to (lllk):

[0415] each X3is selected from O, and S;

[0416] each R7is independently selected from H, halo, hydroxy, amino, Ci-ealkyl, Ci-6alkoxy, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;

[0417] each R8is independently selected halo, hydroxy, amino, Ci-ealkyl, C1-6alkoxy, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2;

[0418] R9is selected from R10, OR10, and N(R10)2;

[0419] each R10is independently selected from H, and C1-6alkyl; and

[0420] n5 is an integer selected from 0 to 4.

[0421] In some embodiments, X3is O. In some embodiments, each R7is independently selected from H, and Ciwalkyl. In some embodiments, each R8is Ci-salkyl. In some embodiments n5 is an integer selected from 0 to 2.

[0422] Representative examples of suitable Cs-wheteroaryl include, but are not limited to, oxazolyl, thiazolyl, 1,3,4-oxadiazolyl, benzoxazolyl, benzothiazolyl, pyrimidinyl, and the like.

[0423] In some embodiments, Z is selected from one of the following structures:

[0424]

[0425] In some preferred embodiments of formula (I):

[0426] Y is formulae (Ila), optionally selected from (lid) and (He); and / or Z is selected from formulae (IIIa) and (lllc).

[0427] In yet further embodiments of formula (I):

[0428] Y is of formula (llj) or (Hr); and / or

[0429] 55718966-2 Z is of formula (IIIa) and V is OR4.

[0430] In some embodiments, the compound is one selected from Table 1 as shown in the Examples section, wherein the compound is not sapanisertib or compound 1225.

[0431] In some embodiments, formula (I) does not include any of the following compounds:

[0432] H2N „

[0433]

[0434] 55718966-2

[0435]

[0436] Pharmaceutical Composition

[0437] Viewed from a fifth aspect, the present disclosure provides a pharmaceutical composition comprising a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, and further comprising one or more pharmaceutically acceptable carriers and / or excipients.

[0438] Pharmaceutically acceptable excipients, or carriers, are well known to those skilled in the art and include, but are not limited to, phosphate buffer solutions and / or saline. Pharmaceutically acceptable carriers may be aqueous or non-aqueous solutions, suspensions, and emulsions. Examples of non-aqueous solvents are propylene glycol, polyethylene glycol, vegetable oils such as olive oil, and injectable organic esters such as ethyl oleate. Aqueous carriers include water, alcoholic / aqueous solutions, emulsions or suspensions, including saline and buffered media. Parenteral vehicles include sodium chloride solution, Ringer's dextrose, dextrose and sodium chloride, lactated Ringer's or

[0439] 55718966-2 fixed oils. Preservatives and other additives may also be present, such as, for example, antimicrobials, antioxidants, chelating agents, inert gases and the like.

[0440] In addition to the aforementioned carrier ingredients the pharmaceutical compositions described above may alternatively or additionally include, an appropriate one or more additional excipients, or carrier ingredients, such as diluents, buffers, flavouring agents, binders, surface active agents, thickeners, lubricants, preservatives (including anti-oxidants) and the like, and substances included for the purpose of rendering the formulation isotonic with the blood of the intended recipient.

[0441] Pharmaceutical compositions may be present in any formulation typical for the administration of a pharmaceutical compound to a subject. Representative examples of typical formulations include, but are not limited to, capsules, granules, tablets, powders, lozenges, suppositories, pessaries, nasal sprays, gels, creams, ointments, sterile aqueous preparations, sterile solutions, aerosols, implants etc.

[0442] A pharmaceutical composition is formulated to be compatible with its intended route of administration. Examples of routes of administration include parenteral, e.g., intravenous, intradermal, subcutaneous, oral, transdermal, topical, transmucosal, vaginal and rectal administration. In some embodiments, the compound is administered orally, parentally, by inhalation or topically.

[0443] The pharmaceutical compositions may include those suitable for oral, parenteral (including subcutaneous, intradermal, intramuscular and intravenous), topical (including dermal, buccal and sublingual), rectal, nasal and pulmonary administration e.g., by inhalation. The composition may, where appropriate, be conveniently presented in discrete dosage units and may be prepared by any of the methods well known in the art of pharmacy. Methods typically include the step of bringing into association an active compound with liquid carriers or finely divided solid carriers or both and then, if necessary, shaping the product into the desired formulation.

[0444] Pharmaceutical compositions suitable for oral administration wherein the carrier is a solid are most preferably presented as unit dose formulations such as boluses, capsules or tablets each containing a predetermined amount of active compound. A tablet may be made by compression or moulding, optionally with one or more accessory ingredients. Compressed tablets may be prepared by compressing in a suitable machine an active compound in a free-flowing form such as a powder or granules optionally mixed with a binder, lubricant, inert diluent, lubricating agent, surface-active agent or dispersing agent. Moulded tablets may be made by moulding an active compound with an inert liquid diluent. Tablets may be optionally coated and, if uncoated, may optionally be

[0445] 55718966-2 scored. Capsules may be prepared by inserting an active compound, either alone or in admixture with one or more accessory ingredients, into the capsule shells and then sealing them in the usual manner. Cachets are analogous to capsules wherein an active compound together with any accessory ingredient(s) is sealed in a rice paper envelope. The compounds may also be formulated as dispersible granules, which may for example be suspended in water before administration, or sprinkled on food. The granules may be packaged, e.g., in a sachet. Compositions suitable for oral administration wherein the carrier is a liquid may be presented as a solution or a suspension in an aqueous or nonaqueous liquid, or as an oil-in-water liquid emulsion. Compositions for oral administration include controlled release dosage forms, e.g., tablets wherein an active compound is formulated in an appropriate release-controlling matrix, or is coated with a suitable release-controlling film.

[0446] Pharmaceutical compositions suitable for parenteral administration include sterile solutions or suspensions of an active compound in aqueous or oleaginous vehicles. Injectable preparations may be adapted for bolus injection or continuous infusion. Such preparations are conveniently presented in unit dose or multi-dose containers, which are sealed after introduction of the formulation until required for use. Alternatively, the compounds may be in powder form, which is constituted with a suitable vehicle, such as sterile, pyrogen-free water, before use.

[0447] The pharmaceutical composition may also be formulated as a long-acting depot preparation, which may be administered by intramuscular injection or by implantation, e.g., subcutaneously or intramuscularly. Depot preparations include, for example, suitable polymeric or hydrophobic materials, or ion-exchange resins.

[0448] Pharmaceutical compositions suitable for topical formulation may be provided for example as gels, creams or ointments.

[0449] The compounds described herein may be present in the pharmaceutical compositions as a pharmaceutically and / or physiologically acceptable salt, solvate or derivative.

[0450] Representative examples of pharmaceutically and / or physiologically acceptable salts of the compounds of the disclosure may include, but are not limited to, acid addition salts formed with organic carboxylic acids such as acetic, lactic, tartaric, maleic, citric, pyruvic, oxalic, malonic, fumaric, oxaloacetic, isethionic, lactobionic and succinic acids; organic sulfonic acids such as methanesulfonic, ethanesulfonic, benzenesulfonic and p-toluenesulfonic acids and inorganic acids such as hydrochloric, hydrobromic, sulfuric, perchloric, phosphoric and sulfamic acids. Other pharmaceutically acceptable salts

[0451] 55718966-2 include (but are not limited to) adipate, alginate, ascorbate, aspartate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2- hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, pivalate, propionate, stearate, thiocyanate, undecanoate, valerate salts, and the like.

[0452] In some examples, salts that may be derived from appropriate bases include alkali metal, alkaline earth metal, ammonium and N+(C1–4alkyl)4salts. Representative alkali or alkaline earth metal salts include, but are not limited to, sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts may include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, lower-alkyl sulfonate and aryl sulfonate.

[0453] Pharmaceutically and / or physiologically functional derivatives of compounds of the present invention are derivatives, which may be converted in the body into the parent compound. Such pharmaceutically and / or physiologically functional derivatives may also be referred to as "pro-drugs" or "bioprecursors". Pharmaceutically and / or physiologically functional derivatives of compounds of the present disclosure may include hydrolysable esters or amides, particularly esters, in vivo.

[0454] It may be convenient or desirable to prepare, purify, and / or handle a corresponding pharmaceutically and / or physiologically acceptable solvate of the compounds described herein, which may be used in the any one of the uses / methods described. The term solvate is used herein to refer to a complex of solute, such as a compound or salt of the compound, and a solvent. If the solvent is water, the solvate may be termed a hydrate, for example a mono-hydrate, di-hydrate, tri-hydrate etc., depending on the number of water molecules present per molecule of substrate.

[0455] In some embodiments, the compounds of the present disclosure may be provided in a conjugate form. For example, the compound may be conjugated (e.g. linked such as covalently bonded) to an additional moiety, such as an antibody or other small molecule or ligand. In some examples, the conjugation may be via a covalent linker which links the compound of formula (I) to the additional moiety. In some embodiments, the additional moiety may act as a targeting moiety to allow targeted delivery and / or release of the compound of formula (I) to a target (e.g. a diseased tissue or cell). In some

[0456] 55718966-2 embodiments, the additional moiety (and optionally the linker where present) may act to release a compound of formula (I) to a target.

[0457] Conjugates

[0458] In some embodiments, the compound of formula (I) is conjugated to a biomolecule. Conjugation to a biomolecule may aid in directing or targeting the compound to a particular site e.g. a tumour in order to limit side effects experienced by subjects (e.g. in which healthy tissue is otherwise targeted indiscriminately by the compound per se). A compound may be ‘deactivated’ or ‘masked’ whilst conjugated, i.e. it may lose some or all activity the parent (non-conjugated) compound exhibits, until the compound is cleaved from the conjugate, wherein its original activity is restored. Such a mechanism may be beneficial to avoid the compound acting in an undesired location. Cleavage may be achieved via the breaking of a chemical bond between the biomolecule and the compound, sometimes via a cleavable moiety in a linker (that is, a group joining the biomolecule with the compound). Cleavage of the bond may be effected by contact with enzymes (e.g. protease, phosphatase, or esterase) or by a change in physical conditions (e.g. a change in pH leading to hydrolysis of a bond).

[0459] In some embodiments, the compound of formula (I) is conjugated to an antibody to provide an antibody drug conjugate (ADC). The skilled person is familiar with numerous techniques and methods to conjugate compounds (payloads) to antibodies, including, for example, the methods described in Site-selective modification strategies in antibody-drug conjugates (Walsh et al., Chem. Soc. Rev., 2021, 50, 1305-1353), Methods for the Generation of Single-Payload Antibody-Drug Conjugates (Wharton and Spring, ChemMedChem, 2025, 20, e202500132), and A review of conjugation technologies for antibody drug conjugates (Fan et al., Antibody Therapeutics, 2025, 8, 157-170), the contents of each of which are incorporated herein by reference. In some embodiments, the compound of formula (I) is conjugated to a peptide to provide a peptide drug conjugate. In some embodiments, the compound of formula (I) is conjugated to a small molecule or ligand. In some embodiments, the compound of formula (I) is conjugated (optionally by way of covalent linker) to a moiety that facilitates and / or promotes degradation of a target protein (e.g. a PROTAC®). In such embodiments, the compound of formula (I) would act to bind a target (i.e. mTOR) and the additional moiety would bind some part of the ubiquitin-proteasome system (UPS) (e.g. an E3 ubiquitin ligase) to facilitate the degradation of the target protein.

[0460] 55718966-2 The biomolecule (e.g. antibody) may conjugate (i.e. join, attach, or link) to the compound at any suitable position on the compound of formula (I). For example, the biomolecule may conjugate to the compound via the amino group of the benzoxazole ring, as depicted in formula (Xa), wherein “Ab” is a biomolecule as noted above, such as an antibody, a peptide, a small molecule or ligand, or a moiety that facilitates and / or promotes degradation of a target protein. The group “Ab” may also include various linker moieties that join the compound of the invention with the biomolecule (antibody) per se.

[0461]

[0462] For the avoidance of doubt, all embodiments of each aspect of the invention described herein apply mutatis mutandis to any conjugate thereof, e.g. an ADC as defined above in respect of the first aspect of the invention.

[0463] Therapeutic Methods and Uses

[0464] The compounds of the present disclosure may find use in therapy and / or be useful as a medicament. Thus, as stated above, there is provided:

[0465] (i) a compound for use in a method of treatment or prophylaxis of a disease, wherein the compound is of formula (I), or a pharmaceutically acceptable salt, or solvate thereof;

[0466] (ii) a method of treatment or prophylaxis of a disease, comprising administering to a subject (e.g. a patient) in need thereof a therapeutically effective amount of a compound of formula (I), ora pharmaceutically acceptable salt, or solvate thereof; and / or

[0467] (iii) a use of compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for the treatment of a disease.

[0468] Further details of uses (i) and (iii), and method (ii) are provided below.

[0469] 55718966-2 As described herein, the compounds of the present disclosure find particular application as kinase inhibitors, specifically mTOR kinase inhibitors. Accordingly, compounds of the present disclosure may be useful in the treatment or prophylaxis of any disease or condition that is modulated or mediated by mTOR. In particular, any disease or condition that can be treated or prevented by the inhibition of mTOR.

[0470] In some embodiments, the disease or condition is selected from a proliferative disorder (such as cancer), an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, a neurological disorder, a microbial disease, a parasitic disease, a metabolic disorder, genetic disorders driven by aberrant mTOR signalling, and a disease acquired from aberrant mTOR signalling due to the administration of a medicament.

[0471] In some embodiments, the subject to be treated is a human subject. Thus, a human subject may have, or be at risk of developing, any one or more of the diseases or conditions defined above and herein.

[0472] In some embodiments, the compounds may be use in veterinary medicine and / or may be useful for treatment or prophylaxis of mTOR driven disorders in animals (such as, but not limited to, parasitic gastroenteritis).

[0473] In some embodiments, the disease or condition is cancer. Representative examples of cancers that may be treated and / or prevented by the compounds of the disclosure include, but are not limited to, solid and liquid cancers at any stage, optionally wherein the cancer is a late stage cancer.

[0474] In some embodiments, the disease is a cancer selected from breast cancer, lung cancer, non-small-cell lung cancer, melanoma, brain cancer, haematological cancer, kidney cancer, renal carcinoma, prostate cancer, liver cancer, ovarian cancer, thyroid cancer, endometrial cancer, lymphoma, renal cell carcinoma, mantle cell lymphoma, soft tissue cancer, endometrial cancer, non-melanoma skin cancer, pancreatic cancer, gastric cancer, bone cancer, pharyngeal cancer, colon cancer, intestinal cancer, tongue cancer, rectal cancer, and testicular cancer.

[0475] In some embodiments, the disease is a cancer selected from colorectal cancer (including cecum adenocarcinoma), breast cancer, lung cancer, melanoma, brain cancer (including glioblastoma multiforme, and primitive neuroectodermal cancer), haematological cancer, soft tissue cancer (including sarcoma of muscular, fat, connective tissue origin), endometrial cancer (including adenocarcinoma), nonmelanoma skin cancer (including skin squamous cell carcinoma), pancreatic cancer (including adenocarcinoma), gastric cancer (including adenocarcinoma and signet ring cell adenocarcinoma), bone cancer (including osteosarcoma), pharyngeal cancer

[0476] 55718966-2 (including hypopharyngeal squamous cell carcinoma), colon cancer (including adenocarcinoma and carcinoma). Intestinal cancer (including duodenal adenocarcinoma), tongue cancer (including squamous cell carcinoma), rectal cancer (including adenocarcinoma), and testicular cancer (including embryonal carcinoma).

[0477] In some embodiments, the compounds of the disclosure find use in the treatment or prophylaxis of a dermatological disease or condition, optionally a dermatological disease or condition associated with a keratin ization disorder with a proliferative, inflammatory and / or immunoallergic component. In some embodiments, the inflammatory disorder may be a dermatological disease or condition. In some embodiments, the inflammatory disorder may be associated with, contributed to, and / or caused by senescence and / or the Senescence Associated Secretory Phenotype (SASP).

[0478] Representative examples of dermatological disease or condition include, but are not limited to, common acne, comedones, polymorphs, acne rosacea, nodulocystic acne, acne conglobata, senile acne, and secondary acnes such as solar acne, medication-related acne or occupational acne, other keratinization disorders, notably ichthyosis, ichthyosiform conditions, Darier's disease, palmoplantar keratoderma, leukoplakia and leukoplakiform conditions, and cutaneous or mucous (buccal) lichen. Further examples include, but are not limited to, psoriasis, (e.g. cutaneous, mucous or ungual psoriasis, and psoriatic rheumatism), or cutaneous atopy, such as atopic dermatitis (or atopic eczema) or respiratory atopy or gingival hypertrophy, all dermal or epidermal proliferations, whether benign or malignant, and whether of viral origin or otherwise, such as common warts, flat warts and verruciform epidermodysplasia, oral or florid papillomatoses, and lesions or proliferations that may be induced by ultraviolet radiation, notably in the case of actinic keratoses, and basal cell and spinal cell epithelioma. In some embodiments, the dermatological disease or condition is selected from psoriasis, atopic dermatitis, actinic keratosis or acne, such as atopic dermatitis.

[0479] The compound may be administered to the subject comprised in a pharmaceutical composition, e.g. any pharmaceutical composition as described herein.

[0480] The compound may be administered to the subject by any suitable route of administration, including orally, parentally, by inhalation or topically.

[0481] Depending upon the disease and patient to be treated, as well as the route of administration, the compounds and compositions of the invention may be administered at varying doses. Suitable daily doses of the compounds of the invention in therapeutic treatment of humans are about 0.1 to about 100 mg / kg, such as 0.15 to about 50 mg / kg.

[0482] 55718966-2 The most effective mode of administration and dosage regimen for the compounds and compositions of the invention depends on several factors, including the particular condition being treated, the extent and localisation of that condition in the patient being treated, as well as the patient's state of health and their reaction to the compound being administered. Accordingly, the dosages of the compounds of the invention should be adjusted to suit the individual patient.

[0483] The compound may be administered in combination with one or more additional therapeutic agents and / or as part of a combinatorial treatment regimen. By way of example, where the disease or condition to be treated is cancer, the compound may be administered with one or more additional chemotherapeutic agents. As used herein, “in combination” encompasses both sequential and concurrent administration to a subject in need thereof of the one or more additional therapeutic agents and a compound of the invention.

[0484] Activity of compounds

[0485] As described herein, compounds of the present disclosure have been found to provide good levels of inhibition against a kinase, in particular compounds of the disclosure can act as mTOR kinase inhibitors.

[0486] The activity of the compounds can be measured by way of an EC50value, e.g. in a cell viability assay. In some embodiments, the compounds comprise an EC50of less than about 1 pM, less than or equal to about 500 nM, less than or equal to about 100 nM, less than or equal to about 10 nM, or less than or equal to about 1 nM. In some examples, EC50values of less than or equal to about 1 nM have been observed for compounds of the disclosure. In some yet further examples, EC50values of less than or equal to about 0.1 nM have been observed for compounds of the disclosure.

[0487] Selectivity of compounds

[0488] As described herein, compounds of the present disclosure have been found to be selective for mTOR kinase, in particular selective for mTOR kinase over other types of kinase. Compounds can be tested for their selectivity at least by measuring inhibition of the target kinase versus one or more off-target kinases. The inhibition of each kinase may be expressed in terms of IC50and thus directly compared and a selectivity ratio calculated. On the other hand, a panel or assay of kinases can be treated with a compound and each kinase that is sufficiently inhibited such that only some kinase

[0489] 55718966-2 activity remains is considered a ‘hit’; if a compound inhibits many kinases, it is considered to be promiscuous or non-selective; a compound that inhibits relatively few kinases, or only the target kinase, is considered to be selective. Such panels are typically known as a kinome screening panel. Thus, in some embodiments, the compounds are selective for mTOR.

[0490] In some embodiments, the compounds of the disclosure hit 30 or less off-target kinases in a kinome screening panel. A ‘hit’ in this case may be defined as inhibition of a kinase by a compound such that the kinase has 50% or less activity remaining after addition of a certain amount of the compound, such as 1 pM. The skilled person will recognise that a ‘hit’ in any particular kinome screen may be subject to a particular or different definition. For the avoidance of doubt, an off-target kinase is a kinase that is not the target kinase of the compounds, that is to say, it is not mTOR.

[0491] In some embodiments, the compounds hit 30 or less, 25 or less, 20 or less, 15 or less, 12 or less, 10 or less, 8 or less, or 5 or less off-target kinases. In some embodiments, the compounds hit less than 10%, less than 8%, less than 6%, less than 5%, less than 4%, or less than 3% of the total number of off-target kinases in the kinase screening panel. In some embodiments, the off-target kinases are selected from DNAPK, PIK3CD / PIK3R1, ACVRL1, DDR2, ACVR1, CK15, PIK3CA / PIK3R1, PIK3CG, CK1E, FYN, ACVR2B, RIPK2, PKN3, BMPR1B, PIK3C2A, ACVR2A, NLK, FGFR2, TGFBR1, BRK, LCK, PDGFRB, CDK8 / CycC, RET, TRKC, and FGR.

[0492] In some embodiments, the compounds hit 15 or less, 12 or less, 10 or less, 8 or less, or 5 or less off-target kinases selected from the tyrosine-kinase (TK) family and tyrosine-kinase-like (TKL) family, such as but not limited to EGFR, ERBB2, LCK, BRK, FGR, FYN, DDR2, TRKC, RET, PDGFRB, RIPK2, ACVRL1, ACVR2B, TGFBR1, BMPR1B, and ACVR1.

[0493] The kinome screening panel may be any well-known or commercially available panel, such as those performed by the skilled person, or provided by research services companies. In some embodiments, the kinome screening panel comprises at least 100, at least 150, at least 200, at least 250, at least 300, or at least 350 off-target kinases. In some embodiments, the kinome screening panel comprises at least wild-type kinases and lipid kinases. In some embodiments, the kinome screening panel is33PanQinaseTM(Reaction Biology, Germany), wherein a hit is defined as inhibition of a kinase by a compound such that the kinase has 50% or less activity remaining after addition of 1 pM of the compound. The skilled person will recognise that a greater number of kinases in a panel will result in a greater likelihood of identifying hits; that is to say, a kinase panel

[0494] 55718966-2 with relatively few kinases may not accurately characterise the selectivity profile of a particular compound.

[0495] As described herein, CK1δ, DNAPK, PKN3, ACVRL1, ACVR1, and PIK3CA / PIK3R1 (generally, off-target kinases) are strongly inhibited by known mTOR inhibitors, such as sapanisertib; compounds disclosed herein demonstrate greater selectivity profiles with respect to these kinases. Therefore, in some embodiments, the compounds disclosed herein are selective for mTOR over any one or more of CK1δ, DNAPK, PKN3, ACVRL1, ACVR1, and PIK3CA / PIK3R1. In some embodiments, the compounds of the disclosure are selective for mTOR over DNAPK; that is to say, the compounds inhibit mTOR to a greater extent than the compounds inhibit DNAPK. As described above, this may be assessed through a kinase screening panel or through direct comparison of IC50 values.

[0496] For example, in some embodiments, the compounds disclosed herein inhibit mTOR and DNAPK in a kinase screening panel such that there is less than 2.5%, less than 2.0%, less than 1.5%, less than 1.0%, or less than 0.5% mTOR activity remaining whilst there is more than 2.5%, more than 3%, more than 4%, more than 5%, more than 7%, more than 9%, or more than 11% DNAPK activity remaining.

[0497] In some embodiments, the compounds disclosed herein exhibit a DNAPK / mTOR selectivity ratio of more than 1, more than 5, more than 10, more than 15, more than 20, more than 25, more than 30, more than 35, more than 40, or more than 45. A DNAPK / mTOR selectivity ratio is defined herein as the ratio between the IC50 (or equivalent) of DNAPK and the IC50 (or equivalent) of mTOR for a particular compound. For example, for a particular compound with an IC50 against DNAPK of 10 nM, and an IC50 against mTOR of 5 nM, the DNAPK / mTOR selectivity ratio would be 2; that is, that particular compound exhibits a 2-fold selectivity for mTOR over DNAPK. A DNAPK / mTOR selectivity ratio may be a good approximator of the overall selectivity of the compounds disclosed herein.

[0498] Methods of manufacture

[0499] Viewed from a sixth aspect, there is provided a method of manufacture of any one of the compounds disclosed herein. The presently disclosed compounds were and can be synthesized using the synthetic procedures set forth in schemes in the Examples detailed below. The carrying out of each individual illustrated step is within the skill of an ordinary artisan guided by this disclosure, who also knows how to modify the synthetic procedures of the below schemes to synthesize the full scope of the compounds

[0500] 55718966-2 disclosed herein. In particular, the synthetic procedure for individual compounds is disclosed in the Examples section below.

[0501] In some embodiments, the method of preparing a compound of formula (I) may comprise a step of reacting a compound of formula (IV) with a compound of formula (V) to provide a compound of formula (I) as illustrated below:

[0502] w4

[0503]

[0504] wherein W1, W2, W3, W4, X1, X2, G1, G2, and G3are as defined for formula (I); and U1and U2are complementary groups that are configured to facilitate formation of a new covalent bond, e.g. in a coupling reaction, such as a metal catalysed cross coupling reaction.

[0505] In some embodiments, the method may be a method of preparing a compound of formula (la) (as defined above), and may comprise a step of reacting a compound of formula (IV) with a compound of formula (V) to provide a compound of formula (la) as illustrated below:

[0506]

[0507] wherein W1, W2, W3, X1, X2, G1, G2, and G3are as defined for formula (la); and U1and U2are complementary groups that are configured to facilitate formation of a new covalent bond, e.g. in a coupling reaction, such as a metal catalysed cross coupling reaction.

[0508] 55718966-2 Typically, U1and U2are not the same. In some embodiments, U1and U2are each independently selected from halo (e.g. I, Br, or Cl), organosulfonate (e.g. trifluoromethanesulfonate (triflate), and the like), boron nucleophile (e.g. boronic acid, boronate ester, potassium organotrifluoroborate, dialkoxy borane, amidoborane, and the like), acid (e.g. boronic acids, carboxylic acids, and the like), and ester (e.g. boronate esters, and the like). In some embodiments, U1a boronic acid or boronate ester. In some embodiments, U2is halo (e.g. Br or I).

[0509] Exemplary synthetic sequences are provided for select compounds (Schemes 1 to 7, additionally Examples 1 to 7, below); the compounds disclosed herein may be prepared according to those synthetic sequences, or by analogy, the skilled person understanding when and how to deviate from the specifically disclosed starting materials, reagents, conditions and the like.

[0510] Br

[0511]

[0512] 1137 Scheme 1. Synthesis of compound 1137.

[0513] 55718966-2

[0514]

[0515] Scheme 2. Synthesis of compound 1177.

[0516] 55718966-2 CBr4PPh3DCM

[0517] 0 °C - r,t; 5 h

[0518] VIII

[0519] Pd(dppf)CI2DCM Potassium acetate 1,4-dioxane 90 °C; 16 h N2

[0520] XI CS2CO3 Pd(dppf)CI2-DCM 1,4-dioxane CS2CO3 130 °C, 16 h 1,4-dioxane / water 110 °C; 16 h N2IX

[0521]

[0522] 1328 Scheme 3. Synthesis of compound 1328.

[0523] 55718966-2

[0524]

[0525] Scheme 4. Synthesis of compound 1341 and 1346.

[0526] XI

[0527] NaH Pd(dppf)CI2DCM DMF CS2CO3 150 °C (pW); 1.5 h 1,4-dioxane / water 110 °C; 16 h N2

[0528]

[0529] Scheme 5. Synthesis of compound 1379 and 1396.

[0530] 55718966-2 XI Cs2CO3Pd(dppf)CI2DCM DMA Cs2CO385 °C; 3 h 1,4-dioxane / water 110 °C; 16 h N2

[0531] 1447

[0532]

[0533] 1446

[0534] Scheme 6. Synthesis of compounds 1442, 1446 and 1447.

[0535] 55718966-2 XI Pd(dppf)CI2DCM CS2CO3 1,4-dioxane / water 110 °C; 16 h N2

[0536] TFA DCM

[0537] r.t.; 2 h 1458 1460

[0538]

[0539] Scheme 7. Synthesis of compounds 1458, 1460, and 1474.

[0540] Stereoisomers and Isotopically labelled compounds

[0541] It will be appreciated that the compounds of the present disclosure may exist in different stereoisomeric forms. The present disclosure includes within its scope the use of all stereoisomeric forms, or the use of a mixture of stereoisomers of the compounds.

[0542] Unless otherwise indicated, the various structures shown herein encompass all isomeric (e.g. enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure). For example, the present disclosure embraces the R and S configurations

[0543] 55718966-2 for each asymmetric centre, and Z and E double bond isomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are to be understood to be within the scope of the present disclosure. Additionally, unless otherwise stated, where present, all tautomeric forms of the compounds described herein are to be understood to be within the scope of the present disclosure.

[0544] By way of example, where the compound comprises one or more chiral centres, the present disclosure encompasses each individual enantiomer of the compound as well as mixtures of enantiomers including racemic mixtures of such enantiomers. Byway of further example, where the compound comprises two or more chiral centres, the present disclosure encompasses each individual diastereomer of the compound, as well as mixtures of the various diastereomers.

[0545] Additionally, unless otherwise stated, structures depicted herein are also meant to include compounds that differ only in the presence of one or more isotopically enriched atoms. For example, compounds as described herein in which one or more hydrogen atoms have been replaced by deuterium or tritium, or in which one or more carbon atoms have been replaced by a13C- or14C-enriched carbon are to be understood to within the scope of the present disclosure. Such molecules may be useful, for example, as analytical tools, as probes in biological assays, or as therapeutic agents in accordance with the present disclosure.

[0546] Accordingly, the disclosure also includes various deuterated forms of the compounds disclosed herein. Each available hydrogen atom attached to a carbon atom may be independently replaced with a deuterium atom. A person of ordinary skill in the art will know how to synthesize deuterated forms of the compounds of the present disclosure. For example, deuterated materials, such as alkyl groups may be prepared by conventional techniques (see for example: methyl-d3-amine available from Aldrich Chemical Co., Milwaukee, Wl, Cat. No.489, 689-2).

[0547] Accordingly the disclosure also includes isotopically-labelled compounds of the compounds of the present disclosure but for the fact that one or more atoms are replaced by an atom having an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature. Examples of isotopes that can be incorporated into compounds of the disclosure include isotopes of hydrogen, carbon, nitrogen, oxygen, fluorine, iodine and chlorine such as3H,11C,14C,18F,123l or125l. Compounds of the present disclosure that contain the aforementioned isotopes and / or other isotopes of other atoms are within the scope of the present disclosure. Isotopically

[0548] 55718966-2 labelled compounds of the present disclosure, for example those into which radioactive isotopes such as3H or14C have been incorporated, are useful in drug and / or substrate tissue distribution assays. Tritiated, i.e.3H, and carbon-14, i.e.14C, isotopes are particularly preferred for their ease of preparation and detectability.11C and18F isotopes are particularly useful in PET (positron emission tomography).

[0549] EXAMPLES

[0550] Synthetic Chemistry

[0551] Chemical and solvents were purchased from Fisher Scientific, Sigma-Aldrich or VWR International Ltd. All the chemical reactions were performed on a heating magnetic stirrer with temperature sensor, or in a Biotage Initiator Third Generation microwave synthesiser. NMR samples were prepared by dissolving compound samples in deuterated solvents commercially available from Sigma-Aldrich or VWR and placed into glass Norrell s400 NMR tubes. NMR spectra were recorded at 278-328 K on a 500 MHz Bruker Avance III DCH cryo-probe spectrometer. Chemical shifts are reported in parts per million (ppm) relative to the solvent peaks (DMSO-d6: δ = 2.50 for1H-NMR and 39.52 for13C-NMR; CDCl3: δ = 7.26 for1H-NMR and 77.2 for13C-NMR). Data are presented as follows: chemical shift (ppm), multiplicity (s = singlet, d = doublet, t = triplet, m = multiplet, q = quartet, br = broad), coupling constant J, and integration. Purifications were carried out using the Isolera One flash chromatography instrument with Biotage Sfär Silica D Duo 60 µm 10 g or 25 g columns, via manual flash column chromatography using commercially available silica gel (220-440 mesh, Sigma-Aldrich) or via semipreparative TLC chromatography on Merck TLC Silica gel 60 F254plates or TLC Aluminium oxide 60 F254 (neutral) plates. All the compounds used in cell studies were >95% pure. Low resolution mass spectrometry (LRMS) analyses and purity assessments were performed on the Agilent 1260 Infinity II Prime LC System using an InfinityLab Poroshell 120 EC-C18 column (3.0 x 100 mm; 2.7 pm). HPLC conditions used: 1) eluent A: water and formic acid (0.1%); eluent B: methanol and formic acid (0.1%); with a gradient from A / B = 95:5 to 5:95 over 4 min followed by a 2 min isocratic period (flow = 1 mL / min); or 2) eluent A: water and formic acid (0.1%); eluent B: acetonitrile and formic acid (0.1%); with a gradient from A / B = 95:5 to 5:95 over 4 min followed by a 2 min isocratic period (flow = 1 mL / min).

[0552] 55718966-2 Example 1. Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1137).

[0553] 1137

[0554] NH2

[0555]

[0556] H Synthesis of 1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound I). A 20 ml_ vial equipped with a stir bar was charged with 5-amino-1 H-pyrazole-4-carbonitrile (3000 mg, 1 Eq, 27.75 mmol) followed by formamide (16 g, 14 ml_, 13 Eq, 351 mmol). The vial was sealed and the mixture stirred at 180 °C for 2 h using microwave irradiation. The reaction was cooled to room temperature and the precipitate formed was filtered off, washed with water (50 ml_) and allowed to dry in the vacuum oven at 40 °C overnight to afford a white solid (3438.5 mg, 25.446 mmol, 92% yield).1H NMR (500 MHz, DMSO-d6) 5 13.30 (bs, 1H), 8.13 (s, 1H), 8.07 (s, 1H), 7.57 (br, 2H).13C NMR (126 MHz, DMSO-d6) 5 157.97, 155.78, 154.79, 132.50, 99.56. LRMS (ESI), m / z 136.00 (M+H).

[0557] 55718966-2

[0558]

[0559] Synthesis of 3-iodo-1H-pyrazolo[3,4-d]pyrimidin-4-amine (compound II). A 20 mL vial equipped with a stir bar was charged with 1 H-pyrazolo[3,4-d]pyrimidin-4-amine (compound I) (3287.8 mg, 1 Eq, 24.331 mmol) followed by DMF (14 ml_). Then, N-iodosuccinimide (6569 mg, 1.2 Eq, 29.197 mmol) was added. The vial was sealed and the mixture stirred at 180 °C for 40 min. The reaction was cooled to room temperature. Then, EtOH (80 ml_) was added and the mixture stirred until a precipitate forms. The precipitate was filtered off, washed with EtOH (3 x 20 ml_) and allowed to dry in the vacuum oven at 40 °C overnight to afford a pale-brown solid (3401.6 mg, 13.031 mmol, 54% yield).1H NMR (500 MHz, DMSO-d6) 5 13.80 (s, 1H), 8.17 (s, 1H), 7.19 (br, 2H).

[0560] 13C NMR (126 MHz, DMSO-d6) 5 157.50, 155.92, 154.99, 102.47, 89.69. LRMS (ESI), 283.90 m / z (M+Na).

[0561]

[0562] Synthesis of tert-butyl 4-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound III). A 20 ml_ vial equipped with a stir bar was charged with 3-iodo-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (compound II) (1000 mg, 1 Eq, 3.831 mmol) followed by DMA (9 ml_). Then, tert-butyl 4-(bromomethyl)piperidine-l-carboxylate (1119 mg, 1.05 Eq, 4.023 mmol) and potassium carbonate (1588.3 mg, 3 Eq, 11.49 mmol) were added. The vial was sealed and the mixture stirred at 85 °C for 3 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 2.5% MeOH in DCM) to afford a pale-yellow solid (913 mg, 1.99 mmol, 52% yield).1H NMR (500 MHz, DMSO-d6) 58.20 (s, 1H), 4.17 (d, J = 7.0 Hz, 2H), 3.91 -3.85 (m, 2H), 2.65 (br, 2H), 2.10 - 1.99 (m, 1H), 1.47 - 1.40 (m, 2H), 1.37 (s, 9H), 1.12 - 1.00 (m, 2H).13C NMR (126 MHz,

[0563] 55718966-2 DMSO-de) 5 157.70, 156.04, 153.80, 153.74, 102.91, 88.80, 78.47, 51.56, 43.34, 36.08, 29.08, 28.05. LRMS (ESI), m / z 458.90 (M+H).

[0564]

[0565] Synthesis of 3-iodo-1 -(piperidin-4-ylmethyl)-1 H-pyrazolo[3,4-d]pyrimidin-4-amine (compound IV). A 10 mL vial equipped with a stir bar was charged with tert-butyl 4-((4- amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound III) (300 mg, 1 Eq, 655 pmol) followed by 1,4-dioxane (1 mL). Then, a hydrogen chloride solution in 1,4-dioxane (291.7 mg, 2 mL, 4 molar, 12.2 Eq, 8 mmol) was added dropwise and the suspension was stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. Then, 4 mL of DCM / MeOH (8:2) and 300 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-yellow solid that was used without further purification in the next reaction step (227.5 mg, 635 pmol, 97% yield).1H NMR (500 MHz, DMSO-de) 58.77 (br, 2H), 8.21 (s, 1 H), 4.20 (d, J = 6.9 Hz, 2H), 3.21 (dt, J = 12.7, 3.4 Hz, 2H), 2.80 (td, J = 12.8, 3.0 Hz, 2H), 2.22 - 2.11 (m, 1H), 1.62 (dd, J = 14.6, 3.6 Hz, 2H), 1.47 - 1.34 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 157.72, 156.12, 153.83, 102.92, 89.32, 51.01, 42.48, 33.88, 25.91. LRMS (ESI), m / z 359.20 (M+H).

[0566]

[0567] Synthesis of isopropyl 4-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound V). A 10 mL vial equipped with a stir bar was charged with 3-iodo-1-(piperidin-4-ylmethyl)-1 H-pyrazolo[3,4-d]pyrimidin-4- amine (compound IV) (150 mg, 1 Eq, 419 pmol) followed by MeOH (5 mL). Then, triethylamine (84.8 mg, 117 pL, 2 Eq, 838 pmol) and isopropyl chloroformate (51.3 mg,

[0568] 55718966-2 419 pL, 1 Eq, 419 pmol) were added and the mixture stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford a white solid that was used without further purification in the next reaction step (160.4 mg, 361 pmol, 86% yield).1H NMR (500 MHz, DMSO-d6) 58.19 (s, 1H), 4.79 -4.68 (m, 1H), 4.17 (d, J = 7.1 Hz, 2H), 3.92 (d, J = 12.2 Hz, 2H), 2.70 (br, 2H), 2.12 - 2.01 (m, 1 H), 1.45 (d, J = 12.6 Hz, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.13 - 1.03 (m, 2H).13C NMR (126 MHz, DMSO-de) 5 157.70, 156.04, 154.19, 153.75, 102.92, 88.82, 67.64, 51.55, 42.89, 36.03, 29.02, 21.96. LRMS (ESI), m / z 445.40 (M+H).

[0569]

[0570] Synthesis of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound VI). A 20 ml_ vial equipped with a stir bar was charged with 5-bromobenzo[d]oxazol-2-amine (1000 mg, 1 Eq, 4.694 mmol), 4, 4, 4', 4', 5, 5, 5', 5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1430.4 mg, 1.2 Eq, 5.633 mmol), potassium acetate (1382 mg, 3 Eq, 14.08 mmol), Pd(dppf)Cl2’DCM (383.3 mg, 0.1 Eq, 469.4 pmol) and 1,4-dioxane (10 ml_). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 60% EtOAc in hexane) to afford pale-brown solid (983.7 mg, 3.782 mmol, 81% yield).

[0571] 1H NMR (500 MHz, DMF) 57.45 (s, 1 H), 7.41 (s, 2H), 7.36 - 7.27 (m, 2H), 1.29 (s, 12H).

[0572] 13C NMR (126 MHz, DMF) 5 162.74, 150.38, 143.38, 126.93, 120.97, 115.23, 108.16, 83.45, 24.66. LRMS (ESI), m / z 261.20 (M+H).

[0573] 55718966-2

[0574]

[0575] Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1137).

[0576] A 10 mL vial equipped with a stir bar was charged with 4-((4-amino-3-iodo-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1-carboxylate (compound V) (50 mg, 1 Eq, 11 pmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound VI) (35 mg, 1.2 Eq, 14 pmol), potassium carbonate (23 mg, 1.5 Eq, 17 pmol), triphenylphosphane (18 mg, 0.6 Eq, 68 pmol), PdOAc2(3.8 mg, 0.15 Eq, 17 pmol), 1,4-dioxane (2 mL) and water (0.2 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 125 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 12.5% MeOH in DCM) to afford a pale-pink solid (26.3 mg, 58.4 pmol, 52% yield).1H NMR (500 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.80 - 4.68 (m, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.93 (d, J = 13.0 Hz, 2H), 2.71 (br, 2H), 2.20 - 2.10 (m, 1H), 1.52 (d, J = 10.7 Hz, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.13 - 1.07 (m, 2H).13C NMR (126 MHz, DMSO-de) 5163.43, 158.17, 155.71, 154.42, 154.21, 148.31, 144.40, 144.08, 128.51, 120.44, 115.00, 108.84, 97.12, 67.63, 51.21, 42.97, 36.07, 29.18, 21.96. LRMS (ESI), m / z 451.10 (M+H).

[0577] 55718966-2 Example 2. Synthesis of 5-(4-amino-7-((8-(oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1328).

[0578] CBr4HCI PPh3Cs2CO31,4-dioxane DCM DMA r.t.; 16 h 0 °C - r,t; 5 h 85 °C; 3 h

[0579]

[0580] VIII

[0581] Ox,0-7- B-B r

[0582] o" 'o"\

[0583] Pd(dppf)CI2DCM

[0584] Potassium acetate

[0585] 1,4-dioxane

[0586] 90 °C; 16 h

[0587] N2

[0588] XI

[0589] Cs2CO3Pd(dppf)CI2-DCM 1,4-dioxane Cs2CO3130 °C, 16 h 1,4-dioxane / water 110 °C; 16 h N2

[0590]

[0591]

[0592] Br

[0593]

[0594] Synthesis of tert-butyl 3-(bromomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound VII). A 20 ml_ vial equipped with a stir bar was charged with exo-8-Boc-8-azabicyclo[3.2.1]octane-3-methanol (1284 mg, 1 Eq, 5.321 mmol) followed by DCM (24 ml_). The solution was cooled to 0 °C. Then, carbon tetrabromide (2647 mg, 1.5 Eq, 7.981 mmol) and triphenylphosphane (2093 mg, 1.5 Eq, 7.981 mmol) were added and the reaction stirred at 0 °C for 5 min and then stirred at room temperature for 16 h. The solvent was evaporated to half of its volume. Hexane / Et₂O (80:20) was added, the

[0595] 55718966-2 mixture cooled to 0 °C and stirred at this temperature for 2 h. The mixture was filtrated through a pad of Celite and the filtrate was concentrated under reduced pressure to afford a clear yellow oil that was used without further purification in the next reaction step (1518.5 mg, 4.991 mmol, 94% yield).

[0596]

[0597] Synthesis of tert-butyl 3-((4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8 -azabi cyclo[3.2.1] octane -8 -carboxy I ate (compound VIII). A 20 ml_ vial equipped with a stir bar was charged with 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (979.9 mg, 1 Eq, 3.768 mmol) followed by DMA (6 ml_). Then, cesium carbonate (3069 mg, 2.5 Eq, 9.420 mmol) and tert-butyl 3-(bromomethyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound VII) (1261 mg, 1.1 Eq, 4.145 mmol) were added. The vial was sealed and the reaction stirred at 85 °C for 3 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 -4% MeOH in DCM) to afford a pale-yellow solid (785.6 mg, 1.625 mmol, 43% yield).1H NMR (500 MHz, DMSO-de) 5 8.09 (s, 1H), 7.47 (s, 1H), 6.57 (br, 2H), 4.03 - 3.98 (m, 2H), 3.93 (d, J = 6.7 Hz, 2H), 2.43 - 2.30 (m, 1H), 1.79 (s, 2H), 1.54 (s, 2H), 1.40 (s, 1H), 1.37 (s, 8H), 1.32 (d, J = 9.7 Hz, 4H).13C NMR (126 MHz, DMSO-d6) 5 157.08, 152.48, 151.73, 149.88, 129.96, 102.70, 78.27, 53.07, 52.34, 49.48, 49.30, 34.83, 34.03, 28.12. LRMS (ESI), m / z 484.50 (M+H).

[0598]

[0599] 55718966-2 Synthesis of 7-((8-azabicyclo[3.2.1]octan-3-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (compound IX). A 10 mL vial equipped with a stir bar was charged with tert-butyl 3-((4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound VIII) (530 mg, 1 Eq, 1.10 mmol) followed by 1,4-dioxane (4 mL). Then, a hydrogen chloride solution in 1,4-dioxane (999 mg, 6.85 mL, 4 molar, 25 Eq, 27.4 mmol) was added dropwise and the suspension stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. Then, 4 mL of DCM / MeOH (8:2) and 500 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-yellow solid that was used without further purification in the next reaction step (420 mg, 1.10 mmol, 100% yield). LRMS (ESI), m / z 384.20 (M+H).

[0600] y=N

[0601]

[0602] Synthesis of 5-iodo-7-((8-(oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (compound X). A 10 mL vial equipped with a stir bar was charged with 7-((8-azabicyclo[3.2.1]octan-3-yl)methyl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (compound IX) (200 mg, 1 Eq, 522 pmol), cesium carbonate (510 mg, 3 Eq, 1.57 mmol), 2-iodooxazole (203 mg, 2 Eq, 1.04 mmol) and 1,4-dioxane (2 mL). The vial was sealed and the reaction stirred at 130 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 3.5% MeOH in DCM) to afford a pale-white solid (111.7 mg, 248 pmol, 48% yield).1H NMR (500 MHz, DMSO-d6) 5 8.08 (s, 1H), 7.57 (d, J = 1.0 Hz, 1H), 7.46 (s, 1H), 6.85 (d, J= 1.0 Hz, 1H), 6.58 (br, 2H), 4.21 -4.15 (m, 2H), 3.87 (d, J = 7.3 Hz, 2H), 2.46 - 2.36 (m, 1 H), 1.93 - 1.84 (m, 2H), 1.67 - 1.60 (m, 2H), 1.43 (td, J = 12.7, 2.8 Hz, 2H), 1.35 - 1.27 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 159.56, 157.10, 151.76,

[0603] 55718966-2 149.83, 133.42, 129.81, 126.87, 102.69, 55.17, 49.53, 49.32, 33.14, 29.24, 27.68. LRMS (ESI), m / z 451.20 (M+H).

[0604]

[0605] Synthesis of 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound XI). A 20 ml_ vial equipped with a stir bar was charged with 5-bromo-4-fluorobenzo[d]oxazol-2-amine (1000 mg, 1 Eq, 4.329 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1429 mg, 1.3 Eq, 5.627 mmol), potassium acetate (1274 mg, 3 Eq, 12.99 mmol), Pd(dppf)Cl2'DCM (707 mg, 0.2 Eq, 865.7 pmol) and 1,4-dioxane (15 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 90 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 55% EtOAc in hexane) to afford pale-yellow solid (885.1 mg, 3.183 mmol, 74% yield).1H NMR (500 MHz, DMSO-d6) 5 7.59 (s, 2H), 7.28 - 7.17 (m, 2H), 1.29 (s, 12H).13C NMR (126 MHz, DMSO-d6) 5 162.70, 155.47, 153.46, 152.85, 152.77, 131.29, 131.15, 127.30, 127.24, 105.18, 105.15, 83.46, 24.61. LRMS (ESI), m / z 279.20 (M+H).

[0606]

[0607] Synthesis of 5-(4-amino-7-((8-(oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)- 7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound

[0608] 55718966-2 1328). A 10 mL vial equipped with a stir bar was charged with 5-iodo-7-((8-(oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-amine (compound X) (40 mg, 1 Eq, 89 pmol), 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound XI) (35 mg, 1.4 Eq, 126 pmol), cesium carbonate (43 mg, 1.5 Eq, 132 mmol), Pd(dppf)Cl2’DCM (11 mg, 0.15 Eq, 13 pmol), 1,4-dioxane (0.6 mL) and water (0.1 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 110 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 10% MeOH in DCM) to afford a pale-white solid (17.1 mg, 36 pmol, 41% yield).1H NMR (500 MHz, DMSO-d6) 5 8.12 (s, 1H), 7.64 (s, 2H), 7.57 (d, J = 1.0 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.85 (d, J= 1.0 Hz, 1 H), 5.99 (br, 2H), 4.24 - 4.17 (m, 2H), 3.96 (d, J = 7.2 Hz, 2H), 2.50 - 2.43 (m, 1 H), 1.93 - 1.87 (m, 2H), 1.70 - 1.62 (m, 2H), 1.49 (td, J = 12.8, 2.9 Hz, 2H), 1.42 - 1.34 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 159.59, 157.14, 151.46, 150.08, 149.43, 149.36, 148.40, 146.44, 133.42, 132.11, 131.98, 126.88, 124.77, 122.21, 117.34, 117.23, 107.43, 105.03, 100.74, 55.23, 49.12, 33.25, 29.25, 27.73. LRMS (ESI), m / z 475.40 (M+H).

[0609] 55718966-2 Example 3. Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol- 5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1341) and prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1346).

[0610] CBr4PPh3Cs2CO3Pd(dppf)CI2DCM DCM DMA Cs2CO30 °C - r.t; 5 h 85 °C; 3 h 1,4-dioxaneAvater 110 °C; 16 h N2VIII

[0611]

[0612] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8 -carboxylate (compound 1341). A 10 ml_ vial equipped with a stir bar was charged with tert-butyl 3-((4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-

[0613] 55718966-2 carboxylate (compound VIII) (230 mg, 1 Eq, 476 pmol), 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound XI) (152 mg, 1.15 Eq, 547 pmol), cesium carbonate (233 mg, 1.5 Eq, 714 pmol), Pd(dppf)Cl2'DCM (77.7 mg, 0.2 Eq, 95.2 pmol), 1,4-dioxane (3 ml_) and water (1 ml_). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 110 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 8% MeOH in DCM) to afford a pale-pink solid (136.5 mg, 269 pmol, 57% yield).1H NMR (500 MHz, DMSO-d6) 5 8.13 (s, 1H), 7.64 (s, 2H), 7.32 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 6.95 (dd, J = 8.1, 7.0 Hz, 1 H), 5.99 (br, 2H), 4.05 - 3.99 (m, 4H), 2.48 - 2.39 (m, 1 H), 1.81 (br, 2H), 1.56 (br, 2H), 1.43 - 1.38 (m, 4H), 1.37 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.15, 152.50, 151.46, 150.14, 149.35, 148.41, 146.45, 137.35, 131.99, 124.95, 122.18, 117.35, 117.25, 107.38, 105.04, 100.77, 78.26, 49.15, 29.28, 28.11. LRMS (ESI), m / z 508.40 (M+H).

[0614]

[0615] Synthesis of 5-(7-((8-azabicyclo[3.2.1]octan-3-yl)methyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound XII). A 10 ml_ vial equipped with a stir bar was charged with tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1341) (121 mg, 1 Eq, 238 pmol) followed by 1,4-dioxane (2 ml_). Then, a hydrogen chloride solution in 1,4-dioxane (291.7 mg, 2 mL, 4 molar, 34 Eq, 8 mmol) was added dropwise and the suspension stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. Then, 2 mL of DCM / MeOH (8:2) and 150 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-brown solid

[0616] 55718966-2 that was used without further purification in the next reaction step (97 mg, 240 pmol, 100% yield). LRMS (ESI), m / z 408.50 (M+H).

[0617] NH2

[0618] N

[0619] Q

[0620]

[0621] O

[0622] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound 1346). A 10 mL vial equipped with a stir bar was charged with 5-(7-((8-azabicyclo[3.2.1]octan-3-yl)methyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound XII) (55 mg, 1 Eq, 135 pmol) followed by MeOH (0.8 mL). Then, triethylamine (55 mg, 75 pL, 4 Eq, 540 pmol) and propargyl chloroformate (19 mg, 16 pL, 1.2 Eq, 162 pmol) were added and the mixture stirred at room temperature for 16 h. The reaction diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO₄, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 8% MeOH in DCM) to afford a white solid (30.9 mg, 63 pmol, 47% yield).1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.64 (s, 2H), 7.32 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J= 8.2, 7.0 Hz, 1H), 5.99 (br, 2H), 4.70 -4.65 (m, 2H), 4.14 (s, 2H), 4.01 (d, J = 7.2 Hz, 2H), 3.49 (t, J = 2.4 Hz, 1 H), 2.49 - 2.42 (m, 1 H), 1.89 - 1.80 (m, 2H), 1.64 - 1.53 (m, 2H), 1.43 - 1.34 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.21, 151.74, 151.56, 150.11, 149.43, 149.36, 148.40, 146.45, 132.12, 131.98, 124.73, 122.20, 117.34, 117.24, 107.44, 105.05, 105.02, 100.77, 79.29, 77.24, 53.09, 52.05, 49.07, 35.26, 34.39, 29.18, 27.94, 27.14. LRMS (ESI), m / z 490.40 (M+H).

[0623] 55718966-2 Example 4. Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound 1224).

[0624] 1224

[0625]

[0626] Synthesis of tert-butyl 4-((3-bromo-4-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XIII). A 20 ml_ vial equipped with a stir bar was charged with 3-bromo-4-chloro-1H-pyrazolo[4,3-c]pyridine (1163 mg, 1 Eq, 5.003 mmol) followed by DMA (9 ml_). Then, tert-butyl 4-(bromomethyl)piperidine-1-carboxylate (1392 mg, 1 Eq, 5.003 mmol) and potassium carbonate (2074 mg, 3 Eq, 15.008 mmol) were added. The vial was sealed and the mixture stirred at 85 °C for 3 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera,

[0627] 55718966-2 25 g column, 35 mL / min, 0 - 40% EtOAc in hexane) to afford a pale-orange solid (649.1 mg, 1.510 mmol, 30% yield).1H NMR (500 MHz, DMSO-d6) 5 8.22 (d, J = 6.1 Hz, 1H), 7.90 (d, J= 6.1 Hz, 1H), 4.35 (d, J= 7.1 Hz, 2H), 3.90 (d, J = 12.4 Hz, 2H), 2.64 (s, 2H), 2.07 (dqd, J = 11.1, 7.3, 3.5 Hz, 1H), 1.45 - 1.39 (m, 2H), 1.37 (s, 9H), 1.12 (qd, J = 12.3, 4.4 Hz, 2H).13C NMR (126 MHz, DMSO-d6) 5 153.71, 145.75, 143.77, 142.94, 119.00, 116.36, 105.91, 78.49, 53.94, 36.40, 28.79, 28.05. LRMS (ESI), m / z 430.70 (M+H).

[0628]

[0629] Synthesis of tert-butyl 4-((3-bromo-4-((2,4-dimethoxybenzyl)amino)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XIV). A 20 mL vial equipped with a stir bar was charged with tert-butyl 4-((3-bromo-4-chloro-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1-carboxylate (compound XIII) (600 mg, 1 Eq, 1.40 mmol) followed by acetonitrile (2 mL). Then, DIPEA (902 mg, 1.22 mL, 5 Eq, 6.98 mmol) and (2,4-dimethoxyphenyl)methanamine (1.17 g, 1.05 mL, 5 Eq, 6.98 mmol) were added. The vial was sealed and the mixture stirred at 150 °C for 30 min using microwave irradiation. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 50% EtOAc in hexane) to afford a pale-yellow solid (544.2 mg, 970.9 pmol, 70% yield). LRMS (ESI), m / z 559.80 (M+H).

[0630] 55718966-2

[0631]

[0632] Synthesis of 3-bromo-1 -(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3-c]pyridin-4-amine (compound XV). A 10 mL vial equipped with a stir bar was charged with tert-butyl 4-((3-bromo-4-((2,4-dimethoxybenzyl)amino)-1 H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XIV) (500 mg, 1 Eq, 892 pmol) followed by TFA (11 g, 7.4 mL, 108 Eq, 96 mmol) and triethylsilane (207 mg, 285 pL, 2 Eq, 1.78 mmol). Then, the vial was sealed and the reaction stirred at 80 °C for 2h. The volatiles were removed under reduced pressure. Then, 5 mL of DCM / MeOH (8:2) and 500 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-brown solid that was used without further purification in the next reaction step (277 mg, 892 pmol, 100% yield). LRMS (ESI), m / z 311.80 (M+H).

[0633]

[0634] Synthesis of isopropyl 4-((4-amino-3-bromo-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XVI). A 10 mL vial equipped with a stir bar was charged with 3-bromo-1-(piperidin-4-ylmethyl)-1 H-pyrazolo[4,3-c]pyridin-4-amine (compound XV) (277 mg, 1 Eq, 893 pmol) followed by MeOH (4 mL). Then, triethylamine (181 mg, 249 pL, 2 Eq, 1.79 mmol) and isopropyl chloroformate (142 mg, 1.16 mL, 1.3 Eq, 1.16 mmol) were added and the mixture stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford a white solid that was used without further purification in the next reaction step (355.4 mg, 893 pmol, 100% yield). LRMS (ESI), m / z 397.80 (M+H).

[0635] 55718966-2

[0636]

[0637] Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound 1224). A 10 mL vial equipped with a stir bar was charged with isopropyl 4-((4-amino-3-bromo-1 H-pyrazolo[4,3-c]pyridin-1-yl)methyl)piperidine-1-carboxylate (compound XVI) (50 mg, 1 Eq, 126 pmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound VI) (42.7 mg, 1.3 Eq, 164 pmol), cesium carbonate (61.7 mg, 1.5 Eq, 189 pmol), Pd(dppf)Cl2’DCM (30.9 mg, 0.3 Eq, 37.9 pmol), 1,4-dioxane (1 mL) and water (0.2 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 115 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 10% MeOH in DCM) to afford a pale-yellow solid (19.3 mg, 42.9 pmol, 34% yield).1H NMR (500 MHz, DMSO-de) 57.74 (d, J = 6.1 Hz, 1H), 7.53 (s, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.39 (d, J = 1.7 Hz, 1H), 7.21 (dd, J = 8.1, 1.7 Hz, 1H), 6.92 (d, J = 6.2 Hz, 1H), 5.83 (s, 2H), 4.79 -4.68 (m, 1H), 4.22 (d, J = 7.0 Hz, 2H), 3.94 (d, J = 12.5 Hz, 2H), 2.70 (br, 2H), 2.17 -2.04 (m, 1H), 1.54- 1.47 (m, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.14 - 1.10 (m, 2H).13C NMR (126 MHz, DMSO-de) 5163.46, 154.17, 153.52, 148.21, 145.63, 145.07, 144.21, 142.87, 128.64, 120.92, 115.55, 108.60, 104.56, 95.70, 67.63, 53.00, 42.97, 36.50, 29.06, 21.97.

[0638] LRMS (ESI), m / z 450.00 (M+H).

[0639] 55718966-2 Example 5. Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound 1225).

[0640]

[0641] Synthesis of 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (compound XVII). A 50 mL round-bottom flask equipped with a stir bar was charged with 4-chloro-1H-pyrrolo[3,2-c]pyridine (1000 mg, 1 Eq, 6.554 mmol) followed by DCM (25 mL). The mixture was cooled at 0 °C. Then, A / -bromosuccinimide (1.230 g, 1.054 Eq, 6.908 mmol) was added and the reaction stirred at 0 °C for 30 min and then at room temperature for 30 min. The precipitate was filtered off, washed with DCM and allowed to dry in the vacuum oven at 40 °C overnight to afford a brown solid that was used without further

[0642] 55718966-2 purification in the next reaction step (1057.4 mg, 6.554 mmol, 70% yield).1H NMR (500 MHz, DMSO-de) 5 12.27 (s, 1 H), 8.00 (d, J = 5.7 Hz, 1 H), 7.77 (d, J = 2.6 Hz, 1 H), 7.47 (d, J = 5.7 Hz, 1H).13C NMR (126 MHz, DMSO-d6) 5 141.24, 140.85, 139.87, 128.38, 118.88, 107.90, 86.81. LRMS (ESI), m / z 232.70 (M+H).

[0643] N

[0644]

[0645] Synthesis of tert-butyl 4-((3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XVIII). A 20 ml_ vial equipped with a stir bar was charged with 3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridine (compound XVII) (1048 mg, 1 Eq, 4.527 mmol) followed by DMA (9 ml_). Then, tert-butyl 4-(bromomethyl)piperidine-l -carboxylate (1259 mg, 1 Eq, 4.527 mmol) and potassium carbonate (1877 mg, 3 Eq, 13.58 mmol) were added. The vial was sealed and the mixture stirred at 85 °C for 3 h. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 45% EtOAc in hexane) to afford a pale-yellow solid (1007.8 mg, 2.351 mmol, 52% yield).1H NMR (500 MHz, DMSO-d6) 5 8.04 (d, J = 5.8 Hz, 1 H), 7.83 (s, 1 H), 7.74 (d, J = 5.9 Hz, 1 H), 4.12 (d, J = 7.3 Hz, 2H), 3.91 (d, J = 11.3 Hz, 2H), 2.61 (br, 2H), 2.03 - 1.91 (m, 1 H), 1.40 (br, 2H), 1.37 (s, 9H), 1.14 - 1.04 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 153.70, 141.48, 141.26, 139.94, 131.59, 118.82, 106.66, 86.41, 78.50, 51.19, 42.56, 36.54, 28.90, 28.05. LRMS (ESI), m / z 429.70 (M+H).

[0646] 55718966-2

[0647]

[0648] Synthesis of tert-butyl 4-((3-bromo-4-((2,4-dimethoxybenzyl)amino)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XIX). A 20 mL vial equipped with a stir bar was charged with tert-butyl 4-((3-bromo-4-chloro-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XVIII) (1004.8 mg, 1 Eq, 2.344 mmol) followed by acetonitrile (3 mL). Then, DIPEA (1514.5 mg, 2.04 mL, 5 Eq, 11.718 mmol) and (2,4-dimethoxyphenyl)methanamine (1959.3 mg, 1.76 mL, 5 Eq, 11.718 mmol) were added. The vial was sealed and the mixture stirred at 150 °C for 30 min using microwave irradiation. The reaction was cooled to room temperature, diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSCU, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 55% EtOAc in hexane) to afford a pale-yellow solid (743.6 mg, 1.329 mmol, 57% yield). LRMS (ESI), m / z 560.80 (M+H).

[0649]

[0650] Synthesis of 3-bromo-1-(piperidin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (compound XX). A 10 mL vial equipped with a stir bar was charged with tert-butyl 4-((3-bromo-4-((2,4-dimethoxybenzyl)amino)-1 H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XIX) (740.6 mg, 1 Eq, 1.324 mmol) followed by TFA (16.6 g, 11.22 mL, 110 Eq, 145.6 mmol) and triethylsilane (307.8 mg, 423 pL, 2 Eq, 2.647 mmol). Then, the vial was sealed and the reaction stirred at 80 °C for 2h. The volatiles were

[0651] 55718966-2 removed under reduced pressure. Then, 5 mL of DCM / MeOH (8:2) and 750 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-brown solid that was used without further purification in the next reaction step (409 mg, 1.324 pmol, 100% yield). LRMS (ESI), m / z 310.80 (M+H).

[0652]

[0653] Synthesis of isopropyl 4-((4-amino-3-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XXI). A 10 mL vial equipped with a stir bar was charged with3-bromo-1-(piperidin-4-ylmethyl)-1H-pyrrolo[3,2-c]pyridin-4-amine (compound XX) (49 mg, 1 Eq, 1.32 mmol) followed by MeOH (7 mL). Then, triethylamine (268 mg, 369 pL, 2 Eq, 2.65 mmol) and isopropyl chloroformate (243 mg, 1.98 mL, 1.5 Eq, 1.98 pmol) were added and the mixture stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 6% MeOH in DCM) to afford a brown oil (505 mg, 1.280 mmol, 96% yield). LRMS (ESI), m / z 396.80 (M+H).

[0654]

[0655] Synthesis of isopropyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound 1225). A 10

[0656] 55718966-2 mL vial equipped with a stir bar was charged with isopropyl 4-((4-amino-3-bromo-1H-pyrrolo[3,2-c]pyridin-1-yl)methyl)piperidine-1 -carboxylate (compound XXI) (62.2 mg, 1 Eq, 157 pmol), 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound VI) (53.2 mg, 1.3 Eq, 205 pmol), cesium carbonate (76.9 mg, 1.5 Eq, 236 pmol), Pd(dppf)Cl2’DCM (38.5 mg, 0.3 Eq, 47.2 pmol), 1,4-dioxane (1 mL) and water (0.2 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 115 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 5% MeOH with 7.5% 5N NH4+in DCM) to afford a pale-yellow solid (55.6 mg, 124 pmol, 79% yield).1H NMR (500 MHz, DMSO-d6) 57.63 (d, J = 6.0 Hz, 1H), 7.45 (s, 2H), 7.39 (d, J = 8.1 Hz, 1H), 7.23 (s, 1H), 7.22 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.89 (d, J = 6.1 Hz, 1 H), 5.38 (s, 2H), 4.74 (hept, J = 6.3 Hz, 1 H), 4.02 (d, J = 7.2 Hz, 2H), 3.96 (d, J = 13.0 Hz, 2H), 2.68 (br, 2H), 2.06- 1.93 (m, 1H), 1.54 - 1.46 (m, 2H), 1.16 (d, J = 6.2 Hz, 6H), 1.15 - 1.08 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 154.14, 152.76, 147.12, 144.08, 140.75, 138.19, 130.37, 125.99, 121.03, 117.12, 115.84, 108.27, 107.44, 97.70, 67.64, 50.66, 42.98, 36.60, 29.11, 21.97. LRMS (ESI), m / z 449.00 (M+H).

[0657] 55718966-2 Example 6. Synthesis of tert-butyl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound 1377) and prop-2-yn-1-yl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound 1394).

[0658] XXII XXIII

[0659] 1377

[0660] 1394

[0661]

[0662] Synthesis of (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (compound XXII). A 20 ml_ vial equipped with a stir bar was charged with tert-butyl ((1r,4ij-4-hydroxycyclohexyl)carbamate (750 mg, 1 Eq, 3.48 mmol) followed by DCM (10 55718966-2 mL). The solution was cooled to 0 °C. Then, triethylamine (529 mg, 728 pL, 1.5 Eq, 5.23 mmol) and methanesulfonyl chloride (483 mg, 328 pL, 1.21 Eq, 4.22 mmol) were added and the reaction stirred at 0 °C for 5 min and then stirred at room temperature for 3 h. The reaction was diluted with DCM, washed with saturated aqueous solution of Na2COs and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure to afford a white solid that was used without further purification in the next reaction step (977.3 mg, 3.331 mmol, 96% yield).

[0663] '2

[0664]

[0665] Synthesis of tert-butyl ((1s,4s)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound XXIII). A 10 mL vial equipped with a stir bar was charged with 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (215 mg, 1 Eq, 828 pmol) followed by DMA (4 mL). Then, cesium carbonate (674 mg, 2.5 Eq, 2.07 mmol) and (1r,4r)-4-((tert-butoxycarbonyl)amino)cyclohexyl methanesulfonate (compound XXII) (255 mg, 1.05 Eq, 869 pmol) were added. The vial was sealed and the reaction stirred at 85 °C for 3 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSC>4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 5% MeOH in DCM) to afford a pale-yellow solid (88.3 mg, 193 pmol, 23% yield).1H NMR (500 MHz, DMSO-d6) 58.08 (s, 1 H), 7.69 (s, 1 H), 7.05 (d, J = 8.9 Hz, 1 H), 6.57 (br, 2H), 4.56 (tt, J = 11.9, 3.9 Hz, 1H), 3.79 (d, J = 7.5 Hz, 1H), 2.04 (qd, J = 12.4, 4.5 Hz, 2H), 1.73 - 1.59 (m, 6H), 1.42 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 157.04, 155.02, 151.51, 148.97, 126.86, 102.63, 77.68, 51.74, 49.64, 43.64, 29.50, 28.32, 26.90. LRMS (ESI), m / z 458.30 (M+H).

[0666] 55718966-2

[0667]

[0668] Synthesis of tert-butyl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound 1377). A 10 mL vial equipped with a stir bar was charged with tert-butyl ((1s,4s)-4-(4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound XXIII) (110 mg, 1 Eq, 241 pmol), 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound XI) (73.6 mg, 1.1 Eq, 265 pmol), cesium carbonate (118 mg, 1.5 Eq, 361 pmol), Pd(dppf)Cl2’DCM (39.3 mg, 0.2 Eq, 48.1 pmol), 1,4-dioxane (1 mL) and water (0.3 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 110 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 8% MeOH in DCM) to afford a pale-brown solid (39.4 mg, 81.8 pmol, 34% yield).1H NMR (500 MHz, DMSO-de) 5 8.12 (s, 1H), 7.64 (s, 2H), 7.58 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 7.08 (d, J = 8.9 Hz, 1H), 6.98 (dd, J = 8.1, 7.0 Hz, 1H), 6.01 (br, 2H), 4.65 (tt, J= 11.8, 3.4 Hz, 1H), 3.80 (s, 1H), 2.13 - 2.04 (m, 2H), 1.75 - 1.67 (m, 6H), 1.41 (s, 9H).13C NMR (126 MHz, DMSO-de) 5 163.21, 157.07, 155.07, 151.15, 149.28, 149.25, 148.34, 146.38, 132.13, 132.00, 122.15, 121.93, 117.51, 117.40, 107.64, 105.05, 100.68, 77.65, 51.34, 43.76, 29.56, 28.31, 27.03. LRMS (ESI), m / z 482.30 (M+H).

[0669] 55718966-2

[0670]

[0671] Synthesis of 5-(4-amino-7-((1s,4s)-4-aminocyclohexyl)-7H-pyrrolo[2,3- d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound XXIV). A 10 mL vial equipped with a stir bar was charged with tert-butyl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound 1377) (19.7 mg, 1 Eq, 40.9 pmol) followed by 1,4-dioxane (0.5 mL). Then, a hydrogen chloride solution in 1,4-dioxane (44.7 mg, 307 pL, 4 molar, 30 Eq, 1.23 mmol) was added dropwise and the suspension stirred at room temperature for 16 h. The volatiles were removed under reduced pressure. Then, 2 mL of DCM / MeOH (8:2) and 20 mg of Amberlyst A-21 cation exchange beads were added and the suspension stirred overnight at room temperature. The solution was filtered and the solvent removed under reduced pressure to afford a pale-brown solid that was used without further purification in the next reaction step (15.6 mg, 40.9 pmol, 100% yield). LRMS (ESI), m / z 382.20 (M+H).

[0672]

[0673] Synthesis of prop-2-yn-1-yl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)carbamate (compound 1394). A 10 mL vial equipped with a stir bar was charged with 5-(4-amino-

[0674] 55718966-2 7-((1s,4s)-4-aminocyclohexyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound XXIV) (15.6 mg, 1 Eq, 40.9 pmol) followed by MeOH (0.8 mL). Then, triethylamine (16.6 mg, 22.8 pL, 4 Eq, 164 pmol) and propargyl chloroformate (5.82 mg, 4.79 pL, 1.2 Eq, 49.1 pmol) were added and the mixture stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSC>4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 9% MeOH in DCM) to afford a white solid (8.6 mg, 19 pmol, 45% yield).1H NMR (500 MHz, DMSO-de) 58.12 (s, 1H), 7.64 (s, 2H), 7.61 (d, J = 8.5 Hz, 1H), 7.52 (s, 1H), 7.28 (d, J = 8.1 Hz, 1 H), 6.98 (dd, J = 8.1, 7.0 Hz, 1 H), 5.99 (br, 2H), 4.65 (d, J = 2.6 Hz, 2H), 3.87 - 3.81 (m, 1H), 3.48 (t, J = 2.4 Hz, 1H), 2.16 - 2.05 (m, 2H), 1.81 - 1.69 (m, 6H), 1.42 - 1.33 (m, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.21, 157.16, 154.70, 151.29, 149.36, 149.30, 148.34, 146.38, 132.13, 131.99, 122.12, 121.69, 117.50, 117.41, 107.68, 105.03, 100.70, 79.34, 77.15, 51.42, 51.21, 44.58, 29.39, 26.93. LRMS (ESI), m / z 364.20 (M+H).

[0675]

[0676] Synthesis of tert-butyl 4-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1 -carboxylate (compound 189). The synthesis of compound 189 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.23 (s, 1H), 7.53 (s, 2H), 7.46 (d, J = 8.2 Hz, 1H), 7.40 (d, J = 1.7 Hz, 1H), 7.23 (dd, J = 8.1, 1.7 Hz, 1H), 4.89 (tt, J = 11.3, 4.2 Hz, 1H), 4.13 - 4.06 (m, 2H), 2.99 (br, 2H), 2.08 - 1.96 (m, 2H), 1.96 - 1.89 (m, 2H), 1.42 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.45, 158.17, 155.48, 153.83, 153.50, 148.33, 144.42, 143.99, 128.59, 120.43, 115.00, 108.85, 97.49, 78.81, 53.32, 42.57, 30.91, 28.07. LRMS (ESI), m / z 451.40 (M+H).

[0677] 55718966-2

[0678]

[0679] Synthesis of tert-butyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 190).

[0680] The synthesis of compound 190 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.24 (s, 1H), 7.52 (s, 2H), 7.46 (dd, J = 8.1, 0.5 Hz, 1H), 7.41 (dd, J = 1.6, 0.6 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.90 (d, J = 13.0 Hz, 2H), 2.67 (br, 2H), 2.18 - 2.07 (m, 1H), 1.55 - 1.48 (m, 2H), 1.37 (s, 9H), 1.18 - 1.06 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.43, 158.17, 155.71, 154.42, 153.83, 148.32, 144.40, 144.08, 128.52, 120.43, 115.00, 108.84, 97.12, 78.46, 51.22, 43.26, 36.13, 29.23, 28.06. LRMS (ESI), m / z 465.30 (M+H).

[0681]

[0682] Synthesis of tert-butyl 4-(2-(4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl)piperidine-1 -carboxylate (compound 194). The synthesis of compound 194 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.24 (s, 1H), 7.52 (s, 2H), 7.46 (dd, J = 8.1, 0.5 Hz, 1H), 7.40 (dd, J = 1.8, 0.6 Hz, 1H), 7.23 (dd, J = 8.1, 1.7 Hz, 1H),

[0683] 55718966-2 4.37 (t, J = 7.1 Hz, 2H), 3.89 (d, J = 12.9 Hz, 2H), 2.62 (br, 2H), 1.84 - 1.76 (m, 2H), 1.75 - 1.68 (m, 2H), 1.38 (s, 9H), 1.28 - 1.20 (m, 1H), 1.08 - 0.97 (m, 2H).13C NMR (126 MHz, DMSO-de) 5 163.42, 158.14, 155.65, 153.95, 153.83, 148.30, 144.39, 144.04, 128.57, 120.42, 114.98, 108.85, 97.23, 78.38, 43.76, 43.11, 35.49, 32.71, 31.32, 28.07.

[0684] LRMS (ESI), m / z 479.40 (M+H).

[0685]

[0686] Synthesis of benzyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1110). The synthesis of compound 1110 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.39 -7.28 (m, 5H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 5.05 (s, 2H), 4.24 (d, J = 7.0 Hz, 2H), 3.98 (dt, J= 13.1, 3.3 Hz, 2H), 2.78 (br, 2H), 2.22 -2.11 (m, 1H), 1.58 - 1.50 (m, 2H), 1.23 - 1.11 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.43, 158.17, 155.71, 154.43, 154.36, 148.31, 144.40, 144.09, 137.04, 128.51, 128.38, 127.75, 127.44, 120.44, 115.01, 108.84, 97.13, 66.03, 51.18, 43.17, 36.00, 29.22. LRMS (ESI), m / z 499.40 (M+H).

[0687]

[0688] 55718966-2 Synthesis of methyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1161). The synthesis of compound 1161 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.92 (br, 2H), 3.56 (s, 3H), 2.74 (br, 2H), 2.22 -2.10 (m, 1H), 1.53 (d, J = 11.6 Hz, 2H), 1.15 (qd, J= 12.2, 4.3 Hz, 2H).13C NMR (126 MHz, DMSO-d6) 5163.43, 158.17, 155.71, 155.02, 154.43, 148.32, 144.40, 144.09, 128.51, 120.44, 115.00, 108.85, 97.13, 52.17, 51.18, 43.09, 35.98, 29.14. LRMS (ESI), m / z 423.30 (M+H).

[0689]

[0690] Synthesis of ethyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1162). The synthesis of compound 1162 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.24 (d, J = 7.0 Hz, 2H), 4.00 (q, J = 7.1 Hz, 2H), 3.94 (d, J = 13.2 Hz, 2H), 2.73 (br, 2H), 2.21 - 2.09 (m, 1H), 1.53 (d, J = 12.4 Hz, 2H), 1.15 (t, J = 7.1 Hz, 3H), 1.20 - 1.08 (m, 2H).13C NMR (126 MHz, DMSO-de) 5 163.43, 158.17, 155.71, 154.57, 154.43, 148.32, 144.40, 144.09, 128.51, 120.44, 115.00, 108.85, 97.13, 60.51, 51.20, 43.01, 36.03, 29.17, 14.57. LRMS (ESI), m / z 437.40 (M+H).

[0691] 55718966-2

[0692]

[0693] Synthesis of isobutyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1163).

[0694] The synthesis of compound 1163 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.24 (s, 1H), 7.52 (s, 2H), 7.46 (dd, J = 8.1, 0.6 Hz, 1H), 7.41 (d, J = 1.6 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.24 (d, J= 7.0 Hz, 2H), 3.95 (d, J = 13.3 Hz, 2H), 3.75 (d, J = 6.5 Hz, 2H), 2.75 (br, 2H), 2.22 -2.10 (m, 1H), 1.89 - 1.78 (m, 1H), 1.54 (d, J = 10.5 Hz, 2H), 1.21 - 1.09 (m, 1H), 0.86 (d, J = 6.7 Hz, 6H).13C NMR (126 MHz, DMSO-d6) 5 163.43, 158.17, 155.71, 154.61, 154.43, 148.32, 144.40, 144.09, 128.51, 120.44, 115.00, 108.84, 97.12, 70.49, 51.19, 43.07, 36.06, 29.21, 27.53, 18.86. LRMS (ESI), m / z 465.40 (M+H).

[0695]

[0696] Synthesis of sec-butyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1164).

[0697] The synthesis of compound 1164 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.63 -4.54 (m, 1H), 4.24 (d, J = 7.0 Hz, 2H), 3.94 (d, J = 13.0 Hz, 2H), 2.73 (br, 2H), 2.22 -2.09 (m, 1H), 1.56- 1.43 (m, 4H), 1.19 - 1.07 (m, 5H), 0.83 (t, J = 7.4 Hz, 3H).13C NMR

[0698] 55718966-2 (126 MHz, DMSO-d6) δ 163.43, 158.17, 155.71, 154.43, 154.38, 148.31, 144.40, 144.08, 128.51, 120.43, 115.00, 108.84, 97.12, 72.03, 51.21, 43.01, 36.10, 29.19, 28.44, 19.62, 9.48. LRMS (ESI), m / z 465.40 (M+H).

[0699]

[0700] Synthesis of cyclopentyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1165).

[0701] The synthesis of compound 1165 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.24 (s, 1H), 7.52 (s, 2H), 7.46 (d, J = 8.1 Hz, 1H), 7.41 (d, J = 1.7 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 4.98 -4.92 (m, 1 H), 4.24 (d, J = 7.0 Hz, 2H), 3.91 (br, 2H), 2.70 (br, 2H), 2.20 - 2.08 (m, 1 H), 1.79 - 1.71 (m, 2H), 1.66 - 1.49 (m, 8H), 1.19 - 1.07 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.43, 158.17, 155.71, 154.42, 154.39, 148.31, 144.40, 144.08, 128.51, 120.43, 115.00, 108.84, 97.12, 76.89, 51.20, 43.00, 36.07, 32.32, 29.18, 23.12. LRMS (ESI), m / z 477.40 (M+H).

[0702]

[0703] Synthesis of phenyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1166). The synthesis

[0704] 55718966-2 of compound 1166 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.25 (s, 1H), 7.53 (s, 2H), 7.47 (dd, J= 8.1, 0.6 Hz, 1H), 7.43 (dd, J = 1.7, 0.6 Hz, 1H), 7.25 (dd, J = 8.1, 1.7 Hz, 1H), 7.23-7.10 (m, 4H), 4.29 (d, J = 7.0 Hz, 2H), 4.12 (d, J = 13.7 Hz, 1H), 3.99 (d, J = 12.6 Hz, 1H), 2.99 (br, 1H), 2.84 (s, 1H), 2.30 - 2.18 (m, 1H), 1.61 (dd, J = 13.6, 3.6 Hz, 2H), 1.37 - 1.20 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.44, 160.14, 158.22, 158.19, 155.74, 154.46, 152.81, 148.33, 147.39, 147.37, 144.41, 144.14, 128.52, 123.66, 123.59, 120.45, 115.79, 115.60, 115.02, 108.86, 97.15, 51.13, 43.81, 43.45, 35.90, 29.32, 28.91.

[0705] LRMS (ESI), m / z 485.50 (M+H).

[0706]

[0707] Synthesis of 4-fluorophenyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1167).

[0708] The synthesis of compound 1167 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 58.25 (s, 1H), 7.53 (s, 2H), 7.47 (dd, J = 8.1, 0.6 Hz, 1H), 7.43 (dd, J = 1.7, 0.6 Hz, 1H), 7.39 - 7.34 (m, 2H), 7.25 (dd, J = 8.1, 1.7 Hz, 1H), 7.23 - 7.17 (m, 1H), 7.13 - 7.07 (m, 2H), 4.29 (d, J = 7.0 Hz, 2H), 4.13 (d, J= 11.6 Hz, 1H), 4.00 (d, J = 12.3 Hz, 1H), 2.99 (br, 1H), 2.85 (br, 1H), 2.30 - 2.18 (m, 1H), 1.61 (d, J = 12.6 Hz, 2H), 1.38 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.44, 158.19, 155.74, 154.46, 152.85, 151.29, 148.33, 144.41, 144.14, 129.18, 128.52, 125.06, 121.86, 120.45, 115.02, 108.85, 97.15, 51.14, 43.84, 43.40, 35.93, 29.38, 28.93. LRMS (ESI), m / z 503.50 (M+H).

[0709] 55718966-2

[0710]

[0711] Synthesis of benzo[d][1,3]dioxol-5-yl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1169). The synthesis of compound 1169 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) δ 8.25 (s, 1 H), 7.52 (s, 2H), 7.47 (d, J = 8.1 Hz, 1H), 7.43 (d, J= 1.7 Hz, 1H), 7.25 (dd, J = 8.1, 1.7 Hz, 1 H), 6.85 (d, J = 8.4 Hz, 1 H), 6.76 (d, J = 2.4 Hz, 1 H), 6.54 (dd, J = 8.4, 2.4 Hz, 1 H), 6.02 (s, 2H), 4.28 (d, J = 7.1 Hz, 2H), 4.08 (br, 1H), 3.98 (br, 1H), 2.96 (br, 1H), 2.83 (br, 1H), 2.29 - 2.16 (m, 1H), 1.63 - 1.56 (m, 2H), 1.34 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.43, 158.18, 155.73, 154.46, 153.07, 148.32, 147.35, 145.65, 144.41, 144.38, 144.13, 128.52, 120.45, 115.01, 114.18, 108.85, 107.61, 104.18, 101.51, 97.14, 51.14, 43.77, 43.44, 35.92, 29.32, 28.93. LRMS (ESI), m / z 529.40 (M+H).

[0712]

[0713] Synthesis of 4-nitrobenzyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)piperidine-1 -carboxylate (compound 1170).

[0714] The synthesis of compound 1170 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) δ 8.26 - 8.19 (m, 3H), 7.63 - 7.57 (m, 2H), 7.52 (s, 2H), 7.46 (d, J= 8.1 Hz, 1H), 7.41 (d, J= 1.7 Hz, 1H), 7.24 (dd, J = 8.1, 1.7 Hz, 1H), 5.20 (s, 2H), 4.26 (d, J = 7.0 Hz, 2H), 4.00 (br, 2H), 2.77 (br, 2H),

[0715] 55718966-2 2.25 - 2.13 (m, 1 H), 1.56 (d, J = 10.6 Hz, 2H), 1.26 - 1.14 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.43, 158.17, 155.72, 154.44, 154.03, 148.32, 146.93, 144.97, 144.41, 144.11, 128.51, 128.03, 123.56, 120.43, 115.00, 108.84, 97.12, 64.93, 51.15, 43.25, 35.96, 29.26, 29.09. LRMS (ESI), m / z 544.40 (M+H).

[0716]

[0717] Synthesis of tert-butyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1176). The synthesis of compound 1176 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 5 8.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.06 (br, 2H), 4.05 (d, J = 7.2 Hz, 2H), 3.91 (d, J = 13.0 Hz, 2H), 2.67 (br, 2H), 2.11 - 1.99 (m, 1H), 1.49 (d, J = 11.6 Hz, 2H), 1.38 (s, 9H), 1.16 - 1.04 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.31, 157.22, 153.79, 151.50, 150.22, 147.12, 144.34, 130.26, 123.71, 120.41, 115.38, 115.21, 108.56, 99.94, 78.46, 48.95, 42.63, 36.26, 29.27, 28.06. LRMS (ESI), m / z 463.90 (M+H).

[0718]

[0719] Synthesis of isopropyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1177).

[0720] The synthesis of compound 1177 was accomplished using a procedure analogous to

[0721] 55718966-2 that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.27 (s, 1H), 7.23 (d, J= 1.7 Hz, 1H), 7.03 (dd, J= 8.1, 1.8 Hz, 1H), 6.06 (br, 2H), 4.80 - 4.69 (m, 1H), 4.06 (d, J = 7.2 Hz, 2H), 3.94 (d, J = 12.9 Hz, 2H), 2.70 (br, 2H), 2.13 - 2.01 (m, 1H), 1.50 (d, J = 11.8 Hz, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.15 - 1.05 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 157.22, 154.18, 151.51, 150.23, 147.12, 144.34, 130.25, 123.70, 120.41, 115.39, 115.21, 108.56, 99.95, 67.64, 48.94, 42.97, 36.21, 29.17, 21.97. LRMS (ESI), m / z 450.00 (M+H).

[0722]

[0723] Synthesis of vinyl 4-((4-amino-3-(2-aminobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)piperidine-1 -carboxylate (compound 1184). The synthesis of compound 1184 was accomplished using a procedure analogous to that described in Example 1.1H NMR (500 MHz, DMSO-d6) 5 8.24 (s, 1H), 7.52 (s, 2H), 7.47 (d, J = 8.1 Hz, 1 H), 7.42 (d, J = 1.7 Hz, 1 H), 7.24 (dd, J = 8.2, 1.7 Hz, 1 H), 7.11 (dd, J = 14.0, 6.3 Hz, 1 H), 4.77 (dd, J = 14.0, 1.5 Hz, 1 H), 4.48 (dd, J = 6.3, 1.5 Hz, 1 H), 4.26 (d, J = 7.0 Hz, 2H), 4.04 - 3.93 (m, 2H), 2.95 -2.71 (m, 2H), 2.26 -2.13 (m, 1H), 1.58 (d, J= 12.9 Hz, 2H), 1.27 - 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.43, 158.18, 155.72, 154.43, 151.54, 148.32, 144.40, 144.12, 142.47, 128.51, 120.44, 115.01, 108.85, 97.14, 95.53, 51.10, 43.22, 35.86, 29.24, 28.88. LRMS (ESI), m / z 434.90 (M+H).

[0724] H2N

[0725]

[0726] O

[0727] 55718966-2 Synthesis of vinyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1189). The synthesis of compound 1189 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 5 8.14 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 1.8 Hz, 1H), 7.11 (dd, J = 14.0, 6.3 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.11 (br, 2H), 4.77 (dd, J = 14.0, 1.5 Hz, 1H), 4.49 (dd, J = 6.3, 1.5 Hz, 1H), 4.08 (d, J = 7.2 Hz, 2H), 4.00 (br, 1H), 3.13 - 3.04 (m, 1H), 2.82 (dt, J = 47.6, 11.9 Hz, 2H), 2.17 -2.07 (m, 1H), 1.55 (d, J = 9.6 Hz, 2H), 1.25- 1.12 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.31, 157.08, 151.53, 151.31, 150.17, 147.14, 144.35, 142.46, 130.19, 123.74, 120.41, 115.52, 115.22, 108.58, 99.92, 95.54, 48.83, 45.63, 43.24, 36.00, 29.24, 28.90, 8.56. LRMS (ESI), m / z 433.90 (M+H).

[0728] Synthesis of prop-2 -yn-1-yl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1192).

[0729]

[0730] The synthesis of compound 1192 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.16 (s, 1H), 7.46 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.24 (d, J= 1.7 Hz, 1H), 7.03 (dd, J= 8.1, 1.8 Hz, 1 H), 6.23 (br, 2H), 4.65 (d, J = 2.4 Hz, 2H), 4.07 (d, J = 7.2 Hz, 2H), 3.94 (br, 2H), 3.48 (t, J = 2.4 Hz, 1H), 2.77 (br, 2H), 2.16 - 2.03 (m, 1H), 1.53 (d, J = 12.9 Hz, 2H), 1.22 -1.08 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.32, 156.60, 153.59, 150.62, 149.95, 147.18, 144.36, 130.00, 123.98, 120.42, 115.75, 115.22, 108.61, 99.80, 79.25, 77.23, 52.40, 48.93, 43.21, 36.06, 29.10. LRMS (ESI), m / z 445.90 (M+H).

[0731] 55718966-2

[0732]

[0733] Synthesis of 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-N, N-dimethylpiperidine-1 -carboxamide (compound 1193). The synthesis of compound 1193 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1 H), 7.45 (s, 2H), 7.40 (dd, J = 8.0, 0.5 Hz, 1 H), 7.28 (s, 1 H), 7.23 (dd, J = 1.7, 0.5 Hz, 1 H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.06 (br, 2H), 4.06 (d, J = 7.3 Hz, 2H), 3.51 (dt, J = 13.7, 3.8 Hz, 2H), 2.70 (s, 6H), 2.61 (td, J = 12.9, 2.5 Hz, 2H), 2.10 - 1.98 (m, 1H), 1.52- 1.45 (m, 2H), 1.26 - 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.96, 163.31, 157.21, 151.50, 150.24, 147.12, 144.34, 130.27, 123.67, 120.41, 115.40, 115.21, 108.56, 99.91, 49.03, 46.09, 38.09, 36.59, 29.20. LRMS (ESI), m / z 434.90 (M+H).

[0734]

[0735] Synthesis of 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-N, N-diethylpiperidine-1 -carboxamide (compound 1194).

[0736] The synthesis of compound 1194 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.14 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J= 1.7 Hz, 1H), 7.03 (dd, J= 8.1, 1.8 Hz, 1 H), 6.10 (br, 2H), 4.06 (d, J = 7.3 Hz, 2H), 3.52 - 3.44 (m, 2H), 3.08 (q, J = 7.0 Hz, 4H), 2.61 (td, J= 12.2, 2.1 Hz, 2H), 2.10 - 1.98 (m, 1H), 1.52 - 1.45 (m, 2H), 1.26 - 1.13 (m, 2H), 1.02 (t, J = 7.0 Hz, 6H).13C NMR (126 MHz, DMSO-d6) 5 163.62, 163.31, 157.07,

[0737] 55718966-2 151.29, 150.16, 147.13, 144.35, 130.22, 123.75, 120.41, 115.46, 115.21, 108.57, 99.88, 49.05, 46.36, 41.27, 36.62, 29.22, 13.04. LRMS (ESI), m / z 462.90 (M+H).

[0738]

[0739] Synthesis of 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-N-ethyl-N-methylpiperidine-1 -carboxamide (compound 1229). The synthesis of compound 1229 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1 H), 7.45 (s, 2H), 7.40 (d, J = 8.0 Hz, 1 H), 7.30 (s, 1 H), 7.23 (d, J = 1.7 Hz, 1 H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.11 (br, 2H), 4.06 (d, J= 7.3 Hz, 2H), 3.49 (dt, J= 13.4, 3.6 Hz, 2H), 3.08 (q, J= 7.1 Hz, 2H), 2.69 (s, 3H), 2.60 (td, J = 12.9, 2.5 Hz, 2H), 2.09 - 1.98 (m, 1H), 1.52 - 1.45 (m, 2H), 1.26 - 1.13 (m, 2H), 1.03 (t, J = 7.1 Hz, 3H).13C NMR (126 MHz, DMSO-d6) δ 163.74, 163.30, 157.01, 151.21, 150.13, 147.12, 144.34, 130.19, 123.76, 120.40, 115.48, 115.20, 108.57, 99.86, 49.06, 46.21, 44.18, 36.60, 35.06, 29.20, 12.39.

[0740] LRMS (ESI), m / z 449.00 (M+H).

[0741]

[0742] Synthesis of 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-N-methyl-N-phenylpiperidine-1 -carboxamide (compound 1230). The synthesis of compound 1230 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1 H),

[0743] 55718966-2 7.45 (s, 2H), 7.39 (d, J = 8.0 Hz, 1H), 7.35 - 7.28 (m, 2H), 7.25 - 7.20 (m, 2H), 7.10 -7.04 (m, 3H), 7.01 (dd, J = 8.1, 1.8 Hz, 1H), 6.09 (br, 2H), 3.99 (d, J = 7.1 Hz, 2H), 3.67 (dt, J = 13.4, 3.3 Hz, 2H), 3.06 (s, 3H), 2.54 (dd, J = 12.4, 2.6 Hz, 2H), 2.02 - 1.91 (m, 1H), 1.35 (dd, J= 13.4, 3.6 Hz, 2H), 1.05 - 0.94 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.29, 160.12, 157.00, 151.20, 150.12, 147.12, 146.63, 144.33, 130.17, 129.24, 123.67, 123.64, 122.61, 120.39, 115.46, 115.19, 108.55, 99.84, 48.82, 45.69, 44.86, 36.33, 28.86. LRMS (ESI), m / z 496.90 (M+H).

[0744]

[0745] Synthesis of (4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1 -yl)(pyrrolidin-1 -yl)methanone (compound 1231). The synthesis of compound 1231 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1 H), 7.45 (s, 2H), 7.40 (d, J = 8.0 Hz, 1 H), 7.30 (s, 1 H), 7.23 (d, J = 1.9 Hz, 1 H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.13 (br, 2H), 4.07 (d, J= 7.3 Hz, 2H), 3.62 (dt, J = 13.1, 3.6 Hz, 2H), 3.25 - 3.19 (m, 4H), 2.65 - 2.55 (m, 2H), 2.10 -2.00 (m, 1H), 1.76 - 1.67 (m, 4H), 1.52 - 1.45 (m, 2H), 1.26 - 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.30, 161.91, 156.94, 151.12, 150.11, 147.13, 144.34, 130.16, 123.79, 120.40, 115.52, 115.20, 108.57, 99.84, 49.08, 47.87, 45.40, 36.61, 29.29, 25.04. LRMS (ESI), m / z 460.90 (M+H).

[0746]

[0747] 55718966-2 Synthesis of (4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1 -y I )( pi peri di n -1 -yl)methanone (compound 1232). The synthesis of compound 1232 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.08 (br, 2H), 4.06 (d, J = 7.3 Hz, 2H), 3.51 (dt, J = 13.4, 3.6 Hz, 2H), 3.06 (t, J = 5.3 Hz, 4H), 2.68 – 2.59 (m, 2H), 2.09 – 1.98 (m, 1H), 1.55 – 1.40 (m, 8H), 1.25 – 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.41, 163.29, 157.13, 151.38, 150.17, 147.11, 144.33, 130.23, 123.72, 120.40, 115.41, 115.20, 108.56, 99.90, 49.05, 47.28, 46.16, 36.59, 29.24, 25.29, 24.19. LRMS (ESI), m / z 475.10 (M+H).

[0748]

[0749] Synthesis of (4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1 -yl)(morpholino)methanone (compound 1233).

[0750] The synthesis of compound 1233 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J= 1.8 Hz, 1H), 7.03 (dd, J = 8.1, 1.9 Hz, 1 H), 6.09 (br, 2H), 4.06 (d, J = 7.2 Hz, 2H), 3.62 - 3.51 (m, 6H), 3.11 - 3.06 (m, 4H), 2.67 (td, J= 12.9, 2.6 Hz, 2H), 2.11 -2.01 (m, 1H), 1.52 - 1.45 (m, 2H), 1.27 - 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.30, 163.14, 157.12, 151.38, 150.18, 147.11, 144.34, 130.22, 123.71, 120.39, 115.44, 115.19, 108.56, 99.89, 65.87, 48.99, 47.03, 45.94, 36.52, 29.21. LRMS (ESI), m / z 477.00 (M+H).

[0751] 55718966-2

[0752]

[0753] Synthesis of (4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1 -yl)(4-methylpiperazin-1-yl)methanone (compound 1234). The synthesis of compound 1234 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.45 (s, 2H), 7.43 – 7.38 (m, 1H), 7.28 (s, 1H), 7.23 (t, J = 1.5 Hz, 1H), 7.02 (dt, J = 8.1, 1.4 Hz, 1H), 6.06 (br, 2H), 4.05 (d, J = 7.3 Hz, 2H), 3.58 – 3.51 (m, 2H), 3.10 (t, J = 4.9 Hz, 4H), 2.69 – 2.60 (m, 2H), 2.26 (t, J = 4.8 Hz, 4H), 2.15 (s, 3H), 2.09 – 1.99 (m, 1H), 1.48 (dd, J = 13.4, 3.7 Hz, 2H), 1.26 – 1.13 (m, 2H).13C NMR (126 MHz, DMSO-d6) 6 163.29, 163.07, 157.20, 151.49, 150.21, 147.10, 144.33, 130.25, 123.68, 120.40, 115.38, 115.19, 108.55, 99.92, 54.32, 49.01, 46.25, 46.05, 45.71, 36.54, 29.21. LRMS (ESI), m / z 490.10 (M+H).

[0754]

[0755] Synthesis of 1 -(4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d] pyri midi n-7-yl)methyl)pi peridi n-1 -yl)-2-fluoropropan-1 -one (compound 1275).

[0756] The synthesis of compound 1275 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.28 (s, 1H), 7.23 (d, J= 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1 H), 6.07 (br, 2H), 5.48 (dd, J = 47.9, 6.8 Hz, 1 H), 4.31 (d, 1 H), 4.07 (dd, J = 7.2, 1.6 Hz, 2H), 3.85 (d, J= 13.6 Hz, 1H), 3.04 -2.92 (m, 1H), 2.62 -2.53 (m, 1H), 2.23 -2.11 (m, 1H), 1.56 (d, J = 12.9 Hz, 2H), 1.43 - 1.31 (m, 3H), 1.22 - 1.03 (m, 2H).13C NMR (126

[0757] 55718966-2 MHz, DMSO-d6) δ 166.85, 166.68, 163.31, 157.21, 151.49, 150.23, 147.13, 144.35, 130.24, 123.69, 120.40, 115.45, 115.21, 108.57, 99.94, 85.65, 84.30, 48.81, 48.72, 44.28, 44.09, 41.22, 41.09, 36.27, 36.23, 30.04, 29.79, 29.09, 29.00, 18.01, 17.80, 17.60.

[0758] LRMS (ESI), m / z 437.90 (M+H).

[0759]

[0760] Synthesis of 1 -(4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidin-1 -yl)-2,2-difluoropropan-1 -one (compound 1276). The synthesis of compound 1276 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.08 (br, 2H), 4.29 (d, J = 13.1 Hz, 1H), 4.07 (d, J = 7.3 Hz, 2H), 3.09 (t, J = 12.9 Hz, 1H), 2.72 (t, J = 12.5 Hz, 1H), 2.28 - 2.15 (m, 1H), 1.78 (t, J = 20.1 Hz, 3H), 1.62 (d, J = 13.0 Hz, 2H), 1.28 - 1.11 (m, 3H).13C NMR (126 MHz, DMSO-d6) 5 163.30, 160.91, 157.17, 151.45, 150.18, 147.12, 144.33, 130.21, 123.68, 120.40, 119.14, 115.46, 115.21, 108.56, 99.95, 48.71, 44.86, 42.46, 36.09, 30.02, 29.05, 22.15, 21.95, 21.75. LRMS (ESI), m / z 455.90 (M+H).

[0761]

[0762] Synthesis of tert-butyl 3-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8-carboxylate (compound

[0763] 55718966-2 1292). The synthesis of compound 1292 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (s, 1H), 7.23 (d, J = 1.8 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.06 (br, 2H), 4.12 – 3.92 (m, 5H), 2.48 -2.39 (m, 1H), 1.81 (br, 3H), 1.57 (br, 2H), 1.39 (s, 1H), 1.36 (s, 9H), 1.26 (s, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.29, 157.13, 152.51, 151.37, 150.30, 147.10, 144.32, 130.27, 123.70, 120.39, 115.44, 115.20, 108.54, 99.82, 78.24, 53.26, 52.46, 49.07, 34.92, 34.11, 29.30, 28.12, 27.95. LRMS (ESI), m / z 489.40 (M+H).

[0764]

[0765] Synthesis of 5-(4-amino-7-((1 -(oxazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (compound 1298). The synthesis of compound 1298 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, ) 5 8.14 (s, 1 H), 7.52 (d, J = 1.0 Hz, 1 H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J= 1.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1 H), 6.82 (d, J = 1.0 Hz, 1 H), 6.07 (br, 2H), 4.08 (d, J = 7.2 Hz, 2H), 3.90 (dt, J = 13.0, 3.5 Hz, 2H), 2.87 (td, J= 12.7, 2.7 Hz, 2H), 2.52 (d, J= 1.9 Hz, OH), 2.17 -2.06 (m, 1H), 1.57 (dd, J = 13.7, 3.5 Hz, 2H), 1.33 - 1.21 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 161.51, 157.23, 151.52, 150.25, 147.13, 144.35, 133.00, 130.26, 126.82, 123.67, 120.42, 115.43, 115.21, 108.57, 99.94, 48.92, 45.34, 35.92, 28.46. LRMS (ESI), m / z 431.30 (M+H).

[0766] 55718966-2

[0767]

[0768] Synthesis of cyclopropyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1299).

[0769] The synthesis of compound 1299 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, ) 58.15 (s, 1 H), 7.46 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.16 (br, 2H), 4.06 (d, J = 7.2 Hz, 2H), 3.96 (tt, J = 6.3, 3.2 Hz, 1 H), 3.84 - 3.77 (m, 2H), 2.70 (br, 2H), 2.13 -2.01 (m, 1H), 1.49 (d, J= 11.3 Hz, 2H), 1.17 - 1.08 (m, 2H), 0.65 - 0.54 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 156.74, 154.89, 150.80, 150.00, 147.17, 144.36, 130.05, 123.92, 120.41, 115.65, 115.21, 108.59, 99.82, 49.04, 48.94, 45.50, 43.09, 36.11, 29.10, 8.49, 4.88. LRMS (ESI), m / z 448.40 (M+H).

[0770]

[0771] Synthesis of tert-butyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-methylpiperidine-1 -carboxylate (compound 1305). The synthesis of compound 1305 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.45 (s, 2H), 7.40 (dd, J = 8.1, 0.5 Hz, 1H), 7.32 (s, 1H), 7.24 (dd, J = 1.8, 0.5 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1 H), 6.07 (br, 2H), 4.12 (ddd, J = 39.7, 13.6, 7.5 Hz, 2H), 3.79 - 3.69 (m, 1 H), 3.56 - 3.48 (m, 1H), 3.19 - 3.09 (m, 1H), 2.20 -2.11 (m, 1H), 1.69 - 1.55 (m, 2H), 1.37

[0772] 55718966-2 (s, 9H), 1.30 - 1.19 (m, 2H), 1.14 (d, J = 6.5 Hz, 3H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 157.19, 154.18, 151.46, 150.25, 147.12, 144.34, 130.26, 123.48, 120.42, 115.54, 115.23, 108.56, 99.89, 78.24, 48.55, 48.32, 36.63, 32.79, 32.55, 28.10, 26.46, 19.86. LRMS (ESI), m / z 478.40 (M+H).

[0773]

[0774] Synthesis of isopropyl 4-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-methylpiperidine-1 -carboxylate (compound 1308). The synthesis of compound 1308 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.33 (s, 1H), 7.24 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.11 (br, 2H), 4.74 (hept, J = 6.2 Hz, 1H), 4.12 (ddd, J = 37.7, 13.6, 7.5 Hz, 2H), 3.82 - 3.71 (m, 1H), 3.58 - 3.50 (m, 1H), 3.24 - 3.14 (m, 1H), 2.21 - 2.13 (m, 1H), 1.70 - 1.55 (m, 2H), 1.30 - 1.21 (m, 2H), 1.15 (dd, J = 6.3, 1.8 Hz, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.31, 157.05, 154.53, 151.26, 150.19, 147.14, 144.34, 130.20, 123.53, 120.42, 115.63, 115.23, 108.57, 99.85, 67.30, 48.69, 48.32, 36.82, 32.74, 32.54, 26.43, 21.96, 19.86. LRMS (ESI), m / z 464.50 (M+H).

[0775]

[0776] 55718966-2 Synthesis of isopropyl 3-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8 -carboxylate (compound 1311). The synthesis of compound 1311 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, ) 5 8.14 (s, 1H), 7.45 (s, 2H), 7.40 (dd, J = 8.1, 0.5 Hz, 1H), 7.31 (s, 1H), 7.23 (dd, J = 1.8, 0.6 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.13 (br, 2H), 4.77 (p, J = 6.3 Hz, 1H), 4.11 - 4.05 (m, 2H), 4.00 (d, J = 6.9 Hz, 2H), 2.49 - 2.43 (m, 1 H), 1.82 (br, 2H), 1.58 (br, 2H), 1.41 - 1.31 (m, 4H), 1.15 (d, J= 6.2 Hz, 6H).13C NMR (126 MHz, DMSO-d6) 5163.31, 156.69, 152.71, 150.73, 150.08, 147.16, 144.35, 130.09, 123.87, 120.40, 115.70, 115.21, 108.58, 99.71, 67.16, 52.84, 49.06, 45.58, 35.00, 34.22, 29.23, 27.91, 27.18, 21.98, 8.53.

[0777] LRMS (ESI), m / z 476.40 (M+H).

[0778]

[0779] Synthesis of cyclopropyl 3-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8 -carboxylate (compound 1312). The synthesis of compound 1312 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, ) 5 8.18 (s, 1H), 7.46 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.35 (s, 1H), 7.24 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 4.13 -3.99 (m, 4H), 2.48-2.43 (m, 1H), 1.81 (br, 2H), 1.57 (d, J = 7.7 Hz, 2H), 1.40 - 1.22 (m, 5H), 0.65 - 0.53 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 163.32, 156.02, 153.19, 149.77, 149.72, 147.22, 144.38, 129.82, 124.19, 120.42, 116.07, 115.23, 108.62, 99.55, 52.92, 49.15, 48.74, 45.56, 35.10, 34.29, 29.21, 27.88, 27.10, 8.52, 4.95. LRMS (ESI), m / z 474.40 (M+H).

[0780] 55718966-2

[0781]

[0782] Synthesis of 5-(4-amino-7-((1 -(thiazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (compound 1317). The synthesis of compound 1317 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, ) 58.14 (s, 1H), 7.45 (s, 2H), 7.40 (dd, J = 8.1, 0.5 Hz, 1H), 7.30 (s, 1H), 7.24 (dd, J = 1.8, 0.5 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1 H), 6.78 (d, J = 3.6 Hz, 1 H), 6.07 (br, 2H), 4.09 (d, J = 7.3 Hz, 2H), 3.87 (dt, J = 13.1, 3.4 Hz, 2H), 2.95 (td, J = 12.6, 2.8 Hz, 2H), 2.21 - 2.09 (m, 1H), 1.64 - 1.57 (m, 2H), 1.38 - 1.26 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 171.24, 163.31, 157.23, 151.53, 150.25, 147.13, 144.35, 139.44, 130.26, 123.68, 120.42, 115.44, 115.22, 108.57, 107.61, 99.95, 48.84, 48.15, 36.08, 28.42. LRMS (ESI), m / z 447.30 (M+H).

[0783]

[0784] Synthesis of isopropyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1320).

[0785] The synthesis of compound 1320 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.64 (s, 2H), 7.31 - 7.25 (m, 2H), 6.96 (dd, J = 8.1, 7.0 Hz, 1H), 5.99 (br, 2H), 4.74 (hept, J = 6.2 Hz, 1 H), 4.07 (d, J = 7.2 Hz, 2H), 3.94 (d, J = 13.2 Hz, 2H), 2.70 (br, 2H), 2.13 - 2.01 (m, 1H), 1.50 (d, J = 12.5 Hz, 2H), 1.16 (d, J = 6.3 Hz, 6H), 1.15 - 1.06 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.22, 157.21, 154.18, 151.57, 150.06, 149.44, 149.37, 148.41,

[0786] 55718966-2 146.46, 132.12, 131.98, 124.94, 122.18, 117.30, 117.20, 107.30, 105.06, 105.03, 100.87, 67.64, 49.00, 42.95, 36.19, 29.17, 21.97. LRMS (ESI), m / z 469.00 (M+H).

[0787]

[0788] Synthesis of 5-(4-amino-7-((8-(oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2 -amine (compound 1326). The synthesis of compound 1326 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 5 8.12 (s, 1H), 7.57 (d, J = 1.0 Hz, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (s, 1 H), 7.23 (d, J = 1.7 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.85 (d, J= 1.0 Hz, 1H), 6.07 (br, 2H), 4.23 -4.17 (m, 2H), 3.94 (d, J = 7.2 Hz, 2H), 2.49 - 2.43 (m, 1 H), 1.93 - 1.87 (m, 2H), 1.71 - 1.63 (m, 2H), 1.48 (td, J= 12.7, 2.8 Hz, 2H), 1.43 - 1.35 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.30, 159.60, 157.14, 151.38, 150.25, 147.11, 144.34, 133.41, 130.27, 126.88, 123.52, 120.42, 115.51, 115.22, 108.55, 99.80, 55.25, 49.06, 33.29, 29.27, 27.72. LRMS (ESI), m / z 457.40 (M+H).

[0789]

[0790] Synthesis of 5-(4-amino-7-((8-(thiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2 -amine (compound 1327). The synthesis of compound 1327 was accomplished using a procedure analogous to that

[0791] 55718966-2 described in Example 2.1H NMR (500 MHz, DMSO-d6) 58.11 (s, 1 H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.31 (s, 1H), 7.23 (d, J = 1.7 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 7.02 (dd, J = 8.1, 1.8 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.07 (br, 2H), 4.21 -4.15 (m, 2H), 3.94 (d, J = 7.3 Hz, 2H), 2.61 - 2.51 (m, 1 H), 1.97 - 1.91 (m, 2H), 1.74 - 1.66 (m, 2H), 1.60 (td, J = 12.8, 2.8 Hz, 2H), 1.43 - 1.35 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 167.18, 163.30, 157.13, 151.36, 150.24, 147.12, 144.34, 139.53, 130.27, 123.52, 120.42, 115.53, 115.22, 108.55, 107.92, 99.80, 57.09, 49.01, 32.55, 29.48, 27.74. LRMS (ESI), m / z 473.30 (M+H).

[0792]

[0793] Synthesis of 5-(4-amino-7-((8-(thiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1329). The synthesis of compound 1329 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1H), 7.64 (s, 2H), 7.32 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.13 (d, J = 3.6 Hz, 1H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.81 (d, J = 3.6 Hz, 1H), 6.02 (br, 2H), 4.22 -4.16 (m, 2H), 3.96 (d, J = 7.3 Hz, 2H), 2.61 - 2.51 (m, 1 H), 1.98 - 1.91 (m, 2H), 1.73 - 1.66 (m, 2H), 1.60 (td, J = 12.8, 2.9 Hz, 2H), 1.42 - 1.34 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 167.17, 163.22, 157.04, 151.31, 150.03, 149.45, 149.37, 148.40, 146.44, 139.52, 132.12, 124.80, 122.20, 117.30, 117.19, 107.93, 107.51, 105.03, 100.72, 57.07, 49.09, 32.51, 29.47, 27.75. LRMS (ESI), m / z 491.30 (M+H).

[0794] 55718966-2

[0795]

[0796] Synthesis of 5-(4-amino-7-((1 -(oxazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1330). The synthesis of compound 1330 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 5 8.14 (s, 1 H), 7.64 (s, 2H), 7.52 (d, J = 1.0 Hz, 1H), 7.31 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.1, 6.9 Hz, 1H), 6.82 (d, J = 1.0 Hz, 1H), 6.00 (br, 2H), 4.10 (d, J= 7.3 Hz, 2H), 3.90 (dt, J= 13.0, 3.5 Hz, 2H), 2.87 (td, J = 12.7, 2.7 Hz, 2H), 2.17 -2.05 (m, 1H), 1.60 - 1.53 (m, 2H), 1.33 - 1.21 (m, 2H).

[0797] 13C NMR (126 MHz, DMSO-d6) 5 163.23, 161.50, 157.22, 151.59, 150.08, 149.44, 149.37, 148.42, 146.46, 133.01, 131.99, 126.82, 124.92, 122.19, 117.31, 117.21, 107.35, 105.04, 100.87, 48.98, 45.32, 35.90, 28.42. LRMS (ESI), m / z 449.30 (M+H).

[0798]

[0799] Synthesis of 5-(4-amino-7-((1 -(thiazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1331). The synthesis of compound 1331 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 58.14 (s, 1 H), 7.64 (s, 2H), 7.32 (s, 1 H), 7.28 (d, J = 8.2 Hz, 1H), 7.12 (d, J = 3.6 Hz, 1H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 6.79 (d, J = 3.6 Hz, 1H), 6.00 (br, 2H), 4.11 (d, J = 7.2 Hz, 2H), 3.87 (dt, J = 13.1, 3.4 Hz, 2H), 2.95 (td, J = 12.7, 2.9 Hz, 2H), 2.22 - 2.09 (m, 1 H), 1.63 - 1.56 (m, 2H), 1.38 - 1.26 (m, 2H).

[0800] 13C NMR (126 MHz, DMSO-d6) 5 171.23, 163.23, 157.23, 151.61, 150.09, 149.45,

[0801] 55718966-2 149.38, 148.42, 146.46, 142.68, 139.44, 132.13, 131.99, 124.92, 122.20, 117.31, 117.21, 107.63, 107.36, 105.07, 100.88, 48.91, 48.13, 36.06, 28.37. LRMS (ESI), m / z 465.30 (M+H).

[0802]

[0803] Synthesis of 5-(4-amino-7-((1 -(5-methyloxazol-2-yl)piperidin-4-yl)methyl)-7H- pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (compound 1334). The synthesis of compound 1334 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.45 (s, 2H), 7.40 (dd, J = 8.1, 0.6 Hz, 1H), 7.29 (s, 1 H), 7.26 - 7.20 (m, 2H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.07 (br, 2H), 4.08 (dd, J= 6.2, 3.5 Hz, 2H), 3.87 (dt, J= 13.1, 3.3 Hz, 2H), 2.84 (td, J = 12.7, 2.7 Hz, 2H), 2.16-2.04 (m, 1H), 1.92 (d, J= 1.4 Hz, 3H), 1.59- 1.52 (m, 2H), 1.31 - 1.19 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5163.31, 160.95, 157.23, 151.53, 150.25, 147.12, 144.35, 135.42, 130.26, 128.13, 123.68, 120.41, 115.43, 115.21, 108.57, 99.94, 48.94, 45.22, 35.95, 28.47, 11.73. LRMS (ESI), m / z 445.30 (M+H).

[0804] H2N

[0805] Ck / / N

[0806]

[0807] Synthesis of 5-(4-amino-7-((1 -(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)benzo[d]oxazol-2-amine (compound 1335). The synthesis of compound 1335 was accomplished using a procedure

[0808] 55718966-2 analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1 H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.29 (s, 1H), 7.24 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.08 (br, 2H), 4.08 (d, J= 7.3 Hz, 2H), 3.78 (dt, J = 13.1, 3.6 Hz, 2H), 2.94 (td, J = 12.7, 2.7 Hz, 2H), 2.31 (s, 3H), 2.20 - 2.07 (m, 1 H), 1.62 - 1.54 (m, 2H), 1.36 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 164.01, 163.31, 157.33, 157.22, 151.51, 150.25, 147.13, 144.35, 130.24, 123.66, 120.41, 115.48, 115.21, 108.58, 99.94, 48.84, 45.65, 35.71, 28.22, 10.58. LRMS (ESI), m / z 446.30 (M+H).

[0809]

[0810] Synthesis of 5-(4-amino-7-((1 -(5-methyloxazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1336).

[0811] The synthesis of compound 1336 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1 H), 7.64 (s, 2H), 7.31 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.22 (q, J= 1.3 Hz, 1H), 6.96 (dd, J= 8.1, 7.0 Hz, 1 H), 6.00 (br, 2H), 4.09 (d, J = 7.3 Hz, 2H), 3.87 (dt, J = 13.0, 3.4 Hz, 2H), 2.84 (td, J = 12.7, 2.7 Hz, 2H), 2.16-2.03 (m, 1H), 1.92 (d, J= 1.4 Hz, 3H), 1.58- 1.51 (m, 2H), 1.31 - 1.19 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5163.23, 160.95, 157.23, 151.60, 150.08, 149.37, 148.42, 146.46, 135.43, 132.12, 131.99, 128.14, 124.93, 122.19, 117.31, 117.21, 107.34, 105.07, 100.87, 49.00, 45.20, 35.93, 28.43, 11.73. LRMS (ESI), m / z 463.40 (M+H).

[0812] 55718966-2

[0813]

[0814] Synthesis of 5-(4-amino-7-((1 -(5-methyl-1,3,4-oxadiazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1337). The synthesis of compound 1337 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.64 (s, 2H), 7.31 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 7.0 Hz, 1H), 6.01 (br, 2H), 4.10 (d, J = 7.3 Hz, 2H), 3.78 (dt, J = 13.1, 3.4 Hz, 2H), 2.94 (td, J = 12.7, 2.8 Hz, 2H), 2.31 (s, 3H), 2.20 - 2.07 (m, 1H), 1.61 - 1.54 (m, 2H), 1.36 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 164.00, 163.23, 157.34, 157.21, 151.57, 150.08, 149.45, 149.38, 148.41, 146.45, 132.13, 124.90, 122.19, 117.29, 117.19, 107.40, 105.06, 100.86, 48.91, 45.63, 35.69, 28.18, 10.59. LRMS (ESI), m / z 464.40 (M+H).

[0815]

[0816] Synthesis of tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1342).

[0817] The synthesis of compound 1342 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1H), 7.64 (s, 2H), 7.29 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 6.96 (dd, J = 8.1, 7.0 Hz, 1 H), 5.99 (br, 2H), 4.07 (d, J = 7.2 Hz, 2H), 3.91 (d, J = 13.1 Hz, 2H), 2.66 (br, 2H), 2.11 - 2.00 (m, 1H), 1.52 -1.44 (m, 2H), 1.38 (s, 9H), 1.16- 1.04 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.22,

[0818] 55718966-2 157.20, 153.79, 151.55, 150.05, 149.44, 149.37, 148.42, 146.46, 132.12, 131.98, 124.96, 122.19, 117.31, 117.20, 107.30, 105.06, 100.86, 78.47, 49.01, 36.24, 29.21, 28.06. LRMS (ESI), m / z 482.30 (M+H).

[0819]

[0820] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-aminobenzo[d]oxazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octane-8 -carboxylate (compound 1345). The synthesis of compound 1345 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.45 (s, 2H), 7.40 (d, J = 8.1 Hz, 1H), 7.30 (s, 1 H), 7.24 (d, J = 1.7 Hz, 1H), 7.03 (dd, J = 8.1, 1.8 Hz, 1H), 6.06 (br, 2H), 4.68 (t, J = 2.4 Hz, 2H), 4.14 (s, 2H), 3.99 (d, J = 7.2 Hz, 2H), 3.49 (t, J = 2.4 Hz, 1H), 2.50 - 2.43 (m, 1H), 1.87 - 1.81 (m, 2H), 1.66 - 1.57 (m, 2H), 1.43 - 1.36 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 163.30, 157.20, 151.74, 151.48, 150.28, 147.11, 144.34, 130.28, 123.49, 120.42, 115.52, 115.22, 108.55, 99.83, 79.30, 77.23, 53.11, 52.04, 49.00, 35.31, 34.45, 29.20, 27.93, 27.13. LRMS (ESI), m / z 472.40 (M+H).

[0821]

[0822] Synthesis of prop-2 -yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-1 -carboxylate (compound 1347). The synthesis of compound 1347 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1 H),

[0823] 55718966-2 7.64 (s, 2H), 7.29 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 7.0 Hz, 1H), 6.00 (br, 2H), 4.65 (d, J = 2.5 Hz, 2H), 4.08 (d, J = 7.2 Hz, 2H), 3.94 (s, 2H), 3.48 (t, J = 2.4 Hz, 1H), 2.77 (br, 2H), 2.16 - 2.03 (m, 1H), 1.52 (d, J = 12.5 Hz, 2H), 1.21 - 1.08 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.21, 153.59, 151.57, 150.07, 149.44, 149.37, 148.41, 146.45, 132.12, 131.99, 124.91, 122.19, 117.30, 117.20, 107.35, 105.07, 105.04, 100.86, 79.25, 77.23, 52.40, 48.92, 43.20, 36.03, 29.02. LRMS (ESI), m / z 464.40 (M+H).

[0824]

[0825] Synthesis of 2-methylbut-3-yn-2-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8- azabicyclo[3.2.1]octane-8-carboxylate (compound 1348). The synthesis of compound 1348 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.13 (s, 1 H), 7.64 (s, 2H), 7.32 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 5.99 (br, 2H), 4.09 -4.04 (m, 2H), 4.01 (d, J = 6.9 Hz, 2H), 3.42 (s, 1 H), 2.49 - 2.41 (m, 1 H), 1.83 (br, 2H), 1.59 (s, 6H), 1.44 - 1.37 (m, 6H).13C NMR (126 MHz, DMSO-d6) 5 163.21, 157.17, 151.51, 151.19, 150.11, 149.42, 149.35, 148.39, 146.44, 132.11, 131.98, 124.85, 122.18, 117.34, 117.23, 107.39, 105.04, 105.01, 100.77, 85.70, 74.39, 70.69, 53.27, 52.68, 49.16, 35.14, 34.34, 29.23, 28.80, 27.92, 27.17. LRMS (ESI), m / z 518.50 (M+H).

[0826] 55718966-2

[0827]

[0828] Synthesis of tert-butyl 2-(3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-8-azabicyclo[3.2.1]octan-8-yl)acetate (compound 1372). The synthesis of compound 1372 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.64 (s, 2H), 7.30 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.2, 7.0 Hz, 1H), 5.98 (br, 2H), 4.02 (d, J = 7.3 Hz, 2H), 3.21 (s, 0H), 2.29 - 2.17 (m, 2H), 1.85 (br, 2H), 1.62 - 1.43 (m, 5H), 1.41 (s, 9H), 1.33 - 1.20 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 163.21, 157.18, 151.50, 150.10, 149.41, 149.34, 148.39, 146.44, 132.12, 131.99, 124.83, 122.18, 117.35, 117.25, 107.32, 105.04, 105.01, 100.78, 59.31, 53.53, 49.10, 34.08, 30.92, 28.54, 27.75, 25.88. LRMS (ESI), m / z 523.1 (M+H).

[0829]

[0830] Synthesis of tert-butyl 6-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-azaspiro[3.3]heptane-2 -carboxylate (compound 1374). The synthesis of compound 1374 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.64 (s, 2H), 7.32 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.03 (br, 2H), 4.16 (d, J = 7.4 Hz, 2H), 3.81 (s, 2H), 3.76 (s, 2H), 2.68 - 2.55 (m, 1H), 2.22 -2.15 (m, 2H), 2.03 - 1.96 (m, 2H), 1.35 (s, 9H).13C NMR (126 MHz, DMSO-

[0831] 55718966-2 d6) 5 163.21, 156.94, 155.37, 151.22, 149.79, 149.44, 149.37, 148.41, 146.45, 132.12, 131.98, 124.51, 122.14, 117.24, 117.13, 107.52, 105.05, 105.02, 100.79, 78.32, 61.11, 48.49, 35.75, 33.74, 29.57, 28.03. LRMS (ESI), m / z 494.40 (M+H).

[0832]

[0833] Synthesis of tert-butyl 6-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 1375). The synthesis of compound 1375 was accomplished using a procedure analogous to that described in Example 6.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.64 (s, 2H), 7.40 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.1, 6.9 Hz, 1H), 6.02 (br, 2H), 4.10 (dd, J = 14.3, 7.1 Hz, 1H), 3.37 (t, J = 9.6 Hz, 2H), 3.30 - 3.20 (m, 3H), 1.72 - 1.68 (m, 2H), 1.34 (s, 9H), 1.08 - 1.00 (m, 1H).13C NMR (126 MHz, DMSO-d6) δ 163.20, 157.07, 153.75, 151.40, 149.72, 149.44, 149.37, 148.41, 146.46, 132.12, 131.98, 124.25, 122.19, 117.31, 117.21, 107.62, 105.06, 105.03, 100.85, 78.41, 47.73, 47.57, 45.05, 28.05, 22.67, 21.73, 20.86. LRMS (ESI), m / z 480.40 (M+H).

[0834] HoN

[0835]

[0836] Synthesis of tert-butyl 6-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azaspiro[3.3]heptane-2 -carboxylate (compound 1376). The synthesis of compound 1376 was accomplished using a procedure

[0837] 55718966-2 analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1 H), 7.64 (s, 2H), 7.54 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 6.04 (br, 2H), 5.10 (p, J = 8.6 Hz, 1 H), 4.01 (s, 2H), 3.86 (s, 2H), 2.77 - 2.65 (m, 4H), 1.38 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.20, 156.97, 155.40, 151.11, 149.63, 149.52, 149.45, 148.41, 146.45, 132.09, 131.96, 122.19, 121.90, 117.20, 117.10, 108.28, 105.04, 101.10, 78.42, 42.95, 40.32, 31.09, 28.05, 21.37. LRMS (ESI), m / z 480.50 (M+H).

[0838]

[0839] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)azetidine-1 -carboxylate (compound 1378). The synthesis of compound 1378 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) 58.15 (s, 1H), 7.64 (s, 2H), 7.40 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J= 8.2, 6.9 Hz, 1H), 6.05 (br, 2H), 4.39 (d, J = 7.3 Hz, 2H), 3.88 (br, 2H), 3.75 - 3.69 (m, 2H), 3.09 - 2.97 (m, 1 H), 1.36 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.21, 157.09, 155.54, 151.46, 149.94, 149.48, 149.41, 148.41, 146.44, 132.11, 131.98, 124.48, 122.14, 117.16, 117.05, 107.80, 105.07, 100.89, 78.47, 51.56, 46.67, 28.79, 28.03. LRMS (ESI), m / z 454.20 (M+H).

[0840]

[0841] 55718966-2 Synthesis of tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1379). The synthesis of compound 1379 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1 H), 7.64 (s, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.21 (d, J= 1.4 Hz, 1H), 6.97 (dd, J= 8.1, 7.0 Hz, 1 H), 6.09 (br, 2H), 4.45 (d, J = 22.1 Hz, 2H), 3.79 (d, J = 13.3 Hz, 2H), 2.96 (br, 2H), 1.75 - 1.55 (m, 4H), 1.39 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.04, 153.68, 151.46, 150.54, 149.55, 149.47, 148.41, 146.45, 132.13, 131.99, 125.22, 122.14, 116.96, 116.86, 108.10, 105.11, 105.08, 100.53, 94.78, 93.38, 78.85, 50.35, 50.18, 31.96, 31.79, 28.02. LRMS (ESI), m / z 500.40 (M+H).

[0842]

[0843] Synthesis of tert-butyl (4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)butyl)(methyl)carbamate (compound 1380). The synthesis of compound 1380 was accomplished using a procedure analogous to that described in Example 6.1H NMR (500 MHz, DMSO-d6) 58.14 (s, 1H), 7.63 (s, 2H), 7.33 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1 H), 6.95 (t, J = 7.5 Hz, 1 H), 6.05 (br, 2H), 4.20 (t, J = 7.0 Hz, 2H), 3.16 (t, J = 7.1 Hz, 2H), 2.71 (s, 3H), 1.75 (t, J = 7.7 Hz, 2H), 1.48 - 1.40 (m, 2H), 1.39 - 1.27 (m, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.20, 156.21, 154.77, 150.16, 149.52, 149.45, 148.41, 146.45, 132.13, 131.99, 124.77, 122.10, 117.01, 116.91, 108.01, 105.09, 105.06, 100.67, 78.26, 47.76, 46.97, 43.54, 33.72, 27.98, 26.92, 24.58, 24.12. LRMS (ESI), m / z 470.40 (M+H).

[0844] 55718966-2

[0845]

[0846] Synthesis of 5-(4-amino-7-((8-(4-methyloxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1381). The synthesis of compound 1381 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.13 (d, J = 6.1 Hz, 1H), 7.64 (s, 2H), 7.32 (d, J = 1.8 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.26 (q, J = 1.3 Hz, 1H), 6.95 (ddd, J = 8.1, 6.9, 3.1 Hz, 1H), 6.04 (br, 2H), 4.20 - 4.15 (m, 1H), 4.13 - 4.06 (m, 1H), 3.98 (dd, J = 14.9, 7.3 Hz, 2H), 2.50 - 2.40 (m, 1H), 1.95 (d, J = 1.1 Hz, 3H), 1.93 - 1.86 (m, 1H), 1.82 - 1.73 (m, 1H), 1.65 (d, J = 7.6 Hz, 1H), 1.57 - 1.33 (m, 3H), 1.31 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.21, 158.98, 156.23, 149.87, 149.47, 149.40, 148.39, 146.43, 135.38, 132.11, 131.98, 128.54, 125.01, 122.17, 117.17, 117.06, 107.64, 105.06, 100.63, 55.01, 52.23, 49.43, 49.16, 34.16, 33.26, 29.26, 27.85, 27.72, 11.72. LRMS (ESI), m / z 489.40 (M+H).

[0847]

[0848] Synthesis of 5-(4-amino-7-((8-(4,5-dimethyloxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyirolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1382). The synthesis of compound 1382 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 6.0 Hz, 1H), 7.64 (s, 2H), 7.33 (d, J = 2.7 Hz, 1H), 7.28 (d, J = 8.1 Hz, 1H), 7.00 - 6.92 (m, 1 H), 6.07 (br, 2H), 4.16 - 4.07 (m, 2H), 3.99 (d, J = 7.3 Hz, 1 H), 3.97 (d,

[0849] 55718966-2 J = 7.2 Hz, 1H), 2.50 - 2.40 (m, 1H), 2.10 (d, J= 0.8 Hz, 3H), 1.93 - 1.83 (m, 3H), 1.82 - 1.74 (m, 1 H), 1.63 (d, J = 7.7 Hz, 1 H), 1.57 - 1.32 (m, 4H), 1.31 - 1.22 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.21, 157.10, 156.53, 156.52, 156.23, 150.59, 149.80, 149.48, 149.41, 148.39, 146.43, 136.08, 132.12, 131.99, 125.08, 122.16, 117.12, 117.01, 107.72, 105.07, 105.04, 100.60, 54.94, 52.23, 49.44, 49.18, 34.15, 33.16, 29.25, 27.84, 27.71, 21.02, 11.12, 9.52. LRMS (ESI), m / z 503.40 (M+H).

[0850]

[0851] Synthesis of 5-(4-amino-7-((8-(benzo[d]oxazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-7H-pyirolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1383). The synthesis of compound 1383 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.11 (s, 1H), 7.64 (s, 2H), 7.41 (dd, J = 8.0, 1.0 Hz, 1H), 7.33 - 7.30 (m, 2H), 7.26 (d, J = 8.1 Hz, 1H), 7.16 (td, J = 7.7, 1.2 Hz, 1H), 7.03 (td, J = 7.7, 1.3 Hz, 1H), 6.92 (dd, J = 8.1, 7.0 Hz, 1H), 6.02 (br, 2H), 4.44 -4.37 (m, 2H), 3.99 (d, J = 7.3 Hz, 2H), 2.63 -2.51 (m, 1 H), 2.04 - 1.97 (m, 2H), 1.78 - 1.70 (m, 2H), 1.64 - 1.55 (m, 2H), 1.50 - 1.41 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.20, 159.60, 156.54, 150.62, 149.76, 149.48, 149.41, 148.50, 148.38, 146.42, 143.18, 132.11, 131.98, 125.10, 123.83, 122.15, 120.48, 117.08, 116.99, 115.87, 108.89, 107.72, 105.06, 105.03, 100.63, 55.23, 49.03, 33.67, 29.19, 27.71. LRMS (ESI), m / z 525.40 (M+H).

[0852] 55718966-2

[0853]

[0854] Synthesis of prop-2 -yn-1-yl 6-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 1391). The synthesis of compound 1391 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1H), 7.63 (s, 2H), 7.31 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 7.0 Hz, 1 H), 5.99 (br, 2H), 4.59 (d, J = 2.4 Hz, 2H), 4.16 (d, J = 7.5 Hz, 2H), 3.96 - 3.84 (m, 4H), 3.47 (t, J = 2.4 Hz, 1H), 2.69 - 2.56 (m, 1H), 2.24 - 2.17 (m, 2H), 2.06 - 1.98 (m, 2H).

[0855] 13C NMR (126 MHz, DMSO-d6) 5 163.20, 157.14, 154.62, 151.50, 149.87, 149.42, 149.35, 148.40, 146.44, 132.10, 131.97, 124.38, 122.15, 117.30, 117.20, 107.42, 105.05, 105.01, 100.83, 79.15, 77.26, 51.90, 48.46, 35.76, 34.25, 29.56. LRMS (ESI), m / z 476.50 (M+H).

[0856]

[0857] Synthesis of prop-2 -yn-1-yl 6-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-azabicyclo[3.1.0]hexane-3-carboxylate (compound 1392). The synthesis of compound 1392 was accomplished using a procedure analogous to that described in Example 6. LRMS (ESI), m / z 462.20 (M+H).

[0858] 55718966-2

[0859]

[0860] Synthesis of prop-2-yn-1-yl 6-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-2-azaspiro[3.3]heptane-2-carboxylate (compound 1393). The synthesis of compound 1393 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.12 (s, 1 H), 7.64 (s, 2H), 7.54 (s, 1H), 7.28 (d, J = 8.2 Hz, 1H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 6.00 (br, 2H), 5.18 - 5.06 (m, 1H), 4.63 (d, J = 2.5 Hz, 2H), 4.12 (br, 2H), 3.97 (br, 2H), 3.49 (t, J = 2.4 Hz, 1 H), 2.79 -2.68 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5163.20, 157.22, 154.66, 151.45, 149.74, 149.49, 149.42, 148.40, 146.44, 132.08, 131.95, 122.19, 121.78, 117.29, 117.18, 108.17, 105.03, 105.00, 101.14, 101.11, 79.16, 77.30, 61.28, 59.90, 51.96, 42.85, 40.32, 31.62. LRMS (ESI), m / z 462.50 (M+H).

[0861]

[0862] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)azetidine-1 -carboxylate (compound 1395).

[0863] The synthesis of compound 1395 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.64 (s, 2H), 7.39 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (ddd, J = 8.4, 6.9, 1.4 Hz, 1H), 6.03 (br, 2H), 4.62 (d, J = 2.4 Hz, 2H), 4.41 (d, J = 7.3 Hz, 2H), 4.05 - 3.92 (m, 2H), 3.83 (br, 2H), 3.49

[0864] 55718966-2 (t, J = 2.4 Hz, 1H), 3.15 -3.03 (m, 1 H).13C NMR (126 MHz, DMSO-d6) δ 163.21, 157.22, 154.81, 151.65, 149.99, 149.47, 148.40, 146.44, 132.10, 131.97, 124.37, 122.16, 117.07, 107.78, 105.06, 100.94, 79.09, 77.35, 51.97, 46.61, 29.26. LRMS (ESI), m / z 436.20 (M+H).

[0865]

[0866] Synthesis of prop-2 -yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1396). The synthesis of compound 1396 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.64 (s, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 1.4 Hz, 1H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 6.05 (br, 2H), 4.67 (d, J = 2.5 Hz, 2H), 4.45 (d, J = 22.3 Hz, 2H), 3.84 (d, J= 13.2 Hz, 2H), 3.50 (t, J = 2.4 Hz, 1H), 3.04 (br, 2H), 1.81 - 1.58 (m, 4H).13C NMR (126 MHz, DMSO-d6) δ 163.22, 157.27, 153.54, 151.78, 150.64, 149.52, 149.45, 148.41, 146.45, 132.12, 131.99, 125.09, 122.15, 117.04, 116.94, 108.02, 105.10, 105.07, 100.57, 94.65, 93.25, 79.12, 77.36, 52.60, 50.30, 50.12, 31.75. LRMS (ESI), m / z 482.40 (M+H).

[0867]

[0868] Synthesis of prop-2 -yn-1-yl (4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)butyl)(methyl)carbamate (compound 1397). The

[0869] 55718966-2 synthesis of compound 1397 was accomplished using a procedure analogous to that described in Example 6.1H NMR (500 MHz, DMSO-d6) δ 8.16 (s, 1H), 7.64 (s, 2H), 7.35 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J= 8.1, 6.9 Hz, 1H), 6.11 (br, 2H), 4.63 (d, J = 2.5 Hz, 2H), 4.20 (t, J = 7.0 Hz, 2H), 3.42 (d, J = 22.5 Hz, 1 H), 3.24 (t, J = 7.2 Hz, 2H), 2.79 (s, 3H), 1.76 (p, J = 7.6 Hz, 2H), 1.46 (p, J = 7.5 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.20, 156.71, 154.64, 150.87, 149.65, 149.48, 149.41, 148.41, 146.45, 132.11, 131.98, 124.51, 122.16, 117.08, 107.77, 105.08, 100.78, 79.27, 77.12, 52.33, 47.91, 47.37, 43.42, 34.19, 33.50, 26.91, 24.49, 24.02. LRMS (ESI), m / z 452.30 (M+H).

[0870]

[0871] Synthesis of tert-butyl 8-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (compound 1398). The synthesis of compound 1398 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.64 (s, 2H), 7.33 (s, 1 H), 7.28 (dd, J = 8.1, 1.6 Hz, 1H), 7.00 - 6.93 (m, 1 H), 6.01 (br, 2H), 3.99 (d, J = 7.9 Hz, 2H), 3.73 (dd, J = 36.8, 12.5 Hz, 2H), 2.79 (d, J = 12.2 Hz, 1H), 2.64 (d, J = 12.5 Hz, 1H), 2.28 - 2.18 (m, 2H), 1.97 - 1.88 (m, 5H), 1.38 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 163.21, 157.17, 154.97, 151.57, 150.08, 149.43, 149.36, 148.40, 146.44, 132.11, 131.98, 124.59, 122.20, 117.30, 117.19, 107.56, 105.05, 105.02, 100.77, 78.42, 49.11, 45.25, 43.14, 36.13, 28.05. LRMS (ESI), m / z 508.50 (M+H).

[0872] 55718966-2

[0873]

[0874] Synthesis of prop-2 -yn-1-yl 8-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-azabicyclo[3.2.1]octane-3-carboxylate (compound 1404). The synthesis of compound 1404 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.64 (s, 2H), 7.34 (s, 1 H), 7.28 (dd, J = 8.2, 2.1 Hz, 1H), 7.01 - 6.93 (m, 1 H), 6.00 (br, 2H), 4.64 (dd, J = 2.5, 1.0 Hz, 2H), 4.00 (d, J = 8.0 Hz, 2H), 3.78 - 3.66 (m, 2H), 3.47 (t, J = 2.4 Hz, 1 H), 2.91 - 2.85 (m, 1 H), 2.81 - 2.75 (m, 1 H), 2.32 - 2.22 (m, 1H), 1.96 (d, J = 7.1 Hz, 4H), 1.49 - 1.35 (m, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.20, 157.21, 154.85, 151.63, 150.11, 149.43, 149.35, 148.39, 146.43, 132.11, 131.98, 124.57, 122.19, 117.30, 117.20, 107.58, 105.05, 105.02, 100.78, 79.24, 77.15, 52.39, 48.83, 45.19, 35.96, 34.55, 34.41, 27.43, 25.01. LRMS (ESI), m / z 490.20 (M+H).

[0875]

[0876] Synthesis of 5-(7-((8-(1,3,4-oxadiazol-2-yl)-8-azabicyclo[3.2.1]octan-3-yl)methyl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1412). The synthesis of compound 1412 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.66 (s, 1H), 8.12 (s, 1H), 7.64 (s, 2H), 7.31 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 5.98 (br, 2H), 4.23 - 4.17 (m, 2H), 3.98 (d, J = 7.2 Hz, 2H), 2.58 -2.50 (m, 1H), 1.98 - 1.92 (m, 2H), 1.75 - 1.66 (m, 2H), 1.51 (td, J = 12.7, 2.9 Hz, 2H),

[0877] 55718966-2 1.45 - 1.36 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.20, 161.66, 157.19, 151.53, 150.08, 149.41, 149.34, 149.07, 148.38, 146.42, 132.10, 131.97, 124.72, 122.18, 117.32, 117.22, 107.42, 105.04, 105.01, 100.75, 55.87, 48.93, 33.05, 29.11, 27.69.

[0878] LRMS (ESI), m / z 476.70 (M+H).

[0879]

[0880] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoroazetidine-1 -carboxylate (compound 1421). The synthesis of compound 1421 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1 H), 7.64 (s, 2H), 7.33 - 7.26 (m, 2H), 6.96 (dd, J = 8.1, 7.0 Hz, 1H), 6.09 (br, 2H), 4.70 (d, J = 21.0 Hz, 2H), 4.26 (ddd, J = 18.9, 10.2, 1.3 Hz, 2H), 3.93 (dd, J = 21.4, 10.2 Hz, 2H), 1.38 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.31, 155.56, 155.54, 151.88, 150.41, 149.56, 149.48, 148.41, 146.45, 132.12, 131.99, 124.76, 122.12, 116.92, 116.82, 108.34, 105.10, 105.07, 100.76, 91.97, 90.31, 79.26, 58.05, 47.07, 46.87, 27.92.

[0881] LRMS (ESI), m / z 472.50 (M+H).

[0882]

[0883] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-fluoroazetidine-1 -carboxylate (compound 1423). The synthesis of compound 1423 was accomplished using a

[0884] 55718966-2 procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.18 (s, 1H), 7.64 (s, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 8.1, 6.9 Hz, 1H), 6.10 (br, 2H), 4.74 (d, J = 21.6 Hz, 2H), 4.66 (d, J = 2.5 Hz, 2H), 4.38 (dd, J = 18.6, 10.2 Hz, 2H), 4.07 - 4.01 (m, 2H), 3.53 (t, J = 2.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) δ 163.22, 157.26, 154.97, 154.94, 151.84, 150.39, 149.56, 149.49, 148.41, 146.45, 132.12, 131.99, 124.82, 122.14, 116.89, 116.79, 108.37, 105.11, 105.07, 100.77, 92.13, 90.46, 78.83, 77.62, 58.21, 52.44, 47.13, 46.94. LRMS (ESI), m / z 454.50 (M+H).

[0885]

[0886] Synthesis of tert-butyl ((1s,4s)-4-(4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)cyclohexyl)(methyl)carbamate (compound 1424). The synthesis of compound 1424 was accomplished using a procedure analogous to that described in Example 6.1H NMR (500 MHz, DMSO-d6) δ 8.13 (s, 1 H), 7.63 (s, 2H), 7.50 (s, 1 H), 7.29 (d, J = 8.2 Hz, 1 H), 6.99 (dd, J = 8.2, 6.9 Hz, 1 H), 5.98 (br, 2H), 4.79 (p, J = 4.2 Hz, 1 H), 2.72 (s, 3H), 2.44 - 2.37 (m, 2H), 2.01 - 1.91 (m, 2H), 1.83 - 1.71 (m, 2H), 1.62 - 1.54 (m, 2H), 1.44 - 1.41 (m, 1H), 1.39 (s, 9H).13C NMR (126 MHz, DMSO-d6) δ 163.19, 157.22, 154.58, 151.25, 150.00, 149.44, 149.36, 148.50, 146.54, 132.11, 131.97, 122.85, 122.31, 117.45, 117.35, 107.32, 105.01, 104.98, 101.19, 78.45, 52.83, 48.63, 29.15, 28.62, 28.10, 25.29. LRMS (ESI), m / z 496.60 (M+H).

[0887] 55718966-2

[0888]

[0889] Synthesis of 5-(4-amino-7-((1 -(4,5-dimethyloxazol-2-yl)-4-fluoropiperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1428). The synthesis of compound 1428 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) δ 8.15 (s, 1H), 7.64 (s, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.21 (d, J = 1.5 Hz, 1H), 6.97 (dd, J = 8.1, 6.9 Hz, 1H), 6.05 (br, 2H), 4.46 (d, J = 22.5 Hz, 2H), 3.72 (dt, J = 13.3, 4.0 Hz, 2H), 3.08 (ddd, J = 14.8, 12.0, 3.0 Hz, 2H), 2.10 (d, J= 1.2 Hz, 3H), 1.87 (d, J = 1.2 Hz, 3H), 1.86 - 1.70 (m, 2H), 1.64 (dd, J = 13.6, 10.0 Hz, 2H).13C NMR (126 MHz, DMSO-d6) δ 163.22, 158.73, 157.28, 151.78, 150.65, 149.52, 149.45, 148.41, 146.45, 136.12, 132.12, 131.99, 129.07, 125.10, 122.15, 117.05, 116.94, 108.01, 105.10, 105.07, 100.56, 94.59, 93.20, 50.34, 50.17, 41.47, 31.07, 30.90, 11.16, 9.51. LRMS (ESI), m / z 495.50 (M+H).

[0890]

[0891] Synthesis of tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H- pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methylpiperidine-1 -carboxylate (compound 1429). The synthesis of compound 1429 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-d6) δ 8.14 (s, 1 H), 7.64 (s, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.24 (s, 1H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 5.99

[0892] 55718966-2 (br, 2H), 4.09 (s, 2H), 3.70 - 3.61 (m, 2H), 3.09 (br, 2H), 1.47 - 1.40 (m, 2H), 1.37 (s, 9H), 1.32 - 1.21 (m, 2H), 0.95 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.19, 153.88, 151.53, 150.80, 149.45, 149.38, 148.43, 146.47, 132.12, 131.98, 125.94, 122.19, 117.25, 117.15, 107.23, 105.05, 105.01, 100.53, 78.46, 53.29, 34.40, 28.06, 21.78. LRMS (ESI), m / z 496.40 (M+H).

[0893]

[0894] Synthesis of prop-2 -yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-methylpiperidine-1 -carboxylate (compound 1431). The synthesis of compound 1431 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 5 8.18 (s, 1H), 7.64 (s, 2H), 7.28 (d, J = 8.0 Hz, 2H), 6.96 (dd, J = 8.1, 6.9 Hz, 1H), 6.10 (br, 2H), 4.74 (d, J = 21.6 Hz, 2H), 4.66 (d, J = 2.5 Hz, 2H), 4.38 (dd, J = 18.6, 10.2 Hz, 2H), 4.08 - 4.01 (m, 2H), 3.53 (t, J = 2.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 157.26, 154.97, 154.94, 151.84, 150.39, 149.56, 149.49, 148.41, 146.45, 132.12, 131.99, 124.82, 122.14, 116.89, 116.79, 108.37, 105.11, 105.07, 100.77, 92.13, 90.46, 78.83, 77.62, 58.21, 52.44, 47.13, 46.94. LRMS (ESI), m / z 478.40 (M+H).

[0895]

[0896] 55718966-2 Synthesis of 5-(4-amino-7-((4-fluoro-1 -(1,3,4-oxadiazol-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1433). The synthesis of compound 1433 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-de) 58.15 (s, 1 H), 8.00 (s, 1 H), 7.64 (s, 2H), 7.29 (d, J = 8.2 Hz, 1 H), 7.20 (d, J = 1.5 Hz, 1 H), 6.97 (dd, J = 8.1, 7.0 Hz, 1H), 6.05 (br, 2H), 4.47 (d, J = 22.1 Hz, 2H), 4.01 (dt, J = 13.8, 4.2 Hz, 1H), 3.62 (dt, J= 14.2, 4.2 Hz, 1H), 3.25 -3.15 (m, 1H), 2.90 -2.81 (m, 1H), 1.81 - 1.54 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 163.22, 160.78, 157.28, 151.79, 150.64, 149.53, 149.46, 148.42, 146.46, 132.13, 131.99, 125.07, 122.15, 117.03, 116.93, 108.05, 105.10, 100.58, 95.48, 94.08, 50.25, 40.54, 34.52, 32.64, 32.47, 31.44, 31.27.

[0897] LRMS (ESI), m / z 468.40 (M+H).

[0898]

[0899] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-methoxyazetidine-1 -carboxylate (compound 1436). The synthesis of compound 1436 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.17 (s, 1H), 7.64 (s, 2H), 7.31 - 7.24 (m, 2H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.06 (br, 2H), 4.55 (s, 2H), 3.96 (d, J = 9.4 Hz, 2H), 3.79 (d, J = 9.4 Hz, 2H), 3.34 (s, 3H), 1.36 (s, 9H).13C NMR (126 MHz, DMSO-de) 5 163.21, 157.21, 155.66, 151.59, 150.47, 149.50, 149.43, 148.41, 146.44, 132.13, 132.00, 124.96, 122.14, 117.09, 116.98, 107.98, 105.08, 105.05, 100.60, 78.85, 74.68, 55.62, 50.75, 45.67, 27.96. LRMS (ESI), m / z 484.50 (M+H).

[0900] 55718966-2

[0901]

[0902] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-cyanoazetidine-1 -carboxylate (compound 1437). The synthesis of compound 1437 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 58.18 (s, 1 H), 7.65 (s, 2H), 7.37 (s, 1H), 7.30 (d, J = 8.2 Hz, 1H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 6.13 (br, 2H), 4.78 (s, 2H), 4.32 (d, J = 8.9 Hz, 2H), 4.16 (d, J = 9.0 Hz, 2H), 1.37 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.24, 157.38, 155.22, 151.94, 150.49, 149.62, 149.54, 148.41, 146.44, 132.16, 132.03, 124.35, 122.05, 120.49, 116.80, 116.70, 108.63, 105.13, 100.88, 79.57, 56.25, 46.79, 32.22, 27.89. LRMS (ESI), m / z 479.60 (M+H).

[0903]

[0904] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-methylazetidine-1 -carboxylate (compound 1442). The synthesis of compound 1442 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 58.15 (s, 1 H), 7.64 (s, 2H), 7.35 (s, 1H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 6.9 Hz, 1H), 6.03 (br, 2H), 4.33 (s, 2H), 3.98 (d, J = 8.4 Hz, 2H), 3.47 (br, 2H), 1.33 (s, 9H), 1.17 (s, 3H).

[0905] 13C NMR (126 MHz, DMSO-de) 5 163.22, 157.25, 155.69, 151.64, 150.46, 149.49, 149.42, 148.42, 146.46, 132.12, 131.98, 125.08, 122.16, 117.17, 117.06, 107.74,

[0906] 55718966-2 105.05, 105.02, 100.72, 78.42, 58.51, 50.42, 35.25, 28.00, 22.87. LRMS (ESI), m / z 468.50 (M+H).

[0907]

[0908] Synthesis of tert-butyl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxyazetidine-1 -carboxylate (compound 1443). The synthesis of compound 1443 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.16 (s, 1H), 7.64 (s, 2H), 7.31 - 7.26 (m, 2H), 6.95 (dd, J = 8.1, 7.0 Hz, 1H), 6.17 (s, 1H), 6.04 (br, 2H), 4.39 (s, 2H), 3.99 (d, J = 8.9 Hz, 2H), 3.66 (d, J = 8.9 Hz, 2H), 1.35 (s, 9H).13C NMR (126 MHz, DMSO-de) 5 163.21, 157.24, 155.76, 151.59, 150.40, 149.46, 149.38, 148.40, 146.44, 132.13, 131.99, 125.56, 122.11, 117.19, 117.09, 107.53, 105.09, 105.06, 100.64, 78.62, 69.00, 59.92, 49.87, 27.99. LRMS (ESI), m / z 470.50 (M+H).

[0909]

[0910] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-methylazetidine-1 -carboxylate (compound 1446). The synthesis of compound 1446 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.16 (s, 1H), 7.64 (s, 2H), 7.35 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 6.9 Hz, 1H), 6.05 (br, 2H), 4.61 (d, J = 2.5 Hz, 2H), 4.37 (s, 2H), 4.10 (br, 2H), 3.57 (br, 2H), 3.48

[0911] 55718966-2 (t, J = 2.4 Hz, 1 H), 1.19 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5163.21, 157.23, 154.92, 151.65, 150.44, 149.50, 149.43, 148.42, 146.46, 132.11, 131.98, 125.11, 122.20, 117.12, 117.02, 107.81, 105.06, 105.03, 100.72, 79.08, 77.34, 57.84, 51.98, 50.47, 35.72, 22.64. LRMS (ESI), m / z 450.60 (M+H).

[0912]

[0913] Synthesis of but-2-yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-methylazetidine-1 -carboxylate (compound 1447). The synthesis of compound 1447 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.15 (s, 1H), 7.64 (s, 2H), 7.35 (s, 1 H), 7.28 (d, J = 8.1 Hz, 1H), 6.96 (dd, J = 8.1, 7.0 Hz, 1 H), 6.04 (br, 2H), 4.56 (q, J = 2.4 Hz, 2H), 4.36 (s, 2H), 4.09 (br, 2H), 3.57 (br, 2H), 1.81 (t, J= 2.4 Hz, 3H), 1.18 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5163.21, 157.26, 155.14, 151.70, 150.45, 149.50, 149.42, 148.42, 146.46, 132.12, 131.98, 125.10, 122.18, 117.14, 117.04, 107.78, 105.06, 105.03, 100.72, 82.73, 74.59, 57.83, 52.53, 50.48, 35.68, 22.67, 3.09. LRMS (ESI), m / z 464.70 (M+H).

[0914]

[0915] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxyazetidine-1 -carboxylate (compound 1448). The synthesis of compound 1448 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6

[0916] 55718966-2 8.16 (s, 1H), 7.63 (s, 2H), 7.34 - 7.25 (m, 2H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 6.26 (s, 1 H), 6.05 (br, 2H), 4.62 (d, J = 2.5 Hz, 2H), 4.43 (s, 2H), 4.11 (br, 2H), 3.75 (br, 2H), 3.50 (t, J = 2.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.20, 157.25, 154.99, 151.66, 150.39, 149.45, 149.38, 148.40, 146.44, 132.12, 131.98, 125.57, 122.13, 117.17, 117.07, 107.55, 105.09, 105.05, 100.64, 79.05, 77.39, 69.35, 60.19, 52.12, 49.87. LRMS (ESI), m / z 452.30 (M+H).

[0917]

[0918] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-methoxyazetidine-1 -carboxylate (compound 1449). The synthesis of compound 1449 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.17 (s, 1H), 7.64 (s, 2H), 7.32 - 7.23 (m, 2H), 6.96 (dd, J = 8.1, 6.9 Hz, 1H), 6.07 (br, 2H), 4.64 (d, J = 2.5 Hz, 2H), 4.58 (s, 2H), 4.08 (br, 2H), 3.91 (br, 2H), 3.51 (t, J = 2.4 Hz, 1H), 3.35 (s, 3H).13C NMR (126 MHz, DMSO-d6) 5 163.21, 157.19, 154.94, 151.61, 150.45, 149.51, 149.44, 148.41, 146.45, 132.12, 131.99, 124.99, 122.16, 117.06, 116.96, 108.01, 105.08, 105.05, 100.59, 78.96, 77.48, 74.96, 56.16, 52.24, 50.82, 45.79.

[0919] LRMS (ESI), m / z 466.60 (M+H).

[0920]

[0921] Synthesis of prop-2 -yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-cyanoazetidine-1 -carboxylate

[0922] 55718966-2 (compound 1450). The synthesis of compound 1450 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.19 (s, 1H), 7.65 (s, 2H), 7.35 (s, 1H), 7.29 (d, J = 8.2 Hz, 1H), 6.96 (dd, J= 8.1, 6.9 Hz, 1 H), 6.14 (br, 2H), 4.82 (s, 2H), 4.67 (d, J = 2.4 Hz, 2H), 4.44 (d, J = 8.7 Hz, 2H), 4.28 (br, 2H), 3.54 (t, J = 2.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.23, 157.37, 154.74, 151.98, 150.47, 149.62, 149.54, 148.41, 146.44, 132.15, 132.02, 124.33, 122.07, 120.23, 116.79, 116.69, 108.64, 105.15, 105.12, 100.90, 78.70, 77.75, 56.43, 52.51, 46.99, 32.65. LRMS (ESI), m / z 461.50 (M+H).

[0923]

[0924] Synthesis of 5-(4-amino-7-((4-fluoro-1 -(pyrimidin-2-yl)piperidin-4-yl)methyl)-7H-pyrrolo[2,3-d]pyrimidin-5-yl)-4-fluorobenzo[d]oxazol-2-amine (compound 1453).

[0925] The synthesis of compound 1453 was accomplished using a procedure analogous to that described in Example 2.1H NMR (500 MHz, DMSO-d6) 5 8.36 (d, J = 4.7 Hz, 2H), 8.14 (s, 1H), 7.64 (s, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.22 (d, J = 1.5 Hz, 1H), 6.98 (dd, J = 8.1, 6.9 Hz, 1 H), 6.63 (t, J = 4.7 Hz, 1 H), 6.05 (br, 2H), 4.50 - 4.42 (m, 4H), 3.20 (ddd, J = 13.9, 11.2, 3.4 Hz, 2H), 1.82- 1.61 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5163.22, 161.00, 158.00, 157.27, 151.75, 150.65, 149.52, 149.44, 148.42, 146.46, 132.12, 131.99, 125.13, 122.16, 117.07, 116.96, 110.10, 107.97, 105.09, 100.56, 95.28, 93.88, 50.44, 50.27, 31.71, 31.54. LRMS (ESI), m / z 478.70 (M+H).

[0926] 55718966-2

[0927]

[0928] Synthesis of but-2-yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1454). The synthesis of compound 1454 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.15 (s, 1H), 7.64 (s, 2H), 7.28 (d, J = 8.1 Hz, 1H), 7.20 (d, J = 1.6 Hz, 1H), 6.97 (dd, J = 8.1, 6.9 Hz, 1H), 6.05 (br, 2H), 4.63 (q, J = 2.5 Hz, 2H), 4.47 (s, 1H), 4.43 (s, 1H), 3.83 (d, J = 12.7 Hz, 2H), 3.03 (br, 2H), 1.82 (t, J = 2.4 Hz, 3H), 1.80 - 1.57 (m, 4H).13C NMR (126 MHz, DMSO-de) 5163.22, 157.28, 153.72, 151.78, 150.64, 149.52, 149.45, 148.41, 146.45, 132.12, 125.09, 122.14, 116.94, 108.01, 105.10, 100.57, 94.68, 93.28, 82.75, 74.62, 53.15, 50.32, 50.14, 31.69, 3.09. LRMS (ESI), m / z 496.30 (M+H).

[0929]

[0930] Synthesis of but-2-yn-1-yl 3-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-3-hydroxyazetidine-1 -carboxylate (compound 1455). The synthesis of compound 1455 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.16 (s, 1H), 7.63 (s, 2H), 7.32 - 7.25 (m, 2H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 6.25 (s, 1 H), 6.06 (br, 2H), 4.58 (q, J = 2.4 Hz, 2H), 4.42 (s, 2H), 4.10 (br, 2H), 3.74 (br, 2H), 1.82 (t, J = 2.4 Hz, 3H).13C NMR (126 MHz, DMSO-de) 5 163.20, 157.21, 155.21, 151.59, 150.37, 149.46, 149.38, 148.40, 146.44, 132.12, 131.99, 125.59, 122.11, 117.16,

[0931] 55718966-2 117.05, 107.56, 105.09, 105.06, 100.63, 82.78, 74.57, 69.33, 60.21, 52.67, 49.88, 25.47, 3.09. LRMS (ESI), m / z 466.70 (M+H).

[0932] 55718966-2 Example 7. Synthesis of:

[0933] tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1458); prop-2-yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1460); and

[0934] tert-butyl 4-((4-amino-5-(2-((tert-butoxycarbonyl)amino)-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1474).

[0935] Pd(dppf)Cl2·DCM Cs2CO31,4-dioxane / water 110 °C; 16 h N2

[0936] TFA DCM

[0937] r.t.; 2 h

[0938] 1458 1460

[0939]

[0940] 55718966-2 NH2

[0941]

[0942] Synthesis of tert-butyl 4-((4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound XXV). A 20 ml_ vial equipped with a stir bar was charged with 5-iodo-7H-pyrrolo[2,3-d]pyrimidin-4-amine (516 mg, 1 Eq, 1.98 mmol) followed by DMF (6 ml_). Then, sodium hydride (119 mg, 1.5 Eq, 2.98 mmol) was added portionwise and the mixture stirred at room temperature for 30 min. tert-butyl 4- (chloromethyl)-4-cyanopiperidine-1 -carboxylate (549 mg, 1.07 Eq, 2.12 mmol) was added, the vial sealed and the reaction stirred at 150 °C for 100 min using microwave irradiation. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 25 g column, 35 mL / min, 0 - 3.5% MeOH in DCM) to afford an off-white solid (41.1 mg, 85 pmol, 4% yield).1H NMR (500 MHz, DMSO-d6) 5 8.20 (s, 1 H), 7.53 (s, 1 H), 4.45 (s, 2H), 4.02 - 3.96 (m, 2H), 2.83 - 2.78 (m, 2H), 1.80 - 1.73 (m, 2H), 1.66 - 1.56 (m, 2H), 1.40 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 155.95, 153.49, 150.22, 150.02, 130.64, 120.79, 102.50, 79.16, 51.72, 49.60, 40.11, 40.02, 39.95, 39.86, 39.78, 39.69, 39.61, 39.52, 39.44, 39.35, 39.19, 39.02, 31.81, 30.66, 28.98, 27.99.

[0943] LRMS (ESI), m / z 483.20 (M+H).

[0944] o

[0945] NH2

[0946] N

[0947]

[0948] 55718966-2 Synthesis of tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1458). A 10 mL vial equipped with a stir bar was charged with tert-butyl 4-((4-amino-5-iodo-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound XXV) (41 mg, 1 Eq, 85 pmol), 4-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzo[d]oxazol-2-amine (compound XI) (24 mg, 1 Eq, 85 pmol), cesium carbonate (42 mg, 1.5 Eq, 129 pmol), Pd(dppf)Cl2'DCM (14 mg, 0.2 Eq, 17 pmol), 1,4-dioxane (1 mL) and water (0.3 mL). The vial was sealed and the mixture purged with nitrogen for 5 min. Then, the reaction was stirred at 110 °C for 16 h. The reaction was cooled to room temperature and then diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 6% MeOH in DCM) to afford a pale-pink solid (23.5 mg, 46 pmol, 55% yield).1H NMR (500 MHz, DMSO-d6) δ 8.28 (s, 1H), 7.67 (s, 3H), 7.45 (s, 1H), 7.31 (dd, J = 8.1, 1.7 Hz, 1 H), 7.02 - 6.93 (m, 1H), 4.55 (s, 2H), 4.02 (d, J = 13.7 Hz, 2H), 3.46 - 3.40 (m, OH), 2.84 (br, 2H), 2.12 - 2.05 (m, OH), 2.01 - 1.91 (m, 1H), 1.87 - 1.80 (m, 2H), 1.72 - 1.62 (m, 2H), 1.40 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.26, 153.52, 149.85, 149.77, 148.43, 146.46, 132.22, 132.09, 125.95, 122.02, 120.89, 115.98, 109.49, 105.29, 105.26, 100.53, 100.33, 79.17, 49.67, 40.46, 38.27, 31.87, 28.88, 28.00. LRMS (ESI), m / z 507.40 (M+H).

[0949]

[0950] Synthesis of 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-4-carbonitrile (compound XXVI). A 10 mL vial equipped with a stir bar was charged with tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1-carboxylate (compound 1458) (23.5 mg, 1 Eq, 46 pmol) and DCM (1 mL). Them, TFA (0.3 g, 0.2 mL, 60 Eq, 96 mmol) was added dropwise and the reaction stirred at room

[0951] 55718966-2 temperature for 2 h. The volatiles were removed under reduced pressure to afford the tittle compound as a TFA salt, and used without further purification in the next reaction step (24 mg, 46 pmol, 100% yield). LRMS (ESI), m / z 407.20 (M+H).

[0952] NH2

[0953] N

[0954] N

[0955] 0.

[0956]

[0957] Synthesis of prop-2 -yn-1-yl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)- 7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1460). A 10 mL vial equipped with a stir bar was charged with 4-((4-amino- 5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)piperidine-4-carbonitrile (compound XXVI) (18.9 mg, 1 Eq, 47 pmol) followed by MeOH (1 mL). Then, triethylamine (23.5 mg, 32 pL, 5 Eq, 233 pmol) and propargyl chloroformate (6.6 mg, 5.4 pL, 1.2 Eq, 56 pmol) were added and the mixture stirred at room temperature for 1 h. The reaction diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 7% MeOH in DCM) to afford a white solid (12 mg, 25 pmol, 53% yield).1H NMR (500 MHz, DMSO-d6) 5 8.16 (s, 1H), 7.65 (s, 2H), 7.33 (s, 1H), 7.30 (d, J = 8.1 Hz, 1H), 6.98 (dd, J = 8.1, 6.9 Hz, 1H), 6.11 (br, 2H), 4.68 (d, J = 2.5 Hz, 2H), 4.52 (s, 2H), 4.05 (d, J = 13.7 Hz, 2H), 3.51 (t, J = 2.4 Hz, 1 H), 2.93 (br, 2H), 1.88 - 1.81 (m, 2H), 1.77 - 1.67 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.24, 157.33, 153.39, 151.86, 150.78, 149.59, 149.52, 148.40, 146.44, 132.16, 132.03, 124.68, 122.07, 120.99, 116.87, 116.76, 108.40, 105.15, 105.12, 100.66, 79.02, 77.48, 52.75, 49.34, 40.61, 31.79. LRMS (ESI), m / z 489.30 (M+H).

[0958] 55718966-2

[0959]

[0960] Synthesis of tert-butyl 4-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1462). The synthesis of compound 1462 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.28 (s, 1 H), 7.71 (s, 2H), 7.34 (d, J = 8.2 Hz, 1 H), 7.09 (dd, J = 8.2, 6.6 Hz, 1 H), 4.61 (d, J = 18.9 Hz, 2H), 3.81 (d, J = 13.2 Hz, 2H), 2.96 (br, 2H), 1.80 - 1.63 (m, 4H), 1.38 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.28, 157.18, 154.88, 154.52, 153.74, 150.89, 150.81, 148.75, 146.76, 139.04, 132.20, 132.07, 121.89, 115.48, 115.39, 105.42, 105.39, 98.50, 94.22, 92.81, 78.83, 53.09, 52.89, 32.25, 32.08, 28.00. LRMS (ESI), m / z 501.40 (M+H).

[0961]

[0962] Synthesis of prop-2 -yn-1-yl 4-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1464). The synthesis of compound 1464 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.26 (s, 1H), 7.70 (s, 2H), 7.33 (d, J = 8.2 Hz, 1H), 7.10 (dd, J = 8.2, 6.6 Hz, 1H), 4.66 (d, J = 2.5 Hz, 2H), 4.62 (s, 1H), 4.58 (s, 1H), 3.85 (d, J = 15.1 Hz, 2H), 3.49 (t, J = 2.4 Hz, 1H), 3.04 (br, 2H), 1.83 - 1.71 (m, 4H).13C NMR (126 MHz, DMSO-de) 5 163.26,

[0963] 55718966-2 157.68, 155.56, 154.75, 153.56, 150.84, 150.77, 148.74, 146.75, 138.83, 132.19, 132.06, 121.93, 115.63, 115.53, 105.40, 105.37, 98.56, 94.07, 92.66, 79.11, 77.34, 53.01, 52.82, 52.59, 32.04. LRMS (ESI), m / z 483.30 (M+H).

[0964]

[0965] Synthesis of tert-butyl 3-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-cyanoazetidine-1 -carboxylate (compound 1466). The synthesis of compound 1466 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 58.29 (s, 1 H), 7.71 (s, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.09 (dd, J = 8.2, 6.6 Hz, 1H), 4.95 (s, 2H), 4.31 (d, J = 8.9 Hz, 2H), 4.17 (d, J = 9.0 Hz, 2H), 1.36 (s, 9H).13C NMR (126 MHz, DMSO-de) 6 163.29, 157.90, 155.98, 155.17, 154.62, 150.94, 150.86, 148.74, 146.75, 139.61, 132.24, 132.12, 121.81, 120.32, 115.47, 115.37, 105.48, 105.45, 98.56, 79.54, 48.89, 31.64, 27.89. LRMS (ESI), m / z 480.30 (M+H).

[0966]

[0967] Synthesis of prop-2 -yn-1-yl 3-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-3-cyanoazetidine-1 -carboxylate (compound 1468). The synthesis of compound 1468 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.28 (s, 1H), 7.71 (s, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.09 (dd, J = 8.2, 6.6 Hz, 1H), 4.99

[0968] 55718966-2 (s, 2H), 4.65 (d, J = 2.4 Hz, 2H), 4.44 - 4.38 (m, 2H), 4.29 (br, 2H), 3.53 (t, J = 2.4 Hz, 1H).13C NMR (126 MHz, DMSO-d6) 5 163.28, 157.97, 156.08, 154.74, 154.65, 150.92, 150.85, 148.73, 146.74, 139.59, 132.23, 132.10, 121.85, 120.11, 115.49, 115.40, 105.47, 105.45, 98.57, 78.68, 77.72, 56.36, 52.49, 48.96, 32.09. LRMS (ESI), m / z 462.30 (M+H).

[0969]

[0970] Synthesis of tert-butyl 4-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1470). The synthesis of compound 1470 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.29 (s, 1H), 7.71 (s, 2H), 7.35 (d, J = 8.1 Hz, 1H), 7.11 (dd, J = 8.2, 6.6 Hz, 1H), 4.65 (s, 2H), 4.00 (d, J = 13.8 Hz, 2H), 2.90 (br, 2H), 1.96 - 1.89 (m, 2H), 1.73 - 1.63 (m, 2H), 1.39 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 163.28, 157.48, 155.30, 154.71, 153.56, 150.93, 150.86, 148.74, 146.76, 139.43, 132.21, 132.09, 121.87, 120.55, 115.44, 115.34, 105.45, 105.42, 98.46, 79.11, 51.75, 31.99, 27.99. LRMS (ESI), m / z 508.40 (M+H).

[0971]

[0972] Synthesis of prop-2 -yn-1-yl 4-((4-amino-3-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-1 H-pyrazolo[3,4-d]pyrimidin-1 -yl)methyl)-4-cyanopiperidine-1 -carboxylate

[0973] 55718966-2 (compound 1472). The synthesis of compound 1472 was accomplished using a procedure analogous to that described in Example 3.1H NMR (500 MHz, DMSO-de) 6 8.27 (s, 1H), 7.71 (s, 2H), 7.35 (d, J = 8.2 Hz, 1H), 7.11 (dd, J = 8.2, 6.6 Hz, 1H), 4.68 (d, J = 2.4 Hz, 2H), 4.65 (s, 2H), 4.07 - 4.00 (m, 2H), 3.51 (t, J = 2.4 Hz, 1 H), 2.95 (br, 2H), 1.99 - 1.92 (m, 2H), 1.79 - 1.69 (m, 2H).13C NMR (126 MHz, DMSO-d6) 5 163.27, 157.97, 155.96, 154.92, 153.43, 150.89, 150.81, 148.74, 146.75, 139.25, 132.21, 132.08, 121.90, 120.49, 115.58, 115.49, 105.42, 105.39, 98.52, 79.02, 77.46, 52.73, 51.66, 40.54, 31.88. LRMS (ESI), m / z 490.30 (M+H).

[0974] HN

[0975]

[0976] Synthesis of tert-butyl 4-((4-amino-5-(2-((tert-butoxycarbonyl)amino)-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1474). A 7 mL vial equipped with a stir bar was charged with tert-butyl 4-((4-amino-5-(2-amino-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1450) (16.6 mg, 1 Eq, 32.8 pmol) followed by THF (0.5 mL). Then, di-tert-butyl dicarbonate (8.58 mg, 1.2 Eq, 39.3 pmol), triethylamine (8.29 mg, 11.4 pL, 2.5 Eq, 81.9 pmol) and 4-(dimethylamino)pyridine (1 mg, 0.25 Eq, 8.19 pmol) were added and the mixture stirred at room temperature for 16 h. The reaction was diluted with EtOAc, washed with water and brine. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (Isolera, 10 g column, 15 mL / min, 0 - 4% MeOH in DCM) to afford an off-white solid (9.2 mg, 15 pmol, 46% yield).1H NMR (500 MHz, DMSO-d6) 5 11.48 (s, 1H), 8.18 (s, 1H), 7.54 (d, J = 8.3 Hz, 1H), 7.39 (s, 1H), 7.24 (dd, J = 8.3, 7.0 Hz, 1H), 6.23 (br, 2H), 4.53 (s, 2H), 4.02 (d, J = 13.9 Hz, 2H), 2.84 (br, 2H), 1.86 - 1.80 (m, 2H), 1.71 - 1.62 (m, 2H), 1.51 (s, 9H), 1.40 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 157.12, 155.97, 153.53,

[0977] 55718966-2 151.60, 150.78, 149.92, 149.80, 149.26, 149.20, 147.80, 129.94, 129.81, 125.59, 125.07, 121.03, 117.41, 117.31, 107.98, 106.45, 106.42, 100.59, 81.43, 79.14, 49.45, 31.92, 27.99, 27.75. LRMS (ESI), m / z 607.60 (M+H).

[0978]

[0979] Synthesis of tert-butyl 4-((5-(2-acetamido-4-fluorobenzo[d]oxazol-5-yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-cyanopiperidine-1 -carboxylate (compound 1475). The synthesis of compound 1475 was accomplished using a procedure analogous to that described in Example 7.1H NMR (500 MHz, DMSO-de) 6 11.83 (s, 1H), 8.17 (s, 1H), 7.58 (d, J = 8.3 Hz, 1H), 7.38 (s, 1H), 7.27 (dd, J = 8.3, 7.0 Hz, 1H), 6.17 (br, 2H), 4.53 (s, 2H), 4.02 (d, J = 12.9 Hz, 2H), 2.84 (br, 2H), 2.24 (s, 3H), 1.86 - 1.79 (m, 2H), 1.71 - 1.62 (m, 2H), 1.40 (s, 9H).13C NMR (126 MHz, DMSO-d6) 5 168.08, 157.38, 155.73, 153.53, 151.95, 150.90, 149.92, 149.10, 149.04, 147.93, 129.69, 129.56, 125.95, 124.96, 121.05, 117.60, 117.50, 107.81, 106.61, 106.57, 100.61, 79.14, 49.43, 31.93, 27.99, 23.89. LRMS (ESI), m / z 549.50 (M+H).

[0980]

[0981] 55718966-2 Synthesis of prop-2-yn-1-yl 4-((5-(2-acetamido-4-fluorobenzo[d]oxazol-5-yl)-4-amino-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1476). The synthesis of compound 1476 was accomplished using a procedure analogous to that described in Example 7.1H NMR (500 MHz, DMSO-de) 6 11.83 (s, 1H), 8.16 (s, 1H), 7.56 (d, J = 8.3 Hz, 1H), 7.30 - 7.23 (m, 2H), 6.12 (br, 2H), 4.67 (d, J = 2.5 Hz, 2H), 4.47 (d, J = 22.3 Hz, 2H), 3.84 (d, J = 12.9 Hz, 2H), 3.50 (t, J = 2.4 Hz, 1H), 3.05 (br, 2H), 2.24 (s, 3H), 1.81 - 1.58 (m, 4H).13C NMR (126 MHz, DMSO-de) 6 168.09, 157.31, 155.69, 153.54, 151.88, 150.77, 149.92, 149.03, 148.97, 147.93, 129.66, 129.53, 126.03, 125.32, 117.77, 117.67, 107.48, 106.54, 106.51, 100.52, 94.65, 93.25, 79.12, 77.37, 52.61, 50.33, 50.16, 31.70, 23.89. LRMS (ESI), m / z 524.40 (M+H).

[0982]

[0983] Synthesis of prop-2-yn-1-yl 4-((4-amino-5-(2-((tert-butoxycarbonyl)amino)-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1 -carboxylate (compound 1477). The synthesis of compound 1477 was accomplished using a procedure analogous to that described in Example 7.1H NMR (500 MHz, DMSO-de) 5 11.47 (s, 1H), 8.16 (s, 1H), 7.52 (d, J = 8.3 Hz, 1 H), 7.27 - 7.20 (m, 2H), 6.11 (br, 2H), 4.67 (d, J = 2.4 Hz, 2H), 4.47 (d, J = 22.3 Hz, 2H), 3.84 (d, J = 13.0 Hz, 2H), 3.50 (t, J = 2.4 Hz, 1 H), 3.05 (br, 2H), 1.84 - 1.58 (m, 4H), 1.51 (s, 9H).

[0984] 13C NMR (126 MHz, DMSO-de) 5 157.31, 155.93, 153.54, 151.86, 150.75, 149.93, 149.79, 149.16, 149.10, 147.80, 129.90, 129.77, 125.68, 125.31, 117.66, 117.56, 107.53, 106.38, 106.34, 100.52, 94.65, 93.25, 81.42, 79.12, 77.37, 52.61, 50.33, 50.15, 31.76, 27.76. LRMS (ESI), m / z 582.50 (M+H).

[0985] 55718966-2

[0986]

[0987] Synthesis of prop-2-yn-1-yl 4-((4-amino-5-(2-(((benzyloxy)carbonyl)amino)-4-fluorobenzo[d]oxazol-5-yl)-7H-pyrrolo[2,3-d]pyrimidin-7-yl)methyl)-4-fluoropiperidine-1-carboxylate (compound 1478). The synthesis of compound 1478 was accomplished using a procedure analogous to that described in Example 7.1H NMR (500 MHz, DMSO-de) 5 11.92 (s, 1H), 8.16 (s, 1H), 7.54 (d, J = 8.3 Hz, 1 H), 7.50 - 7.35 (m, 5H), 7.28 - 7.22 (m, 2H), 6.12 (br, 2H), 5.26 (s, 2H), 4.67 (d, J = 2.5 Hz, 2H), 4.47 (d, J = 22.3 Hz, 2H), 3.84 (d, J = 13.0 Hz, 2H), 3.50 (t, J = 2.4 Hz, 1H), 3.04 (br, 2H), 1.81 - 1.57 (m, 4H).13C NMR (126 MHz, DMSO-d6) 5 157.31, 155.69, 153.54, 151.87, 151.12, 150.76, 149.83, 149.20, 149.14, 147.83, 135.76, 128.49, 128.27, 128.18, 125.85, 125.32, 117.75, 117.65, 107.50, 106.45, 106.42, 100.52, 94.65, 93.25, 79.12, 77.37, 67.02, 52.61, 50.33, 50.15, 31.78. LRMS (ESI), m / z 616.40 (M+H).

[0988] Biological Methods

[0989] Cell lines: The human colorectal adenocarcinoma cell lines HCT116, SW480, SW48 and HKH2 (HCT116 KRAS knockout), were selected as cell-based models to identify hits of novel mTOR inhibitors using phenotypic screening. Using multiple colorectal cancer cell lines helps recapitulate the varied response of mTOR inhibitors across colorectal cancer subtypes such as that of the CMS1 and CMS4 subtypes, to represent early and late-stage colorectal cancer and the influence of the mTOR pathway on both. An extended panel of human lung carcinoma A549, human breast adenocarcinoma MCF7, MDA-MB-231, and CAMA1, human chronic myeloid leukaemia K562, human T-cell leukemia Jurkat, human glioblastoma T98G and U87MG cells, were used to confirm the potency of the top hits across cancer types. EC50 values were calculated as the primary endpoint, using a 10-point half-log dose response curve (10 pM

[0990] 55718966-2 to 0.00001 pM, i.e., 10 pM to 0.01 nM). Cell viability scores collected at day 5 using PrestoBlue® reagent, were used to calculate EC50values. A PerkinElmer Envision 2101 Plate Reader was used for spectrofluorometric analyses.

[0991] Cell Culture General: Adherent HCT-116, SW480, SW48, HKH2, A549, MCF7, MDA-MB-231, CAMA1, T98G, and U87MG cells were maintained in DMEM supplemented with 10% FBS, and 2 mM L-Glutamine, and incubated at 5% CO2at 37 °C in a Heracell 240I tissue culture incubator. Semi-adherent K562 and Jurkat cells were maintained in RPMI 1640 supplemented with 10% FBS, and incubated at 5% CO2at 37°C in a Heracell 240I tissue culture incubator. Cells were passaged when 80-90% confluent for maintenance.

[0992] Phenotypic Screening For Hit Identification: Cells were seeded into 96-well plates at the following densities with a working volume of 100 pL: HCT116, SW480, HKH2, MDA-MB-231, MCF7, CAMA1, T98G, U87MG, Jurkat, and A549 at 1000 cells / well, and SW48 at 4500 cells / well. K562 cells were seeded at 3000 cells / well, in a 95 pL working volume. Seeding densities were decided using prior seeding density assays. All plates were incubated for 2 days, prior to treatment, apart from K562 and Jurkat cells which were seeded and treated on the same day. Drugs were prepared in DMSO with a working volume of 50 pL with concentration range(s) from 10 mM to 0.001 mM, 1 mM to 0.0001 mM, and / or 0.1 mM to 0.00001 mM by serial dilution. To dilute drugs to the desired concentrations before adding to the cell plates, intermediate plates were freshly prepared, using 245 pL of DMEM and RPMI media and 5 pL of drug at each concentration. 5 pL of this solution was then added to 95 pL media in the cell plate to achieve a final dilution of 1000x and 0.01% DMSO from the initial drug plates.

[0993] On day 2, media was aspirated and replaced with 95pL fresh media before adding 5 pL of each drug from freshly prepared intermediate plates. Plates were then incubated for a further 5 days for drug treatment. PrestoBlue® dye was added to an additional seeded cell plate for each cell line to normalize for viability from the 2-day incubation. PrestoBlue® dye was incubated for 90 minutes. After incubation, absorbance was read on a PerkinElmer Envision 2101 plate reader at an emission wavelength of 590 nm. After 5 days of drug treatment, all plates were incubated with PrestoBlue®. All drug concentrations were transformed into logarithmic scale, with all conditions being converted into percentage viability compared to untreated cells (100% viability). Percentage viability values were used to calculate EC50values for each condition, using non-linear regression variable slope (four parameters) in GraphPad Prism 9.

[0994] 55718966-2 Kinome screening: Kinome screening on 350 wild-type protein kinases and 14 lipid kinases, was performed by Reaction Biology (German site) using their33PanQinaseTMassay. Results were then analysed for hits, being defined where ≤50% remaining activity remained after 1 pM treatment. The resulting data was then used in the Coral software (Phanstiel lab) to generate kinome trees for overall kinase hit identification.

[0995] KPN organoid screen and size analysis: KPN (KRAS, P53, Notch mutations) organoids were grown and maintained in Advanced DMEM / F12 Culture Media (CM) containing 1x HEPES, L-glutamine (2 mM), N2, B27, 50 ng / ml EGF, 100 ng / ml Noggin, in 90% v / v Matrigel domes in 6-well plates. When confluent, domes were disrupted and digested with TrypLE™ Express Enzyme (1X) and organoids were broken up into single cells. 1000 cells / well were then seeded in 90% v / v 5 pL Matrigel domes and inverted and incubated at 37 °C for 20 minutes to allow for dome formation. When formed, 100 pL of CM was added to each well and organoids were incubated at 37 °C for 2 days to allow for organoid formation. Media was aspirated and cells were treated with 95 pL CM + 5 pL drugs at desired concentrations (10-point half-log dose response concentration range from 100 mM - 0.001 mM) and incubated in the Incucyte® S3 inside a Heracell 240i tissue culture incubator for 3 days. Images were taken using the spheroid module within the Incucyte® software every 12 h during the incubation period. After 3 days, plates were incubated with PrestoBlue®. All drug concentrations were transformed into logarithmic scale, with all conditions being converted into percentage viability compared to untreated cells (100% viability). Percentage viability values were used to calculate EC50values for each condition, using non-linear regression variable slope (four parameters) in GraphPad Prism 9. Images for organoid size were analysed using the Incucyte software.

[0996] Scratch wound healing assay: Adherent HCT116 and HKH2 colorectal cancer cells were seeded in Essen Bioscience 96-well ImageLock® plates in 100 pL working volume, and grown until 100% confluency. Once confluent, cells were scratched with the Incucyte® 96-Well Woundmaker Tool and washed twice with media. After washing, cells were replenished with 95 pL of media, and 5 pL of drugs were added in their desired concentrations, with the final concentration of DMSO vehicle at 0.1% v / v. Plates were then transferred to the Incucyte® S3 inside a Heracell 240i tissue culture incubator, and incubated for 24 h. The Scratch Wound module within the Incucyte® software was used to image wells every 4 h. Wound Width (WW) (pm) was calculated and extracted, and normalised to 0 h and values were used to calculate WW % of DMSO control. Technical and biological triplicates were performed.

[0997] 55718966-2 Western blotting: MCF7 and SW48 cells were seeded into 60 mm tissue culture dishes until 90% confluent in a 5 mL working volume, after which media was replaced for a further 24 h incubation. Cells were then treated with drugs with a final concentration of DMSO vehicle at 0.1% v / v, for 3 h. Following drug treatment, were then lysed using 1x RIPA buffer. Lysates were incubated on ice for 30 minutes, being mixed every 5 minutes and sonicated every 15 minutes. Lysates were then centrifuged for 10 minutes at 4°C 12,000 xg, and supernatants were extracted. The Pierce™ BCA Protein Assay Kit was then used to calculate protein concentrations, and supernatants were normalised to 20 pg per loading volume of 20 pL with 1 x Laemmli buffer. Loading samples were then boiled at 95°C for 5 minutes and mixed by vortex. Samples were loaded into 12 well 4-15% Mini-PROTEAN® TGX™ Precast Protein Gels, with 1x TGS running buffer and ran for 60 minutes at 120 V, with reference Precision Plus Protein Dual Color Standards. Protein bands were then transferred onto nitrocellulose membranes using the Biorad Trans-Blot Turbo Transfer System. Membranes were blocked with 5% BSA TBST solution for 1 h, and washed with TBST 3 times. After washing, membranes were cut and incubated with primary antibody overnight. Membranes were then washed with TBST 3 times and incubated with the appropriate HRP-linked secondary antibody for 2 h. Membranes were washed 3 times with TBST, before being developed using Biorad ECL substrate. Total proteins were incubated in ECL for 2 minutes and phosphoproteins for 8 minutes. Membranes were then exposed and imaged using the Biorad ChemiDoc MP Imaging System. Both chemiluminescent and colorimetric images were taken for each protein band, with Beta Actin used as a housekeeping protein control. Phosphoproteins and total proteins were blotted for simultaneously by running 2x of the same sample on the same gel and then probed and blotted for on separate membrane pieces. Beta Actin used as a housekeeping protein control was done for both phosphoproteins and total proteins.

[0998] Results and discussion

[0999] While mTOR is key in driving tumorigenesis and metastases itself, this kinase can also contribute to acquired drug resistance to radiotherapy and chemotherapy such as cisplatin regimens, but also targeted approaches such as anti-PD-1, EGFR, PI3K, RAF, and MEK therapies. mTOR mediates cisplatin resistance through NF-KB repression which drives FANCD2 expression, part of the Fanconi anaemia DNA repair pathway, to upregulate DNA repair in response to alkylating agents, through upregulation of the ATM-Chk2 checkpoint. This resistance is shown to be reversible through treatment

[1000] 55718966-2 of second generation mTOR inhibitors such as AZD8055. mTOR itself mediates resistance to anti-PD-1, EGFR, PI3K, RAF, and MEK therapies, and this phenotype can be reversed through use of both first- and second-generation mTOR inhibitors. The fact mTOR and its pathway is implicated in such a large array of drug resistance cases, such as these listed among others, demonstrates the absolute need for a specific and tolerable mTOR inhibitor for not only targeting neoplasms driven by mTOR, but also for cancers that use the interconnected mTOR network as a means of escape. The potential for using mTOR inhibitors in combination with other drugs such as MNK inhibitors to treat aggressive and resistant cancers, such KRAS mutant cancers, is demonstrated by Knight et al., in ‘MNK Inhibition Sensitizes KRAS-Mutant Colorectal Cancer to mTORC1 Inhibition by Reducing elF4E Phosphorylation and c-MYC Expression’, Cancer Discov., 2021, 11, (5), pp. 1228-1247. The option of combination therapy in clinical populations with current inhibitors is likely unfeasible due to the toxicity and promiscuity of the compounds.

[1001] Additionally, having the opportunity to combine a second-generation mTOR inhibitor with other drugs may provide a solution to acquired resistance arising from chronic and prolonged treatment with mTOR inhibitors. Resistance to first-generation mTOR inhibitors mainly arises from incomplete inhibition of mTOR, from absent mTORC2 inhibition, leading to incomplete inhibition of mTORCI, due to the crosstalk between the two complexes. Incomplete mTORCI inhibition also arises from perturbation of intrinsic inhibition. Specifically, in energy stress, it is suggested that AMPK phosphorylates Raptor, part of mTORCI, at its serine 792 residue to exert complete complex inhibition. It is thought that if this Raptor phosphorylation is disturbed, cells do not undergo growth arrest and instead continue cycling at inappropriate rates before undergoing apoptosis. This is of clinical significance, especially in colorectal cancer, due to cancer cells’ ability to resist apoptosis through tumour suppressor protein mutation, such as APC mutation present in the majority of colorectal cancer cases and crucial for development. Thus, promiscuous therapies such as current mTOR inhibitors like sapanisertib may perturb phosphorylation events such as these, leading to uncontrolled cell cycling, through the combination of disturbing growth arrest checkpoints and cancer cells using their ability to resist apoptosis. This would result in lack of efficacy in a clinical setting and faster acquired resistance to treatment with such inhibitors, highlighting the importance for specific mTOR inhibitors. Further to this, in Hereditary Haemorrhagic Telangiectasia (HHT), PI3K and mTOR hyperactivity is a pathogenic phenotype, especially where ALK1 (also known as ACVRL1) activity is

[1002] 55718966-2 perturbed / deficient (Ruiz et al., ‘Correcting Smad1 / 5 / 8, mTOR, and VEGFR2 treats pathology in hereditary haemorrhagic telangiectasia models’, J. Clin. Invest., 2020, 130, (2), pp. 942-957). This is of significance here, because it can be postulated that ALK1 also acts as a negative regulator to mTORCI, perhaps through interaction with mTORCI specific components such as Raptor. Additionally, ALK1 has been characterised to negatively regulate VEGFR2, a potent inducer of the mTOR pathway through PI3K / Akt, and angiogenesis, by cooperating with Notch (Ruiz etal., ‘Correcting Smad1 / 5 / 8, mTOR, and VEGFR2 treats pathology in hereditary hemorrhagic telangiectasia models’, J. Clin. Invest., 2020, 130; Trinh et al., ‘The VEGF pathway and the AKT / mTOR / p70S6K1 signalling pathway in human epithelial ovarian cancer’, Br. J. Cancer, 2009, 100; Larrivee etal., ‘ALK1 signaling inhibits angiogenesis by cooperating with the Notch pathway’, Dev. Cell, 2012, 22). Inhibiting VEGFR2 with a peptidomimetic has shown to downregulate mTOR pathway activation and disease burden (Namjoo et al., ‘A VEGFB-Based Peptidomimetic Inhibits VEGFR2-Mediated PI3K / Akt / mTOR and PLCgamma / ERK Signaling and Elicits Apoptotic, Antiangiogenic, and Antitumor Activities’, Pharmaceuticals (Basel), 2023, 16). Kinome data presented herein identifies ALK1 as a potent target of sapanisertib, giving further strength and importance to using super-selective mTOR inhibitors in mTOR driven pathologies like cancer and blood disorders, to ensure robust and complete mTOR inhibition to avoid cycling, growth, and disease progression.

[1003] Pathways both upstream (such as FAP and the MAPK cascade) and downstream (such as the HIF-1a / Notch pathway) of mTOR drive resistance to both first- and second-generation mTOR inhibitors through constitutive activation of mTOR, bypassing inhibition (Formisano et al., ‘Mechanisms of resistance to mTOR inhibitors’, Crit. Rev. Oncol. Hemat., 2020, 147). Thus, without being bound by theory, a more selective second-generation mTOR inhibitor with an increased therapeutic window could prove valuable for both enhancing other therapies and giving opportunities to circumvent resistance in the treatment of mTOR itself.

[1004]

[1005] For Hit Identification Several compounds disclosed herein display superior antiproliferative activity across the extended cancer cell line panel compared to those in the prior art, including commercially available second-generation mTOR inhibitors tested here (such as sapanisertib), especially against colorectal cancer cell lines where sapanisertib is not as effective at reducing cell proliferation. The compounds disclosed herein also display superior selectivity for mTOR kinase over other closely

[1006] 55718966-2 related kinases. To illustrate, selected closely related kinases CK1 delta, DNAPK, PKN3 and PIK3CA / PIK3R1 are strongly inhibited by compounds described in the prior art, such as sapanisertib, where only DNAPK is affected by novel derivatives (by way of example, compounds 1328 and 1396) showing novel super-selectivity for mTOR kinase. Despite also inhibiting DNAPK, novel derivatives display high selectivity for mTOR kinase over DNAPK, in comparison to sapanisertib which displays only a small amount of selectivity for mTOR kinase over closely related DNAPK. These kinome screening results indicate the compounds disclosed herein have super-selectivity for mTOR kinase, to complement their novel potency, far exceeding existing second-generation mTOR inhibitors such as sapanisertib. It is anticipated that these properties may lead to several benefits including but not limited to higher clinical efficacy, patient safety, and utility. Results for the extended kinase screening panel with 350 wild-type protein kinases and 14 lipid kinases are also disclosed herein (Fig. 2) for the prior art (e.g., sapanisertib) and the compounds disclosed herein. This data helps to demonstrate the super-selective nature of the compounds of the invention for mTOR kinase. Table 1 follows.

[1007] 55718966-2 Table 1

[1008] The compounds disclosed herein display superior antiproliferative activity, mTOR kinase inhibition, and / or mTOR kinase selectivity in phenotypic and kinome screens compared to compounds described in the prior art (including but not limited to sapanisertib).

[1009] EC50and IC50= >1000 nM “NA” >500 nM “+” >100 nM “++” >10 nM “+++” >1 nM > “++++” >0.1 nM“+++++”; mTOR selectivity = >1 “+” >15 “++” >30 “+++” >45 “++++”.

[1010] mTOR Antiproliferative Kinase inhibition

[1011] Code Structure selectivity activity (EC50) (IC50)

[1012] SW480: +++

[1013] CK1 delta: +++

[1014] HCT116: ++

[1015] Sapaniser DNAPK: +++

[1016] HKH2: +++ DNAPK / m tib mTOR: ++++

[1017] SW48: ++++ TOR: + (prior art) PKN3: +++

[1018] T98G: +++

[1019] PIK3CA / PIK3R1: ++

[1020] U87MG: +++

[1021] NHj

[1022] SW480: ++

[1023] T-A

[1024] N j HCT116: ++

[1025] 190

[1026] HKH2: +++

[1027] SW48: +++

[1028] 6 p.

[1029] H2NT-O

[1030] N.^p" P

[1031] V:, / NH2

[1032] T98G: ++

[1033] N!i 1 U87MG: +++

[1034] SW480: +

[1035] 194

[1036] HCT116: ++

[1037] HKH2: ++

[1038] SW48: ++

[1039] O ’SQ

[1040]

[1041] 55718966-2 SW480: ++

[1042] HCT116: ++

[1043] 1110

[1044] HKH2: +++

[1045] SW48: +++

[1046] HzVo

[1047] II V T98G: +++

[1048] \== / NH2U87MG: +++

[1049] DNAPK: +++

[1050] SW480: ++ DNAPK / m 1137 mTOR: ++++

[1051] HCT116: ++ TOR: ++

[1052] PIK3CA / PIK3R1: + HKH2: +++

[1053] V-N

[1054] r°y- SW48: +++

[1055] "<4

[1056] '=sZ NH2SW480: ++

[1057] Z V V CM - HCT116: +++

[1058] 1161 o S

[1059] HKH2: +++

[1060] SW48: +++

[1061] N < z

[1062] X

[1063] 0

[1064] H2Vv

[1065] N\

[1066] w NH2SW480: ++

[1067] HCT116: +++

[1068] 1162 o S

[1069] HKH2: +++

[1070] SW48: +++

[1071] X-N

[1072] 0

[1073] V T98G: ++

[1074] N" X T

[1075] x=Z NH2U87MG: +++

[1076] SW480: +++

[1077] 1163

[1078] HCT116: +++

[1079] HKH2: +++

[1080] X— -N.

[1081] r°u SW48: ++++

[1082] 0 \

[1083]

[1084] 55718966-2N'A

[1085] NH2SW480: ++

[1086] HCT116: ++ 1164

[1087] HKH2: ++ SW48: +++ \^N

[1088] ° / x

[1089] T98G: ++ U87MG: +++ SW480: +++ 1165

[1090] HCT116: +++ HKH2: +++ SW48: ++++

[1091] H2NY% CM

[1092] n T98G: ++ NH2U87MG: +++N\X J SW480: +++ 1166N

[1093] N-^N^

[1094] HCT116: +++ HKH2: ++++ SW48: ++++ o

[1095] X NH2SW480: ++ hf5 HCT116: ++ 1167 N-^N^

[1096] HKH2: +++ SW48: +++ y

[1097] o

[1098] O

[1099] \^= / NH2

[1100] SW480: ++ HCT116: ++ 1169

[1101] HKH2: +++ Q SW48: +++ ^y>

[1102]

[1103] 55718966-2 X

[1104] NH2SW480: ++

[1105] HCT116: ++

[1106] 1170

[1107] HKH2: ++

[1108] Q SW48: +++

[1109] yo^r y-N°2

[1110] o '

[1111] SW480: ++

[1112] HCT116: ++

[1113] 1176

[1114] HKH2: +++

[1115] SW48: +++

[1116] H2NY°V

[1117] NH Z < \ -2SW480: +++

[1118] DNAPK: +++

[1119] HCT116: +++ DNAPK / m 1177 QS mTOR: ++++

[1120] ■ HKH2: +++ TOR: ++ ^z' SW48: +++

[1121] M C Z

[1122] X \-^N

[1123] YV

[1124] ° /

[1125] V

[1126] '=a / NH2SW480: ++ DNAPK: ++

[1127] HCT116: +++ mTOR: ++++ DNAPK / m 1184

[1128] N-^N^ HKH2: +++ PKN3: + TOR: +++

[1129] SW48: +++ PIK3CA / PIK3R1: +

[1130] Nr°\^

[1131] o

[1132] H2Vv

[1133] ^==Z NH2SW480: +++

[1134] HCT116: +++

[1135] 1189 <huN

[1136] HKH2: +++

[1137] SW48: ++++

[1138] O

[1139] 0

[1140]

[1141] 55718966-2H2NV F-O

[1142] Y NH2SW480: +++

[1143] DNAPK: ++

[1144] HCT116: +++ DNAPK / m 1192 oS mTOR: ++++

[1145] HKH2: +++ TOR: +++ i SW48: ++++

[1146] z

[1147] v 0 °^

[1148] H2Ny Yo

[1149] 2CK1 delta: +

[1150] \=== / v N / xH SW480: ++

[1151] DNAPK: +++

[1152] HCT116: +++ DNAPK / m 1193 I mTOR: ++++

[1153] HKH2: +++ TOR: ++

[1154] PKN3: +

[1155] SW48: ++++

[1156] PIK3CA / PIK3R1: ++ Qu

[1157] 0

[1158] H!Vv

[1159] Ny r

[1160] NH2SW480: ++

[1161] HCT116: +++

[1162] 1194 o S

[1163] N^N> HKH2: +++

[1164] SW48: +++

[1165] QyL

[1166] o

[1167] V

[1168] N\

[1169] \=s= / NH2SW480: ++

[1170] DNAPK: +

[1171] HCT116: +++ DNAPK / m 1224NbuNmTOR: +++

[1172] HKH2: +++ TOR: +++ SW48: +++

[1173] b

[1174] rv

[1175] ° /

[1176] T98G: NA

[1177] U87MG: NA

[1178] SW480: +

[1179] 1225 mTOR: ++

[1180] HCT116: +

[1181] HKH2: ++

[1182] SW48: ++

[1183]

[1184] 55718966-2 T98G: +++ y= / NH2

[1185] U87MG: +++ SW480: +++ 1229 <uuN

[1186] HCT116: +++ HKH2: +++ SW48: ++++ \_-N 1

[1187] H2NY°V

[1188] T98G: ++ ^== / NH2

[1189] U87MG: +++ SW480: ++ 1230 <buN

[1190] HCT116: ++ HKH2: ++ X~-N / SW48: +++0O

[1191] H2NY°v

[1192] Njy

[1193] NH2SW480: ++

[1194] HCT116: +++ 1231 hA

[1195] N^hT HKH2: +++

[1196] SW48: ++++ o

[1197] H’Nyo

[1198] II

[1199] NsA

[1200] '«== / NH2SW480: ++

[1201] HCT116: +++ 1232

[1202] HKH2: +++ SW48: ++++ ^yO

[1203] 0

[1204]

[1205] 55718966-2N

[1206] XaZ NH2SW480: ++

[1207] HCT116: ++ 1233 oS

[1208] N^-N^ HKH2: +++

[1209] SW48: +++ o

[1210] VNXaZ NH2SW480: ++

[1211] HCT116: + 1234 oS

[1212] HKH2: ++ SW48: +++ V-N N"

[1213] rN^

[1214] 0 \ LiA

[1215] \ y zi cx—

[1216] z e z / z— / / —o ^ Z x^

[1217] H2Vv

[1218] N\

[1219] \=Z NH2SW480: ++ y o--- A'

[1220] HCT116: ++ 1275 }z= o\

[1221] zN

[1222] M C HKH2: +++ T SW48: +++ ( / F

[1223] 0

[1224] SW480: +++ HCT116: +++ 1276

[1225] HKH2: +++ SW48: +++

[1226]

[1227] 55718966-2H2Vv

[1228] \=== / NH2

[1229] SW480: +++

[1230] DNAPK: ++

[1231] HCT116: +++ DNAPK / m 1292 i K> I z ro oS mTOR: +++

[1232] Z HKH2: +++ TOR: ++

[1233] SW48: +++

[1234] V°r ^

[1235] V°z h ^

[1236] CZ0 / x Z ' \ N5 - / \

[1237] ZI °Y

[1238] vz

[1239] CK1 delta: +

[1240] SW480: +++

[1241] DNAPK: +++

[1242] HCT116: +++ DNAPK / m 1298 mTOR: ++++

[1243] HKH2: +++ TOR: + o'^ PKN3: ++

[1244] k V zM C — SW48: ++++

[1245] PIK3CA / PIK3R1: + QH IZ °

[1246] o A K

[1247] ^z=

[1248] I CM z

[1249] SW480: +++

[1250] HCT116: +++

[1251] 1299

[1252] HKH2: +++

[1253] SW48: ++++

[1254] SW480: +++

[1255] HCT116: ++

[1256] 1305

[1257] HKH2: +++

[1258] SW48: +++

[1259]

[1260] 55718966-2H2VV

[1261] \==Z NH2

[1262] SW480: +++

[1263] HCT116: +++

[1264] 1308 I oS

[1265] i K> z ho HKH2: +++

[1266] Z SW48: ++++

[1267] TY JTY J VN

[1268] / y V

[1269] 0 /

[1270] ^H Zz-H2VV Vz

[1271] NH2SW480: +++

[1272] DNAPK: ++

[1273] HCT116: +++ DNAPK / m 1311 OSNmTOR: ++++

[1274] HKH2: ++++ TOR: ++++ SW48: ++++

[1275] VN

[1276] rv

[1277] ° /

[1278] SW480: +++ CK1 delta: +

[1279] HCT116: +++ DNAPK: ++ DNAPK / m 1312

[1280] HKH2: ++++ mTOR: ++++ TOR: ++++ SW48: ++++

[1281] CK1 delta: +

[1282] SW480: +++

[1283] DNAPK: +++

[1284] HCT116: +++ DNAPK / m 1317 mTOR: ++++

[1285] HKH2: +++ TOR: +

[1286] PKN3: ++

[1287] SW48: ++++

[1288]

[1289] 55718966-2 NH2

[1290] Yf NH2SW480: +++

[1291] F \ 1 DNAPK: +++

[1292] HCT116: +++ DNAPK / m 1319 X K> mTOR: ++++

[1293] z HKH2: +++ TOR: + Y J SW48: ++++

[1294] Y J

[1295] Vy

[1296] ° /

[1297] H2Vy '\z-N\

[1298] SW480: +++

[1299] DNAPK: +++

[1300] HCT116: +++ DNAPK / m 1320FY6 mTOR: ++++

[1301] HKH2: ++++ TOR: ++ SW48: ++++

[1302] ¥y

[1303] o /

[1304] H2VV

[1305] NyA

[1306] \=Z NH2

[1307] SW480: +++ CK1 delta: +

[1308] HCT116: +++ DNAPK: +++ DNAPK / m 1326 <bu

[1309] yN^N

[1310] HKH2: ++++ mTOR: ++++ TOR: +++ SW48: ++++ PKN3: +

[1311] N

[1312] 0^

[1313] SW480: +++

[1314] DNAPK: +++

[1315] HCT116: +++ DNAPK / m 1327 mTOR: ++++

[1316] HKH2: ++++ TOR: ++

[1317] PKN3: ++

[1318] SW48: ++++

[1319]

[1320] 55718966-2 H2N SW480: +++

[1321] Y°v

[1322] HCT116: +++

[1323] NH2HKH2: ++++

[1324] F\ 1 CK1 delta: +

[1325] SW48: ++++

[1326] DNAPK: +++ DNAPK / m 1328 A549: ++++

[1327] mTOR: ++++ TOR: +++ MCF7: ++++

[1328] MDA-MB-231:

[1329] VN ++++

[1330] K562: +++

[1331] SW480: +++

[1332] DNAPK: +++

[1333] HCT116: +++ DNAPK / m 1329 mTOR: ++++

[1334] HKH2: ++++ TOR: ++

[1335] PKN3: +

[1336] QH! Z SW48: ++++

[1337] A

[1338] y

[1339] H, N }

[1340] YXNAF / = / \ N 1H2SW480: +++ CK1 delta: +

[1341] HCT116: +++ DNAPK: +++ DNAPK / m 1330 CO HKH2: ++++ mTOR: ++++ TOR: +

[1342] SW48: ++++ PKN3: ++

[1343] V-N

[1344] oC

[1345] H2VV

[1346] NY

[1347] fZ=X / \ N 1H2SW480: +++ CK1 delta: +

[1348] HCT116: +++ DNAPK: +++ DNAPK / m 1331 c HKH2: ++++ mTOR: ++++ TOR: +

[1349] SW48: ++++ PKN3: ++

[1350] A-N

[1351]

[1352] sC

[1353] 55718966-2 SW480: ++ CK1 delta: +

[1354] I HCT116: ++ DNAPK: +++ DNAPK / m 1334 z

[1355] HKH2: +++ mTOR: ++++ TOR: ++ SW48: +++ PKN3: ++

[1356] °^ / / 7

[1357] -H2VN^hV

[1358] VJS / NH2

[1359] SW480: ++ CK1 delta: +

[1360] T HCT116: ++ DNAPK: +++ DNAPK / m 1335

[1361] HKH2: ++ mTOR: ++++ TOR: + SW48: +++ PKN3: ++

[1362] \_-N

[1363] V=N

[1364] o / N

[1365] 'f

[1366] H2NY%

[1367] NY^

[1368] F / === / \ N 1H2

[1369] SW480: ++

[1370] DNAPK: +++

[1371] HCT116: +++ DNAPK / m 1336 mTOR: ++++

[1372] HKH2: +++ TOR: ++

[1373] PKN3: ++

[1374] SW48: +++

[1375] \-N

[1376] \=N

[1377] °?

[1378] H2V

[1379] Nv

[1380] Y / =^

[1381] F / \ N 1H2

[1382] SW480: ++ CK1 delta: +

[1383] CT jNHCT116: ++ DNAPK: +++ DNAPK / m 1337

[1384] HKH2: +++ mTOR: ++++ TOR: ++ SW48: +++ PKN3: +

[1385] Y=N

[1386] 0^'N

[1387]

[1388] 55718966-2 "to

[1389] NtoA

[1390] NH2SW480: +++

[1391] DNAPK: ++

[1392] HCT116: +++ DNAPK / m 1341Fto mTOR: ++++

[1393] HKH2: ++++ TOR: +++

[1394] PKN3: NA

[1395] SW48: ++++

[1396] X- N

[1397] rv

[1398] 0 A

[1399] H2VX

[1400] / = / NH2SW480: +++

[1401] DNAPK: +++

[1402] HCT116: +++ DNAPK / m 1342Fto mTOR: ++++

[1403] HKH2: +++ TOR: ++

[1404] PKN3: +

[1405] SW48: ++++

[1406] V-N

[1407] 0AV

[1408] A SW480: +++

[1409] HCT116: +++

[1410] XNHKH2: ++++

[1411] \«= / NH2CK1 delta: ++

[1412] SW48: ++++

[1413] DNAPK: +++ DNAPK / m 1345 o b A549: ++++

[1414] N-^N^ mTOR: ++++ TOR: +++

[1415] MCF7: ++++

[1416] PKN3: +

[1417] MDA-MB-231:

[1418] N

[1419] ++++

[1420] 0

[1421] K562: +++

[1422] SW480: +++

[1423] H2Vv HCT116: ++++

[1424] N\

[1425] 2HKH2: ++++

[1426] / = / NH CK1 delta: +

[1427] SW48: ++++

[1428] DNAPK: +++ DNAPK / m 1346Fto A549: ++++

[1429] mTOR: ++++ TOR: +++ MCF7: ++++

[1430] MDA-MB-231:

[1431] A— N

[1432] ++++

[1433] 0 K562: ++++

[1434]

[1435] 55718966-2

[1436]

[1437] 55718966-2 SW480: +++ I ho HCT116: +++ 1376 Z

[1438] -n HKH2: ++++

[1439] SW48: ++++ < ro

[1440] H2V\

[1441] NYX

[1442] / === / NH2

[1443] F \ 1 Z vM C - / / i SW480: ++ \z z

[1444] oj HCT116: ++ 1377

[1445] HKH2: +++ / \z A v<-o- SW48: +++ fn Y rv

[1446] / zO=

[1447] M C z

[1448] I HN

[1449] 0XV

[1450] A

[1451] SW480: +++ HCT116: +++ 1378

[1452] HKH2: +++ SW48: ++++

[1453] HV<

[1454] N\

[1455] / = / NH

[1456] F2

[1457] \ 1 SW480: +++

[1458] HCT116: +++ 1379 co

[1459] HKH2: ++++ SW48: ++++F / \

[1460] X-N

[1461] o^°X

[1462]

[1463] 55718966-2 V

[1464] N

[1465] F / \= / NH

[1466] \ 12

[1467] SW480: ++ T HCT116: ++ 1380 i M

[1468] z HKH2: +++ Y z=

[1469] SW48: +++ A A°r — N

[1470] 0AV A

[1471] Q / "i~ o- r

[1472] SW480: ++ HCT116: ++ 1381

[1473] HKH2: +++ SW48: +++

[1474] H2NV°v

[1475] N

[1476] A= / NH

[1477] F2

[1478] \ 1 SW480: ++ V l HCT116: +++ 1382

[1479] HKH2: +++ SW48: +++ A-N

[1480] y=N

[1481] —

[1482] H2Vv

[1483] 2^= / NH

[1484] f2

[1485] \ 1 SW480: +++

[1486] J* HCT116: +++ 1383

[1487] HKH2: +++ SW48: +++ h

[1488] ^=N

[1489] °A)

[1490]

[1491] 55718966-2H2Vv

[1492] N\ / = / NH2SW480: +++

[1493] HCT116: +++

[1494] 1391 to6

[1495] HKH2: +++

[1496] SW48: +++

[1497] 0

[1498] Vv

[1499] Ntol

[1500] / = / NH2 SW480: +++

[1501] HCT116: +++

[1502] 1392Fto

[1503] HKH2: +++

[1504] SW48: +++

[1505] V-N

[1506] \ ZM C - O / / ^ X

[1507] \z z

[1508] tototo

[1509] fn YV

[1510] / z O=

[1511] M C z

[1512] T SW480: +++

[1513] HCT116: +++

[1514] 1393

[1515] HKH2: +++

[1516] SW48: ++++

[1517] SW480: +++

[1518] HCT116: +++

[1519] HHKH2: +++

[1520] to

[1521] SW48: ++++

[1522] / = / NH2

[1523] F \ 1 A549: ++++

[1524] DNAPK: ++++ DNAPK / m 1395 to j MCF7: +++++

[1525] mTOR: +++++ TOR: + MDA-MB-231:

[1526] ++++

[1527] □n

[1528] r0^ K562: +++

[1529] 0

[1530]

[1531] 55718966-2 T98G: ++++

[1532] U87MG: ++++

[1533] SW480: ++++

[1534] HCT116: ++++

[1535] XNHKH2: ++++ CK1 delta: +F / \= / NH

[1536] \ 12SW48: ++++ PKN3: ++

[1537] A549: ++++ DDR2: + DNAPK / m 1396

[1538] MCF7: +++++ mTOR: +++++ TOR: ++++ MDA-MB-231: DNAPK: +++

[1539] Fb ++++

[1540] 0 K562: ++++

[1541] Jurkat: ++++-1- CAMA1: +++++

[1542] X

[1543] Nyx

[1544] X / NH2

[1545] FSW480: +++

[1546] \ 1

[1547] XX J1HCT116: +++

[1548] 1397

[1549] HKH2: +++

[1550] SW48: ++++

[1551] ^-N

[1552] 0

[1553] H2Vv

[1554] Nx l

[1555] X= / NH2

[1556] F \ 1 SW480: +++

[1557] HCT116: +++

[1558] 1398 J1

[1559] HKH2: ++++

[1560] SW48: ++++

[1561] VN

[1562] H2Vv

[1563] X / NH2SW480: +++

[1564] HCT116: +++

[1565] 1404 X N^dX HKH2: ++++

[1566] SW48: ++++

[1567] Q

[1568] r0^

[1569] 0

[1570]

[1571] 55718966-2 "22

[1572] 2=== / NH2

[1573] f\ 1 SW480: +++

[1574] rfNi HCT116: +++

[1575] 1412

[1576] HKH2: ++++

[1577] SW48: ++++

[1578] \=N

[1579] O^N

[1580] V

[1581] 2=2 NH2SW480: +++

[1582] FV JL HCT116: +++

[1583] 1421 < nN

[1584] HKH2: ++++

[1585] SW48: ++++

[1586] O.o

[1587] o / \

[1588] SW480: ++++

[1589] HCT116: ++++

[1590] " Yv HKH2: ++++

[1591] N\ C

[1592] 2== / NH2SW48: ++++-1-f\ 1

[1593] A549: ++++ DNAPK: ++++ DNAPK / m 1423 cO MCF7: +++++ mTOR: +++++ TOR: +

[1594] MDA-MB-231:

[1595] +++++ K562: ++++

[1596] 0

[1597] H!Vv

[1598] N\ C

[1599] NH2

[1600] f\ 1 SW480: +++

[1601] O J HCT116: +++

[1602] 1428

[1603] HKH2: +++

[1604] F / \ SW48: +++

[1605] \-N

[1606] y=N

[1607]

[1608] 55718966-2H2VV

[1609] N\

[1610] / == / NH2

[1611] F \ 1 SW480: +++

[1612] HCT116: +++ 1429 co

[1613] HKH2: ++++ SW48: ++++ X— N

[1614] 0 / x

[1615] SW480: ++++H2NVHCT116: ++++ HKH2: +++++

[1616] NH2 SW48: +++++

[1617] A549: +++++ 1431 i

[1618] MCF7: +++++ MDA-MB-231:

[1619] +++++

[1620] 0 K562: ++++H2Vv

[1621] N" O

[1622] 2^= / NH2

[1623] f\ 1 SW480: +++

[1624] HCT116: +++ 1433 cO

[1625] N^rT HKH2: +++ SW48: +++F / \

[1626] N

[1627] \=N

[1628] o

[1629] H2VO

[1630] Il

[1631] N\ C SW480: ++++

[1632] NH2

[1633] FI X HCT116: ++++ 1436 O J HKH2: ++++

[1634] SW48: ++++ P L1MCF7: +++++ Vv

[1635] 0 / \

[1636]

[1637] 55718966-2 SW480: ++++

[1638] V HCT116: ++++

[1639] / = / NH2 HKH2: +++++

[1640] F l A SW48: ++++-1- 1437 I z N) K J J1A549: +++++

[1641] N> z z MCF7: +++++

[1642] fZ= -n -n

[1643] MDA-MB-231:

[1644] V "NY°^ LN ++++-1- Xrqy- j

[1645] f^f r)o

[1646] )0 / \ K562: ++++

[1647] O) OZ Z zz z z^ / —^ / —

[1648] NSW480: ++++

[1649] HCT116: ++++

[1650] 1442 HKH2: ++++

[1651] SW48: +++++ MCF7: +++++

[1652] SW480: +++

[1653] HCT116: +++

[1654] 1443 HKH2: +++

[1655] SW48: ++++

[1656] MCF7: ++++

[1657] SW480: ++++

[1658] H’Vv HCT116: ++++

[1659] N\ HKH2: ++++

[1660] 2= / NH2

[1661] SW48: +++++ DNAPK: ++++ DNAPK / m 1446FA6 A549: +++++

[1662] N^-N^ mTOR: +++++ TOR: +

[1663] MCF7: +++++

[1664] L— N MDA-MB-231:

[1665] ++++-1- 0 Y°^

[1666] K562: ++++

[1667]

[1668] 55718966-2 SW480: ++++

[1669] HCT116: +++++

[1670] HKH2: +++++

[1671] SW48: +++++

[1672] 1447 T A549: +++++

[1673] NJ

[1674] z MCF7: +++++

[1675] MDA-MB-231:

[1676] +++++

[1677] O)Z z z^ / — K562: +++++

[1678] SW480: +++

[1679] H2Y JI O HCT116: +++

[1680] NX HKH2: +++

[1681] 2=Z NH2

[1682] SW48: ++++

[1683] DNAPK: +++ DNAPK / m 1448FX6 A549: +++

[1684] mTOR: +++++ TOR: ++ MCF7: ++++

[1685] HOMDA-MB-231:

[1686] LTN N

[1687] r°v^

[1688] 0 <o z z z £^—z= K562: +++

[1689] SW480: ++++

[1690] H2V z OO HCT116: ++++

[1691] )= N=-Xl HKH2: ++++

[1692] CM z

[1693] T / = / NH2

[1694] SW48: +++++ DNAPK: ++++ DNAPK / m 1449F<6 A549: ++++

[1695] mTOR: +++++ TOR: ++ MCF7: +++++

[1696] 9J1MDA-MB-231:

[1697] ' y°^ ++++

[1698] 0

[1699] K562: ++++

[1700] SW480: ++++

[1701] HCT116: ++++

[1702] HKH2: ++++

[1703] SW48: +++++ DNAPK: ++++ DNAPK / m 1450 A549: ++++

[1704] mTOR: +++++ TOR: + MCF7: +++++

[1705] MDA-MB-231:

[1706] ++++-1- K562: ++++

[1707]

[1708] 55718966-2 "to

[1709] sh

[1710] / = / NH2SW480: ++++

[1711] F\ 1

[1712] HCT116: ++++

[1713] 1453 HKH2: ++++

[1714] SW48: +++++ MCF7: +++++

[1715] to-N

[1716] \-—N

[1717] NIT

[1718] xto

[1719] H! Nyo

[1720] Jl

[1721] to SW480: ++++

[1722] / = / NH2

[1723] HCT116: ++++

[1724] 1454Fto HKH2: ++++

[1725] SW48: +++++ MCF7: +++++

[1726] FV

[1727] 0

[1728] H2NV-O

[1729] Il.

[1730] Nto\ SW480: +++

[1731] / = / NH2HCT116: +++

[1732] 1455Fto HKH2: +++

[1733] SW48: +++++ MCF7: +++++

[1734] 0

[1735] HINY%

[1736] NVto

[1737] / = / NH SW480: ++++

[1738] F2

[1739] \ 1 HCT116: ++++

[1740] <to j DNAPK: +++ DNAPK / m 1458 HKH2: +++++

[1741] mTOR: +++++ TOR: ++ SW48: +++++ MCF7: +++++

[1742] > — N

[1743] to

[1744] ° A

[1745] H2NY°V

[1746] N^to

[1747] 2^= / NH2SW480: ++++

[1748] F \ 1

[1749] HCT116: ++++ DNAPK: +++ DNAPK / m 1460 CT!

[1750] HKH2: ++++ mTOR: +++++ TOR: ++++ SW48: +++++

[1751] N^ 4

[1752] \-N

[1753] 0

[1754]

[1755] 55718966-2H2NVO

[1756] IT

[1757] / == / NH2SW480: ++

[1758] HCT116: ++

[1759] 1462F<6 HKH2: +++

[1760] FSW48: +++

[1761] / \

[1762] 0A

[1763] H2VV T98G: +++

[1764] / == / NH2U87MG: +++

[1765] DNAPK / m SW480: +++ DNAPK: ++

[1766] 1464F<6 TOR:

[1767] HCT116: +++ mTOR: ++++

[1768] ++++FHKH2: ++

[1769] / \

[1770] \— N SW48: +++

[1771] o

[1772] X

[1773] / = / NH2SW480: +++

[1774] HCT116: +++

[1775] 1466

[1776] N-^N^ HKH2: +++

[1777] SW48: ++++

[1778] N^ LJ

[1779] o zv / \

[1780] H2NY°v

[1781] T98G: ++

[1782] N" / A= / NH2U87MG: +++

[1783] DNAPK / m SW480: +++ DNAPK: +++

[1784] 1468FTOR:

[1785] HCT116: ++ mTOR: ++++

[1786] HKH2: +++

[1787] N^ LN SW48: ++++

[1788] 0 Y°^

[1789]

[1790] 55718966-2 V

[1791] NH2SW480: +++

[1792] HCT116: +++

[1793] 1470

[1794] HKH2: +++

[1795] SW48: ++++

[1796] N^"7

[1797] '^N

[1798] o rv / X

[1799] N\

[1800] NH2SW480: +++

[1801] DNAPK / m HCT116: +++ DNAPK: ++

[1802] 1472F<6 TOR:

[1803] HKH2: +++ mTOR: +++++

[1804] ++++ SW48: ++++

[1805] o7^'

[1806] Z < \ CIX - 0

[1807] °yd?ocV^ <

[1808] HN

[1809] Y% SW480: ++++

[1810] / = / NH2HCT116: ++++

[1811] 1474 F \ 1 HKH2: +++++

[1812] CO SW48: +++++ MCF7: +++++

[1813] N^7 \

[1814] X— N

[1815] 0YV

[1816] A SW480: ++++

[1817] HCT116: ++++

[1818] 1475 HKH2: ++++

[1819] SW48: +++++ MCF7: +++++

[1820]

[1821] 55718966-2 SW480: +++

[1822] HCT116: +++ 1476 O, HKH2: ++++

[1823] ' -n SW48: ++++ J 7 -n MCF7: +++++ L / ~~z / ^

[1824] V * / Z ' \ io> —

[1825] o

[1826] °y°^ I

[1827] HNv IIo

[1828] SW480: +++N\ A HCT116: +++ / =ZNH2

[1829] 1477F\ 1 HKH2: ++++

[1830] 1 SW48: ++++

[1831] MCF7: +++++F / \

[1832] '^-N

[1833] 0

[1834] r-O

[1835] °yc> ^

[1836] HN.n

[1837] SW480: ++N\ HCT116: ++

[1838] NH 14782

[1839] F\ 1 HKH2: +++

[1840] SW48: +++ MCF7: +++Fb

[1841] 0

[1842]

[1843] 55718966-2 Kinome screening: results of kinome screening experiments show sapanisertib to be highly promiscuous, also inhibiting 26 other kinases, aside from mTOR where hits are defined as <50% remaining kinase activity after 1 pM treatment. Sapanisertib hits clusters around the Tyrosine Kinase-Like (TKL) family, Tyrosine Kinase (TK) family, the Casein Kinases (CK), and the PI3K isoforms. The TKL and TK families are implicated in a wide variety of cell processes and so are integral for homeostatic functioning, and the CKs are important in cell cycle progression, cell structure, and signal transduction. The PI3K isoforms are also key for cell survival. Targeting several or all of these kinases simultaneously is, without being bound by theory, very likely to disrupt homeostasis and functioning of not only cancer cells but healthy parenchyma also. In contrast, the compounds disclosed herein inhibit fewer kinases (by way of example, compounds 1346 and 1396 inhibit only 6 and 7, respectively), and do not hit a wide range of other TLK or TKs, unlike compounds disclosed in the prior art such as sapanisertib. Without being bound by theory, less off-target kinase inhibition is likely to lead to lower toxicity and higher efficacy when used in vivo. Kinome inhibition profiles of select compounds are shown in Fig. 1A-F.

[1844] Fig. 2 shows the comparison between the kinome inhibition profile of select compounds (1137, 1177, 1328, 1346, and 1396) versus the prior art (sapanisertib). All kinases with less than 50% activity remaining after compound addition are shown. Compounds were screened at 1 pM.

[1845] Oncolines screening panel of compound 1396: the novel compound 1396 disclosed herein displays superior antiproliferative activity in the Oncolines® Human Cancer Cell Line Panel compared to those in the prior art, including commercially available second-generation mTOR inhibitors tested here (such as sapanisertib). Novel compound 1396 exerts cytostatic activity on 93 / 102 cell lines tested in the panel, and exerts cytotoxic activity in 9 / 102 cell lines tested. Novel compound 1396 displays antiproliferative activity ranging from 0.69nM - 33nM in cell lines of the following heterogenous cancer types: Epithelioid sarcoma; Endometrial adenocarcinoma; Ovarian clear cell adenocarcinoma; Papillary renal cell carcinoma; Medulloblastoma; Skin sguamous cell carcinoma; Pancreatic adenocarcinoma; Gastric adenocarcinoma; Osteosarcoma; Embryonal rhabdomyosarcoma; Invasive breast carcinoma of no special type; Breast adenocarcinoma; Diffuse large B-cell lymphoma; Primitive neuroectodermal tumour; Endometrial adenosguamous carcinoma; Chronic myelogenous leukaemia; BCR-ABL1 positive; Gastric signet ring cell adenocarcinoma; Hypopharyngeal

[1846] 55718966-2 squamous cell carcinoma; Cervical squamous cell carcinoma, not otherwise specified; Lung adenocarcinoma; Biphasic synovial sarcoma; Childhood T acute lymphoblastic leukaemia; Fibrosarcoma; Melanoma; Breast carcinoma; Bladder carcinoma; Colon carcinoma; Duodenal adenocarcinoma; Lung large cell carcinoma; Astrocytoma; Renal cell carcinoma; Tongue squamous cell carcinoma; Glioblastoma; Adult T acute lymphoblastic leukaemia; Blast phase chronic myelogenous leukaemia, BCR-ABL1 positive; High grade ovarian serous adenocarcinoma; Lung squamous cell carcinoma; Cutaneous melanoma; Prostate carcinoma; Neuroblastoma; Ovarian mixed germ cell tumour; Diffuse large B-cell lymphoma germinal center B-cell type; Liposarcoma; Adult B acute lymphoblastic leukaemia; Hereditary thyroid gland medullary carcinoma; Alveolar rhabdomyosarcoma; Colon adenocarcinoma; Cecum adenocarcinoma; Pancreatic ductal adenocarcinoma; Amelanotic melanoma; Childhood T lymphoblastic lymphoma; Adult acute myeloid leukaemia; Gestational choriocarcinoma; Cervical carcinoma; Childhood acute monocytic leukaemia; Testicular embryonal carcinoma; Anaplastic large cell lymphoma, ALK-positive; Lung small cell carcinoma; Rectal adenocarcinoma.

[1847] It is important to highlight that having strong antiproliferative activity on such a genetically diverse number of cancer cell lines indicates translation of antiproliferative activity against tumours that may be complex and heterogenous due to cancer progression and drug resistance, or those that are poorly differentiated and of high grade. Novel compound 1396 is cytotoxic against cell lines of tumour types: prostate carcinoma; diffuse large B-cell lymphoma germinal center B-cell type; endometrial adenocarcinoma; breast carcinoma; Anaplastic large cell lymphoma, ALK-positive; gastric adenocarcinoma; chronic myelogenous leukemia, BCR-ABL1 positive; invasive breast carcinoma of no special type; diffuse large B-cell lymphoma. This may indicate that these cancer types might be more dependent on mTOR signalling and therefore, more suitable to be treated with the compounds of the invention. Notably, novel compound 1396 did not induce cell death against cell lines of organ tissues, but not limited to: kidney, bowel, brain, lung, skin, and thyroid. Table 2 follows.

[1848] 55718966-2 Table 2

[1849] The compound 1396 disclosed herein displays superior antiproliferative activity (EC50), max effect, antiproliferative activity (GI50), and / or lethal dose in the Oncolines® Human Cancer Cell Line Panel. LD50: NL = Non lethal concentration >316nM

[1850] Cell line Disease Anti prolife rati Max Antiproliferati Lethal name ve activity of effect of ve activity of Dose of 1396 1396 (%) 1396 1396 EC50(nM) GI50(nM) LD50 (n M) A-204 Embryonal 0.69 89 0.78 NL rhabdomyosarcoma

[1851] VA-ES- Epithelioid sarcoma 1.2 92 0.95 NL BJ

[1852] A-498 Renal cell carcinoma 1.2 94 1.1 NL AN3-CA Endometrial adenocarcinoma 1.3 97 1.2 114 MCF-7 Invasive breast carcinoma of 1.4 87 1.2 NL no special type

[1853] KG-1 Adult acute myeloid leukemia 1.6 81 1.5 NL SNU-5 Gastric adenocarcinoma 1.8 84 2.3 NL Hs 578T Invasive breast carcinoma of 1.9 88 1.8 NL no special type

[1854] A-427 Lung adenocarcinoma 2.2 78 3.3 NL A-172 Glioblastoma 2.2 88 2 NL LoVo Colon adenocarcinoma 2.6 92 2.6 NL TCCSU Bladder carcinoma 2.6 93 2.7 NL P ACHN Papillary renal cell carcinoma 2.6 97 2.8 NL ES-2 Ovarian clear cell 2.6 98 2.7 NL adenocarcinoma

[1855] T24 Bladder carcinoma 2.9 89 3.4 NL Daoy Medulloblastoma 2.9 96 3 NL A-388 Skin squamous cell 3.0 83 3.6 NL carcinoma

[1856] Hs 766T Pancreatic adenocarcinoma 3.1 92 2.8 NL U- Astrocytoma 3.3 86 3.8 NL 118MG

[1857] U2OS Osteosarcoma 3.3 93 3.4 NL CCRF- Childhood T acute 3.3 99 2.3 NL CEM lymphoblastic leukemia

[1858] MG-63 Osteosarcoma 3.4 95 3.4 NL

[1859]

[1860] 55718966-2 Cell line Disease Anti prolife rati Max Antiproliferati Lethal name ve activity of effect of ve activity of Dose of 1396 1396 (%) 1396 1396 EC50(nM) GI50(nM) LD50 (n M) PFSK-1 Primitive neuroectodermal 3.5 88 3.4 NL tumor

[1861] AU565 Breast adenocarcinoma 3.5 90 2.8 NL RL Diffuse large B-cell 3.5 98 3.6 292 lymphoma

[1862] SU- Diffuse large B-cell 3.5 99 3.3 44 DHL-6 lymphoma germinal center

[1863] B-cell type

[1864] RL95-2 Endometrial adenosquamous 3.6 93 3.2 NL carcinoma

[1865] KLE Endometrial adenocarcinoma 3.7 82 2.3 NL FaDu Hypopharyngeal squamous 3.8 90 4.1 NL cell carcinoma

[1866] KATO Gastric signet ring cell 3.8 91 3.4 NL III adenocarcinoma

[1867] DU145 Prostate carcinoma 3.8 92 4 NL Ku812 Chronic myelogenous 3.8 94 2.8 196 leukemia, BCR-ABL1

[1868] positive

[1869] C-33 A Cervical squamous cell 3.9 93 3.5 NL carcinoma, not otherwise

[1870] specified

[1871] RPMI- Melanoma 3.9 93 4 NL 7951

[1872] SW982 Biphasic synovial sarcoma 4.2 85 4.7 NL BT-20 Invasive breast carcinoma of 4.3 77 4.1 NL no special type

[1873] RT-4 Bladder carcinoma 4.3 86 3.8 NL HT-1080 Fibrosarcoma 4.4 97 6.1 NL Hs Gastric adenocarcinoma 4.5 94 3.1 157 746. T

[1874] DU4475 Breast carcinoma 4.5 99 4 139 NCI- Lung large cell carcinoma 4.6 92 5.4 NL H460

[1875] LS411N Cecum adenocarcinoma 4.7 92 5.3 NL SW948 Colon adenocarcinoma 4.9 87 4.8 NL A-704 Renal cell carcinoma 5.0 63 4.2 NL

[1876]

[1877] 55718966-2 Cell line Disease Anti prolife rati Max Antiproliferati Lethal name ve activity of effect of ve activity of Dose of 1396 1396 (%) 1396 1396 EC50(nM) GI50(nM) LD50 (n M) G-361 Melanoma 5.0 91 4.1 NL HCT 116

[1878] RKO Colon carcinoma 5.1 91 5.8 NL HuTu Duodenal adenocarcinoma 5.1 94 5.4 NL 80

[1879] Jurkat Childhood T acute 5.1 95 3.2 NL E6.1 lymphoblastic leukemia

[1880] T98G Glioblastoma 5.2 95 5.1 NL SK-N-FI Neuroblastoma 5.4 78 5.2 NL CAL-27 Tongue squamous cell 5.5 87 6.4 NL carcinoma

[1881] COLO Cutaneous melanoma 5.7 86 5.1 NL 829

[1882] BxPC-3 Pancreatic ductal 5.7 89 4.5 NL adenocarcinoma

[1883] MOLT-4 Adult T acute lymphoblastic 5.7 95 5.2 NL leukemia

[1884] A-549 Lung adenocarcinoma 5.7 97 4.6 NL NCI- Lung large cell carcinoma 5.8 82 6.4 NL H661

[1885] K-562 Blast phase chronic 5.9 98 6.2 NL myelogenous leukemia,

[1886] BCR-ABL1 positive

[1887] RD Embryonal 6.1 93 5.9 NL rhabdomyosarcoma

[1888] OVCAR High grade ovarian serous 6.2 86 4.1 NL -3 adenocarcinoma

[1889] SW900 Lung squamous cell 6.2 91 5.8 NL carcinoma

[1890] BT-549 Invasive breast carcinoma of 6.2 98 4.3 239 no special type

[1891] PC-3 Prostate carcinoma 6.3 93 5.5 NL SW48 Colon adenocarcinoma 6.4 67 10 NL LS174T Colon adenocarcinoma 6.4 87 7.5 NL PA-1 Ovarian mixed germ cell 6.5 96 6.8 NL tumor

[1892]

[1893] 55718966-2 Cell line Disease Anti prolife rati Max Antiproliferati Lethal name ve activity of effect of ve activity of Dose of 1396 1396 (%) 1396 1396 EC50(nM) GI50(nM) LD50 (n M) SW626 Colon adenocarcinoma 6.8 84 6.7 NL J82 Bladder carcinoma 6.8 92 6.9 NL MeWo Cutaneous melanoma 7.0 76 7.8 NL HCT 15 Colon adenocarcinoma 7.1 90 8.5 NL SW872 Liposarcoma 7.2 93 6.8 NL CCF- Astrocytoma 7.3 89 6.4 NL STTG1

[1894] RS4;11 Adult B acute lymphoblastic 7.5 87 6.7 NL leukemia

[1895] 5637 Bladder carcinoma 7.5 88 7.7 NL HT Diffuse large B-cell 7.6 92 7 NL lymphoma germinal center

[1896] B-cell type

[1897] SK-N- Neuroblastoma 7.6 92 7.2 NL AS

[1898] 786-0 Renal cell carcinoma 7.6 94 7.9 NL TT Hereditary thyroid gland 7.7 64 4.8 NL medullary carcinoma

[1899] 769-P Renal cell carcinoma 7.9 91 8.1 NL Rh30 Alveolar rhabdomyosarcoma 8.5 93 6.9 NL AsPC-1 Pancreatic ductal 8.9 74 9.6 NL adenocarcinoma

[1900] LNCaP Prostate carcinoma 9.2 92 5.3 33 clone

[1901] FGC

[1902] U-87MG Glioblastoma 9.5 90 11 NL ATCC COLO Colon adenocarcinoma 9.6 96 8.5 NL 205

[1903] DB Diffuse large B-cell 9.8 91 8.5 NL lymphoma germinal center

[1904] B-cell type

[1905] DLD-1 Colon adenocarcinoma 9.8 94 11 NL SW480 Colon adenocarcinoma 11 86 11 NL A-375 Amelanotic melanoma 11 89 11 NL SUP-T1 Childhood T lymphoblastic 11 96 9.4 NL lymphoma

[1906]

[1907] 55718966-2 Cell line Disease Anti prolife rati Max Antiproliferati Lethal name ve activity of effect of ve activity of Dose of 1396 1396 (%) 1396 1396 EC50(nM) GI50(nM) LD50 (n M) MIA Pancreatic ductal 12 90 13 NL PaCa-2 adenocarcinoma

[1908] SNU- Cecum adenocarcinoma 13 51 25 NL C2B

[1909] JAR Gestational choriocarcinoma 13 90 13 NL SU- Anaplastic large cell 13 96 13 NL DHL-1 lymphoma, ALK-positive

[1910] DoTc2 Cervical carcinoma 14 76 18 NL 4510

[1911] THP-1 Childhood acute monocytic 15 81 11 NL leukemia

[1912] NCC-IT Testicular embryonal 16 89 14 NL carcinoma

[1913] NCI-H82 Lung small cell carcinoma 18 81 26 NL HL-60 Adult acute myeloid leukemia 23 77 33 NL SW620 Colon adenocarcinoma 23 94 25 NL SR Anaplastic large cell 25 99 27 141 lymphoma, ALK-positive

[1914] SW837 Rectal adenocarcinoma 32 78 43 NL SHP-77 Lung small cell carcinoma 33 86 35 NL

[1915]

[1916] 55718966-2 Antibody Drug Conjugates (ADCs): Novel compounds 1396 and 1458 were phenotypically screened against the following FDA-approved ADC payloads: exatecan, staurosporine, SN-38, paclitaxel, and MMAE (Monomethyl auristatin E). This was carried out to test the potential of the novel compounds disclosed herein to be conjugated to a biomolecule e.g. an antibody, to provide an ADC, in addition to monotherapy. Novel compound 1396 outperformed both the multi-kinase inhibitor staurosporine, and inhibitor compound SN-38. SN-38 is the active metabolite of irinotecan and the payload incorporated in the approved ADC ‘sacituzumab govitecan’. Compound 1458 outperformed almost all ADC payloads. Table 3 below provides the activity of compounds 1396 and 1458 compared to various ADC payloads. EC50curves comparing compound 1458 and FDA approved ADC payload MMAE in HKH2, SW48, and MCF7 cells are provided in Fig. 4.

[1917] To illustrate the possibility of conjugating the compounds of the invention (e.g. to ligands or antibodies), compound 1396 was modified at the primary amino group of the benzo[d]oxazole ring. Without being bound by theory, this amino group (as either a primary amino group (-NH2) or a secondary amino group (-NHR)) is thought to be important for the interaction of the compounds with the target. As shown by the activity of compounds 1474, 1475, 1476 and 1477, small secondary amino groups such as -NH(acyl) and -NH(C(O)OR) groups are tolerated for activity; larger groups, however, appear to reduce activity. Thus, this amino group appears to be a suitable candidate group to conjugate to biomolecules (such as antibodies) through appropriate linker technologies or to be masked to generate prodrugs. As a proxy to mimic the chemical strategy to incorporate the compounds of the invention into a conjugate (e.g. into an ADC to be used as an anticancer payload) at this group, the benzyloxycarbonyl (or carboxybenzoyl, Cbz) modified compound 1478 was synthesised and tested against SW480, HCT116, HKH2, SW48, and MCF7 cancer cells. Analysis of the activity of 1478 compared to 1396 (Table 3 below) demonstrates that conjugation to the amino group to a large group (the benzyloxycarbonyl group) leads to a reduction in activity (up to 63.5-fold), demonstrating the opportunity for the generation of prodrugs and conjugates (i.e. compounds with masked or latent activity). Associated EC50curves are also found in the drawings in Fig. 5.

[1918] Table 3

[1919] Novel compound 1458 outperforms almost all ADC payloads tested. Modification of compound 1396 with a benzyloxycarbonyl group (compound 1478) leads to reduction

[1920] 55718966-2 of activity, demonstrating proof of concept for transformation into an ADC. EC50 values are displayed in nM.

[1921] Drug SW480 HCT116 HKH2 SW48 MCF7

[1922] 1478 >300 >300 88.4 40.1 12.7

[1923] 1396 9.69 4.79 5.70 1.41 0.20

[1924] 1458 1.89 1.41 0.50 0.26 0.03

[1925] Exatecan 2.19 1.21 1.37 1.58 0.38 Staurosporine 19.12 10.63 9.77 4.35 6.39

[1926] SN-38 6.90 4.58 7.31 4.74 2.26 Paclitaxel 10.22 3.01 1.89 2.07 1.15 MMAE 1.39 0.78 0.58 0.16 0.19

[1927]

[1928] KPN organoid screen and size analysis: In KPN colorectal cancer organoids, novel derivatives 1328 and 1346 outperform both sapanisertib and rapamycin in antiproliferative capacity, with similar potency to their potency in the 2D colorectal cancer cell lines. Without being bound by theory, this demonstrates the compounds disclosed herein are more potent in both 2D and 3D. For example, compound 1346 exhibited strong antiproliferative capacity overall, in both 2D and 3D. Regarding organoid size, compound 1346 also outperformed sapanisertib in reducing organoid size after 72h of treatment, being able to significantly reduce organoid size compared to DMSO, down to 30 nM, whereas sapanisertib was ineffective below 100 nM. Compound 1328 performs similarly to sapanisertib despite having a higher antiproliferative activity, and rapamycin is ineffective at reducing organoid size, matching its ineffective antiproliferative capacity. The data is displayed in Tables 4 and 5 below.

[1929] Table 4

[1930] The compounds disclosed herein display superior antiproliferative activity, compared to the prior art (such as sapanisertib and rapamycin), in mouse-derived KPN liver metastasis organoids from primary colorectal tumour, with KRAS, P53, and Notch mutations; EC50= >1000 nM “NA” >500 nM “+” >100 nM “++” >10 nM “+++” >1 nM > “++++”.

[1931] Code Antiproliferative activity (EC50)

[1932] Sapanisertib ++

[1933]

[1934] 55718966-2 Rapamycin NA

[1935] 1328 +++

[1936] 1346 ++++

[1937]

[1938] Table 5

[1939] Compound 1346 displayed superior activity to reduce organoid size at 72h treatment, compared to sapanisertib. Compound 1328 performed similarly to sapanisertib. Rapamycin was ineffective in reducing organoid size; % Relative Organoid size vs DMSO p value = >0.05 “NA” >0.01 >0.001 “**” >0.0001 “***" >0.00001 “****".

[1940] Concentration (nM) Sapanisertib Rapamycin 1328 1346 10,000 **** NA **** **** 3000 **** NA **** **** 1000 **** NA **** **** 300 **** NA **** **** 100 **** NA **** **** 30 NA NA NA ***

[1941] 10 NA NA NA NA

[1942]

[1943] Scratch wound healing assay: In HCT116 and HKH2 cells at 12h, compounds 1328 and 1346 moderately inhibited wound healing capacity at all concentrations, superior to that of sapanisertib which is not active below 100 nM. This was especially evident at 100 nM in HCT116 cells where compound 1346 is significantly better when compared to rapamycin. In HKH2 cells, the compounds disclosed herein performed significantly better than sapanisertib at 10 nM (where sapanisertib was not active), and rapamycin at all concentrations; rapamycin was ineffective at inhibiting wound healing capacity. In HCT116 and HKH2 cells at 24h, the compounds disclosed herein strongly inhibited wound healing capacity at all concentrations tested, whereas sapanisertib did not inhibit at 10 nM in either cell line. Rapamycin does not inhibit wound healing capacity at any concentration in both of the cell lines tested. Compound 1346 for example displays excellent wound healing inhibitory capacity across the 2 colorectal cancer cell lines. Compound 1396 also displays excellent wound healing inhibitory capacity across the 2 colorectal cancer cell lines at 24h at all concentrations tested, being significantly better than rapamycin at every concentration in HKH2 cells and at 100 nM and 10 nM in HCT116 cells. Compound 1396 also significantly outperforms sapanisertib at 10 nM in

[1944] 55718966-2 HKH2 cells. Broadly, the compounds disclosed herein displayed superior inhibition to wound healing capacity of colorectal cancer cell lines, inhibiting at all concentrations. This is in contrast to the prior art (such as sapanisertib and rapamycin) which displays no anti-wound healing capabilities below 30 nM, at both 12 h (Table 6) and 24 h (Table 7); Wound Width percentage decrease = <20% “NA” <30% “+” <40% “++” <50% “+++” <60% “++++” <100% “+++++”.

[1945] Table 6

[1946] 12h Wound Width percentage decrease

[1947] 100 nM 30 nM 10 nM DMSO Sapanisertib HCT 116 ++ + NA NA

[1948] Rapamycin HCT116 NA NA NA NA

[1949] 1328 HCT116 ++ ++ + NA

[1950] 1346 HCT116 +++ +++ ++ NA

[1951] 1396 HCT116 NA + NA NA Sapanisertib HKH2 +++ + NA NA

[1952] Rapamycin HKH2 NA NA NA NA

[1953] 1328 HKH2 +++ +++ ++ NA

[1954] 1346 HKH2 +++ ++ + NA

[1955] 1396 HKH2 +++ +++ + NA

[1956]

[1957] 55718966-2 Table 7

[1958] 24h Wound Width percentage decrease

[1959] 100 nM 30 nM 10 nM DMSO Sapanisertib HCT 116 +++ + NA NA

[1960] Rapamycin HCT116 NA NA NA NA

[1961] 1328 HCT116 ++++ +++ ++ NA

[1962] 1346 HCT116 ++++ +++ +++ NA

[1963] 1396 HCT116 ++ ++ + NA Sapanisertib HKH2 +++ ++ + NA

[1964] Rapamycin HKH2 NA NA NA NA

[1965] 1328 HKH2 ++++ +++ +++ NA

[1966] 1346 HKH2 ++++ ++++ ++ NA

[1967] 1396 HKH2 ++++ +++ +++

[1968]

[1969] Western Blotting: To validate mTOR as a (or, the) target of the compounds disclosed herein (as indicated by the kinome screen), mTOR kinase and its substrates were blotted for, post 3h drug treatment with compound 1396 in SW48 and MCF7 cells. In MCF7 cells, the compound completely inhibited mTOR phosphorylation of downstream substrates S6 and P70S6K (mTORC1 substrates) and AKT (mTORC2 substrate) at all concentrations, with only the lowest dose of 1 nM showing partial (less than 90%) phosphorylation (see Figure 3A and 3B). Notably, UPF1 phosphorylation (substrate of SMG1, a member of the PIKK family, to which mTOR belongs) was not affected by the treatment. In SW48 cells, compound 1396 fully inhibits mTOR phosphorylation of AKT down to the lowest dose of 0.3nM and partially S6 phosphorylation down to the lowest dose of 0.3nM. Overall, these blots indicate, without being bound by theory, compound 1396 to be an mTOR kinase inhibitor superior potency and selectivity than sapanisertib. These properties are key for clinical application.

[1970] In vivo PK studies: In vivo PK studies in mice by IV (1 mg / kg) and oral administration (3 mg / kg) for a compound of the present disclosure, in particular compound 1396. Analytical runs met calibration standard and QC acceptance criteria. The IV 1 mg / kg and PO 3 mg / kg dose formulations were 94.3% and 111% of their nominal concentrations and were both clear solutions. Nominal doses were used in PK parameter determinations. Following IV administration of a compound of the present

[1971] 55718966-2 disclosure, in particular compound 1396, at 1 mg / kg, a blood clearance of 17.6 ± 0.735 mL / min / kg and a volume of distribution of 1.61 ± 0.241 L / kg were determined. Following PO administration of a compound of the present disclosure, in particular compound 1396, at 3 mg / kg, a Cmax of 682 ± 97.9 ng / mL was observed at a median Tmaxof 0.5 h. The average bioavailability was 72.4 ± 5.52% using AUCinf. No adverse effects were observed following administration of a compound of the present disclosure, in particular compound 1396, by any of the routes.

[1972] In vivo toxicity studies: Tolerability study by performing single dose escalation study in immunocompetent mice. Study: n= 3 mice / dose level. 3 dose levels plus 1 vehicle. Increasing dose if no signs observed in preceding dose. Based on compound 1396’s PK and target potency, the starting dose was 10 mg / Kg, which showed no adverse effects. At 30 mg / Kg, mice experienced bodyweight loss and some of them showed clinical signs (reduced activity and slight piloerection). Notably, daily oral doses of 1396 at 10 mg / Kg for 10 consecutive days were tolerated by the mice. 1396 demonstrates far superior tolerability than sapanisertib in mice, which has a recommended dose of 2 mg / Kg every other day (Wei et al. Efficacy, Tolerability, and Pharmacokinetics of Combined Targeted MEK and Dual mTORC1 / 2 Inhibition in a Preclinical Model of Mucosal Melanoma. Mol Cancer Ther. 2020 Nov; 19(11):2308-2318).

[1973] In vivo efficacy and PD studies: Studies performed in immunocompromised mice anesthetised by isoflurane and implanted in the left fourth mammary fat pad with one million human breast cancer cells. Tumours allowed to grow until they reached around 40 mm3in size, after which, mice are randomly allocated into two groups. Mice treated with vehicle or a compound of the invention (1 to 10 mg / kg, dissolved at 4 mg / mL in vehicle) once daily by oral gavage (100 pL per 10 g mouse weight) for 28 days. Tumour size measured by calliper and mice weighed twice a week. >60% difference in tumour growth between vehicle and treatment with a compound of the present disclosure, e.g., compound 1396, is considered active. Mice culled by cervical dislocation once tumour size reached 15 mm in diameter. Once tumour endpoint is reached, mice are culled and tumours are dissected and weights recorded. Tumour tissues fixed in neutral buffered formalin and paraffin embedded for IHC (mTOR substrates) and H& E analysis.

[1974] Clinical trial in human subjects: advanced malignancies: A compound of the present disclosure is administered to human subjects suffering from advanced malignancies, followed by an Expansion Phase in participants with renal cell carcinoma, endometrial cancer or urothelial cancer who have measurable disease. Subject

[1975] 55718966-2 response to the compound administration is evaluated by Objective Response Rat...

Claims

CLAIMS1. A compound for use in a method of treatment or prophylaxis of a disease, wherein the compound is of formula (I), or a pharmaceutically acceptable salt, or solvate thereof:w4wherein:W1, W2, and W3are each independently selected from H, halo, and ORW;W4is selected from H, R11, C(O)R12, and C(O)OR13; wherein R11is selected from Ci-ealkyl, Cs-scycloalkyl, C2-6alkenyl, Cs-scycloalkenyl, and C2-6alkynyl; R12is selected from C1-5alkyl, C3-7cycloalkyl, C2-5alkenyl, C3-7cycloalkenyl, and C2-5alkynyl; and R13is selected from C1-4alkyl, C3-6cycloalkyl, C2-4alkenyl, C3-6cycloalkenyl, C2-4alkynyl, and benzyl; wherein R11, R12, and R13are each optionally substituted one or more times with halo, such as fluoro;each Rwis independently selected from Ci-ealkyl, Ci-ehaloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl;G1and G2are each independently selected from H, halo, and amino;X1is N or CH;X2is N; andG3is:Y-^n1 / Zwherein:n1 is an integer selected from 0, 1, and 2;Y is selected from (Ila) to (lie):55718966-2(Ha)wherein ring A is a 3- to 12-membered N-heterocycloalkylene;(Hb)wherein ring B is a 3- to 12-membered cycloalkylene;R3(lie).n22wherein n2 is an integer selected from 1 to 6;wherein each R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Cs-wheteroaryl, Ce-waryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;ring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (He) are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl,55718966-2Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and*1 indicates a bond to Z and *2 indicates a bond to*n1of G3;Z is selected from (IIIa) to (I lie):JVVV / ^O(IIIa) v;wherein:V is selected from OR4, CFHR4, CF2R4, CF3, and Cs-eheterocyclyl; wherein the Cs-eheterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Ce-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;R4is selected from Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, Cs-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;7V IWp5 Z ^OR" N\c(lllb)R6;wherein:R5and R6are each independently selected from Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, N(R10)2, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-55718966-26alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci_6alkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce- aryl, Cs-wheteroaryl, Ce-waryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; orR5and R6combine with the nitrogen atom to form a 3- to 12-membered A / -heterocycle, wherein the 3- to 12-membered A / -heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci_6alkoxy, phenylCi-2alkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; and(lllc) Ce-wheteroaryl;wherein:the Ce-wheteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-6alkoxy, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Ce-wheteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl and Cs-ecycloalkenyl are optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;and further wherein:each R9is independently selected from R10, OR10, and N(R10)2; andeach R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Ce-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino.55718966-22. The compound for use of claim 1, wherein G1is amino.

3. The compound for use of claim 1 or 2, wherein G2is H.

4. The compound for use of any one preceding claim, wherein W1, W2, and W3are each independently H or fluoro.

5. The compound for use of any one preceding claim, wherein:W1is H or fluoro; andW2and W3are each H.

6. The compound for use of any one preceding claim, wherein W4is selected from H, -C(O)Ci-5alkyl, and -C(O)OCi-4alkyl.

7. The compound for use of any one preceding claim, wherein W4is H.

8. The compound for use of any one preceding claim, wherein n1 is 1.

9. The compound for use of any one preceding claim, wherein X1is CH.

10. The compound for use of any one preceding claim, wherein Y is selected from formulae (lld-i):wherein:an optional C1-3alkylene group bridges carbon 1 or 2 to carbon 3 or 4 in formula (IIe);55718966-2each R1is independently selected from H, halo (e.g. F), C1-3alkyl, C1-3alkoxy, cyano, hydroxy and C1-3haloalkyl (e.g. C1-2fluoroalkyl);each R2is independently selected from halo, oxo, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, phenylC1-2alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, wherein the C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, phenylC1-2alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;R3, R9, and R10are as defined in claim 1;n' is an integer selected from 0 to 6;n" is an integer selected from 0 to 5;n’” is an integer selected from 0 to 3; andn”” is an integer selected from 0 to 1.

11. The compound for use of any one preceding claim, wherein Y is selected from formulae (I Ij-r):wherein:R1is as defined in claim 9;R2is H or as defined in claim 9;R3, R9, and R10are as defined in claim 1;n3 is an integer selected from 0 to 3; andn4 is an integer selected from 0 to 2.55718966-212. The compound for use of any one preceding claim, wherein Y is selected from one of the following structures:wherein:R1is selected from H, fluoro, methyl, hydroxy, methoxy and cyano (e.g. selected from H, fluoro and methyl); andR3is Ci-3alkyl.

13. The compound for use of any one preceding claim, wherein Z is of formula (IIIa)v (IIIa);wherein:V is selected from OR4, and C3-6heterocyclyl;R4is selected from C1-6alkyl, phenylC1-4alkyl, C6-10aryl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, wherein the C1-6alkyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, and C3-6cycloalkenyl, are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, nitro, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;wherein the C3-6heterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, amino, cyano, C1-C6alkyl, C1-C6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;wherein R9is selected from R10, OR10, and N(R10)2; andeach R10is independently selected from H, and C1-6alkyl.

14. The compound for use of any one preceding claim, wherein V is OR4.

15. The compound for use of any one preceding claim, wherein R4is selected from C1-4alkyl, C2-5alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl C6-10aryl, and C5-10heteroaryl; wherein the C1-4alkyl, C2-5alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, and C5-10heteroaryl are each optionally substituted one or more times (e.g. 1 or 2 times) with fluoro.55718966-216. The compound for use of any one preceding claim, wherein Z is selected from the following structures:

17. The compound for use of any one of claims 1 to 12, wherein Z is of formula (II lb):w IwR6(lllb);and further wherein:R5and R6are each independently selected from C1-6alkyl and phenyl, wherein the C1-6alkyl and phenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, C1-6alkyl, and C1-6alkoxy; orR5and R6combine with the nitrogen atom to form a 5- to 6-membered N-heterocycle, wherein the 5- to 6-membered N-heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, C1-6alkyl, and C1-6alkoxy.55718966-218. The compound for use of claim 17, wherein Z is selected from one of the following structures:

19. The compound for use of any one of claims 1 to 12, wherein Z is selected from formulae (llld-f):wherein:ring C is 5- or 6-membered carbocycle or heterocycle;X3is selected from O, and S;each X is independently selected from CR7, N, O, and S;each X' is independently selected from C, and N;each R7is independently selected from H, halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;each R8is independently selected halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;R9is selected from R10, OR10, and N(R10)2;each R10is independently selected from H, and C1-6alkyl; andn5 is an integer selected from 0 to 4.

20. The compound for use of claim 19, wherein Z is selected from formulae (lllg-k):55718966-2wherein:X3, R7, R8, and n5 are as defined in claim 19.

21. The compound for use of claim 19 or 20, wherein Z is selected from one of the following structures:« / vvv22. The compound for use of any one preceding claim, wherein Y is selected from formulae (Ila), optionally (lid) and (lie), further optionally (llj).

23. The compound for use of any one preceding claim, wherein Z is selected from formulae (IIIa) and (I lie), optionally (IIIa).

24. The compound for use of any one of claims 10 to 23, wherein each R1is independently selected from H, fluoro, C1-3alkyl, C1-3alkoxy, and cyano, optionally wherein each R1is independently selected from H, fluoro, methyl, and cyano.

25. The compound for use of any one of claims 10 to 24, wherein each R2is independently selected from fluoro, and methyl, or is absent (i.e. n’ is 0).

26. The compound for use of any one preceding claim, wherein:55718966-2n2 is selected from 2, 3, and 4, optionally 3.

27. The compound for use of any one of claims 11 to 26, wherein:n3 is 0 or 2; and / orn4 is selected from 2, 3, and 4, optionally 1 or 3.

28. The compound for use of claim 1, wherein the compound is selected from those compounds shown in Table 1, and wherein the compound is not sapanisertib or compound 1225.

29. The compound for use of claim 1, wherein the compound is any one selected from:

30. The compound for use of any one preceding claim, wherein the disease is mediated by mTOR.

31. The compound for use of any one preceding claim, wherein the disease is selected from a proliferative disorder such as cancer, an inflammatory disorder, an autoimmune disorder, a fibrotic disorder, a neurological disorder, a microbial disease, a parasitic disease, a metabolic disorder, genetic disorders driven by aberrant mTOR signalling, and a disease acquired from aberrant mTOR signalling due to the administration of a medicament.

32. The compound for use of claim 31, wherein the disease is cancer.55718966-233. The compound for use of claim 32, wherein the cancer is selected from solid and liquid cancers at any stage, optionally wherein the cancer is a late stage cancer, and / or wherein the cancer is selected from: colorectal cancer including, but not limited to, colon carcinoma and adenocarcinoma, cecum adenocarcinoma, and rectal adenocarcinoma; breast cancer including, but not limited to, invasive breast carcinoma of no special type, breast carcinoma and adenocarcinoma; lung cancer including, but not limited to, lung adenocarcinoma, lung large cell carcinoma, lung squamous cell carcinoma, and lung small cell carcinoma; melanoma including but, not limited to, cutaneous melanoma, and amelanotic melanoma; non-melanoma cancer including, but not limited to, skin squamous cell carcinoma; brain cancer including, but not limited to, glioblastoma multiforme, medulloblastoma, primitive neuroectodermal tumour, astrocytoma, and neuroblastoma; haematological cancer including, but not limited to, leukaemia of myeloid and / or lymphoid origin including, but not limited to, diffuse large B-cell lymphoma including those that are germinal center B-cell type, chronic myelogenous leukaemia, childhood T acute lymphoblastic leukaemia and lymphoma, Adult T acute lymphoblastic and myeloid leukaemia, blast phase chronic myelogenous leukaemia including those that are BCR-ABL1 positive, adult B acute lymphoblastic leukaemia, childhood acute monocytic leukaemia, and anaplastic large cell lymphoma including those that are ALK-positive; soft tissue cancers including, but not limited to, epithelioid sarcoma, biphasic synovial sarcoma, fibrosarcoma, liposarcoma, alveolar rhabdomyosarcoma, and embryonal rhabdomyosarcoma; cancers of reproductive origin including, but not limited to, endometrial adenocarcinoma, ovarian clear cell adenocarcinoma, endometrial adenosquamous carcinoma, cervical squamous cell carcinoma, high grade ovarian serous adenocarcinoma, prostate carcinoma, ovarian mixed germ cell tumour, cervical carcinoma, testicular embryonal carcinoma, and gestational choriocarcinoma; pancreatic cancer including, but not limited to, pancreatic adenocarcinoma, and pancreatic ductal adenocarcinoma; renal cancer including, but not limited to, papillary renal cell carcinoma, and renal cell carcinoma; gastric cancer including, but not limited to, gastric adenocarcinoma, and gastric signet ring cell adenocarcinoma; intestinal cancer including, but not limited to, duodenal adenocarcinoma; bone cancer including, but not limited to, osteosarcoma; pharyngeal cancer including, but not limited to, hypopharyngeal squamous cell carcinoma; bladder cancer including, but not limited to, bladder carcinoma; tongue cancer including, but not limited to, tongue squamous cell carcinoma; and thyroid cancer including, but not limited to, hereditary thyroid gland medullary carcinoma.55718966-234. The compound for use of any one preceding claim, wherein the compound is conjugated to a biomolecule, such as an antibody.

35. The compound for use of any one preceding claim, wherein the compound is in a pharmaceutical composition further comprising one or more pharmaceutically acceptable carriers and / or excipients.

36. The compound for use of any one preceding claim, wherein the method comprises the use of one or more additional therapeutic agents, optionally wherein the compound is administered in combination with one or more additional therapeutic agents.

37. The compound for use of claim 35 or 36, wherein the compound is administered orally, parentally, by inhalation or topically.

38. The compound for use of any one of claims 35 to 37, wherein the pharmaceutical composition is a cream, a gel, an ointment, a lotion, a transdermal patch, a spray, an aerosol, a tablet, a pill, a capsule, or a syrup.

39. A method of treatment or prophylaxis of a disease, comprising administering to a subject in need thereof a therapeutically effective amount of a compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, optionally wherein the disease is as defined in any one of claims 30 to 33.

40. Use of compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, in the manufacture of a medicament for the treatment of a disease, optionally wherein the disease is as defined in any one of claims 30 to 33.

41. A compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof:55718966-2wherein:W1, W2, and W3are each independently selected from H, halo, and ORW;W4is selected from H, R11, C(O)R12, and C(O)OR13; wherein R11is selected from Ci-ealkyl, Cs-scycloalkyl, C2-6alkenyl, Cs-scycloalkenyl, and C2-6alkynyl; R12is selected from C1-5alkyl, C3-7cycloalkyl, C2-5alkenyl, C3-7cycloalkenyl, and C2-5alkynyl; and R13is selected from C1-4alkyl, C3-6cycloalkyl, C2-4alkenyl, C3-6cycloalkenyl, C2-4alkynyl, and benzyl; wherein R11, R12, and R13are each optionally substituted one or more times with halo, such as fluoro; each Rwis independently selected from Ci-ealkyl, Ci-ehaloalkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl;G1and G2are each independently selected from H, halo, and amino;X1and X2are each independently N or CH; andG3is:wherein:n1 is an integer selected from 0, 1, and 2;Y is selected from (Ila) to (lie):(Ha)wherein ring A is a 3- to 12-membered N-heterocycloalkylene;55718966-2(Hb)wherein ring B is a 3- to 12-membered cycloalkylene;(He)wherein n2 is an integer selected from 1 to 6;wherein each R3is independently selected from Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; andring A of formula (Ila), ring B of formula (lib), and the alkylene group of formula (lie) are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, phenylC1-4alkyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the Ci-ealkyl, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, C3-ecycloalkenyl, and phenylCi-4alkyl are each optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-6alkoxy, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;Z is selected from (IIIa) to (I He):(IIIa)v;wherein:V is selected from OR4, CFHR4, CF2R4, CF3, and C3-6heterocyclyl;55718966-2wherein the Cs-eheterocyclyl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, phenylCi-2alkyl, C2-6alkenyl, Cs-ealkynyl, Cs-ecycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;R4is selected from Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce-waryl, C5-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, C3-6alkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-ehaloalkyl, phenylCi-4alkyl, Ce- aryl, C5-wheteroaryl, Cs-eheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-6alkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Ce-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2;(IIIb)R6;wherein:R5and R6are each independently selected from Ci-ealkyl, Ci-6haloalkyl, Ce-waryl, Cs-wheteroaryl, C3-10heterocycloalkyl, N(R10)2, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, Ci-6haloalkyl, Ce-waryl, Cs-wheteroaryl, C3-wheterocycloalkyl, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are each optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, Ci-ealkyl, Ci-ehaloalkyl, Ci-ealkoxy, C2-ealkenyl, C3-ealkynyl, Cs-ecycloalkyl, Cs-ecycloalkenyl, Ce-waryl, Cs-wheteroaryl, Ce-waryloxy, Cs-wheteroaryloxy, C(O)R9, and N(R10)2; orR5and R6combine with the nitrogen atom to form a 3- to 12-membered N-heterocycle, wherein the 3- to 12-membered N-heterocycle is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, phenylC1-2alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and(IIIc) C5-10heteroaryl;55718966-2wherein the C5-10heteroaryl is optionally substituted one or more times with any one or a combination selected from: halo, hydroxy, oxo, cyano, nitro, amino, C1-6alkyl, C1-6haloalkyl, C1-6alkoxy, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl, C3-6cycloalkenyl, C6-10aryl, C5-10heteroaryl, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2; and wherein the C1-6alkyl, C2-6alkenyl, C3-6alkynyl, C3-6cycloalkyl and C3-6cycloalkenyl are optionally substituted one or more (e.g., from 1 to 6) times with any one or a combination selected from: halo, hydroxy, amino, C1-6alkyl, C1-6alkoxy, C6-10aryloxy, C5-10heteroaryloxy, C(O)R9, and N(R10)2;and further wherein:each R9is independently selected from R10, OR10, and N(R10)2; andeach R10is independently selected from H, Ci-ealkyl, phenylCi-2alkyl, Ce- aryl, Ce-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl, wherein the Ci-ealkyl, phenylCi-2alkyl, Ce- aryl, Ce-wheteroaryl, C3-10heterocycloalkyl, C2-ealkenyl, Cs-ealkynyl, Cs-ecycloalkyl, and Cs-ecycloalkenyl are optionally substituted one or more times with any one or a combination selected from halo, hydroxy, oxo, cyano, Ci-ealkyl, Ci-ealkoxy, nitro, and amino;with the proviso that when:(a) W1, W2, W3, and W4are each H;(b) X1and X2are each N;(c) G1is amino; and(d) G2is H;then G3is not one of the following groups:55718966-242. A pharmaceutical composition comprising the compound of formula (I), or a pharmaceutically acceptable salt, or solvate thereof, and further comprising one or more pharmaceutically acceptable carriers and / or excipients.55718966-2

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