Substituted heterocyclic compounds, compositions comprising them and uses thereof

Abstract

The present application discloses substituted polycyclic heterocycles compound of Formula (I), pharmaceutically acceptable salt and / or solvate and pharmaceutical compositions thereof useful in the treatment of proliferative disease or condition characterized by a dysregulation of the RAS-ERK pathway such as neoplasm disease or disorder, inflammatory disease or immune system disorder.

Description

[0001] SUBSTITUTED HETEROCYCLIC COMPOUNDS, COMPOSITIONS COMPRISING THEM AND USES THEREOF

[0002] RELATED APPLICATION

[0003] The present application claims priority under applicable law to United States provisional application No. 63 / 648,912 filed on Mai 17, 2024, the content of which is incorporated herein by reference in its entirety and for all purposes.

[0004] TECHNICAL FIELD

[0005] This disclosure generally relates to heterocyclic compounds, pharmaceutical compositions comprising the same and their use in the treatment and prevention of diseases characterized by dysregulation of the RAS-ERK pathway (e.g. cancer, RASopathies).

[0006] BACKGROUND

[0007] The RAS-RAF-MEK-ERK (RAS: rat sarcoma; RAF: rapidly accelerated fibrosarcoma; MEK: mitogen-activated protein kinase; ERK: extracellular signal-regulated kinase) signaling pathway (hereafter referred to as the RAS-ERK pathway) plays a critical role in transmitting proliferation signals generated by growth factor receptors from the plasma membrane to the nucleus. The pathway is dysregulated in a large proportion of cancers by constitutively activating mutations in RAS genes (H-, K- and NRAS; overall 30% of cancers) as well as in genes that encode upstream (EGFR, NF1) or downstream (BRAF) pathway constituents. The prevalence of KRAS mutations is especially high in pancreatic (>90%), colorectal (50%), and lung (30%) cancers and the majority of mutations occur at the glycine 12, glycine 13 or glutamine 61 residues (G12, G13 or Q61) (Prior et al. PMID: 32209560).

[0008] RAS proteins are small GTPases that convey extracellular growth signals to intracellular effectors to control vital processes such as cell differentiation, proliferation, and survival (Nat. Rev. Cancer 2003, 3, 459). Physiological activation of RAS occurs at the plasma membrane after stimulation of RTKs (Receptor Tyrosine Kinases), leading to GTP loading and thus activation of the GTPase. The intrinsic rate of exchange of GDP for GTP being extremely slow, conversion requires the action of guanine nucleotide exchange factors (GEFs) such as the son of sevenless gene products (SOS1 or SOS2 in human). Activated RAS then interacts and activates a battery of effector molecules, with the RAF kinases being the most critical RAS interactors in the context of cancer development (Nature Rev. Drug Discov. 2014, 13, 828). Mammalian cells express three RAF paralogs (ARAF, BRAF, and CRAF) that share a conserved C-terminal kinase domain (KD) (Nat. Rev. Mol. Cell Biol. 2015, 16, 281) and are activated through direct engagement of their N- terminal RAS-binding domain (RBD) by GTP-RAS. In unstimulated cells, RAF proteins are sequestered in the cytoplasm as monomers. Binding to GTP-RAS through their RBD induces membrane anchoring of RAF kinases, their dimerization and catalytic activation (Nature 2009, 461 , 542; Nat. Rev. Mol. Cell Biol. 2015, 16, 281). Activated RAF proteins in turn convey signals through a phosphorylation cascade from RAF to MEK and then MEK to ERK, leading to phosphorylation by ERK of an array of substrates eliciting cell-specific responses (Nat. Rev. Mol. Cell Biol. 2020, Oct;21 (10), 607). After transmission to downstream effectors, GTP-RAS signaling can be terminated when it is no longer required through hydrolysis of GTP. RAS possesses an intrinsically low hydrolysis activity that absolutely requires catalysis through the action of GTPase activating proteins (GAPs) such as the neurofibromatosis type 1 (NF1) gene product. Oncogenic mutations at the G12, G13, or Q61 positions in RAS isoforms lead to bypassing the need for GEF- mediated GTP loading as well as escaping intrinsic and GAP-mediated GTP hydrolysis. Together, these events lead to evasion of oncogenic mutants from normal regulatory mechanisms, a buildup of the pool of mutated GTP-RAS and a resulting aberrant and constitutive downstream signaling in tumors (Nat. Rev. Cancer 2003, 3, 459).

[0009] RAS proteins were long considered undruggable for several reasons. Firstly, the development of nucleotide-competitive inhibitors of RAS is precluded given the extremely strong binding affinity of RAS for the regulatory guanine nucleotides (picomolar range for GDP and GTP). Second, RAS is a small globular protein that offers only shallow or very transient pockets. Despite these limitations, the past decade has seen the development of KRAS inhibitors that started answering one of the most prominent unmet medical needs in oncology (Moore et al. 2020; PMID: 32528145).

[0010] The first productive efforts towards KRAS inhibition have focused on covalent inhibitors of the G12C allele. Initial hits sharing an acrylamide warhead were identified through mass- spectrometry-based screening for compounds enabling covalent adduct formation with the nucleophilic cysteine 12 sulfhydryl group (Ostrem et. al. 2013; PMID: 24256730). Interestingly, harnessing of covalent compounds onto cysteine-mutated KRAS revealed a pocket named the Switch II pocket (Swll) that is normally transient but is stabilized in the presence of smallmolecules anchored to cysteine 12 (Ostrem et. al. 2013; PMID: 24256730). The initial KRAS G12C hits showed only low affinities and poor cellular potencies. Yet, optimization of Swll pocket engagement and tuning of the reactivity and selectivity of acrylamide warheads eventually led to the identification of clinical compounds such as sotorasib and adagrasib. These have demonstrated remarkable efficacy in early clinical trials against non-small cell lung cancer (NSCLC) harboring the KRAS G12C allele and were granted an accelerated approval by the FDA for treating this patient population (Skoulidis et al. 2021 ; PMID: 34096690; Janne et al. 2022; PMID: 35658005). Clinical responses to these agents arise from potent and prolonged target engagement that leads to locking RAS in the GDP-bound inactive conformation and into a resulting suppression of downstream pathways (Moore et al. 2020; PMID: 32528145). An added benefit of this approach is that since they selectively engage the KRAS G12C mutant and not the WT protein, these inhibitors demonstrate a wide therapeutic index. Unfortunately, as for most other RAS-ERK pathway inhibitors, acquired resistance to these agents invariably develops, which is mostly caused by re-activation of the cascade through mechanisms that include elevation of RTK signaling, RAS mutations that block engagement of the inhibitors or activation of downstream pathway components like RAF and MEK (Awad et a. 2021 ; PMID: 34161704). Yet, the advent of KRAS G12C inhibitors represents an important leap forward in targeting what was considered as an undruggable target for decades and allows demonstrating the clinical feasibility of directly disrupting aberrant KRAS signaling in solid tumors.

[0011] Importantly, results obtained with G12C inhibitors also hinted at a potential for non-covalent targeting of KRAS through occupancy of the Swll pocket (Vasta et al. 2022; PMID: 35314814). However, for this to be possible, more affine binding to the Swll pocket needed to be achieved through optimized scaffolds. First successes at non-covalently targeting Swll were obtained over the past few years. In order to productively engage KRAS in a non-covalent fashion, the G12D allele turned out as an ideal handle. In fact, it was found that the acidic nature of this mutation (aspartic acid) could allow the formation of a strong ionic bond with a basic moiety replacing the acrylamide warhead found in covalent KRAS G12C inhibitors (Wang et al. 2022; PMID: 34889605; Vasta et al. 2022; PMID: 35314814). These efforts led to the discovery of highly potent and selective inhibitors of KRAS G12D such as MRTX1133 (Wang et al. 2022; PMID: 34889605). Follow up work recently led to the development of inhibitors displaying lower allele selectivity that therefore not only target the charged aspartate mutation but also other KRAS glycine 12 substitutions (G12X inhibitors) (Kim et al. 2023; PMID: 37258666; WG2022132200A1 , Mirati; WO2023183585A1 , Loxo Lilly; WO2023099592A1 , Boehringer Ingelheim; WO2023154766A1 , Quanta therapeutics). However, the clinical development of both G12D and G12X inhibitors has so far been slowed down due to their relatively poor DMPK properties. There is therefore a dire need for inhibitors that potently block KRAS signaling and cellular proliferation in human tumor cells bearing a variety of KRAS alleles. The development of such inhibitors that potently and non-covalently target a variety of KRAS alleles is highly desirable.

[0012] SUMMARY According to one aspect, the present technology relates to a compound of Formula I, II or III:

[0013] Formula III wherein L, R1, R2, R3, R11, R12, X1, X2, X3, and X4are as herein defined, or a pharmaceutically acceptable salt and / or solvate thereof.

[0014] In some embodiments, the compound of Formula I is a compound of Formula l-A, l-B, l-C, or l-D:

[0015] wherein L, R1, R2, R3, R4, and R5are as herein defined, or a pharmaceutically acceptable salt and / or solvate thereof.

[0016] In other embodiments, the compound of Formula I is a compound of Formula l-E: wherein R1, R2, R9, R9’, R10, R10’, X1, X2, X3, and p are as herein defined, or a pharmaceutically acceptable salt and / or solvate thereof.

[0017] The compounds of Formulae I, l-A to l-E, II, and III are also defined according to any of the embodiments, alone or in combination, and examples described throughout the present document.

[0018] According to another aspect, the present technology relates to a pharmaceutical composition for a use as defined in any one of the aforementioned embodiments, the composition comprising a compound as herein defined together with a pharmaceutically acceptable carrier, diluent or excipient.

[0019] In a further aspect, the present technology relates to the use of a compound as herein defined for the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), or an inflammatory disease or an immune system disorder. The present technology also further relates to a method for the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), or an inflammatory disease or an immune system disorder, comprising administering a compound as herein defined to a subject in need thereof. A method for inhibiting abnormal proliferation of cells, comprising contacting the cells with a compound as defined herein is also contemplated.

[0020] In one embodiment of the above uses and methods, the disease or disorder is selected from a neoplasm and a developmental anomaly, for instance, a disease or disorder associated with a RAS gene mutation (e.g. KRAS, HRAS, NRAS). In one embodiment, the disease or disorder is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

[0021] For instance, the disease or disorder is a neoplasm, such as those selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, ovarian, breast cancer, uterine cancer, endometrial cancer, testicular cancer, renal and bladder cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, Barret's adenocarcinoma, glioma (e.g. ependymoma), lung cancer (e.g. non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, and hairy-cell leukemia. For instance, the neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma. For instance, any of the present uses and methods comprises inhibiting the RAS-ERK signaling pathway.

[0022] Additional objects and features of the present compound, compositions, methods and uses will become more apparent upon reading of the following non-restrictive description of exemplary embodiments and examples section, which should not be interpreted as limiting the scope of the invention.

[0023] DETAILED DESCRIPTION

[0024] All technical and scientific terms and expressions used herein have the same definitions as those commonly understood by a person skilled in the art to which the present technology pertains. The definition of some terms and expressions used is nevertheless provided below. To the extent the definitions of terms in the publications, patents, and patent applications incorporated herein by reference are contrary to the definitions set forth in this specification, the definitions in this specification will control. The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter disclosed.

[0025] / . Definitions

[0026] Chemical structures described herein are drawn according to conventional standards. Also, when an atom, such as a carbon atom, as drawn seems to include an incomplete valency, then the valency is assumed to be satisfied by one or more hydrogen atoms even though these are not necessarily explicitly drawn. Hydrogen atoms should be inferred to be part of the compound.

[0027] The terminology used herein is for the purpose of describing particular embodiments only and is not intended to be limiting. It should be noted that, the singular forms "a", "an", and "the" include plural forms as well, unless the content clearly dictates otherwise. Thus, for example, reference to a composition containing "a compound" also contemplates a mixture of two or more compounds. It should also be noted that the term "or" is generally employed in its sense including "and / or" unless the context clearly dictates otherwise. Furthermore, to the extent that the terms “including”, "includes", "having", "has", "with", or variants thereof are used in either the detailed description and / or the claims, such terms are intended to be inclusive in a manner similar to the term "comprising”.

[0028] The term "about" or "approximately" means within an acceptable error range for the particular value as determined by one of ordinary skill in the art, which will depend in part on how the value is measured or determined, i.e., the limitations of the measurement system. For example, "about" can mean within 1 or more than 1 standard deviation, per the practice in the art. Alternatively, "about" can mean a range of up to 20%, preferably up to 10%, more preferably up to 5%, and more preferably still up to 1 % of a given value. Alternatively, particularly with respect to biological systems or processes, the term can mean within an order of magnitude, preferably within 5-fold, and more preferably within 2-fold, of a value. Where particular values are described in the application and claims, unless otherwise stated the term "about" meaning within an acceptable error range for the particular value should be assumed.

[0029] As used herein, the terms "compounds”, “compounds herein described”, “compounds of the present application”, “9 / 7-purine compounds”, “1 / 7-imidazo[4,5,c]pyridine compounds”, “3 / 7- imidazo[4,5-b]pyridine compounds”, “7 / 7-pyrrolo[2,3,d] pyrimidine compounds”, “pyrimido[4,5,b][1 ,6]naphthyridine compounds”, “3 / 7-imidazo[4’,5’:5,6]pyrido[4,3,d]pyrimidine compounds”, and equivalent expressions refer to compounds described in the present application, e.g. those encompassed by structural Formulae I, l-A to l-E, II and III, optionally with reference to any of the applicable embodiments, and also includes exemplary compounds, such as the compounds of Examples 1 to 200 as well as their pharmaceutically acceptable salts, solvates, esters, and prodrugs when applicable. When a zwitterionic form is possible, the compound may be drawn as its neutral form for practical purposes, but the compound is understood to also include its zwitterionic form. Embodiments herein may also exclude one or more of the compounds. Compounds may be identified either by their chemical structure or their chemical name. In a case where the chemical structure and chemical name would conflict, the chemical structure will prevail.

[0030] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, and geometric (or conformational)) forms of the structure when applicable; for example, the R and S configurations for each asymmetric center. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, and geometric (or conformational) mixtures of the present compounds are within the scope of the present description. The therapeutic compound unless otherwise noted, also encompasses all possible tautomeric forms of the illustrated compound, if any. The term also includes isotopically labeled compounds where one or more atoms have an atomic mass different from the atomic mass most abundantly found in nature. Examples of isotopes that may be incorporated into the present compounds include, but are not limited to,2H (D),3H (T),11C,13C,14C,15N,18O,17O, any one of the isotopes of sulfur, etc. The compound may also exist in unsolvated forms as well as solvated forms, including hydrated forms. The compound may exist in multiple crystalline or amorphous forms. In general, all physical forms are equivalent for the uses contemplated herein and are intended to be within the scope of the present invention.

[0031] Where a particular enantiomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer and may also be enantiomerically enriched. "Enantiomerically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer. Preferred enantiomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high- pressure liquid chromatography (HPLC) on chiral support and the formation and crystallization of chiral salts or be prepared by asymmetric syntheses.

[0032] The expression "pharmaceutically acceptable salt" refers to those salts of the compounds of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge, et al. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 1-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the present description, or separately by reacting a free base function of the compound with a suitable organic or inorganic acid (acid addition salts) or by reacting an acidic function of the compound with a suitable organic or inorganic base (base-addition salts).

[0033] The term “solvate” refers to a physical association of one of the present compounds with one or more solvent molecules, including water and non-aqueous solvent molecules. This physical association may include hydrogen bonding. In certain instances, the solvate will be capable of isolation, for example when one or more solvent molecules are incorporated in the crystal lattice of a crystalline solid. The term “solvate” encompasses both solution-phase and isolable solvates. Exemplary solvates include, without limitation, hydrates, hemihydrates, ethanolates, hemiethanolates, n-propanolates, / so-propanolates, 1 -butanolates, 2-butanolate, and solvates of other physiologically acceptable solvents, such as the Class 3 solvents described in the International Conference on Harmonization (ICH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compound as herein described also includes each of its solvates and mixtures thereof.

[0034] As used herein, the expression "pharmaceutically acceptable ester" refers to esters of the compounds formed by the process of the present description which may hydrolyze in vivo and include those that break down readily in the human body to leave the parent compound or a salt thereof. Suitable ester groups include, for example, those derived from pharmaceutically acceptable aliphatic carboxylic acids, particularly alkanoic, alkenoic, cycloalkanoic and alkanedioic acids, in which each alkyl or alkenyl moiety advantageously has not more than 6 carbon atoms. Examples of particular esters include, but are not limited to, formates, acetates, propionates, butyrates, acrylates, and ethylsuccinates of hydroxyl groups, and alkyl esters of an acidic group. Other ester groups include, for example, sulfonate or sulfate esters.

[0035] The expression "pharmaceutically acceptable prodrugs" as used herein refers to those prodrugs of the compounds formed by the process of the present description which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals with undue toxicity, irritation, allergic response, and the like, commensurate with a reasonable benefit / risk ratio, and effective fortheir intended use. "Prodrug", as used herein means a compound which is convertible in vivo by metabolic means (e.g. by hydrolysis) to afford any compound delineated by the formulae of the instant description.

[0036] Abbreviations may also be used throughout the application, unless otherwise noted, such abbreviations are intended to have the meaning generally understood by the field. Examples of such abbreviations include Me (methyl), Et (ethyl), Pr (propyl), / -Pr (isopropyl), Bu (butyl), t-Bu (tert-butyl), / -Bu ( / so-butyl), s-Bu (sec-butyl), c-Bu (cyclobutyl), Ph (phenyl), Bn (benzyl), Bz (benzoyl), CBz or Cbz or Z (carbobenzyloxy), Boc or BOC (tert-butoxycarbonyl), and Su or Sue (succinimide). For more certainty, additional definitions of specific abbreviations are also included in the introduction of the Examples section.

[0037] The number of carbon atoms in a hydrocarbyl substituent can be indicated by the prefix "Cx-Cy" or "Cx-y" where x is the minimum and y is the maximum number of carbon atoms in the substituent. However, when the prefix “Cx-Cy” or "Cx-y" is associated with a group incorporating one or more heteroatom(s) by definition (e.g. heterocycloalkyl, heteroaryl, etc.), then x and y define respectively the minimum and maximum number of atoms in the cycle or cycles, including carbon atoms as well as heteroatom (s).

[0038] The term "alkyl" as used herein, refers to a saturated, straight- or branched-chain hydrocarbon radical typically containing from 1 to 20 carbon atoms. For example, "Ci-Cs alkyl" contains from one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, fert-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.

[0039] The term "alkenyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more double bonds and typically from 2 to 20 carbon atoms. For example, "C2- salkenyl" contains from two to eight carbon atoms. Alkenyl groups include, but are not limited to, for example, ethenyl, propenyl, butenyl, l-methyl-2-buten-l-yl, heptenyl, octenyl and the like.

[0040] The term "alkynyl" as used herein, denotes a straight- or branched-chain hydrocarbon radical containing one or more triple bonds and typically from 2 to 20 carbon atoms. For example, "C2- salkynyl" contains from two to eight carbon atoms. Representative alkynyl groups include, but are not limited to, for example, ethynyl,1-propynyl, 1-butynyl, heptynyl, octynyl and the like.

[0041] The terms “cycloalkyl”, “alicyclic”, “carbocycle”, “carbocyclic” and equivalent expressions refer to a group comprising a saturated or partially unsaturated (non aromatic) carbocyclic ring in a monocyclic or polycyclic ring system, including spiro (sharing one atom), fused (sharing at least one bond) or bridged (sharing two or more bonds) carbocyclic ring systems, having from three to fifteen ring members. Examples of cycloalkyl groups include, without limitation, cyclopropyl, cyclobutyl, cyclopentyl, cyclopenten-1-yl, cyclopenten-2-yl, cyclopenten-3-yl, cyclohexyl, cyclohexen-1-yl, cyclohexen-2-yl, cyclohexen-3-yl, cycloheptyl, bicyclo[4,3,0]nonanyl, norbornyl, and the like. The term cycloalkyl includes both unsubstituted cycloalkyl groups and substituted cycloalkyl groups. For example, the term “Cs-ncycloalkyl” refers to a cycloalkyl group having from 3 to the indicated “n” number of carbon atoms in the ring structure. Unless the number of carbons is otherwise specified, “lower cycloalkyl” groups as herein used, have at least 3 and equal or less than 8 carbon atoms in their ring structure.

[0042] As used herein, the terms "heterocycle", "heterocycloalkyl", "heterocyclyl", "heterocyclic radical", and "heterocyclic ring" are used interchangeably and refer to a chemically stable 3- to 7- membered monocyclic or 7-10-membered bicyclic heterocyclic moiety that is either saturated or partially unsaturated, and having, in addition to carbon atoms, one or more, preferably one to four, heteroatoms, as defined above. When used in reference to a ring atom of a heterocycle, the term "nitrogen" includes a substituted nitrogen. As an example, in a saturated or partially unsaturated ring having 1-3 heteroatoms selected from oxygen, sulfur or nitrogen, the nitrogen may be N (as in 3,4-dihydro-2H-pyrrolyl), NH (as in pyrrolidinyl), or NR (as in N-substituted pyrrolidinyl). A heterocyclic ring can be attached to its pendant group at any heteroatom or carbon atom that results in a chemically stable structure and any of the ring atoms can be optionally substituted. Examples of heterocycloalkyl groups include, but are not limited to, 1 ,3-dioxolanyl, pyrrolidinyl, pyrrolidonyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, thiophenyl, tetrahydrofuranyl, tetrahydropyranyl, tetrahydrothiopyranyl, tetrahydrodithienyl, tetrahydrothienyl, thiomorpholino, thioxanyl, azetidinyl, oxetanyl, thietanyl, homopiperidinyl, oxepanyl, thiepanyl, oxazepinyl, diazepinyl, thiazepinyl, 1 ,2,3,6-tetrahydropyridinyl, 2-pyrrolinyl, 3-pyrrolinyl, 2H- pyranyl, 4H-pyranyl, dioxanyl, dithianyl, dithiolanyl, dihydropyranyl, dihydrothienyl, di hydrofuranyl, 3-azabicyclo[3,1 ,0]hexanyl, 3-azabicyclo[4,1 ,0]heptanyl, quinolizinyl, quinuclidinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, and the like. Heterocyclic groups also include groups in which a heterocyclic ring is fused to one or more aryl, heteroaryl, or cycloaliphatic rings, such as indolinyl, 3H-indolyl, benzothiazolyl, benzothiophenyl, chromanyl, chromenyl, phenanthridinyl, 2-azabicyclo[2.2.1]heptanyl, octahydroindolyl, or tetrahydroquinolinyl, where the radical or point of attachment is on the heterocyclyl ring. A heterocyclyl group may be mono- or bicyclic. The term "heterocyclylalkyl" refers to an alkyl group substituted by a heterocyclyl, wherein the alkyl and heterocyclyl portions independently are optionally substituted. The term “Cs-n heterocycloalkyl” refers to a heterocycloalkyl group having from 3 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0043] As used herein, the term "partially unsaturated" refers to a ring moiety that includes at least one double or triple bond between ring atoms but is not aromatic. The term "partially unsaturated" is intended to encompass rings having multiple sites of unsaturation but is not intended to include aryl or heteroaryl moieties, as herein defined.

[0044] The term "aryl" used alone or as part of a larger moiety as in "aralkyl", "aralkoxy", "aryloxy", or "aryloxyalkyl", refers to aromatic groups having 4n+2 conjugated ir(pi) electrons, wherein n is an integer from 1 to 3, in a monocyclic moiety or a bicyclic or tricyclic fused ring system having a total of six to 15 ring members, wherein at least one ring in the system is aromatic and wherein each ring in the system contains three to seven ring members. The term "aryl" may be used interchangeably with the term "aryl ring". In certain embodiments of the present description, "aryl" refers to an aromatic ring system which includes, but not limited to, phenyl, biphenyl, naphthyl, azulenyl, anthracyl and the like, which may bear one or more substituents. The term "aralkyl" or "arylalkyl" refers to an alkyl residue attached to an aryl ring. Examples of aralkyl include, but are not limited to, benzyl, phenethyl, and the like. Also included within the scope of the term “aryl”, as it is used herein, is a group in which an aromatic ring is fused to one or more non-aromatic rings, such as indanyl, indenyl, phthalimidyl, naphthimidyl, fluorenyl, phenanthridinyl, or tetrahydronaphthyl, and the like. For example, the term “Ce-naryl” refers to an aryl group having from 6 to the indicated “n” number of atoms in the ring structure.

[0045] The term "heteroaryl", used alone or as part of a larger moiety, e.g., "heteroaralkyl", or "heteroaralkoxy", refers to aromatic groups having 4n+2 conjugated ir(pi) electrons, wherein n is an integer from 1 to 3 (e.g. having 5 to 18 ring atoms, preferably 5, 6, or 9 ring atoms; having 6, 10, or 14 TT electrons shared in a cyclic array); and having, in addition to carbon atoms, from one to five heteroatoms. The term "heteroatom" includes but is not limited to nitrogen, oxygen, or sulfur, and includes any oxidized form of nitrogen or sulfur, and any quaternized form of a basic nitrogen. A heteroaryl may be a single ring, or two or more fused rings. The term "heteroaryl", as used herein, also includes groups in which a heteroaromatic ring is fused to one or more aryl, cycloaliphatic, or heterocyclic rings, where the radical or point of attachment is on the heteroaromatic ring. Nonlimiting examples of heteroaryl groups include thienyl, furanyl (furyl), pyrrolyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiazolyl, isothiazolyl, thiadiazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, indolyl, 3H-indolyl, isoindolyl, indolizinyl, benzothienyl (benzothiophenyl), benzofuranyl, dibenzofuranyl, indazolyl, benzimidazolyl, benzoxazolyl, benzothiazolyl, benzotriazolyl, pyrrolopyridinyl (e.g. pyrrolo[3,2- b]pyridinyl or pyrrolo[3,2-c]pyridinyl), pyrazolopyridinyl (e.g. pyrazolo[1,5-a]pyridinyl), furopyridinyl, purinyl, imidazopyrazinyl (e.g. imidazo[4,5-b]pyrazinyl), quinolyl (quinolinyl), isoquinolyl (isoquinolinyl), quinolonyl, isoquinolonyl, cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl, 4H-quinolizinyl, naphthyridinyl, and pteridinyl carbazolyl, acridinyl, phenanthridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, and pyrido[2,3-b]-l,4-oxazin-3(4H)-one. A heteroaryl group may be mono- or bicyclic. Heteroaryl groups include rings that are optionally substituted. The term "heteroaralkyl" refers to an alkyl group substituted by a heteroaryl, wherein the alkyl and heteroaryl portions independently are optionally substituted. Examples include, but are not limited to, pyridinylmethyl, pyrimidinylethyl and the like. For instance, the term “Cs-nheteroaryl” refers to a heteroaryl group having from 5 to the indicated “n” number of atoms in the ring structure, including carbon atoms and heteroatoms.

[0046] As described herein, compounds of the present description may contain "optionally substituted" moieties. In general, the term "substituted", whether preceded by the term "optionally" or not, means that one or more hydrogens of the designated moiety are replaced with a suitable substituent. Unless otherwise indicated, an "optionally substituted" group may have a suitable substituent at each substitutable position of the group, and when more than one position in any given structure may be substituted with more than one substituent selected from a specified group, the substituent may be either the same or different at each position. Combinations of substituents envisioned under the present description are preferably those that result in the formation of chemically stable or chemically feasible compounds. The term "chemically stable", as used herein, refers to compounds that are not substantially altered when subjected to conditions to allow for their production, detection, and, in certain embodiments, their recovery, purification, and use for one or more of the purposes disclosed herein.

[0047] The term “halo” designates a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0048] The term "optionally substituted" refers to groups that are substituted or unsubstituted by independent replacement of one, two, or three or more of the hydrogen atoms thereon with substituents including, but not limited to F, Cl, Br, I, OH, CO2H, alkoxy, oxo, thiooxo, NO2, CN, CF3, NH2, NHalkyl, NHalkenyl, NHalkynyl, NHcycloalkyl, NHaryl, NHheteroaryl, NHheterocyclic, dialkylamino, diarylamino, diheteroarylamino, O-alkyl, O-alkenyl, O-alkynyl, O-cycloalkyl, O-aryl, O-heteroaryl, O-haloalkyl, O-heterocyclic, C(O)alkyl, C(O)alkenyl, C(O)alkynyl, C(O)cycloalkyl, C(O)aryl, C(O) heteroaryl, C(O)heterocycloalkyl, CO2alkyl, CO2alkenyl, CO2alkynyl, CChcycloalkyl, CCharyl, CO2heteroaryl, CChheterocycloalkyl, OC(O)alkyl, OC(O)alkenyl, OC(O)alkynyl, OC(O)cycloalkyl, OC(O)aryl, OC(O)heteroaryl, OC(O)heterocycloalkyl, C(O)NH2, C(O)NHalkyl, C(O)NHalkenyl, C(O)NHalkynyl, C(O)NHcycloalkyl, C(O)NHaryl, C(O)NH heteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCChalkenyl, OCChalkynyl, OCChcycloalkyl, OCCharyl, OCChheteroaryl, OCChheterocycloalkyl, OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkenyl, OC(O)NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O)NH heteroaryl, OC(O)NHheterocycloalkyl, NHC(O)alkyl, NHC(O)alkenyl, NHC(O)alkynyl, NHC(O)cycloalkyl, NHC(O)aryl, NHC(O)heteroaryl, NHC(O)heterocycloalkyl, NHCO2alkyl, NHCChalkenyl, NHCChalkynyl, NHCChcycloalkyl, NHCCharyl, NHCChheteroaryl, NHCChheterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O)NH heteroaryl, NHC(O)NHheterocycloalkyl, NHC(S)NH2, NHC(S)NHalkyl, NHC(S)NHalkenyl, NHC(S)NHalkynyl, NHC(S)NHcycloalkyl, NHC(S)NHaryl, NHC(S)NHheteroaryl, NHC(S)NHheterocycloalkyl, NHC(NH)NH2, NHC(NH)NHalkyl, NHC(NH)NHalkenyl, NHC(NH)NHalkenyl, NHC(NH)NHcycloalkyl, NHC(NH)NHaryl, NHC(NH)NHheteroaryl, NHC(NH)NHheterocycloalkyl, NHC(NH)alkyl, NHC(NH)alkenyl, NHC(NH)alkenyl, NHC(NH)cycloalkyl, NHC(NH)aryl, NHC(NH)heteroaryl, NHC(NH)heterocycloalkyl, C(NH)NHalkyl, C(NH)NHalkenyl, C(NH)NHalkynyl, C(NH)NHcycloalkyl, C(NH)NHaryl, C(NH)NHheteroaryl, C(NH)NHheterocycloalkyl, P(O)(alkyl)2, P(O)(alkenyl)2, P(O)(alkynyl)2, P(O)(cycloalkyl)2, P(O)(aryl)2, P(O)(heteroaryl)2, P(O)(heterocycloalkyl)2, P(O)(Oalkyl)2, P(O)(OH)2, P(O)(Oalkenyl)2, P(O)(Oalkynyl)2, P(O)(Ocycloalkyl)2, P(O)(Oaryl)2, P(O)(Oheteroaryl)2, P(O)(Oheterocycloalkyl)2, S(O)alkyl, S(O)alkenyl, S(O)alkynyl, S(O)cycloalkyl, S(O)aryl, S(O)2alkyl, S(O)2alkenyl, S(O)2alkynyl, S(O)2cycloalkyl, S(O)2aryl, S(O)heteroaryl, S(O)heterocycloalkyl, SO2NH2, SChNHalkyl, SChNHalkenyl, SChNHalkynyl, SChNHcycloalkyl, SChNHaryl, SChNHheteroaryl, SChNHheterocycloalkyl, NHSChalkyl, NHSChalkenyl, NHSChalkynyl, NHSChcycloalkyl, NHSCharyl, NHSO2heteroaryl, NHSChheterocycloalkyl, CH2NH2, CH2SO2CH3, alkyl, alkenyl, alkynyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, heterocycloalkyl, cycloalkyl, carbocyclic, heterocyclic, polyalkoxyalkyl, polyalkoxy, methoxymethoxy, methoxyethoxy, SH, S-alkyl, S- alkenyl, S-alkynyl, S-cycloalkyl, S-aryl, S-heteroaryl, S-heterocycloalkyl, or methylthiomethyl.

[0049] / / . Compounds

[0050] The recitation of a listing of chemical groups in any definition of a variable herein includes definitions of that variable as any single group or combination of listed groups. The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. As such, the following embodiments are present alone or in combination if applicable.

[0051] The present compounds present a heterocyclic core structure to which is attached defined substituents to achieve the product’s beneficial activity. Examples of compounds as defined herein are illustrated by general Formula I:

[0052] Formula I wherein:

[0053] X1is N or C(R4);

[0054] X2is N or C(R5);

[0055] X3is N, CH, or C-halo, provided that at least one of X2or X3is N;

[0056] R1is H, halo, OH, NH2, or a substituted or unsubstituted group selected from OR6, SR6, NHR6, N(R6)2, C(O)Ci-4alkyl, C(O)Ci-4alkenyl, C4-9cycloalkyl, C4- heterocycloalkyl, Ce-waryl, and Cs-wheteroaryl, or a Ci-3alkyl group substituted with an optionally substituted C3- gcycloalkyl, C4-9heterocycloalkyl, Ce- aryl, and Cs-wheteroaryl;

[0057] R2is selected from substituted Cs-wcycloalkyl, C4-wheterocycloalkyl, Ce-waryl, and Cs- wheteroaryl;

[0058] R3is OH, halo, SR7, OR7, NHR7, N(R7)2, or an optionally substituted Ci-salkyl;

[0059] R4is H, halo, or a substituted or unsubstituted Ci-4alkyl;

[0060] R5is H, CN, halo, CONH2, CONHR8, CON(R8)2, CO2R8, or SO2R8;

[0061] R6is independently in each occurrence a substituted or unsubstituted group selected from Ci-salkyl, C4-9cycloalkyl, C4-9heterocycloalkyl, or when two R6are present on a nitrogen atom, then the two R6may be taken together with their adjacent nitrogen atom to form an optionally substituted C4-wheterocycloalkyl; R7is independently in each occurrence an optionally substituted Ci-salkyl, C2-salkenyl, C2- salkynyl, or a group of formula -(C(R9)2)m-N(R10)2, or when two R7are present on a nitrogen atom, then the two R7may be taken together with their adjacent nitrogen atom to form an optionally substituted C^heterocycloalkyl;

[0062] R8is a substituted or unsubstituted Ci-3alkyl;

[0063] R9is independently in each occurrence selected from H, halo, and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group;

[0064] R10is independently in each occurrence selected from H and an optionally substituted Ci- salkyl, C^cycloalkyl, or C^heterocycloalkyl group; or at least two R9, or two R10, or at least one R9and one R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-i2heterocycloalkyl group; m is an integer selected from 1 to 4 (e.g. 2 or 3);

[0065] L is a Ci-3alkylene optionally substituted with a Ci-4alkyl, or CChCi^alkyl group, the alkyl being optionally further substituted, preferably L being an optionally substituted Cialkylene; or a pharmaceutically acceptable salt and / or solvate thereof; wherein when X1, X2, and X3are each N, L-R2is benzyl, and R3is 4-amino-4-methyl-1- piperidine or 2,7-diazaspiro[3.5]nonan-7-yl (spiro[azetidienpiperidinyl]), then R1is other than -N(benzyl)2.

[0066] For example, the compound is of any one of Formulae l-A to l-D:

[0067] wherein L, R1, R2, R3, R4, and R5are as defined above and hereinbelow, or a pharmaceutically acceptable salt and / or solvate thereof. In a preferred embodiment, the compound of Formula I is a compound of Formula l-A or l-B.

[0068] In another example, the compound is of Formula l-E: wherein:

[0069] R1, R2, X1, X2, and X3are as defined above and hereinbelow;

[0070] R9and R9’ are independently in each occurrence selected from H, halo, and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; and R10and R10’ are independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; or

[0071] R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C^heterocycloalkyl group, and R10and R10’ are independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; or

[0072] R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9and R9’ are independently in each occurrence selected from H, halo, and an optionally substituted Cisalkyl, C^cycloalkyl, or C^heterocycloalkyl group; or

[0073] R9and R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9’ is selected from H, halo, and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, and R10’ is selected from H and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4- gheterocycloalkyl group; or

[0074] R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group, and R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group; or

[0075] R9and R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9’ and R10’ are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4- i2heterocycloalkyl group, and p is a number selected from 0, 1 , and 2; or a pharmaceutically acceptable salt and / or solvate thereof.

[0076] In preferred examples, R9and R9’ are each independently selected from H, Ci-salkyl, or R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-ecycloalkyl or C4-6heterocycloalkyl group.

[0077] In another preferred embodiment, R10and R10’ are each an optionally substituted Ci-salkyl or R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group.

[0078] In a further preferred embodiment, R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-gheterocycloalkyl group, and R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group.

[0079] Other examples of compounds as defined herein are illustrated by general Formula II:

[0080] Formula II wherein L, R1, R2, R3, and X3are as defined above and hereinbelow, R11is defined as for R1, wherein at least one of R1and R11is H, or a pharmaceutically acceptable salt and / or solvate thereof. In one preferred embodiment of Formula II, R3is NHR7or N(R7)2.

[0081] Further examples of compounds as defined herein are illustrated by general Formula III:

[0082] Formula III wherein:

[0083] R1, R2, R3, and X3are as defined above and hereinbelow;

[0084] X4is N, CH, C-halo, C-OCi-3alkyl, C-OC3.5cycloalkyl, C-CN, C-C(O)NH2, C-Ci-3alkyl, or C- C3-5cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted; and

[0085] R11is defined as for R1, wherein at least one of R1and R11is H;

[0086] R12is selected from H, halo (e.g. F, Cl), or optionally substituted Ci-3alkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

[0087] In a preferred embodiment of Formula II or III, R3is NHR7or N(R7)2.

[0088] In some examples of the compounds of Formula II or III, X3may be N.

[0089] In some examples of the present compounds, X2is N. Alternatively, X2is C(R5). In preferred examples, X2is N, CH, CCN, C-halo, CCONH2, CCO2R8, or CSO2R8, more preferably, X2is N, CH, CCN, or C-halo. In the present compounds, R1may be H, halo, OH, or NH2. Alternatively, R1is a substituted or unsubstituted group selected from NHR6, N(R6)2C4-9cycloalkyl, and C4- heterocycloalkyl.

[0090] In some preferred embodiments, R1is N(R6)2, for instance, R1is N(R6)2 and the two R6are taken together with their adjacent nitrogen atom to form an optionally substituted C4- heterocycloalkyl. In some preferred examples, the optionally substituted C4- heterocycloalkyl is a monocyclic C4- yheterocycloalkyl or a bridged, fused or spiro bicyclic Cy-wheterocycloalkyl.

[0091] As mentioned above, in some cases, the R1group contains an optionally substituted functional group. In such cases, the functional group may be substituted with at least one group selected from halo, oxo, CN, OR13, N(R13)2, N(R13)C(O)R13, OC(O)R13, C(O)R13, C(O)OR13, CON(R13)2, SO2R13, SO2OR13, SO2N(R13)2, or R13, wherein R13is H or a Ci-salkyl, Cs-ecycloalkyl, C4- eheteroalkyl, or Cs-gheteroaryl group optionally substituted with halo, oxo, CN, OH, OCi-salkyl, NH2, N(Ci-5alkyl)2, NHC(O)Ci-5alkyl, C(O)H, OC(O)Ci-5alkyl, C(O)Ci-5alkyl, C(O)OCi-5alkyl, CON(Ci-5alkyl)2, C(O)NH2, SO2Ci-5alkyl, SO2OCi-5alkyl, SO2NH2 and SO2N(Ci-5alkyl)2.

[0092] Non-limiting examples of R1groups are illustrated as follows:

[0093] wherein (— ) represents a bond serving as a point of attachment between R1and the rest of the molecule.

[0094] In one embodiment, R1is selected from: wherein (— ) represents a bond serving as a point of attachment between R1and the rest of the molecule.

[0095] In order embodiments, R1is selected from: wherein (— ) represents a bond serving as a point of attachment between R1and the rest of the molecule.

[0096] In further embodiments of the present compounds, R2is selected from substituted Cs- cycloalkyl and C4-ioheterocycloalkyl, the cycloalkyl or heterocycloalkyl being saturated or partially unsaturated, preferably partially unsaturated. In alternative embodiments, R2is selected from substituted Ce- aryl and Cs- heteroaryl groups.

[0097] For instance, R2may be selected from: wherein: X5is NH, O, or S;

[0098] X6and X7are each independently CH, C(R14), or N;

[0099] R14is selected from halo, CN, OR15, N(R15)2, N(R15)C(O)R15, OC(O)R15, C(O)R15, C(O)OR15, CON(R15)2, SO2R15, SO2OR15, SO2N(R15)2, and optionally substituted Ci-salkyl, C2-4alkynyl, Cs-ecycloalkyl, or C^heterocycloalkyl; R15is independently H or a Ci-salkyl, Cs-scycloalkyl, C^heteroalkyl, or Cs-gheteroaryl group optionally substituted with halo, oxo, CN, OH, OCi-salkyl, NH2, N(Ci-salkyl)2, NHC(O)Ci- salkyl, C(O)H, OC(O)Ci-5alkyl, C(O)Ci-5alkyl, C(O)OCi-5alkyl, CON(Ci-5alkyl)2, C(O)NH2, SO2Ci-salkyl, SO2OCi-salkyl, SO2NH2 and SO2N(Ci-5alkyl)2; n is an integer selected such that the total number of R14on the R2group is from 1 to 4; and - - designates a bound between R2and the rest of the compound.

[0100] Non-limiting examples of R2a group selected from: wherein (— ) represents a bond serving as a point of attachment between R2and the rest of the molecule.

[0101] For instance, R2may be a group selected from:

[0102] wherein (— ) represents a bond serving as a point of attachment between R2and the rest of the molecule.

[0103] In some examples, R2is selected from: wherein (— ) represents a bond serving as a point of attachment between R2and the rest of the molecule.

[0104] In another embodiment of the present compounds, R3is OH, halo, or an optionally substituted Cisalkyl. Alternatively, R3is SR7, OR7, NHR7, or N(R7)2, preferably OR7, NHR7, or N(R7)2, wherein R7is as defined above. In some instances, R7is, in one occurrence, a group of formula -(C(R9)2)m- N(R10)2, wherein R9, R10, and m are as defined above (preferably m is 2 or 3). For example, R9and R10may be independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, wherein at least two R9and / or R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-9cycloalkyl or C4-i2heterocycloalkyl group. In other instances, R7is, in one occurrence, a group of formula CH2C(R9)(R9’)(CH2)PN(R10)(R10’), wherein R9, R9’, R10, R10’, and p are as defined above with respect to Formula l-E.

[0105] Non-limiting examples of R3groups may be illustrated as follows:

[0106] wherein (— ) represents a bond serving as a point of attachment between R3and the rest of the molecule.

[0107] In some preferred embodiments, especially but not limited to Formula l-E, R3groups may be illustrated as follows:

[0108] wherein (— ) represents a bond serving as a point of attachment between R3and the rest of the molecule.

[0109] For instance, R3may be selected from:

[0110] wherein (— ) represents a bond serving as a point of attachment between R3and the rest of the molecule.

[0111] Exemplary compounds as defined herein include, without limitation, Examples 1 to 200 defined as follows:

[0112]

[0113] Example 94 Example 95 Example 96

[0114] Example 112 Example 113 Example 114

[0115]

[0116]

[0117] Example 156

[0118]

[0119] Example 193 Example 194 Example 195

[0120] Example 199 Example 200 or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0121] In some instances, the compound is selected from Examples 1 to 200, or from Examples 1 to 155 and 174 to 200, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof. Examples of preferred compounds are, namely, Examples 10, 11 , 15, 17, 27, 31 , 34, 35, 42, 44, 49, 54-56, 58, 60, 61 , 65, 74, 79, 82, 89, 92, 98-101 , 103, 104, 106, 110-112, 115, 117, 118, 121 , 123-125, 128-140, 144, 145, 147-152, 154, 155, 174-185, 187, 189-191 , 193-200 or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0122] Examples of more preferred compounds include Examples 31 , 34, 35, 42, 54, 55, 58, 60, 61 , 82, 89, 99-101 , 106, 111 , 112, 115, 117, 118, 121 , 123, 128, 129, 131 , 133-140, 144, 145, 148, 152, 155, 174-185, 187, 189-191 , 193, 194, 197 or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0123] Examples of most preferred compounds include Examples 82, 111 , 112, 115, 117, 128, 129, 131 , 133, 134, 136-140, 145, 147, 148, 152, 155, 178, 180, 182-185, 194, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0124] It is understood that any of the above compounds may be in any amorphous, crystalline or polymorphic form, including any salt or solvate form, or a mixture thereof. The compounds of the present description may be further modified by appending various functionalities via any synthetic means delineated herein to enhance selective biological properties. Such modifications are known in the art and include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0125] These compounds may be prepared by conventional chemical synthesis, such as those exemplified in the Schemes and Examples of the present disclosure. As can be appreciated by the skilled artisan, further methods of synthesizing the compounds of the formulae herein will be evident to those of ordinary skill in the art. Additionally, the various synthetic steps may be performed in an alternate sequence or order to give the desired compounds.

[0126] Hi. Methods, Uses, Formulations and Administration

[0127] As used herein, the term "effective amount" means that amount of a drug or pharmaceutical agent that will elicit the biological or medical response of a tissue, system, animal or human that is being sought, for instance, by a researcher or clinician. Furthermore, the term "therapeutically effective amount" means any amount which, as compared to a corresponding subject who has not received such amount, results in treatment, healing, prevention, or amelioration of a disease, disorder, or symptom thereof, or a decrease in the rate of advancement of a disease or disorder. The term also includes within its scope amounts effective to enhance normal physiological function. As used herein, the terms "treatment," "treat," and "treating" refer to reversing, alleviating, delaying the onset of, or inhibiting the progress of a disease or disorder, or one or more symptoms thereof, as described herein. In some embodiments, treatment may be administered after one or more symptoms have developed. In other embodiments, treatment may be administered in the absence of symptoms. For example, treatment may be administered to a susceptible individual prior to the onset of symptoms (e.g., in light of a history of symptoms and / or in light of genetic or other susceptibility factors). Treatment may also be continued after symptoms have resolved, for example to prevent or delay their recurrence.

[0128] In one embodiment, the disease or condition to be treated is a proliferative disease or disorder or a kinase-mediated disease or disorder. More specifically, the disease or disorder to be treated include a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), an inflammatory disease or an immune system disorder.

[0129] According to some examples, the proliferative disease or disorder to be treated is a neoplasm, an inflammatory disease or condition or a developmental anomaly, involving a constitutively activating mutation in RAS genes (e.g. KRAS, HRAS, NRAS). The disease or disorder may also be further associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function). For instance, the compounds as defined herein are inhibitors of the signaling enzyme which is involved in controlling cell proliferation. Thus, the present compounds may be used for example for the treatment of diseases connected with the activity of this signaling enzyme and characterized by excessive or abnormal cell proliferation.

[0130] According to one embodiment, the disease or disorder is characterized by uncontrolled cell proliferation, i.e. a “proliferative disorder” or “proliferative disease”. More specifically, these diseases and disorders relate to cells having the capacity for autonomous growth, i.e. an abnormal state of condition characterized by rapidly proliferating cell growth which generally forms a distinct mass that show partial or total lack of structural organization and functional coordination with normal tissue.

[0131] For instance, the proliferative disorder or disease is defined as a “neoplasm”, “neoplastic disorder”, “neoplasia” “cancer,” and “tumor” which terms are collectively meant to encompass hematopoietic neoplasms (e.g. lymphomas or leukemias) as well as solid neoplasms (e.g. sarcomas or carcinomas), including all types of pre-cancerous and cancerous growths, or oncogenic processes, metastatic tissues or malignantly transformed cells, tissues, or organs, irrespective of histopathologic type or stage of invasiveness. Hematopoietic neoplasms are malignant tumors affecting hematopoietic structures (structures pertaining to the formation of blood cells) and components of the immune system, including leukemias (related to leukocytes (white blood cells) and their precursors in the blood and bone marrow) arising from myeloid, lymphoid or erythroid lineages, and lymphomas (related to lymphocytes). Solid neoplasms include sarcomas, which are malignant neoplasms that originate from connective tissues such as muscle, cartilage, blood vessels, fibrous tissue, fat or bone. Solid neoplasms also include carcinomas, which are malignant neoplasms arising from epithelial structures, including external epithelia (e.g., skin and linings of the gastrointestinal tract, lungs, and cervix), and internal epithelia that line various glands (e.g., breast, pancreas, thyroid). Examples of neoplasms include leukemia, and hepatocellular cancers, sarcoma, vascular endothelial cancers, breast cancers, central nervous system cancers (e.g. astrocytoma, gliosarcoma, neuroblastoma, oligodendroglioma and glioblastoma), prostate cancers, lung and bronchus cancers, larynx cancers, esophagus cancers, colon cancers, colorectal cancers, gastro-intestinal cancers, melanomas, ovarian and uterine endometrial cancer, testicular cancer, renal and bladder cancer, liver cancer, endocrine cancer (e.g. thyroid), and pancreatic cancer. For instance, the disease or disorder is selected from colon cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and skin cancer. Examples of neoplasm include melanoma, papillary thyroid carcinoma, colorectal, ovarian, breast cancer, endometrial cancer, liver cancer, sarcoma, stomach cancer, Barret's adenocarcinoma, glioma (including ependymoma), lung cancer (including non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, and hairy-cell leukemia.

[0132] In an embodiment, patients presenting one of the above-mentioned hematopoietic or solid neoplasms have previously received treatment with a RAS-ERK pathway-targeted inhibitor (including RTK, RAF, MEK or ERK inhibitor) but have developed resistance to the said inhibitor. The inhibitor includes standard of care treatments such as sotorasib, adagrasib, vemurafenib, dabrafenib, encorafenib, binimetinib, cobimetinib, selumetinib, trametinib, YERVOY, OPDIVO or any combination of these pharmaceutical agents.

[0133] In an embodiment, the disease to be treated is defined by developmental anomalies caused by dysregulation of the RAS-ERK signaling cascade (RASopathies: e.g. Noonan syndrome, Costello syndrome, LEOPARD syndrome, cardiofaciocutaneous syndrome and hypertrophic cardiomyopathy). The term "patient or subject" as used herein refers to an animal such as a mammal. A subject may therefore refer to, for example, mice, rats, dogs, cats, horses, cows, pigs, guinea pigs, primates including humans and the like. Preferably the subject is a human.

[0134] The present description therefore further relates to a method of treating a subject, such as a human subject, suffering from a proliferative disease or disorder, e.g. a mutated RAS-driven cancer. The method comprises administering a therapeutically effective amount of a compound as defined herein, to a subject in need of such treatment.

[0135] In certain embodiments, the present description provides a method of treating a disorder (as described herein) in a subject, comprising administering to the subject identified as in need thereof, a compound of the present description. The identification of those patients who are in need of treatment for the disorders described above is well within the ability and knowledge of one skilled in the art. Certain of the methods for identification of patients which are at risk of developing the above disorders which can be treated by the subject method are appreciated in the medical arts, such as family history, and the presence of risk factors associated with the development of that disease state in the subject patient. A clinician skilled in the art can readily identify such candidate patients, by the use of, for example, clinical tests, physical examination, medical / family history, and genetic determination.

[0136] A method of assessing the efficacy of a treatment in a subject includes determining the pretreatment symptoms of a disorder by methods well known in the art and then administering a therapeutically effective amount of a compound of the present description, to the subject. After an appropriate period of time following the administration of the compound (e.g., 1 week, 2 weeks, one month, six months), the symptoms of the disorder are determined again. The modulation (e.g., decrease) of symptoms and / or of a biomarker (e.g. pERK or pMEK) of the disorder indicates efficacy of the treatment. The symptoms and / or biomarker of the disorder may be determined periodically throughout treatment. For example, the symptoms and / or biomarker of the disorder may be checked every few days, weeks or months to assess the further efficacy of the treatment. A decrease in symptoms and / or biomarker of the disorder indicates that the treatment is efficacious.

[0137] In some embodiments, the therapeutically effective amount of a compound as defined herein can be administered to a patient alone or in a composition, admixed with a pharmaceutically acceptable carrier, adjuvant, or vehicle. The expression "pharmaceutically acceptable carrier, adjuvant, or vehicle" and equivalent expressions, refer to a non-toxic carrier, adjuvant, or vehicle that does not destroy the pharmacological activity of the compound with which it is formulated. Pharmaceutically acceptable carriers, adjuvants or vehicles that may be used in the compositions of this disclosure include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose- based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-polyoxypropylene-block polymers, polyethylene glycol and wool fat.

[0138] Compositions described herein may be administered orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intraarticular, intrasynovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Other modes of administration also include intradermal or transdermal administration.

[0139] Liquid dosage forms for oral administration include, but are not limited to, pharmaceutically acceptable emulsions, microemulsions, solutions, suspensions, syrups and elixirs. In addition to the active compounds, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1 ,3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofurfuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. Besides inert diluents, the oral compositions can also include adjuvants such as wetting agents, emulsifying and suspending agents, surfactants, sweetening, flavoring, and perfuming agents.

[0140] Injectable preparations, for example, sterile injectable aqueous or oleaginous suspensions may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution, suspension or emulsion in a nontoxic parenterally acceptable diluent or solvent, for example, as a solution in 1 ,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer's solution, ll.S.P. and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil can be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid are used in the preparation of injectables.

[0141] Injectable formulations can be sterilized, for example, by filtration through a bacterial -retaining filter, or by incorporating sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

[0142] In order to prolong the effect of a provided compound, it is often desirable to slow the absorption of the compound from subcutaneous or intramuscular injection. This may be accomplished by the use of a liquid suspension of crystalline or amorphous material with poor water solubility. The rate of absorption of the compound then depends upon its rate of dissolution that, in turn, may depend upon crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered compound form is accomplished by dissolving or suspending the compound in an oil vehicle. Injectable depot forms are made by forming microencapsule matrices of the compound in biodegradable polymers such as polylactide-polyglycolide. Depending upon the ratio of compound to polymer and the nature of the particular polymer employed, the rate of compound release can be controlled.

[0143] Examples of other biodegradable polymers include poly(orthoesters) and poly(anhydrides). Depot injectable formulations are also prepared by entrapping the compound in liposomes or microemulsions that are compatible with body tissues.

[0144] Compositions for rectal administration are preferably suppositories which can be prepared by mixing the compounds of the present description with suitable non-irritating excipients or carriers such as cocoa butter, polyethylene glycol or a suppository wax which are solid at ambient temperature but liquid at body temperature and therefore melt in the rectum and release the active compound.

[0145] Solid dosage forms for oral administration include capsules, tablets, pills, powders, and granules. In such solid dosage forms, the active compound is mixed with at least one inert, pharmaceutically acceptable excipient or carrier such as sodium citrate or dicalcium phosphate and / or a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone (PVP), sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. In the case of capsules, tablets and pills, the dosage form may also comprise buffering agents.

[0146] Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes. Solid compositions of a similar type may also be employed as fillers in soft and hard-filled gelatin capsules using such excipients as lactose or milk sugar as well as high molecular weight polyethylene glycols and the like.

[0147] The composition can also be in micro-encapsulated form with one or more excipients as noted above. The solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release controlling coatings and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms the active compound may be admixed with at least one inert diluent such as sucrose, lactose or starch. Such dosage forms may also comprise, as is normal practice, additional substances other than inert diluents, e.g., tableting lubricants and other tableting aids such a magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may also comprise buffering agents. They may optionally contain opacifying agents and can also be of a composition that they release the active ingredient(s) only, or preferentially, in a certain part of the intestinal tract, optionally, in a delayed manner. Examples of embedding compositions that can be used include polymeric substances and waxes.

[0148] Dosage forms for topical or transdermal administration of a compound of the present description include ointments, pastes, creams, lotions, gels, powders, solutions, sprays, inhalants or patches. The active component is admixed under sterile conditions with a pharmaceutically acceptable carrier and any needed preservatives or buffers as may be required. Ophthalmic formulation, ear drops, and eye drops are also contemplated as being within the scope of the present description. Additionally, the description contemplates the use of transdermal patches, which have the added advantage of providing controlled delivery of a compound to the body. Such dosage forms can be made by dissolving or dispensing the compound in the proper medium. Absorption enhancers can also be used to increase the flux of the compound across the skin. The rate can be controlled by either providing a rate controlling membrane or by dispersing the compound in a polymer matrix or gel.

[0149] Pharmaceutically acceptable compositions provided herein may also be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promotors to enhance bioavailability, fluorocarbons, and / or other conventional solubilizing or dispersing agents.

[0150] Pharmaceutically acceptable compositions provided herein may be formulated for oral administration. Such formulations may be administered with or without food. In some embodiments, pharmaceutically acceptable compositions of this disclosure are administered without food. In other embodiments, pharmaceutically acceptable compositions of this disclosure are administered with food.

[0151] The amount of compound that may be combined with carrier materials to produce a composition in a single dosage form will vary depending upon the patient to be treated and the particular mode of administration. Provided compositions may be formulated such that a dosage of between 0.01 - 100 mg / kg body weight / day of the inhibitor can be administered to a patient receiving these compositions.

[0152] It should also be understood that a specific dosage and treatment regimen for any particular patient will depend upon a variety of factors, including age, body weight, general health, sex, diet, time of administration, rate of excretion, drug combination, the judgment of the treating physician, and the severity of the symptoms associated with the proliferative disease or disorder. The amount of a provided compound in the composition will also depend upon the particular compound in the composition.

[0153] Compounds or compositions described herein may be administered using any amount and any route of administration effective for treating or lessening the severity of the symptoms as contemplated herein. The exact amount required will vary from subject to subject, depending on the species, age, and general condition of the subject, the severity of the infection, the particular agent, its mode of administration, and the like. Provided compounds are preferably formulated in unit dosage form for ease of administration and uniformity of dosage. The expression "unit dosage form" as used herein refers to a physically discrete unit of agent appropriate for the patient to be treated. It will be understood, however, that the total daily usage of the compounds and compositions of the present disclosure will be decided by the attending physician within the scope of sound medical judgment.

[0154] Pharmaceutically acceptable compositions of this disclosure can be administered to humans and other animals orally, rectally, parenterally, intracisternally, intraperitoneally, topically (as by powders, ointments, or drops), buccally, as an oral or nasal spray, or the like, depending on the severity of the infection being treated. In certain embodiments, provided compounds may be administered orally or parenterally at dosage levels of about 0.01 mg / kg to about 50 mg / kg and preferably from about 1 mg / kg to about 25 mg / kg of subject body weight per day, one or more times a day, to obtain the desired therapeutic effect.

[0155] It will be understood that the total daily usage of the compounds and compositions of the present description will be decided by the attending physician within the scope of sound medical judgment. The total daily inhibitory dose of the compound of the present description administered to a subject in single or in divided doses can be in amounts, for example, from 0.01 to 50 mg / kg body weight or more usually from 0.1 to 25 mg / kg body weight. Single dose compositions may contain such amounts or submultiples thereof to make up the daily dose. In one embodiment, treatment regimens according to the present description comprise administration to a patient in need of such treatment from about 10 mg to about 1000 mg of the compound(s) of the present description per day in single or multiple doses.

[0156] Depending upon the disease or disorder to be treated, additional therapeutic agents may also be present in the compositions of this disclosure or administered separately as part of a dosage regimen, e.g. an additional chemotherapeutic agent. Non-limiting examples of additional therapeutic agents which could be used in combination with the present compounds include antiproliferative compounds such as aromatase inhibitors; anti-estrogens; anti-androgens; gonadorelin agonists; topoisomerase I inhibitors; topoisomerase II inhibitors; microtubule active agents; alkylating agents; retinoids, carotenoids, tocopherol; cyclooxygenase inhibitors; MMP inhibitors; antimetabolites; platin compounds; methionine aminopeptidase inhibitors; bisphosphonates; antiproliferative antibodies; heparanase inhibitors; inhibitor of Ras oncogenic isoforms; telomerase inhibitors; proteasome inhibitors; compounds used in the treatment of hematologic malignancies; kinesin spindle protein inhibitors; Hsp90 inhibitors; mTOR inhibitors; PI3K inhibitors; Flt-3 inhibitors; CDK4 / 6 inhibitors; HER2 inhibitors (Herceptin, Trastuzumab); EGFR inhibitors (Iressa, Tarceva, Nerlynx, Tykerb, Erbitux); SHP2 inhibitors (TNO255); SOS inhibitors; RAS inhibitors; RAF oncogenic form inhibitors; M EK inhibitors (Trametinib, Binimetinib, Cobimetinib); ERK inhibitors (Ulixertinib); anti-PD-1 antibodies (Opdivo, Keytruda); anti-CTI_A4 antibodies (Yervoy); antitumor antibiotics; nitrosoureas; compounds targeting / decreasing protein or lipid kinase activity, compounds targeting / decreasing protein or lipid phosphatase activity, or any further anti-angiogenic compounds.

[0157] The treatment may also be complemented with other treatments or interventions such as surgery, radiotherapy (e.g., gamma-radiation, neutron beam radiotherapy, electron beam radiotherapy, proton therapy, brachytherapy, and systemic radioactive isotopes), a biologic response modifier (e.g., an interferon, an interleukin, tumor necrosis factor (TNF), and agents used to attenuate an adverse effect.

[0158] The recitation of an embodiment for a variable herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof. The recitation of an embodiment herein includes that embodiment as any single embodiment or in combination with any other embodiments or portions thereof.

[0159] EXAMPLES

[0160] List of Abbreviations

[0161] 6xHis: affinity tag comprising a repetition of 6 histidine residues

[0162] Ac: acetyl

[0163] AcOEt: ethyl acetate

[0164] AcOH: acetic acid

[0165] ADDP: 1 ,1 '-(azodicarbonyl)dipiperidine

[0166] Aq. or Aqu.: aqueous

[0167] Ar: aryl

[0168] ATCC: American Type Culture Collection

[0169] ATP: adenosine triphosphate

[0170] BINOL: [1 ,1'-binaphthalene]-2,2'-diol

[0171] Boc: terf-butyloxycarbonyl

[0172] BOP: (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate

[0173] Bpin: Pinacol borane br: broad brs or br.s.: broad singlet

[0174] BSA: bovine serum albumin CCL: cancer cell lines

[0175] CDCh: deuterated chloroform

[0176] Cy5: cyanine 5 dye d: doublet dd: doublet of doublets

[0177] DCE: 1 ,2-dichloroethane

[0178] DCM: dichloromethane

[0179] DHP: 3,4-dihydro-2H-pyran

[0180] DIAD: diisopropyl azodicarboxylate

[0181] DI PEA: / V, / V-diisopropylethylamine (Hunig’s base)

[0182] DMA : dimethylacetamide

[0183] DMAP: 4-dimethylaminopyridine

[0184] DME: 1 ,2-dimethoxyethane

[0185] DMF: / V, / V-dimethylformamide

[0186] DMPK: drug metabolism and pharmacokinetics

[0187] DMSO: dimethylsulfoxide

[0188] DMSO-d6: deuterated dimethylsulfoxide

[0189] DTT: dithiothreitol

[0190] 5 ppm:1H NMR shift in ppm relative to residual NMR solvent

[0191] E. coir. Escherichia coli

[0192] EA or EtOAc: ethyl acetate

[0193] EC50: half-maximal effective concentration

[0194] ECL: enhanced chemiluminescence

[0195] EDTA: ethylenediamine tetraacetic acid

[0196] Et2O: diethyl ether

[0197] EtOH: ethanol

[0198] EGFR: epidermal growth factor receptor

[0199] ERK: extracellular signal-regulated kinase

[0200] FBS: fetal bovine serum

[0201] GAP: GTPase-activating protein

[0202] GEF: guanine nucleotide exchange factor

[0203] GST: glutathion S-transferase

[0204] GDP: guanosine diphosphate

[0205] GTP: guanosine triphosphate HATLI: O-(7-azabenzotriazol-1-yl)- / V, / \ / , / \ / ’, / \ / ’,-tetramethyluronium hexafluorophosphate

[0206] HEPES: 4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid

[0207] HMDS: hexamethyldisilazane

[0208] Het: heterocycle

[0209] Hex: hexanes

[0210] HRMS: high resolution mass spectrometry

[0211] HPLC: high performance liquid chromatography

[0212] HRP: horseradish peroxidase

[0213] Hz: hertz

[0214] IC50: half-maximal inhibitory concentration

[0215] I PA: isopropanol

[0216] / PrOH: isopropanol

[0217] LAH: Lithium aluminum hydride

[0218] LCMS: liquid chromatography mass spectrometry

[0219] LHMDS Lithium hexamethyldisilazane m: multiplet

[0220] MCPBA: mefa-chloroperbenzoic acid

[0221] MeCN: acetonitrile

[0222] MEK: mitogen-activated protein kinase

[0223] MeOH: MeOH mM: millimolar

[0224] MOM: methoxymethyl ether

[0225] MS: mass spectrometry

[0226] NF1 : neurofibromatosis type 1 nm: nanometer nM: nanomolar

[0227] NMP: / V-methylpyrrolidone

[0228] NMR: nuclear magnetic resonance

[0229] OAc: Acetate

[0230] ON: overnight

[0231] PBS: phosphate buffered saline pERK: phosphorylated extracellular signal-regulated kinase

[0232] Ph: Phenyl

[0233] PMB: para-methoxybenzyl PMSF: phenylmethylsulfonyl fluoride

[0234] PyBroP: bromo-tris-pyrrolidinophosphonium hexafluorophosphate q: quartet quant.: quantitative quin.: quintet

[0235] RAS: rat sarcoma

[0236] RBD: RAS-binding domain

[0237] Rf: retention factor

[0238] RPMI-1640: Roswell Park Memorial Institute medium formulation 1640

[0239] RT: room temperature

[0240] RTK: receptor tyrosine kinase s: singlet

[0241] Sat.: saturated

[0242] SDS: sodium dodecylsulfate

[0243] SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis

[0244] SEM: trimethylsilylethoxymethyl

[0245] SNAr: Nucleophilic aromatic substitution

[0246] SOS: son of sevenless

[0247] SOS1 : son of sevenless homolog 1

[0248] SOS2: son of sevenless homolog 2

[0249] SOScat : residues 566-1049 of human son of sevenless homolog 1

[0250] SPR: surface plasmon resonance

[0251] Swll: switch II pocket t: triplet

[0252] TBST: Tris buffered saline with 0.2% Tween-20

[0253] TBTLI: O-(benzotriazol-1-yl)- / V, / \ / , / \ / ’, / \ / ’-tetramethyluronium tetrafluoroborate

[0254] TEV: tobacco etch virus protease

[0255] TFA: trifluoroacetic acid

[0256] THF: tetrahydrofuran

[0257] THP: tetrahydropyran

[0258] TIPS: triisopropylsilyl

[0259] TLC: silica gel thin layer chromatography

[0260] TR-FRET: time-resolved Forster’s resonance energy transfer

[0261] Ts: para-Toluenesulfonate pL: microliter pM: micromolar WT: wild type YMIN: minimal data point of a dosage-activity curve

[0262] The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.

[0263] The Examples set forth herein below provide syntheses and experimental results obtained for certain exemplary compounds. As it is well known to a person skilled in the art, reactions are performed in an inert atmosphere (nitrogen or argon) where necessary to protect reaction components from air and moisture. Temperatures are given in degrees Celsius (°C). Solution percentages and ratios express a volume-to-volume relationship, unless otherwise stated. The reactants used in the examples below may be obtained either as described herein, or if not described herein, are themselves either commercially available or may be prepared from commercially available materials by methods known in the art. Flash chromatography is carried out on silica (SiCh) using a Teledyne Isco Rf Combiflash instrument at 254 nm using commercial normal phase silica. Mass spectra analyses are recorded using electrospray mass spectrometry. NMR are recorded on a 400 MHz Bruker instrument. Chemical shift listings and coupling constants are as provided by the ACD labs NMR processor software (www.acdlabs.com)

[0264] Preparative HPLC was performed using an Agilent 1260 Infinity or a Teledyne ISCO Easy Prep instrument using a Phenomenex-Kinetex C18, (21x100mm, 5 pm) column at a flow rate of 20 mL / min (RT) or (30x100mm, 5 pm) column at a flow rate of 40 mL / min (RT). LIV detection was performed at 220 and 254 nm. The mobile phase consisted of Solvent A (5% MeOH, 95% water + 0.1 % formic acid) and Solvent B (95% MeOH, 5% water + 0.1% formic acid) unless stated otherwise. As specified in the text, 0.05% TFA or 0.1 % AcOH or other additives such as 10 mM NH4CO3 were occasionally used instead of 0.1% formic acid in both solvents. MeCN was also used instead of MeOH in both mobile phases for more challenging separations as specified in the text. Specific gradient conditions are provided in the examples but the following is representative: T(0) — > T(3 min) isocratic using between 10 to 50% solvent B depending on compound polarity, followed by a 12 minutes gradient to 100% solvent B. Last 5 minutes 100% solvent B.

[0265] LCMS analyses were performed on an Agilent instrument. Liquid chromatography was performed on a Phenomenex Kinetex C18 column (2.6 pm; 100 A; 3 X 30 mm) at a flow rate of 1.25 mL / min (RT) with UV detection at 220 and 254 nm. The mobile phase consisted of solvent A (95% H2O / 5% MeOH 1 0.05% formic acid) and solvent B (95% MeOH 1 5% H20 1 0.05% formic acid) using the following gradient: T(0) 100% A — > T(0.5 min) 100% B — > isocratic 100% B to T(2 min). MS detection was performed in parallel using APCI detection in both positive and negative modes.

[0266] Unless otherwise indicated, all numbers expressing quantities of ingredients, reaction conditions, concentrations, properties, stabilities, and so forth used in the specification and claims are to be understood as being modified in all instances by the term “about.” At the very least, each numerical parameter should at least be construed in light of the number of reported significant digits and by applying ordinary rounding techniques. Accordingly, unless indicated to the contrary, the numerical parameters set forth in the present specification and attached claims are approximations that may vary depending upon the properties sought to be obtained. Notwithstanding that the numerical ranges and parameters setting forth the broad scope of the embodiments are approximations, the numerical values set forth in the specific examples are reported as precisely as possible. Any numerical value, however, inherently contain certain errors resulting from variations in experiments, testing measurements, statistical analyses and such.

[0267] Name of molecules throughout are as provided by ChemDraw software (Revvity Signal Software Inc.) using IUPAC nomenclature.

[0268] Synthesis, biological activity and characterization of examples:

[0269] All compounds as herein defined were prepared according to the general synthetic Schemes and detailed experimental procedures as provided below. Characterization data by mass spectrometry and NMR are provided for each of the Examples. The variables groups (Ri, R2, R3, etc.) may or may not correspond to the variables used in the above description with respect to Formulae I to III and should be read within the context of the examples.

[0270] The compounds are tested in the assays described in the biological Experimental section. The convention used for reporting biological data is provided as a footnote in the respective Tables.

[0271] General synthetic schemes

[0272] Formula (I) The subject compounds of Formula (I) of the invention can be prepared by methods well known to one skilled in the art following the general synthetic sequences and general conditions described herein in accompanying schemes or modifications thereof, and using the appropriate starting materials and reagents obtained from commercial sources, synthesized according to known literature procedures, or prepared as described herein. More detailed procedures are also exemplified for specific compounds of the invention.

[0273] Scheme 1

[0274] (major)

[0275] (minor)

[0276] 1. R,H base 2. Deprotection or

[0277] Pd-catalyzed amination

[0278] Commercially available 2,6-dichloropurine 1 [CAS 5451-40-1] undergoes regioselective aromatic nucleophilic substitution (SNAr) of the 2-chloro substituent with alcohols and amines containing a free NH in the presence of an alkali inorganic base such as CS2CO3 or K2CO3, a metal hydride (e.g. (NaH or KH) or an organic base (e.g. LiHMDS, iP^EtN , EtsN) and the likes at temperatures ranging from 0 °C to 150 °C in inert solvents selected from tetrahydrofuran, dioxane, DMF, DMSO, NMP, DMA and the likes, to give intermediate 2. Using Mitsunobu alkylating conditions and variations thereof, intermediate 2 can be alkylated to provide mixtures of 7- and 9-regioisomeric / V-alkylated products 3 and 4. The desired A^-alkylated products 3 are generally obtained as the major or single isomer which can be separated by flash or reversed-phase chromatography on silica gel. Mitsunobu alkylations protocols are well known to one skilled in the art and generally involve the use of a phosphine (e.g. triphenylphosphine, tri n-butylphosphine and the likes) and a diazo compound such as diethyl or diisopropyldiazodicarboxylate (DEAD or DIAD) or 1 ,T- (azodicarbonyl)dipiperidine (ADDP) in anhydrous inert solvents such as THF, DME or dioxane at temperatures ranging from RT to 140 °C. Conversion to final compounds of formula (I) requires replacement of the remaining 6-chloro substituent by amines RiH containing a free NH under SNAr conditions as described above and if necessary, removal of protecting groups (e.g. Boc, MOM, TIPS) by methods known to one skilled in the art. Alternatively, the Ri substituent can be introduced using palladium-catalyzed amination conditions using Pd catalysts such as Pd- PEPPSI-IPentCI-o-Picoline in the presence of a strong base such as potassium or sodium tert- butoxide in an oxygen-free (degassed) inert solvent such as THF, dioxane or DME at temperatures ranging from 80 °C to 160 °C under regular or microwave heating conditions. Scheme 2

[0279] Commercially available 2-chloro-6-fluoropurine 5 [CAS 1651-29-2] undergoes regioselective displacement of the 2-chloro substituent with inorganic thiol anions derived from thiols such as benzylthiol, 4-terf-butylbenzylthiol or methyl or ethylmercaptan and an inorganic base such as NaH or KH under usual SNAr conditions in the presence of solvents such as DMF, NMP, DMA or DMSO at temperatures ranging from 0 °C to 60 °C to provide intermediate 6. Using Mitsunobu / V-alkylation conditions as described for Scheme 1 , intermediate 6 can be reacted with alcohols to provide a mixture of regioisomers 8 and 9 with the desired isomer 8 as the main component. Regioisomer 8 can usually be separated from regioisomer 9 by flash or reversed-phase chromatography on silica gel. Substituent Ri can then be introduced by a SNAr amination procedure as described in Scheme 1 to provide intermediate 10. Conversion of intermediate 10 to compounds of Formula (I) is accomplished through a two-step procedure which involves first oxidation of the sulfide moiety to the corresponding sulfoxide or sulfone (or a mixture thereof) using an organic peracid such as mefa-chloroperbenzoic acid (MCPBA) and the likes. The resulting sulfoxide or sulfone (or the mixture of both entities) is then reacted with alcohols or amines containing a free NH group under standard SNAr conditions such as those described in Scheme 1 to provide after removal of protecting groups examples of Formula (I).

[0280] Alternatively, the sequence for introducing substitutions can be modified. For example, substituent Ri can be introduced first on intermediate 6 using standard SNAr amination protocols as described in Scheme 1. Oxidation of the sulfide moiety followed by a SNAr reaction allows introduction of R3 as described above to provide intermediate 11. The Mitsunobu reaction is then used in the final step to provide separable mixtures of Examples of compounds of Formula (I) and its regioisomer after removal of protecting groups.

[0281] Formula (II)

[0282] Compounds of Formula (II) of this invention can be prepared by following or adapting general methods as described in Scheme 3.

[0283] Scheme 3

[0284] X = CN, COOMe

[0285] 4,6-Dichloro-1 H-imidazo[4,5-c]pyridine-7-carboxylic acid 12 is prepared and then converted to nitrile 13 following procedures described in WO 2012 / 097478. Carboxylic acid 12 can also be converted to methyl ester 14 using trimethylsilyldiazomethane or similar. Both 13 and 14 are then converted to intermediate 15 following general procedures described in Scheme 2 for the replacement of the 4-chloro group by thiols using SNAr reaction conditions. Oxidation of the sulfide to a sulfoxide / sulfone using organic peracids as in Scheme 2 allows introduction of R3 using alcohols and amine containing a free NH under standard SNAr conditions to provide intermediates 17. Finally, compounds of Formula (II) where X = CN or COOMe of the present invention are generated as a separable mixture of regioisomers via standard Mitsunobu protocols as described previously, followed by any necessary deprotection steps.

[0286] Note: if desired, the order of introduction of the / V-alkyl and R3 substituents can be inverted through the use of the same chemical steps in a modified sequence as described in more details in specific examples herein.

[0287] Formula (III)

[0288] Examples of compounds of Formula (III) can be prepared by two alternative sequences using the general methods described in Scheme 4.

[0289] Scheme 4

[0290] Formula (III) (major)

[0291] 5,7-dichloro-1 H-imidazo[4,5-b]pyridine 18 undergoes the usual regiospecific SNAr substitution of

[0292] Cl by thiols under conditions described in the previous schemes to provide intermediate 19. / -

[0293] Alkylation of the imidazole ring with alcohols under Mitsunobu conditions described previously provide intermediate 20 as the major regioisomer (minor regioisomer not shown). The preparation of compounds of Formula (III) follows the two-step oxidation of the thiol and SNAr displacement by R3 alcohols or amines containing a free NH group as described in previous general methods and deprotection steps as necessary. Alternatively, compound 18 can undergo initial SNAr reaction with R3 of the types described above to give intermediate 22. Mitsunobu alkylation of the imidazole ring occurs under usual conditions and provides intermediate 23 as the major regioisomer. Substituent R1 is then introduced as described in previous schemes to provide Examples of Formula (III) after deprotection steps.

[0294] Formula (IV)

[0295] Pyrrolopyrimidine examples of general Formula (IV) can be accessed through the general methods provided in Scheme 5.

[0296] Scheme 5

[0297] 2,4-Dichloro-7 / 7-pyrrolo[2,3-c(]pyrimidine 24 undergoes a regioselective SNAr reaction with thiols as previously described to provide intermediate 25. The Ri substituent is then introduced in the manner previously described (usually through a second SNAr reaction with amines containing a free NH). Substituent R3 is then incorporated through the standard two step oxidation / SNAr displacement with alcohols or amines containing a free NH function to give intermediate pyrrole 27. The remaining substitution on the pyrrole nitrogen can be introduced through an / V-alkylation process using electrophilic substrates such as alkyl halides, sulfonate esters and the likes in the presence of inorganic hydrides (e.g. NaH, KH) or organic bases (e.g. alkyllithiums, LiHMDS) to give compounds of formula (IV) after removal of protecting groups. Tricyclic examples of Formula (V) can be obtained using the general sequence described in

[0298] Scheme 6 or adaptations thereof.

[0299] Scheme 6 Commercially available ethyl 4-amino-6-chloro-5-fluoronicotinate 29 (which can also be prepared in two steps from 4-amino-2-chloro-3-fluoropyridine 28 as described in WO 2023 / 225252) can be converted to aldehyde 30 following the procedure described in WO 2023 / 146957. Condensation with malonitrile in the presence of an organic base such as piperidine in an alcoholic solvent (e.g. EtOH) at temperatures ranging from 80 °C to 100 °C provides aminonitrile 31 that is then hydrolyzed to the corresponding carboxamide 32 using an alkali metal hydroperoxide ethanolic solution generated from an alkali hydroxide and hydrogen peroxide. Treatment with neat oxalyl chloride at temperatures around 100-125 °C followed by phosphorous oxychloride in the presence of an organic base such as DIEA or / V, / V-dimethylaniline at temperatures ranging from 0 °C to 10 °C yields dichloropyrimidine 33. Ri and R3 substituents are then introduced in the usual manner using SNAr chemistry as described previously to provide intermediates 34 and 35. Final conversion to examples of Formula (V) requires a transition metal-catalyzed cross-coupling reaction (e.g. Suzuki-Miyaura, Stille or Negishi cross-couplings and variations thereof) with an organometallic reagent R2M such as boronic acids, boronate esters, trialkyltin or organozinc species under catalysis by a palladium catalyst (e.g. cataCXium® A Palladacycle Gen. 3) under conditions of temperatures (80-150 °C), degassed solvents (e.g. THF, dioxane, DME, water and mixtures thereof) and additives as necessary (CsF, inorganic bases such as alkali carbonates, or tertiary amines) that are well known to one skilled in the art.

[0300] Formula (VI)

[0301] Tricyclic examples of Formula (VI) can be obtained using the general sequence described in

[0302] Scheme 7 or adaptations thereof.

[0303] Scheme 7 Commercially available ethyl 4,6-dichloro-5-nitro-3-pyridinecarboxylate 37 (which can also be prepared from ethyl 1,6-dihydro-4-hydroxy-6-oxo-3-pyridinecarboxylate 36, CAS# [6975-44-6] in two steps as described in WO 2009 / 106419) is reacted with ammonia in dioxane solutions along with a co-solvent such as DCM to provide diamino intermediate 38. Amino acid 38 can be converted to thiomethyl intermediate 39 using a three-step procedure involving initial treatment with neat phosphorous oxytrichloride followed by ammonium thiocyanate in a solvent such as THF and then alkylation with a methylating agent such as iodomethane or dimethylsulfate in the presence of a strong base such as an alkali alkoxide (e.g., NaOMe, KOtBu) in a solvent such as DMF or NMP. Introduction of the R1 substituent to give intermediate 40 is accomplished through a SNAr process in the usual manner. Closure of the imidazole ring requires reduction of the nitro group which can be accomplished using conditions familiar to one skilled in the art (e.g., SnCh, Fe, Zn) followed by ring closure using trimethylorthoformate and formic acid in a solvent such as MeOH and temperatures ranging from 60 °C to 100 °C to give intermediate 42. The final substitution of the tricyclic core is carried out under the standard Mitsunobu conditions to give after deprotection as necessary examples of Formula (VI) as the major regioisomer.

[0304] Synthesis of intermediates

[0305] INT A-1A INT A-1

[0306] Step 1

[0307] 8-Ethyl-1 -naphthaldehyde (INT A-1A). At -78 °C, under argon, to a solution of 1-bromo-8- ethylnaphthalene (676 pL, 4.25 mmol) in THF (25 mL) was added dropwise n-butyllithium (1.6 M in hexanes) (3.00 mL, 4.80 mmol) and the reaction mixture was stirred for 30 min. Then, DMF (988 pL, 12.8 mmol) was added and the reaction mixture was stirred at -78 °C for 30 min and was then allowed to reach room temperature. After 30 min, HCI 1M was added and the reaction mixture was concentrated under reduced pressure. The crude was dissolved in ethyl acetate. The organic layer was washed with water and brine. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-1A (475 mg, 61% yield) as an off-white solid.1H NMR (400 MHz, CDCI3) 6 ppm 10.83 (s, 1 H) 8.02 - 8.08 (m, 1 H) 7.94 (dd, J = 7.1 , 1.1 Hz, 1 H) 7.76 - 7.84 (m, 1 H) 7.47 - 7.60 (m, 3H) 3.14 (q, J = 7.4 Hz, 2H) 1.40 (t, J = 7.4 Hz, 3H).

[0308] Step 2

[0309] (8-Ethylnaphthalen-1-yl)methanol (INT A-1). To a solution of INT A-1A (475 mg, 2.58 mmol) in MeOH (10 mL) at 0 °C was added in small portions, sodium borohydride (150 mg, 3.97 mmol). The mixture was allowed to reach room temperature and was stirred for 16 h. Then, a solution of HCI 1 M was added and the reaction mixture was stirred for 10 min or until no more gas release before being concentrated under reduced pressure. Ethyl acetate was added, and the layers were separated. The organic layer was washed with HCI 1 M, dried over Na2SO4, filtered and concentrated under reduced pressure to afford INT A-1 (476 mg, 99% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.85 (d, J = 8.1 Hz, 1 H), 7.71 - 7.81 (m, 1 H), 7.57 (d, J = 6.8 Hz, 1 H), 7.35 - 7.48 (m, 3H), 5.19 (s, 2H), 3.36 (q, J = 7.4 Hz, 2H), 1.35 (t, J = 7.4 Hz, 3H), 1.28 (d, J = 3.1 Hz, 1 H).

[0310] INT A-2

[0311] Ethyl 2-(8-ethylnaphthalen-1-yl)-2-hydroxyacetate (INT A-2). To a solution of 1-bromo-8- ethylnaphthalene (400 mg, 1.70 mmol) in THF (8.51 mL) at -78 °C under argon was added dropwise n-butyllithium (2.5 M in hexanes) (749 pL, 1.87 mmol) and the reaction mixture was stirred for 30 min. Then, glyoxylic acid ethyl ester polymer form (45-50% in toluene) (382 pL, 1.87 mmol) was added and the reaction mixture was stirred at -78 °C for 5 min before being allowed to reach room temperature. The reaction mixture was stirred for 3 h. Then, the solution was cooled to 0 °C and sat. NH4CI was added. The reaction mixture was concentrated under reduced pressure to remove THF. The remaining aqueous phase was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSCH filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-35% EtOAc in hexanes) to afford INT A-2 (118 mg, 27% yield).1H NMR (400 MHz, CDCh) 6 ppm 7.86 (dd, J = 1.9, 7.5 Hz, 1 H), 7.75 (dd, J = 2.1 , 7.4 Hz, 1 H), 7.38 - 7.48 (m, 4H), 6.17 (d, J = 6.4 Hz, 1 H), 4.19 - 4.35 (m, 2H), 3.48 (d, J = 6.4 Hz, 1 H), 3.39 - 3.46 (m, 1 H), 3.24 - 3.37 (m, 1 H), 1.45 (t, J = 7.5 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H).

[0312] Step 1

[0313] 1-Bromo-3-chloro-2-cyclopropylbenzene (INT A-3A). To a mixture of 1-bromo-3-chloro-2- iodobenzene (1.00 g, 3.15 mmol) in 1 ,4-dioxane (8 mL) were added cyclopropylboronic acid (812 mg, 9.45 mmol), anhydrous potassium phosphate (2.68 g, 12.6 mmol) and Pd(PPh3)4 (364 mg, 315 pmol). The reaction mixture was thoroughly degassed with argon and then heated at 150 °C for 30 min. Then, the reaction mixture was cooled down to room temperature, diluted with ethyl acetate and filtered over Na2SO4. The filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (100% hexanes) to afford INT A-3A (704 mg, 96% yield).1H NMR (400 MHz, DMSO-d6) 5 ppm 7.59 (d, J = 8.0 Hz, 1 H), 7.45 (d, J = 8.0 Hz, 1 H), 7.18 (t, J = 8.0 Hz, 1 H), 1.79 (quin, J = 7.0 Hz, 1 H), 1.16 (q, J = 7.0 Hz, 2H), 0.68 (q, J = 5.5 Hz, 2H).

[0314] Step 2

[0315] 2-(3-Bromo-5-chloro-4-cyclopropylphenyl)-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (INT A- 3B). To a solution of b / s(pinacolato)diboron (4.94 g, 19.4 mmol) and INT A-3A (1.50 g, 6.48 mmol) in hexanes (4.32 mL) under nitrogen were added di-mu-methoxob / s(1 ,5-cyclooctadiene)diiridium (I) (219 mg, 0.324 mmol) and 4,4'-di-terf-butyl-2,2'-dipyridyl (104 mg, 389 pmol) and the reaction mixture was heated to 60 °C for 2 h. Then, the reaction mixture was concentrated under reduced pressure to afford INT A-3B (2.30 g, 99% yield) which was used directly in the next step without further purification. LCMS: m / z = 389 [M+MeOH]+.

[0316] Step 3

[0317] 3-Bromo-5-chloro-4-cyclopropylphenol (INT A-3C). To a solution of INT A-3B (2.30 g, 6.43 mmol) in THF (21.4 mL) and water (10.7 mL) at 0 °C were added acetic acid (23.9 mL, 418 mmol) and hydrogen peroxyde (14.6 mL, 129 mmol) and the reaction mixture was stirred for 1 h. Upon completion, the reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layers were dried over MgSCH filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-3C (1.28 g, 80% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.01 (d, J = 2.5 Hz, 1 H), 6.85 (d, J = 2.6 Hz, 1 H), 1.68 (tt, J = 5.8, 8.4 Hz, 1 H), 1.09 - 1.21 (m, 2H), 0.72 (q, J = 5.5 Hz, 2H).

[0318] Step 4

[0319] 1-Bromo-3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzene (INT A-3D). To a solution of INT A-3C (1.28 g, 5.17 mmol) in ethyl acetate (17 mL) was added DIPEA (4.50 mL, 25.9 mmol) followed by chloromethyl methyl ester (1.18 mL, 15.5 mmol) and DMAP (63.2 mg, 517 pmol) and the reaction mixture was stirred at room temperature for 18 h. Then, the salts were filtered off and the solution was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-15% EtOAc in hexanes) to afford INT A-3D (1.20 g, 80% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.20 (d, J = 2.5 Hz, 1 H), 7.04 (d, J = 2.5 Hz, 1 H), 5.10 - 5.14 (m, 2H), 3.31 - 3.53 (m, 3H), 1.62 - 1.79 (m, 1 H), 1.11 - 1.21 (m, 2H), 0.73 (q, J = 5.6 Hz, 2H).

[0320] Step 5

[0321] Ethyl 3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzoate (INT A-3E). Under nitrogen, to a solution of Pd(dppf)Ch DCM complex (770 mg, 943 pmol) and INT A-3D (2.75 g, 9.43 mmol) in ethanol (47.2 mL) was added triethylamine (4.73 mL, 34.0 mmol). The mixture was purged with CO three times and was heated to 80 °C under a CO balloon atmosphere for 4 hours. Then, the reaction mixture was filtered to remove insolubles, and the filter cake was washed with 1 ,4- dioxane. The filtrate was concentrated under reduced pressure. The crude product was purified by flash column chromatography on silica gel (1-8% EtOAc in hexanes) to afford INT A-3E (1.30 g, 48% yield). LCMS: m / z = 285.4 [M+H]+.

[0322] Step 6

[0323] (3-Chloro-2-cyclopropyl-5-(methoxymethoxy)phenyl)methanol (INT A-3). To a solution of INT A-3E (2.79 g, 9.80 mmol) in THF (65.3 mL) at 0 °C was added lithium aluminum hydride (1 M in THF) (10.8 mL, 10.8 mmol) and the reaction mixture was then stirred at room temperature for 30 min. The reaction mixture was diluted with diethyl ether and cooled to 0 °C. Then, water (0.409 mL) was added, followed by a solution of 15% aqueous NaOH (0.409 mL) and water (1.23 mL). The reaction mixture was allowed to reach room temperature and was stirred for 15 min. MgSCL was added and the reaction mixture was stirred for 15 min before being filtered to remove the salts. The filtrate was concentrated under reduced pressure to afford INT A-3 (2.21 g, 93% yield) as a transparent yellow oil.1H NMR (400 MHz, DMSO-cfe) 6 ppm 7.10 (d, J = 2.5 Hz, 1 H), 6.93 (d, J = 2.4 Hz, 1 H), 5.23 (t, J = 5.5 Hz, 1 H), 5.17 (s, 2H), 4.67 (d, J = 5.5 Hz, 2H), 3.36 (s, 3H), 1 .62 (tt, J = 8.4, 5.7 Hz, 1 H), 0.94 - 1.00 (m, 2H), 0.51 - 0.57 (m, 2H).

[0324]

[0325] Step 1

[0326] 7-Fluoro-8-((triisopropylsilyl)ethynyl)naphthalene-1,3-diol (INT A-4A). 7-Fluoronaphthalene- 1 ,3-diol (9.11 g, 51.1 mmol) was dissolved in 1 ,4-dioxane (250 mL) and the solution was purged of air by bubbling nitrogen through the stirred solution for 15 minutes. (Bromoethynyl)triisopropylsilane (12.5 mL, 51.1 mmol) and dichloro(p-cymene)ruthenium(ll) dimer (3.13 g, 5.11 mmol) were added and the reaction mixture was heated to 110 °C for 3 h. Then, the reaction mixture was cooled down to room temperature and was filtered through a pad of Celite®. The pad was rinsed with ethyl acetate and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (25% EtOAc in hexanes) to afford INT A-4A (13.65 g, 74% yield).1H NMR (400 MHz, CDCI3) 5 ppm 9.17 (s, 1 H), 7.60 (dd, J = 9.1 , 5.6 Hz, 1 H), 7.17 (t, J = 8.8 Hz, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.66 (d, J = 2.4 Hz, 1 H), 4.96 (br. s., 1 H), 1.15 - 1.23 (m, 21 H).

[0327] Step 2

[0328] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-ol (INT A-4B). Under nitrogen, INT A-4A (13.7g, 38.1 mmol) and DIPEA (20 mL, 114 mmol) were dissolved in dichloromethane (130 mL) and the reaction mixture was cooled to 0 °C. Then, MOM-CI (3.00 mL, 39.5 mmol) was added, and the reaction mixture was stirred at 0 °C for 2 h. The reaction mixture was washed with water and the aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were dried over MgSO4, filtered concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (15-25% EtOAc in hexanes) to afford INT A-4B (8.2 g, 53% yield) as a yellow solid.1H NMR (400 MHz, CDCI3) 5 ppm 9.14 (s, 1 H), 7.68 (dd, J = 9.1 , 5.6 Hz, 1 H), 7.20 (t, J = 8.8 Hz, 1 H), 6.99 (d, J = 2.4 Hz, 1 H), 6.82 (d, J =

[0329] 2.4 Hz, 1 H), 5.27 (s, 2H), 3.52 (s, 3H), 1.16 - 1.30 (m, 21 H).

[0330] Step 3

[0331] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl trifluoromethanesulfonate (INT A-4C). To a solution of INT A-4B (8.90 g, 22.1 mmol) in dichloromethane (111 mL) under argon was added DI PEA (8.0 mL, 45.9 mmol) and the reaction mixture was cooled to -40 °C. Then, triflic anhydride (4.25 mL, 24.3 mmol) was added dropwise and the reaction mixture was stirred at -40 °C for 1 h before being allowed to reach room temperature. Then, the reaction mixture was diluted with ethyl acetate, hexanes and water, and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A- 4C (11.9 g, quant, yield) as a dark orange oil.1H NMR (400 MHz, CDCI3) 6 ppm 7.71 (dd, J = 9.0,

[0332] 5.4 Hz, 1 H), 7.43 (d, J = 2.4 Hz, 1 H), 7.29 - 7.38 (m, 2H), 5.28 (s, 2H), 3.52 (s, 3H), 1.13 - 1.30 (m, 21 H).

[0333] Step 4

[0334] Methyl 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1 -naphthoate (INT A- 4D). To a solution of INT A-4C (1.07 g, 2.00 mmol) in ethanol (20 mL) were added potassium acetate (1.18 g, 12.0 mmol), hexacarbonylmolybdenum 2.4 g 9.1 mmol) and PdCh(dppf) DCM complex (146 mg, 200 pmol), and the reaction mixture was heated at 80 °C for 16 h. Then, the reaction mixture was concentrated under reduced pressure and the residue was dissolved in water and ethyl acetate. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSCH filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (10% EtOAc in hexanes) to afford INT A-4D (220 mg, 24% yield) as a beige solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.72 (dd, J = 9.0, 5.6 Hz, 1 H), 7.45 - 7.48 (m, 1 H), 7.24 - 7.30 (m, 2H), 5.28 (s, 2H), 4.45 (q, J = 7.1 Hz, 2H), 3.51 (s, 3H), 1.37 (t, J = 7.1 Hz, 3H), 1.10 - 1.25 (m, 21 H).

[0335] Step 5

[0336] Methyl 8-ethynyl-7-fluoro-3-(methoxymethoxy)-1 -naphthoate (INT A-4E). To solution of INT A-4D (220 mg, 0.480 mmol) in DMF (5 mL) was added cesium fluoride (730 mg, 4.80 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then, the reaction mixture was concentrated under reduced pressure azeotroping with heptane. The residue was dissolved in ethyl acetate and water. The layers were separated, and the organic layer was washed with water. The organic layer was dried over MgSC filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (25% EtOAc in hexanes) to afford INT A-4E (105 mg, 72% yield) as a colorless film.1H NMR (400 MHz, CDCI3) 5 ppm 7.77 (dd, J = 9.1 , 5.7 Hz, 1 H), 7.48 (d, J = 2.5 Hz, 1 H), 7.43 (d, J = 2.5 Hz, 1 H), 7.31 (t, J = 8.9 Hz, 1 H), 5.29 (s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 3.69 - 3.75 (m, 1 H), 3.51 (s, 3H), 1.40 (t, J = 7.2 Hz, 3H).

[0337] Step 6

[0338] Methyl 8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthoate (INT A-4F). To a solution of INT A-4E (105 mg, 347 pmol) in ethanol (30 mL) was added Pd on carbon (10% by weight Pd on a dry basis, 50% by weight water; 15 mg, 141 pmol). The flask was sealed with a septum, then H2 gas was bubbled through the solution via syringe and balloon. The mixture was stirred at room temperature for 3 h under positive pressure of H2 via balloon. The reaction mixture was filtered through a pad of Celite® over cotton to remove the Pd on carbon and the pad was rinsed with ethyl acetate. The filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (15% EtOAc in hexanes) to afford INT A-4F (94 mg, 88% yield) as a colourless film.1H NMR (400 MHz, CDCI3) 6 ppm 7.62 (dd, J = 9.0, 5.8 Hz, 1 H), 7.47 (d, J = 2.6 Hz, 1 H), 7.32 (d, J = 2.5 Hz, 1 H), 7.26 (t, J = 9.3 Hz, 1 H), 5.28 (s, 2H), 4.46 (q, J = 7.2 Hz, 2H), 3.52 (s, 3H), 2.92 (qd, J = 7.4, 2.5 Hz, 2H), 1.44 (t, J = 7.1 Hz, 3H), 1.24 (t, J = 7.4 Hz, 3H).

[0339] Step 7

[0340] (8-Ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methanol (INT A-4). To a solution of INT A-4F (94 mg, 310 pmol) in THF (10 mL) was added UAIH4 (60 mg, 1.58 mmol) and the reaction mixture was stirred at room temperature for 1 h. Then, sodium sulfate decahydrate was added to quench excess LAH and the suspension was stirred at room temperature for 16 h. The solution was decanted from the solids and the solids were washed with ethyl acetate. The obtained solution was concentrated under reduced pressure (30% EtOAc in hexanes) to afford INT A-4 (62 mg, 76% yield) as a white solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.62 (dd, J = 8.9, 6.00 Hz, 1 H), 7.34 - 7.44 (m, 2H), 7.24 (t, J = 9.3 Hz, 1 H), 5.29 (s, 2H), 5.14 (s, 2H), 3.53 (s, 3H), 3.27 (qd, J = 7.4, 3.3 Hz, 2H), 1.24 - 1.37 (m, 3H).

[0341] INT A-5

[0342] (3-(Methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methanol (INT A-5). This intermediate was prepared according to the procedure described for INT A-4 (steps 1 to 4 then step 7) using naphthalene-1 ,3-diol as starting diol.1H NMR (400 MHz, CDCh) 6 ppm 7.78 (dd, J = 8.3, 1.1 Hz, 1 H), 7.72 (dd, J = 7.3, 1.3 Hz, 1 H), 7.37 - 7.41 (m, 1 H), 7.36 (d, J = 2.9 Hz, 1H),

[0343] 7.32 (d, J = 2.6 Hz, 1 H), 5.40 (s, 2H), 5.30 (s, 2H), 3.52 (s, 3H), 1.16 - 1.23 (m, 21 H).

[0344] INT A-6

[0345] (8-Ethyl-3-(methoxymethoxy)naphthalen-1-yl)methanol (INT A-6). This intermediate was prepared according to the procedure described for INT A-4 using naphthalene-1 ,3-diol as starting diol.1H NMR (400 MHz, CDCh) 6 ppm 7.64 (dd, J = 8.1, 1.1 Hz, 1H), 7.35 - 7.41 (m, 3H), 7.29

[0346] (s, 1 H), 5.31 (s, 2H), 5.17 (s, 2H), 3.53 (s, 3H), 3.28 (q, J = 7.5 Hz, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0347] INT A-7

[0348] (8-Cyclopropylnaphthalen-1-yl)methanol (INT A-7). This intermediate was prepared from 1,8- dibromonaphthalene according to the described procedures for INT A-3 (step 1 then steps 5 and 6).1H NMR (400 MHz, CDCh) 6 ppm 7.83 (d, J = 8.1 Hz, 1 H), 7.70 - 7.78 (m, 1 H), 7.64 (d, J =

[0349] 6.9 Hz, 1 H), 7.34 - 7.49 (m, 3H), 5.57 (d, J = 6.1 Hz, 2H), 2.81 - 2.93 (m, 1H), 1.69 (t, J = 6.1 Hz, 1 H), 1.04 - 1.14 (m, 2H), 0.87 - 0.95 (m, 2H).

[0350] INT A-8 INT A-8D

[0351] Step 1

[0352] 4-Bromo-Af,Af-b / s(4-methoxybenzyl)-6-methylpyridin-2-amine (INT A-8A). To a solution of 4- bromo-6-methylpyridin-2-amine (1.00 g, 5.19 mmol) and 4-methoxybenzyl chloride (1.85 g, 11.8 mmol) in DMF (8 mL) at 0 °C was added NaH (554 mg, 13.8 mmol) in one portion and the reaction mixture was stirred for 5 h while reaching 15 °C. Then, the reaction mixture was quenched with formic acid (522 pL, 13.8 mmol). The reaction mixture was diluted with water and diethyl ether. The layers were separated. The aqueous layer was extracted 3 times with diethyl ether. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0- 40% EtOAc in hexanes) to afford INT A-8A (1.90 g, 86% yield) as a white solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.15 (d, J = 8.6 Hz, 4H), 6.85 (d, J = 8.6 Hz, 4H), 6.62 (s, 1 H), 6.45 (s, 1 H), 4.67 (s, 4H), 3.81 (s, 6H), 2.39 (s, 3H).

[0353] Step 2

[0354] 4-Bromo-5-iodo- / V, / V-b / s(4-methoxybenzyl)-6-methylpyridin-2-amine (INT A-8B). To a solution of INT A-8A (1.80 g, 4.21 mmol) in a mixture of acetonitrile (18 mL) and DMF (3.6 mL) was added / V-iodosuccinimide (2.00 g, 8.89 mmol) in one portion and the reaction mixture was stirred at room temperature for 2 h. Then, the reaction mixture was concentrated under reduced pressure to remove acetonitrile. The remaining DMF solution was diluted with water to obtain a precipitate which was filtered on a Buchner. The cake was washed with water, then 50% aqueous acetonitrile, and was dried under reduced pressure to afford INT A-8B (2.20 g, 94% yield) as a light brown solid.1H NMR (400 MHz, CDCh) 6 ppm 7.13 (d, J = 8.5 Hz, 4H), 6.85 (d, J = 8.6 Hz, 4H), 6.62 (s, 1 H), 4.64 (s, 4H), 3.81 (s, 6H), 2.74 (s, 3H). Step 3

[0355] 4-Bromo-5-cyclopropyl-Af,Af-b / s(4-methoxybenzyl)-6-methylpyridin-2-amine (INT A-8C). To a degassed solution (purged with argon gas) of INT A-8C (400 mg, 0.723 mmol), cyclopropylboronic acid (155 mg, 1.81 mmol) and potassium phosphate (460 mg, 2.17 mmol) in 1 ,4-dioxane (8 mL) was added Pd(PPha)4 (83.6 mg, 0.0723 mmol) and the reaction mixture was heated under argon atmosphere at 105 °C for 18 h. Then, the reaction mixture was cooled to room temperature and diluted with water and ethyl acetate. The layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-8C (165 mg, 49% yield) as white solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.15 (d, J = 8.5 Hz, 4H), 6.82 - 6.86 (m, 4H), 6.54 (s, 1 H), 4.63 (s, 4H), 3.80 (s, 6H), 2.54 (s, 3H), 1.60 - 1 .67 (m, 1 H), 1.00 - 1.07 (m, 2H), 0.57 - 0.63 (m, 2H).

[0356] Step 4

[0357] Ethyl 6-(b / s(4-methoxybenzyl)amino)-3-cyclopropyl-2-methylisonicotinate (INT A-8D). To a suspension of INT A-8C (288 mg, 0.616 mmol) in ethanol (48 mL) was added Pd(dppf)Ch DCM complex (175 mg, 0.239 mmol) and triethylamine (310 pL, 2.22 mmol). The suspension was purged with CO for 5 min and the reaction mixture was heated to 85 °C under CO balloon atmosphere for 18 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to afford INT A-8D (200 mg, 70% yield) as light purple oil.1H NMR (400 MHz, CDCI3) 6 ppm 7.14 (d, J = 8.6 Hz, 5H), 6.83 (d, J = 8.6 Hz, 4H), 6.39 (s, 1 H), 4.67 (s, 4H), 4.28 - 4.36 (m, 2H), 3.80 (s, 6H), 2.55 (s, 3H), 1.80 - 1.89 (m, 1 H), 1.35 (t, J = 8.0 Hz, 3H), 0.86 - 0.93 (m, 2H), 0.37 - 0.42 (m, 2H).

[0358] Step 5

[0359] (6-(b / s(4-Methoxybenzyl)amino)-3-cyclopropyl-2-methylpyridin-4-yl)methanol (INT A-8). To a solution of INT A-8D (200 mg, 0.434 mmol) in THF (4 mL) at 0 °C was added lithium aluminum hydride (194 mg, 1 .30 mmol) in one portion and the reaction mixture was stirred at 0 °C for 5 min. Then, the cooling bath was removed, and the reaction mixture was stirred for 1 h. The reaction mixture was cooled back to 0 °C and diluted with diethyl ether. Then, the reaction mixture was carefully quenched with aqueous 15% NaOH solution (0.5 mL) and the cooling bath was removed. The reaction mixture was filtered over a pad of Celite®. The cake was rinsed with diethyl ether and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford INT A-8 (130 mg, 72% yield) as light-yellow solid.1H NMR (400 MHz, CDCI3) 5 ppm 7.17 (d, J = 8.6 Hz, 4H), 6.80 - 6.85 (m, 4H), 6.45 (s, 1 H), 4.77 (d, J = 6.0 Hz, 2H), 4.69 (s, 4H), 3.77 - 3.82 (m, 6H), 2.53 (s, 3H), 1.59 - 1.64 (m, 1 H), 0.91 - 1.00 (m, 2H), 0.46 - 0.55 (m, 2H).

[0360] INT A-9A INT A-9

[0361] R = Me or allyl)

[0362] Step 1

[0363] Methyl 7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1 -naphthoate, (INT A- 9A, R = Me). To a solution of commercially available ((2-fluoro-6-(methoxymethoxy)-8-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1-yl)ethynyl)triisopropylsilane (1.0 g, 1.95 mmol), triphenylphosphine (51 mg, 195 pmol) and 1 ,4-benzoquinone (211 mg, 1.95 mmol) in MeOH (50 mL) under nitrogen at -78 °C, was added Pd(OAc)2 (22 mg, 97.6 pmol). Then, the suspension was purged with CO for 10 min at -78 °C before being allowed to reach room temperature. The reaction mixture was stirred under CO balloon atmosphere for 16 h. Then, the reaction mixture was filtered over a pad of Celite® and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to afford INT A-9A (689 mg, 90% pure, 71% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.69 - 7.75 (m, 1 H), 7.46 (s, 2H), 7.29 (s, 1 H), 5.25 - 5.31 (m, 2H), 3.97 (s, 3H), 3.51 (s, 3H), 1.18 (s, 21 H).

[0364] Allyl 7 -fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1 -naphthoate (INT A-9A, R = allyl). Adapting a published procedure (Adv. Synth. Catal. 2010 Feb 15; 352 (2-3), 478-92), a 1000 mL pear-shaped flask, fitted with a three way inlet tube, was charged with a solution of ((2- fluoro-6-(methoxymethoxy)-8-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-1- yl)ethynyl)triisopropylsilane (10.0 g, 19.5 mmol) and 1 ,4-benzoquinone (4.73 g, 42.9 mmol) in allylic alcohol (400 mL). This was cooled to -78 °C under an argon balloon, resulting in a thick brown slurry. The flask was evacuated for a period of 10-15 min and then back-filled with CO gas at ambient pressure. This exercise was done twice more. The reaction was then warmed to RT under an ambient pressure of CO gas. The inlet tube was replaced with a septum with a vent needle to allow for bubbling of CO gas through the stirred reaction mixture. After 15-20 min, palladium acetate (657 mg, 2.93 mmol) and triphenylphosphine (1.54 g, 5.85 mmol) were added and CO gas continued to be bubbled through for another 15-20 min. The vent needle was removed, and the reaction was stirred for about 4 h after the addition of the catalyst and ligand, after which there is less than 5% of SM remaining by LCMS analysis. During the reaction time, the mixture went from brown slightly turbid to a black mixture with black fine particulates. The reaction was left to continue stirring overnight at RT.

[0365] This procedure was repeated a second time on the same scale and the two reactions combined, filtered through a celite plug using several small portions of EtOAc for washings. Volatiles were then evaporated from the filtrate and the residue purified on a 330 g silica gel column, eluting with a 20 to 100% DCM / hexane gradient to give a white waxy solid on drying under high vacuum (70% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.72 (dd, J = 5.6, 9.1 Hz, 1 H), 7.47 (s, 1 H), 7.25 - 7.33 (m, 2H), 5.96 - 6.10 (m, 1 H), 5.33 - 5.43 (m, 1 H), 5.23 - 5.31 (m, 1 H), 5.28 (s, 2H), 4.90 (td, J = 1.3, 5.8 Hz, 2H), 3.51 (s, 3H), 1.18 (s, 21 H). LCMS: m / z = 471.2 [M+H]+.

[0366] Step 2

[0367] (7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methanol (INT A-9 from INT A-9A, R = Me). This intermediate was prepared according to the procedure described for INT A-4 (step 7).1H NMR (400 MHz, CDCh) 6 ppm 7.75 (dd, J = 5.9, 9.0 Hz, 1 H), 7.35 (s, 2H), 7.24 - 7.26 (m, 1 H), 5.39 (br. s., 2H), 5.29 (s, 2H), 3.52 (s, 3H), 1.14 - 1.25 (m, 21 H). (7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)methanol (INT A-9 from INT A-9A, R = allyl). To a cold (0 °C) solution of the allyl ester of INT A-9A (12.4 g, 26.4 mmol) in dry THF (100 mL) was added portion wise 1M LAH in THF (68.7 mL, 68.7 mmol) over a period of 15-20 min. The cooling bath was then removed, and the resultant light-yellow suspension was stirred at rt for 3 h (LCMS showed complete consumption of the SM). The reaction mixture was cooled again with an ice-bath and water (2.70 mL) was added dropwise over a period of 30 min. A stream of nitrogen gas was applied to help disperse the hydrogen gas generated. Following this, 15% w / w aqueous NaOH (5.60 mL) was added, also slowly and dropwise over a period of 5 min. Upon addition, an appreciable amount of a granular white solid had formed. Diethyl ether (200 mL) was added, and the solids filtered and washed with more ether (200 mL). The filtrate and washings were combined and concentrated under reduced pressure. The desired compound was isolated on a 220 g silica gel column using a 0 to 20% ethyl acetate / hexane gradient. INT A-9 (8.00 g, 73 %) was isolated as a clear colourless oil that solidified under high vacuum to a white wax-like solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.74 (dd, J = 5.9, 9.0 Hz, 1 H), 7.35 (q, J = 2.6 Hz, 2H), 7.26 (t, J = 8.8 Hz, 1 H), 5.39 (s, 2H), 5.29 (s, 2H), 3.52 (s, 3H), 2.86 (br. s. 1 H), 1.14 - 1.31 (m, 3H), 1.21 (s, 18H). LCMS: m / z = 417.2 [M+H]+.

[0368] INT A-1 A INT A-10

[0369] 1-(8-Ethylnaphthalen-1-yl)ethan-1-ol (INT A-10). To a solution of INT A-1A (350 mg, 1.90 mmol) in THF (4.7 mL) at 0 °C was added dropwise methylmagnesium bromide (697 pL, 2.09 mmol). The mixture was stirred at 0 °C for 30 min before quenching with sat. NH4CI. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0- 35% EtOAc in hexanes) to afford INT A-10 (380 mg, quantitative yield).1H NMR (400 MHz, CDCI3) 5 ppm 7.96 (d, J = 7.3 Hz, 1 H), 7.81 (d, J = 8.0 Hz, 1 H), 7.72 - 7.79 (m, 1 H), 7.49 (t, J = 7.7 Hz, 1 H), 7.40 (d, J = 4.8 Hz, 2H), 5.91 (q, J = 6.2 Hz, 1 H), 3.23 (dq, J = 4.4, 7.4 Hz, 2H), 1.98 (s, 1 H), 1 .58 - 1.70 (m, 3H), 1 .37 (t, J = 7.4 Hz, 3H). iNT A-11

[0370] Tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (INT A-11). To a solution of c / s-5- benzyltetrahydropyrrolo[3,4-c]pyrrole-1 , 3(2 / 7, 3a / - / )-dione (100 mg, 434 pmol) in MeOH (4.3 mL) under nitrogen, was added Pd / C 10% (46.2 mg, 43.4 pmol). Hydrogen was bubbled through the solution for 5 min and the reaction was stirred under hydrogen for 72 h. Then, the reaction mixture was filtered through a 0.45 pm syringe filter and the filtrate was concentrated under reduced pressure to afford INT A-11 (61 mg, quantitative yield). LCMS: m / z = 141.2 [M+H]+.

[0371] INT A-12A INT A-12

[0372] 1-Bromo-3-chloro-5-(methoxymethoxy)-2-(trifluoromethyl)benzene (INT A-12A). This intermediate was synthesized according to the procedure described for INT A3-D (steps 2-4) using 1-bromo-3-chloro-2-(trifluoromethyl)benzene as a starting material.1H NMR (400 MHz, CDCh) 6 ppm 7.33 (d, J = 2.4 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 5.20 (s, 2H), 3.49 (s, 3H).

[0373] (3-Chloro-5-(methoxymethoxy)-2-(trifluoromethyl)phenyl)methanol (INT A-12). This intermediate was prepared from INT A-12A according to the procedure described for INT A-1.1H NMR (400 MHz, CDCh) 6 ppm 7.33 (d, J = 1.9 Hz, 1 H), 7.12 (d, J = 2.3 Hz, 1 H), 5.23 (s, 2H), 4.88 (dd, J = 6.1 , 2.3 Hz, 2H), 3.49 (s, 3H), 1.94 (t, J = 6.2 Hz, 1 H).

[0374] INT A-13G INT A-13

[0375] Step 1 tert-Butyl (tert-butoxycarbonyl)(4-methylbenzo[d]thiazol-2-yl)carbamate (INT A-13A). To a solution of 2-amino-4-methylbenzothiazole (1.03 g, 6.09 mmol) and DMAP (149 mg, 1.22 mmol) in dichloromethane (30 mL) was added di-te / t-butyl-dicarbonate (4.20 mL, 18.3 mmol) and the reaction was stirred at room temperature for 16 h. Then, the reaction was filtered, and the filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-13A (2.16 g, 97% yield).1H NMR (400 MHz, CDCh) 6 ppm 7.63 (dd, J = 7.2, 1.8 Hz, 1 H), 7.17 - 7.27 (m, 2H), 2.64 (s, 3H), 1.57 - 1.67 (m, 18H).

[0376] Step 2 tert-Butyl (tert-butoxycarbonyl)(4-(dibromomethyl)benzo[d]thiazol-2-yl)carbamate (INT A- 13B). A mixture of INT A-13A (2.16 g, 5.93 mmol), / V-bromosuccinimide (1.79 g, 10.1 mmol) and 2,2'-azob / s(2-methylpropionitrile) (214 mg, 1.30 mmol) in CCI4 (25 mL) was heated at 80 °C for 6 h. The reaction was filtered to remove the insoluble material and the solid was washed with a mixture of dichloromethane and hexanes. The filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-13B (2.10 g, 68% yield) as a mixture of mono-brominated compound (LCMS: m / z = 286.7, 288.7 [M+H]+) and b / s-brominated compound (LCMS: m / z = 364.8, 366.8 [M+H]+).

[0377] Step 3 tert-Butyl (4-(bromomethyl)benzo[oQthiazol-2-yl)(tert-butoxycarbonyl)carbamate (INT A- 13C). To a solution of INT A-13B (2.05 g, 4.63 mmol) in THF (10 mL) at 0°C under nitrogen were added diethyl phosphite (2.37 mL, 18.5 mmol) and DIPEA (3.23 mL, 18.5 mmol) and the reaction mixture was allowed to reach room temperature and stirred for 24 h. Then, ice and solid NaCI were added to the reaction which was diluted with ethyl acetate. The layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-13C (1.44 g, 70% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.75 (d, J = 7.9 Hz, 1 H), 7.47 (d, J = 7.4 Hz, 1 H), 7.22 - 7.33 (m, 1 H), 4.93 (s, 2H), 1.64 (s, 18H).

[0378] Step 4

[0379] (2-(b / s(tert-Butoxycarbonyl)amino)benzo[d]thiazol-4-yl)methyl acetate (INT A-13D). To a solution of INT A-13C (500 mg, 1.13 mmol) in DMF (5 mL) under nitrogen was added potassium acetate (332 mg, 3.38 mmol) and the reaction mixture was stirred at 50 °C for 24 h. Then, the reaction mixture was cooled to room temperature. Ethyl acetate and water were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford INT A-13D (490 mg, quantitative yield).1H NMR (400 MHz, CDCh) 6 ppm 7.78 (d, J = 7.9 Hz, 1 H), 7.45 (d, J = 7.4 Hz, 1 H), 7.30 - 7.37 (m, 1 H), 5.53 (s, 2H), 2.13 (s, 3H), 1.62 (s, 18H).

[0380] Step 5 tert-Butyl (4-(hydroxymethyl)benzo[d]thiazol-2-yl)carbamate (INT A-13E). To a solution of INT A-13D (453 mg, 1.07 mmol) in THF (3.66 mL) and MeOH (3.66 mL) was added NaOH (129 mg, 3.22 mmol) in water (1 .61 mL) and the reaction mixture was stirred at room temperature for 90 min. Then, the reaction mixture was acidified with a 2N-HCI solution (until pH 5 was reached) and concentrated under reduced pressure. Ethyl acetate and water were added, and the layers were separated. The organic layer was washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford INT A-13E (314 mg, quantitative yield). LCMS: m / z = 281.0 [M+H]+.

[0381] Step 6 tert-Butyl (4-(((tert-butyldimethylsilyl)oxy)methyl)benzo[d]thiazol-2-yl)carbamate (INT A- 13F). To a solution of INT A-13E (842 mg, 3.00 mmol) and te / t-butyl-dimethylsilyl chloride (543 mg, 3.60 mmol) in dichloromethane (23.8 mL) was added DIPEA (634 pL, 3.60 mmol), followed by DMAP (14.7 mg, 120 pmol) and the reaction mixture was stirred for 18 h. Then, the reaction mixture was washed with sat. aq. NH4CI solution and extracted 3 times with dichloromethane. The combined organic layers were dried over MgSC filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0- 20% EtOAc in hexanes) to afford INT A-13F (995 mg, 84% yield).1H NMR (400 MHz, CDCh) 6 ppm 7.65 (d, J = 7.9 Hz, 1 H), 7.54 (d, J = 7.4 Hz, 1 H), 7.19 - 7.32 (m, 1 H), 5.14 (s, 2H), 1.52 (s, 9H), 0.95 (s, 9H), 0.11 (s, 6H).

[0382] Step 7 tert-Butyl (tert-butoxycarbonyl)(4-(((tert-butyldimethylsilyl)oxy)methyl)benzo[d] thiazol-2- yljcarbamate (INT A-13G). This intermediate was prepared according to the procedure described for INT A-13A.1H NMR (400 MHz, CDCh) 6 ppm 7.68 (d, J = 7.9 Hz, 1 H), 7.59 (d, J = 7.5 Hz, 1 H), 7.33 (t, J = 7.7 Hz, 1 H), 5.19 (s, 2H), 1.59 (s,18H), 0.97 (s, 9H), 0.07 - 0.17 (m, 6H).

[0383] Step 8 tert-Butyl (tert-butoxycarbonyl)(4-(hydroxymethyl)benzo[d]thiazol-2-yl)carbamate (INT A- 13). To a solution of INT A-13G (1.25 g, 2.52 mmol) in THF (2.5 mL) was added tetrabutylammonium fluoride (1M-solution in THF) (5 mL, 5.04 mmol) and the reaction mixture was stirred at room temperature for 3 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to afford INT A-13 (690 mg, 72% yield).1H NMR (400 MHz, CDCh) 6 ppm 7.72 (d, J = 7.5 Hz, 1 H), 7.30 (d, J = 4.6 Hz, 2H), 5.01 (s, 2H), 3.65 (s, 1 H), 1.61 (s, 18H). Step 1

[0384] Methyl 6-hydroxy-1 -naphthoate (INT A-14A). To a solution of 6-hydroxy-1-naphtoic acid (3.00 g, 15.9 mmol) in MeOH (30 mL) were added 10 drops of concentrated sulfuric acid and the reaction mixture was refluxed for 6 h and then stirred at 60 °C for 4 days. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure to one third of its volume. The resulting mixture was diluted with ethyl acetate and washed 3 times with a NaHCOs solution (1 :1 sat. NaHCOs and water). The combined aqueous layers were back extracted once with ethyl acetate. The combined organic layers were washed with brine, dried over MgSC filtered and concentrated under reduced pressure to afford INT A-14A (2.72 g, 84% yield) as a pale pink solid.1H NMR (400 MHz, CDCh) 5 ppm 8.86 (d, J = 9.1 Hz, 1 H), 8.04 (dd, J = 7.3, 1.0 Hz, 1 H), 7.86 (d, J = 8.3 Hz, 1 H), 7.45 (t, J = 7.8 Hz, 1 H), 7.18 - 7.26 (m, 2H), 5.18 (s, 1 H), 4.01 (s, 3H).

[0385] Step 2

[0386] Methyl 6-((tert-butyldimethylsilyl)oxy)-1-naphthoate (INT A-14B). This intermediate was prepared according to the procedure described for INT A-13F.1H NMR (400 MHz, CDCh) 6 ppm 8.81 (d, J = 9.3 Hz, 1 H), 8.04 (dd, J = 7.3, 1.0 Hz, 1 H), 7.87 (d, J = 8.3 Hz, 1 H), 7.44 (t, J = 7.8 Hz, 1 H), 7.24 (d, J = 2.4 Hz, 1 H), 7.21 (dd, J = 9.3, 2.5 Hz, 1 H), 4.00 (s, 3H), 1.03 (s, 9H), 0.27 (s, 6H).

[0387] Step 3

[0388] (6-((tert-Butyldimethylsilyl)oxy)naphthalen-1-yl)methanol (INT A-14). This intermediate was prepared according to the procedure described for INT A-4 (step 7).1H NMR (400 MHz, CDCh) 5 ppm 8.04 (d, J = 9.1 Hz, 1 H), 7.68 (dd, J = 7.7, 1.8 Hz, 1 H), 7.35 - 7.44 (m, 2H), 7.24 (d, J = 2.5 Hz, 1 H), 7.15 (dd, J = 9.1 , 2.5 Hz, 1 H), 5.12 (d, J = 5.6 Hz, 2H), 1.70 (t, J = 5.8 Hz, 1 H), 1.04 (s, 9H), 0.26 (s, 6H).

[0389] INT A-15A INT A-15B INT A-15

[0390] Step 1

[0391] 1-Bromo-3-chloro-2-(prop-1-en-1-yl)benzene (INT A-15A). To a solution of (ethyl)triphenyllphosphonium bromide (6.77 g, 18.2 mmol) in THF (30.4 mL) at 78 °C, was added n-butyllithium (2.5 M in hexanes) (7.11 mL, 17.8 mmol) and the reaction mixture was stirred at - 78 °C for 10 min and at 0 °C for 50 min. Then, a solution of 2-bromo-6-chlorobenzaldehyde (2.00 g, 9.11 mmol) in THF (10 mL) was added and the resulting reaction mixture was stirred at 0 °C for 1 h. Then, sat. NH4CI and water were added. The reaction mixture was concentrated under reduced pressure to remove THF. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was solubilized using the minimum amount of dichloromethane. Diethyl ether was added and OPPha precipitated from the mixture. The mixture was passed through a pad of silica gel which was rinsed with diethyl ether. The solution was concentrated under reduced pressure to afford INT A-15A (1.50 g, 71% yield) as a mixture of isomers (1 :1), as a colorless oil. Only the trans isomer is reported here.1H NMR (400 MHz, CDCI3) 5 ppm 7.32 - 7.40 (m, 2H), 6.98 (t, J = 8.0 Hz, 1 H), 6.30 - 6.38 (m, 1 H), 6.10 - 6.22 (m, 1 H), 1.96 (dd, J = 1.6, 6.5 Hz, 3H).

[0392] Step 2

[0393] 1-Bromo-3-chloro-2-((1S,2S)-2-methylcyclopropyl)benzene (INT A-15B). To a solution of diethylzinc (1M in hexanes) (86.4 mL, 86.4 mmol) in dichloromethane (43.2 mL) at -40 °C was added a solution of trifluoroacetic acid (6.61 mL, 86.4 mmol) in dichloromethane and the reaction mixture was stirred at -40 °C for 30 min. Then, at -40 °C, a solution of diiodomethane (7.11 mL, 86.4 mmol) in dichloromethane (1 mL) was added dropwise and the reaction was stirred at this temperature for 30 min. Finally, at -40 °C, a solution of INT A15A (5.00 g, 21.6 mmol) in dichloromethane (1 mL) was added dropwise and the reaction was allowed to reach room temperature and stirred for 16 h. The reaction mixture was quenched with sat. NH4CI. The aqueous mixture was extracted 3 times with dichloromethane. The combined organic layers were washed with brine, dried over NaaSCL, filtered and concentrated under reduced pressure. Note, the cis isomer remains unreacted under the reaction condition.1H NMR (400 MHz, CDCI3) 6 ppm 7.38 (d, J = 8.0 Hz, 1 H), 7.22 (d, J = 7.9 Hz, 1 H), 6.90 (t, J = 8.0 Hz, 1 H), 1.35 (td, J = 5.5, 8.4 Hz, 1 H), 1.22 (d, J = 5.9 Hz, 3H), 0.80 - 1.06 (m, 3H).

[0394] Steps 3 to 6

[0395] (3-Chloro-5-(methoxymethoxy)-2-((1 S,2S)-2-methylcyclopropyl)phenyl)methanol (INT A- 15). This intermediate was prepared according to the procedure described for INT A-3 (steps 2 to 6). Note: the unreacted c / s-alkene isomer was separated at the ester stage. LCMS: m / z = 255.0 [M+H]+.

[0396] INT A-16A INT A-16B INT A-16

[0397] Step 1

[0398] (E)-A / '-(4-Bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)-A / ,A / -dimethylformimidamide (INT A-16A). To a solution of 2-amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile (500 mg, 1.84 mmol) in ethanol (18 mL) was added 1 ,1-dimethoxytrimethylamine (1.22 mL, 9.22 mmol) and the reaction mixture was heated at 55 °C for 18 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was triturated with diethyl ether and the reaction mixture was filtered. Then, the obtained solid was triturated with ethyl acetate and was filtered on a Buchner. The cake was washed with ethyl acetate and was then dried under reduced pressure to afford INT A-16A (491 mg, 82% yield) as a yellow solid.1H NMR (400 MHz, CDCI3) 6 ppm 7.88 (s, 1 H), 7.46 (dd, J = 8.6, 4.8 Hz, 1 H), 6.84 (t, J = 8.6 Hz, 1 H), 3.23 (d, J = 5.6 Hz, 6H).

[0399] Step 2

[0400] (E)- / V-(3-Cyano-7-fluoro-4-vinylbenzo[b]thiophen-2-yl)- / V, / V-dimethylformimidamide (INT A-16B). To a solution of INT A-16A (200 mg, 613 pmol) in toluene (5.7 mL) under argon, was added tributyl(vinyl)tin (358 pL, 1.23 mmol) and b / s(tri-tert-butylphosphine)palladium(0) (31.3 mg, 61.3 pmol). And the reaction mixture was heated at 65 °C for 18 h. Then, the reaction mixture was cooled to room temperature and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-45% EtOAc in hexanes) to afford INT A- 16B (159 mg, 95% yield).1H NMR (400 MHz, MeCN-cfe) 6 ppm 7.97 (s, 1 H), 7.70 (dd, J = 17.2, 10.9 Hz, 1 H), 7.50 (dd, J = 8.5, 5.3 Hz, 1 H), 6.99 (t, J = 9.0 Hz, 1 H), 5.72 (d, J = 17.1 Hz, 1 H), 5.39 (d, J = 11.0 Hz, 1 H), 3.13 (s, 3H), 3.16 (s, 3H).

[0401] Step 3

[0402] (E)-A / '-(3-Cyano-7-fluoro-4-(hydroxymethyl)benzo[b]thiophen-2-yl)- / V, / V-dimethylformimi- damide (INT A-16). At -78 °C, a mixture of ozone and oxygen (generated from a portable ozone generator) was bubbled through a solution of INT A-16B (39.8 mg, 146 pmol) in MeOH (6 mL) and dichloromethane (6 mL) containing a pinch of Sudan II (red color) as an indicator. The reaction mixture was stirred until it turned to light orange. Then, ozone was turned off and the reaction purged with oxygen. At - 78°C, sodium borohydride (27.5 mg, 728 pmol) was added in one portion and the reaction was stirred for 1 h at this temperature. Then, the reaction mixture was quenched with water, allowed to reach room temperature and stirred for 1 h. The reaction mixture was concentrated under reduced pressure. The crude was diluted with dichloromethane and brine. The layers were separated, and the aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0- 20% MeOH in dichloromethane) to afford INTA-16 (36 mg, 89% yield).1H NMR (400 MHz, CDCI3) 5 ppm 7.88 (s, 1 H), 7.34 (dd, J = 7.8, 5.4 Hz, 1 H), 6.95 (t, J = 8.7 Hz, 1 H), 5.51 (br. s., 1 H), 5.14 (s, 2H), 3.24 (s, 3H), 3.22 (s, 3H).

[0403] INT A-17 INT A-17E INT A-17D

[0404] Step 1

[0405] (E)-2-(4-Fluorobenzylidene)succinic acid (INT A-17A). To a solution of dimethyl succinate (19 mL, 145 mmol) in terf-butanol (60 mL) was added potassium terf-butoxide (16.3 g, 145 mmol) and the reaction mixture was stirred for 30 min at room temperature. Then, a solution of 4- fluorobenzaldehyde (13 mL, 121 mmol) in terf-butanol (60 mL) was added dropwise and the reaction mixture was stirred at 85 °C for 16 h. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The crude was suspended in THF (91 mL) and water (30 mL), lithium hydroxide monohydrate (2.89 g, 121 mmol) was added in one portion and the resulting solution was stirred at room temperature for 2 h. The reaction mixture was then concentrated under reduced pressure. The resulting aqueous suspension was acidified to pH 2 with concentrated HCI to obtain a white precipitate which was filtered on a Buchner. The cake was washed with water and was then dried under reduced pressure to afford INT A-17A (19.4 g, 72% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 12.40 (br. s., 2H), 7.73 (s, 1 H), 7.45 - 7.50 (m, 2H), 7.27 - 7.33 (m, 2H), 3.36 - 3.38 (m, 2H). Step 2

[0406] 6-Fluoro-4-hydroxy-2-naphthoic acid (INT A-17B). A solution of INT A-17A (10.0 g, 44.6 mmol) in concentrated sulfuric acid (36 mL) was stirred at room temperature for 16 h. Then, the reaction mixture was carefully poured over cold water (1 mL) and the reaction mixture was allowed to crystallize overnight in the fridge. The crystals were filtered and washed with water. The crude product was recrystallized from ethanol to afford INT A-17B (747 mg, 8% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 12.83 - 13.02 (m, 1 H), 10.59 (s, 1 H), 8.14 (dd, J = 9.0, 5.8 Hz, 1 H), 8.12 (s, 1 H), 7.77 (dd, J = 10.5, 2.6 Hz, 1 H), 7.49 (td, J = 8.8, 2.7 Hz, 1 H), 7.41 (s, 1 H).

[0407] Step 3

[0408] 4-(Benzyloxy)-6-fluoro-2-naphthoic acid (INT A-17C). To a solution of INT A-17B (300 mg, 1.46 mmol) and K2CO3 (704 mg, 5.09 mmol) in DMF (970 pL) was added benzyl bromide (519 pL, 4.37 mmol) and the reaction mixture was stirred at room temperature for 18 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was suspended in THF (970 pL) and water (970 pL), lithium hydroxide monohydrate (105 mg, 4.37 mmol) was added, and the reaction mixture was stirred for 2 h at room temperature. Then, the reaction mixture was concentrated under reduced pressure. The resulting aqueous suspension was acidified to pH 2 with concentrated HCI to obtain a white precipitate which was filtered on a Buchner. The cake was washed with water and was then dried under reduced pressure to afford INT A-17C (261 mg, 61% yield) as a white solid. LCMS: m / z = 295.0 [M+H]+.

[0409] Step 4 tert-Butyl (4-(benzyloxy)-6-fluoronaphthalen-2-yl)carbamate (INT A-17D). A solution of INT A-17C (261 mg, 881 pmol), triethylamine (246 pL, 1.76 mmol) and diphenyl phosphoryl azide (364 mg, 1.32 mmol) in toluene (3.3 mL) and f-BuOH (3.3 mL) was heated to 90 °C for 2.5 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-70% EtOAc in hexanes) to afford INT A-17D (190 mg, 59% yield) as a yellow oil.1H NMR (400 MHz, DMSO-cfe) 6 ppm 9.50 (s, 1 H), 7.81 (dd, J = 9.3, 5.8 Hz, 1 H), 7.72 (s, 1 H), 7.66 (dd, J = 10.5, 2.5 Hz, 1 H), 7.56 (s, 2H), 7.41 - 7.52 (m, 2H), 7.31 - 7.39 (m, 2H), 7.24 (s, 1 H), 5.23 (s, 2H), 1.50 (s, 9H).

[0410] Step 5 tert-Butyl (6-fluoro-4-hydroxynaphthalen-2-yl)carbamate (INT A-17E). To a solution of INT A- 17D (190 mg, 517 pmol) in MeOH (2.6 mL) was added 10% Pd / C (220 g, 103 pmol). A balloon with H2 was adapted to the flask and the reaction was stirred at room temperature for 18 h. Then, the reaction mixture was filtered through a pad of Celite® and the filtrate was concentrated under reduced pressure to afford INT A-17D (140 mg, 98% yield) as white solid. LCMS: m / z = 276.2 [M- H]+.

[0411] Final steps tert-Butyl (6-fluoro-4-(hydroxymethyl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-yl)carba- mate (INT A-17). This intermediate was prepared according to the procedure described for INT A-4E (step 1 then steps 3 to 5). LCMS: m / z = 472.2 [M-H .

[0412] INT A-18A INT A-18

[0413] Step 1

[0414] 1-Bromo-8-propylnaphthalene (INT A-18A). To a solution of 1 ,8-dibromonaphtalene (2.0 g, 6.99 mmol) in THF (25 mL) at - 78 °C under nitrogen, was added dropwise over 10 min, n- butyllithium (1 .6 M in hexanes) (4.8 mL, 7.69 mmol) and the reaction mixture was stirred at -78 °C for 20 min. Then, 1-iodopropane (1.36 mL, 14 mmol) in THF (10 mL) was added dropwise over 5 min. After 25 min, the reaction mixture was allowed to reach room temperature and was stirred for 1 h. Sat. NH4CI and toluene were added. The layers were separated. The aqueous layer was extracted 3 times with toluene. The combined organic layers were washed with brine, dried over MgSCL, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (100% hexanes) to afford INT-A-18A (1.47 g, 84% pure, 76% yield) as a clear syrup. Note: inseparable mixture with 1-bromo-naphtalene.1H NMR (400 MHz, CDCI3) 6 ppm 7.85 (d, J = 7.6 Hz, 1 H), 7.78 - 7.83 (m, 1 H), 7.70 - 7.76 (m, 1 H), 7.36 - 7.43 (m, 2H), 7.22 (t, J = 7.8 Hz, 1 H), 3.42 - 3.52 (m, 2H), 1.76 (dq, J = 15.2, 7.4 Hz, 2H), 1.03 (t, J = 7.3 Hz, 3 H).

[0415] Final steps

[0416] (8-Propylnaphthalen-1-yl)methanol (INT A-18). This intermediate was prepared according to the procedure described for INT A-3 (steps 5 and 6).1H NMR (400 MHz, CDCI3) 6 ppm 7.85 (dd, J = 8.1 , 1.4 Hz, 1 H), 7.75 (dd, J = 6.5, 3.1 Hz, 1 H), 7.55 - 7.60 (m, 1 H), 7.38 - 7.46 (m, 3H), 5.16 (d, J = 5.9 Hz, 2H), 3.23 - 3.32 (m, 2H), 1 .58 - 1 .76 (m, 3H), 1.06 (t, J = 7.3 Hz, 3H).

[0417] Step 1

[0418] Racemic 2-amino-3-cyano-4,5,6,7-tetrahydrobenzo[b]thiophene-4-carboxylic acid (INT A- 19A). This intermediate was prepared according to a literature procedure (see WO2021245051).1H N MR (400 MHz, DMSO-cfe) 6 ppm 12.37 (br. s., 1 H), 6.93 (s, 2H), 3.38 (t, J = 4.9 Hz, 1 H), 2.34 - 2.47 (m, 2H), 1.92 - 2.00 (m, 1 H), 1.81 - 1.90 (m, 1 H), 1.68 - 1.78 (m, 2H).

[0419] Step 2

[0420] 2-Amino-4-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophene-3-carbonitrile (INT A- 19B). To a solution of INT A-19A (306 mg, 1.38 mmol) in THF (6.9 mL) under nitrogen, was added / V, / V-carbonyldiimidazole (246 mg, 1.51 mmol) and the reaction mixture was heated at 50 °C for 1 h. Then, the reaction mixture was cooled to room temperature, sodium borohydride (156 mg, 4.13 mmol) was added portion wise, and the reaction mixture was stirred at room temperature for 1 h before being quenched with water. THF was removed under reduced pressure. Ethyl acetate was added, and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSCH filtered and concentrated under reduced pressure to afford INT A-19B (287 mg, quant, yield) as a light-yellow oil. LCMS: m / z = 208.8 [M+H]+.

[0421] Step 3

[0422] (E)-A / '-(3-Cyano-4-(hydroxymethyl)-4,5,6,7-tetrahydrobenzo[b]thiophen-2-yl)- / V, / V-dimethyl formimidamide (INT A-19). This intermediate was prepared according to the procedure described for INT A-16A.1H NMR (400 MHz, CDCI3) 6 ppm 7.67 (s, 1 H), 3.92 - 3.99 (m, 1 H), 3.71 - 3.78 (m, 1 H), 3.08 - 3.10 (m, 5H), 2.91 - 2.95 (m, 1 H), 2.53 - 2.62 (m, 2H), 2.06 - 2.13 (m, 1 H), 1.71 - 1.90 (m, 3H). ((8-(Bromomethyl)-2-fluoro-6-(methoxymethoxy)naphthalen-1- yl)ethynyl)triisopropylsilane (INT A-20). To a solution of INT A-9 (97 mg, 233 pmol) and carbon tetrabromide (28 pL, 288 pmol) in dichloromethane (2.5 mL) at 0 °C, was added triphenylphosphine (76 mg, 291 pmol) and the reaction mixture was stirred for 1 h at 0 °C before being stirred at room temperature for 1 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% EtOAc in hexanes) to afford INT A-20 (70 mg, 63% yield).1H NMR (400 MHz, CDCI3) 5 ppm 7.71 (dd, J = 8.9, 5.9 Hz, 1 H), 7.37 (s, 2H), 7.25 - 7.29 (m, 1 H), 5.68 (s, 2H), 5.28 (s, 2H), 3.52 (s, 3H), 1.11 - 1.33 (m, 21 H).

[0423] Step 1

[0424] (E)-A / '-(4-Allyl-3-cyano-7-fluorobenzo[b]thiophen-2-yl)- / V, / V-dimethylformimidamide (INT A- 21 A). This intermediate was prepared according to the procedure described for INT A-16B (step 2) using tributyl(allyl)tin rather than tributyl(vinyl)tin.1H NMR (400 MHz, DMSO-cfe) 5 ppm 8.22 (s, 1 H), 7.17 (dd, J = 8.3, 5.5 Hz, 1 H), 7.10 (dd, J = 9.4, 8.3 Hz, 1 H), 6.05 (ddt, J = 17.3, 10.0, 6.1 , 6.1 Hz, 1 H), 5.07 (dq, J = 10.1 , 1.8 Hz, 1 H), 4.95 (dq, J = 17.1 , 1.8 Hz, 1 H), 3.80 (d, J = 6.1 Hz, 2H), 3.20 (s, 3H), 3.10 (s, 3H).

[0425] Step 2

[0426] (E)-A / '-(3-Cyano-7-fluoro-4-(2-hydroxyethyl)benzo[b]thiophen-2-yl)- / V, / V-dimethylformi- midamide (INT A-21). This intermediate was prepared according to the procedure described for the synthesis of INT A-16 (step 3).1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.21 (s, 1 H), 7.18 (dd, J = 8.4, 5.5 Hz, 1 H), 7.06 (t, J = 9.3 Hz, 1 H), 4.64 (t, J = 5.1 Hz, 1 H), 3.68 (dd, J = 11.9, 6.8 Hz, 2H), 3.20 (s, 3H), 3.18 (t, J = 6.4 Hz, 2H), 3.10 (s, 3H).

[0427]

[0428] Step 1

[0429] Methyl 1-(4-(trifluoromethyl)piperidine-1-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Aa). To a solution of cyclopropane-1 ,1 -dicarboxylic acid methyl ester (1.17 g, 8.12 mmol) and HATLI (3.09 g, 8.12 mmol) in DCM was added DIPEA (1.41 mL, 8.12 mmol) and the reaction mixture was stirred for 10 min. Then, 4-(trifluoromethyl)piperidine hydrochloride (1.54 g, 8.12 mmol) was added and the reaction mixture was stirred for 18 h. The reaction mixture was quenched with sat. NaHCCh and diluted with dichloromethane. The layers were separated, and the aqueous layer was extracted 3 times with dichloromethane. The crude was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford INT A-22Aa (1.40 g, 62% yield) as a colorless oil.1H NMR (400 MHz, CDCI3) 6 ppm 4.72 (d, J = 13.3 Hz, 1 H), 4.07 (d, J = 13.6 Hz, 1 H), 3.74 (s, 3H), 3.03 (br. s., 1 H), 2.63 (br. s., 1 H), 2.14 - 2.41 (m, 1 H), 1.82 - 1.98 (m, J = 12.9, 12.9 Hz, 2H), 1.18 - 1.71 (m, 6H). Step 2

[0430] (1-((4-(Trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl)methanol (INT A-22a). To a solution of INT A-22Aa (2.27 g, 8.13 mmol) in THF (40.6 mL) at 0 °C was added lithium aluminum hydride (679 mg, 17.9 mmol) and the reaction mixture was stirred for 10 min. Then, the reaction mixture was allowed to reach room temperature and was stirred for 2 h. The reaction mixture was diluted with diethyl ether and was cooled down to 0 °C. Water (0.8 mL) was added followed by NaOH 1 N (0.8 mL) and water (3 mL). The resulting mixture was allowed to reach room temperature and was stirred for 15 min. Then, MgSCL was added, the reaction mixture was stirred for 15 min before being filtered and concentrated under reduced pressure to afford INT A-22a (1.90 g, 99% yield).1H NMR (400 MHz, CDCI3) 6 ppm 3.54 (s, 2H), 3.31 (d, J = 11.9 Hz, 2H), 2.48 (s, 2H), 1.55 - 1.97 (m, 8H), 0.50 - 0.58 (m, 2H), 0.33 - 0.40 (m, 2H).

[0431] Intermediates INT-A-22A(b-z) and INT-A-22(b-z) were prepared in a similar fashion using the appropriate amines:

[0432] Methyl 1-((4,4-difluoropiperidin-1-yl)methyl)cyclopropane-1 -carboxylate (INT A-22Ab): 4,4- difluoropiperidine hydrochloride was used as the amine.1H NMR (400 MHz, CDCI3) 6 ppm 3.70 - 3.83 (m, 5H), 3.62 (t, J = 5.6 Hz, 2H), 1.90 - 2.09 (m, 4H), 1.49 - 1.57 (m, 2H), 1.28 - 1.37 (m, 2H).

[0433] (1-((4,4-Difluoropiperidin-1-yl)methyl)cyclopropyl)methanol (INT A-22b)1H NMR (400 MHz, CDCI3) 6 ppm 5.09 (br. s, 1 H), 3.55 (s, 2H), 2.62 - 2.87 (m, 4H), 2.52 (s, 2H), 1.92 - 2.10 (m, 4H), 0.50 - 0.61 (m, 2H), 0.25 - 0.43 (m, 2H).

[0434] Methyl (S)-1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropane-1 -carboxylate (INT A-22Ac): (S)- 3-fluoropyrrolidine hydrochloride was used as the amine.1H NMR (400 MHz, CDCI3) 6 ppm 5.28 (dt, J = 50.0, 4.0 Hz, 1 H), 3.47 - 3.93 (m, 7H), 2.20 - 2.39 (m, 1 H), 1.93 - 2.20 (m, 1 H), 1.37 - 1 .60 (m, 3H), 1.21 - 1.37 (m, 1 H).

[0435] (S)-(1-((3-Fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (INT A-22c):1H NMR (400 MHz, CDCI3) 6 ppm 5.23 (dt, J = 52.0, 4.0 Hz, 1 H), 3.51 - 3.60 (m, 2H), 2.76 - 3.07 (m, 3H), 2.54

[0436] - 2.71 (m, 3H), 1.95 - 2.20 (m, 2H), 0.46 - 0.58 (m, 2H), 0.33 - 0.45 (m, 2H).

[0437] Methyl (R)-1-((3-fluoropyrrolidin-1-yl)methyl)cyclopropane-1 -carboxylate (INT A-22Ad): (R)-3-fluoropyrrolidine hydrochloride was used as the amine.1H NMR (400 MHz, CDCI3) 6 ppm 5.28 (dt, J = 50.0, 4.0 Hz, 1 H), 3.47 - 3.93 (m, 7H), 2.20 - 2.39 (m, 1 H), 1.93 - 2.20 (m, 1 H), 1.37

[0438] - 1.60 (m, 3H), 1.21 - 1.37 (m, 1 H). (R)-(1-((3-Fluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (INT A-22d):1H NMR (400 MHz, CDCh) 6 ppm 5.23 (dt, J = 52.0, 4.0 Hz, 1 H), 3.51 - 3.60 (m, 2H), 2.76 - 3.07 (m, 3H), 2.54

[0439] - 2.71 (m, 3H), 1.95 - 2.20 (m, 2H), 0.46 - 0.58 (m, 2H), 0.33 - 0.45 (m, 2H).

[0440] Methyl 1-(morpholinomethyl)cyclopropane-1 -carboxylate (INT A-22Ae): this intermediate was prepared in a similar fashion except the coupling proceeded through the acid chloride instead of HATLI activation. Oxalyl chloride (1.44 mL, 17 mmol) was added to a mixture of cyclopropane- 1 ,1 -dicarboxylic acid, mono methyl ester (2.00 g, 13.6 mmol) in DCM (19.8 mL) and DMF (217 pL). The mixture was stirred for 3h at RT and concentrated under reduced pressure to provide the desired acid chloride as a semi-solid. The crude material was dissolved in DCM (10 mL) and this solution was added dropwise to a solution of morpholine (1.32 mL, 14. 9 mmol) and trimethylamine (2.84 mL, 20.4 mmol) in DCM (20 mL) at 0 °C. After stirring for 18h at RT, water (50 mL) was added and the product extracted into EtOAc. The organic phase was washed with 5% aqueous citric acid and brine and then dried over Na2SC>4. After concentration, the residue was purified by flash chromatography on silica gel to provide INT A-22Ae as a yellow oil. LCMS: m / z = 214 [M+H]+.

[0441] (1-(Morpholinomethyl)cyclopropyl)methanol (INT A-22e): This intermediate is available from commercial sources (CAS# [1267956-65-9]).

[0442] Methyl 1-((3,3-difluoropyrrolidin-1-yl)methyl)cyclopropane-1 -carboxylate (INT A-22Af): 3,3- difluoropyrrolidine hydrochloride was used as the amine.1H NMR (400 MHz, CDCh) 6 ppm 3.62

[0443] - 3.93 (m, 7H), 2.19 - 2.52 (m, 2H), 1.48 - 1.56 (m, 2H), 1.28 - 1.41 (m, 2H). LCMS: m / z = 234.1 [M+H]+.

[0444] (1-((3,3-Difluoropyrrolidin-1-yl)methyl)cyclopropyl)methanol (INT A-22f): 1 H NMR (400 MHz, CDCh) 6 ppm 4.49 (br. s., 1 H), 3.54 (s, 2H), 3.00 (t, J = 13.0 Hz, 2H), 2.84 (t, J = 7.0 Hz, 2H), 2.57 (s, 2H), 0.43 - 0.59 (m, 2H), 0.34 - 0.40 (m, 2H). LCMS: m / z = 192.1 [M+H]+.

[0445] Methyl 1-(((2S,6R)-rel-2,6-dimethylmorpholino)methyl)cyclopropane-1 -carboxylate (INT A- 22Ag): the acid chloride procedure of INT A-22Ae and (2S,6R)-rel-2,6-dimethylmorpholine were used as the amine.1H NMR (400 MHz, CDCh) 6 ppm 1.20 (t, J = 6.0 Hz, 3H), 1.25 - 1.43 (m, 2H), 1.43 - 1.60 (m, 2H), 2.41 (dd, J = 13.3, 10.8 Hz, 1 H), 2.77 (dd, J = 13.0, 10.6 Hz, 1 H), 3.49 - 3.63 (m, 2H), 3.70 (dt, J = 13.2, 2.1 Hz, 1 H), 3.73 (s, 3H), 4.41 (dt, J = 13.3, 2.1 Hz, 1 H). LCMS: m / z = 242.1 [M+H]+.

[0446] (1-(((2S,6R)-rel-2,6-Dimethylmorpholino)methyl)cyclopropyl)methanol (INT A-22g):1H NMR (CDCh) 6 ppm 5.45 (br. s., 1 H), 3.69 (br. s., 2H), 3.55 (s, 2H), 3.06 (brs., 2H), 2.48 (brs., 2H), 1.72 (brs., 2H), 1.17 (d, J = 6.3 Hz, 6H), 0.48 - 0.58 (m, 2H), 0.34 - 0.42 (m, 2H). LCMS: m / z = 200.3 [M+H]+.

[0447] Methyl 1-(((3R,5S)-3,5-dimethylmorpholino)methyl)cyclopropane-1 -carboxylate (INT A- 22Ah): the acid chloride procedure of INT A-22Ae and (3R,5S)-rel-3,5-dimethylmorpholine were used.1H NMR (400 MHz, CDCh) 5 ppm 1.39 (d, J = 6.0 Hz, 8 H), 1.48 (brs., 2 H), 3.55 (d, J = 8.1 Hz, 2 H), 3.65 - 3.83 (m, 5 H), 3.96 (brs., 1 H), 4.30 - 4.60 (m, 1 H). LCMS: m / z = 242.1 [M+H]+.

[0448] (1-(((3R,5S)-rel-3,5-Dimethylmorpholino)methyl)cyclopropyl)methanol (INT A-22h):1H NMR (CDCh) 6 ppm 5.81 (brs., 1 H), 3.65 - 3.81 (m, 2H), 3.55 (brs., 2H), 3.20 - 3.37 (m, 2H), 2.69 (br s., 2H), 2.48 - 2.62 (m, 2H), 1.18 (d, J = 4.0 Hz, 6H), 0.49 - 0.62 (m, 2H), 0.35 - 0.46 (m, 2H). LCMS: m / z = 200.2 [M+H]+.

[0449] Methyl 1-(2-oxa-5-azabicyclo[2.2.1]heptane-5-carbonyl)cyclopropane-1 -carboxylate (INT A-22Ai): the acid chloride procedure of INT A-22Ae and 2-oxa-5-azabicyclo[2.2.1]heptane were used.1H NMR (400 MHz, CDCh) 6 ppm 4.66 (d, J = 13.6 Hz, 1 H), 3.88 (t, J = 7.5 Hz, 1 H), 3.81 (dt, J = 7.5, 2.0 Hz, 1 H), 3.74 (s, 3 H), 3.37 - 3.51 (m, 2 H), 1.87 - 1.95 (m, 1 H), 1.83 (dd, J = 9.9, 2.3 Hz, 1 H), 1.50 - 1.57 (m, 1 H), 1.32 - 1.38 (m, 2 H), 1.22 - 1.29 (m, 2 H). LCMS: m / z = 226.0 [M+H]+.

[0450] (1-((2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)methyl)cyclopropyl)methanol (INT A-22i):1H NMR (400 MHz, CDCh) 6 ppm 4.41 (s, 1 H), 3.94 (d, J = 8.1 Hz, 1 H), 3.68 - 3.77 (m, 2 H), 3.60 - 3.66 (m, 1 H), 3.38 (d, J = 11.0 Hz, 1 H), 3.05 (dd, J = 10.4, 1.8 Hz, 1 H), 2.89 (d, J=12.5 Hz, 1 H), 2.54 - 2.62 (m, 2 H), 1.72 - 1.81 (m, 2 H), 0.51 - 0.60 (m, 2 H), 0.39 - 0.48 (m, 2 H), 0.26 - 0.33 (m, 1 H). LCMS: m / z = 184.0 [M+H]+.

[0451] Methyl 1 -(2, 2-dimethylmorpholine-4-carbonyl)cyclopropane-1 -carboxylate (INT A-22Aj): the acid chloride procedure of INT A-22Ae and 2,2-dimethylmorpholine were used.1H NMR (400 MHz, CDCh) 6 ppm 3.74 (s, 3 H), 3.48 (t, J = 5.1 Hz, 1 H), 3.45 (t, J = 5.3 Hz, 1 H), 1.41 - 1.61 (m, 6 H), 1.35 (quin, J = 3.9 Hz, 2 H), 1.21 - 1.29 (m, 6 H). LCMS: m / z = 242.2 [M+H]+.

[0452] (1-((2,2-Dimethylmorpholino)methyl)cyclopropyl)methanol (INT A-22j):1H NMR (400 MHz, CDCh) 6 ppm 3.76 (t, J = 4.9 Hz, 2 H), 3.56 (s, 2 H), 2.52 (br. s., 2 H), 2.43 (s, 3 H), 2.36 (br. s., 2 H), 1.25 (s, 6 H), 0.52 (dd, J = 5.9, 4.8 Hz, 2 H), 0.37 (dd, J = 5.6, 4.8 Hz, 2 H). LCMS: m / z = 200.2 [M+H]+.

[0453] Methyl (S)-1-(2-methylmorpholine-4-carbonyl)cyclopropane-1 -carboxylate (INT A-22Ak): the acid chloride procedure of INT A-22Ae and (S)-2-methylmorpholine were used.1H NMR (400 MHz, CDCh) 6 ppm 4.37 (t, J = 13.0 Hz, 1 H), 3.90 (t, J = 13.0 Hz, 1 H), 3.74 (s, 3 H), 3.53 (td, J= 1 1.6, 2.6 Hz, 2 H), 3.21 (td, J = 13.1 , 3.4 Hz, 1 H), 2.80 - 2.91 (m, 1 H), 2.52 (dd, J = 13.3,

[0454] 10.5 Hz, 1 H), 1.44 - 1.57 (m, 2 H), 1.27 - 1.40 (m, 2 H), 1.19 (t, J = 6.6 Hz, 3 H). LCMS: m / z = 228.0 [M+H]+.

[0455] (S)-(1-((2-Methylmorpholino)methyl)cyclopropyl)methanol (INT A-22k):1H NMR (400 MHz, CDCh) 6 ppm 3.77 (ddd, J = 11.5, 3.1 , 1.5 Hz, 1 H), 3.55 (td, J = 11.6, 2.5 Hz, 2 H), 3.44 (s, 2 H), 2.92 (ddq, J = 16.3, 11.1, 1.5, 1.5, 1.5 Hz, 2 H), 2.37 (s, 2 H), 1.99 (td, J = 11.4, 3.4 Hz, 1 H), 1.68 (dd, J = 11.1 , 10.2 Hz, 1 H), 1.05 (d, J = 6.3 Hz, 3 H), 0.39 - 0.44 (m, 3 H), 0.26 (dd, J = 5.6, 4.6 Hz, 2 H). LCMS: m / z = 186.2 [M+H]+.

[0456] Methyl (S)-1-(3-methylmorpholine-4-carbonyl)cyclopropane-1 -carboxylate (INT A-22AI): the acid chloride procedure of INT A-22Ae and (S)-3-methylmorpholine were used.1H NMR (400 MHz, CDCh) 6 ppm 4.54 (dd, J = 15.5, 9.9 Hz, 1 H), 3.87 (t, J = 13.5 Hz, 1 H), 3.72 (s, 3 H), 3.57 (quin, J = 10.0 Hz, 2 H), 3.43 (t, J = 11.0 Hz, 1 H), 1.80 - 1.92 (m, 2 H), 1.40 - 1.57 (m, 2 H), 1.33 - 1.39 (m, 2 H), 1.28 (d, J = 6.8 Hz, 3 H). LCMS: m / z = 228.0 [M+H]+.

[0457] (1-(((2S,3S)-2,3-dimethylmorpholino)methyl)cyclopropyl)methanol (INT A-22I):1H NMR (400 MHz, CDCh) 6 ppm 3.96 (d, J = 11.0 Hz, 1 H), 3.80 (dt, J = 11.6, 3.4 Hz, 1 H), 3.64 - 3.75 (m, 2 H), 3.21 - 3.41 (m, 3 H), 3.12 (d, J = 11.3 Hz, 1 H), 2.46 (s, 1 H), 2.29 (t, J = 9.4 Hz, 1 H), 1.80 (d, J = 12.3 Hz, 1 H), 1.06 (d, J = 6.3 Hz, 3 H), 0.73 (dt, J = 9.4, 4.9 Hz, 1 H), 0.53 (s, 1 H), 0.50 (dt, J = 9.4, 4.9 Hz, 1 H), 0.30 (dt, J = 9.4, 4.9 Hz, 1 H), 0.22 (dt, J = 9.4, 4.9 Hz, 1 H). LCMS: m / z = 186.2 [M+H]+.

[0458] Methyl 1 -(hexahydro-1 H-furo[3,4-c]pyrrole-5-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Am): the acid chloride procedure of INT A-22Ae and (3aR,6aS)-rel-hexahydro-1 H-furo[3,4- c]pyrrole hydrochloride was used.1H NMR (400 MHz, CDCh) 6 ppm 3.89 - 3.96 (m, 2 H), 3.71 - 3.76 (m, 3 H), 3.52 - 3.71 (m, 5 H), 3.40 (dd, J = 11.1 , 4.0 Hz, 1 H), 2.96 (ddt, J = 10.3, 6.9, 3.5,

[0459] 3.5 Hz, 2 H), 1.45 - 1.50 (m, 2 H), 1.29 - 1.38 (m, 2 H). LCMS: m / z = 240.0 [M+H]+.

[0460] (1-((Tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)methyl)cyclopropyl)methanol (INT A-22m): ):1H NMR (400 MHz, CDCh) 6 ppm 3.82 (dd, J = 9.1 , 6.8 Hz, 2 H), 3.56 (dd, J = 9.0, 3.4 Hz, 2 H), 3.54 (s, 2 H), 2.79 (td, J = 6.4, 3.9 Hz, 2 H), 2.67 (dd, J = 9.4, 6.8 Hz, 2 H), 2.60 (dd, J = 9.4, 3.1 Hz, 2 H), 2.54 (s, 2 H), 0.50 (dd, J = 6.1 , 4.6 Hz, 2 H), 0.36 (dd, J = 5.6, 4.6 Hz, 2 H). ). LCMS: m / z = 198.2 [M+H]+.

[0461] Methyl 1-(2-(3-hydroxy-3-methylpiperidin-1-yl)acetyl)cyclopropane-1 -carboxylate (INT A- 22An): the acid chloride procedure of INT A-22Ae and 3-methylpiperidin-3-ol hydrochloride was used. LCMS: m / z = 242.2 [M+H]+. 1-((1-(Hydroxymethyl)cyclopropyl)methyl)-3-methylpiperidin-3-ol (INT A-22n). LCMS: m / z =

[0462] 200.2 [M+H]+.

[0463] Methyl 1-(7-oxa-2-azaspiro[3.5]nonane-2-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Ao): the acid chloride procedure of INT A-22Ae and 7-oxa-2-azaspiro[3.5]nonane hydrochloride was used.1H NMR (400 MHz, DMSO-cfe) 6 ppm 3.77 (s, 2 H), 3.66 (s, 3 H), 3.62 (s, 2 H), 3.48 - 3.52 (m, 4 H), 1.66 (t, J = 5.3 Hz, 4 H), 1.24 (t, J = 3.3 Hz, 2 H), 1.21 (t, J = 2.4 Hz, 2 H). LCMS: m / z = 254.2 [M+H]+.

[0464] (1-((7-oxa-2-azaspiro[3.5]nonan-2-yl)methyl)cyclopropyl)methanol (INT A-22o):1H NMR (400 MHz, CDCh) 6 ppm 3.56 - 3.62 (m, 4 H), 3.47 - 3.51 (m, 2 H), 3.06 - 3.12 (m, 4 H), 2.57 - 2.61 (m, 2 H), 1.68 - 1.78 (m, 4 H), 0.40 - 0.45 (m, 2 H), 0.31 - 0.36 (m, 2 H).

[0465] Methyl 1-(bis(methyl-d3)carbamoyl)cyclopropane-1 -carboxylate (INT A-22Ap): the acid chloride procedure of INT A-22Ae and dimethyl-d6-amine hydrochloride was used.1H NMR (400 MHz, CDCh) 6 ppm 3.74 (s, 3H), 1.47 - 1.52 (m, 2H), 1.31 - 1.37 (m, 2H). LCMS: m / z = 178.2 [M+H]+.

[0466] (1-((Bis(methyl-d3)amino)methyl)cyclopropyl)methanol (INT A-22p):1H NMR (400 MHz, CDCh) 6 ppm 3.56 (s, 2H), 2.49 (s, 2H), 0.49 - 0.56 (m, 2H), 0.34 - 0.41 (m, 2H). LCMS: m / z =

[0467] 136.3 [M+H]+.

[0468] Methyl 1-(1,4-oxazepane-4-carbonyl)cyclopropane-1 -carboxylate (INT A-22Aq): the acid chloride procedure of INT A-22Ae and 1 ,4-oxazepane was used.1H NMR (400 MHz, CDCh) 6 ppm 3.70 - 3.82 (m, 6H), 3.74 (s, 3H), 3.63 - 3.69 (m, 2H), 1.89 - 2.00 (m, 2H), 1.49 - 1.55 (m, 2H), 1.33 - 1.39 (m, 2H). LCMS: m / z = 228.1 [M+H]+.

[0469] (1-((1,4-Oxazepan-4-yl)methyl)cyclopropyl)methanol (INT A-22q):1H NMR (400 MHz, CDCh) 5 ppm 3.73 - 3.83 (m, 4H), 3.57 (s, 2H), 2.88 (br. s., 4H), 2.67 (s, 2H), 1.99 (br. s., 2H), 0.48 - 0.59 (m, 2H), 0.34 - 0.42 (m, 2H). LCMS: m / z = 186.1 [M+H]+.

[0470] Methyl 1-(3-oxa-8-azabicyclo[3.2.1]octane-8-carbonyl)cyclopropane-1-carboxylate (INT A- 22Ar): the acid chloride procedure of INT A-22Ae and 3-oxo-8-aza-bicyclo[3.2.1]octane hydrochloride was used.1H NMR (400 MHz, CDCh) 6 ppm 4.56 - 4.65 (m, 1 H), 4.07 - 4.12 (m, 1 H), 3.74 (s, 3H), 3.70 (t, J = 9.0 Hz, 2H), 3.58 - 3.67 (m, 2H), 1.87 - 2.09 (m, 4H), 1.43 - 1 .52 (m, 2H), 1.24 - 1.40 (m, 2H). LCMS: m / z = 240.1 [M+H]+.

[0471] (1-((3-Oxa-8-azabicyclo[3.2.1]octan-8-yl)methyl)cyclopropyl)methanol (INT A-22r):1H NMR (400 MHz, CDCh) 6 ppm 6.10 (br. s., 1 H), 3.71 (br. s., 2H), 3.60 (s, 2H), 3.50 - 3.57 (m, 2H), 3.31 (br. s., 2H), 2.45 (br. s., 2H), 1.74 - 1.96 (m, 4H), 0.45 - 0.56 (m, 2H), 0.30 - 0.38 (m, 2H). LCMS: m / z = 198.1 [M+H]+.

[0472] Methyl 1-(4-methylpiperazine-1-carbonyl)cyclopropane-1 -carboxylate (INT A-22As): the acid chloride procedure of INT A-22Ae and N-methylpiperazine was used.1H NMR (400 MHz, CDCh) 6 ppm 1.29 - 1.37 (m, 2H), 1.46 - 1.53 (m, 2H), 2.32 (s, 3H), 2.35 - 2.44 (m, 4H), 3.49 - 3.57 (m, 2H), 3.63 - 3.70 (m, 2H), 3.73 (s, 3H). LCMS: m / z = 214.1 [M+H]+.

[0473] (1-((4-Methylpiperazin-1-yl)methyl)cyclopropyl)methanol (INT A-22s):1H NMR (400 MHz, CDCh) 6 ppm 0.33 - 0.41 (m, 2H), 0.48 - 0.56 (m, 2H), 2.29 (s, 3H), 2.3 - 2.6 (m, 4H), 3.54 (s, 2H), 5.6 (br. s, 1 H). LCMS: m / z = 185.3 [M+H]+.

[0474] Methyl 1-(8-oxa-3-azabicyclo[3.2.1]octane-3-carbonyl)cyclopropane-1-carboxylate (INT A- 22At): the acid chloride procedure of INT A-22Ae and 8-oxa-3-azabicyclo[3.2.1]octane hydrochloride were used: LCMS: m / z = 240.1 [M+H]+.

[0475] (1-((8-Oxa-3-azabicyclo[3.2.1]octan-3-yl)methyl)cyclopropyl)methanol (INT A-22t):1H NMR (400 MHz, CDCh) 6 ppm 5.52 (br. s, 1 H), 4.31 (br. s., 2H), 3.55 (s, 2H), 2.95 (td, J = 1.4, 11.3 Hz, 2H), 2.46 (s, 2H), 2.33 - 2.25 (m, 2H), 1 .93 (d, J = 2.3 Hz, 4H), 0.50 (dd, J = 4.8, 5.9 Hz, 2H), 0.35 (dd, J = 4.6, 5.6 Hz, 2H). LCMS: m / z = 198.2 [M+H]+.

[0476] Methyl 1-(2-oxa-8-azaspiro[4.5]decane-8-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Au): ): the acid chloride procedure of INT A-22Ae and 2-oxa-8-azaspiro[4,5]decane were used: LCMS: m / z = 268.2 [M+H]+.

[0477] (1-((2-Oxa-8-azaspiro[4.5]decan-8-yl)methyl)cyclopropyl)methanol (INT A-22u):1H NMR (400 MHz, CDCh) 6 ppm 3.84 (t, J = 7.1 Hz, 2H), 3.54 (s, 2H), 3.53 (s, 2H), 2.47 (s, 2H), 2.36 - 2.69 (m, 4H), 1.72 (t, J = 7.1 Hz, 2H), 1.63 (t, J = 5.6 Hz, 4H), 0.51 (t, J = 4.8 Hz, 2H), 0.35 (t, J = 4.8 Hz, 2H). LCMS: m / z = 226.2 [M+H]+.

[0478] Methyl 1-(3-azabicyclo[3.1.0]hexane-3-carbonyl)cyclopropane-1-carboxylate (INT A-22Av): the acid chloride procedure of INT A-22Ae and 3-azabicyclo[3.1.0]hexane hydrochloride were used:1H NMR (400 MHz, CDCh) 6 ppm 3.89 (d, J = 11.9 Hz, 1 H), 3.73 (s, 3H), 3.64 (d, J = 10.4 Hz, 1 H), 3.51 (dd, J = 10.4, 2.6 Hz, 1 H), 3.39 (dd, J = 11.9, 2.8 Hz, 1 H), 1.46 - 1.56 (m, 3H), 1.35 - 1.44 (m, 2H), 1.17 - 1.24 (m, 1 H), 0.71 (td, J = 7.8, 5.1 Hz, 1 H), 0.14 (q, J = 4.2 Hz, 1 H). LCMS: m / z = 210.1 [M+H]+.

[0479] (1-((3-Azabicyclo[3.1.0]hexan-3-yl)methyl)cyclopropyl)methanol (INT A-22v):1H NMR (400 MHz, CDCh) 6 ppm 3.52 (s, 2H), 3.27 (d, J = 8.9 Hz, 2H), 2.56 (s, 2H), 2.27 (d, J = 8.8 Hz, 2H), 1.30 - 1.40 (m, 2H), 0.54 (q, J = 4.0 Hz, 1 H), 0.43 - 0.48 (m, 2H), 0.39 (td, J = 7.8, 4.8 Hz, 1 H), 0.31 - 0.36 (m, 2H). LCMS: m / z = 168.3 [M+H]+.

[0480] Methyl (S)-1-(2-(hydroxymethyl)pyrrolidine-1-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Aw and THP-protected intermediate): The procedure of INT A-22Aa and S-(+)-2- pyrrolidinemethanol were used: LCMS: m / z = 228.1 [M+H]+. This material was protected as the THP ether under standard conditions (DHP I cat. TsOH I THF / 70 °C):1H NMR (400 MHz, CDCh) 5 ppm 4.64 - 4.53 (m, 1 H), 4.33 - 4.23 (m, 1 H), 3.91 - 3.75 (m, 1 H), 3.72 (d, J = 2.4 Hz, 3 H), 3.71 - 3.59 (m, 1 H), 3.57 - 3.47 (m, 2 H), 3.47 - 3.37 (m, 1 H), 2.11 - 1.94 (m, 3 H), 1.91 - 1.76 (m, 2 H), 1 .76 - 1.65 (m, 1 H), 1.63 - 1.57 (m, 2 H), 1 .57 - 1.45 (m, 4 H), 1.45 - 1.34 (m, 2 H), 1.32

[0481] - 1.20 (m, 1 H). LCMS: m / z = 228.1 [M+H]+.

[0482] (1-(((2S)-2-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)pyrrolidin-1- yl)methyl)cyclopropyl)methanol (INT A-22w):1H NMR (400 MHz, CDCh) 6 ppm 4.63 (br. s., 1 H), 4.02 (ddd, J = 1.8, 11.0, 21.4 Hz, 1 H), 3.95 - 3.86 (m, 1 H), 3.80 (ddd, J = 5.1 , 10.0, 28.4 Hz, 1 H), 3.74 - 3.67 (m, 1 H), 3.66 - 3.60 (m, 1 H), 3.58 - 3.48 (m, 2 H), 3.40 (ddd, J = 5.8, 9.8, 12.5 Hz, 1 H), 3.06 (ddd, J = 2.1 , 11.0, 19.6 Hz, 1 H), 2.72 - 2.60 (m, 1 H), 2.21 - 2.11 (m, 1 H), 1.95 - 1 .80 (m, 3 H), 1 .80 - 1.68 (m, 3 H), 1 .68 - 1.49 (m, 4 H), 0.74 - 0.65 (m, 1 H), 0.53 - 0.45 (m, 1 H), 0.30 - 0.17 (m, 2 H). LCMS: m / z = 270.2 [M+H]+.

[0483] Methyl 1-(3-hydroxy-3-methylpyrrolidine-1-carbonyl)cyclopropane-1 -carboxylate (INT A- 22Ax): The procedure of INT A-22Aa and racemic 3-methylpyrrolidin-3-ol were used: LCMS: m / z = 228.1 [M+H]+.

[0484] 1-((1-(Hydroxymethyl)cyclopropyl)methyl)-3-methylpyrrolidin-3-ol (INT A-22x):1H NMR (400 MHz, CDCh) 6 ppm 3.54 (s, 2H), 3.03 - 3.14 (m, 1 H), 2.91 (d, J = 10.1 Hz, 1 H), 2.54 - 2.69 (m, 3H), 2.49 (d, J = 10.1 Hz, 1 H), 1.87 - 1.94 (m, 2H), 1.38 (s, 3H), 0.49 - 0.53 (m, 2H), 0.33 - 0.41 (m, 2H). LCMS: m / z = 186.1 [M+H]+.

[0485] Methyl 1-(4-fluoropiperidine-1-carbonyl)cyclopropane-1 -carboxylate (INT A-22Ay): The acid chloride procedure of INT A-22Ae and 4-fluoropiperidine were used:1H NMR (400 MHz, CDCh) 6 ppm 3.74 (s, 3H), 1.47 - 1.52 (m, 2H), 1.31 - 1.37 (m, 2H). LCMS: m / z = 230.3 [M+H]+.

[0486] (1-((4-Fluoropiperidin-1-yl)methyl)cyclopropyl)methanol (INT A-22y):1H NMR (400 MHz, CDCh) 6 ppm 4.60 - 4.82 (m, 1 H), 3.54 (s, 2H), 2.53 - 2.72 (m, J = 4.0 Hz, 4H), 2.47 (s, 2H), 1.82

[0487] - 1.98 (m, 4H), 0.51 (t, J = 5.0 Hz, 2H), 0.36 (t, J = 4.9 Hz, 2H). LCMS: m / z = 188.2 [M+H]+.

[0488] Methyl 1-(1-oxo-8-azaspiro[4.5]decane-8-carbonyl)cyclopropane-1 -carboxylate (INT A-

[0489] 22Az): commercially available tert-butyl 1-oxo-8-azaspiro[4.5]decane-8-carboxylate was deprotected using 4N HCI in dioxane. The acid chloride procedure of INT A-22Ae and the deprotected amine hydrochloride were used to provide INT A-22Az: LCMS: m / z = 280.2 [M+H]+.

[0490] 8-((1-(Hydroxymethyl)cyclopropyl)methyl)-8-azaspiro[4.5]decan-1-ol (INT A-22z): Prepared by concomitant reduction of the three carbonyl functions of INT A-22Az using LAH in the usual maner:1H NMR (400 MHz, DMSO-cfe) 6 ppm 4.73 (br. s., 1 H), 4.37 (d, J = 4.8 Hz, 1 H), 3.53 (q, J = 5.0 Hz, 1 H), 2.60 - 2.77 (m, 2H), 2.25 (s, 2H), 1.98 - 2.12 (m, 2H), 1.73 - 1.89 (m, 1 H), 1.39 - 1.68 (m, 6H), 1.21 - 1.34 (m, 2H), 1.04 - 1.20 (m, 1 H), 0.37 - 0.46 (m, 2H), 0.14 - 0.24 (m, 2H). LCMS: m / z = 240.2 [M+H]+.

[0491] INT A-23A INT A-23

[0492] Step 1 tert-Butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (INT A-23A). To a solution of commercially available 2-amino-4-bromo-7-fluoro-benzothiophene-3-carbonitrile (1.50 g, 5.53 mmol) and DIPEA (1.44 mL, 8.24 mmol) in DMF (7.5 mL) and dichloromethane (7.5 mL) were added DMAP (67 mg, 548 pmol) and di-terf-butyldicarbonate (1.41 mL, 6.14 mmol) and the reaction mixture was stirred for 18 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was dissolved in ethyl acetate and water. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed 3 times with HCI 1 N and with sat. NH4CI, dried over MgSCH filtered and concentrated under reduced pressure to afford INT A-23A (2 g, 97% yield). LCMS: m / z = 373.0 [M+H]+.

[0493] Step 2 tert-Butyl (3-Cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2- yljcarbamate (INT A-23). To a solution of INT A-23A (2.00 g, 5.39 mmol) and b / s(neopentyl- glycolato)diboron (2.43 g, 10.8 mmol) in 1 ,4-dioxane (39 mL) under argon was added KOAc (1.59 g, 16.2 mmol) and the reaction mixture was stirred at 50 °C for 1 h. Then dichloro[b / s(2- (diphenylphosphino)phenyl)ether]palladium(ll) (397 mg, 544 pmol) was added and the reaction mixture was stirred at 95 °C for 2 h. The reaction mixture was concentrated under reduced pressure. The crude was dissolved in ethyl acetate and water and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-20% EtOAc in hexanes) to afford INT A-23 (1.53 g, 70% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 11.59 (br. s., 1 H), 7.60 (dd, J = 7.9, 6.1 Hz, 1 H), 7.19 (t, J = 8.9 Hz, 1 H), 3.78 (s, 4 H), 1.54 (s, 9 H), 1.03 (s, 6 H).

[0494] INT A-24A INT A-24

[0495] Step 1

[0496] Isopropyl 1-(piperidine-1-carbonyl)cyclobutane-1 -carboxylate (INT A-24A) : 1-

[0497] (methoxycarbonyl)cyclobutane-l -carboxylic acid was prepared according to the method described in J. Org. Chem. 2014, 79, 2430-2452. Following the procedure described for INT A- 22Ae, the carboxylic acid was converted to the corresponding acid chloride and reacted with morpholine to provide INT A-24A in 91% yield.1H NMR (400 MHz, CDCI3) 6 ppm 1.84 - 1.99 (m, 1 H), 2.00 - 2.13 (m, 1 H), 2.47 - 2.59 (m, 2 H), 2.60 - 2.72 (m, 2 H), 3.11 - 3.20 (m, 2 H), 3.52 - 3.60 (m, 2 H), 3.6 - 3.7 (m, 4 H), 3.77 (s, 3 H). LCMS: m / z = 228.1 [M+H]+.

[0498] Step 2

[0499] (1-(Morpholinomethyl)cyclobutyl)methanol (INT A-24): Following the procedure described for INT A-22e the cyclobutyl analog of Example INT A-24 was obtained in 96% yield.1H NMR (400 MHz, CDCI3) 6 ppm 1.77 - 1.90 (m, 5 H), 1.91 - 2.05 (m, 2 H), 2.50 (br. s., 4 H), 2.55 (s, 2 H), 3.68 (t, J = 4.6 Hz, 4 H), 3.80 (s, 2 H). LCMS: m / z = 186.1 [M+H]+.

[0500] Step 1

[0501] (3aR,7aS)-5-Benzyl-2,2,3a-trimethylhexahydro-[1 ,3]dioxolo[4,5-c]pyridine (INT A-25A): (3R,4S)-1-benzyl-3-methylpiperidine-3,4-diol was prepared following the procedures described in US200502398226A1 using AD-MIX-a for the asymmetric dihydroxylation step.1H NMR (400 MHz, DMSO-cfe) 6 ppm 1.07 (s, 3 H), 1.56 - 1.64 (m, 2 H), 1.98 (d, J = 11.0 Hz, 1 H), 2.13 (br. s., 1 H), 2.37 (d, J = 10.7 Hz, 1 H), 3.18 (q, J = 5.4 Hz, 1 H), 3.44 (dd, J = 20.3, 13.9 Hz, 2 H), 3.71 - 3.77 (m, 1 H), 4.21 (d, J = 5.4 Hz, 1 H), 7.19 - 7.27 (m, 1 H), 7.28 - 7.32 (m, 4 H). LCMS: m / z = 222.2 [M+H]+.

[0502] Following a similar procedure to that described in W02005 / 077932, the diol from above (900 mg, 4.07 mmol) was dissolved in DCM (5.5 mL) and 2,2-dimethoxypropane (860 mg, 8.26 mmol) was added followed by p-toluenesulfonic acid monohydrate (38.7 mg, 0.20 mmol). The mixture was stirred at RT for 4h, diluted with DCM 20 mL) and the solution washed with 1 N NaOH and brine. After drying (Na2SO4), volatiles were removed under reduced pressure and the residue used directly in step 2.1H NMR (400 MHz, DMSO-cfe) 6 ppm 7.21 - 7.34 (m, 5 H), 3.83 (dd, J = 3.3, 1 .8 Hz, 1 H), 3.06 (s, 2 H), 2.51 - 2.56 (m, 1 H), 2.39 (dd, J = 10.8, 1.4 Hz, 1 H), 2.00 - 2.10 (m, 2 H), 1.90 (ddd, J = 14.8, 4.9, 2.1 Hz, 1 H), 1.74 - 1.84 (m, 1 H), 1.36 (s, 3 H), 1.25 (s, 6 H). LCMS: m / z = 262.2 [M+H]+.

[0503] Step 2

[0504] (3aR,7aS)-2,2,3a-Trimethylhexahydro-[1,3]dioxolo[4,5-c]pyridine INT A-25): Intermediate INT A-25A (500 mg, 1.91 mmol) was dissolved in 2-propanol (10 mL) and 10% Pd on charcoal (25 mg) was added. The reaction mixture was stirred for 18h under a balloon atmosphere of hydrogen gas. After filtration through a pad of celite®, removal of volatiles gave INT A-25.1H NMR (400 MHz, DMSO-cfe) 6 ppm 4.34 (d, J = 4.1 Hz, 1 H), 3.85 (t, J = 2.9 Hz, 1 H), 3.78 (td, J=6.1 , 3.9 Hz, 1 H), 2.57 - 2.64 (m, 1 H), 2.55 (d, J = 7.8 Hz, 1 H), 1.61 - 1.72 (m, 1 H), 1.38 (s, 2 H), 1.26 (s, 3 H), 1.05 (s, 3 H), 1.04 (s, 3 H). LCMS: m / z = 172.0 [M+H]+.

[0505] Step 1

[0506] 7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)-1 -naphthaldehyde (INT A-26A): to a solution of INT A-9 (307 mg, 0.74 mmol) in DCM (7.4 mL) at 0 °C was added Dess-Martin periodinane (313 mg, 0.74 mmol). After stirring for 5 min at 0 °C, the suspension was allowed to warm up to RT and stirred an additional 30 min. Aqueous sodium sulfite was added to quench the reaction and the product extracted into DCM. After drying (Na2SC>4), volatiles were removed under reduced pressure and the residue purified by flash chromatography to provide INT A-26A (226 mg, 74% yield).1H NMR (400 MHz, CDCI3) 6 ppm 11.74 (s, 1 H), 7.82 (d, J = 2.6 Hz, 1 H), 7.79 (dd, J = 5.7, 9.1 Hz, 1 H), 7.59 (d, J = 2.8 Hz, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 5.31 (s, 2H), 3.52 (s, 3H), 1.15 - 1.25 (m, 21 H). LCMS: m / z = 415.2 [M+H]+.

[0507] Step 2

[0508] 1-(7-Fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl)naphthalen-1-yl)ethan-1-ol

[0509] INT A-26): INT A-26A (226 mg, 0.54 mmol) was dissolved in dry THF (5.45 mL) and the solution cooled to 0 °C. Methylmagnesium bromide (3M in THF, 363 pL, 1.09 mmol) was added and the mixture stirred at RT for 10 min. The reaction mixture was quenched with aqueous formic acid, THF was removed under reduced pressure and the residue extracted with EtOAc. After drying (Na2SC>4) and removal of solvent, the resulting material was purified by flash chromatography to provide INT A-26 (196 mg, 83% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.73 (dd, J = 6.0, 9.0 Hz, 1 H), 7.67 (d, J = 2.6 Hz, 1 H), 7.31 (d, J = 2.6 Hz, 1 H), 7.20 - 7.26 (m, 1 H), 6.88 (d, J = 6.3 Hz, 1 H), 5.30 (s, 2H), 3.53 (s, 3H), 2.42 - 2.62 (m, 1 H), 1.65 (d, J = 6.4 Hz, 3H), 1.15 - 1.25 (m, 21 H). LCMS: m / z = 415.2 [M+H]+.

[0510] INT A-27A INT A-27

[0511] Step 1

[0512] Methyl 2,2-dimethyl-3-morpholino-3-oxopropanoate (INT A-27A): Following the procedure described for INT A-22Aa and using morpholine as the amine, INT A-27A was obtained in 96% yield as a colorless oil.1H NMR (400 MHz, CDCI3) 6 ppm 1.45 (s, 6 H), 3.45 (br. s., 3 H), 3.63 (br. s., 5 H), 3.75 (s, 3 H). LCMS: m / z = 216.1 [M+H]+.

[0513] Step 2

[0514] 2,2-Dimethyl-3-morpholinopropan-1-ol (INT A-27): Reduction with LAH of INT A-27A as described for INT A-22a provided INT A-27.1H NMR (400 MHz, CDCI3) 6 ppm 3.73 - 3.66 (m, 4 H), 3.51 (s, 2 H), 2.60 (br. s., 4 H), 2.40 (s, 2 H), 0.94 (s, 6 H). LCMS: m / z = 174.2 [M+H]+. Step 1

[0515] Methyl 1-(3-(hydroxymethyl)morpholine-4-carbonyl)cyclopropane-1 -carboxylate (INT A- 28A) : using the procedure described for the preparation of INT A22-Aa and using morpholin-3- ylmethanol hydrochloride as the amine, provided INT A-28A: LCMS: m / z = 244.1 [M+H]+.

[0516] Step 2

[0517] Methyl 1-(3-(((tetrahydro-2H-pyran-2-yl)oxy)methyl)morpholine-4-carbonyl)cyclopropane- 1 -carboxylate (INT A-28B): a solution of INT A-28A (370 mg, 1.52 mmol) and 3,4-dihydro-2H- pyran (215 pL, 2.28 mmol) in dry DCM (10.7 mL) containing pyridinium p-toluenesulfonate (39.0 mg, 152 pmol) is stirred for 4 h at room temperature. The mixture is then heated at reflux for 18 h. The reaction mixture was concentrated under vacuo, the residue was dissolved in THF (10 mL) and another portion of 3,4-dihydro-2H-pyran (138 uL) was added. The mixture was then heated at 70 °C for 2 h. The reaction mixture was concentrated and the crude was purified by column chromatography (SiC>2, (Hexanes / EtOAc 0 to 100%) to give the desired INT A-28B as a colorless oil. LCMS: m / z = 244.1 [M+H-THP]+.

[0518] Step 3

[0519] (1-((3-(((Tetrahydro-2H-pyran-2-yl)oxy)methyl)morpholino)methyl)cyclopropyl)methanol (INT A-28): INT A-28B was reduced with LAH to provide INT A-28 using the procedure described for INT A-22a (step 2):1H NMR (400MHz ,CDCI3) 6 ppm 4.63 - 4.54 (m, 1 H), 3.93 - 3.73 (m, 5 H), 3.73 - 3.47 (m, 5 H), 3.45 - 3.25 (m, 2 H), 3.24 - 3.11 (m, 1 H), 2.66 (d, J = 2.9 Hz, 1 H), 2.42 (ddd, J = 3.2, 8.3, 11.9 Hz, 1 H), 2.28 (s, 1 H), 2.08 (t, J = 11.5 Hz, 1 H), 1.88 - 1.77 (m, 1 H), 1 .75 - 1.66 (m, 1 H), 1.66 - 1.58 (m, 2 H), 0.70 - 0.57 (m, 1 H), 0.51 - 0.44 (m, 1 H), 0.42 - 0.36 (m, 1 H), 0.28 (s, 1 H). LCMS: m / z = 286.2 [M+H]+.

[0520] Step 1

[0521] 1-(Morpholine-4-carbonyl)cyclopropane-1-carbonitrile (INT A-29A): 1-Cyano-1- cyclopropanecarboxylic acid (500 mg, 4.50 mmol) was weighed in a 50 mL flame-dried flask and suspended in DCM (15.0 mL). The suspension was cooled in an ice bath then a small drop of DMF was added followed by oxalyl chloride (507 pL, 5.85 mmol). The mixture was then allowed to warm to RT. After 2 h of stirring at RT, gas evolution had stopped and a clear solution was obtained. The mixture was allowed to stir for another 15 minutes then 4 mL of toluene was added to the mixture which was then concentrated under reduced pressure to a colorless semi-solid which was further dried under high vac.

[0522] The residue from above was dissolved in THF (20.0 mL) and the solution was cooled in an ice bath. Morpholine (512 pL, 5.85 mmol) was added dropwise, affording a milky white mixture. DIEA (1.57 mL, 9.00 mmol) was then added and the resulting mixture was allowed to warm to RT. The mixture was allowed to stir at RT for 2 days then concentrated to dryness. The residue was taken up in EtOAc (30 mL) and washed with 10 mL of a saturated solution of NaHCOs. The aqueous layer was extracted 3x with 20 mL of EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was further dried under high vacuum to provide the desired amide (595 mg, 73 %) as a pale yellow oil:1H NMR (400MHz ,CDCh) 6 ppm 3.76 (br. s., 8H), 1.58 - 1.66 (m, 2H), 1.50 - 1.58 (m, 2H). LCMS: m / z = 181.0 [M+H]+.

[0523] Step 2

[0524] (1-(Morpholinomethyl)cyclopropyl)methanamine (INT A-29): 1-(Morpholine-4- carbonyl)cyclopropane-1-carbonitrile from step 1 (592 mg, 3.29 mmol) was charged in a 50 mL flask and dissolved in THF (16.0 mL). The solution was cooled in an ice bath then lithium aluminum hydride (394 mg, 9.86 mmol) was added slowly and carefully (effervescence). Once the addition was complete, the mixture was allowed to stir for 15 minutes at 0 °C then for 15 minutes at RT. The flask was fitted with a reflux condenser and the mixture was heated at 50 °C overnight. Another portion of lithium aluminum hydride (131 mg, 3.29 mmol) was added at RT then the mixture was stirred at 50 °C overnight. Despite the presence of some unreacted material as shown by LCMS analysis, the reaction was stopped, allowed too cool to RT then cooled in an ice bath. Na2SO4-10H2O (1.2 g) was added slowly and the mixture was stirred for 1 h at RT and filtered through a pad of Celite®, rinsing with diethyl ether. The mixture was concentrated to a volume of 5-6 mL then cooled in an ice bath and a 4M dioxane solution of HCI (2.05 mL, 8.21 mmol) was added dropwise, affording a white precipitate. Once the addition was complete, the mixture was centrifuged and most of the supernatant was decanted out. The resulting solid was transferred into another flask using methanol, concentrated and dried under reduced pressure, affording (1-(morpholinomethyl)cyclopropyl)methanamine dihydrochloride as a white hygroscopic foam:1H NMR (400 MHz, DMSO-cfe) 6 ppm 10.97 (br. s., 1 H), 8.20 (br. s., 3H), 3.85 - 4.03 (m, 4H), 3.46 (d, J = 12.1 Hz, 2H), 3.27 (d, J = 4.9 Hz, 2H), 2.96 - 3.15 (m, 4H), 0.78 - 0.92 (m, 2H), 0.65 - 0.78 (m, 2H). LCMS: m / z = 171.2 [M+H]+.

[0525] Step 1

[0526] 2-(1-Aminocyclopropyl)ethan-1-ol hydrochloride (INT A-30A): To a stirred solution of tertbutyl (1-(2-hydroxyethyl)cyclopropyl)carbamate (500 mg, 2.48 mmol) in DCM (4.0 mL) was added TFA (4.0 mL, 52 mmol). The reaction mixture was stirred at RT for 3 h, volatiles were evaporated and traces of TFA removed azeotropically using toluene. 1 N aqueous HCI was added and the solution was then evaporated and the residue lyophilized using water-acetonitrile to give 2-(1- aminocyclopropyl)ethan-1-ol hydrochloride (400 mg, 117 %) as a colorless gum. This material was used as such in the next step:1H NMR (400 MHz, DMSO-cfe) 5 ppm 8.26 (br. s., 3H), 3.58 (t, J = 6.3 Hz, 2H), 1.72 (t, J = 6.3 Hz, 2H), 0.84 - 0.92 (m, 2H), 0.64 - 0.72 (m, 2H).

[0527] Step 2

[0528] 2-(1-(Dimethylamino)cyclopropyl)ethan-1-ol (INT A-30): To a stirred mixture of 2-(1- aminocyclopropyl)ethan-1-ol hydrochloride from step 1 (400 mg, 2.91 mmol), 37% aqueous formaldehyde (866 pL, 11.6 mmol) and Et3N (407 pL, 2.91 mmol) was added portion wise sodium triacetoxyborohydride (1.33 g, 6.10 mmol) at RT. The resultant reaction mixture was stirred at RT for 3 h. The reaction mixture was then diluted with DCM, MgSCL was added and after stirring for 30 min, the suspension was filtered through a pad of Celite® using DCM for rinses. The filtrate was concentrated to give crude product containing a large excess of triethylamine salts. The residue was dissolved in water, washed with EtOAc and the aqueous solution was concentrated to give a colorless oil (600 mg) which still contained triethylammonium salts. The residue was suspended in dry ether (10 mL), K2CO3 (1.2 g) was added and the mixture stirred overnight. The organic solution was collected and concentrated to give 2-(1-(dimethylamino)cyclopropyl)ethan- 1-ol (270 mg, 72 %) as a colorless oil that was used without further purification:1H NMR (400MHz ,CDCI3) 5 ppm 3.82 (t, J = 5.6 Hz, 2H), 2.21 (s, 6H), 1.62 (t, J = 5.6 Hz, 2H), 0.75 - 0.81 (m, 2H), 0.31 - 0.38 (m, 2H). LCMS: m / z = 130.2 [M+H]+. Step 1

[0529] 1-(Morpholinomethyl)cyclopropane-1-carbaldehyde (INT A-31A): To a cold (-78 °C) stirred solution of oxalyl chloride (350 mg, 2.76 mmol) in DCM (7.0 mL) was added a solution of DMSO (400 pL, 5.61 mmol) in DCM (2.50 mL). After stirring for 5 min, a solution of (1- (morpholinomethyl)cyclopropyl)methanol (400 mg, 2.34 mmol) in DCM (3.5 mL) was added and the resultant solution was stirred for another 30 min. Et3N (1 .64 mL, 11.7 mmol) was then added and after stirring for 15 min, the cooling bath was removed and stirring continued for 1 h. The reaction mixture was then treated with brine solution and extracted with DCM. Combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (40 g SiCh) using a gradient of EtOAc in hexanes as eluant to give 1- (morpholinomethyl)cyclopropane-l-carbaldehyde (450 mg, 100 %) as a light yellow oil. This material was used as such in the next step:1H NMR (400MHz ,CDCh) 6 ppm 9.36 (s, 1 H), 3.69 (t, J = 4.0 Hz, 4H), 2.69 (s, 2H), 2.48 (t, J = 4.0 Hz, 4H), 1.23 - 1.27 (m, 2H), 0.95 - 1.02 (m, 2H). LCMS: m / z = 170.3 [M+H]+.

[0530] Step 2

[0531] 1-(1-(Morpholinomethyl)cyclopropyl)ethan-1-ol (INT A-31): To a cold (-30 °C) stirred solution of 1-(morpholinomethyl)cyclopropane-1-carbaldehyde from step 1 (450 mg, 2.34 mmol) in THF (10.0 mL) was added a solution of 3M methylmagnesium bromide in THF (2.34 mL, 7.0 mmol) over a period of 5 min. The resulting white suspension was stirred for 2 h while reaching a bath temperature of 0 °C. The reaction mixture was cooled again to -30 °C, sat. ammonium chloride solution was added and the mixture warmed up to RT. The organic phase was separated, the aqueous solution was extracted with EtOAc, the combined extracts were washed with brine, dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (40 g SiO2) using a gradient of EtOAc in hexanes (10% to 100%) as eluant to give 1-(1- (morpholinomethyl)cyclopropyl)ethan-1-ol (304 mg, 70 %) as a colorless oil. Overall yield of 70% for two steps starting from the primary alcohol:1H NMR (400MHz ,CDCh) 6 ppm 5.96 (br. s., 1 H), 3.66 - 3.78 (m, 4H), 3.32 (q, J = 6.5 Hz, 1 H), 2.94 (d, J = 13.0 Hz, 1 H), 2.73 (br. s., 2H), 2.47 (br. s., 2H), 2.02 (d, J = 12.9 Hz, 1 H), 1.21 (d, J = 6.5 Hz, 3H), 0.70 (dt, J = 9.5, 5.0 Hz, 1 H), 0.40 - 0.49 (m, 1 H), 0.31 - 0.40 (m, 1 H), 0.21 (dt, J = 9.2, 5.2 Hz, 1 H). LCMS: m / z = 186.1 [M+H]+.

[0532] Step 1 tert-Butyl (3aR,6aS)-5-acetylhexahydropyrrolo[3,4-c]pyrrole-2(1 H)-carboxylate (INT A- 32A): A RB flask was charged with a magnetic stir bar, cis-2-boc-hexahydropyrrolo[3,4-c]pyrrole (400 mg, 1.83 mmol), THF (10.0 mL), saturated NaHCCh (10 mL) and then to the stirred solution was slowly added acetyl chloride (261 pL, 3.66 mmol). The reaction was stirred at RT for 3 h. The mixture was then diluted with EtOAc (70 mL), the aqueous layer removed, then the organic layer was washed with water (50 mL), dried over MgSCH filtered and solvent removed in vacuo. The resulting residue was purified by column chromatography (4 g SiC>2 column, gradient elution: DCM to 90 / 10 DCM / methanol to provide INT A-32A (185 mg, 40 %) as a white film:1H NMR (400MHz ,CDCI3) 6 ppm 3.69 (dd, J = 10.1 , 7.8 Hz, 2H), 3.60 (dd, J = 10.8, 7.6 Hz, 2H), 3.41 (d, J = 10.0 Hz, 1 H), 3.33 (dd, J = 10.6, 5.1 Hz, 1 H), 3.29 (br. s., 1 H), 3.22 (br. s., 1 H), 2.91 - 3.02 (m, 1 H), 2.79 - 2.91 (m, 1 H), 2.01 - 2.11 (m, 3H), 1.39 - 1.52 (m, 9H).

[0533] Step 2

[0534] 1-((3aR,6aS)-Hexahydropyrrolo[3,4-c]pyrrol-2(1 H)-yl)ethan-1-one hydrochloride (INT A- 32): the Boc protecting group of INT A-32A from step 1 was removed using 4N HCI in dioxane under the usual conditions to provide INT A-32 as an oil:1H NMR (400 MHz, MeOH-ck) 6 ppm 3.92 (dd, J = 11 .9, 7.4 Hz, 1 H), 3.75 - 3.84 (m, 1 H), 3.63 - 3.75 (m, 3H), 3.53 - 3.63 (m, 3H), 3.16 - 3.29 (m, 3H), 2.23 (s, 3H).

[0535] Step 1

[0536] 2-Chloro-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine (INT R1-1A). to a solution of 2,6-dichloropurine (1.00 g, 5.29 mmol) and hexahydro-1 / 7-pyrrolizin-7a-ylMeOH (822 mg, 5.82 mmol) in THF (17 mL) at 0 °C was added in portions NaH (741 mg, 18.5 mmol) and the reaction mixture was stirred for 5 min. Then, the reaction mixture was allowed to reach room temperature and was stirred for 16 h. The reaction mixture was cooled down to 0 °C and quenched with acetic acid (1 mL) in acetonitrile (5 mL). Then, triethylamine (1 mL) was added to neutralize the excess of acetic acid and the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (10% MeOH in dichloromethane, 0.1 % NH4OH) to afford INT R1-1A (1.52 g, 98% yield) as a white solid.1H NMR (400 MHz, DMSO- cfe) 6 ppm 8.37 (s, 1 H), 4.24 (s, 2H), 2.93 - 3.01 (m, 2H), 2.58 (dt, J = 9.9, 6.8 Hz, 2H), 1.88 - 1.96 (m, 3H), 1.76 - 1.85 (m, 4H), 1.57- 1.66 (m, 2H).

[0537] Step 2

[0538] 2-Chloro-9-((8-ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purine (INT R1-1). To a solution of INT R1-1A (200 mg, 681 pmol), INT A-1 (254 mg, 1.36 mmol) and triphenylphosphine (214 mg, 817 pmol) in THF (7 mL) at 0 °C was added DIAD (160 pL, 817 pmol) dropwise. The reaction mixture was allowed to reach room temperature and was stirred for 2 h. After removal of volatiles, the crude material consisted of a 6:1 mixture of regioisomers which was purified by reversed phase chromatography using MeOH in water (20-100%, 0.1% formic acid) as a gradient to afford the major component INT R1-1 (267 mg, 85% yield).1H NMR (400 MHz, CDCI3) 6 ppm 8.31 (brs., 1 H), 7.93 (d, J = 8.1 Hz, 1 H), 7.80 (d, J = 7.9 Hz, 1 H), 7.37 - 7.49 (m, 4H), 7.21 (d, J = 7.0 Hz, 1 H), 5.93 (s, 2H), 4.74 (s, 2H), 3.70 (td, J = 6.5, 11.4 Hz, 2H), 3.01 (q, J = 7.4 Hz, 2H), 2.83 - 2.92 (m, 2H), 2.25 - 2.34 (m, 2H), 2.18 (td, J = 6.7, 13.2 Hz, 2H), 2.03 (td, J = 6.6, 13.1 Hz, 2H), 1.86 - 1.96 (m, 2H), 1.33 (t, J = 7.4 Hz, 3H).

[0539] INT R1-2

[0540] 2-Chloro-9-(1-(8-ethylnaphthalen-1-yl)ethyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purine (INT R1-2). This intermediate was prepared as a single regioisomer according to the procedure described for INT R1-1 using INT A-10 as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 7.85 - 7.95 (m, 1 H), 7.77 (dd, J = 1 .7, 7.6 Hz, 1 H), 7.64 (s, 1 H), 7.36 - 7.48 (m, 4H), 6.88 (d, J = 6.9 Hz, 1 H), 4.56 - 4.70 (m, 2H), 3.48 - 3.62 (m, 2H), 2.96 - 3.22 (m, 2H), 2.73 - 2.87 (m, 2H), 2.18 - 2.30 (m, 2H), 2.07 - 2.16 (m, 2H), 1.93 - 2.06 (m, 5H), 1.79 - 1.90 (m, 2H), 1.42 (t, J = 7.4 Hz, 3H).

[0541] 2-Chloro-9-(3-chloro-2-cyclopropyl-5-(methoxymethoxy)benzyl)-6-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purine (INT R1-3). This example was prepared according to the procedure described for INT R1-1 using INT A-3 as alcohol. INT A-3 was obtained in 76% yield as the major regioisomer after purification. LCMS: m / z = 518.2 [M+H]+.

[0542] Step 1

[0543] 6-(Benzylthio)-2-fluoro-9H-purine (INT R2-1A). To a solution of a-toluenethiol (297 mg, 2.39 mmol) in THF (8 mL) at 0 °C, was added 6-chloro-2-fluoropurine (400 mg, 2.32 mmol) and the reaction mixture was stirred for 5 min. Then, NaH (325 mg, 8.11 mmol) was added in portions and the reaction mixture was allowed to reach room temperature and was stirred for 3 h. Then, the reaction mixture was cooled down to 0 °C, carefully quenched with sat. NH4CI and diluted with water and ethyl acetate. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with brine, dried over MgSCH filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (20-100% EtOAc in hexanes) to afford INT R2-1A (529 mg, 88% yield) as a white solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 13.69 (br. s., 1 H), 8.46 (s, 1 H), 7.47 (d, J = 7.5 Hz, 2H), 7.33 (t, J = 7.3 Hz, 2H), 7.26 (t, J = 7.3 Hz, 1 H), 4.61 (s, 2H).

[0544] Step 2 tert-Butyl (1R,5S)-3-(6-(benzylthio)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxy- -late (INT R2-1B). A solution of INT R2-1A (515 mg, 1.98 mmol) and tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate (504 mg, 2.37 mmol) in DMF (10 mL) was heated to 80 °C for 18 h. Then, the reaction mixture was cooled to 0 °C and quenched with sat. NaHCOs (5 mL) and water (25 mL). The thick suspension was diluted with ethyl acetate and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with water and brine, dried over MgSCH filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (40-100% EtOAc in hexanes) to afford INT R2-1B (960 mg, 85% pure, quant, yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 12.72 (br. s., 1 H), 7.97 (s, 1 H), 7.44 (d, J = 7.5 Hz, 2H), 7.30 (t, J = 7.1 Hz, 2H), 7.23 (t, J = 7.3 Hz, 1 H), 4.55 (s, 2H), 4.37 (br. d, J = 10.8 Hz, 2H), 4.22 (br. s., 2H), 3.02 (d, J = 12.4 Hz, 2H), 1.80 (br. s., 2H), 1.50 - 1.70 (m, 2H), 1.43 (s, 9H).

[0545] Step 3

[0546] Mixture of tert-butyl (1R,5S)-3-(6-(benzylsulfonyl)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1] octane-8-carboxylate and tert-butyl (1R,5S)-3-(6-(benzylsulfinyl)-9H-purin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT R2-1C). To a suspension of INT R2-1 B (150 mg, 331 pmol) in dichloromethane (4 mL) was added 3-chloroperoxybenzoic acid (134 mg, 597 pmol) and the reaction mixture was stirred for 1 h. Then, the reaction mixture was diluted with dichloromethane and washed twice with a 1 :1 mixture of water and sat. NaHCOs. The combined aqueous layers were back extracted once with dichloromethane and the combined organic layers were dried over MgSCL, filtered, and concentrated under reduced pressure to afford INT R2-1C (151 mg, 94% yield) as a mixture of sulfoxide (minor) and sulfone (major). Only the sulfone is reported here.1H NMR (400 MHz, CDCI3) 6 ppm 8.14 (s, 1 H), 7.15 - 7.26 (m, 4H), 6.97 - 7.04 (m, 1 H), 4.68 (s, 1 H), 4.29 - 4.53 (m, 4H), 3.25 (br. s., 2H), 1.94 - 1.99 (m, 2H), 1.71 - 1.76 (m, 2H), 1.52 (s, 9H).

[0547] Step 4 tert-Butyl (1 R,5S)-3-(6-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT R2-1). This intermediate was prepared according to the procedure described for INT R1-1A (step 1) using INT R2-1C and hexahydro-1 H-pyrrolizin- 7a-yl methanol as starting materials.1H NMR (400 MHz, CDCh) 6 ppm 10.62 (br. s., 1 H), 7.71 (s, 1 H), 4.38 (d, J = 12.5 Hz, 3H), 4.25 (br. s., 3H), 3.03 - 3.31 (m, 4H), 2.66 (dt, J = 10.2, 6.9 Hz, 2H), 2.02 - 2.18 (m, 2H), 1.81 - 2.01 (m, 6H), 1.60 - 1.78 (m, 4H), 1.51 (s, 9H).

[0548] Boc

[0549] INT R2-2 tert-Butyl (1R,5S)-3-(6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylat (INT R2-2). This intermediate was prepared according to the procedure described for INT R2-1 using commercially available (2R,7aS)-2-fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as an alcohol.1H NMR (400 MHz, CDCh) 6 ppm 7.75 (s, 1 H), 5.23 - 5.44 (m, 1 H), 4.24 - 4.49 (m, 6H), 3.37 - 3.54 (m, 2H), 3.28 (dd, J = 19.4, 14.5 Hz, 1 H), 3.16 (br. s., 3H), 2.35 - 2.41 (m, 1 H), 2.26 - 2.34 (m, 1 H), 2.19 - 2.26 (m, 1 H), 2.00 - 2.05 (m, 4H), 1.88 - 1.97 (m, 2H), 1.67 - 1.77 (m, 2H), 1.50 (s, 9H).

[0550] INT R2-3

[0551] (R)-1-(6-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3- methylpiperidin-3-ol (INT R2-3). This intermediate was prepared according to the procedure described for INT R2-1 using (3R)-3-methyl-piperidin-3-ol hydrochloride as amine and (2R,7aS)- 2-fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as an alcohol. LCMS: m / z = 391.2 [M+H]+.

[0552] INT R2-4

[0553] 3-Methyl-1-(6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)piperidin-3-ol

[0554] (INT R2-4). This intermediate was prepared according to the procedure described for INT R2-1 using racemic 3-methylpiperidin-3-ol hydrochloride as amine.1H NMR (400 MHz, CDCh) 6 ppm 7.70 (s, 1 H), 4.47 (d, J = 13.1 Hz, 1 H), 4.27 - 4.38 (m, 3H), 3.17 - 3.38 (m, 2H), 3.05 (d, J = 13.3

[0555] Hz, 1 H), 2.95 - 3.03 (m, 1 H), 2.59 - 2.80 (m, 2H), 2.04 - 2.22 (m, 2H), 1.83 - 2.04 (m, 5H), 1.66 - 1.83 (m, 3H), 1.46 - 1.66 (m, 2H), 1.27 (s, 3H).

[0556] INT R2-5

[0557] 1-(6-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3- methylpiperidin-3-ol (INT R2-5). This intermediate was prepared according to the procedure described for INT R2-1 using racemic 3-methylpiperidin-3-ol hydrochloride as amine and (2R,7aS)-2-fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as alcohol. LCMS: m / z = 391.2 [M+H]+.

[0558] INT R2-6

[0559] (R)-3-Methyl-1-(6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)piperidin-3- ol (INT R2-6). This intermediate was prepared according to the procedure described for INT R2- 1 using (3R)-3-methyl-piperidin-3-ol hydrochloride as amine.1H NMR (400 MHz, CDCh) 6 ppm 7.72 (s, 1 H), 4.48 (d, J = 13.3 Hz, 1 H), 4.32 (d, J = 13.4 Hz, 1 H), 4.29 (dd, J = 16.4, 10.5 Hz, 2H), 3.13 - 3.32 (m, 2H), 3.07 (d, J = 13.3 Hz, 1 H), 2.97 - 3.05 (m, 1 H), 2.62 - 2.74 (m, 2H), 2.05 - 2.19 (m, 2H), 1.92 (dt, J = 12.4, 6.2 Hz, 5H), 1.79 (d, J = 13.4 Hz, 1 H), 1.70 (dt, J = 13.6, 7.4 Hz, 2H), 1.45 - 1.65 (m, 2H), 1.27 (s, 3H).

[0560] Boc

[0561] INT R2-7 tert-Butyl 5-(6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-2,5-diaza- bicyclo[2.2.2]octane-2-carboxylate (INT R2-7). This intermediate was prepared according to the procedure described for INT R2-1 using tert-butyl 2,5-diazabicyclo[2.2.2]octane-2-carboxylate as amine.1H NMR (400 MHz, CDCI3) 6 ppm 7.70 (s, 1 H), 5.01 (br. s., 1 H), 4.43 (br. s., 1 H), 4.20

[0562] - 4.36 (m, 2H), 3.77 - 3.89 (m, 1 H), 3.58 - 3.69 (m, 2H), 3.44 - 3.57 (m, 1 H), 3.22 (br. s., 2H), 2.62

[0563] - 2.72 (m, 2H), 1.99 - 2.17 (m, 4H), 1.78 - 1.98 (m, 6H), 1.68 - 1.76 (m, 2H), 1.41 - 1.53 (m, 9H).

[0564] Boc

[0565] INT R2-8 tert-Butyl (1R,5S)-3-(6-(2-(1H-pyrazol-1-yl)ethoxy)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (INT R2-8). This intermediate was prepared according to the procedure described for INT R2-1 using 2-(1 H-pyrazol-1-yl)ethanol as alcohol.1H NMR (400 MHz, CDCI3) 6 ppm 7.78 (s, 1 H), 7.59 (d, J = 2.1 Hz, 1 H), 7.53 (d, J = 1.5 Hz, 1 H), 6.23 (t, J = 2.0 Hz, 1 H), 4.86 (t, J = 5.4 Hz, 2H), 4.63 (t, J = 5.4 Hz, 2H), 4.23 - 4.49 (m, 4H), 3.17 (br. s., 2H), 1.88 - 1.97 (m, 2H), 1.71 (q, J = 6.8 Hz, 2H), 1.51 (s, 9H).

[0566] INT R2-9 tert-Butyl (1R,5S)-3-(6-(2-(1 / - / -imidazol-1-yl)ethoxy)-9 / - / -purin-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (INT R2-9). This intermediate was prepared according to the procedure described for INT R2-1 using 1-(2-hydroxyethyl)-imidazole as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 8.26 (s, 1 H), 7.97 (s, 1 H), 7.79 (s, 1 H), 7.14 (s, 1 H), 7.11 (s, 1 H), 4.76 (t, J = 5.2 Hz, 2H), 4.47 (t, J = 5.3 Hz, 2H), 4.21 - 4.37 (m, 4H), 3.17 (br. s., 2H), 1.86 - 1.97 (m, 2H), 1.68 - 1.76 (m, 2H), 1.51 (s, 9H).

[0567] INT R2-10 tert-Butyl 5-(6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2- yl)-2,5-diazabicyclo[2.2.2]octane-2-carboxylate (INT R2-10). This intermediate was prepared according to the procedure described for INT R2-7 using (2R,7aS)-2-fluorohexahydro-1 / 7- pyrrolizine-7a-methanol as alcohol.1H NMR (400 MHz, CDCI3) 6 ppm 7.62 (s, 1 H), 5.14 - 5.34 (m, 1 H), 4.09 - 4.40 (m, 3H), 3.75 (t, J = 11.3 Hz, 1 H), 3.51 - 3.62 (m, 2H), 3.37 - 3.50 (m, 1 H), 3.31 (br. s., 1 H), 3.10 - 3.24 (m, 1 H), 2.95 (d, J = 5.3 Hz, 1 H), 2.05 - 2.23 (m, 3H), 1.84 - 2.05 (m, 6H), 1.65 - 1.84 (m, 3H), 1 .41 (s, 4H), 1.39 (s, 5H). tert-Butyl (1R,5S)-3-(6-(2-(2-oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-9H-purin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT R2-11). This intermediate was prepared according to the procedure described for INT R2-1 using 2-(2-oxa-5-azabicyclo[2.2.1]heptan-5- yl)ethan-1-ol as alcohol.1H NMR (400 MHz, CDCI3) 6 ppm 8.33 (s, 1 H), 7.76 (s, 1 H), 4.73 (t, J = 4.9 Hz, 2H), 4.52 (s, 1 H), 4.29 - 4.36 (m, 3H), 4.22 (d, J = 9.3 Hz, 1 H), 4.13 (br. s., 1 H), 3.78 (d, J = 8.3 Hz, 2H), 3.40 - 3.48 (m, 2H), 3.30 - 3.38 (m, 1 H), 3.17 (br. s., 2H), 2.96 (d, J = 10.6 Hz, 1 H), 2.15 (d, J = 10.6 Hz, 1 H), 1.89 - 1.99 (m, 3H), 1.69 - 1.76 (m, 2H), 1.51 (s, 9H).

[0568] INT R2-12 tert-Butyl (1R,5S)-3-(6-(3-amino-3-methylazetidin-1-yl)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (INT R2-12). To a suspension of INT R2-1C (275 mg, 568 pmol) and 3-methylazetidin-3-amine hydrochloride (99 mg, 624 pmol) in 2-MeTHF (5 mL) at 0 °C, was added DI PEA (395 pL, 2.27 mmol) and the reaction mixture was stirred at 50 °C for 18 h. Then, THF (5 mL) was added, followed by NaH (90.8 mg, 2.27 mmol) and the reaction mixture was stirred at room temperature for 2 days. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by reverse phase chromatography (C-18 Biotage column) using MeOH in water (30-100%, 0.1 % formic acid) as a gradient to afford INT R2-12 (80.0 mg, 34% yield) as a colorless gum.1H NMR (400 MHz, CDCh) 6 ppm 7.74 (br. s., 1 H), 4.39 (br. s., 10H), 3.28 (br. s., 2H), 2.64 (s, 3H), 1.94 - 2.02 (m, 2H), 1.70 (br. s., 2H), 1.48 (s, 9H). First steps

[0569] (S)-2-(4-(6-(Benzylthio)-9H-purin-2-yl)piperazin-2-yl)acetonitrile (INT R2-13A). This intermediate was prepared according to the procedure described for INT R2-1B using (S)-2- (piperazin-2-yl)acetonitrile dihydrochloride as an amine.1H NMR (400 MHz, MeOH-ck) 6 ppm 7.94 (s, 1 H), 7.45 (d, J = 7.4 Hz, 2H), 7.27 - 7.34 (m, 2H), 7.20 - 7.26 (m, 1 H), 4.76 (dd, J = 13.0, 2.1 Hz, 1 H), 4.54 - 4.62 (m, 3H), 3.09 - 3.24 (m, 3H), 3.01 (dd, J = 13.1 , 9.8 Hz, 1 H), 2.84 - 2.93 (m, 1 H), 2.70 (d, J = 6.5 Hz, 2H). tert-Butyl (S)-4-(6-(benzylthio)-9H-purin-2-yl)-2-(cyanomethyl)piperazine-1 -carboxylate (INT R2-13B). To a solution of INT R2-13A (250 mg, 608 pmol) in THF (3 mL) at 0 °C, were sequentially added DIPEA (265 pL, 1.52 mmol) and di-te / t-butyl-dicarbonate (211 pL, 915 pmol) and the reaction mixture was stirred for 2 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by reversed phase chromatography (C-18 Biotage column) using MeOH in water (30-100%, 0.1 % formic acid) as a gradient to afford INT R2-13B (280 mg, 99% yield) as yellow solid.1H NMR (400 MHz, CDCh) 6 ppm 7.95 (s, 1 H), 7.45 (d, J = 7.3 Hz, 2H), 7.24 - 7.36 (m, 3H), 4.81 (d, J = 13.8 Hz, 1 H), 4.55 - 4.72 (m, 4H), 3.24 (dd, J = 13.7, 3.6 Hz, 1 H), 2.99 - 3.12 (m, 2H), 2.68 (s, 1 H), 2.52 - 2.64 (m, 2H), 1.50 - 1.61 (m, 9H).

[0570] Final steps tert-Butyl (S)-2-(cyanomethyl)-4-(6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-2-yl)piperazine-1-carboxylate (INT R2-13). This intermediate was prepared according to the procedure described for INT R2-1 using (2R,7aS)-2-fluorohexahydro- 1 / 7-pyrrolizine-7a-methanol as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 8.44 (br. s., 1 H), 7.82 (s, 1 H), 5.33 - 5.51 (m, 1 H), 4.87 (d, J = 13.1 Hz, 1 H), 4.49 - 4.71 (m, 4H), 3.71 - 4.05 (m, 3H), 3.32 - 3.46 (m, 1 H), 3.11 - 3.25 (m, 2H), 2.91 - 3.10 (m, 2H), 2.71 (dd, J = 16.4, 9.3 Hz, 1 H), 2.42 - 2.58 (m, 2H), 2.38 (br. s., 1 H), 2.24 - 2.35 (m, 1 H), 2.08 - 2.22 (m, 3H), 1.51 (s, 9H).

[0571] INT R2-14

[0572] (S)-1-(6-(((2R,7aS)-2-Fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3- methylpiperidin-3-ol (INT R2-14). This intermediate was prepared according to the procedure described for INT R2-1 using (3S)-3-methyl-piperidin-3-ol hydrochloride as amine and (2R,7aS)- 2-fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as alcohol. LCMS: m / z = 391.2 [M+H]+.

[0573] Boc tert-Butyl (1R,5S)-3-(6-(2-(dimethylamino)ethoxy)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (INT R2-15). This intermediate was prepared according to the procedure described for INT R2-1 using 2-(dimethylamino)ethanol as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 7.76 (s, 1 H), 4.63 (t, J = 5.9 Hz, 2H), 4.30- 4.38 (m, 4H), 3.18 (br. s., 2H), 2.88 (t, J = 6.0 Hz, 2H), 2.32 - 2.48 (m, 6H), 1.83 - 1.99 (m, 2H), 1.64 - 1.83 (m, 2H), 1.51 (s, 9H).

[0574] INT R2-16 tert-Butyl (1R,5S)-3-(6-(((R)-1-methylpyrrolidin-3-yl)oxy)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (INT R2-16). This intermediate was prepared according to the procedure described for INT R2-1 using (R)-(-)-1-methyl-3-pyrrolidinol as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 7.77 (s, 1 H), 5.68 (br. s., 1 H), 4.22 - 4.51 (m, 4H), 3.40 (br. s., 1 H), 3.17 (br. s., 2H), 2.79 - 3.02 (m, 3H), 2.56 (s, 3H), 2.47 (dt, J = 14.6, 7.52 Hz, 1 H), 2.16 - 2.36 (m, 1 H), 1.81 - 2.01 (m, 2H), 1.72 (d, J = 7.3 Hz, 2H), 1.51 (s, 9H).

[0575] Boc tert-Butyl (1R,5S)-3-(6-(3-(dimethylamino)propoxy)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (INT R2-17). This intermediate was prepared according to the procedure described for INT R2-1 using 3-dimethylamino-1 -propanol as alcohol.1H NMR (400 MHz, CDCh) 5 ppm 7.72 (s, 1 H), 4.57 (t, J = 6.2 Hz, 2H), 4.38 (d, J = 12.5 Hz, 4H), 3.18 (br. s., 2H), 2.76 (t, J = 7.5 Hz, 2H), 2.38 - 2.49 (m, 6H), 2.12 - 2.26 (m, 2H), 1.84 - 1.99 (m, 2H), 1.73 (q, J = 6.6 Hz, 2H), 1.51 (s, 9H).

[0576] Boc tert-Butyl (1R,5S)-3-(6-((1-methylpiperidin-4-yl)oxy)-9 / - / -purin-2-yl)-3,8-diazabicyclo [3.2.1] octane-8-carboxylate (INT R2-18). This intermediate was prepared according to the procedure described for INT R2-1 using 1-methyl-4-piperidinol as alcohol.1H NMR (400 MHz, CDCh) 6 ppm 7.72 (s, 1 H), 5.36 (br. s., 1 H), 4.43 (br. s., 1 H), 4.33 (d, J = 12.3 Hz, 3H), 3.18 (br. s., 2H), 2.79 - 3.05 (m, 3H), 2.59 (br. s., 2H), 2.31 - 2.50 (m, 6H), 2.15 - 2.31 (m, 2H), 1.98 - 2.15 (m, 3H), 1.83 - 1.98 (m, 2H), 1.63 - 1.83 (m, 3H), 1.51 (s, 9H).

[0577] Boc

[0578] INT R2-19 tert-Butyl (1 S,4S)-5-(6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-9H- purin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (INT R2-19). This intermediate was prepared according to the procedure described for INT R2-1 using (1 S,4S)-2-f-Boc-2,5- diazabicyclo[2.2.1]heptane as amine and (2R,7aS)-2-fluorohexahydro-1 / 7-pyrrolizine-7a- methanol as alcohol. LCMS: m / z = 474.3 [M+H]+.

[0579] INT R2-20 tert-Butyl (1R,5S)-3-(6-(3-(dimethylamino)-2,2-dimethylpropoxy)-9H-purin-2-yl)-3,8-diaza bicyclo[3.2.1]octane-8-carboxylate (INT R2-20). This intermediate was prepared according to the procedure described for INT R2-1 using 3-dimethylamino-2,2-dimethyl-1-propanol as alcohol.1H NMR (400 MHz, CDCI3) 6 ppm 7.76 (s, 1 H), 4.31 - 4.46 (m, 4H), 4.28 (s, 2H), 3.17 (br. s., 2H), 2.57 (br. s., 2H), 2.47 (br. s., 6H), 1.88 - 1.97 (m, 2H), 1.70 - 1.79 (m, 2H), 1.51 (s, 9H), 1.13 (s, 6H).

[0580] (S)-3-Methyl-1-(6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)piperidin-3- ol (INT R2-21). This intermediate was prepared according to the procedure described for INT R2- 1 using (S)-3-methyl-piperidin-3-ol hydrochloride as amine.1H NMR (400 MHz, MeOH-ck) 6 ppm 7.78 (s, 1 H), 4.26 (s, 2H), 3.80 - 3.92 (m, 1 H), 3.75 (d, J = 13.0 Hz, 1 H), 3.53 - 3.65 (m, 2H), 3.02

[0581] - 3.12 (m, 2H), 2.61 - 2.72 (m, 2H), 1.99 - 2.10 (m, 2H), 1.80 - 1.54 (m, 10H) 1.17 (s, 3H). tert-Butyl (1R,5S)-3-(6-((1-((4-(trifluoromethyl)piperidin-1-yl)methyl)cyclopropyl) methoxy)- 9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT R2-22). This intermediate was prepared according to the procedure described for INT R2-1 using INT A-22a. LCMS: m / z = 566.3 [M+H]+. Boc

[0582] Boc tert-Butyl (1 R,5S)-3-(6-(benzylsulfonyl)-9-((8-ethylnaphthalen-1 -yl)methyl)-9H-purin-2-yl)- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT R4-1). The intermediate was prepared according to the procedure described for INT R1-1 (step 2), using INT R2-1B as starting material and INT A-1 as alcohol, followed by the procedure described for INT R2-1 (step 3).1H NMR (400 MHz, CDCI3) 6 ppm 7.96 (d, J = 8.3 Hz, 1H), 7.83 (d, J = 8.0 Hz, 1 H), 7.38 - 7.56 (m, 4H), 7.15 - 7.38 (m, 5H), 5.87 (d, J = 4.3 Hz, 2H), 4.61 (d, J = 12.9 Hz, 1 H), 4.43 (d, J = 13.0 Hz, 1H), 4.35 (br. s., 4H), 3.21 (br. s., 2H), 3.08 (q, J = 7.3 Hz, 2H), 1.94 (br. s., 2H), 1.66 (d, J = 6.9 Hz, 2H), 1.43 - 1.57 (m, 9H), 1.39 (t, J = 7.4 Hz, 3H).

[0583] 6-(Benzylthio)-9-((8-ethylnaphthalen-1-yl)methyl)-2-fluoro-9H-purine (INT R4-2). This intermediate was prepared according to the procedure described for INT R1-1 (step 2) using INT A-1 as alcohol. INT R4-2 was isolated as the major regioisomer. LCMS: m / z = 429.2 [M+H]+. tert-Butyl (1 R,5S)-3-(6-(benzylsulfonyl)-9-((3-cyano-2-(((E)-(dimethylamino)methylene) amino)-4,5,6,7-tetrahydrobenzo[b]thiophen-4-yl)methyl)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1]octane-8-carboxylate (INT R4-3). This intermediate was prepared as the major regioisomer (2:1 mixture) from INT R2-1B according to the procedure described for INT R4-1 using INT A-19 as alcohol. LCMS: m / z = 731.2 [M+H]+. tert-Butyl (1 S,4S)-5-(6-(benzylthio)-9H-purin-2-yl)-2,5-diazabicyclo[2.2.1]heptane-2- carboxylate (INT R4-4A). This intermediate was prepared according to the synthesis described for INT R2-1B using (1 S,4S)-2-t-Boc-2,5-diazabicyclo[2.2.1]heptane as amine.1H NMR

[0584] (400 MHz, acetone-cfe) 6 ppm 11.56 (br. s., 1H), 7.88 (s, 1 H), 7.49 (d, J = 7.4 Hz, 2H), 7.15 - 7.36

[0585] (m, 3H), 5.02 (br. s., 1H), 4.62 - 4.76 (m, 1 H), 4.44 - 4.62 (m, 2H), 3.76 (s, 1H), 3.60 (br. s., 2H), 3.21 - 3.46 (m, 2H), 1.84 - 2.01 (m, 2H), 1.44 (s, 4H), 1.38 (s, 5H).

[0586] Final steps tert-Butyl (1 S,4S)-5-(6-(benzylsulfonyl)-9-((3-cyano-2-(((E)-(dimethylamino) methylene) amino)-7-fluorobenzo[b]thiophen-4-yl)methyl)-9H-purin-2-yl)-2,5-diazabicyclo[2.2.1] heptane-2-carboxylate (INT R4-4). This intermediate was prepared according to the procedure described for INT R4-1 using INT A-16 as alcohol. INT R4-4B was obtained as the major regioisomer (7 : 3 ratio). LCMS: m / z = 730.2 [M+H]+. 6-(Benzylthio)-2-fluoro-9-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl) ethynyl) naphthalen-1-yl)methyl)-9H-purine (INT R4-5). This intermediate was prepared according to the procedure described for INT R4-2 using INT A-9 as alcohol. The ratio of separable regioisomers was approximately 6 : 1 in favor of INT R4-5.1H NMR (400 MHz, CDCh) 6 ppm 7.97 (s, 1 H), 7.73 - 7.79 (m, 1H), 7.50 (d, J = 7.1 Hz, 2H), 7.28 - 7.40 (m, 5H), 6.86 (d, J = 2.4 Hz, 1H),

[0587] 6.54 (s, 2H), 5.19 (s, 2H), 4.64 (s, 2H), 3.44 (s, 3H), 1.06 - 1.09 (m, 21H).

[0588] INT R4-6

[0589] 1-(6-(Benzylsulfonyl)-9-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)methyl)-9H-purin-2-yl)-4-methylpiperidin-4-ol (INT R4-6). This intermediate was prepared according to the procedure described for INT R4-4 using 4-methylpiperidin-4-ol as amine and INT A-9 as alcohol. The desired regioisomer in the Mitsunobu step was obtained in a 10 : 1 ratio. LCMS: m / z = 754.4 [M+H]+.

[0590] (R,E)- / V-(4-((6-(Benzylsulfonyl)-2-(3-hydroxy-3-methylpiperidin-1-yl)-9 / - / -purin-9- yl)methyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)- / V, / V-dimethylformimidamide (INT R4-7 ( / ?)) and (S,E)-A / '-(4-((6-(Benzylsulfonyl)-2-(3-hydroxy-3-methylpiperidin-1 -yl)-9H-purin-9- yl)methyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)- / V, / V-dimethylformimidamide (INT R4-7 (S)). These intermediate was prepared according to the procedure described for INT R4-4 using (3R)- or (3S)-methyl-piperidin-3-ol hydrochloride as amines. LCMS: m / z = 647.1 [M+H]+.

[0591] 5-(6-(Benzylsulfonyl)-9-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methyl)- 9H-purin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole-1,3(2H,3aH)-dione (INT R4-8). This intermediate was prepared according to the procedure described for INT R4-4 using INT A-11 as amine and INT A-9 as alcohol. Note: TIPS was removed by prolonged heating in the SNAr step. LCMS: m / z = 639.2 [M+H]+.

[0592] INT R4-9

[0593] 4-(6-(Benzylsulfonyl)-9-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)methyl)-9H-purin-2-yl)-6-methyl-1,4-oxazepan-6-ol (INT R4-9). This intermediate was prepared according to the procedure described for INT R4-4 using 6-methyl- 1 ,4-oxazepan-6-ol hydrochloride as amine and INT A-9 as alcohol. The desired regioisomer was obtained almost exclusively after the Mitsunobu step. LCMS: m / z = 803.5 [M+H]+. 2-(6-(Benzylsulfonyl)-9-((8-ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methyl)- 9H-purin-2-yl)hexahydro-2H-pyrazino[1,2-a]pyrazine-6, 9-dione (INT R4-10). This intermediate was prepared according to the procedure described for INT R4-4 using racemic hexahydro-1 / 7-pyrazino[1 ,2-a]pyrazine-1 ,4(6 / 7)-dione as amine and INT A-9 as alcohol. Note: TIPS was deprotected in the SNAr step LCMS: m / z = 684.3 [M+H]+.

[0594] Step 1

[0595] (3S,4R)-1-(6-(Benzylthio)-9H-purin-2-yl)pyrrolidine-3,4-diol (INT R4-11A): INT R2-1A (300 mg, 1.15 mmol), cis-pyrrolidine-3,4-diol hydrochloride (164 mg, 1.15 mmol) and Na2COs (242 mg, 2.88 mmol) were suspended in DMSO (3.84 mL) and activated 4A molecular sieves were added. The mixture was stirred at 80 °C under a nitrogen atmosphere for 18h. After cooling to RT, the reaction mixture was poured into water with vigorous stirring and the resulting precipitate was collected by filtration and dried. The product was washed with water and dried to give INT R4- 11A as a white solid (349 mg, 88% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 12.63 (br. s., 1 H), 7.93 (s, 1 H), 7.41 - 7.44 (m, 2H), 7.28 - 7.32 (m, 2H), 7.21 - 7.26 (m, 1 H), 4.53 (s, 2H), 4.34 (s, 1 H), 4.13 - 4.20 (m, 2H), 3.43 - 3.51 (m, 2H), 1.41 - 1.51 (m, 4H), 1.14 (s, 3H). LCMS: m / z 356.2 [M+H]+.

[0596] Step 2

[0597] (3aR,6aS)-5-(6-(Benzylthio)-9H-purin-2-yl)-2,2-dimethyltetrahydro-4H-[1,3]dioxolo[4,5- c]pyrrole (INT R4-11): INT R4-11A (300 mg, 0.87 mmol) was suspended in acetone (2.9 mL) and 2, 2, -dimethoxypropane (0.43 mL, 3.49 mmol) was added followed by para-TsOH monohydrate (16.6 mg, 87 pmol). DMSO (1 mL) was added to solubilize reactants and the mixture was heated to 50 °C for 18h. Additional 2,3-dimethoxypropane (0.43 mL, 3.49 mmol) was then added to complete the reaction (77 °C for 18 h). The reaction mixture was then cooled to RT and volatiles removed under reduced pressure. The oily residue was added to water (20 mL) with vigorous stirring and the resulting precipitate was collected by filtration, washed with water and dried to give INT R4-11 as a white solid (326 mg, 97% yield).1H NMR (400MHz, DMSO-cfe) 6 ppm 12.75 (s, 1 H), 7.96 (s, 1 H), 7.45 (d, J = 7.3 Hz, 2H), 7.27 - 7.33 (m, 2H), 7.20 - 7.26 (m, 1 H), 4.83 - 4.89 (m, 2H), 4.57 (s, 2H), 3.87 - 3.95 (m, 2H), 3.43 - 3.53 (m, 2H), 1.35 (s, 3H), 1.29 (s, 3H). LCMS: m / z = 384.2 [M+H]+.

[0598] INT S-1G INT S-1 H Step 1

[0599] 2-Chloro-3-fluoro-5-iodopyridin-4-amine (INT S-1A). To a solution of 2-chloro-3-fluoropyridin- 4-amine (10.0 g, 68.0 mmol) and / V-iodosuccinimide (18.4 g, 81.6 mmol) in acetonitrile (70 mL) was added p-toluenesulfonic acid monohydrate (648 mg, 3.41 mmol) and the mixture was stirred at 70 °C for 16 h. Then, the reaction mixture was diluted with water and ethyl acetate and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with sat. Na2COs, sat. Na2SOs and brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-30% EtOAc in hexanes) to afford INT S-1A (13.0 g, 70% yield). LCMS: m / z = 273.0 [M+H]+. Step 2

[0600] Ethyl 4-amino-6-chloro-5-fluoronicotinate (INT S-1B). This intermediate was prepared from INT S-1A according to the carbomethoxylation procedure described for INT A-3E (step 5). LCMS: m / z = 219.1 [M+H]+. Step 3

[0601] (4-Amino-6-chloro-5-fluoropyridin-3-yl)methanol (INT S-1C). This intermediate was prepared from INT S-1B according to the reduction procedure described for INT A-3 (step 6). LCMS: m / z = 177.1 [M+H]+.

[0602] Step 4

[0603] 4-Amino-6-chloro-5-fluoronicotinaldehyde (INT S-1 D). To a solution of INT S-1C (2.30 g, 13 mmol) in ethyl acetate (130 mL) was added MnCh (21.3 g, 208 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then, the mixture was filtered over a pad of Celite®, which was washed with 1 % MeOH in EtOAc. The filtrate was concentrated under reduced pressure to afford INT S-1D (1.90 g, 84% yield) as a beige solid. LCMS: m / z = 175.1 [M+H]+.

[0604] Step 5

[0605] 2-Amino-7-chloro-8-fluoro-1,6-naphthyridine-3-carbonitrile (INT S-1E). To a solution of INT

[0606] 5-1 D (485 mg, 2.78 mmol) and malonitrile (367 mg, 5.56 mmol) in ethanol (24 mL) was added piperidine (68.6 pL, 695 pmol) and the reaction mixture was stirred at 80 °C for 30 min. Then, the mixture was cooled to 0 °C, and filtered on a Buchner. The cake was washed with water and was dried under reduced pressure to afford INT S-1E (526 mg, 85% yield) as a beige solid. LCMS: m / z = 223.1 [M+H]+.

[0607] Step 6

[0608] 2-Amino-7-chloro-8-fluoro-1,6-naphthyridine-3-carboxamide (INT S-1F). To a solution of INT S-1 E (670 mg, 3.01 mmol) in ethanol (3 mL) was added KOH (199 mg, 3.01 mmol), followed by H2O2 (30% in water, 6.84 mL, 60.2 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction mixture was diluted with water and ethyl acetate. The layers were separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to afford INT S-1 F (600 mg, 83% yield) as a pale-yellow solid. LCMS: m / z = 241.1 [M+H]+.

[0609] Step 7

[0610] 8-Chloro-9-fluoropyrimido[4,5-b][1,6]naphthyridine-2,4(1H,3H)-dione (INT S-1G). To a suspension of INT S-1 F (600 mg, 2.49 mmol) in toluene (30 mL) was added oxalyl chloride (4.28 mL, 49.9 mmol) and the reaction mixture was stirred at 115 °C for 20 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was suspended in ethyl acetate and water and the pH was adjusted to 7 with solid NaHCOs. The layers were separated and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried with Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by reversed phase chromatography (C-18 Biotage column) using acetonitrile in water (0-60%, 0.1% formic acid) as a gradient to afford INT S-1G (570 mg, 86% yield) as a beige solid. LCMS: m / z = 267.0 [M+H]+.

[0611] Step 8

[0612] 2,4,8-Trichloro-9-fluoropyrimido[4,5-b][1,6]naphthyridine (INT S-1H). To a solution of INT S- 1G (360 mg, 1.35 mmol) in POCh (30 mL, 319 mmol) at 5 °C, was added DIPEA (1.18 mL, 6.75 mmol) and the reaction mixture was stirred for 30 min. Then, the reaction mixture was concentrated under reduced pressure to afford INT S-1G (410 mg, quant, yield) as a brown oil. LCMS: m / z = 303.1 [M+H]+.

[0613] Step 1 tert-Butyl 4-(2,8-dichloro-9-fluoropyrimido[4,5-b][1,6]naphthyridin-4-yl)piperazine-1- carboxylate (INT S-11), to a solution of INT S-1 H (410 mg, 1.35 mmol) and DIPEA (1.30 mL, 7.47 mmol) in dichloromethane (12 mL) at -40 °C under argon, was added terf-butyl 1- piperazinecarboxylate (252 mg, 1 .35 mmol) and the reaction mixture was stirred for 30 min. Then, the reaction mixture was poured onto an ice-cold mixture of dichloromethane and water. The aqueous layer was extracted 3 times with dichloromethane. The combined organic layers were washed with 10% aqueous NaHCOs and brine, dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0- 100% EtOAc in hexanes) to afford INT S-11 (232 mg, 38% yield) as a pale-yellow solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 9.62 (s, 1 H), 9.35 (s, 1 H), 4.13 - 4.19 (m, 4H), 3.64 (s, 4H), 1.45 (s, 9H). Step 2 tert-Butyl 4-(8-chloro-2-((2-(dimethylamino)ethyl)(methyl)amino)-9-fluoropyrimido [4,5-b] [1,6]naphthyridin-4-yl)piperazine-1 -carboxylate (INT S-1). To a solution of INT S-11 (70 mg, 154 pmol) in THF (2 mL) was added / V, / V, / \ / ”-trimethylethylenediamine (300 L, 2.32 mmol) and the reaction mixture was stirred at 70 °C for 1 h. Then, the reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-40% MeOH in dichloromethane) to afford INT S-1 (72 mg, 90% yield) as a pale-yellow oil. LCMS: m / z = 519.2 [M+H]+.

[0614] INT S-2 tert-Butyl (1 / ?,5S)-3-(8-chloro-2-((2-(dimethylamino)ethyl)(methyl)amino)-9-fluoropyrimido [4,5-b][1,6]naphthyridin-4-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT S-2). This intermediate was prepared according to the procedure described for INT S-1 using tert-butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate as amine.1H NMR (400 MHz, DMSO-cfe) 6 ppm 9.07 (s, 1 H), 9.00 (s, 1 H), 4.45 (br. s, 2H), 4.23 (br. s., 2H), 3.86 (t, J = 6.6 Hz, 1 H), 3.79 (t, J = 7.1 Hz, 1 H), 3.59 - 3.69 (m, 2H), 3.26 (s, 3H), 2.53 - 2.58 (m, 2H), 2.22 (s, 6H), 1.80 - 1.89 (m, 2H), 1.72

[0615] (d, J = 7.6 Hz, 2H), 1.47 (s, 9H).

[0616]

[0617] INT T-1H INT T-11 INT T-1 J INT T-1

[0618] Step 1

[0619] Ethyl 4,6-dihydroxy-5-nitronicotinate (INT T-1A). At 0 °C, to a solution of ethyl 4,6- dihydroxynicotinate (10.0 g, 53.5 mmol) in sulfuric acid (79.9 mL, 1.50 mol) was added dropwise nitric acid 90% fuming (3.20 mL, 69.0 mmol) and the reaction mixture was stirred for 1 h, before being warmed up to room temperature and stirred for 1 h. Then, the solution was poured into ice water and the resulting mixture was stirred for 10 min. The reaction mixture was filtered on a Buchner. The cake was washed with water and was then dried under reduced pressure to afford INT T-1 A (11.8 g, 97% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 12.82 (brs., 1 H), 8.23 (s, 1 H), 4.33 (q, J = 7.1 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H).

[0620] Step 2

[0621] Ethyl 4,6-dichloro-5-nitronicotinate (INT T-1B). A suspension of INT T-1 A (11.8 g, 51.7 mmol) in POCI3 (40 mL) was stirred at 80 °C for 24 h. Then, the reaction mixture was concentrated to half of its volume and poured into ice water. The suspension was stirred for 10 min. Ethyl acetate was added and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford INT T-1B (13.3 g, 94% yield) as a yellow solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 9.08 (s, 1 H), 4.40 (q, J = 7.0 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H).

[0622] Step 3

[0623] Ethyl 4,6-diamino-5-nitronicotinate (INT T-1C). At 0 °C, to a solution of INT T-1B (6.00 g, 22.6 mmol) in dichloromethane (35 mL) was added ammonia in 1 ,4-dioxane (92.0 mmol). The reaction mixture was warmed to room temperature and stirred for 24 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-90% EtOAc in hexanes) to afford INT T-1C (1.33 g, 26% yield) as a beige solid. LCMS: m / z = 227.1 [M+H]+. Note: ethyl 4-amino-6-chloro-5-nitronicotinate (3.93 g, 71 % yield) was also obtained.

[0624] Step 4

[0625] 4,6-Diamino-5-nitronicotinic acid (INT T-1 D). To a solution of INT T-1C (2.07 g, 9.15 mmol) in THF (20 mL) was added NaOH (4 M in water) (9.15 mL, 36.6 mmol) and the reaction mixture was stirred at room temperature for 18 h. Then, the pH of the solution was adjusted to 2 using 2 M HCI. The reaction mixture was filtered on a Buchner. The cake was washed with water and was then dried under reduced pressure to afford INT T-1D (1.8 g, quant, yield). LCMS: m / z = 199.2 [M+H]+.

[0626] Step 5

[0627] 7-Amino-8-nitro-2-thioxo-2,3-dihydropyrido[4,3-cf]pyrimidin-4(1H)-one (INT T-1 E). A suspension of INT T-1 D (1.8 g, 9.15 mmol) in POCh (18 mL) was stirred at 90 °C for 2 h. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in THF (12.7 mL) and a solution of ammonium thiocyanate (1.39 g, 18.3 mmol) in THF (24.4 mL) was added dropwise at room temperature. The reaction mixture was stirred for 24 h and was then diluted with ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated in ethyl acetate to afford INT T-1 E (1.43 g, 64% yield) as a yellow solid. LCMS: m / z = 240.0 [M+ H]+.

[0628] Step 6

[0629] 7-Amino-2-(methylthio)-8-nitropyrido[4,3-d]pyrimidin-4(3H)-one (INT T-1 F). To a solution of INT T-1 E (1.43 g, 5.98 mmol) in DMF (240 mL) at 0 °C was added sodium methoxide (375 mg, 6.93 mmol) and the reaction mixture was stirred for 10 min, Then, iodomethane (439 pL, 7.05 mmol) was added dropwise and the reaction mixture was allowed to reach room temperature and was stirred for 3 h. The reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The residue was triturated in ethyl acetate to afford INT T-1F (920 mg, 61% yield) as a yellow solid. LCMS: m / z = 254.1 [M+H]+.

[0630] Step 7 tert-Butyl 4-(7-amino-2-(methylthio)-8-nitropyrido[4,3-d]pyrimidin-4-yl)piperazine-1 -carboxylate (INT T-1G). To a solution of INT T-1 F (816 mg, 3.22 mmol) in THF (245 mL) were added PyBroP (1.65 g, 3.54 mmol), triethylamine (1.12 mL, 8.06 mmol) and tert-butyl 1- piperazinecarboxylate (780 mg, 4.19 mmol) and the reaction mixture was stirred at room temperature for 4 h. Then, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (10-90% EtOAc in hexanes) to afford INT T-1G (1.02 g, 75% yield) as a pale-yellow solid. LCMS: m / z = 422.1 [M+H]+.

[0631] Step 8 tert-Butyl 4-(7,8-diamino-2-(methylthio)pyrido[4,3-c / ]pyrimidin-4-yl)piperazine-1 -carboxylate- (INT T-1H). To a solution of INT T-1G (1.02 g, 2.42 mmol) in DMF (60 mL) was added tin(ll) chloride (9.37 g, 48.4 mmol) and the reaction mixture was stirred at 80 °C for 1 h. Then, the reaction mixture was diluted with ethyl acetate and water. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered and concentrated under reduced pressure to afford INT T-1 H (530 mg, 56% yield) as a brown solid. LCMS: m / z = 392.2 [M+H]+.

[0632] Step 9 tert-Butyl 4-(8-(methylthio)-3H-imidazo[4',5':5,6]pyrido[4,3-d]pyrimidin-6-yl) piperazine-1- carboxylate (INT T-11). To a solution of INT T-1H (530 mg, 1.35 mmol) in MeOH (53.4 mL) were added trimethyl orthoformate (53.0 mL, 483 mmol) and formic acid (10.6 mL, 282 mmol), and the reaction mixture was stirred at 85 °C for 1 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-30% MeOH in dichloromethane) to afford INT T-1 H (250 mg, 46% yield) as a yellow solid. LCMS: m / z = 402.1 [M+H]+. Step 10 tert-Butyl 4-(8-(methylsulfonyl)-3H-imidazo[4',5':5,6]pyrido[4,3-d]pyrimidin-6-yl) piperazine-1 -carboxylate (INT T-1J). This intermediate was prepared according to the procedure described for INT R2-1C (step 3). LCMS: m / z = 434.1 [M+H]+.

[0633] Step 11 tert-Butyl 4-(8-((2-(dimethylamino)ethyl)(methyl)amino)-3H-imidazo[4',5':5,6]pyrido [4, 3-d] pyrimidin-6-yl)piperazine-1-carboxylate (INT T-1). This intermediate was prepared according to the procedure described for INT S-1 (step 2). LCMS: m / z = 456.3 [M+H]+.

[0634] Step 1

[0635] 7-Amino-8-nitropyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (INT T-2A). To a solution of INT T- 1C (1.04 g, 4.23 mmol) in THF (10 mL) was added trichloroacetyl isocyanate (631 pL, 5.08 mmol) and the reaction mixture was stirred at room temperature for 16 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was dissolved in ammonia in MeOH (3.02 mL, 21.2 mmol) and the reaction mixture was stirred at 70 °C for 16 h. The reaction mixture was concentrated and acidified to pH 2 using 1 M aq. HCI. The suspension was lyophilized, and the resulting solid was triturated in ethanol to afford INT T-2A (730 mg, 77% yield) as a yellow solid. LCMS: m / z = 224.1 [M+H]+.

[0636] Step 2

[0637] 7,8-Diaminopyrido[4,3-d]pyrimidine-2,4(1H,3H)-dione (INT T-2B). This intermediate was prepared according to the procedure described for INT T-1 H (step 8). LCMS: m / z = 194.1 [M+H]+. Step 3

[0638] 3,9-Dihydro-6 / - / -imidazo[4',5':5,6]pyrido[4,3-c / ]pyrimidine-6,8(7 / - / )-dione (INT T-2C). To a solution of INT T-2B (600 mg, 3.11 mmol) in DMSO (150 mL) were added trimethyl orthoformate (18 mL, 164 mmol) and formic acid (12 mL, 317 mmol) and the reaction mixture was stirred at 100 °C for 20 h. Then, the reaction mixture was poured into ice-water and stirred for 30 min. The precipitate was filtered and the obtained solid was suspended in acetonitrile / water mixture (1 :1) and lyophilized to afford INT T-2C (590 mg, 93% yield) as a yellow solid. LCMS: m / z = 204.1 [M+H]+.

[0639] Step 4 e.S-Dichloro-SH-imidazo^'.S'zS.ejpyrido^.S-cfjpyrimidine (INT T-2D). At 0 °C, to a suspension of INT T-2C (300 mg, 1.48 mmol) in POCI3 (69.9 mL, 743 mmol) was added DIPEA (3.01 mL, 17.3 mmol) and the reaction mixture was allowed to reach room temperature and was stirred for 1 h. Then, the reaction mixture was concentrated under reduced pressure to afford INT T-2D (354 mg, quant, yield). LCMS: m / z = 240.0 [M+H]+.

[0640] Step 5 tert-Butyl 4-(8-chloro-3 / - / -imidazo[4',5':5,6]pyrido[4,3-d]pyrimidin-6-yl)piperazine-1 -carboxylate (INT T-2E). At 0 °C, to a solution of INT T-2D (354 mg, 1 .47 mmol) in dichloromethane (20 mL) were added tert-butyl 1 -piperazinecarboxylate (398 mg, 3.22 mmol) and DIPEA (3.01 mL, 17.3 mmol) and the reaction mixture was allowed to reach room temperature and was stirred for 2 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by reversed phase chromatography (C-18 Biotage column) using acetonitrile in water (10-80%, 0.1 % formic acid) to afford INT T-2E (453 mg, 79% yield) as a beige solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 13.92 (s, 1 H), 9.17 (s, 1 H), 8.54 (s, 1 H), 3.97 - 4.06 (m, 4H), 3.60 (s, 4H), 1.44 (s, 9H).

[0641] Step 6 tert-Butyl 4-(8-(((2 / ?,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-3H-imidazo [4', 5':5,6]pyrido[4,3-o(lpyrimidin-6-yl)piperazine-1 -carboxylate (INT T-2). This intermediate was prepared according to the procedure described for INT R1-1A (step 1) using (2R,7aS)-2- fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as the alcohol.1H NMR (400 MHz, DMSO-cfe) 6 ppm 13.46 (br. s, 1 H), 9.03 (s, 1 H), 8.40 (s, 1 H), 4.20 (d, J = 10.4 Hz, 1 H), 4.10 (d, J = 10.4 Hz, 1 H), 3.90 (s, 4H), 3.58 (s, 4H), 3.02 - 3.12 (m, 4H), 2.01 - 2.16 (m, 3H), 1.75 - 1.92 (m, 4H), 1.44 (s, 9H).

[0642] First steps

[0643] 7-Bromo-4,6-dichloro-1H-imidazo[4,5-c]pyridine (U-1A). This intermediate was prepared according to a literature procedure starting from 2,6-dichloro-3-nitro-4-aminopyridine (see WO20 12097478). LCMS: m / z = 265.8, 267.8, 269.8 [M+H]+.

[0644] Step 2

[0645] 4,6-Dichloro-1H-imidazo[4,5-c]pyridine-7-carboxylic acid (INT U-1 B). To a solution of INT U- 1A (1.26 g, 4.73 mmol) and / V, / V, / V" / V'-tetramethylethylenediamine (1.27 g, 10.9 mmol) in THF (14.7 mL) at -60 °C under nitrogen, was added dropwise n-butyllithium (1.6 M in hexanes, 6.81 mL, 10.9 mmol) and the reaction mixture was stirred for 1 h. Dry carbon dioxide was bubbled into the reaction mixture for 1 h. Then, the reaction mixture was allowed to reach room temperature and was quenched with water. The THF layer was removed under reduced pressure. Ethyl acetate was added, and layers were separated. The aqueous layer was acidified to pH 1 using a 2.5 M solution of HCI. The reaction mixture was filtered on a Buchner. The cake was washed with water and was then dried under reduced pressure to afford INT U-1 B (800 mg, 73% yield). LCMS: m / z = 231.9, 233.9 [M+H]+.

[0646] Step 3

[0647] Methyl 4,6-dichloro-1H-imidazo[4,5-c]pyridine-7-carboxylate (INT U-1C). To a suspension of INT U-1 B (800 mg, 3.45 mmol) in a mixture of EtOAc:MeOH (9:1) was added dropwise (trimethylsilyl)diazomethane (2M in hexanes) (1.90 mL, 3.79 mmol) until all solid dissolved. Then, acetic acid (100 pL, 1.72 mmol) was added slowly to quench the excess of (trimethylsilyl)diazomethane and the reaction mixture was concentrated under reduced pressure to afford INT U-1C (747 mg, 80% yield). LCMS: m / z = 245.9, 248.0 [M+H]+.

[0648] Step 4

[0649] Methyl 4-((4-(tert-butyl)benzyl)thio)-6-chloro-1H-imidazo[4,5-c]pyridine-7-carboxylate (INT U-1). To a solution of INT U-1C (695 mg, 2.82 mmol) and 4-terf-butylbenzyl mercaptan (764 mg, 4.24 mmol) in DMF (9.4 mL) was added DIPEA (984 pL, 5.65 mmol) and the reaction mixture was heated at 80 °C for 24 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (30-100% EtOAc in hexanes) to afford INT U-1 (885 mg, 80% yield). LCMS: m / z = 390.2 [M+H]+.

[0650] INT U-2

[0651] Step 1

[0652] Methyl 4-((4-(tert-butyl)benzyl)thio)-6-chloro-1-((7-fluoro-3-(methoxymethoxy)-8-((triisopro pylsilyl)ethynyl)naphthalen-1-yl)methyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate (INT U- 2A). This intermediate was prepared according to the procedure described for INT R1-2, except that the reaction mixture was heated to 80 °C instead of room temperature, using INT A-9 as the alcohol. The desired regioisomer was obtained as the minor component (40 : 60 ratio). LCMS: m / z = 788.2 [M+H]+.

[0653] Step 2

[0654] Methyl 6-((1 / ?,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-((4-(tert- butyl)benzyl)thio)-1-((7-fluoro-3-(methoxymethoxy)-8-((triisopropylsilyl)ethynyl) naphthalen-1-yl)methyl)-1H-imidazo[4,5-c]pyridine-7-carboxylate (INT U-2). To a solution of INT U-2A (323 mg, 410 pmol) in 1 ,4-dioxane (4.1 mL) were added DIPEA (164 pL, 942 pmol), 4 MS (200 mg) and fert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (522 mg, 2.46 mmol). The reaction mixture was flushed with nitrogen and heated at 120 °C for 24 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-40% EtOAc in hexanes) to afford INT U-2 (169 mg, 43% yield).1H NMR (400 MHz, CDCI3) 6 ppm 7.77 (s, 1 H), 7.73 (dd, J = 5.8, 9.1 Hz, 1 H), 7.41 - 7.48 (m, 2H), 7.34 - 7.40 (m, 2H), 7.29 - 7.34 (m, 2H), 7.28 (s, 1 H), 6.36 - 6.82 (m, 2H), 6.22 (s, 1 H), 5.12 (s, 2H), 4.59 (s, 2H), 4.17 (s, 2H), 3.38 (s, 3H), 3.17 - 3.33 (m, 2H), 3.13 (s, 3H), 1.76 (d, J = 17.4 Hz, 5H), 1.48 (s, 9H), 1.34 (s, 9H), 1.10 - 1.19 (m, 21 H), 1.10 - 1.11 (m, 1 H).

[0655] Step 1

[0656] Methyl 6-((1 / ?,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-((4-(tert- butyl)benzyl)thio)-1H-imidazo[4,5-c]pyridine-7-carboxylate (INT U-3A). Under nitrogen, a solution of INT U-1 (100 mg, 256 pmol), terf-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (436 mg, 2.05 mmol) and DIPEA (103 pL, 590 pmol) in dioxane (2.6 mL) was stirred at 120 °C for 36 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford INT U-3A (145 mg, quant, yield). LCMS: m / z = 566.4 [M+H]+.

[0657] Step 2

[0658] Methyl 6-((1 / ?,5S)-8-(tert-butoxycarbonyl)-3,8-diazabicyclo[3.2.1]octan-3-yl)-4-((4-(tert- butyl)benzyl)thio)-1-((3-cyano-2-(((E)-(dimethylamino)methylene)amino)-7- fluorobenzo[b]thiophen-4-yl)methyl)-1 H-imidazo[4,5-c]pyridine-7-carboxylate (INT U-3).

[0659] This intermediate was prepared according to the procedure described for INT R1-1 (step 2), except that the reaction mixture was heated to 70 °C instead of room temperature, using INT A- 16 as the alcohol. Regioisomers were obtained in approximately equal proportions in this step.1H NMR (400 MHz, CDCI3) 6 ppm 7.89 (s, 1 H), 7.69 - 7.76 (m, 1 H), 7.38 - 7.43 (m, 2H), 7.31 - 7.37 (m, 2H), 6.71 - 6.81 (m, 1 H), 6.25 - 6.33 (m, 1 H), 6.01 (br. s., 2H), 4.55 (s, 2H), 4.04 - 4.31 (m, 2H), 3.37 - 3.61 (m, 2H), 3.33 (s, 3H), 3.15 - 3.30 (m, 8H), 1.78 (d, J = 5.6 Hz, 4H), 1.47 (s, 9H), 1.30 - 1.33 (m, 9H).

[0660] INT U-4

[0661] Methyl ( / ?)-4-((4-(tert-butyl)benzyl)thio)-1-((7-fluoro-3-(methoxymethoxy)-8-((triisopropyl- silyl)ethynyl)naphthalen-1 -yl)methyl)-6-(3-hydroxy-3-methylpiperidin-1 -yl)-1 H-imidazo

[0662] [4,5-c]pyridine-7-carboxylate (INT U-4). This intermediate was prepared according to the procedure described for INT U-2 using (S)-3-methyl-piperidin-3-ol hydrochloride as the amine. The Mitsunobu step yielded a 1:1 mixture of regioisomers (INT U-4 most polar isomer). LCMS: m / z = 867.6 [M+H]+.

[0663] INT V-1

[0664] Step 1

[0665] 7-((4-(tert-Butyl)benzyl)thio)-5-chloro-3H-imidazo[4,5-b]pyridine (INT V-1A). To a solution of 2,4-Dichloro-7 / 7-pyrrolo[2,3-c(]pyrimidine (500 mg, 2.58 mmol) and 4-terf-butylbenzyl mercaptan (1.47 mL, 7.74 mmol) in NMP (13 mL) was added DIPEA (2.47 mL, 14.2 mmol) and the reaction mixture was stirred under microwave irradiation at 160 °C for 50 min. Then, the reaction mixture was cooled down to room temperature and diluted with brine and ethyl acetate. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over Na2SC>4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-100%, EtOAc in hexanes) to afford INT V-1A (200 mg, 23% yield) as an orange solid.1H NMR (400 MHz, DMSO-cfe) 6 ppm 13.29 (br. s, 1 H), 8.37 (s, 1 H), 7.36 - 7.39 (m, 4H), 7.24 (s, 1 H), 4.53 (s, 2H), 1 .26 (s, 9H).

[0666] Step 2

[0667] 7-((4-(tert-Butyl)benzyl)thio)-5-chloro-3-((7-fluoro-3-(methoxymethoxy)-8-((triisopropyl- silyl)ethynyl)naphthalen-1-yl)methyl)-3H-imidazo[4,5-b]pyridine (INT V-1B). To a solution of INT V-1A (173 mg, 521 pmol), INT A-9 (282 mg, 678 pmol) and ADDP (403 mg, 1.56 mmol) in THF (5.2 mL) at 0 °C, was added tri-n-butylphosphine (390 pL, 1.56 mmol) and the reaction mixture was stirred for 30 min. Then, the reaction mixture was allowed to reach room temperature and was stirred for 2 h. Heptane was added and the solid formed was filtered through a pad of Celite®. The filtrate was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-100% EtOAc in hexanes) to afford INT V-1B (191 mg, 50% yield) as the main regioisomer (>10 : 1).1H NMR (400 MHz, DMSO-cfe) 5 ppm 8.29 (s, 1 H), 8.05 - 8.10 (m, 1 H), 7.55 - 7.61 (m, 2H), 7.39 (d, J = 3.9 Hz, 4H), 7.34 (s, 1 H), 6.51 - 6.54 (m, 1 H), 6.47 (s, 2H), 5.21 (s, 2H), 4.56 (s, 2H), 3.31 (d, J = 2.4 Hz, 6H), 1.26 (s, 9H), 1.00 (s, 18H).

[0668] Step 3 tert-Butyl (1 / ?,5S)-3-(7-((4-(tert-butyl)benzyl)thio)-3-((7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)-3H-imidazo[4,5-b]pyridin-5-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT V-1). A mixture of INT V1-B (136 mg, 186 pmol), terf-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (47 mg, 223 pmol), cesium carbonate (242 mg, 743 pmol) and Pd-PEPPSI-IPentCI-o-Picoline (39 mg, 46 pmol) in DME (2.7 mL) was degassed with nitrogen and stirred at 105 °C for 2 h. Then, the reaction mixture was cooled down to room temperature and was diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were washed with water, dried over Na2SO4, filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-30 % MeOH in dichloromethane) to afford INT V-1 (125 mg, 74% yield) as a yellow solid. LCMS: m / z = 906.4 [M+H]+.

[0669]

[0670] INT W-1 INT W-1C

[0671] Step 1

[0672] 4-((4-(tert-Butyl)benzyl)thio)-2-chloro-7H-pyrrolo[2,3-d]pyrimidine (INT W-1A). To a suspension of NaH (213 mg, 5.32 mmol) in DMF (21 mL) was added 4-terf-butylbenzyl mercaptan (1.00 mL, 5.36 mmol) and the reaction mixture was stirred for 10 minutes before being cooled down to 0 °C. Then, 2,4-dichloro-7H-pyrrolo[2,3-d]pyrimidine (1.00 g, 5.32 mmol) was added and the reaction mixture was allowed to reach room temperature and was stirred for 16 h. The reaction mixture was diluted with ethyl acetate and water and the layers were separated. The aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSCL, filtered and concentrated under reduced pressure. The residue was suspended in hexanes and the obtained mixture was filtered on a Buchner. The cake was washed with dichloromethane and was then dried under reduced pressure to afford INT W-1A (1.33 g, 84% pure, 63% yield).1H NMR (400 MHz, CDCI3) 6 ppm 11.12 (br. s., 1 H), 7.41 - 7.49 (m, 2H), 7.35 - 7.41 (m, 2H), 7.26 (dd, J = 3.5, 2.3 Hz, 1 H), 6.52 (dd, J = 3.5, 2.0 Hz, 1 H), 4.62 (s, 2H), 1.25 - 1.37 (m, 9H).

[0673] Step 2 tert-Butyl (1 / ?,5S)-3-(4-((4-(tert-butyl)benzyl)thio)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT W-1B). A suspension of INT W-1A (1.33 g, 4.01 mmol), K2CO3 (800 mg, 5.79 mmol) and fert-butyl 3,8-diazabicyclo[3.2.1]octane-8- carboxylate (1.00 g, 4.73 mmol) in NMP (15 mL) was stirred at 100 °C for 5 days. The reaction mixture was diluted with ethyl acetate and water. The layers were separated, and the aqueous layer was extracted 3 times with ethyl acetate. The combined organic layers were dried over MgSC filtered and concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-50% EtOAc in hexanes) to afford INT W-1 B (410 mg, 20% yield).1H NMR (400 MHz, CDCh) 5 ppm 9.24 (br. s., 1 H), 7.32 - 7.46 (m, 4H), 6.83 (dd, J = 3.6, 2.1 Hz, 1 H), 6.34 (dd, J = 3.6, 2.0 Hz, 1 H), 4.53 - 4.60 (m, 2H), 4.45 (d, J = 12.4 Hz, 2H), 4.20 - 4.42 (m, 2H), 3.21 (br. s., 2H), 1.87 - 2.01 (m, 2H), 1.72 - 1.80 (m, 2H), 1.46 - 1.58 (m, 9H), 1.31 - 1.37 (m, 9H).

[0674] Step 3 tert-Butyl (1R,5S)-3-(4-((4-(tert-butyl)benzyl)sulfinyl)-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (INT W-1C). This intermediate was prepared according to the procedure described for INT R2-1C (step 3).1H NMR (400 MHz, CDCh) 6 ppm 8.72 (br. s., 1 H), 7.29 (d, J = 8.4 Hz, 2H), 7.14 (d, J = 8.3 Hz, 2H), 6.90 (dd, J = 3.6, 2.1 Hz, 1 H), 6.76 (dd, J = 3.6, 1.9 Hz, 1 H), 4.27 - 4.48 (m, 5H), 4.23 (d, J = 12.9 Hz, 1 H), 3.19 (br. s., 2H), 1.83 - 2.01 (m, 2H), 1.59 - 1.83 (m, 2H), 1.37 - 1.58 (m, 9H), 1.25 - 1.37 (m, 9H).

[0675] Step 4 tert-Butyl (1R,5S)-3-(4-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-7H- pyrrolo[2,3-oQpyrimidin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (INT W-1). This intermediate was prepared according to the procedure described for INT R1-1A using (2R,7aS)- 2-fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as an alcohol and 2-Me-THF instead of THF.1H NMR (400 MHz, CDCh) 6 ppm 9.22 (br. s., 1 H), 6.76 (dd, J = 3.4, 2.1 Hz, 1 H), 6.34 (dd, J = 3.4, 2.1 Hz, 1 H), 5.30 (d, J = 53.9 Hz, 1 H), 4.21 - 4.49 (m, 5H), 4.14 (d, J = 9.6 Hz, 1 H), 3.23 - 3.39 (m, 2H), 3.05 - 3.23 (m, 3H), 2.92 - 3.05 (m, 1 H), 2.04 - 2.30 (m, 3H), 1.82 - 2.04 (m, 5H), 1.69 - 1.77 (m, 2H), 1.50 (s, 9H). Step 1

[0676] 4.6-Dichloro-1 H-imidazo[4,5-c]pyridine-7-carboxamide (INT X-1 A). A suspension of INT U-1 B (155 mg, 668 pmol) in thionyl chloride (2.50 mL, 668 pmol) was heated at 75 °C for 2 h. Then, the reaction mixture was concentrated under reduced pressure. The residual thionyl chloride was coevaporated with toluene twice. The residue was dissolved in THF (2.50 mL), and the reaction mixture was cooled to 0 °C. Then, aqueous ammonia (0.5 mL, 668 pmol) was added. The reaction mixture was allowed to reach room temperature and was stirred for 18 h. The reaction mixture was concentrated under reduced pressure to afford INT X-1A (150 mg, 97% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.53 (s, 1 H), 8.20 (br. s., 1 H), 8.02 (br. s., 1 H).

[0677] Step 2

[0678] 4.6-Dichloro-1H-imidazo[4,5-c]pyridine-7-carbonitrile (INT X-1 B). A suspension of INT X-1 A (150 mg, 649 pmol) in POCh (2 mL) was heated to 90 °C for 3 h. Then, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and water and the layers were separated. The organic layer was washed with sat. NaHCOs, water, and brine, dried over Na2SC>4, filtered and concentrated under reduced pressure to afford INT X-1 B (120 mg, 87% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.76 (s, 1 H). LCMS: m / z = 213.0 [M+H]+.

[0679] Step 3

[0680] 4-((4-(tert-Butyl)benzyl)thio)-6-chloro-1H-imidazo[4,5-c]pyridine-7-carbonitrile (INT X-1). To a solution of INT X-1B (2.31 g, 10.8 mmol) in DMF (108 mL) were added 4-terf-butylbenzyl mercaptan (2.93 g, 16.3 mmol) and DIPEA (3.78 mL, 21.7 mmol), and the reaction mixture was heated at 90 °C for 18 h. The reaction mixture was concentrated under reduced pressure. The residue was suspended in dichloromethane and the obtained mixture was filtered on a Buchner. The cake was washed with dichloromethane and was then dried under reduced pressure to afford INT X-1 (3.11 g, 80% yield)1H NMR (400 MHz, DMSO-cfe) 6 ppm 14.11 (br. s., 1 H), 8.57 (br. s., 1 H), 7.37 - 7.42 (m, 2H), 7.30 - 7.36 (m, 2H), 4.56 (s, 2H), 1.24 (s, 9H).

[0681]

[0682] Step 1

[0683] 6-((4-(tert-Butyl)benzyl)thio)-2-fluoro-9H-purine (INT Y-1A): To an ice-cold solution of 6- chloro-2-fluoropurine (10.0 g, 58 mmol) and 4-tert-butyl mercaptan (11.6 mL, 60 mmol) in THF (190 mL) was added NaH (60% oil dispersion, 7.19 g, 180 mmol) portion wise over 10 min. The reaction mixture was then stirred for 1 h at RT until complete. The reaction was then cooled again in an ice-water bath and quenched by careful addition of AcOH (10.3 mL, 180 mmol) followed by water (100 mL). The product was extracted into EtOAc (2 x 50 mL), washed with brine and dried (Na2SC>4). Removal of solvent gave a white solid that was triturated with 1 :1 ether-hexane (100 mL). The product was collected by filtration and dried under vacuum to give INT Y1A as an off- white solid (16.4 g, 89% yield).1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.43 (s, 1 H), 7.36 - 7.40 (m, 2H), 7.30 - 7.36 (m, 2H), 4.57 (s, 2H), 1.24 (s, 9H). LCMS: m / z = 317.1 [M+H]+.

[0684] Step 2

[0685] 6-((4-(tert-Butyl)benzyl)thio)-2-fluoro-9-((7-fluoro-3-(methoxymethoxy)-8- ((triisopropylsilyl)ethynyl)naphthalen-1-yl)methyl)-9H-purine (INT Y-1): A solution of INT A-

[0686] 9 (1.10 g, 2.64 mmol), INT Y-1A (919 mg, 2.90 mmol) and triphenylphosphine (762 mg, 2.90 mmol) in DCM (26.5 mL) was cooled in an ice-water bath. DIAD (0.57 mL, 2.90 mmol) in DCM (2 mL) was added dropwise and the mixture allowed to warm up to RT and stirred for 16 h. LCMS showed formation of two regioisomers in a 2:1 ratio in favor of the less polar, desired INT Y-1 which was isolated by flash chromatography (1.12 g, 59% yield).1H NMR (400 MHz, DMSO-cfe) 5 ppm 8.33 (s, 1 H), 8.08 (dd, J = 9.3, 6.1 Hz, 1 H), 7.55 - 7.61 (m, 2 H), 7.41 (d, J = 8.4 Hz, 2 H), 7.35 (d, J = 8.4 Hz, 2 H), 6.67 (d, J = 2.1 Hz, 1 H), 6.44 (s, 2 H), 5.21 (s, 2 H), 4.61 (s, 2 H), 3.31 (s, 3 H), 1.26 (s, 9 H), 1.00 (s, 21 H). LCMS: m / z = 715.4 [M+H]+. EXAMPLE 1

[0687] Example 1

[0688] Step 1 tert-Butyl 3-(9-((8-ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl) methoxy)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 1A). Under nitrogen, to a microwave vial containing Ruphos Pd G3 (20.9 mg, 24.5 pmol), cesium carbonate (120 mg, 368 pmol) and terf-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (28.6 mg, 135 pmol) was added a solution of INT R1-1 (56.6 mg, 123 pmol) in 1 ,4-dioxane (1.23 mL) and the reaction mixture was heated to 100 °C and stirred for 4 h. Then, the reaction mixture was cooled to room temperature and filtered through a filter which was washed with THF. The reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (0-10% MeOH in dichloromethane, 1 % triethylamine) to afford Example 1A (25 mg, 32% yield). LCMS: m / z = 638.4 [M+H]+.

[0689] Step 2

[0690] 2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purine (Example 1). To a solution of Example 1A (25 mg, 39.2 pmol) in dichloromethane (2 mL) and MeOH (1 mL) was added HCI (4M in 1 ,4-dioxane) (3.92 mL, 15.7 mmol) and the reaction mixture was stirred for 15 min. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by reversed phase chromatography (C-18 Biotage column) using MeOH in water (10-65%, 0.1 % formic acid) as a gradient to afford Example 1 (4 mg, 19% yield).1H NMR (400 MHz, MeOH-ck) 6 ppm 7.87 - 7.94 (m, 1 H), 7.78 - 7.84 (m, 1 H), 7.71 (s, 1 H), 7.42 - 7.47 (m, 2H), 7.34 - 7.41 (m, 1 H), 7.15 (d, J = 6.6 Hz, 1 H), 5.97 (s, 2H), 4.68 (s, 2H), 4.55 (d, J = 13.8 Hz, 2H), 4.05 (br. s., 2H), 3.72 (td, J = 6.6, 11.6 Hz, 2H), 3.23 - 3.29 (m, 4H), 3.19 (q, J = 7.5 Hz, 2H), 2.30 - 2.40 (m, 2H), 2.15 - 2.28 (m, 4H), 2.06 - 2.14 (m, 2H), 1.98 - 2.05 (m, 2H), 1.79 - 1.92 (m, 2H), 1.35 (t, J = 7.4 Hz, 3H). LCMS: m / z = 538.2 [M+H]+.

[0691] EXAMPLE 2

[0692] 1 -(9-((8-Ethylnaphthalen-1 -yl)methyl)-6-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 1A (step 1) using racemic 3-methylpiperidin-3-ol as the amine.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.53 (s, 1 H), 7.90 (d, J = 8.0 Hz, 1 H), 7.80 (dd, J = 3.0, 6.5 Hz, 1 H),

[0693] 7.50 (s, 1 H), 7.35 - 7.45 (m, 3H), 7.17 (d, J = 7.0 Hz, 1 H), 5.94 (d, J = 15.1 Hz, 1 H), 5.88 (d, J =

[0694] 15.4 Hz, 1 H), 4.71 (d, J = 12.0 Hz, 1 H), 4.62 (d, J = 11.9 Hz, 1 H), 3.96 (ddd, J = 3.8, 6.6, 12.9 Hz, 1 H), 3.86 (d, J = 13.0 Hz, 1 H), 3.70 (qd, J = 6.2, 12.0 Hz, 2H), 3.57 - 3.65 (m, 2H), 3.20 - 3.27 (m, 2H), 3.10 - 3.19 (m, 2H), 2.65 (s, 1 H), 2.29 - 2.41 (m, 2H), 2.14 - 2.25 (m, 4H), 2.01 - 2.13 (m, 3H), 1.81 (ddd, J = 4.2, 8.47, 12.9 Hz, 1 H), 1.63 - 1.75 (m, 2H), 1.49 - 1.62 (m, 1 H), 1.34 (t, J =

[0695] 7.4 Hz, 4H), 1.20 (s, 3H). LCMS: m / z = 541.4 [M+H]+.

[0696] EXAMPLE 3

[0697] (1-(9-((8-Ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)azepan-3-yl)methanol. This example was prepared according to the procedure described for Example 1 (step 1) using azepan-3-yl methanol as the amine.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.51 (br. s., 1 H), 7.92 (d, J = 8.0 Hz, 1 H), 7.81 (dd, J = 2.6, 6.9 Hz, 1 H), 7.34 -

[0698] 7.51 (m, 4H), 7.22 (d, J = 7.0 Hz, 1 H), 5.91 (s, 2H), 4.62 - 4.76 (m, 2H), 4.01 (ddd, J = 5.6, 7.7, 13.7 Hz, 1 H), 3.63 - 3.80 (m, 2H), 3.39 - 3.58 (m, 3H), 3.22 - 3.29 (m, 2H), 3.14 (q, J = 7.4 Hz, 2H), 2.29 - 2.40 (m, 2H), 2.15 - 2.28 (m, 4H), 2.05 - 2.14 (m, 2H), 2.02 (br. s., 1 H), 1.91 (br. s., 1 H), 1.75 - 1.84 (m, 1 H), 1.63 - 1.74 (m, 2H), 1.32 (m, 5H). (1 H formic). LCMS: m / z = 555.4 [M+H]+.

[0699] EXAMPLE 4

[0700] 2-(9-((8-Ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)-2,5-diazabicyclo[2.2.2]octane. This example was prepared according to the procedure described for Example 1 using 2-Boc-2,5-diazabicyclo(2.2.2)octane as the amine.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.48 (s, 2H), 7.89 (d, J = 8.1 Hz, 1 H), 7.80 (t, J = 4.7 Hz, 1 H), 7.68 (s, 1 H), 7.41 - 7.47 (m, 2H), 7.37 (t, J = 7.6 Hz, 1 H), 7.12 (br. s., 1 H), 5.97 (s, 2H), 4.71 (s, 2H), 3.97 (br. s., 1 H), 3.83 (br. s., 1 H), 3.70 - 3.78 (m, 2H), 3.44 (br. s., 2H), 3.24 - 3.29 (m, 2H), 3.19 (q, J = 7.4 Hz, 2H), 2.30 - 2.42 (m, 2H), 2.03 - 2.29 (m, 8H), 1.89 - 2.02 (m, 3H), 1.36 (t, J = 7.3 Hz, 3H). (2H formic). LCMS: m / z = 538.4 [M+H]+.

[0701] EXAMPLE 5

[0702] 1 -(9-((8-Ethylnaphthalen-1 -yl)methyl)-6-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)-3-methylpiperidin-3-amine. This example was prepared according to the procedure described for Example 1 using racemic terf-butyl (3-methylpiperidin-3-yl)carbamate as the amine.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s., 2H), 7.91 (d, J = 8.1 Hz, 1 H), 7.77 - 7.85 (m, 1 H), 7.65 (s, 1 H), 7.45 (d, J = 4.6 Hz, 2H), 7.37 (t, J = 7.6 Hz, 1 H), 7.07 (d, J = 7.1 Hz, 1 H), 5.90 - 6.05 (m, 2H), 4.60 - 4.73 (m, 2H), 4.10 - 4.24 (m, 2H), 3.66 - 3.75 (m, 2H), 3.62 (d, J = 13.6 Hz, 1 H), 3.46 - 3.56 (m, 1 H), 3.11 - 3.29 (m, 4H), 2.28 - 2.40 (m, 2H), 2.13 - 2.26 (m, 4H), 2.02 - 2.13 (m, 2H), 1.71 - 1.93 (m, 4H), 1.31 - 1.40 (m, 6H). LCMS: m / z = 540.4 [M+H]+.

[0703] EXAMPLE 6

[0704] 2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-propylnaphthalen-1-yl)methyl)-6-

[0705] ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine (Example 6). This example was prepared from INT R2-1 according to the procedure described for INT R1-1 (step 2) using INT A- 18, ADDP and tri-n-butylphosphine for the Mitsunobu reaction (step 1) and the deprotection procedure described for Example 1 (step 2).1H NMR (400 MHz, MeOH-ck) 6 ppm 8.51 (br. s., 2H), 7.90 - 7.96 (m, 1 H), 7.82 (dd, J = 2.0, 7.6 Hz, 1 H), 7.54 (s, 1 H), 7.38 - 7.46 (m, 3H), 7.24 (d, J = 6.4 Hz, 1 H), 5.89 (s, 2H), 4.68 (s, 2H), 4.58 (d, J = 13.8 Hz, 2H), 4.05 (br. s., 2H), 3.65 - 3.78 (m, 2H), 3.21 - 3.30 (m, 4H), 2.98 - 3.07 (m, 2H), 2.33 (dd, J = 6.7, 12.57 Hz, 2H), 2.20 (td, J = 6.7, 9.5 Hz, 4H), 1 .99 - 2.14 (m, 4H), 1.86 (d, J = 7.8 Hz, 2H), 1.66 - 1.77 (m, 2H), 1.01 (t, J = 7.3 Hz, 3H). (2H formic) LCMS: m / z = 552.4 [M+H]+.

[0706] EXAMPLE 7 ethyl 2-(2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)-2-(8-ethylnaphthalen-1-yl)acetate. This example was prepared according to the procedure described for Example 6 using INT A-2 as the alcohol and DIAD / triphenylphosphine for the Mitsunobu step.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.48 (s, 2H), 8.09 (dd, J = 1.1 , 8.1 Hz, 1 H), 7.88 (dd, J = 2.0, 7.5 Hz, 1 H), 7.65 - 7.70 (m, 1 H), 7.56 - 7.63 (m, 1 H), 7.43 - 7.52 (m, 3H), 7.29 (s, 1 H), 4.55 - 4.72 (m, 4H), 4.32 (dq, J = 1 .7, 7.1 Hz, 2H), 4.09 (br. s., 2H), 3.64 - 3.75 (m, 2H), 3.36 (s, 2H), 3.21 - 3.28 (m, 2H), 3.08 - 3.19 (m, 1 H), 2.85 - 2.98 (m, 1 H), 2.28 - 2.39 (m, 2H), 2.13 - 2.27 (m, 4H), 2.04 - 2.13 (m, 4H), 1.92 (d, J = 10.9 Hz, 2H), 1.40 (t, J = 7.4 Hz, 3H), 1.24 (t, J = 7.1 Hz, 3H). (2H formic) LCMS: m / z = 610.4 [M+H]+.

[0707] EXAMPLE 8

[0708] 3-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-chloro-4-cyclopropylphenol. This example was prepared according to the procedure described for Example 6 using INT A-3 as the alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.48 (s, 2H), 8.06 (s, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.29 (d, J = 2.5 Hz, 1 H), 5.57 (s, 2H), 4.68 (s, 2H), 4.60 (d, J = 13.4 Hz, 2H), 4.10 (br. s., 2H), 3.74 (td, J = 6.7, 11.7 Hz, 2H), 3.23 - 3.29 (m, 2H), 2.30 - 2.41 (m, 2H), 2.16 - 2.28 (m, 4H), 2.00 - 2.15 (m, 4H), 1.82 - 1.93 (m, 2H), 1.55 - 1.66 (m, 1 H), 1.09 - 1.18 (m, 2H), 0.69 - 0.76 (m, 2H). LCMS: m / z = 550.3 [M+H]+.

[0709] EXAMPLE 9

[0710] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-ethyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 6 using INT A-4 as the alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 9.09 (br. s., 1 H), 7.66 (dd, J = 8.9, 6.0 Hz, 1 H), 7.27 (t, J = 9.3 Hz, 1 H), 7.15 - 7.24 (m, 1 H), 6.89 - 7.01 (m, 1 H), 6.09 (br. s., 2H), 4.81 (br. s., 2H), 4.43 - 4.73 (m, 2H), 4.15 (br. s., 2H), 3.77 - 3.87 (m, 2H), 3.71 - 3.77 (m, 2H), 3.63 - 3.71 (m, 3H), 3.54 - 3.63 (m, 2H), 3.36 - 3.54 (m, 2H), 3.11 (d, J = 5.1 Hz, 2H), 2.67 (s, 3H), 2.40 (br. s., 2H), 2.19 - 2.33 (m, 4H), 2.12 - 2.19 (m, 2H), 2.08 (br. s., 2H), 1.88 (br. s., 2H), 1.37 (t, J = 6.6 Hz, 3H). LCMS: m / z = 572.3 [M+ H]+. EXAMPLE 10

[0711] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-((triisopropylsilyl)ethynyl)naphthalen-2-ol (Example 10A). This example was prepared from INT R2-1 according to the procedure described for Example 6 using INT A-5 as the alcohol and ADDP / tri-n-butylphosphine as Mitsunobu reagent.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s., 1 H), 8.09 (s, 1 H), 7.76 (d, J = 8.3 Hz, 1 H), 7.67 (d, J = 6.3 Hz, 1 H), 7.41 (t, J = 7.8 Hz, 1 H), 7.12 (d, J = 2.1 Hz, 1 H), 6.55 - 6.58 (m, 1 H), 6.54 (s, 2H), 4.71 (s, 2H), 4.55 (d, J = 13.1 Hz, 2H), 4.07 (br. s., 2H), 3.68 - 3.82 (m, 2H), 3.20 - 3.29 (m, 2H), 2.31 - 2.42 (m, 2H), 1.99 - 2.29 (m, 8H), 1.86 (d, J = 7.0 Hz, 2H), 1.10 (s, 21 H).

[0712] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynylnaphthalen-2-ol (Example 10). A solution of 10A (41.1 mg, 48 pmol) in MeOH (0.5 mL) and 4N HCI-dioxane (0.5 mL) was stirred at RT for 1 h to remove the Boc and MOM protecting groups (the TIPS protecting group was also partially removed). Volatiles were removed under reduced pressure and the residue purified by preparative reversed-phase HPLC. To a solution of the partially deprotected material (13.0 mg, 48.4 pmol) in DMF (500 pL) was added CsF (37 mg, 0.282 mmol) and the reaction mixture was stirred at room temperature for 2 h. Then, the reaction was quenched with formic acid (50 pL), diluted with DMSO and purified by reversed phase chromatography (Kinetex 5pm C18 column) using MeOH in water (10-100%, 0.1% formic acid) as a gradient to afford Example 10 (4.5 mg, 16% yield) as a beige solid.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.52 (br. s., 1 H), 7.94 (s, 1 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.63 (dd, J = 7.1 , 1.1 Hz, 1 H), 7.34 - 7.41 (m, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 6.65 (d, J = 2.5 Hz, 1 H), 6.36 (s, 2H), 4.66 (s, 2H), 4.54 (d, J = 13.5 Hz, 2H), 3.99 (br. s., 2H), 3.85 (s, 1 H), 3.65 - 3.75 (m, 2H), 3.19 - 3.29 (m, 4H), 2.28 - 2.38 (m, 2H), 2.14 - 2.26 (m, 4H), 2.05 - 2.14 (m, 2H), 1.96 - 2.04 (m, 2H), 1.81 - 1.89 (m, 2H). LCMS: m / z = 550.4 [M+H]+. EXAMPLE 11

[0713] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 10 using INT A-9 as the alcohol.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.53 (br. s., 1 H), 7.90 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.33 (t, J = 8.9 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 6.72 (d, J = 2.0 Hz, 1 H), 6.32 (s, 2H), 4.60 (s, 2H), 4.46 (d, J = 13.3 Hz, 2H), 4.15 (s, 1 H), 3.83 (br. s., 2H), 3.54 - 3.69 (m, 2H), 3.09 - 3.22 (m, 4H), 2.25 - 2.38 (m, 2H), 2.09 - 2.25 (m, 4H), 2.05 (dq, J = 12.5, 6.3 Hz, 2H), 1.86 - 1.98 (m, 2H), 1.71 - 1.86 (m, 2H). LCMS: m / z = 568.3 [M+H]+.

[0714] EXAMPLE 12

[0715] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-ethylnaphthalen-2-ol. This example was prepared according to the procedure described for Example 6 using INT A-6 as an alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.47 (br. s., 1 H), 7.85 (s, 1 H), 7.57 (d, J = 7.6 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 6.6 Hz, 1 H), 7.12 (d, J = 2.6 Hz, 1 H), 6.58 (d, J = 2.5 Hz, 1 H), 5.94 (s, 2H), 4.69 (s, 2H), 4.50 - 4.62 (m, 3H), 4.04 (br. s., 2H), 3.73 (br. s, 2H), 3.22 - 3.28 (m, 3H), 3.16 (q, J = 7.5 Hz, 2H), 2.29 - 2.40 (m, 2H), 2.06 - 2.28 (m, 6H), 2.01 (br. s., 2H), 1.86 (d, J = 7.8 Hz, 2H), 1.36 (t, J = 7.4 Hz, 3H). LCMS: m / z = 554.3 [M+H]+.

[0716] EXAMPLE 13 tert-Butyl (1 / ?,5S)-3-(9-((8-cyclopropylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin -7a(5H)-yl)methoxy)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 13A). This example was prepared according to the procedure described for Example 6A (step 1) using INT A-7 as the alcohol.1H NMR (400 MHz, CDCI3) 5 ppm 7.85 (d, J = 8.0 Hz, 1 H), 7.75 (d, J = 7.9 Hz, 1 H), 7.41 - 7.50 (m, 1 H), 7.31 - 7.41 (m, 2H), 7.17 (d, J = 7.1 Hz, 1 H), 6.25 (s, 2H), 4.82 (br. s., 2H), 4.35 (br. s., 4H), 3.92 (br. s., 2H), 3.04 - 3.21 (m, 2H), 2.97 (dd, J = 11.0, 5.4 Hz, 2H), 2.32- 2.49 (m, 3H), 2.19 - 2.32 (m, 2H), 2.07 - 2.19 (m, 2H), 2.01 (dd, J = 13.1 , 6.7 Hz, 2H), 1.88 (br. s., 2H), 1.69 (br. s., 2H), 1.48 (s, 9H), 1.11(d, J = 8.3 Hz, 2H), 0.94 (d, J = 4.3 Hz, 2H)

[0717] 2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-cyclopropylnaphthalen-1-yl)methyl)-6- ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine (Example 13). To a solution of Example 13A (50.4 mg, 77.6 pmol) in dichloromethane (1.5 mL) was added trifluoracetic acid (1.47 mL, 14.0 mmol) and the reaction mixture was stirred for 30 min. Then, the reaction mixture was concentrated under reduced pressure to afford Example 13 (22 mg, 52% yield).1H NMR (400 MHz, MeOH-d4) 6 ppm 7.77 (d, J = 7.8 Hz, 1 H), 7.70 (s, 1 H), 7.69 (d, J = 8.4 Hz, 1 H), 7.41 (d, J = 7.1 Hz, 1 H), 7.20 - 7.35 (m, 2H), 7.00 (d, J = 7.0 Hz, 1 H), 6.32 (s, 2H), 4.57 (s, 2H), 4.42 (d, J = 13.9 Hz, 2H), 3.93 (br. s., 2H), 3.63 (dt, J = 11.7, 6.7 Hz, 2H), 3.05 - 3.20 (m, 4H), 2.43 (m, J = 5.6 Hz, 1 H), 2.18 - 2.32 (m, 2H), 1.87 - 2.17 (m, 10H), 1.62 - 1.78 (m, 2H), 0.96 - 1.09 (m, 2H), 0.74 - 0.88 (m, 2H). LCMS: m / z = 550.2 [M+H]+.

[0718] EXAMPLE 14 tert-Butyl (1 / ?,5S)-3-(9-((6-(b / s(4-methoxybenzyl)amino)-3-cyclopropyl-2-methylpyridin-4- yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (Example 14A). This example was prepared from INT R2-1 according to the procedure described for Example 6A (step 1) using INT A-8 as the alcohol. LCMS: m / z = 870.4 [M+H]+.

[0719] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-cyclopropyl-6-methylpyridin-2-amine (Example 14). A solution of Example 14A (93.0 mg, 0.107 mmol) in TFA (3.5 mL) was heated at 60 °C for 3 h. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by reversed phase chromatography (Kinetex 5pm C18 column) using MeOH in water (5-100%, 0.1% formic acid) as a gradient to afford Example 14 (23.0 mg, 34% yield) as beige solid.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s., 1 H), 6.21 (s, 1 H), 5.73 (s, 2H), 4.77 (s, 2H), 4.65 (d, J = 14.5 Hz, 2H), 4.18 (br. s., 2H), 3.73 - 3.85 (m, 2H), 3.33 - 3.42 (m, 3H), 2.62 (s, 3H), 2.33 - 2.43 (m, 2H), 2.06 - 2.33 (m, 8H), 1.90 - 1.99 (m, 2H), 1.70 - 1.80 (m, 1 H), 1.16 - 1.26 (m, 2H), 0.71 - 0.81 (m, 2H). LCMS: m / z = 530.3 [M+H]+.

[0720] EXAMPLE 15

[0721] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol.

[0722] This example was prepared according to the procedure described for Example 10 using INT A- 9 as the alcohol, ADDP and tri-n-butylphosphine for the Mitsunobu step. Regioisomers were isolated in a 6 : 1 ratio in favor of the Example 15.1H NMR (400 MHz, MeOH-ck) 6 ppm 8.53 (s, 1 H), 7.88 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 6.66 (d, J = 2.3 Hz, 1 H), 6.32 (s, 2H), 5.42 (br. s., 1 H), 4.47 - 4.63 (m, 3H), 4.27 - 4.43 (m, 2H), 4.16 (d, J = 0.88 Hz, 1 H), 3.96 (br. s., 2H), 3.37 - 3.44 (m, 3H), 3.19 (d, J = 14.0 Hz, 2H), 3.07 (td, J = 9.6, 5.63 Hz, 1 H), 2.40 - 2.47 (m, 1 H), 2.30 - 2.39 (m, 1 H), 2.21 - 2.30 (m, 1 H), 2.11 - 2.21 (m, 1 H), 1.81 - 2.11 (m, 7H), 1.60 - 1.69 (m, 1 H), 1.52 - 1.60 (m, 2H). LCMS: m / z = 586.2 [M+H]+.

[0723] EXAMPLE 16

[0724] 3-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-chloro-4-cyclopropylphenol. This example was prepared according to the procedure described for Example 8 using INT R2-2.1H NMR (400 MHz, DMSO-cfe) 5 ppm 9.74 (br. s, 1 H), 9.25 (br. s, 2H), 8.09 (s, 1 H), 6.72 (s, 1 H), 6.19 (s, 1 H), 5.49 (s, 2H), 4.40 (d, J = 13.3 Hz, 4H), 4.08 - 4.16 (m, 4H), 3.24 - 3.30 (m, 2H), 1.89 - 2.41 (m, 10H), 1.56 - 1.78 (m, 4H), 1.12 (dt, J = 10.5, 4.8 Hz, 1 H), 0.68 (dt, J = 10.1 , 4.8 Hz, 2H). LCMS: m / z = 568.4 [M+H]+.

[0725] EXAMPLE 17

[0726] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynylnaphthalen-2-ol. This example was prepared according to the procedure described for Example 10 using INT R2-2.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s., 1 H), 7.92 (s, 1 H), 7.75 (d, J = 8.1 Hz, 1 H), 7.63 (d, J = 7.1 Hz, 1 H), 7.38 (t, J = 7.8 Hz, 1 H), 7.12 (d, J = 2.5 Hz, 1 H), 6.61 (s, 1 H), 6.35 (s, 2H), 5.42 (m, 1 H), 4.58 (d, J = 13.6 Hz, 3H), 4.38 - 4.49 (m, 2H), 4.05 (br. s., 2H), 3.38 - 3.61 (m, 3H), 3.11 - 3.28 (m, 3H), 2.28 - 2.58 (m, 2H), 2.06 - 2.28 (m, 3H), 1.93 - 2.06 (m, 4H), 1.84 - 1.93 (m, 2H). LCMS: m / z = 568.3 [M+H]+.

[0727] EXAMPLE 18

[0728] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-ethylnaphthalen-2-ol. This example was prepared according to the procedure described for Example 12 using INT R2-2.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.46 (d, J = 15.5 Hz, 1 H), 7.80 (s, 1 H), 7.56 (d, J = 7.9 Hz, 1 H), 7.32 (t, J = 7.6 Hz, 1 H), 7.21 (d, J = 6.5 Hz, 1 H), 7.11 (d, J = 2.5 Hz, 1 H), 6.57 (s, 1 H), 5.93 (s, 2H), 5.32 - 5.55 (m, 1 H), 4.53 - 4.62 (m, 3H), 4.41 - 4.52 (m, 2H), 4.06 (br. s., 2H), 3.44 - 3.55 (m, 2H), 3.10 - 3.27 (m, 5H), 1.84 - 2.52 (m, 10H), 1.36 (t, J = 7.4 Hz, 3H). LCMS: m / z = 572.3 [M+H]+.

[0729] Example 19

[0730] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-(fluoromethyl)naphthalen-2-ol. This example was prepared according to the procedure described for Example 9 using INT R2-2 and alcohol INT A-4.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.96 (br. s., 1 H), 7.65 (dd, J = 8.9, 6.0 Hz, 1 H), 7.27 (t, J = 9.3 Hz, 1 H), 7.20 (d, J = 2.1 Hz, 1 H), 6.87 - 6.99 (m, 1 H), 6.07 (s, 2H), 5.62 (d, J = 51.9 Hz, 1 H), 4.60 (br. s., 2H), 4.14 (br. s., 2H), 3.92 - 4.09 (m, 1 H), 3.88 (t, J = 15.1 Hz, 1 H), 3.71 - 3.81 (m, 2H), 3.61 - 3.71 (m, 4H), 3.54 - 3.61 (m, 2H), 3.42 - 3.54 (m, 1 H), 3.38 (d, J = 13.3 Hz, 1 H), 3.10 (d, J = 5.3 Hz, 2H), 2.74 - 2.88 (m, 1 H), 2.58 (br. s., 1 H), 2.49 (br. s., 1 H), 2.38 (br. s., 2H), 2.26 (d, J = 13.6 Hz, 1 H), 2.08 (br. s., 2H), 1 .88 (br. s., 2H), 1.36 (t, J = 7.0 Hz, 3H). LCMS: m / z = 590.3 [M+ H]+.

[0731] EXAMPLE 20 Step 1 tert-Butyl (1R,5S)-3-(6-(3-(dimethylamino)propoxy)-9-((8-ethylnaphthalen-1-yl)methyl)-9H- purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 20A). This intermediate was prepared from INT R4-1 according to the procedure described for INT R2-1 (step 4) using alcohol INT R2-17.1H NMR (400 MHz, CDCI3) 6 ppm 7.88 (d, J = 8.1 Hz, 1 H), 7.78 (d, J = 7.8 Hz, 1 H), 7.35 - 7.47 (m, 3H), 7.22 (s, 1 H), 7.18 (d, J = 7.1 Hz, 1 H), 5.80 (s, 2H), 4.57 (t, J = 6.3 Hz, 2H), 4.42 (d, J = 12.9 Hz, 2H), 4.35 (br. s., 2H), 3.13 (bs, 2H), 3.10 (q, J = 7.3 Hz, 2H), 2.63 - 2.78 (m, 2H), 2.39 (s, 6H), 2.07 - 2.20 (m, 2H), 1.85 - 1.99 (m, 2H), 1.68 - 1.81 (m, 2H), 1.50 (s, 9H) 1.36 (t, J = 7.44 Hz, 3H). LCMS: m / z = 600.4 [M+H]+.

[0732] Step 2

[0733] 3-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-9H- purin-6-yl)oxy)- / V, / V-dimethylpropan-1 -amine (Example 20). This example was prepared according to the procedure described for Example 1 (step 2).1H NMR (400 MHz, MeOH-ck) 6 ppm 8.86 (s, 1 H), 7.97 (d, J = 8.1 Hz, 1 H), 7.85 (dd, J = 5.8, 3.9 Hz, 1 H), 7.41 - 7.52 (m, 3H), 7.37 (d, J = 7.0 Hz, 1 H), 6.13 (s, 2H), 4.73 (t, J = 6.0 Hz, 2H), 4.57 (br. s., 2H), 4.15 (br. s., 2H), 3.70 - 3.77 (m, 1 H), 3.62 - 3.70 (m, 2H), 3.55 - 3.62 (m, 1 H), 3.33 - 3.44 (m, 4H), 3.19 (q, J = 7.4 Hz, 2H), 2.94 (s, 6H), 2.30 - 2.40 (m, 2H), 1.97 - 2.13 (m, 2H), 1.86 (br. s., 2H), 1.38 (t, J = 7.4 Hz, 3H). LCMS: m / z = 500.3 [M+H]+.

[0734] EXAMPLE 21

[0735] 2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-6-

[0736] (((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine. This example was prepared according to the procedure described for Example 20 using (2R,7aS)-2- fluorohexahydro-1 / 7-pyrrolizine-7a-methanol as the alcohol.1H NMR (400 MHz, MeOH-ck) 6 ppm 8.28 (br. s., 1 H), 7.94 (dd, J = 8.2, 0.9 Hz, 1 H), 7.78 - 7.86 (m, 1 H), 7.44 - 7.50 (m, 2H), 7.37 - 7.44 (m, 1 H), 7.24 (d, J = 6.1 Hz, 1 H), 6.05 (s, 2H), 5.60 (dt, J = 51.7, 3.5 Hz, 1 H), 4.78 (s, 2H), 4.61 (d, J = 14.3 Hz, 2H), 4.08 - 4.17 (m, 2H), 3.82 - 4.08 (m, 3H), 3.55 - 3.78 (m, 1 H), 3.42 - 3.55 (m, 1 H), 3.34 (br. s., 1 H), 3.19 (q, J = 7.4 Hz, 2H), 2.82 (dd, J = 15.5, 4.4 Hz, 1 H), 2.68 - 2.77 (m, 1 H), 2.66 (s, 1 H), 2.54 - 2.63 (m, 1 H), 2.41 - 2.50 (m, 1 H), 2.30 - 2.41 (m, 2H), 2.13 - 2.30 (m, 1 H), 2.00 - 2.13 (m, 2H), 1.87 (d, J = 8.13 Hz, 2H), 1.37 (t, J = 7.4 Hz, 3H). LCMS: m / z = 556.3 [M+H]+. EXAMPLE 22

[0737] 2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-6-((1- methylpiperidin-4-yl)oxy)-9H-purine. This example was prepared according to the procedure described for Example 20 using 1-methyl-4-piperidinol as the alcohol.1H NMR (400 MHz, MeOH- d4) 6 ppm 8.63 (s, 1 H), 7.96 (d, J = 8.0 Hz, 1 H), 7.80 - 7.87 (m, 1 H), 7.47 - 7.51 (m, 2H), 7.41 - 7.47 (m, 1 H), 7.30 - 7.36 (m, 1 H), 6.05 - 6.15 (m, 2H), 5.75 (t, J = 2.56 Hz, 1 H), 4.55 (d, J = 13.4 Hz, 2H), 4.15 (br. s., 2H), 3.62 - 3.77 (m, 2H), 3.33 - 3.55 (m, 5H), 3.19 (qd, J = 7.4, 2.9 Hz, 2H), 2.91 - 2.97 (m, 3H), 2.52 (d, J = 11.4 Hz, 1 H), 2.32 - 2.45 (m, 1 H), 2.20 - 2.32 (m, 1 H), 2.00 - 2.18 (m, 3H), 1.85 (d, J = 7.6 Hz, 2H), 1.38 (t, J = 7.4 Hz, 3H). LCMS: m / z = 512.3 [M+H]+.

[0738] EXAMPLE 23

[0739] ( / ?)-1-(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)methyl)-6-(((2 / ?,7aS)-2-fluoro- tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 6 (step 1) using ADDP / tri n-butylphosphine as Mitsunobu reagents and INT R2-3 and INT A-9 as the alcohol. A 4 : 1 mixture of regioisomers was obtained.

[0740] The protected intermediate from above (37.5 mg, 47.5 pmol) was dissolved in DCM (1 mL) and MeOH (100 pL) and 4M HCI in dioxane (356 pL, 1.43 mmol) was added. The reaction mixture was stirred at RT for 3 h (removal of MOM protecting group). The mixture was diluted with toluene (1 mL) and concentrated to dryness. The residue was dissolved in ammonium hydroxide (10% in MeOH, 1 mL) and concentrated to dryness once again. The crude residue was dissolved in DMF (1 mL) and CsF (36.1 mg, 238 pmol) was added followed by 4M KOH (50 pL, 200 pmol). After stirring at RT for 16 h, the reaction mixture was diluted with 1 : 1 water-MeOH (2 mL) containing 0.1 mL formic acid. Purification by reversed-phase HPLC gave Example 23 as an off-white solid.1H NMR (400 MHz, MeOH-d4) 5 ppm 7.79 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.70 (br. s., 1 H), 7.31 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 6.73 (d, J = 1.6 Hz, 1 H), 6.26 (s, 2H), 5.39 (br. d, J = 53.2 Hz, 1 H), 4.58 (br. s., 1 H), 4.35 - 4.48 (m, 2H), 4.13 (s, 1 H), 3.94 (ddd, J = 12.7, 6.4, 3.8 Hz, 1 H), 3.84 (d, J = 13.0 Hz, 1 H), 3.50 - 3.71 (m, 3H), 3.35 - 3.50 (m, 3H), 3.07 - 3.19 (m, 1 H), 2.19 - 2.54 (m, 3H), 2.05 - 2.17 (m, 2H), 1.89 - 2.05 (m, 1 H), 1.75 - 1.89 (m, 1 H), 1.62 - 1.75 (m, 3H), 1.49 - 1.62 (m, 2H), 1.29 (br. s., 2H), 1.18 (s, 3H). LCMS: m / z = 589.4 [M+H]+.

[0741] EXAMPLE 24

[0742] 2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-9-(1-(8-ethylnaphthalen-1-yl)ethyl)-6-

[0743] ( (tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine. This example was prepared according to the procedure described for Example 1 using INT R1-2 and terf-Butyl 3,8- diazabicyclo[3.2.1]octane-8-carboxylate as amine.1H NMR (400 MHz, MeOH-ck) 5 ppm 8.53 (br. s., 2H), 8.19 (s, 1 H), 7.73 - 7.86 (m, 2H), 7.47 - 7.53 (m, 1 H), 7.41 - 7.47 (m, 1 H), 7.31 - 7.38 (m, 1 H), 7.23 - 7.29 (m, 1 H), 6.70 - 6.80 (m, 1 H), 4.60 (s, 2H), 4.30 - 4.46 (m, 1 H), 4.02 - 4.22 (m, 1 H), 3.89 (d, J = 5.6 Hz, 1 H), 3.79 (br. s., 1 H), 3.64 - 3.76 (m, 2H), 3.16 - 3.29 (m, 4H), 3.07 (d, J = 14.0 Hz, 2H), 2.26 - 2.36 (m, 2H), 2.03 - 2.25 (m, 9H), 1.80 - 1.99 (m, 3H), 1.74 (d, J = 11.6 Hz, 1 H), 1.54 (t, J = 7.4 Hz, 3H). (2H formic). LCMS: m / z = 552.2 [M+H]+.

[0744] EXAMPLE 25

[0745] 3-((2-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-6-((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)- 9H-purin-9-yl)methyl)-5-chloro-4-cyclopropylphenol. This example was prepared according to the procedure described for Example 1 using INT R1-3 and fert-butyl 2,5- diazabicyclo[2.2.2]octane-2-carboxylate as amine.1H NMR (400 MHz, MeOH-ck) 5 ppm 8.49 (s, 2H), 8.03 (s, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.26 (br. s., 1 H), 5.50 - 5.63 (m, 2H), 4.93 - 5.07 (m, 1 H), 4.67 (s, 2H), 3.97 (d, J = 11.9 Hz, 1 H), 3.81 (br. s., 2H), 3.72 (td, J = 6.7, 11.7 Hz, 2H), 3.44 (br. s., 2H), 3.16 - 3.29 (m, 2H), 2.29 - 2.41 (m, 2H), 2.16 - 2.27 (m, 4H), 2.10 (td, J = 6.5, 18.9s., 1 H), 1.08 - 1.20 (m, 2H), 0.68 - 0.82 (m, 2H). LCMS: m / z = 550.4 [M+ H]+.

[0746] EXAMPLE 26

[0747] 1-(9-(3-Chloro-2-cyclopropyl-5-hydroxybenzyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 6 (Step 1) using INT R2-4 and INT A-3 as alcohol. A 3 : 1 mixture of regioisomers was obtained.1H NMR (400 MHz, MeOH-ck) 5 ppm 8.54 (br. s., 1 H), 7.91 (s, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.30 (d, J = 2.5 Hz, 1 H), 5.56 (d, J = 15.8 Hz, 1 H), 5.52 (d, J = 15.8 Hz, 1 H), 4.63 (d, J = 11.9 Hz, 1 H), 4.56 (d, J = 11.8 Hz, 1 H), 3.93 - 4.06 (m, 1 H), 3.87 (d, J = 13.1 Hz, 1 H), 3.50 - 3.69 (m, 4H), 3.02 - 3.23 (m, 2H), 2.24 - 2.40 (m, 2H), 2.08 - 2.24 (m, 4H), 1.93 - 2.08 (m, 2H), 1.81 (dtt, J = 12.7, 8.3, 4.0 Hz, 1 H), 1.61 - 1.75 (m, 3H), 1.47 - 1.61 (m, 1 H), 1.19 (s, 3H), 1.09 - 1.18 (m, 2H), 0.67 - 0.81 (m, 2H). LCMS: m / z = 553.3 [M+H]+.

[0748] EXAMPLE 27

[0749] 1 -(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1 -yl)methyl)-6-((tetrahydro-1 H-pyrrolizin- 7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 23 using INT R2-4 and INT A-9 as the alcohol. Removal of the protecting groups was carried out as follows: The protected intermediate from above (54 mg, 70 pmol) was dissolved in MeOH and 4M HCI in dioxane (175 pL, 700 pmmol) was added. After stirring at RT for 23 h the MOM group was removed. The reaction mixture was evaporated under reduced pressure and the residue taken up in DMF (1.2 mL). CsF (2 x 53 mg, 1.05 mmol) from RT to 45 °C did not significantly cleave the acetylenic TIPS protecting group so ammonium hydrogen fluoride (58 mg, 1.05 mmol) was added. After stirring for an additional 18 h at RT, only 10% deprotection of the TIPS group was observed. Finally, hydrogen fluoride (48%, 102 pL, 2.8 mmol) was added followed by KOH (236 mg, 4.2 mmol) and after stirring for an additional 18 h at RT, deprotection was complete. The reaction mixture was acidified with 1 N HCI, neutralized with sat. aqu. NaHCOs and extracted 3 x with EtOAc. After drying (MgSO4) and filtration, the material was purified by preparative reversed-phase HPLC to provide Example 27.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.56 (br. s., 1 H), 7.79 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.71 (s, 1 H), 7.31 (t, J = 8.9 Hz, 1 H), 7.16 (d, J = 2.5 Hz, 1 H), 6.75 (d, J = 2.3 Hz, 1 H), 6.26 (dd, J = 17.6, 16.4 Hz, 2H), 4.53 (q, J = 10.7 Hz, 2H), 4.12 (d, J = 0.8 Hz, 1 H), 3.92 - 4.04 (m, 1 H), 3.88 (d, J = 13.1 Hz, 1 H), 3.52 - 3.65 (m, 2H), 3.40 - 3.52 (m, 2H), 3.05 (dt, J = 11.9, 6.1 Hz, 2H), 2.18 - 2.33 (m, 2H), 2.01 - 2.18 (m, 4H), 1.96 (dt, J = 12.6, 6.8 Hz, 2H), 1.81 (dtt, J = 12.8, 8.5, 4.0 Hz, 1 H), 1.61

[0750] - 1.75 (m, 2H), 1.47 - 1.61 (m, 1 H), 1.19 (s, 3H). LCMS: m / z = 571.4 [M+H]+.

[0751] EXAMPLE 28

[0752] 1 -(9-((8-Ethynyl-3-hydroxynaphthalen-1 -yl)methyl)-6-(((2 / ?,7aS)-2-fluorotetrahydro-1 H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 6 (step 1) using ADDP / tri-n- butylphosphine for the Mitsunobu step using INT R2-5 and INT A-5 as the alcohol. The two regioisomers were obtained in an approximately 3 : 1 ratio. Removal of MOM and TIPS protecting groups was accomplished in a two-step process: the material from above (34 mg, 44 pmol) was dissolved in DCM (1 mL) and MeOH (100 pL) and 4M HCI in dioxane (331 pL, 1.32 mmol) was added. The MOM group was cleaved after stirring for 1 h at RT. The reaction mixture was concentrated under reduced pressure and the residue dissolved in 10% NH4OH in MeOH. Volatiles were then removed under reduced pressure and the residue dissolved in DMF (1 mL). CsF (33.5 mg, 220 pmol) was added, and the mixture stirred at RT overnight. The mixture was purified by preparative reversed-HPLC to provide Example 28 as an off-white solid (12 mg, 45% yield).1H NMR (400 MHz, MeOH-d4) 6 ppm 7.75 (dd, J = 8.4, 0.9 Hz, 1 H), 7.69 (s, 1 H), 7.62 (dd, J = 7.1 , 1.1 Hz, 1 H), 7.37 (dd, J = 8.1 , 7.4 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 6.22 - 6.35 (m, 2H), 5.40 (d, J = 53.0 Hx, 1 H), 4.58 (br. s., 1 H), 4.31 - 4.53 (m, 2H), 3.94 (ddt, J = 13.0, 6.6, 3.3 Hz, 1 H), 3.84 (dd, J = 13.0, 3.3 Hz, 1 H), 3.81 (s, 1 H), 3.63 - 3.70 (m, 1 H), 3.55

[0753] - 3.63 (m, 2H), 3.35 - 3.53 (m, 3H), 3.09 - 3.22 (m, 1 H), 2.29 - 2.58 (m, 2H), 2.19 - 2.29 (m, 1 H), 2.05 - 2.18 (m, 2H), 1.91 - 2.05 (m, 1 H), 1.75 - 1.89 (m, 1 H), 1.49 - 1.75 (m, 5H), 1.29 (s, 1 H), 1.19 (s, 3H). LCMS: m / z = 571.4 [M+H]+.

[0754] EXAMPLE 29

[0755] (R)-1-(9-((8-Ethynyl-3-hydroxynaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 28 using INT R2-6 and INT A-5 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.54 (br. s., 1 H), 7.75 (dd, J = 8.3, 0.6 Hz, 1 H), 7.72 (s, 1 H), 7.62 (dd, J = 7.1 , 1.1 Hz, 1 H), 7.37 (t, J = 7.6 Hz, 1 H), 7.14 (d, J = 2.4 Hz, 1 H), 6.70 (d, J = 2.4 Hz, 1 H), 6.29 (dd, J = 17.1 , 16.5 Hz, 2H), 4.63 (d, J = 11.8 Hz, 1 H), 4.57 (d, J = 11.8 Hz, 1 H), 4.00 (ddd, J = 12.9, 6.1 , 4.1 Hz, 1 H), 3.89 (d, J = 13.1 Hz, 1 H), 3.50 - 3.69 (m, 4H), 3.16 (dt, J = 11.4, 5.8 Hz, 2H), 2.24 - 2.39 (m, 2H), 2.08 - 2.24 (m, 4H), 1.96 - 2.08 (m, 2H), 1.81 (dtt, J = 12.8, 8.4, 4.0 Hz, 1 H), 1.63 - 1.75 (m, 2H), 1 .49 - 1.63 (m, 1 H), 1 .20 (s, 3H). LCMS: m / z = 553.3 [M+ H]+.

[0756] EXAMPLE 30

[0757] (R)-1-(9-((8-Ethynyl-3-hydroxynaphthalen-1-yl)methyl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 28 using INT R2-3 and INT A-5 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 7.75 (d, J = 8.1 Hz, 1 H), 7.69 (s, 1 H), 7.62 (dd, J = 7.1 , 1.0 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.13 (d, J = 2.5 Hz, 1 H), 6.68 (d, J = 2.4 Hz, 1 H), 6.21 -

[0758] 6.36 (m, 2H), 5.39 (dt, J = 53.4, 2.9 Hz, 1 H), 4.43 (d, J = 11.1 Hz, 1 H), 4.40 (d, J = 11.3 Hz, 1 H), 3.94 (ddd, J = 12.6, 6.4, 3.8 Hz, 1 H), 3.84 (d, J = 13.1 Hz, 1 H), 3.81 (s, 1 H), 3.56 - 3.70 (m, 2H),

[0759] 3.36 - 3.56 (m, 3H), 3.07 - 3.20 (m, 1 H), 2.18 - 2.56 (m, 3H), 2.04 - 2.17 (m, 2H), 1.90 - 2.03 (m, 1 H), 1.75 - 1.87 (m, 1 H), 1.48 - 1.75 (m, 4H), 1.29 (br. s., 1 H), 1.19 (s, 3H). LCMS: m / z = 571.4 [M+H]+.

[0760] EXAMPLE 31

[0761] 4-((2-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 9H-purin-9-yl)methyl)-5-ethynylnaphthalen-2-ol. This example was prepared according to the procedure described for Example 10 using INT R2-7, ADDP and tri-n-butyl phosphine for the Mitsunobu step. Removal of protecting groups was accomplished as described for Example 28.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.48 (br. s., 1 H), 7.87 (s, 1 H), 7.74 (d, J = 8.1 Hz, 1 H), 7.62 (d, J = 6.5 Hz, 1 H), 7.37 (t, J = 7.7 Hz, 1 H), 7.07 - 7.17 (m, 1 H), 6.66 (br. s., 1 H), 6.33 (s, 2H), 4.53 - 4.67 (m, 2H), 3.85 (s, 1 H), 3.69 - 3.83 (m, 4H), 3.37 - 3.56 (m, 2H), 3.19 - 3.29 (m, 2H), 1 .90 - 2.45 (m, 12H) [two protons under the solvent water peak], LCMS: m / z = 550.2 [M+H]+. EXAMPLE 32

[0762] 4-((6-(2-(1H-Pyrazol-1-yl)ethoxy)-2-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9H-purin-9- yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-8 and INT A-9 as alcohol.1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.24 (s, 1 H), 7.96 (s, 1 H), 7.90 (dd, J = 9.2, 6.1 Hz, 1 H), 7.78 (d, J = 2.1 Hz, 1 H), 7.43 - 7.50 (m, 2H), 7.15 (d, J = 2.4 Hz, 1 H), 6.35 - 6.41 (m, 1 H), 6.25 (t, J = 2.0 Hz, 1 H), 6.20 (s, 2H), 4.87 (s, 1 H), 4.79 - 4.85 (m, 2H), 4.58 (t, J = 5.3 Hz, 2H), 4.15 (d, J = 12.1 Hz, 2H), 3.59 (br. s., 2H), 2.97 (d, J = 12.8 Hz, 2H), 1.61 - 1.73 (m, 2H), 1.49 - 1.59 (m, 2H). LCMS: m / z = 539.2 [M+H]+.

[0763] EXAMPLE 33

[0764] 4-((6-(2-(1H-lmidazol-1-yl)ethoxy)-2-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9H-purin-9- yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-9 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.53 (br. s., 1 H), 7.91 (s, 1 H), 7.79 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.75 (s, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.25 (s, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 6.91 (s, 1 H), 6.61 (d, J = 2.3 Hz, 1 H), 6.31 (s, 2H), 4.59 (br. s., 2H), 4.44 - 4.56 (m, 4H), 4.17 (s, 1 H), 4.01 (br. s., 2H), 3.13 - 3.24 (m, 2H), 1.96 - 2.05 (m, 2H), 1.80 - 1.90 (m, 2H). LCMS: m / z = 539.3 [M+ H]+.

[0765] EXAMPLE 34

[0766] 4-((2-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)- 9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-7 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.41 (br. s., 1 H), 7.80 (s, 1 H), 7.70 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.23 (t, J = 8.9 Hz, 1 H), 7.05 (d, J = 2.3 Hz, 1 H), 6.57 (br. s., 1 H), 6.23 (s, 2H), 4.83 - 4.87 (m, 1 H), 4.54 (s, 2H), 4.07 (s, 1 H), 3.78 - 3.92 (m, 1 H), 3.51 - 3.71 (m, 4H), 3.25 - 3.35 (m, 2H), 3.06 - 3.17 (m, 2H), 2.17 - 2.27 (m, 2H), 1.90 - 2.15 (m, 8H), 1.79 - 1.90 (m, 2H). LCMS: m / z = 568.2 [M+H]+.

[0767] EXAMPLE 35

[0768] 4-((2-(2,5-Diazabicyclo[2.2.2]octan-2-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin- 7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-10 and INT A- 9 as alcohol.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.53 (br. s., 1 H), 7.86 (s, 1 H), 7.79 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.14 (d, J = 2.3 Hz, 1 H), 6.63 (br. s., 1 H), 6.32 (s, 2H), 5.26 - 5.47 (m, 1 H), 4.94 (br. s., 1 H), 4.29 - 4.43 (m, 2H), 4.17 (s, 1 H), 3.93 (d, J = 12.4 Hz, 1 H), 3.68 - 3.82 (m, 2H), 3.35 - 3.46 (m, 3H), 3.02 - 3.13 (m, 1 H), 2.00 - 2.46 (m, 8H), 1.90 - 1.99 (m, 3H) [one proton is under the solvent peak], LCMS: m / z = 586.2 [M+H]+.

[0769] EXAMPLE 36

[0770] 4-((6-(2-(2-Oxa-5-azabicyclo[2.2.1]heptan-5-yl)ethoxy)-2-((1R,5S)-3,8-diazabicyclo[3.2.1] octan-3-yl)-9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-11 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.52 (br. s., 1 H), 7.89 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.33 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 6.67 (d, J = 2.1 Hz, 1 H), 6.33 (s, 2H), 4.67 (t, J = 5.6 Hz, 2H), 4.57 (d, J = 13.6 Hz, 2H), 4.44 (s, 1 H), 4.17 (s, 1 H), 3.99 - 4.08 (m, 3H), 3.78 (s, 1 H), 3.66 (dd, J = 8.2, 1.6 Hz, 1 H), 3.02 - 3.26 (m, 5H), 2.78 (d, J = 10.6 Hz, 1 H), 1.97 - 2.06 (m, 2H), 1.84 - 1.97 (m, 3H), 1.81 (d, J = 10.1 Hz, 1 H). LCMS: m / z = 570.2 [M+H]+.

[0771] EXAMPLE 37

[0772] 4-((6-(3-amino-3-methylazetidin-1-yl)-2-((1R,5S)-3,8-diazabicyclo[3.2.1]octan-3-yl)-9H- purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-12 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.52 (br. s., 1 H), 7.79 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.75 (s, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.13 (d, J = 2.4 Hz, 1 H), 6.60 (d, J = 2.0 Hz, 1 H), 6.27 (s, 2H), 4.59 (d, J = 12.8 Hz, 2H), 4.24 (br. s., 4H), 4.17 (s, 1 H), 4.00 (br. s., 2H), 3.15 (d, J = 13.9 Hz, 2H), 1.99 (d, J = 9.0 Hz, 2H), 1.86 - 1.95 (m, 2H), 1.56 (s, 3H). LCMS: m / z = 513.2 [M+H]+.

[0773] EXAMPLE 38

[0774] 2-((S)-4-(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)methyl)-6-(((2R,7aS)-2-fluoro- tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)piperazin-2-yl)acetonitrile. This example was prepared according to the procedure described for Example 31 using INT R2-13 and INT A-9 as an alcohol.1H NMR (400 MHz, MeOH-d4) 5 ppm 7.85 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.17 (br. s, 1 H), 6.78 (s, 1 H), 6.30 (s, 2H), 5.42 - 5.62 (m, 1 H), 4.56 - 4.72 (m, 3H), 4.39 (d, J = 13.3 Hz, 1 H), 4.13 (s, 1 H), 3.69 - 4.05 (m, 3H), 3.36 - 3.43 (m, 1 H), 3.19 - 3.28 (m, 1 H), 3.00 - 3.17 (m, 3H), 2.47 - 2.87 (m, 7H), 2.34 - 2.45 (m, 1 H), 2.07 - 2.33 (m, 3H). LCMS: m / z = 599.3 [M+H]+. EXAMPLE 39

[0775] 4-(6-(Benzylthio)-9-((8-ethylnaphthalen-1-yl)methyl)-9H-purin-2-yl)-1,4-oxazepane

[0776] (Example 39A). To a solution of INT R4-2 (70 mg, 163 pmol) and 1 ,4-oxazepane hydrochloride (27 mg, 196 pmol) in THF (1.63 mL) was added NaHCOs (16.5 mg, 196 pmol) and the reaction mixture was stirred at 80 °C for 16 h. Then, a drop of water was added to solubilize all the solids and the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (20-100% EtOAc in hexanes) to afford Example 39A (53 mg, 64% yield). LCMS: m / z = 510.3 [M+H]+.

[0777] 4-(9-((8-Ethylnaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H- purin-2-yl)-1,4-oxazepane (Example 39). The example was prepared according to the procedure described for INT R2-1 (steps 3 and 4).1H NMR (400 MHz, MeOH-ck) 6 ppm 8.53 (br. s., 1 H), 7.91 (d, J = 8.1 Hz, 1 H), 7.80 (dd, J = 3.2, 6.4 Hz, 1 H), 7.56 (s, 1 H), 7.35 - 7.47 (m, 3H), 7.19 (d, J = 7.0 Hz, 1 H), 5.92 (s, 2H), 4.63 (s, 2H), 3.90 (br. s., 4H), 3.76 (br. s., 2H), 3.63 - 3.72 (m, 4H), 3.20 - 3.28 (m, 2H), 3.11 - 3.19 (m, 2H), 2.28 - 2.39 (m, 2H), 2.13 - 2.26 (m, 4H), 2.03 - 2.12 (m, 2H), 1.91 (br. s., 2H), 1.33 (t, J = 7.4 Hz, 3H). LCMS: m / z = 527.4 [M+H]+.

[0778] EXAMPLE 40

[0779] 2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-6-

[0780] ( (tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine. This example was prepared according to the procedure described for Example 39 using ('lR,4R)-tert- butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as amine followed by Boc deprotection in DCM using 4M HCI in dioxane.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.47 (s, 2H), 7.90 (d, J = 8.0 Hz, 1 H), 7.81 (t, J = 4.8 Hz, 1 H), 7.70 (s, 1 H), 7.45 (d, J = 4.9 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1 H), 7.09 (d, J = 6.8 Hz, 1 H), 5.98 (s, 2H), 4.97 - 5.12 (m, 1 H), 4.63 - 4.75 (m, 2H), 4.44 (s, 1 H), 3.64 - 3.83 (m, 4H), 3.35 (br. s., 2H), 3.24 - 3.30 (m, 2H), 3.16 - 3.24 (m, 2H), 2.34 (td, J = 6.0, 12.4 Hz, 2H), 2.16 - 2.28 (m, 5H), 2.06 - 2.15 (m, 2H), 2.02 (d, J = 11.3 Hz, 1 H), 1.37 (t, J = 7.4 Hz, 3H). LCMS: m / z = 524.4 [M+H]+. EXAMPLE 41

[0781] 2-((1 S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-9-((8-ethylnaphthalen-1-yl)methyl)-6-

[0782] ((tetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purine. This example was prepared according to the procedure described for Example 40 using (1 S,4S)-terf-butyl 2,5- diazabicyclo[2.2.1]heptane-2-carboxylate as amine followed by a Boc deprotection.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.46 (br. s., 2H), 7.90 (d, J = 8.3 Hz, 1 H), 7.81 (t, J = 4.2 Hz, 1 H), 7.69 (s, 1 H), 7.44 (d, J = 4.9 Hz, 2H), 7.37 (t, J = 7.7 Hz, 1 H), 7.10 (d, J = 6.7 Hz, 1 H), 5.98 (s, 2H), 4.98 - 5.14 (m, 1 H), 4.63 - 4.79 (m, 2H), 4.46 (br. s., 1 H), 3.66 - 3.85 (m, 4H), 3.34 (br. s., 2H), 3.24 - 3.30 (m, 2H), 3.16 - 3.24 (m, 2H), 2.29 - 2.42 (m, 2H), 2.16 - 2.28 (m, 5H), 2.07 - 2.15 (m, 2H), 1 .99 - 2.07 (m, 1 H), 1 .37 (t, J = 7.4 Hz, 3H). LCMS: m / z = 524.4 [M+ H]+.

[0783] EXAMPLE 42

[0784] INT R4-8 Example 42A Example 42

[0785] Step 1

[0786] 5-(9-((8-Ethynyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)methyl)-6-(((2 / ?,7aS)-2- fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)tetrahydropyrrolo[3, 4- c]pyrrole-1,3(2H,3aH)-dione (Example 42A). To a solution of (2R,7aS)-2-fluorohexahydro-1 / 7- pyrrolizine-7a-methanol (12.4 mg, 77.7 pmol) and INT R4-8 (28 mg, 35.3 pmol) in THF (1.8 mL) was added 1M NaHMDS (124 pL, 124 pmol) and the reaction mixture was stirred for 5 min. Then, the reaction mixture was concentrated under reduced pressure. The crude was purified by flash column chromatography on silica gel (20-100% EtOAc-in hexanes followed by 4-20% MeOH in dichloromethane) to afford Example 42A (8 mg, 40% pure, 14% yield). LCMS: m / z = 658.4 [M+H]+.

[0787] Step 2

[0788] 5-(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)methyl)-6-(((2 / ?,7aS)-2-fluorotetra- hydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)tetrahydropyrrolo[3,4-c]pyrrole- 1,3(2H,3aH)-dione (Example 42). The MOM group in Example 42a was removed using 4N HCI in dioxane to provide Example 42.1H NMR (400 MHz, MeOH-d4) 6 ppm 7.80 (dd, J = 5.4, 9.2 Hz, 1 H), 7.75 (s, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.18 (d, J = 2.5 Hz, 1H), 6.79 (d, J = 2.3 Hz, 1H), 6.28 (s, 2H), 5.38 - 5.60 (m, 1H), 4.53 - 4.66 (m, 2H), 4.30 (d, J = 11.0 Hz, 2H), 4.06 (s, 1H), 3.40 - 3.92 (m, 8H), 2.57 - 2.70 (m, 1H), 2.41 - 2.53 (m, 1H), 2.30 - 2.40 (m, 1H), 2.19 - 2.29 (m, 2H), 2.01 - 2.16 (m, 1H). LCMS: m / z = 614.4 [M+H]+.

[0789] EXAMPLE 43

[0790] (S)-1-(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)methyl)-6-(((2R,7aS)-2- fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol.

[0791] This example was prepared according to the procedure described for Example 28 using INT R2- 14 and INTA-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.48 (s, 1H), 7.79 (dd, J = 5.9, 9.1 Hz, 1H), 7.71 (s, 1H), 7.31 (t, J = 8.9 Hz, 1H), 7.16 (d, J = 2.4 Hz, 1H), 6.75 (d, J = 2.0 Hz, 1H), 6.26 (d, J = 2.6 Hz, 2H), 5.36 - 5.58 (m, 1H), 4.60 (d, J = 11.5 Hz, 1H), 4.45 - 4.52 (m, 1H), 4.12 (s, 1H), 3.92 - 4.05 (m, 1H), 3.83 - 3.92 (m, 1H), 3.68 - 3.83 (m, 1H), 3.52 - 3.64 (m, 3H), 3.23- 3.29 (m, 1H), 2.61 (d, J = 4.5 Hz, 1H), 2.38 - 2.52 (m, 1H), 2.27 - 2.37 (m, 1H), 2.15 - 2.26 (m, 2H), 1.99- 2.13 (m, 1H), 1.80 (td, J = 4.3, 8.6 Hz, 1H), 1.62- 1.73 (m, 2H), 1.56 (ddd, J = 3.4, 6.4, 9.6 Hz, 1H), 1.19 (s, 3H). LCMS: m / z = 589.3 [M+H]+.

[0792] EXAMPLE 44

[0793] 1-(9-((8-Ethynyl-7-fluoro-3-hydroxynaphthalen-1-yl)methyl)-6-(((2R,7aS)-2-fluoro- tetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 28 using INT R2-5 and INTA-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 7.79 (dd, J = 9.1, 5.9 Hz, 1H), 7.70 (s, 1H), 7.32 (t, J = 8.9 Hz, 1H), 7.16 (d, J = 2.5 Hz, 1H), 6.73 (d, J = 2.3 Hz, 1H), 6.26 (s, 2H), 5.41 (dt, J = 53.7, 3.2 Hz, 1H), 4.58 (s, 1 H), 4.33 - 4.53 (m, 2H), 4.12 (s, 1 H), 3.89 - 4.01 (m, 1H), 3.85 (dd, J = 13.2, 2.9 Hz, 1H), 3.55 - 3.71 (m, 3H), 3.35 - 3.55 (m, 3H), 3.08 - 3.21 (m, 1H), 2.20 - 2.57 (m, 3H), 2.06 - 2.18 (m, 2H), 1.90 - 2.06 (m, 1H), 1.80 (dtd, J = 12.7, 8.4, 4.0 Hz, 1H), 1.62 - 1.74 (m,2H), 1.48-1.62 (m, 1H), 1.29 (s, 1H), 1.19 (s,3H) 1 extra H. LCMS: m / z = 589.3 [M+H]+.

[0794] EXAMPLE 45

[0795] 1-(9-((8-Ethynyl-3-hydroxynaphthalen-1-yl)methyl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-2-yl)-3-methylpiperidin-3-ol. This example was prepared according to the procedure described for Example 28 using INT R2-4 and INT A-5 as alcohol.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.54 (br. s., 1H), 7.75 (d, J = 8.1 Hz, 1H), 7.71 (s, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.37 (t, J = 7.7 Hz, 1H), 7.13 (d, J = 2.3 Hz, 1H), 6.70 (d, J = 1.9 Hz, 1H), 6.16 - 6.40 (m, 2H), 4.53 (q, J = 11.5 Hz, 2H), 3.92 - 4.07 (m, 1 H), 3.87 (d, J = 13.0 Hz, 1 H), 3.81 (s, 1 H), 3.54 - 3.69 (m, 2H), 3.42 - 3.53 (m, 2H), 2.96 - 3.11 (m, 2H), 2.26 (dq, J = 12.0, 6.0 Hz, 2H), 2.02 - 2.19 (m, 4H), 1.90 - 2.02 (m, 2H), 1.75 - 1.87 (m, 1 H), 1.62 - 1.75 (m, 2H), 1.47 - 1.62 (m, 1 H), 1.19 (s, 3H). LCMS: m / z = 553.4 [M+H]+.

[0796] EXAMPLE 46

[0797] 3-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-chloro-4-(trifluoromethyl)phenol. This example was prepared according to the procedure described for Example 31 using INT A-12 as alcohol and deprotected using 4M HCI in dioxane.1H NMR (400 MHz, MeOH-ck) 6 ppm 8.52 (br. s., 1 H), 8.01 (s, 1 H), 6.91 (d, J = 2.1 Hz, 1 H), 6.31 (d, J = 1.9 Hz, 1 H), 5.52 (d, J = 1.6 Hz, 2H), 4.65 (s, 2H),

[0798] 4.54 (d, J = 13.5 Hz, 2H), 3.98 (br. s., 2H), 3.69 (dt, J = 11.6, 6.6 Hz, 2H), 3.16 - 3.28 (m, 4H), 2.33 (dt, J = 12.9, 6.4 Hz, 2H), 2.13 - 2.28 (m, 4H), 2.04 - 2.13 (m, 2H), 1.94 - 2.04 (m, 2H), 1.78 - 1.89 (m, 2H). LCMS: m / z = 578.3 [M+H]+.

[0799] EXAMPLE 47

[0800] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(2-(dimethylamino)ethoxy)-9H-purin-9- yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 31 using INT R2-15 and INT A-9 as alcohol. Deprotection was carried out as follows: the crude material from above (53 mg, 65 pmol) was dissolved in MeCN (4 mL) and CsF (180 mg, 1.19 mmol) was added. After stirring for 16 h at RT, removal of the TIPS protecting group was complete. The solvent was evaporated under reduced pressure, the residue suspended in EtOAc and filtered. The filtrate was concentrated and dissolved in 4M HCI in dioxane and MeOH (100 pL) and stirred for 1 h at RT when the Boc and MOM groups were cleaved. Volatiles were removed under reduced pressure and the residue redissolved in MeOH and the pH adjusted to pH 8 with sat. aq. NaHCOs solution. Purification by preparative reversed phase HPLC provided Example 47 (17.4 mg, 28% yield) as an amorphous white solid.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.54 (br. s., 1 H), 7.88 (s, 1 H), 7.79 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.32 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H), 6.69 (d, J = 2.1 Hz, 1 H), 6.32 (s, 2H), 4.71 (t, J = 5.6 Hz, 2H), 4.52 (d, J = 13.1 Hz, 2H), 3.95 (br. s., 2H), 3.20 (d, J = 13.6 Hz, 2H), 3.08 (t, J = 5.5 Hz, 2H),

[0801] 2.55 (s, 6H), 1.91 - 2.06 (m, 2H), 1.81 - 1.91 (m, 2H). LCMS: m / z = 516.3 [M+H]+.

[0802] EXAMPLE 48

[0803] 4-((2-((1 / ?,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((( / ?)-1-methylpyrrolidin-3-yl)oxy)-9H- purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 47 using INT R2-16 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s., 1 H), 7.93 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.33 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.3 Hz, 1 H), 6.68 (s, 1 H), 5.79 (br. s., 1 H), 4.55 (d, J = 13.9 Hz, 2H), 4.18 (s, 1 H), 4.05 (br. s., 2H), 3.35 - 3.42 (m, 2H), 3.24 (d, J = 14.0 Hz, 2H), 3.02 - 3.09 (m, 1 H), 2.73 (s, 3H), 2.66 (s, 1 H), 2.57 (dq, J = 14.5, 7.5 Hz, 1 H), 2.23 - 2.37 (m, 1 H), 1.99 - 2.11 (m, 2H), 1.89 (d, J = 7.6 Hz, 2H). LCMS: m / z = 528.2 [M+H]+.

[0804] EXAMPLE 49

[0805] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-(3-(dimethylamino)propoxy)-9H-purin-9- yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 47 using INT R2-17 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.51 (s, 2H), 7.91 (s, 1 H), 7.80 (dd, J = 9.1 , 5.9 Hz, 1 H), 7.33 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.4 Hz, 1 H), 6.68 (d, J = 2.3 Hz, 1 H), 6.33 (s, 2H), 4.61 (t, J = 5.9 Hz, 2H), 4.56 (d, J = 13.4 Hz, 2H), 4.17 (s, 1 H), 4.02 (br. s., 2H), 3.23 (d, J = 13.9 Hz, 2H), 3.12 - 3.19 (m, 2H), 2.75 (s, 6H), 2.18 - 2.27 (m, 2H), 1.95 - 2.07 (m, 2H), 1.83 - 1.93 (m, 2H). LCMS: m / z = 530.3 [M+H]+.

[0806] EXAMPLE 50

[0807] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((1-methylpiperidin-4-yl)oxy)-9H-purin- 9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol. This example was prepared according to the procedure described for Example 47 using INT R2-18 and INT A-9 as alcohol.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.51 (s, 2H), 7.93 (s, 1 H), 7.80 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.33 (t, J = 8.9 Hz, 1 H), 7.15 (d, J = 2.5 Hz, 1 H), 6.68 (d, J = 2.1 Hz, 1 H), 6.33 (s, 2H), 5.55 (br. s., 1 H), 4.54 (d, J = 12.9 Hz, 2H), 4.19 (s, 1 H), 4.04 (br. s., 2H), 3.22 (s, 2H), 3.25 (s, 2H), 3.06 (br. s., 2H), 2.71 (s, 3H), 2.66 (s, 1 H), 2.24 (br. s., 1 H), 2.19 (br. s., 4H), 1.97 - 2.10 (m, 2H), 1.83 - 1.93 (m, 2H). LCMS: m / z = 542.3 [M+H]+.

[0808] EXAMPLE 51

[0809] 4-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)benzo[cf]thiazol-2-amine. This example was prepared according to the procedure described for Example 28 using INT A-13 as alcohol. The product was obtained as a 3 : 1 mixture of regioisomers favoring the desired one. Removal of Boc protecting groups was accomplished using 4N HCI in dioxane.1H NMR (400 MHz, MeOH-d4) 5 ppm 8.49 (s, 1 H), 8.19 (s, 1 H), 7.55 (dd, J = 7.8, 1.1 Hz, 1 H), 7.17 (d, J = 6.6 Hz, 1 H), 6.99 (t, J = 7.7 Hz, 1 H), 5.58 (s, 2H), 4.59 - 4.73 (m, 4H), 4.11 (br. s., 2H), 3.72 (dt, J = 11.8, 6.7 Hz, 3H), 3.15 - 3.29 (m, 3H), 2.31 (dd, J = 12.4, 6.7 Hz, 2H), 2.02 - 2.26 (m, 8H), 1.90 (d, J = 7.9 Hz, 2H).

[0810] LCMS: m / z = 532.2 [M+H]+.

[0811] EXAMPLE 52

[0812] Step 1 tert-Butyl (1R,5S)-3-(6-(benzylthio)-9-((6-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl) methyl)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 52A). This intermediate was prepared according to the procedure described for INT R1-1 (step 2) using INT R2-1B as substrate and INT A-14 as the alcohol. The product was obtained as a separable mixture of isomers favoring the desired one.1H NMR (400 MHz, CDCI3) 6 ppm 7.95 (d, J = 9.1 Hz, 1 H), 7.71 (d, J = 8.4 Hz, 1H), 7.49 (s, 1 H), 7.45 (d, J = 7.4 Hz, 2H), 7.38 (t, J = 7.6 Hz, 1H), 7.30 (t, J = 7.8 Hz, 2H), 7.19 - 7.26 (m, 3H), 7.08 (dd, J = 9.1, 2.4 Hz, 1 H), 5.61 (s, 2H), 4.56 (s, 2H), 4.54 (d, J = 12.5 Hz, 2H), 4.35 (br. s., 2H), 3.20 (br. s., 2H), 1.82 - 2.00 (m, 2H), 1.64 - 1.82 (m, 2H), 1.51 (s, 9H), 1.02 (s, 9H), 0.25 (s, 6H).

[0813] Step 2 tert-Butyl (1R,5S)-3-(6-(benzylsulfonyl)-9-((6-((tert-butyldimethylsilyl)oxy) naphthalen-1- yl)methyl)-9H-purin-2-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (Example 52B). This intermediate was prepared by oxidation of 52A with MCPBA according to the procedure described for INT R2-1C. Mixture of sulfone (major): LCMS: m / z = 755.4 [M+H]+and sulfoxide (minor): LCMS: m / z = 739.4 [M+H]+. Step 3 tert-Butyl (1R,5S)-3-(9-((6-((tert-butyldimethylsilyl)oxy)naphthalen-1-yl)methyl)-6-((tetra hydro-1 H-pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-2-yl)-3,8-diazabicyclo [3.2.1]octane-8- carboxylate (Example 52C). This intermediate was prepared from 52B according to the procedure described for INT R2-1. The product was obtained as a mixture of 52C and partially deprotected phenol that was used directly in step 4. LCMS: m / z = 741.0 [M+H]+.

[0814] Step 4

[0815] 5-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)naphthalen-2-ol (Example 52). This example was prepared according to the procedure described for Example 1 (step 2).1H NMR (400 MHz, MeOH-ck) 6 ppm 8.52 (br. s., 2H), 8.10 (d, J = 9.0 Hz, 1 H), 7.97 (s, 1 H), 7.66 (d, J = 8.4 Hz, 1 H), 7.35 (t, J = 7.7 Hz, 1 H), 7.21 (d, J = 7.0 Hz, 1 H), 7.16 (d, J = 2.4 Hz, 1 H), 7.09 (dd, J = 9.1 , 2.5 Hz, 1 H), 5.76 (s, 2H), 4.56 - 4.69 (m, 4H), 4.03 (br. s., 2H), 3.68 (dt, J = 12.5, 6.5 Hz, 2H), 3.18 - 3.30 (m, 4H), 2.31 (dt, J = 12.8, 6.4 Hz, 2H), 2.12 - 2.26 (m, 4H), 1.97 - 2.12 (m, 4H), 1.88 (dd, J = 13.1 , 5.4 Hz, 2H). LCMS: m / z = 526.3 [M+H]+.

[0816] EXAMPLE 53

[0817] 3-((2-((1R,5S)-3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-((tetrahydro-1H-pyrrolizin-7a(5H)- yl)methoxy)-9H-purin-9-yl)methyl)-5-chloro-4-((1 S,2S)-2-methylcyclopropyl) phenol . This example was prepared from INT R2-1 using the procedure described for Example 6 (step 1) using ADDP / tri-n-butylphosphine for the Mitsunobu step and using INT A-15 as the alcohol. Removal of the MOM and Boc protecting groups was performed using 1 :2 TFA-DCM at room temperature.1H NMR (400 MHz, MeOH-d4) 6 ppm 8.50 (br. s, 1 H), 8.01 (s, 1 H), 6.74 (d, J = 2.5 Hz, 1 H), 6.23 (d, J = 2.4 Hz, 1 H), 5.38 - 5.65 (m, 2H), 4.63 (s, 2H), 4.53 (d, J = 1.0 Hz, 2H), 3.95 (s, 2H), 3.61 - 3.75 (m, 2H), 3.16 - 3.28 (m, 4H), 2.18 (d, J = 10.6 Hz, 12H), 1.28 (d, J = 5.9 Hz, 4H), 1.00 - 1.15 (m, 1 H), 0.85 - 0.99 (m, 2H). LCMS: m / z = 564.3 [M+H]+.

[0818] EXAMPLE 54

[0819] 4-((2-((1 S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-6-(((2R,7aS)-2-fluorotetrahydro-1H- pyrrolizin-7a(5H)-yl)methoxy)-9H-purin-9-yl)methyl)-5-ethynyl-6-fluoronaphthalen-2-ol.

[0820] This example was prepared according to the procedures described for Example 6 and Example 10 using INT R2-19 and INT A-9 as the alcohol.1H NMR (400 MHz, DMSO-cfe) 6 ppm 8.32 (s, 1 H...

Claims

1. CLAIMS1. A compound of Formula I:wherein:X1is N or C(R4);X2is N or C(R5);X3is N, CH, or C-halo, provided that at least one of X2or X3is N;R1is H, halo, OH, NH2, or a substituted or unsubstituted group selected from OR6, SR6, NHR6, N(R6)2, C(O)Ci-4alkyl, C(O)Ci-4alkenyl, C4-9cycloalkyl, C4- heterocycloalkyl, Ce-waryl, and Cs-wheteroaryl, or a Ci-3alkyl group substituted with an optionally substituted C3- gcycloalkyl, C4-9heterocycloalkyl, Ce- aryl, and Cs-wheteroaryl;R2is selected from substituted Cs-wcycloalkyl, C4-wheterocycloalkyl, Ce-waryl, and Cs- wheteroaryl;R3is OH, halo, SR7, OR7, NHR7, N(R7)2, or an optionally substituted Ci-salkyl;R4is H, halo, or a substituted or unsubstituted Ci-4alkyl;R5is H, CN, halo, CONH2, CONHR8, CON(R8)2, CO2R8, or SO2R8;R6is independently in each occurrence a substituted or unsubstituted group selected from Ci-salkyl, C4-9cycloalkyl, C4-9heterocycloalkyl, or when two R6are present on a nitrogen atom, then the two R6may be taken together with their adjacent nitrogen atom to form an optionally substituted C4-wheterocycloalkyl;R7is independently in each occurrence an optionally substituted Ci-salkyl, C2-salkenyl, C2. salkynyl, or a group of formula -(C(R9)2)m-N(R10)2, or when two R7are present on a nitrogen atom, then the two R7may be taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl;R8is a substituted or unsubstituted Ci-3alkyl;R9is independently in each occurrence selected from H, halo, and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group;R10is independently in each occurrence selected from H and an optionally substituted Cisalkyl, C^cycloalkyl, or C^heterocycloalkyl group; or at least two R9, or two R10, or at least one R9and one R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-i2heterocycloalkyl group; m is an integer selected from 1 to 4 (e.g. 2 or 3);L is a Ci-3alkylene optionally substituted with a Ci-4alkyl, or CChCi^alkyl group, the alkyl being optionally further substituted, preferably L is an optionally substituted Cialkylene; or a pharmaceutically acceptable salt and / or solvate thereof; wherein when X1, X2, and X3are each N, L-R2is benzyl, and R3is 4-amino-4-methyl-1- piperidine or 2,7-diazaspiro[3.5]nonan-7-yl (spiro[azetidienpiperidinyl]), then R1is other than -N(benzyl)2.

2. The compound of claim 1 , wherein said compound of Formula I is a compound of Formula l-A:Formula l-A wherein L, R1, R2, and R3are as defined in claim 1 , or a pharmaceutically acceptable salt and / or solvate thereof.

3. The compound of claim 1 , wherein said compound of Formula I is a compound of Formula l-B:wherein L, R1, R2, R3, and R5are as defined in claim 1 , or a pharmaceutically acceptable salt and / or solvate thereof.

4. The compound of claim 1 , wherein said compound of Formula I is a compound of Formula l-C:wherein L, R1, R2, and R3are as defined in claim 1, or a pharmaceutically acceptable salt and / or solvate thereof.

5. The compound of claim 1 , wherein said compound of Formula I is a compound of FormulaI-D:wherein L, R1, R2, R3, and R4are as defined in claim 1 , or a pharmaceutically acceptable salt and / or solvate thereof.

6. The compound of claim 1 , wherein said compound of Formula I is a compound of Formula l-E:Formula l-E wherein:R1, R2, X1, X2, and X3are as defined above and hereinbelow;R9and R9’ are independently in each occurrence selected from H, halo, and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; and R10and R10’ are independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; orR9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C^heterocycloalkyl group, and R10and R10’ are independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C^cycloalkyl, or C^heterocycloalkyl group; orR10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9and R9’ are independently in each occurrence selected from H, halo, and an optionally substituted Ci- salkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group; orR9and R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9’ is selected from H, halo, and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, and R10’ is selected from H and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4- gheterocycloalkyl group; orR9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-gheterocycloalkyl group, and R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group; orR9and R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, and R9’ and R10’ are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4- i2heterocycloalkyl group, and p is a number selected from 0, 1 , and 2; or a pharmaceutically acceptable salt and / or solvate thereof.

7. The compound of claim 6, wherein R9and R9’ are each independently selected from H, Cisalkyl, or R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-ecycloalkyl or C4-6heterocycloalkyl group.

8. The compound of claim 6 or 7, wherein R10and R10’ are each an optionally substituted Cisalkyl or R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group.

9. The compound of claim 6, wherein R9and R9’ are taken together with their adjacent carbon atom to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4- gheterocycloalkyl group, and R10and R10’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group.

10. A compound of Formula II:Formula II wherein L, R1, R2, R3, and X3are as defined in claim 1 , and R11is defined as for R1, wherein at least one of R1and R11is H, or a pharmaceutically acceptable salt and / or solvate thereof.

11. A compound of Formula III:Formula III wherein:R1, R2, R3, and X3are as defined in claim 1 ;X4is N, CH, C-halo, C-OCi-3alkyl, C-OC3.5cycloalkyl, C-CN, C-C(O)NH2, C-Ci-3alkyl, or C- C3-5cycloalkyl, wherein the alkyl or cycloalkyl is optionally substituted; andR11is defined as for R1, wherein at least one of R1and R11is H;R12is selected from H, halo, or optionally substituted Ci-3alkyl; or a pharmaceutically acceptable salt and / or solvate thereof.

12. The compound of claim 10 or 11 , wherein R3is NHR7or N(R7)2.

13. The compound of any one of claims 10 to 12, wherein X3is N.

14. The compound of any one of claims 1 and 6 to 9, wherein X2is N.

15. The compound of any one of claims 1 and 6 to 9, wherein X2is CH, CCN, CCONH2, CCO2R8, or CSO2R8, preferably X2is N, CH, CCN, or C-halo.

16. The compound of any one of claims 1 to 15, wherein R1is H, halo, OH, or NH2.

17. The compound of any one of claims 1 to 15, wherein R1is a substituted or unsubstituted group selected from NHR6, N(R6)2, C^cycloalkyl, and C4- heterocycloalkyl.

18. The compound of claim 17, wherein R1is N(R6)2.

19. The compound of claim 17, wherein R1is N(R6)2and the two R6are taken together with their adjacent nitrogen atom to form an optionally substituted C4- heterocycloalkyl.

20. The compound of claim 19, wherein the optionally substituted C4- heterocycloalkyl is a monocyclic C4-7heterocycloalkyl or a bridged, fused or spiro bicyclic Cy-wheterocycloalkyl.

21. The compound of any one of claims 17 to 20, wherein R1is substituted with at least one group selected from halo, oxo, CN, OR13, N(R13)2, N(R13)C(O)R13, OC(O)R13, C(O)R13, C(O)OR13, CON(R13)2, SO2R13, SO2OR13, SO2N(R13)2, or R13, wherein R13is H or a Ci-5alkyl, Cs-ecycloalkyl, C^heteroalkyl, or Cs-gheteroaryl group optionally substituted with halo, oxo, CN, OH, OCi.5alkyl, NH2, N(Ci-5alkyl)2, NHC(O)Ci-5alkyl, C(O)H, OC(O)Ci-5alkyl, C(O)Ci- salkyl, C(O)OCi.5alkyl, CON(Ci-5alkyl)2, C(O)NH2, SO2Ci-5alkyl, SO2OCi-5alkyl, SO2NH2and SO2N(Ci-5alkyl)2.wherein - - designates a bound between R1and the rest of the compound.

23. The compound of claim 22, wherein R1is selected from:wherein - - designates a bound between R1and the rest of the compound.

24. The compound of claim 22, wherein R1is selected from:wherein - - designates a bound between R1and the rest of the compound.

25. The compound of any one of claims 1 to 24, wherein R2is selected from substituted Cs- locycloalkyl and C4- heterocycloalkyl, the cycloalkyl or heterocycloalkyl being saturated or partially unsaturated, preferably partially unsaturated.

26. The compound of any one of claims 1 to 24, wherein R2is selected from substituted Ce- aryl and Cs-wheteroaryl.

27. The compound of claim 26, wherein R2is selected from:X5is NH, O, or S;X6and X7are each independently CH, C(R14), or N;R14is selected from halo, CN, OR15, N(R15)2, N(R15)C(O)R15, OC(O)R15, C(O)R15, C(O)OR15, CON(R15)2, SO2R15, SO2OR15, SO2N(R15)2, and optionally substituted Ci-salkyl, C2-4alkynyl, Cs-ecycloalkyl, or C^heterocycloalkyl;R15is independently H or a Ci-salkyl, Cs-scycloalkyl, C^heteroalkyl, or Cs-gheteroaryl group optionally substituted with halo, oxo, CN, OH, OCi-salkyl, NH2, N(Ci-salkyl)2, NHC(O)Ci- salkyl, C(O)H, OC(O)Ci-5alkyl, C(O)Ci-5alkyl, C(O)OCi-5alkyl, CON(Ci-5alkyl)2, C(O)NH2, SO2Ci-salkyl, SO2OCi-salkyl, SO2NH2 and SO2N(Ci-5alkyl)2; n is an integer selected such that the total number of R14on the R2group is from 1 to 4; and- - designates a bound between R2and the rest of the compound.

28. The compound of any one of claims 1 to 24, wherein R2is selected from:wherein - - designates a bound between R2and the rest of the compound.

29. The compound of claim 28, wherein R2is selected from:wherein - - designates a bound between R2and the rest of the compound.

30. The compound of claim 28, wherein R2is selected from:wherein - - designates a bound between R2and the rest of the compound.

31. The compound of any one of claims 1 to 30, wherein R3is OH, halo, or an optionally substituted Ci-salkyl.

32. The compound of any one of claims 1 to 30, wherein R3is SR7, OR7, NHR7, or N(R7)2, preferably OR7, NHR7, or N(R7)2.

33. The compound of claim 32, wherein R7is in one occurrence a group of formula -(C(R9)2)m- N(R10)2.

34. The compound of claim 33, wherein R9and R10are independently in each occurrence selected from H and an optionally substituted Ci-salkyl, C4-9cycloalkyl, or C4- gheterocycloalkyl group, wherein at least two R9and / or R10are taken together with their adjacent atom(s) to form an optionally substituted monocyclic or polycyclic C4-9cycloalkyl or C4-i2heterocycloalkyl group.

35. The compound of any one of claims 1 to 30, wherein R3is selected from:wherein - - designates a bound between R3and the rest of the compound.

36. The compound of claim 35, wherein R3is selected from:wherein - - designates a bound between R3and the rest of the compound.

37. The compound of claim 35, wherein R3is selected from:wherein - - designates a bound between R3and the rest of the compound.

38. The compound of claim 1 , wherein said compound is selected from Examples 1 to 200 as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

39. The compound of claim 38, wherein said compound is selected from Examples 1 to 155 and 174 to 200 as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

40. The compound of claim 38, wherein said compound is selected from Examples 10, 11 , 15, 17, 27, 31 , 34, 35, 42, 44, 49, 54-56, 58, 60, 61 , 65, 74, 79, 82, 89, 92, 98-101 , 103, 104, 106, 110-112, 115, 117, 118, 121 , 123-125, 128-140, 144, 145, 147-152, 154, 155, 174- 185, 187, 189-191 , and 193-200, or a pharmaceutically acceptable salt and / or solvate thereof.

41. The compound of claim 38, wherein said compound is selected from Examples 31 , 34, 35, 42, 54, 55, 58, 60, 61 , 82, 89, 99-101 , 106, 111 , 112, 115, 117, 118, 121 , 123, 128, 129, 131 , 133-140, 144, 145, 148, 152, 155, 174-185, 187, 189-191 , 193, 194, and 197 or a pharmaceutically acceptable salt and / or solvate thereof.

42. The compound of claim 38, wherein said compound is selected from Examples 82, 111 , 112, 115, 117, 128, 129, 131 , 133, 134, 136-140, 145, 147, 148, 152, 155, 178, 180, 182- 185, and 194, or a pharmaceutically acceptable salt and / or solvate thereof.

43. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 42, together with a pharmaceutically acceptable carrier, diluent or excipient.

44. Use of a compound as defined in any one of claims 1 to 42 or a pharmaceutical composition as defined in claim 43, for the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade, an inflammatory disease, or an immune system disorder.

45. The use of claim 44, wherein the disease or disorder is selected from a neoplasm and a developmental anomaly.

46. The use of claim 44 or 45, wherein said disease or disorder is associated with a RAS gene mutation (e.g. KRAS, HRAS, NRAS).

47. The use of any one of claims 44 to 46, wherein said disease or disorder is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation or amplification in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

48. The use of any one of claims 44 to 47, wherein said disease of disorder is a neoplasm.

49. The use of claim 48, wherein said neoplasm is selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, ovarian, breast cancer, uterine cancer, endometrial cancer, testicular cancer, renal and bladder cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, Barret's adenocarcinoma, glioma (e.g. ependymoma), lung cancer (e.g. non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, and hairy-cell leukemia.

50. The use of claim 48, wherein said neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma.

51. A method for the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade (RASopathies), or an inflammatory disease or an immune system disorder, comprising administering a compound as defined in any one of claims 1 to 42, or a pharmaceutical composition as defined in claim 43, to a subject in need thereof.

52. The method of claim 51 , wherein the disease or disorder is selected from a neoplasm and a developmental anomaly.

53. The method of claim 51 or 52, wherein said disease or disorder is associated with a RAS mutation (e.g. KRAS, HRAS, NRAS).

54. The method of any one of claims 51 to 53, wherein said disease or disorder is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation or amplification in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

55. The method of any one of claims 51 to 54, wherein said disease or disorder is a neoplasm.

56. The method of claim 55, wherein said neoplasm is selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, ovarian, breast cancer, uterine cancer, endometrial cancer, testicular cancer, renal and bladder cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, Barret's adenocarcinoma, glioma (e.g. ependymoma), lung cancer (e.g. non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, non-Hodgkin's lymphoma, and hairy-cell leukemia.

57. The method of claim 55, wherein said neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma.

58. A method for inhibiting abnormal proliferation of cells, comprising contacting the cells with a compound as defined in any one of claims 1 to 42 or a pharmaceutical composition as defined in claim 43.

59. The method of claim 58, wherein said cells comprise a mutated RAS gene (e.g. mutated KRAS, HRAS, NRAS).

60. The method of claim 58 or 59, wherein said abnormal proliferation is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation or amplification in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

61. The method of any one of claims 58 to 60, wherein said cells are selected from melanoma cells, thyroid carcinoma cells (e.g. papillary thyroid carcinoma cells), colorectal, ovarian, uterine, breast cancer cells, endometrial cancer cells, renal or bladder cancer cells, liver cancer cells, sarcoma cells, stomach cancer cells, pancreatic carcinoma cells, Barret's adenocarcinoma cells, glioma cells (e.g. ependymoma cells), lung cancer cells (e.g. nonsmall cell lung cancer cells), head and neck cancer cells, acute lymphoblastic leukemia cells, acute myelogenous leukemia cells, non-Hodgkin's lymphoma cells, and hairy-cell leukemia cells.

62. The method of any one of claims 58 to 60, wherein said cells are selected from colon or colorectal cancer cells, lung cancer cells, pancreatic cancer cells, thyroid cancer cells, breast cancer cells and melanoma cells.

63. The method of any one of claims 58 to 62, wherein said contacting is done in vivo.

64. The method of any one of claims 58 to 62, wherein said contacting is done ex vivo.

65. A compound as defined in any one of claims 1 to 42 or a pharmaceutical composition as defined in claim 43, for use in the treatment of a disease or disorder selected from a proliferative disease or disorder, a developmental anomaly caused by dysregulation of the RAS-ERK signaling cascade, an inflammatory disease, or an immune system disorder.

66. The compound or pharmaceutical composition for use of claim 65, wherein the disease or disorder is selected from a neoplasm and a developmental anomaly.

67. The compound or pharmaceutical composition for use of claim 65 or 66, wherein said disease or disorder is associated with a RAS gene mutation (e.g. KRAS, HRAS, NRAS).

68. The compound or pharmaceutical composition for use of any one of claims 65 to 67, wherein said disease or disorder is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation or amplification in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

69. The compound or pharmaceutical composition for use of any one of claims 65 to 68, wherein said disease of disorder is a neoplasm.

70. The compound or pharmaceutical composition for use of claim 69, wherein said neoplasm is selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, ovarian, breast cancer, uterine cancer, endometrial cancer, testicular cancer, renal and bladder cancer, liver cancer, sarcoma, stomach cancer, pancreatic carcinoma, Barret's adenocarcinoma, glioma (e.g. ependymoma), lung cancer (e.g. non-small cell lung cancer), head and neck cancer, acute lymphoblastic leukemia, acute myelogenous leukemia, nonHodgkin's lymphoma, and hairy-cell leukemia.

71. The compound or pharmaceutical composition for use of claim 69, wherein said neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma.

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