Substituted heterocyclic compounds, compositions comprising them and uses thereof

Abstract

Compounds, compositions, and their use in the treatment of a proliferative disease or condition such as a said proliferative disease or disorder characterized by dysregulation of the RAS-ERK pathway (e.g. cancer, RASopathies), for instance a disease or disorder associated with a KRAS gene mutation or an amplification of the KRAS locus. The compounds disclosed are of Formula (I) as defined herein, or a pharmaceutically acceptable salt and / or solvate thereof.

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 / 711,451 filed on October 24, 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 paralogous 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 conserved 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 small-molecules 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; Jänne 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). Interestingly, molecules with a G12X inhibition profile, such as BI-2493, demonstrated enhanced efficacy in KRAS wild-type amplified models, opening opportunities to target KRAS in patient populations with significant unmet medical needs (Tedeschi et al. 2025; PMID: 39711431). However, the clinical development of both G12D and G12X Swll inhibitors has so far been slowed down due to their relatively poor DMPK properties.

[0012] In addition, due to isoform specific substitutions in the Swll pocket of RAS isoforms, the inhibitors published thus far have shown selectivity for KRAS over HRAS and NRAS. One key site imparting KRAS selectivity is residue 95, which consists of a histidine in KRAS and that contributes to compound binding. In contrast, the HRAS and NRAS isoforms respectively comprise a glutamine and a leucine at residue 95, a substitution which has been proven to be the key driver of the KRAS selectivity index (Kim et al. 2023; PMID: 37258666; Keats et al 2022 PMID:37339170).

[0013] There is therefore a dire need for small molecule inhibitors that potently block KRAS signaling and cellular proliferation in human tumor cells bearing a variety of KRAS alleles. In addition, an added value could consist of blocking parallel reactivation of the HRAS and NRAS isoforms through Swll pocket targeting. The development of such inhibitors that potently and non-covalently target a variety of KRAS alleles is highly desirable.

[0014] SUMMARY

[0015] According to one aspect, the present technology relates to a compound of Formula I, II, III or IV:

[0016]

[0017] wherein L, R1, R2, R3, R4, R5, R6, and X are as herein defined, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0018] In some embodiments, the compound of Formula I is a compound of Formula II, III or IV:

[0019]

[0020] Formula II Formula III Formula IV wherein L, R1, R2, R3, R4, R5and R6are as herein defined, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0021] In other embodiments, the compound of Formula I is a compound of Formula II-A, II-B, III-A, IV-A or IV-B:

[0022]

[0023] wherein R1, R2, R3, R4, R5, R6and R7are as herein defined, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0024] In other embodiments, the compound of Formula I is a compound of Formula II-C, III-B, IV-C, V-C or VI-C:

[0025]

[0026]

[0027] Formula II-D Formula II-E Formula IV-D wherein R3, R4, R5, R6, and R7are as herein defined, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0028] The compounds of Formulae l-l V, I l-A to E, lll-A to B, and IV-A to D are also defined according to any of the embodiments, alone or in combination, and examples described throughout the present document.

[0029] According to another aspect, the present technology relates to a pharmaceutical composition comprising a compound as herein defined together with a pharmaceutically acceptable carrier, diluent or excipient. For instance, the compounds and compositions are for a use as defined herein and in any one of the described aspects, embodiments, and examples.

[0030] 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), an inflammatory disease, or an immune system disorder.

[0031] 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.

[0032] 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).

[0033] For instance, the disease or disorder is a neoplasm, such as those selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, oesphageal, 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.

[0034] 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.

[0035] DETAILED DESCRIPTION

[0036] 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.

[0037] / . Definitions

[0038] 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. 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”.

[0039] 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.

[0040] As used herein, the terms "compounds”, “compounds herein described”, “compounds of the present application”, “benzothiazole compounds”, “benzimidazole compounds”, “6,8-dihydoisobenzofuro[5,4-d]thiazole compounds”, “6,8-dihydro-1H-isobenzofuro[4,5[d]imidazole compounds”, and equivalent expressions refer to compounds described in the present application, e.g. those encompassed by structural Formulae I to IV, and I l-A to I l-E, lll-A, lll-B, or IV-A to IV-D, optionally with reference to any of the applicable embodiments, and also includes exemplary compounds, such as the compounds of Examples 1 to 592 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.

[0041] Unless otherwise stated, structures depicted herein are also meant to include all isomeric (e.g., enantiomeric, diastereomeric, atropisomeric, and geometric (or conformational)) forms of the structure when applicable; for example, the R and S configurations for each asymmetric center or M and P configurations for atropisomers. Therefore, single stereochemical isomers as well as enantiomeric, diastereomeric, atropisomeric, 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.

[0042] Where a particular enantiomer or atropisomer is preferred, it may, in some embodiments be provided substantially free of the corresponding enantiomer or atropisomer and may also be enantiomerically or atopisomerically enriched. "Enantiomerically or atropisomerically enriched" means that the compound is made up of a significantly greater proportion of one enantiomer or atropisomer. In certain embodiments the compound is made up of at least about 90% by weight of a preferred enantiomer or atropisomer. In other embodiments the compound is made up of at least about 95%, 98%, or 99% by weight of a preferred enantiomer or atropisomer. Preferred enantiomers or atropisomers may be isolated from racemic mixtures by any method known to those skilled in the art, including high-pressure liquid chromatography (HPLC) or supercritical fluid chromatography (SFC) on chiral support and the formation and crystallization of chiral salts or be prepared by asymmetric syntheses.

[0043] The term "atropisomer" refers to a stereoisomer resulting from restricted rotation about single bonds where the rotation barrier is high enough to permit isolation of the isomeric species. Typically, rotation about the single bond in the molecule is prevented, or greatly slowed, as a result of steric interactions with other parts of the molecule and the substituents at both ends of the single bond are asymmetrical, resulting in a stereogenic unit termed a "chiral axis".

[0044] For instance, the absolute configuration of the chiral axes, for instance in exemplary compounds, is assigned using the Cahn-lngold-Prelog (CIP) chirality rule, with stereodescriptors (aR) or (aS), or the CIP helicity rule, with stereodescriptors (P) or (M) (V. Prelog and G. Helmchen, Angewandte Chemie International Edition, 21(8): 567-583, 1982, http: / / doi.org / 10.1002 / anie.198205671; P. Mata, A. M. Lobo, C. Marshall, and A. P. Johnson, Tetrahedron: Asymmetry, 4(4): 657-688, 1993, https: / / doi.org / 10.1016 / S0957-4166(00)80173-1; both cited in H. A. Favre and W. H. Powell, Nomenclature of Organic Chemistry: IUPAC Recommendations and Preferred Names 2013 (the IUPAC "Blue Book"), Cambridge, UK: Royal Soc. of Chem., 2014, https: / / doi.org / 10.1039 / 9781849733069, Chapter P-9, "Specification of Configuration and Conformation", https: / / doi.org / 10.1039 / 9781849733069-01156).

[0045] 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).

[0046] 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 (I CH), Guide for Industry, Q3C Impurities: Residual Solvents (1997). Accordingly, the compound as herein described also includes each of its solvates and mixtures thereof.

[0047] 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.

[0048] 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 for their 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.

[0049] 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 (te / Y-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 (te / Y-butoxycarbonyl), and Su or Sue (succinimide). For more certainty, additional definitions of specific abbreviations are also included in the introduction of the Examples section.

[0050] 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).

[0051] 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, "C1-C8alkyl" contains from one to eight carbon atoms. Examples of alkyl radicals include, but are not limited to, methyl, ethyl, propyl, isopropyl, n-butyl, terf-butyl, neopentyl, n-hexyl, heptyl, octyl radicals and the like.

[0052] 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, "C2-8alkenyl" 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. 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.

[0053] 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.

[0054] 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, dihydrofuranyl, 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. In other words, the term “Cs-n heterocycloalkyl” refers to a 3- to n-membered heterocycloalkyl.

[0055] 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.

[0056] 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 π(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 “C6-naryl” refers to an aryl group having from 6 to the indicated “n” number of atoms in the ring structure.

[0057] 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 π(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 π 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. In other words, the term “Cs-n heteroaryl” refers to a 5- to n-membered heteroaryl.

[0058] 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. The term “halo” designates a halogen atom, i.e. a fluorine, chlorine, bromine or iodine atom, preferably fluorine or chlorine.

[0059] 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, CO2cycloalkyl, CO2aryl, CO2heteroaryl, CO2heterocycloalkyl, 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) NHheteroaryl, C(O)NHheterocycloalkyl, OCO2alkyl, OCO2alkenyl, OCO2alkynyl, OCO2cycloalkyl, OCO2aryl, OCO2heteroaryl, OCO2heterocycloalkyl, OC(O)NH2, OC(O)NHalkyl, OC(O)NHalkenyl, OC(O) NHalkynyl, OC(O)NHcycloalkyl, OC(O)NHaryl, OC(O) NHheteroaryl, 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, NHCO2alkenyl, NHCO2alkynyl, NHCO2cycloalkyl, NHCO2aryl, NHCO2heteroaryl, NHCO2heterocycloalkyl, NHC(O)NH2, NHC(O)NHalkyl, NHC(O)NHalkenyl, NHC(O)NHalkenyl, NHC(O)NHcycloalkyl, NHC(O)NHaryl, NHC(O)NHheteroaryl, 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, SO2NHalkyl, SO2NHalkenyl, SO2NHalkynyl, SO2NHcycloalkyl, SO2NHaryl, SO2NHheteroaryl, SO2NHheterocycloalkyl, NHSO2alkyl, NHSO2alkenyl, NHSO2alkynyl, NHSO2cycloalkyl, NHSO2aryl, NHSO2heteroaryl, NHSO2heterocycloalkyl, 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. ii. Compounds

[0060] 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.

[0061] 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:

[0062]

[0063] Formula I

[0064] wherein:

[0065] X is S, O or N;

[0066] R1is H, halo, OR8, C(O)OR9, substituted or unsubstituted Ci-4alkyl, or R1and R2are taken together with their adjacent carbon atoms to form an optionally substituted C4- yheterocycloalkyl;

[0067] R2is selected from H, halo, CN, OR8, substituted or unsubstituted Ci-4alkyl, or R1and R2are taken together with their adjacent carbon atoms to form an optionally substituted C4- yheterocycloalkyl;

[0068] R3is an optionally substituted C6-10aryl or C5-10heteroaryl; R4is H, halo (e.g. F or Cl), CN, OR8, a substituted or unsubstituted Ci-4alkyl, or a substituted or unsubstituted C3-5cycloalkyl or a C4-5heterocycloalkyl;

[0069] R5is H, a substituted or unsubstituted C1-9alkyl, a substituted or unsubstituted C3-9cycloalkyl or a substituted or unsubstituted C4-9heterocycloalkyl, or R5is absent when X is S or O;

[0070] L is O or NR7, preferably L being NR7when X is O;

[0071] R6is independently in each occurrence a substituted or unsubstituted group selected from C1-5alkyl, C4-9cycloalkyl, C4-9heterocycloalkyl;

[0072] R7is independently in each occurrence H or an optionally substituted C1-6alkyl, or R6and R7are taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl or an optionally substituted C5-9heteroaryl;

[0073] or L is a carbon atom, and L and R7are taken together to form an optionally substituted C4-9heterocycloalkyl or an optionally substituted C5-9heteroaryl;

[0074] R8or R9is a substituted or unsubstituted Ci-3alkyl;

[0075] or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0076] For example, the compound is of any one of Formulae II, III or IV:

[0077]

[0078] wherein L, R1, R2, R3, R4, R5and R6are as defined above and hereinbelow, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0079] In another example, the compound is of any one of Formula II-A, II-B, III-A, IV-A or IV-B:

[0080]

[0081] Formula IV-A Formula IV-B

[0082] wherein R1, R2, R3, R4, R5, R6and R7are as defined above and herein below, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0083] In the present compounds, R1may be H, or R1is an optionally substituted Ci-3alkyl, or R1together with R2form an optionally substituted C4-7heterocycloalkyl.

[0084] In another embodiment of the present compounds, R1is H, or an optionally substituted C1-5alkyl, for instance, in any one of Formula II-A, II-B, III-A, IV-A, or IV-B.

[0085] In another embodiment of the present compounds, R1is H, for instance, in any one of Formula II-A, II-B, III-A, IV-A, or IV-B.

[0086] In the present compounds, R2may be selected from H, halo, CN, OR8, a substituted Ci-3alkyl or R2together with R1form an optionally substituted C4-7heterocycloalkyl.

[0087] In another embodiment of the present compounds, R2is H, Cl, F, CF3, OMe or R2with R1are part of a fused C4-7heterocycloalkyl. In another embodiment of the present compounds, R2is Cl or CF3. In another embodiment of the present compounds, R2is Cl.

[0088] In another embodiment of the present compounds, R1and R2are taken together with their adjacent carbon atoms form an optionally substituted C4-7heterocycloalkyl. In some instances, the C4-7heterocycloalkyl is of the formula:

[0089]

[0090] wherein

[0091] R13and R13’ are independently in each occurrence selected from H, and an optionally substituted Ci-3alkyl, or two R13and R13’ on the same carbon are taken together with their adjacent carbon atom to form a carbonyl;

[0092] R14and R14’ are independently in each occurrence selected from H, and an optionally substituted Ci-3alkyl;

[0093] or two R13and R13’ or two R14and R14’ are taken together with their adjacent carbon atom to form an optionally substituted C3-4cycloalkyl;

[0094] q is an integer selected from 0 to 3, r is an integer selected from 1 to 4, wherein 1 < q + r < 4; and (===) represents a point of attachment between the cycle and the rest of the molecule.

[0095] In one embodiment, r and q are such their sum equals 2 or 3. In a preferred embodiment, r is 1, in another preferred embodiment, r is 2. In further embodiments, q is 1, or q is 2.

[0096] In another embodiment, R13, R13’, R14, and R14’ are each hydrogen atoms. Alternatively, R13and R13’ in one instance may be taken together with their adjacent carbon atom to form a carbonyl adjacent to the oxygen atom of the ring, preferably the remaining R13, R13’, R14and R14’ are each hydrogen atoms.

[0097] In another embodiment of the present compounds, R2together with R1form an optionally substituted C5-6heterocycloalkyl. For example, the compound may be of any one of Formula II-C / D / E, lll-B or IV-C / D:

[0098]

[0099]

[0100] Formula II-D Formula II-E Formula IV-D wherein R3, R4, R5, R6, and R7are as defined above and herein below, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0101] R3is selected from substituted C6-10aryl and C5-10heteroaryl. For instance, R3may be selected from:

[0102]

[0103] wherein:

[0104] X5is NH, O, or S;

[0105] X6, X7, and X8are each independently CH, C(R10), or N;

[0106] R10is independently in each occurrence 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 C1-5alkyl, C2-4alkynyl, C3-6cycloalkyl, and C4-6heterocycloalkyl optionally substituted with one or more substituents, preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, and / or optionally substituted Ci-3alkyl; R15is independently H or a C1-5alkyl, C3-6cycloalkyl, C4-6heteroalkyl, or C5-9heteroaryl group optionally substituted with one or more substituents preferably selected from halo, oxo, CN, OH, OC1-5alkyl, NH2, N(C1-5alkyl)2, NHC(O)C1-5alkyl, C(O)H, OC(O)C1-5alkyl, C(O)C1-5alkyl, C(O)OC1-5alkyl, CON(C1-5alkyl)2, C(O)NH2, SO2C1-5alkyl, SO2OC1-5alkyl, SO2NH2and SO2N(C1-5alkyl)2;

[0107] n is an integer selected such that the total number of R10on the R3group is from 1 to 4; and - - designates a bound between R3and the rest of the compound.

[0108] In preferred examples, the present compound forms atropisomers where the bond formed between the R3group, especially when being a bicyclic aryl or heteroaryl (e.g. as define above), and the rest of the molecule has two possible configurations due to restricted rotation. The two configurations may be illustrated as Atropisomers 1 and 2:

[0109]

[0110] In one particular embodiment, the compounds having a configuration corresponding to that of Atropisomer 1 is preferred. As a non-limitng example, the present atropisomers Example 12A and Example 12B may be illustrated as follows:

[0111]

[0112] dihydroisobenzofuro[5,4-d]thiazol-5- dihydroisobenzofuro[5,4-d]thiazol-5- yl)benzo[b]thiophene-3-carbonitrile yl)benzo[b]thiophene-3-carbonitrile

[0113]

[0114] , dihydroisobenzofuro[5,4-d]thiazol-5- dihydroisobenzofuro[5,4-d]thiazol-5- yl)benzo[b]thiophene-3-carbonitrile yl)benzo[b]thiophene-3-carbonitrile

[0115] As can be observed, the configation of Example 12A (aS, P) corresponds to Atropisomer 1 as illustrated above and as showed improved properties compared to Example 12B (aR, M) which corresponds to Atropisomer 2’s configuration. However, depending on the size of the substituents on each side, especially the R2and R4groups, correspondence of P and M configurations may correspond to a different atropisomer. Indeed, Example 1 for which R2is Cl, is in the M configuration but still corresponds to the Atropisomer 1 configuration as defined above.

[0116] In some embodiments, the R3group configuration is such that the compound is enriched in an atropisomer, for example at least 90%, or at least 95%, or at least 98%, preferably the atropisomer being in a configuration corresponding to Atropisomer 1 as defined herein.

[0117] For instance, in some preferred examples, R3is selected from:

[0118]

[0119] wherein X5, X6, X7, X8, R10, and n are as previously defined,

[0120] the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration (corresponding to Atropisomer 1 as defined herein).

[0121] Preferably, R3is selected from:

[0122]

[0123] wherein X5, X6, X7, X8, R10, and n are as previously defined,

[0124] the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98, having the depicted configuration (corresponding to Atropisomer 1 as defined herein).

[0125] Preferably, R3is of a formula:

[0126]

[0127] wherein X5, X6, X7, X8, R10, and n are as previously defined,

[0128] the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration (corresponding to Atropisomer 1 as defined herein).

[0129] In some preferred embodiments, X5is S, X6and X7are both C(R10), X8is CH, and R10is independently in each occurrence selected from halo (e.g. F or Cl), CN, OR15, N(R15)2, and C1-5alkyl, wherein R15is independently H or a C1-5alkyl.

[0130] Non-limiting examples of R3groups are illustrated as follows:

[0131]

[0132]

[0133] wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the molecule, or an enriched atropisomer thereof, preferably mainly having a configuration as in Atropisomer 1 as defined herein.

[0134] In one embodiment, R3is selected from:

[0135]

[0136] wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the molecule, or an enriched atropisomer thereof, preferably mainly having a configuration as in Atropisomer 1 as defined herein.

[0137] In one embodiment, R3is selected from:

[0138]

[0139] wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the molecule, or an enriched atropisomer thereof, preferably mainly having a configuration as in Atropisomer 1 as defined herein.

[0140] In a preferred embodiment, R3is selected from:

[0141]

[0142] wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the molecule,

[0143] the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98, having the depicted configuration (corresponding to Atropisomer 1 as defined herein).

[0144] In another embodiment of the present compounds, R4is H, halo (e.g. F or Cl), CN, OR8or a substituted or unsubstituted C3-5cycloalkyl or a C4-5heterocycloalkyl.

[0145] In another embodiment of the present compounds, R4is a substituted or unsubstituted Ci-4alkyl (e.g. Me), F or Cl, preferably F or Cl, most preferably Cl. In another embodiment of the present compounds, X is N-R5and R5is H, or R5is an optionally substituted C1-9alkyl, C3-9cycloalkyl, or C4-9heterocycloalkyl.

[0146] Non-limiting examples of R5groups may be illustrated as follows:

[0147]

[0148] wherein (---) represents a point of attachment between R5and N.

[0149] In another embodiment of the present compounds, L is O and the compound is of Formula II-A or IV-A as defined above.

[0150] In another embodiment of the present compounds, L is NR7and the compound is of Formula II-B, III-A, or IV-B as defined above. In some embodiments, R7is H or an optionally substituted C1-6alkyl. In another embodiment, R6and R7are taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl.

[0151] In yet another embodiment of the present compounds, L is NR7, R6and R7are taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl, the compound is of Formula II-C as defined above, and R3is of the formula:

[0152]

[0153] wherein X5, X6, X7, X8, R10, and n are as previously defined. Preferably, wherein X5is S, X6and X7are each independently C(R10), X8is CH, and R10is independently in each occurrence selected from halo (e.g. F or Cl), CN, OR15, N(R15)2, and C1-5alkyl, wherein R15is independently H or a Cisalkyl; and wherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98, having the depicted configuration (corresponding to Atropisomer 1 as defined herein).

[0154] In a further embodiment of the present compounds, R6in L-R6is selected from a substituted or unsubstituted group selected from C1-5alkyl, C4-9cycloalkyl, C4-9heterocycloalkyl.

[0155] In one embodiment, L-R6is of the formula:

[0156]

[0157] wherein:

[0158] R11and R11’ are independently in each occurrence selected from H, OH, Ci-salkoxy, halo (e.g. F), CN, and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, and / or two R11and R11’ are taken together with their adjacent carbon atom to form a carbonyl, and / or at least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group;

[0159] R12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, or R12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, or at least one of R11and R11’ and one of R12and R12’ are taken together with their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group;

[0160] p is 0 or 1; and

[0161] ( — ) represents a point of attachment between L-R6and the rest of the molecule.

[0162] In other embodiments, L-R6is of the formula:

[0163] R11R11R11R11'

[0164] y-N^3R12'

[0165] R7R11R11' R12

[0166] wherein: R7is selected from H or an optionally substituted C1-6alkyl, or R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-9heterocycloalkyl group;

[0167] R11and R11’ are independently in each occurrence selected from H, OH, Ci-salkoxy, halo (e.g. F), CN, and an optionally substituted C1-5alkyl, C4-6cycloalkyl, or C4-9heterocycloalkyl group, and / or two R11and R11’ are taken together with their adjacent carbon atom to form a carbonyl, and / or at least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group;

[0168] R12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, or R12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, or at least one of R11and R11’ and one of R12and R12’ are taken together with their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group;

[0169] p is 0 or 1; and

[0170] ( — ) represents a point of attachment between L-R6and the rest of the molecule.

[0171] In some preferred examples of the above formulae:

[0172] R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-9heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or - N(Ci-3alkyl)2; or

[0173] at least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or - N(Ci-3alkyl)2; or R12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci- 2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2; or at least one of R11and R11’ and one of R12and R12’ are taken together with their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4- i2heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2.

[0174] In one preferred embodiment, R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-gheterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2.

[0175] In a preferred embodiment, the optionally substituted C4-i2heterocycloalkyl or C4-9heterocycloalkyl group is an optionally substituted C5-7heterocycloalkyl group, more preferably an optionally substituted 5- to 7-membered lactam, or an optionally substituted pyrrolidine, piperidine, piperazine, or morpholine ring. In particular, the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2.

[0176] In some examples, L-R6is selected from:

[0177]

[0178] wherein:

[0179] p is 0 or 1;

[0180] R11ais H, OH, halo (e.g. F), C1-5alkyl, preferably H or OH;

[0181] R11a’ is H or C1-5alkyl, preferably H;

[0182] R11band R11b’ are independently in each occurrence selected from H and C1-5alkyl optionally substituted with one or more substituents, preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2, preferably R11band R11b’ are independently H or Me;

[0183] R11and R11’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, the optional substituent being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2, and / or two R11’ are taken together to form an Ci-2alkylene bridge; and

[0184] R12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-6cycloalkyl, or C4-6heterocycloalkyl group, or R12and R12’ are taken together with the nitrogen atom bearing them to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, the optional substituent being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2. In one embodiment, R12and R12’ are independently in each occurrence selected from H, C1-5alkyl, C4-6cycloalkyl, or C4-6heterocycloalkyl group, or R12and R12’ are taken together with the nitrogen atom bearing them to form a monocyclic C4-6heterocycloalkyl group.

[0185] Non-limiting examples of L-R6may be illustrated as follows:

[0186]

[0187]

[0188]

[0189]

[0190]

[0191]

[0192]

[0193]

[0194]

[0195]

[0196] wherein (---) represents a point of attachment between L-R6and the rest of the molecule. In some preferred examples, L-R6is selected from:

[0197]

[0198]

[0199] wherein (---) represents a point of attachment between L-R6and the rest of the molecule.

[0200] In a preferred embodiment of the present compounds, the compound is of Formula II-C, R3is of the formula:

[0201]

[0202] wherein X5, X6, X7, X8, R10, and n are as previously defined, preferably X5is S, X6and X7are each independently C(R10), X8is CH, and R10is independently in each occurrence selected from halo (e.g. F or Cl), CN, OR15, N(R15)2, and C1-5alkyl, wherein R15is independently H or a C1-5alkyl; wherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98, having the depicted configuration (corresponding to Atropisomer 1 as defined herein);

[0203] and

[0204] L-R6is selected from:

[0205]

[0206] Exemplary compounds as defined herein include, without limitation, Examples 1 to 592 defined as follows:

[0207]

[0208]

[0209]

[0210] Example 24B Example 25 Example 26

[0211]

[0212]

[0213]

[0214]

[0215]

[0216]

[0217]

[0218] Example 82A Example 82B Example 83

[0219]

[0220]

[0221]

[0222]

[0223]

[0224]

[0225]

[0226]

[0227]

[0228]

[0229] Example 165 Example 166 Example 167

[0230]

[0231]

[0232] Example 186 Example 187 Example 188

[0233]

[0234]

[0235]

[0236]

[0237] Example 226

[0238]

[0239] Example 228

[0240]

[0241] Example 232 Example 233 Example 234

[0242]

[0243]

[0244] Example 243 Example 244

[0245]

[0246]

[0247]

[0248] Example 249 Example 250 Example 251

[0249]

[0250] Example 258 Example 259 Example 260

[0251]

[0252]

[0253]

[0254]

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261]

[0262]

[0263]

[0264]

[0265]

[0266]

[0267] Example 377 Example 378 Example 379

[0268]

[0269]

[0270] Example 392

[0271] Example 393

[0272]

[0273]

[0274]

[0275] Example 414 Example 415 Example 416

[0276]

[0277] Example 425

[0278]

[0279]

[0280]

[0281] Example 447 Example 448 Example 449

[0282]

[0283] Example 451

[0284]

[0285]

[0286]

[0287] Example 456 Example 457 Example 458

[0288]

[0289] Example 467B Example 468 Example 469

[0290]

[0291]

[0292]

[0293]

[0294]

[0295]

[0296]

[0297]

[0298]

[0299]

[0300]

[0301]

[0302] Example 537 Example 538 Example 539

[0303]

[0304]

[0305] Example 547 Example 548 Example 549

[0306]

[0307]

[0308]

[0309] Example 571 Example 572 Example 573

[0310]

[0311]

[0312] or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof. In some instances, the compound is selected from Examples 12A, 38A, 40A, 41 A, 52, 57A, 66, 68B, 69-71, 78A, 79B, 81, 82B, 83, 87, 88, 92-112, 114-127, 130, 132-135, 137, 138, 140-162, 164, 165, 167-191, 193-197, 199-322, 324-355, 357-396, 398-445, 452, 455-463, 465-470, 471B, 473-504, 506-513, 515, 517-528, 531-554, 556-592 or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0313] Examples of preferred compounds are, namely, Examples 12A, 40A, 79B, 100, 107, 118-120, 122, 127, 133-135, 140, 148, 149, 156, 158, 160, 169, 170, 172, 182, 188-190, 194A, 194B, 195B, 201, 203-205, 207, 208, 211, 214, 216-219, 224, 227, 228, 230-239B, 242, 245, 248-252, 255, 260, 266, 268, 270-273, 275, 276, 278, 282-286, 293, 301-305, 310, 316, 319, 327, 330, 332-334, 336-338, 340, 347, 348, 353-355, 357, 358, 360, 362, 367-371, 373-377, 379, 380, 382, 383, 384B, 385, 388-393, 398, 404, 407-408B, 411-413, 416, 419, 424, 428, 432, 433, 436, 442, 451, 456, 466-467B, 470, 471 B, 479, 480, 483, 484, 486, 488, 490, 494-496, 498, 500, 501, 503, 508, 510, 513, 519, 522, 532, 536, 540, 542, 545A, 545B, 548, 551, 556, 557, 559, 561, 563, 564, 566, 569, 572, 573, 575, 576, 581-583, 585, 586, 587 and 591 or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

[0314] Even more preferred compounds are, namely, Examples 40A, 79B, 100, 118-120, 133, 134, 140, 148, 170, 189, 205, 218, 228, 236, 242, 252, 268, 272, 303, 316, 334, 347, 368, 377, 380, 404, 407, 408B, 411, 467B, 479, 483, 488, 496, 500, 508, 519, 522, 545A, 548, 557, 561, 572, 573, 576, 581-583, 586 and 587.

[0315] 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. 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. iii. Methods, Uses, Formulations and Administration

[0316] 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.

[0317] 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.

[0318] 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.

[0319] Accrodingly, the invention relates to a compound as previsously defined 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.

[0320] 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, for example a KRAS gene mutation, or involving an amplification of the KRAS locus. The disease or disorder may also be further associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) ora 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.

[0321] 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.

[0322] 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.

[0323] 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.

[0324] 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). In an embodiment, the disease to be treated is a RAS-driven tumor, in particular a KRAS-driven tumor cell.

[0325] 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.

[0326] 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, in particular a KRAS-driven cancer. The method comprises administering a therapeutically effective amount of a compound as defined herein, to a subject in need of such treatment.

[0327] 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.

[0328] The present description also relates to compounds as previously defined for use in treating a subject, such as a human subject, suffering from a proliferative disease or disorder, e.g. a mutated RAS-driven cancer, in particular a KRAS-driven cancer. The use comprises administering a therapeutically effective amount of a compound as defined herein, to a subject in need of such treatment.

[0329] 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. 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.

[0330] 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.

[0331] 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.

[0332] 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.

[0333] 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.

[0334] 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, U.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.

[0335] 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.

[0336] 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.

[0337] 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.

[0338] 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.

[0339] 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] 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.

[0344] 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.

[0345] 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.

[0346] 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.

[0347] 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.

[0348] 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.

[0349] 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.

[0350] 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-CTLA4 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.

[0351] 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.

[0352] 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.

[0353] EXAMPLES

[0354] List of Abbreviations

[0355] 1,10-Phen: 1,10-Phenanthroline

[0356] 6xHis: affinity tag comprising a repetition of 6 histidine residues

[0357] Ac: acetyl

[0358] AcOEt: ethyl acetate

[0359] AcOH: acetic acid

[0360] Aq. orAqu.: aqueous

[0361] Ar: aryl

[0362] ATCC: American Type Culture Collection

[0363] ATP: adenosine triphosphate

[0364] BINOL: [1,1'-binaphthalene]-2,2'-diol

[0365] Bn: Benzyl

[0366] Boc: terf-butyloxycarbonyl

[0367] Bpin: Pinacol borane

[0368] BSA: bovine serum albumin

[0369] cataCXiumAPdG3®: methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl- 2-yl)palladium(ll)

[0370] Cbz: carbobenzyloxy

[0371] CCL: cancer cell lines

[0372] CDCl3: deuterated chloroform

[0373] Cy5: cyanine 5 dye

[0374] DCE: 1,2-dichloroethane

[0375] DCM: dichloromethane

[0376] DHP: 3,4-dihydro-2H-pyran

[0377] DIAD: Diisopropyl azodicarboxylate

[0378] DI PEA or DIEA: A / , / V-diisopropylethylamine (Hunig’s base)

[0379] DMA: / V, / V-di methylacetamide

[0380] DMC: dimethylcarbonate

[0381] DMAP: 4-dimethylaminopyridine

[0382] DME: 1,2-dimethoxyethane DMF: / V, / V-dimethylformamide

[0383] DMPK: drug metabolism and pharmacokinetics

[0384] DMSO: dimethylsulfoxide

[0385] DMSO-d6: deuterated dimethylsulfoxide

[0386] DTT: dithiothreitol

[0387] 5 ppm:1H NMR shift in ppm relative to residual NMR solvent

[0388] E. coli: Escherichia coli

[0389] EA or EtOAc: ethyl acetate

[0390] EC50: half-maximal effective concentration

[0391] ECL: enhanced chemiluminescence

[0392] EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide

[0393] EDTA: ethylenediamine tetraacetic acid

[0394] Equiv. or eq.: equivalent

[0395] Et2O: diethyl ether

[0396] EtOH: ethanol

[0397] EGFR: epidermal growth factor receptor

[0398] ERK: extracellular signal-regulated kinase

[0399] FA: Formic acid

[0400] FBS: fetal bovine serum

[0401] GAP: GTPase-activating protein

[0402] GEF: guanine nucleotide exchange factor

[0403] GST: glutathion S-transferase

[0404] GDP: guanosine diphosphate

[0405] GTP: guanosine triphosphate

[0406] HATU: O-(7-azabenzotriazol-1-yl)- / V, / \ / , / \ / ’, / \ / ’,-tetramethyluronium hexafluorophosphate HEPES: 4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid

[0407] HMDS: hexamethyldisilazane

[0408] Het: heterocycle

[0409] Hex: hexanes

[0410] HRMS: high resolution mass spectrometry

[0411] HPLC: high performance liquid chromatography

[0412] HRP: horseradish peroxidase

[0413] Hz: hertz

[0414] IC50: half-maximal inhibitory concentration I PA: isopropanol

[0415] / PrOH: isopropanol

[0416] LAH: Lithium aluminum hydride

[0417] LCMS: liquid chromatography mass spectrometry

[0418] LHMDS or LiHMDS: Lithium hexamethyldisilazane

[0419] MCPBA: mefa-chloroperbenzoic acid

[0420] MeCN: acetonitrile

[0421] MEK: mitogen-activated protein kinase

[0422] MeOH: Methanol

[0423] mM: millimolar

[0424] MOM: methoxymethyl ether

[0425] MPLC: medium pressure liquid chromatography

[0426] MS: mass spectrometry

[0427] NA: Not Available

[0428] NF1: neurofibromatosis type 1

[0429] nm: nanometer

[0430] nM: nanomolar

[0431] NMP: / V-methylpyrrolidone

[0432] NMR: nuclear magnetic resonance

[0433] OAc: Acetate

[0434] ON: overnight

[0435] PBS: phosphate buffered saline

[0436] Pd-117: dichloro(bis(2-(diphenylphosphino)phenyl)ether)palladium (II) pERK: phosphorylated extracellular signal-regulated kinase

[0437] Ph: Phenyl

[0438] PMB: para-methoxy benzyl

[0439] PMSF: phenylmethylsulfonyl fluoride

[0440] PyBroP: bromo-tris-pyrrolidinophosphonium hexafluorophosphate quant.: quantitative

[0441] RAS: rat sarcoma

[0442] RBD: RAS-binding domain

[0443] RBF: Round-bottomed flask

[0444] RPMI-1640: Roswell Park Memorial Institute medium formulation 1640 RT: Room Temperature rt: retention time

[0445] RTK: receptor tyrosine kinase

[0446] Sat.: saturated

[0447] SDS: sodium dodecylsulfate

[0448] SDS-PAGE: sodium dodecyl sulfate polyacrylamide gel electrophoresis SEM: trimethylsilylethoxymethyl

[0449] SM: Starting material

[0450] SFC: Supercritical fluid chromatography

[0451] SNAr: Nucleophilic aromatic substitution

[0452] SOS: son of sevenless

[0453] SOS1: son of sevenless homolog 1

[0454] SOS2: son of sevenless homolog 2

[0455] SOScat: residues 566-1049 of human son of sevenless homolog 1 SPR: surface plasmon resonance

[0456] Swll: switch II pocket

[0457] TBDMS: tert-butyldimethylsilyl

[0458] TBME: tert-butyl methyl ether

[0459] TBST: Tris buffered saline with 0.2% Tween-20

[0460] TBTLI: O-(benzotriazol-1-yl)- / V, / \ / , / \ / ’, / \ / ’-tetramethyluronium tetrafluoroborate tBu: tert-Butyl

[0461] TCP: 1, 1”-thiocarbonyldi-2(1 H)-pyridone

[0462] TEV: tobacco etch virus protease

[0463] TFA: trifluoroacetic acid

[0464] THF: tetra hydrofuran

[0465] THP: tetrahydropyran

[0466] TLC: silica gel thin layer chromatography

[0467] TPP: Triphenylphosphine

[0468] TPPO: Triphenylphosphine oxide

[0469] TR-FRET: time-resolved Forster’s resonance energy transfer

[0470] Ts: para-Toluenesulfonate

[0471] pL: microliter

[0472] pM: micromolar

[0473] WT: wild type The following non-limiting examples are illustrative embodiments and should not be construed as further limiting the scope of the present invention.

[0474] 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 (SiO2) 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 in deuterated solvents such as deuterated chloroform, methanol or DMSO. Chemical shift listings and coupling constants are as provided by the ACD labs NMR processor software (www.acdlabs.com). Chemical shifts are expressed in parts per million (ppm), signals are expressed as follows: s = singlet, d = doublet, t = triplet, q = quadruplet, sept = septuplet, sxt = sexstet, dd = double doublet, dt = double triplet, m = multiplet, br = broad, H = proton, Hz = Hertz, J = coupling constant.

[0475] 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). UV 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. Analyses were also performed using a Kinetex biphenyl 3 pm column (50 x 3 mm) at a flow rate of 1.15 mL / min using gradient of 40 to 55% MeOH (containing 5% water / 0.05% HCOOH) over 8 minutes. 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 / 0.05% formic acid) and solvent B (95% MeOH / 5% H₂O / 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. Separation of enantiomeric atropisomers on a preparative scale was performed by HPLC on chiral supports using a Lux 5 pm cellulose-1 (OD) column (150 x 21.2 mm) at a flow rate of 10 mL / min using an isocratic gradient of 12% iPrOH in hexane (250 mg / injection in 5% DCM / 25% EtOH / 70% hexane). Analysis of fractions was performed using a Lux 3 pm cellulose-1 (OD) column (50 x 2 mm) at a flow rate of 0.3 mL / min using an isocratic gradient of 7.5% EtOH + 7.5% in hexane. Alternatively, separation of enantiomeric atropisomers on a preparative scale was achieved using a Lux 5 pm cellulose-1 (AD) column (150x21.2 mm) at a flow rate of 10 mL / min using an isocratic gradient of 5%EtOH / 5%MeOH in hexane (175 mg / injection in 5% DCM / 15% MeOH / 10% EtOH / 70% hexane). Analysis of fractions was performed using a Lux 3 pm cellulose-1 (AD) column (50 x 2 mm) at a flow rate of 0.3 mL / min using an isocratic gradient of 7.5% EtOH + 7.5% MeOH in hexane.

[0476] 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. Name of molecules throughout are as provided by ChemDraw software (Revvity Signal Software Inc.) using IUPAC nomenclature.

[0477] Synthesis, biological activity and characterization of examples:

[0478] 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 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.

[0479]

[0480] 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.

[0481] Scheme A (preparation of compounds of formula I l-A and 11- B; R1= H, R2= Cl and R4= F, Cl):

[0482]

[0483] protecting group removal a: X = F

[0484] b: X = Cl

[0485]

[0486] Commercially available boronate A-1 can undergo palladium catalyzed Suzuki-Miyaura cross- coupling with aryl or heteroaryl halides of general formula R3-X (X = halogen or equivalent) using conditions well-known to a person skilled in the art to provide intermediates A-2. Chlorination of A-2 can be accomplished in a regioselective manner with reagents such as N-chlorosuccinimide or N, N-dichloro-5,5-dimethylhydantoin in solvents such as 2-Me-THF or DMF at ambient temperatures to provide 4-chloroaniline intermediate A-3. Intermediates A-3 generally exist as mixtures of geometrical atropisomers that are carried through to the end of the sequence. Ring closure of A-3 to aminobenzothiazole A-4 occurs upon treatment with a halogen such as bromine in the presence of an inorganic thiocyanate (e.g. KSCN) in a solvent such as AcOH at temperatures ranging from 10 °C to 50 °C. Aminobenzothiazole A-4 is then converted to 2-chlorobenzothiazole A-5 using a Sandmeyer reaction protocol using for example an organic nitrite (e.g. tBuNO₂) in the presence of a chloride source such a Cu(II) chloride in an appropriate solvent such as MeCN at temperatures ranging from -10 °C to 80 °C. Alternatively, an inorganic nitrite (e.g. NaNO₂) can be used in combination with elemental copper and aqueous hydrochloric acid. Intermediate A-5 then serves as a substrate for introduction of H-LR6(e.g. amines HNR6R7or alcohols HOR6) under SNAr conditions using a base such as LiHMDS in THF or 2-Me-THF for alcohols or DIEA or Inorganic bases (e.g. Cs₂CO₃ or K₂CO₃) in DMF, MeCN, NMP, DMA or DMSO for amines at temperatures ranging from -40 °C to 100 °C. Removal of any existing protecting group in the molecule under appropriate conditions (e.g. TFA or HCI to remove Boc protecting groups) provides compounds of Formula ll-A or ll-B of this invention. In cases where substituent L-R6contains asymmetric centers, compounds of formula ll-A or ll-B may exist as separable diastereomeric mixtures. When no other chiral center is present in the molecule, geometrical atropisomers can be separated by chromatographic technics (e.g. HPLC or SFC) on chiral supports. Alternatively, geometric atropisomers can be separated at an earlier stage of this synthetic sequence (e.g. intermediates A-3 or A-4 or the protected forms of final compounds ll-A or ll-B) through processes well established in the literature, including chromatographic separations (e.g. HPLC or SFC) on normal or chiral supports, selective crystallization of diastereomeric salts using chiral acids or the formation of diastereomeric derivatives.

[0487] Scheme B (alternative preparation of compounds of formula ll-B; R1= H, R2= Cl and R4= F):

[0488]

[0489] Cui

[0490] 1,10-Phen a: X = F protecting group removal b: X = Cl K2CO3

[0491]

[0492] Formula ll-B

[0493] Intermediate A-3 (Scheme A) can be reacted with elemental iodine in the presence of silver sulfate at ambient temperatures in protic solvents such as EtOH to provide iodoaniline intermediate B-1.

[0494] Treatment with 1,1”-thiocarbonyldi-2(1H)-pyridone at RT in an inert solvent such as DCM or MeCN in the presence of an organic base (e.g. DIEA) followed by addition of a primary or secondary amines (R6R7NH) provides thiourea intermediate B-2. Intermediate B-2 can undergo a copper-mediated cyclization to benzothiazole derivatives in the presence of ligands such as 1,10-phenanthroline or proline and an inorganic base (e.g. potassium or cesium carbonate) in solvents such as dioxane or DME and temperatures in the 60 °C to 100 °C range. The latter, after removal of protecting groups provides compounds of formula ll-B. As described previously, geometric atropisomers can be separated at any appropriate stage along the sequence by any of the methods described in Scheme A.

[0495] Scheme C (alternative preparation of compounds of formula ll-B; R1= H, R2= Cl and R4= F):

[0496]

[0497] Treatment of intermediate B-1a / b with 1,1”-thiocarbonyldi-2(1H)-pyridone at RT in an inert solvent such as DCM or MeCN followed by addition of ammonia at temperature ranging from RT to 100 °C yields thiourea intermediate B-2a / b, which can undergo a copper-mediated cyclization to 2-aminobenzothiazole derivatives A-4a / b in the presence of ligands such as 1,10-phenanthroline or proline and an inorganic base (e.g. potassium or cesium carbonate) in solvents such as dioxane and temperatures in the 60 °C to 100 °C range. 2-Aminobenzothiazole A-4a / b is then converted via a Sandmeyer reaction to chlorobenzothiazole A-5a / b as described in Scheme A. Final products of formula I l-B are then obtained via a SNAr reaction with nucleophilic amines also as described in Scheme A followed by removal of protecting groups.

[0498] S

[0499]

[0500]

[0501] Formula IV-A, IV-B

[0502] Reaction of intermediate B-1 with 1,1”-thiocarbonyldi-2(1H)-pyridone at RT in an inert solvent such as DCM followed by addition of a primary amine (R5NH2) provides thiourea intermediate D-1. S-alkylation of intermediate D-1 using an alkyl halide such as 4-tert-butylbenzyl bromide in the presence of an inorganic base such as cesium carbonate in a solvent such as MeCN at ambient temperatures provides isothiourea D-2 which undergoes a copper-mediated cyclization to benzimidazole intermediate D-3 in the presence of ligands such as 1,10-phenanthroline or proline and an inorganic base (e.g. potassium carbonate) in solvents such as dioxane and temperatures in the 60 °C to 100 °C range. Alternatively, S-alkylation of D-1 can be performed using Etl. 2-Thiobenzimidazoles such as D-3 (or the corresponding ethylsulfide) undergo oxidation to sulfones D-4 using oxidizing agents such as MCPBA in inert solvents such as DCM at ambient temperatures and subsequent SNAr displacement of the sulfone moiety by nucleophilic amines or alcohols to provide protected forms of compounds of Formula IV-A or IV-B. When amines are used as nucleophile, this last step is accomplished by reacting intermediate D-4 with a primary or secondary amine (HNR6R7) in conjunction or absence (when the amine is used in excess) of a tertiary organic (e.g. TEA or DIEA) or inorganic base (e.g. K₂CO₃, Cs2CO3) in protic solvents such as DMSO, NMP, DMA or DMF) at temperatures ranging from 80 °C to 150 °C by thermal heating or microwave irradiation. When alcohols are used as nucleophiles, the SNAr step is accomplished using a strong base such as LiHMDS, KOtBu or NaH and the likes in dry organic solvents such as THF or 2-Me-THF at temperatures ranging from -40 °C to 60 °C. Protecting group removal (e.g. treatment with TFA or HCI for Boc protecting groups) then provides the desired compounds of Formula IV-A or IV-B. As described previously, geometric atropisomers can be separated at any appropriate stage along the sequence by any of the methods described in Scheme A.

[0503] Scheme E (preparation of key intermediates E-4; X = F, Cl):

[0504]

[0505] Intermediates E-4a and E-4b (X = F, Cl) are key building blocks for the synthesis of compounds of general formula ll-C, lll-B and IV-C. They can be prepared following reported procedures described in WO2023 / 183585. Alternative procedures can be used for some of the steps described in Scheme E or adapted from X = F to X = Cl and vice versa. For instance, in the case where X = F, the two step procedure (DI BAL then Et₃SiH / TFA sequential reductions) described in WO2023 / 183585 for converting E-2a to E-3a can be accomplished directly through the use of EtaSiH in the presence of a catalytic amount of InBra in an adaptation of a procedure described in J. Org. Chem. 2007, 72(15), 5920-5922. This same procedure can be used to convert E-1a into E-5a. The conversion of E-5b (X = Cl) to E-6b and then E-3b has been reported in WO2023 / 183585. In yet another alternative, phthalic anhydrides E-7a or E-7b (X = Cl or F) can be reduced to diols E-8a / b as described in WO2023 / 183585 for X = Cl and cyclized to halogenated phthalanes E-5a / b also described in WO2023 / 183585 for X = Cl. WO2023 / 153585 also describes the chemoselective reduction of nitrophthalanes E-3a / b to anilines E-4a / b using iron under acidic conditions.

[0506] Scheme F (preparation of compounds of Formula II-C; R4= F, Cl):

[0507] R3-B(OR)2 / Pd cat.

[0508] (Suzuki-Miyaura)

[0509]

[0510] Formula ll-C

[0511] The preparation of compounds of general Formula II-C follows a similar sequence to those described in Scheme A or B. Intermediates E-4a / b (Scheme E) are initially converted to boronate esters F-1a / b using diboron reagents and palladium catalysts and then engaged in Suzuki- Miyaura cross-couplings to provide intermediates F-2a / b according to procedures well known to people skilled in the art (e.g. as described in WO2023 / 183585). Alternatively, aryl bromide E-4a / b undergoes Suzuki-Miyaura cross-coupling with boronate esters from commercial sources or prepared from aryl bromide following procedures that people skilled in the art will be familiar with. Other types of cross-coupling protocols can be utilized in the conversion of E-4a / b to F-2a / b such as Stille couplings using organotin species or Negishi couplings using zinc intermediates. The procedures are well known to people skilled in the art of organic synthesis. The remainder of the sequence from intermediates F-2a / b

[0512]

[0513] I l-C follows adaptations of procedures described in Scheme A for the preparation of compounds of Formula ll-B. As described previously, geometric atropisomers are generated during the formation of intermediate F-2a / b and can be separated at that stage or in any subsequent steps along the sequence by any of the methods described in Scheme A.

[0514] Scheme G (alternative preparation of compounds of Formula ll-C; R4= F, Cl):

[0515]

[0516] pg gup x = R4= F, ci

[0517] Formula ll-C

[0518] Intermediate F-2a / b (Scheme F) can be converted to compounds of formula ll-C through conversion to iodoaniline G-1a / b followed by formation of thiourea G-2a / b and copper-catalyzed ring closure to ll-C following similar protocols to those described in Scheme B. As described previously, geometric atropisomers are generated during the formation of intermediate F-2a / b and can be separated at that stage or in any subsequent steps along the sequence by any of the methods described in Scheme A.

[0519] Scheme H (preparation of compounds of Formula IV-C; R4= F, Cl):

[0520]

[0521]

[0522] Formula IV-C

[0523] Starting from intermediate G-1a / b (Scheme G) compounds of Formula IV-C can be prepared (Scheme H) following adaptations of the same synthetic sequence described in Scheme D for the preparation of compounds of Formula IV-A or IV-B. As described previously, geometric atropisomers are generated during the formation of several intermediates along this sequence or at the final step and can be separated at any of those stages along the sequence by any of the methods described in Scheme A.

[0524] Scheme I (general method for the preparation of compounds of Formula ll-C):

[0525]

[0526] F-4a / b Formula ll-C

[0527]

[0528] Compounds of Formula ll-C can be prepared from intermediates F-4a or F-4b through a SNAR reaction with primary or secondary amine in solvents such as MeCN, DMF, DMSO, NMP, DMA and the likes at temperatures ranging from RT to 150 °C in the presence of a base such as DIEA or TEA. The substitution can be carried out on mixtures or separated atropisomers or epimers can be separated at the final product stage using chromatographic technics on normal or chiral supports as described previously.

[0529] Scheme J (preparation of compounds of Formula lll-A):

[0530]

[0531] Benzoxazole compounds of Formula lll-A can be prepared from key intermediate J-6 that can be accesses from commercially available 1-fluoro-3-methoxy-2-nitrobenzene using methods well known to those skilled in the art of organic synthesis. Intermediate J-6 can be subjected to crosscoupling protocols as described above for other intermediates (e.g. Suzuki-Miyaura coupling using boronic acid derivatives) to provide intermediate J-7. The R2substituent (e.g. Cl) can then be introduced at this stage and resulting J-8 converted to compounds of Formula lll-A (R2= Cl) through introduction of amines under SNAr conditions as described previously. Alternatively, intermediate J-7 can be converted directly to compounds of Formula lll-A where R2= H via SNAr displacement of the trifluoroethoxy leaving group.

[0532] Synthesis of intermediates

[0533] Preparation of tert-butyl (3-cyano-4-(2,6-dichloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (general method A; intermediate A-5a):

[0534]

[0535] Step 1: tert-Butyl (4-(3-amino-2-fluorophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (A-2a): A mixture of tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate-1 (5.20 g, 14.0 mmol), 2-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (3.65 g, 15.4 mmol), dioxane (128 mL), water (32.1 mL), and K₂CO₃ (5.81 g, 42.0 mmol) were placed in a 250 mL RBF, fitted with a small reflux condenser. The mixture was degassed for 30 mins with Ar gas, Pd(PPh3)4 (696 mg, 0.602 mmol) was added and degassing continued for another 15 mins. The vessel was then placed in an oil-bath pre-heated to 100 °C. After 3.5 h, the reaction was judged to be complete by LCMS. After cooling to RT, the reaction mixture was diluted with 75 mL water and extracted with 2 x 100 mL EtOAc. After drying over Na2SO4and removal of volatiles, the residue was purified by flash chromatography (silica, EtOAc in DCM, 0-10%) to yield A-2a obtained as a light-yellow solid (5.52 g, 98 %).1H NMR (400 MHz, DMSO-d6) 5 11.56 (br. s., 1H), 7.29 (d, J = 7.4 Hz, 2H), 6.87 - 6.95 (m, 1H), 6.76 - 6.87 (m, 1H), 6.40 - 6.50 (m, 1H), 5.14 (br. s., 2H), 1.51 (s, 9H). LCMS: m / z 400.0 [M-H]’. Step 2: tert-Butyl (4-(3-amino-6-chloro-2-fluorophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (A-3a): intermediate A-2a (2.12 g, 5.28 mmol) was dissolved in 2-Me-THF (53.0 mL) in a 100 mL RBF. 1,3-Dichloro-5,5-dimethylhydantoin (1.20 g, 6.08 mmol) was added in 5 portions over 1.5 h. The solution turned pink after the first addition but remained somewhat opaque. By the time of the last addition, the solution was clear. The reaction was transferred to a separatory funnel with ethyl acetate and washed with aqueous sodium thiosulfate. The aqueous layer was extracted with 2X EtOAc. The combined organic fractions were washed with brine and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography (silica, EtOAc in hexanes, 0-30%) to afford intermediate A-3a (1.93 g, 84 %) as a dark orange solid.1H NMR (DMSO-d6) 5: 11.65 (s, 1H), 7.26 - 7.36 (m, 2H), 7.06 (dd, J = 8.6, 1.3 Hz, 1H), 6.84 (t, J = 9.1 Hz, 1H), 5.34 (br. s., 2H), 1.51 (s, 9H). LCMS: m / z 434.0 [M-H]'.

[0536] SStep 3: tert-Butyl (4-(2-amino-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (A-4a): To a suspension of A-3a (1.54 g, 3.53 mmol) in AcOH (8.83 mL) was added KSCN (1.39 g, 14.1 mmol) at RT affording a beige suspension. The mixture was stirred for about 5 minutes then bromine (399 pL, 7.77 mmol) was added dropwise, over 10 minutes. The mixture was allowed to stir at RT for 5 minutes and was then warmed to 35 °C in a pre-heated oil bath. After stirring at this temperature for 1 h, the mixture was monitored by LCMS. The desired product was found to be the major peak. Heating was stopped and the mixture was stirred RT for another 2 h. A saturated solution of sodium thiosulfate was added to the mixture (5 mL) and the mixture stirred vigorously for 5 minutes. The reaction mixture was then diluted with DCM and water (about 100 mL each) and the mixture was concentrated to dryness. To the resulting orange solids was added 150 mL of water and the mixture was sonicated to obtain a suspension. The solids were collected on a hardened paper filter and washed with a bit of water. The solids were then dried under reduced pressure. They were adsorbed onto silica gel with DCM and purified by flash chromatography (silica, MeOH in DCM, 0-16%) to afford A-4a (750 mg, 43 %) as a yellow solid. Product rf = 0.32 @ 5% methanol 95% DCM and 0.42 @ 30% EtOAc 70% DCM. Contaminated fractions containing the desired product were pooled separately and concentrated then purified a second time to afford a second crop of A-4a (467.5 mg, 27%) albeit a little less pure:1H NMR (DMSO-d6) 6: 11.68 (s, 1H), 7.89 (s, 2H), 7.81 (s, 1H), 7.30 - 7.42 (m, 2H), 1.51 (s, 9H). LCMS: m / z = 493.0 [M-H]'.

[0537] Step 4: tert-Butyl (3-cyano-4-(2,6-dichloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (A-5a): to a green to brown suspension of CuCh (211 mg, 1.57 mmol) in MeCN (20.0 mL) was added dropwise tert-butylnitrite, (tech., 242 pL, 1.83 mmol). The suspension became darker and was left to stir for 5 min. Then intermediate A-4a (646 mg, 1.31 mmol) was added as a solid in one portion and the reaction mixture was heated at 60 °C. Gas evolution was noticed, and the mixture became a brown suspension. The mixture was allowed to stir at that temperature for 1 h. LCMS shows the reaction to be finished. The mixture was allowed to cool to RT, diluted with 25 mL of DCM and filtered through a short pad of celite, rinsing with DCM. The filtrate was diluted to about 100 mL with DCM and washed twice with 25 mL of a 0.5N aq. HCI solution (aqueous layer is slightly blue due to presence of copper). The combined aqueous layers were extracted 3 times with DCM and the combined organic layers (cloudy) were washed once with brine (becomes less cloudy) and dried over anhydrous MgSO4, filtered and concentrated. After drying under reduced pressure, intermediate A-5a (646 mg, 1.31 mmol) was obtained as a yellow solid and used as such.1H NMR (DMSO-d6) 5: 11.78 (s, 1 H), 8.32 (d, J = 0.8 Hz, 1H), 7.46 (dd, J = 8.3, 5.3 Hz, 1H), 7.41 (t, J = 8.8 Hz, 1H), 1.51 (s, 9H). LCMS: m / z 510.0 [M-H]'.

[0538] Preparation of tert-butyl (4-(3-amino-6-chloro-2-fluoro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate B-1a):

[0539]

[0540] To a solution of intermediate A-3a (857 mg, 1.87 mmol) in EtOH (15 mL) was added silver sulfate (606 mg, 1.94 mmol), followed by the addition of iodine (493 mg, 1.94 pmol). The reaction was left to stir in the dark for 2.5 h at RT. The reaction was transferred to a separatory funnel with EtOAc and diluted with water and aqueous sodium thiosulfate. The aqueous layer is extracted with 3x EtOAc. The combined organic fractions were washed with brine 2x and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue purified by flash chromatography (silica, EtOAc in hexanes, 0-30%) to afford intermediate B-1a (898 mg, 86 %) as a yellow-orange foam.1H NMR (CDCl3) 5: 7.80 (br. s., 1 H), 7.63 (d, J = 1.8 Hz, 1 H), 7.24 (dd, J = 8.3, 4.9 Hz, 1 H), 7.09 - 7.15 (m, 1 H), 4.23 (s, 2 H), 1.58 (s, 10 H). LCMS: m / z 560.0 [M-H]'.

[0541] Preparation of tert-butyl (4-(3-amino-2,6-dichloro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate B-1b):

[0542]

[0543] Step 1: tert-Butyl (4-(3-amino-2,6-dichlorophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate A-3b: tert-butyl (4-(3-amino-2-chlorophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate A-2b (0.920 g, 2.20 mmol) was dissolved in 2-MeTHF (23.2 mL) in a 200 mL flask and placed into an ice bath. 1,3-Dichloro-5,5-dimethylhydantoin (521 mg, 2.64 mmol) was added in 5 portions (-100 mg each) over the course of 2 h. The flask was allowed to slowly come to RT. The reaction was then quenched with aqueous sodium thiosulfate, transferred to a separatory funnel with ethyl acetate and diluted with water. The aqueous layer was extracted with ethyl acetate 3X. The combined organic fractions were washed with brine 2X and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (flash chromatography (silica, EtOAc in hexanes, 0-40%) to give the desired compound A-3b (753 mg, 76 %) as a yellow foam:1H NMR (DMSO-d6) 5: 11.62 (s, 1 H), 7.33 (t, J = 8.8 Hz, 1 H), 7.25 - 7.21 (m, 1 H), 7.19 (d, J = 8.9 Hz, 1 H), 6.88 (d, J = 8.9 Hz, 1 H), 5.57 (s, 2 H), 1.51 (s, 9 H). LCMS: m / z 510.0 [M-H]'.

[0544] Step 2: tert-butyl (4-(3-Amino-2,6-dichloro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate B-1b: To a solution of A-3b (500 mg, 1.11 mmol) in EtOH (11.1 mL) was added iodine (295 mg, 1.16 mmol) and silver sulfate (365 mg, 1.16 mmol). The resulting suspension was stirred at RT for 18 h. Then, the solvent was removed under reduced pressure and the crude was absorbed onto silica. The crude was purified by flash chromatography (silica, EtOAc in hexanes, 0-40%) to afford B-1b (558 mg, 87 %) as a yellow solid:1H NMR (DMSO-d6) 6: 11.69 (s, 1 H), 7.79 (s, 1 H), 7.34 (t, J = 8.8 Hz, 1H), 7.24 (dd, J = 8.6, 5.4 Hz, 1H), 5.48 (s, 2 H), 1.51 (s, 9 H). LCMS m / z 576.0 [M-H]'.

[0545] 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (intermediate E-4a):

[0546] Routes A and B:

[0547]

[0548] Step 1: Commercially available lactone E-1a can be regiospecifically nitrated and brominated as described in WO2023 / 183585 (step 1).

[0549] Step 2 (Route A): Reduction of lactone E-2a to phthalane derivative E-3a can be accomplished by the two step DIBAL-H then Et₃SiH / TFA reduction (step 2) followed by conversion of the nitro function to the corresponding aniline E-4a (sStep 3) also as described in the same patent document.

[0550] Step 2 (Route B): Conversion of lactone E-2a to phthalane E-3a was carried out in a single step using an indium tribromide-catalyzed I triethylsilane reduction adapting a procedure described in J. Org. Chem. 2007, 72, 5920 and detailed herein: argon was bubbled through distilled CHCh (40.0 mL) for 5 min. Lactone E-2a (2.00 g, 7.25 mmol) was added followed by indium tribromide (899 mg, 2.54 mmol) and triethylsilane (5.00 mL, 31.0 mmol). The reaction vessel was sealed, and the mixture was stirred at 60 °C for 3 h. The mixture was then cooled to RT, diluted with DCM (100 mL) then washed with water (50 mL). The aqueous phase was extracted with EtOAc (2 x 50 mL). The organic extracts (DCM and EtOAc) were dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, EtOAc and hexanes, 0-30%) to obtain E-3a (1.02 g, 54 %) as a yellow solid, identical in all respects to material obtain using Route A.1H NMR (DMSO-d₆) δ: 8.15 (d, J = 6.3 Hz, 1H), 5.16 (s, 2H), 5.08 (s, 2H).

[0551] SStep 3: Reduction of the nitro group provided aniline E-4a as described in WO2023 / 183585. Route C:

[0552]

[0553] Step 1: (4-Fluoro-,2-phenylene)dimethanol-2 (intermediate E-8a): To a stirred solution of LAH (1M, 391 mL, 391 mmol) in a 3-necked, 1L RBF, fitted with a thermometer and cooled in an ice / water bath, was cannulated over a 15 min period a solution of 4-fluorophthalic anhydride (34.0 g, 205 mmol) in THF (102 mL). Following the slight exothermic initial reaction, the mixture (clear and homogeneous, but yellow in color) was warmed to RT, then warmed to 45 °C for 45-60 mins. LCMS showed the complete consumption of the SM. The mixture was cooled again in an ice / water bath and a mixture of water (11 mL) in THF (40 mL) was added dropwise over a period of 1 h while flushing the system with a stream of nitrogen gas (caution: H2 gas evolution). EtOAc (200 mL) was added to the resulting white solid suspension, followed by slow addition of 300 mL of 2M H2SO4, then an additional 100 mL water. The phases were separated and the aqueous portion extracted with 2 x 100 mL EtOAc. Combined organic portions were washed with 100 m L sat'd NaHCO₃ and 2 x 100 mL brine. Drying over Na2SO4and removal of volatiles provided diol E-8a as a white solid (31.0 g, 97 %):1H NMR (DMSO-d₆) δ: 7.37 (dd, J = 8.3, 6.1 Hz, 1H), 7.19 (dd, J = 10.3, 2.7 Hz, 1H), 7.01 (td, J = 8.6, 2.8 Hz, 1H), 5.24 (t, J = 5.5 Hz, 1H), 5.09 (t, J = 5.4 Hz, 1H), 4.54 (d, J = 5.5 Hz, 2H), 4.46 (d, J = 5.5 Hz, 2H).

[0554] Step 2: 5-Fluoro-1,3-dihydroisobenzofuran (intermediate E-5a): To a mixture of E-8a from step 1 (23.5 g, 151 mmol) in MeCN (350 mL) was added dimethylcarbonate (50.8 mL, 603 mmol), followed by the portion wise addition of solid sodium methoxide (16.3 g, 302 mmol) resulting in a white suspension. This mixture was heated to 80 °C for 18 h. The reaction was quench by addition of water (50 mL) and the MeCN was removed under reduced pressure (caution: product is volatile). EtOAc (150 mL) and brine (50 mL) were added and 4N HCI was added dropwise under vigorous stirring (caution: gas evolution). The organic phase was separated and the aqueous phase extracted with EtOAc (150 mL). Combined organic phases were dried (Na2SO4), evaporated and the product purified by flash chromatography (silica, DCM in hexanes, 0-40%). Obtained 5-fluoro-1,3-dihydroisobenzofuran E-5a (14.0 g, 67 %) as a clear colorless oil:1H NMR (CDCl3) δ: 7.18 (dd, J = 8.1, 4.9 Hz, 1H), 6.90 - 7.01 (m, 2 H), 5.08 (s, 2H), 5.09 (s, 2 H).

[0555] SStep 3: 5-Fluoro-6-nitro-1,3-dihydroisobenzofuran (intermediate E-6a): To cold (-30 °C) cone, sulfuric acid (60.0 mL) was added neat 5-fluoro-,3-dihydroisobenzofuran E-5a from step 2 (10.0 g, 72.4 mmol), producing a light-yellow solution. To this solution, a cold (0-4 °C) freshly prepared solution of KNO3 (7.39 g, 72.4 mmol) in sulfuric acid (40.0 mL) was added through an addition funnel over a period of 15 min. The resultant light-yellow mixture was slowly brought to -10 °C over 30 min. LCMS showed complete consumption of E-5a. The reaction mixture was poured onto crushed ice-water (450 g) and the product was collected by filtration, washed with water (500 mL) and dried under vacuum to give 5-fluoro-6-nitro-,3-dihydroisobenzofuran E-6a (11.4 g, 86 %) as a beige solid:1H NMR (CDCl₃) δ: 7.94 (d, J = 6.6 Hz, 1H), 7.18 (d, J = 10.0 Hz, 1H), 5.15 (br. s., 2H), 5.14 (br. s., 2H). LCMS m / z 182.1 [M-H]’.

[0556] Step 4: 4-Bromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (intermediate E-3a): To a cold (-15 °C) stirred solution of 5-fluoro-6-nitro-,3-dihydroisobenzofuran E-6a from sStep 3 (6.50 g, 35.5 mmol) in sulfuric acid (130 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (10.2 g, 35.8 mmol) in portions over 50 min. The reaction temperature was maintained between -10 to -5 °C during the addition. After the addition is complete, the reaction mixture was stirred at the same temperature for 2 h (conversion is monitored by LCMS) then poured into crushed ice (750 g). After 1 h, the product gradually crashed out, was collected by filtration and rinsed with water (20 mL). The crude material was dissolved in DCM, washed with aq 10% aq. sodium thiosulfate and brine, and dried (Na2SO4). After removal of volatiles, the residue was purified by flash chromatography flash chromatography (silica, EtOAc in hexanes, 0-35% to give 5-fluoro-6-nitro-,3-dihydroisobenzofuran E-3a as a white solid (4.79 g, 52 %):1H NMR (CDCI3) 5: 7.86 (d, J = 5.8 Hz, 1H), 5.25 (s, 2H), 5.15 (s, 2H).

[0557] 4,7-Dibromo-5-fluoro-6-nitro-1,3-dihydroisobenzofuran (1.84 g, 15 %) was also obtained as a side product: 1H NMR (DMSO-d₆) δ: 5.21 (s, 2H), 5.17 (br. s, 2H).

[0558] Further elution gave unreacted SM E-3a (700 mg, 10.7%).

[0559] Step 5: 7-Bromo-6-fluoro-1,3-dihydroisobenzofuran-5-amine (intermediate E-4a): Reduction of the nitro group to the corresponding aniline proceeded as described in WO2023 / 183585.

[0560] Route D:

[0561]

[0562] Step 1: 5-Fluoro-1,3-dihydroisobenzofuran (intermediate E-5a): distilled CHCh (30 mL) was degassed with argon for 5 min. 5-fluoroisobenzofuran-1(3H)-one E-1a (1.00 g, 6.57 mmol) was added followed by indium tribromide (816 mg, 2.30 mmol) and triethylsilane (4.20 mL, 26.0 mmol). The reaction vessel was sealed and the mixture was stirred at 60 °C for 2.5 h. After cooling to RT, the reaction mixture was diluted with DCM (50 mL) and washed with water (20 mL). The aqueous phase was extracted with EtOAc (2 x 20 mL). The organic extracts (DCM and EtOAc) were dried (Na2SO4) and concentrated (caution: product is volatile). The crude material was purified by flash chromatography (silica, EtOAc in hexanes, 0-50%) to obtain 5-fluoro-1,3-dihydroisobenzofuran E-5a (586 mg, 65 %) as a colorless oil.1H NMR (DMSO-d₆) δ: 7.32 (dd, J = 8.2, 5.1 Hz, 1H), 7.16 (dd, J = 8.9, 2.0 Hz, 1H), 7.05 - 7.12 (m, 1H), 4.98 (s, 2H), 4.96 (s, 2H).

[0563] Remaining steps: as described for steps 3-5 of route C.

[0564] 7-Chloro-6-fluoro-1,3-dihydroisobenzofuran-5-amine (intermediate E-4b):

[0565]

[0566] The preparation of intermediate E-4b from 4-chlorophtahlic anhydride E-7b proceeded as described in WO2023 / 183585.

[0567] tert-Butyl (4-(2-chloro-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate F-4a): Route A:

[0568]

[0569] Step 1: 6-Fluoro-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3-dihydroisobenzofuran-5-amine (intermediate F-1a): In a microwave vial (20 ml) containing a magnetic stir bar was weighed intermediate E-4a (534 mg, 2.30 mmol) along with bis(pinacolato)diboron (818 mg, 3.22 mmol) and KOAc (678 mg, 6.90 mmol). Dioxane (7.5 mL) was added and the resulting suspension was degassed by bubbling argon through it for 15 minutes and another 5 minutes with sonication.

[0570] [1,1'-bis(diphenylphosphino)ferrocene]dichloropalladium(ll), DCM adduct (94.0 mg, 115 μmol) was then added and argon was bubbled through the dark red suspension for another 5 minutes. The vial was capped and immersed in an oil bath at 100 °C and stirred overnight. LCMS after 18 h showed complete consumption of the starting material and the appearance of the desired product. The mixture was allowed to cool to RT then filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated on silica gel and the product isolated by flash chromatography (silica, EtOAc in hexanes, 0-20%). Boronate F-1a was obtained as an off-white solid (390 mg, 61 %).1H NMR (CDCl3) δ: 6.75 (d, J = 7.9 Hz, 1 H), 5.13 (s, 2 H), 5.00 (br. s., 2 H), 3.71 (br. s., 2 H), 1.36 (s, 12 H). LCMS m / z 280.0 [M+H]+.

[0571] Alternatively, 7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1,3-dihydroisobenzofuran-5-amine can be prepared as follows and used in step 2 to provide F-2a: In an oven dried vial (20 mL) was weighed intermediate E-4a (375 mg, 1.62 mmol) along with potassium acetate (476 mg, 4.85 mmol) and bis(neopentylglycolato)diboron (559 mg, 2.42 mmol). Dioxane (7.00 mL) was added and the resulting suspension was degassed by bubbling argon through it for 15 minutes. Dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(l I) (116 mg, 162 μmol) was then added and argon was bubbled through the dark red suspension for another 5 minutes. The vial was capped and heated at 95 °C for 2h. LCMS after 2h hours showed complete consumption of the starting material and the appearance of the desired product. The mixture was allowed to cool to RT then filtered through a pad of Celite, rinsing with EtOAc. The filtrate was concentrated and purified by flash chromatography (silica, EtOAc in hexanes, 0-20%) to give 7-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-6-fluoro-1,3-dihydroisobenzofuran-5-amine (388 mg, 91 %) as a white solid:1H NMR (CDCl3) δ: 6.75 (d, J = 7.9 Hz, 1H), 5.12 (t, J = 2.0 Hz, 2H), 4.99 (br. s, 2H), 3.80 (s, 4H), 1.05 (s, 6H). LCMS m / z 266.0 [M+H]+.

[0572] Step 2: tert-Butyl (4-(6-amino-5-fluoro-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate F-2a): commercially available tert-butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate-2 (472 mg, 1.27 mmol) and intermediate F-1a (390 mg, 1.40 mmol) were weighed in a vial and suspended in dioxane (7.5 mL) and water (1.9 mL). K₂CO₃ (527 mg, 3.81 mmol) was added then argon was bubbled through the mixture for 5 minutes with sonication. Tetrakis(triphenylphosphine)palladium(0) (73.4 mg, 63.5 μmol) was then added and argon was bubbled through the mixture for another 5 minutes with sonication. The vial was capped and placed in a block pre-heated at 75 °C. After 4 h of vigorous stirring at that temperature LCMS showed partial conversion to the desired product. The reaction mixture was cooled to RT, poured into EtOAc and brine was added. The organic layer was separated and washed with brine, dried over Na2SO4, filtered and concentrated. The material was adsorbed on silica and purified by flash chromatography (silica, EtOAc in hexanes, 0-50%). Intermediate F-2a was obtained as a yellow foam (295 mg, 52%):1H NMR (CDCl₃) δ: 7.82 (br. s., 1H), 7.27 (d, J = 5.0 Hz, 1H), 7.11 (dd, J = 9.1, 8.3 Hz, 1H), 6.79 (d, J = 7.50 Hz, 1H), 4.99 - 5.15 (m, 2H), 4.88 (d, J = 11.9 Hz, 1 H), 4.69 (d, J = 11.9 Hz, 1 H), 3.84 (s, 2H), 1.59 (s, 9H).

[0573] SStep 3: tert-Butyl (4-(2-amino-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate (F-3a): To a suspension of F-2a (235 mg, 530 μmol) in AcOH (1.0 mL) in an ice-bath was added KSCN (208 mg, 2.12 mmol) affording a yellow suspension. The mixture was stirred for about 5 minutes then bromine (59.9 μL, 1.17 mmol) in 180 μL of AcOH was added dropwise, over 10 minutes. The mixture was allowed to stir at RT for 5 minutes and was then warmed to 35 °C in a pre-heated block. After 1 h, LCMS, indicated consumption of the SM and the appearance of the desired product. The mixture was cooled, and the product was crashed with H2O, filtered, washed with H2O, and allowed to air-dry giving the crude material as a bright yellow solid (270 mg). The crude product was purified by flash chromatography (silica, EtOAc in DCM, 0-100%):1H NMR (CDCl3) δ: 7.80 (br. s., 1H), 7.27 - 7.32 (m, 1H), 7.11 (t, J = 8.7 Hz, 1H), 5.58 (br. s., 2H), 5.12 - 5.28 (m, 2H), 4.94 (d, J = 12.5 Hz, 1H), 4.83 (d, J = 12.4 Hz, 1H), 1.58 (s, 9H). LCMS m / z 500.9 [M+H]+.

[0574] Step 4: tert-Butyl (4-(2-chloro-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate F-4a): See route B (step 4) below.

[0575] Route B:

[0576]

[0577] Step 1: tert-Butyl (4-(6-amino-5-fluoro-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate F-2a): A mixture of E-4a (5.55 g, 23.9 mmol), dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(ll) (3.49 g, 4.78 mmol), cesium carbonate (24.5 g, 75.3 mmol) and tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (14.5 g, 35.9 mmol) in THF (300 mL) was sparged with Ar gas through the stirred mixture for 15 mins, then placed in an oil bath pre-heated to 70 °C. This mixture was stirred for 90 mins, after which LCMS indicated that the limiting reagent had been consumed. The reaction was cooled to RT, then filtered over a glass fiber filter disk and the solids were washed with several small portions of THF. The filtrates and washings were combined and evaporated to give a black oil. To this was added 100 mL of DCM and the mixture stirred at RT. Rapidly, a grey solid forms. The resultant suspension was stirred for 30 mins, then the solids were filtered over a filter paper (NOTE: This material is the Cs salt of F-2a. This material was combined with 250 mL EtOAc and 100 mL water was added. To this stirred triphasic mixture was added 9 mL of acetic acid (Caution: CO2 gas evolution). Following the dissolution of all the solids, the organic portion was separated, washed with 50 mL sat'd NaHCC>3(aq), dried over Na2SO4, filtered and evaporated. The material was purified by flash chromatography (silica, EtOAc in hexanes, 10-50%). Intermediate F-2a was obtained (8.77 g, 83 %) as a light pink solid:1H NMR (DMSO-d₆) δ: 11.59 (br. s., 1 H), 7.15 - 7.45 (m, 2H), 6.74 (d, J = 7.5 Hz, 1H), 5.13 (br. s., 2H), 4.87 - 4.99 (m, 2H), 4.67 (d, J = 11.6 Hz, 1 H), 4.50 (d, J = 11.5 Hz, 1 H), 1.51 (s, 9H). LCMS: m / z 568.0 [M-H]-.

[0578] Separation of F-2a atropisomers:

[0579]

[0580] (more active P-atropisomer) Separation of geometrical atropisomers on a preparative scale was performed by HPLC on a chiral support using a Lux 5 pm cellulose-1 (OD) column (150 x 21.2 mm) at a flow rate of 10 mL / min using an isocratic gradient of 12% iPrOH in hexane (250 mg / injection in 5% DCM / 25% EtOH / 70% hexane). Analysis of fractions was performed using a Lux 3 pm cellulose-1 (OD) column (50 x 2 mm) at a flow rate of 0.3 mL / min using an isocratic gradient of 7.5% EtOH + 7.5% MeOH in hexane. The second eluting component was found to provide more active analogs (P-atropisomer).

[0581] Step 2: tert-butyl (4-(6-amino-5-fluoro-7-iodo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate G-1a): To a stirred solution of intermediate F-2a (432 mg, 0.974 mmol) in ethanol (10.0 mL) was sequentially added iodine (247 mg, 0.974 mmol) and silver sulfate (304 mg, 0.974 mmol). The resultant reaction mixture was stirred at RT in the dark for 3 h. Beige solids were precipitated, and the iodine color disappeared. The reaction mixture was diluted with ethyl acetate (40 mL) and washed with aq. 10% sodium thiosulfate. The aqueous phase was extracted with ethyl acetate (2 x 20 mL) and combined organic extracts were dried (Na2SO4) and concentrated. The residue was purified by flash chromatography (silica, EtOAc in hexanes, 10-60%) to give intermediate G-1a (480 mg, 87 %) as a light yellow solid:1H NMR (DMSO-d₆) δ: 11.67 (s, 1H), 7.26 - 7.42 (m, 2H), 5.20 (s, 2H), 4.83 - 4.94 (m, 3H), 4.67 -4.76 (m, 1H), 1.52 (s, 9H). LCMS: m / z 568.0 [M-H]’. SStep 3: tert-Butyl (4-(2-amino-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate F-3a): A mixture of G-1a (1.44 g, 2.53 mmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (1.17 g, 5.06 mmol) in ACN (28 mL) was stirred at 80 °C for 1 h. The reaction mixture was quenched with NH4OH (1.18 mL, 17.7 mmol) and stirred for 0.5 h. Volatiles were evaporated in vacuo, and the residue was dissolved in DME (42.2 mL). Then, copper (I) iodide (96.3 mg, 506 μmol), 1,10-phenanthroline (182 mg, 1.01 mmol) and cesium carbonate (1.65 g, 5.06 mmol) were added and the mixture was stirred at 70 °C for 0.5 h. The crude was purified by flash chromatography (silica, EtOAc in DCM, 0-100%) to yield F-3a (1.10 g, 87 %) as a white powder:1H NMR (DMSO-d₆) δ: 11.64 (s, 1 H), 7.81 (s, 2H), 7.40 (dd, J = 8.0, 5.6 Hz, 1H), 7.32 (t, J = 8.7 Hz, 1H), 5.08 (s, 2H), 4.84 (d, J = 12.3 Hz, 1H), 4.65 (d, J = 12.0 Hz, 1H), 1.51 (s, 9H). LCMS m / z 501.2 [M+H]+.

[0582] Step 4: To a green suspension of cupric chloride dihydrate (195 mg, 1.14 mmol) in ACN (6.3 mL) in a 100-mL RBF under argon, was added tert-butylnitrite, tech. (189 μL, 1.43 mmol) dropwise at 0 °C. The suspension became darker. Then, intermediate F-3a (476 mg, 951 μmol) was added portion-wise to the reaction mixture at 0 °C. The suspension was stirred for 50 min at 0 °C (LCMS conversion shows 68% of product, clean conversion). Then, the reaction was stirred for an additional 60 min at RT (LCMS conversion shows 90%). The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in EtOAc and washed with NaHCO₃, then brine. The organic phase was separated and dried over Na2SO4and then concentrated under reduced pressure to afford crude material that was absorbed onto silica from a DCM solution and purified by flash chromatography (Silica, EtOAc in hexanes, 0-35%) to afford chlorothiazole intermediate F-4a (444 mg, 90 %) as a pink solid:1H NMR (DMSO-d₆) δ: 11.74 (s, 1H), 7.50 (dd, J = 8.1, 5.4 Hz, 1H), 7.37 (t, J = 9.3 Hz, 1H), 5.26 (br. s., 2H), 4.99 (d, J = 13.4 Hz, 1H), 4.76 (d, J = 13.3 Hz, 1H), 1.51 (s, 9H). LCMS m / z 418.0 [M-Boc-H]’.

[0583] Preparation of tert-Butyl (4-(6-amino-5-chlororo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate F-2b) and separation of the two atropisomers by HPLC on a chiral support:

[0584]

[0585] 1steluting isomer 2ndeluting peak

[0586] (F-2b more active P-isomer) (F-2b less active / W-isomer)

[0587] Step 1: In a 500-mL oven-dried flask was placed intermediate E-4b (5.00 g, 20.1 mmol), Cs2CO3(16.5 g, 50.7 mmol), tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (9.76 g, 24.1 mmol) and dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(ll) (2.35 g, 3.22 mmol) in THF (300 mL). The flask was fitted with a reflux condenser and a rubber septum, an argon filled balloon and a vent needle. The mixture was stirred and sparged with argon gas for 10 min. then the vent needle was removed, and the flask placed in an oil bath pre-heated to 70 °C. The reaction was stirred at this temperature under a static atmosphere of argon. After 3 h of stirring, the reaction mixture was cooled to RT, then filtered through a glass fiber filter disk, and then the filter cake (this filter cake was conserved, called cake A) was washed with 2 x 100 mL THF. The filtrate and washings were combined and then concentrated under reduced pressure. This gives a dark red / black mixture to which was added 100 mL DCM and warmed slightly to 35 °C under gentle stirring. A light-grey solid formed and this suspension was left stirring for 30 mins before allowing to stand in an ice bath before filtering and rinsing the solids with several small portions of cold DCM. The light-grey solids (Cs salt of intermediate F-2b) were dried under vacuum to constant mass (10.0 g):1H NMR (DMSO-d₆) δ: 6.84 - 6.90 (m, 1H), 6.76 - 6.82 (m, 1H), 6.71 (s, 1H), 5.75 (s, 2H), 5.25 (s, 2H), 4.87 - 4.97 (m, 2H), 4.40 - 4.55 (m, 2H), 1.40 (s, 9H). LCMS m / z 458.1 [M-H]’.

[0588] The filtrate and washings from above were combined with cake A and EtOAc (200 mL) and water (100 mL) was added followed by slow addition (caution, gas evolution) of AcOH (10 mL). After stirring for 15 mins, the phases were separated, and the organic portion washed with 100 mL saturated NaHCC>3(aq) and 50 mL brine. After drying over Na2SO4and removal of volatiles, the residue was chromatographed on silica gel to provide product as the neutral form (0.500 g, 6.8 %).

[0589] The neutral product and the Cs salt from above were mixed with EtOAc (150 mL) and water (50 mL). To this stirred tri-phasic mixture was added AcOH (2 mL) and after stirring for 10 min. the layers were separated, and the organic portion was washed with 25 mL sat'd NaHCO3(aq), dried over Na2SO4, filtered and evaporated. Intermediate F-2b was obtained as a light green solid (6.00 g, 84 %): ):1H NMR (DMSO-d6) δ: 11.57 (br. s., 1 H), 7.18 - 7.35 (m, 2H), 6.79 (s, 1 H), 5.38 (s, 2H), 4.83 - 5.05 (m, 2H), 4.57 (d, J = 11.5 Hz, 1H), 4.41 (d, J = 11.5 Hz, 1H), 1.51 (s, 9H). LCMS m / z 458.1 [M-H]-. LCMS m / z 460.1 [M+H]+.

[0590] Separation of F-2b atropisomers:

[0591] Separation of geometrical atropisomers on a preparative scale could be achieved by HPLC on a chiral support using a Lux 5 pm cellulose-1 (AD) column (150 x 21.2 mm) at a flow rate of 10 mL / min using an isocratic gradient of 5% EtOH / 5% MeOH in hexane (175 mg / injection in 5% DCM / 15% MeOH / 10% EtOH in 70% hexane). Analysis of fractions was performed using a Lux 3 pm cellulose-1 (AD) column (50 x 2 mm) at a flow rate of 0.3 mL / min using an isocratic gradient of 7.5% EtOH + 7.5% MeOH in hexane. The first eluting component was found to provide more active analogs (P-atropisomer).

[0592] Separation of geometrical atropisomers on a preparative scale could also be achieved by SFC on a chiral support using a Lux 5 pm cellulose-1 (AD) column (250 x 50 mm) at a flow rate of 250 mL / min using an isocratic gradient of 30% MeOH (63 mg / injection) and an oven temperature of 40 °C. The more active P-atropisomer was the first eluting peak.

[0593] Preparation of tert-butyl (3-cyano-4-(2,4-dichloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (racemic or chiral intermediate F-4b): prepared from intermediate F-2b (racemic or chiral) following the same procedures described in route B for intermediate F-4a.

[0594]

[0595]

[0596] Step 1: tert-Butyl (4-(6-amino-5-chloro-7-iodo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate G-1b): To a stirred solution of racemic intermediate F-2b (500 mg, 1.09 mmol) in 1:1 EtOH-DCM (10.0 mL) was sequentially added silver sulfate (339 mg, 1.09 mmol) and iodine (276 mg, 1.09 mmol) at RT. The reaction flask was protected from light and stirred at RT for 1.5 h when LCMS showed complete consumption of the starting material. The resultant white suspension was diluted with DCM, adsorbed onto silica (10 g) and purified by flash chromatography (silica, EtOAc in hexanes, 10-70%) to give intermediate G-1b (610 mg, 96 %) as a pink solid:1H NMR (DMSO-d6) δ: 11.65 (s, 1H), 7.25 - 7.36 (m, 2H), 5.35 (s, 2H), 4.84 - 4.96 (m, 2H), 4.79 (d, J = 11.8 Hz, 1 H), 4.63 (d, J = 11.8 Hz, 1 H), 1.52 (s, 9H). LCMS m / z 584.0 [M-H]’.

[0597] Step 2: tert-Butyl (4-(2-amino-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate F-3b): a mixture of intermediate G-1b from step 1 (3.20 g, 5.46 mmol) and 1,1'-Thiocarbonyldi-2(1H)-pyridone (2.67 g, 10.9 mmol) in toluene (61 mL) was stirred at 80 °C for 22h. LCMS at 22h shows less than 10% of starting material left. The yellow suspension was cooled down to RT and then ammonium hydroxide (3.69 mL, 54.6 mmol) was added in one portion. The resulting suspension was stirred for 30 min at RT (LCMS shows complete conversion to the thiourea). The reaction mixture was concentrated under reduced pressure, and the residue was resuspended in DME (91 mL). To this solution was added copper (I) iodide (208 mg, 1.09 mmol), 1,10-phenanthroline (394 mg, 2.18 mmol) and Cs2CO3(3.56 g, 10.9 mmol). The mixture was stirred at 70 °C for 30 min (LCMS shows complete conversion to the aminobenzothiazole). After this, the mixture was allowed to cool down to RT and then, 200 mL of water / ice were added to precipitate the crude product. After stirring for 10 min at 0 °C (ice water bath), the suspension was filtered and the solid was washed with cold water several times. The crude solid was dried under vacuum for 18h to obtain the desired aminobenzothiazole F-3b (3.14 g, 111 %) of a brown solid that was used without further purification: LCMS m / z 517.0 [M+H]+.

[0598] SStep 3: tert-Butyl (3-cyano-4-(2,4-dichloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (Intermediate F-4b): To a green suspension of cupric chloride dihydrate (258 mg, 1.51 mmol) in ACN (8.39 mL) in a 100-ml RBF under argon, was added tert-butylnitrite, tech. (250 pL, 1.89 mmol) dropwise at 0 °C. Intermediate F-3b from above (651 mg, 1.26 mmol) was then added portion wise to the reaction mixture at 0 °C. The suspension was stirred for 45 min (LCMS conversion shows 50% of product, clean conversion). Then, the reaction was stirred for an additional 45 min at RT (LCMS conversion shows >90%). The reaction mixture was then concentrated under reduced pressure, and the crude was re-dissolved in EtOAc and washed with NaHCO₃, then brine. The organic phase was separated and dried over Na2SC>4 and then concentrated under reduced pressure to afford the crude material. The crude was absorbed onto silica from a DCM solution and purified by flash chromatography (silica, EtOAc in hexanes, 0-35%), the pure fractions were pooled and concentrated to dryness to afford racemic intermediate F-4b (588 mg, 87 %) as a yellow solid:1H NMR (DMSO-d6) δ: 11.71 (s, 1H), 7.34 -7.43 (m, 2H), 5.28 (t, J = 2.1 Hz, 2H), 4.88 (dt, J = 13.0, 2.5 Hz, 1H), 4.68 (dt, J = 13.0, 2.4 Hz, 1H), 1.51 (s, 9H). LCMS m / z 536.0 / 538.0 [M-H]’.

[0599] (See following section for isolation and characterization of enantiomerically pure (P)-F-5b).

[0600] Preparation of tert-butyl (P)-(3-cyano-4-(2,4-dichloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate P-F-4b) and tert-butyl (4-(4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate P-F-5b):

[0601]

[0602] (P)-F-2b (P)-G-1c (P)-F-3b

[0603] (chiral P-atropisomer)

[0604]

[0605] Step 1: tert-Butyl (P)-(4-(6-amino-7-bromo-5-chloro-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate P-G-1c): tert-butyl (P)-(4-(6-amino-5-chloro-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (2.00 g, 4.09 mmol; contained 6% MeOH) was charged in a 500 mL rb flask and dissolved in anhydrous THF (81.8 mL). The flask was immersed in an ice / water bath and the pale tan solution was stirred for 15 minutes. Recrystallized N-bromosuccinimide (720 mg, 4.05 mmol) was then added in one portion. The resulting reaction mixture was allowed to stir in the ice / water bath for 30 minutes and was then monitored by LCMS which revealed the reaction was clean and complete. Saturated sodium thiosulfate solution (2 mL) was diluted in 10 mL of water and added to the mixture. The flask was removed from the cooling bath and stirred vigorously for 30 minutes. The mixture was then gently concentrated (without heating) under reduced pressure until the volume was about 1 / 4 of what it was originally. Some crystals could be observed. Water (~30 mL) was added, and crystallization occurred rapidly. The mixture was stirred vigorously for 10 minutes then the solids were collected by filtration on a hardened filter paper in a Buchner funnel, washing with water (~30 mL). After air-drying on the filter, the pale-yellow solids were transferred into a flask and further dried under vacuum to afford intermediate (P)-G-1c (2.18 g, 99 %) as a pale yellow solid:1H NMR (DMSO-d6) δ: 11.66 (s, 1H), 7.19 - 7.41 (m, 2H), 5.48 (s, 2H), 4.89 - 5.07 (m, 2H), 4.74 (d, J = 11.8 Hz, 1 H), 4.58 (d, J = 11.9 Hz, 1 H), 1.51 (s, 9H). LCMS m / z 482.0 [M-C4H7]+.

[0606] Step 2: tert-Butyl (P)-(4-(2-amino-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate P-F-3b): The bromoaniline from step 1 (6.01 g, 10.6 mmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (3.81 g, 15.9 mmol) were suspended in toluene (35.3 mL) and the flask was flushed with nitrogen and placed under a balloon atmosphere of nitrogen. The mixture was placed in an oil bath preheated at 80 °C and stirred for 23 h, affording a clear orange solution. The mixture was then allowed to cool to RT, concentrated aqueous ammonium hydroxide (6.06 mL, 84.8 mmol) was added and stirring at RT resumed for 2 h. LCMS analysis indicated the thiourea intermediate was formed. The mixture was concentrated to dryness and further dried under reduced pressure.

[0607] The crude material from above was dissolved in DME (53 mL). Nitrogen was bubbled through the mixture for 5-6 minutes then K₂CO₃ (2.93 g, 21.2 mmol) was added followed by copper (I) iodide (101 mg, 530 pmol) and 1,10-phenanthroline (193 mg, 1.06 mmol). Nitrogen was bubbled through with sonication for another 3-4 minutes and the mixture was heated in an oil bath set to 70 °C under an atmosphere of nitrogen. After 4 h, LCMS analysis showed -50% conversion. Another portion of 1,10-phenanthroline (193 mg, 1.06 mmol) and copper (I) iodide (101 mg, 530 pmol) were added and after stirring an additional 30 min at 70 °C, the conversion was complete. The mixture was allowed to cool to RT and diluted with EtOAc (500 mL) and water (100 mL). The mixture was carefully made acidic with a 1 N solution of HCI and filtered through a plug of cotton to remove insoluble particles. The layers were separated, and the aqueous layer was extracted with two more 100 mL portions of EtOAc. The combined organic layers were washed with brine then dried over anhydrous MgSO4, filtered and concentrated. The resulting off-white solid was further dried under reduced pressure to provide the desired aminothiazole in 90% purity (6.11 g, 100 %) that was used as such in the next step: LCMS m / z 517.1 [M+H]+.

[0608] SStep 3: tert-Butyl (P)-(3-cyano-4-(2,4-dichloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (intermediate P-F-4b): A 500 mL round-bottomed flask was charged with tert-butyl (P)-(4-(2-amino-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (6.90 g, 13.35 mmol ), anhydrous copper (II) chloride (3.05 g, 22.7 mmol), acetonitrile (90 mL) and 1,2-dichloroethane (90 mL). The reaction mixture was then maintained under a light vacuum (50 mbar) for 2 min and then flushed with nitrogen (this process was repeated three times). The mixture was treated at 23 °C with isopentyl nitrite (3.23 mL, 24.0 mmol) in acetonitrile (15 mL), added dropwise over 45 minutes. The resulting black mixture was stirred for 18 h. The reaction mixture was concentrated under reduced pressure, and the dark residue was partitioned between EtOAc (500 mL), saturated aqueous ammonium chloride (125 mL) and water (100 mL). The organic phase was collected. The aqueous phase was extracted with EtOAc (2 x 100 mL) and the combined organic phases washed with brine and dried over MgSO4. Evaporation of the solvent under reduced pressure yielded 7.48 g of a light orange-brown amorphous residue that was purified by flash chromatography (silica, EtOAc in DCM 1-4% to elute P-F-4b and then 30% EtOAc to elute side product P-F-5b.

[0609] Int-P-F-4b (5.45 g, 74%):1H NMR (CDCl3) 5: 7.78 (br. s, 1 H), 7.24 (dd, J= 8.3, 4.9 Hz, 1 H), 7.14 (t, J=8.7 Hz, 1 H), 5.24 - 5.37 (m, 2 H), 4.89 - 4.96 (m, 1 H), 4.82 (dt, J = 12.9, 2.4 Hz, 1 H), 1.57 (s, 9 H). LCMS m / z 479.8 [M+H-tBu]+. LCMS m / z 534.0 [M-H]’.

[0610] Int-P-F-5b (0.58 g, 8%):1H NMR (CDCl3) 5: 9.13 (s, 1 H), 7.77 (br. s. 1 H), 7.24 - 7.31 (m, 1 H), 7.15 (t, J = 8.6 Hz, 1 H), 5.32 - 5.45 (m, 2 H), 4.94 - 5.00 (m, 1 H), 4.86 (dt, J = 12.8, 2.5 Hz, 1 H), 1.57 (s, 9 H). LCMS m / z 502.0 [M+H]+.

[0611] tert-Butyl (3-cyano-7-fluoro-4-(4-fluoro-2-(2,2,2-trifluoroethoxy)benzo[d]oxazol-5-yl)benzo[b]thiophen-2-yl)carbamate (intermediate J-7):

[0612]

[0613] Step 1: 1-Bromo-2-fluoro-4-methoxy-3-nitrobenzene J-1: Bromine (35 g, 570 mmol) was added dropwise to a solution of 3-fluoro-2-nitroanisole (24.5 g, 142 mmol) in AcOH (285 mL). The reaction mixture was warmed to 55 °C and stirred for 17 h, after which time the reaction mixture was concentrated in vacuo to give a crude solid. The crude solid was suspended in saturated NaHCO₃ solution and extracted with EtOAc. Layers were separated and the organic phase was washed with saturated NaHCO3solution, dried with Na2SO4, filtered, and concentrated in vacuo to give the desired product 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene-1 J-1 (35.2 g, 99 %) as a yellow solid that was used without purification:1H NMR (DMSO-d6) δ: 7.97 (dd, J = 8.0, 9.3 Hz, 1H), 7.23 (dd, J = 1.8, 9.4 Hz, 1H), 3.95 (s, 3H).

[0614] Step 2: 3-Bromo-2-fluoro-6-methoxyaniline J-2: To a mixture of 1-bromo-2-fluoro-4-methoxy-3-nitrobenzene (35 g, 140 mmol), MeOH (192 mL), water (192 mL) and NH4CI (30.3 g, 567 mmol) was added iron metal (23.5 g, 421 mmol). The reaction mixture was heated to 60 °C for 2 h. The reaction mixture was then cooled to RT and filtered over a Celite® pad. The volatiles were removed under reduced pressure and the product was extracted with EtOAc. The organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 3-bromo-2-fluoro-6-methoxyaniline J-2 (19.7 g, 64 %) as a solid.1H NMR (DMSO-d6) δ: 6.76 (dd, J = 8.8, 7.5 Hz, 1H), 6.65 (dd, J = 8.8, 1.4 Hz, 1H), 4.96 (s, 2H), 3.78 (s, 3H). LCMS m / z 219.9 [M+H]+. SStep 3: 2-Amino-4-bromo-3-fluorophenol J-3: A solution of boron tribromide (25.0 g, 99.7 mmol) in DCM (100 mL) was added dropwise to a suspension of 3-bromo-2-fluoro-6-methoxyaniline J-2 (9.07 g, 41.2 mmol) in DCM (288 mL) at 0 °C. The reaction mixture was stirred at RT for 18 h. The reaction mixture was then cooled to 0 °C and carefully quenched with a saturated solution of NaHCO₃. The mixture was diluted with DCM and the aqueous layer was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 2-amino-4-bromo-3-fluorophenol J-3 (7.97 g, 94 %) as a solid:1H NMR (DMSO-d6) δ: 9.73 (br. s., 1H), 6.63 (dd, J = 8.5, 7.6 Hz, 1H), 6.48 (dd, J = 8.6, 1.6 Hz, 1H), 4.71 (br. s., 2H).

[0615] Step 4: 5-Bromo-4-fluorobenzo[d]oxazol-2(3H)-one J-4: A 15% solution of phosgene (33.1 mL, 46.4 mmol) in toluene was added slowly to a solution of 2-amino-4-bromo-3-fluorophenol J-3 (7.97 g, 38.7 mmol) in THF (193 mL) at 0 °C. The reaction mixture was stirred for 2 h and quenched with cold water. The aqueous layer was extracted with EtOAc. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to give the title compound 5-bromo-4-fluorobenzo[d]oxazol-2(3H)-one J-4 (8.78 g, 98 %) as a solid:1H NMR (DMSO-d6) δ: 12.50 (s, 1H), 7.38 (dd, J = 8.5, 6.8 Hz, 1H), 7.16 (dd, J = 8.6, 0.7 Hz, 1 H). LCMS m / z 229.8 and 231.8 [M-H]’.

[0616] Step 5: 5-Bromo-2-chloro-4-fluorobenzo[d]oxazole J-5: A mixture of 5-bromo-4-fluorobenzo[d]oxazol-2(3H)-one J-4 (4.64 g, 20.0 mmol), PCIs (37.5 g, 180 mmol) and POCI3 (80.0 mL, 858 mmol) was heated to 120-125 °C for 6 h and then cooled to RT. The reaction mixture was poured into 3 L of crushed ice and shaken manually. The mixture was stirred until the quench was completed (no more endotherm). The solid was filtered and summarily air-dried. The solid was recovered in DCM, dried over MgSO4and filtered. The solvent was concentrated under reduced pressure to give the title compound 5-bromo-2-chloro-4-fluorobenzo[d]oxazole J-5 (1.54 g, 31 %):1H NMR (DMSO-d6) δ: 7.79 (dd, J = 8.9, 6.5 Hz, 1H), 7.67 (dd, J = 8.8, 0.7 Hz, 1H).

[0617] Step 6: 5-Bromo-4-fluoro-2-(2,2,2-trifluoroethoxy)benzo[d]oxazole J-6: DIEA(105 pL, 600 pmol) was added to a suspension of J-5 (150 mg, 600 pmol) in 2,2,2-trifluorethanol (1.75 mL, 24.0 mmol). ACN (1.75 mL) was added and the reaction mixture was stirred for 2 h at RT. Volatiles were removed under reduced pressure and the residue purified by flash chromatography (silica, EtOAc in hexanes, 0-20%) to give J-6 (165 mg, 88 %) as a solid:1H NMR (DMSO-d6) δ: 7.61 (dd, J = 8.7, 6.4 Hz, 1H), 7.51 (dd, J = 8.8, 0.4 Hz, 1H), 5.36 (q, J = 8.5 Hz, 2H). LCMS m / z 314.0 and 315.8 [M-H]’. Step 7: tert-Butyl (3-cyano-7-fluoro-4-(4-fluoro-2-(2,2,2-trifluoroethoxy)benzo[d]oxazol-5-yl)benzo[b]thiophen-2-yl)carbamate J-7a: A small microwave reaction vessel under N2 was loaded with intermediate J-6 (165 mg, 525 pmol), tert-butyl N-[3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluoro-benzothiophen-2-yl]carbamate (234 mg, 578 pmol), Cs2CO3(505 mg, 1.55 mmol), dichloro[bis(2-(diphenylphosphino)phenyl)ether]palladium(ll) (76.8 mg, 105 pmol) and degassed THF (3.1 mL)). The reaction vessel was sealed and heated to 70 °C for 2 h. The reaction mixture was partitioned between EtOAc (75 mL) and a saturated solution of NH4CI (50 mL) and the organic layer was washed with water, brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was dissolved in DCM and silica gel (500 mg) was added. The solvent was concentrated under reduced pressure. The dry-loaded product was purified by flash chromatography (silica, EtOAc in / hexanes, 0-50%) to give the title compound J-7 (138 mg, 50 %) as a solid:1H NMR (DMSO-d6) δ: 11.66 (s, 1 H), 7.59 (d, J = 8.4 Hz, 1H), 7.27 - 7.42 (m, 3H), 5.31 - 5.49 (m, 2H), 1.51 (s, 9H). LCMS m / z 524.0 [M+H]+.

[0618] 5-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4-fluoro-2-(2,2,2-trifluoroethoxy)benzo[d]oxazole J-7b: Prepared following the procedure described for J-7a above but using commercially available 2-(8-ethyl-7-fluoro-3-(methoxymethoxy)naphthalen-1-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane and methanesulfonato(diadamantyl-n-butylphosphino)-2'-amino-1,1'-biphenyl-2-yl)palladium(ll) as the catalyst in step 7. Intermediate J-7b was obtained as a 2:1 mixture of starting boronate and desired J-7b: LCMS m / z 468.0 [M+H]+.

[0619] EXAMPLE 1

[0620] ( / W)-2-amino-4-(6-chloro-4-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile:

[0621]

[0622] Step 1: To a solution of (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol prepared as described in WO2023 / 099592 (61.0 mg, 0.472 mmol) in 3 mL dry THF under Argon at 0° C was added excess NaH (60% oil dispersion; 43 mg, 1.07 mmol). The mixture was left to stir for 5 min. Then a solution of intermediate A-5a (110 mg, 0.215 mmol) in 3 mL dry THF was added to the above mixture dropwise and the reaction was left to stir for another 5 min. The flask was removed from the ice bath and the reaction was left to stir ON after which LCMS showed full conversion. A mixture of 20 mL of EtOAc and 20 mL of saturated NH4CI was cooled in an ice bath and the reaction mixture was added dropwise. The organic phase was separated and the aqueous phase was extracted 3x with 20 mL of EtOAc. The organic phases were combined and washed with 20 mL 1 N HCl and then brine (10 mL). The organic phase was dried over MgSO4 and the volatiles removed under reduced pressure. The crude mixture of diastereomers was used in the next step without further purification. LCMS: m / z 605.2 [M+H]+.

[0623] Step 2: To a solution of the crude diastereomeric mixture of carbamates from above (124 mg, 0.205 mmol) in DCM (4.00 mL) was added TFA (2.0 mL, 26.0 mmol) dropwise and the reaction was left to stir for 30 min at RT. Volatiles were removed under vacuum and the crude was dissolved in 1.5 mL of DMSO and purified by preparative reversed-phase HPLC in 3 separate portions (ACN, 10-75% over 19 min) to afford the compound of Example 1 (more active ( / W)-diastereomer, second eluting peak).1H NMR (MeOH-d4) δ: 8.51 (s, 1H), 7.78 (s, 1H), 7.17 (dd, J = 8.4, 5.1 Hz, 1H), 7.02 (dd, J = 9.5, 8.5 Hz, 1H), 5.42 (quin, J = 6.8 Hz, 1H), 3.14 - 3.24 (m, 1H), 2.73 - 2.82 (m, 1H), 2.72 (s, 3H), 2.12 - 2.22 (m, 1H), 1.89 - 2.01 (m, 2H), 1.76 - 1.89 (m, 1H), 1.53 (d, J = 6.3 Hz, 3H), 1.31 - 1.37 (m, 1H), 2H exchangeable. LCMS: m / z 506.0 [M+H]+.

[0624] EXAMPLE 2

[0625] 2-Amino-4-(6-chloro-4-fluoro-2-((3-morpholinopropyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (atropisomer mixture):

[0626] Step 1: In a flame-dried 4 mL vial, at RT, was weighed 3-morpholinopropylamine (37.1 pL, 254 pmol) and intermediate A-5a (65.0 mg, 127 pmol). Anhydrous K₂CO₃ (78.9 mg, 571 pmol) was added followed by anhydrous MeCN (2.0 mL) previously stored over molecular sieves. The reaction was stirred at 40 °C 18 h. LCMS analysis at that point indicated complete consumption of the starting material and the desired product as the major component. The mixture was diluted with 2 mL of EtOAc and celite® was added. After mixing, the mixture was filtered through a short pad of celite®, rinsing with EtOAc. The filtrate was concentrated to dryness and the residue was used as such for removal of the Boc protecting group (step 2).

[0627] Step 2: To the crude residue from Step 1 was added DCM (2.0 mL) and TFA (600 pL, 7.84 mmol). The resulting solution was stirred at RT for 1 h. Toluene (1 mL) was added to the mixture which was then concentrated to dryness. The residue was purified using reversed phase chromatography (MeOH-water with 0.1% FA, 30-100%) to obtain the compound of Example 2 as a beige solid (racemic atropisomers).1H NMR (DMSO-d6) δ: 8.41 (br. s., 1 H), 8.03 (s, 2H), 7.80 (s, 1 H), 7.17 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.61 (br. s., 4H), 3.40 - 3.50 (m, 2H), 2.44 (br. s., 6H), 1.84 (br. s., 2H). LCMS: m / z 520.2 [M+H]+.

[0628] EXAMPLES 3A and 3B

[0629] ( / V?)- and (P)-2-Amino-4-(6-chloro-4-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomeric atropisomers:

[0630] The procedure of Example 2 was followed for step 1, except (S)-(1-methylpyrrolidin-2-yl)methanamine dihydrochloride was used as the amine and a larger excess of K₂CO₃ (6 equivalents) was used. The protected forms of Example 3A and 3B were partially separated by reversed-phase HPLC and deprotected separately with TFA as described for step 2. A second purification by pre-HPLC provided the two partially separated diastereomeric atropisomers: Example 3A (first eluting, more active / W-isomer, 74% enriched):1H NMR (DMSO-d6) δ: 8.29 (t, J = 5.1 Hz, 1H), 8.03 (s, 2H), 7.77 (s, 1H), 7.17 (dd, J = 8.3, 5.4 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 3.51 - 3.69 (m, 1H), 3.22 - 3.29 (m, 1H), 2.89 - 3.03 (m, 1H), 2.35 - 2.46 (m, 1H), 2.30 (s, 3H), 2.15 (q, J = 8.8 Hz, 1H), 1.82 - 1.96 (m, 1H), 1.48 - 1.75 (m, 3H). LCMS: m / z 490.0 [M+H]+. Example 3B (2ndeluting, less active P-isomer, 93% enriched):1H NMR (DMSO-d6) δ: 8.29 (t, J = 5.1 Hz, 1H), 8.02 (s, 2H), 7.77 (d, J = 0.9 Hz, 1H), 7.17 (dd, J = 8.3, 5.4 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1 H), 3.54 - 3.67 (m, 1 H), 3.24 - 3.29 (m, 1 H), 2.97 (ddd, J = 8.8, 6.5, 2.4 Hz, 1 H), 2.36 - 2.45 (m, 1H), 2.15 (q, J = 8.8 Hz, 1H), 1.82 - 1.95 (m, 1H), 1.51 - 1.75 (m, 3H). LCMS: m / z 490.0 [M+H]+.

[0631] EXAMPLES 4 and 5

[0632] 2-Amino-4-(6-chloro-2-((2-(dimethylamino)ethyl)amino)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 4) and 2-amino-4-(6-chloro-2-(dimethylamino)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 5) 1:1 mixture of atropisomers: Prepared following the procedures of Example 2 using N, N-dimethyl-ethylenediamine as the amine. This reaction yielded the desired compound of Example 4 as well as the compound of Example 5 as a side product. These two compounds were separated by reversed-phase HPLC as racemic atropisomers: Example 4:1H NMR (DMSO-d6) 6: 8.34 (t, J = 5.1 Hz, 1H), 8.16 (br. s., 1H), 8.03 (s, 2H), 7.78 (s, 1H), 7.17 (dd, J = 8.4, 5.3 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 3.50 (q, J = 5.6 Hz, 2H), 2.51 - 2.54 (m, 2H), 2.22 (s, 6H). LCMS: m / z 464.2 [M+H]+.

[0633] Example 5:1H NMR (DMSO-d6) 6: 8.03 (s, 2H), 7.89 (d, J = 1.0 Hz, 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (dd, J = 9.5, 8.3 Hz, 1H), 3.18 (s, 6H). LCMS: m / z 421.0 [M+H]+.

[0634] EXAMPLE 6

[0635] 2-Amino-4-(6-chloro-4-fluoro-2-(methyl(3-morpholinopropyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers):

[0636]

[0637] Step 1: 3-Morpholinopropylamine (272 pL, 1.86 mmol) was weighed in a 20 vial and diluted with anhydrous EtOH (2.00 mL). Ethyl formate (375 pL, 4.65 mmol) was then added and the vial was sealed and heated at 80 °C for 1 h. The mixture was concentrated to dryness and used without further purification.1H NMR (presence of two conformers in a 4:1 ratio; CDCl3) 6: 8.15 (s, 0.8H), 8.04 (d, J = 12.1 Hz, 0.2H), 6.77 (br. s., 0.8H), 6.29 (br. s., 0.2H), 3.71 (t, J = 4.6 Hz, 4H), 3.40 (q, J = 5.9 Hz, 1.6H), 3.33 (q, J = 6.3 Hz, 0.4H), 2.37 - 2.55 (m, 6H), 1.71 (quin, J = 6.4 Hz, 2H). LCMS: m / z 173.2 [M+H]+.

[0638] Step 2: In a 25 mL flame-dried flask under nitrogen was added LAH (98.8 mg, 2.47 mmol). The flask was placed in an ice bath then 3.5 mL of diethyl ether was added. To the grey suspension was added dropwise a solution of N-(3-morpholinopropyl)formamide from step 1 (284 mg, 1.65 mmol) in 2.5 mL of diethyl ether. Effervescence was noted and the mixture formed a hard solid crust. The crust was broken up with a spatula to facilitate stirring and the mixture was removed from the ice bath and allowed to warm to RT. The flask was fitted with a reflux condenser and placed in a pre-heated oil bath at 50 °C. The mixture was refluxed for 3 h then stirred at RT overnight. LCMS analysis indicated the starting formamide remained in significant quantity (about 1:1 with product). Another portion of LAH (98.8 mg, 2.47 mmol) was added, and the mixture was refluxed for another 4 h. By then, LCMS indicated very little of the starting formamide remained. The mixture was cooled in an ice bath and 0.5 g of sodium sulfate decahydrate was slowly added. The mixture was then allowed to warm to RT, diluted with 10 mL of THF and stirred rapidly for 1 h. Celite® was added to the mixture and it was then filtered through a short pad of celite®, rinsing with THF. The filtrate was carefully concentrated to about 2 mL then diluted with ether (5 mL). Hydrochloric acid (1.03 mL, 4.12 mmol) as a 4M solution in dioxane was added dropwise affording a white solid. The mixture was sonicated and diluted with 3 mL of toluene then concentrated to dryness. The white powder was further dried under reduced pressure affording N-methyl-3-morpholinopropan-1-amine dihydrochloride (368 mg, 96 %) as a white solid.1H NMR (DMSO-d6) 5: 11.28 (br. s., 1H), 9.03 (br. s., 2H), 3.95 (d, J = 11.8 Hz, 2H), 3.84 (t, J = 12.3 Hz, 2H), 3.37 -3.45 (m, 2H), 3.19 (q, J = 5.9 Hz, 2H), 2.89 - 3.12 (m, 4H), 2.53 (t, J = 5.3 Hz, 3H), 2.09 (quin, J = 7.5 Hz, 2H). LCMS: m / z 159.2 [M+H]+.

[0639] Example 6: The remaining steps leading to the final compound of Example 6 follow the procedures of Example 2 using N-methyl-3-morpholinopropan-1-amine dihydrochloride (from step 2) as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.89 (d, J = 0.5 Hz, 1H), 7.17 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.62 (br. s., 6H), 3.17 (s, 3H), 2.50 (br. s., 6H), 1.89 (br. s., 2H). LCMS: m / z 534.2 [M+H]+.

[0640] EXAMPLES 7A and 7B

[0641] ( / V?)- and (P)-2-Amino-4-(6-chloro-4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 1:1 mixture of diastereomeric atropisomers:

[0642]

[0643] Example 7A (M)-isomer Example 7B (P)-isomer

[0644] Step 1: tert-Butyl (4-(6-chloro-2-fluoro-4-iodo-3-(3-methylthioureido)phenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: Intermediate B-1a (300 mg, 534 pmol) was dissolved in DCM (3.0 mL) in a 4 mL scintillation vial. 1,1'-thiocarbonyldi-2(1H)-pyridone (97%; 310 mg, 1.34 mmol) was added in one portion, open to atmosphere. The reaction was left to stir overnight at RT. After 18 h, a methylamine solution (2.0M in THF; 1.34 mL, 2.67 mmol) was added in one portion. After 1 h, the solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (silica, EtOAc in hexanes, 10-40%) to afford the desired thiourea (308 mg, 91 %) as a light beige solid.1H NMR (CDCh) 6 ppm 7.94 (d, J = 1.6 Hz, 1 H), 7.70 - 7.86 (m, 1 H), 7.41 (br. s., 1 H), 7.25 (dd, J = 8.3, 4.9 Hz, 1 H), 7.12 - 7.18 (m, 1 H), 6.27 - 6.35 (m, 1 H), 3.10 (d, J = 4.6 Hz, 3 H), 1.59 (s, 9 H). LCMS: m / z 635.1 [M+H]+.

[0645] Step 2: tert-Butyl (Z)-(4-(3-((((4-(tert-butyl)benzyl)thio)(methylamino)methylene)amino)-6-chloro-2-fluoro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: The thiourea from step 1 (245 mg, 386 pmol) was dissolved in ACN (2.0 mL) in a 4 mL scintillation vial in an ice bath. DCM (1.0 mL) was then added to solubilize the material. Cs2CO3(252 mg, 773 pmol) and then 4-tert-butylbenzyl bromide (88 mg, 386 pmol) were added in one portion. Quickly thereafter, the solution became a white suspension. The solution was left to stir in the ice bath for 30 min and then at RT for 18 h. The reaction was transferred to a separatory funnel with ethyl acetate and diluted with water and brine. The aqueous layer was extracted 2x with EtOAc, and the combined organic fractions washed with brine. The solution was dried with Na2SO4, and the solvent evaporated under reduced pressure. The product (302 mg) was used in the next step without purification. LCMS: m / z 781.2 [M+H]+.

[0646] SStep 3: tert-Butyl (4-(2-((4-(tert-butyl)benzyl)thio)-6-chloro-4-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: The crude product from step 2 (287 mg) was dissolved in dioxane (2.5 mL) in a 20 mL scintillation vial. 1,10-Phenanthroline (14.1 mg, 77.3 pmol), cuprous iodide (7.36 mg, 38.6 pmol) and K₂CO₃ (107 mg, 773 pmol) were added to the vial and the solution degassed for 5 minutes with argon and sonication. The vial was sealed and then heated at 85 °C for 2 h. The reaction was then diluted with DCM and volatiles evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, EtOAc in hexanes, 5-25%) to provide the desired benzimidazole derivative.1H NMR (CDCl3) 5 ppm 7.88 (br. s., 1 H), 7.37 (s, 4 H), 7.29 (dd, J=8.25, 5.00 Hz, 1 H), 7.25 (s, 1 H), 7.11 - 7.17 (m, 1 H), 4.60 - 4.70 (m, 2 H), 3.63 (s, 3 H), 1.58 (s, 9 H), 1.32 (s, 9 H). LCMS: m / z 653.3 [M+H]+.

[0647] Step 4: tert-Butyl (4-(2-((4-(tert-butyl)benzyl)sulfonyl)-6-chloro-4-fluoro-1-methyl-1H-benzo[d]imidazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: The 2-thiobenzimidazole from SStep 3 (28.8 mg, 44.1 pmol) was dissolved in DCM (500 pL) and placed in an ice bath. MCPBA (15.2 mg, 88.2 pmol) was added and the reaction was left to stir at RT for 10 minutes (LCMS shows two mono oxidized products: LCMS: m / z = 669.1 [M+H]+). Oxidation proceeded to the sulfone upon addition of another portion of MCPBA (9.88 mg, 44.1 pmol). The reaction was transferred to a separatory funnel with EtOAc and diluted with water and sat. NaHCO₃. The aqueous layer was extracted with EtOAc 3 times. The combined organic fractions were washed with brine 2x and dried with Na2SO4. The solvent was evaporated under reduced pressure to afford the desired sulfone (27.0 mg, 89 %) as a colorless solid that was used in the next step without further purification. LCMS: m / z 685.2 [M+H]+.

[0648] Step 5: tert-Butyl (4-(6-chloro-4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: (S)-(1-methylpyrrolidin-2-yl)methanol (13.7 pL, 119 pmol) was dissolved in dry THF (500 pL) in a 4 mL scintillation vial and placed in an ACN dry ice bath (-40 °C). LiHMDS (1M in THF, 271 pL, 271 pmol) was added under argon and the mixture left to stir for 5 minutes. The sulfoxide from step 4 (39.1 mg, 57.0 pmol), dissolved in 200 pL of dry THF was added under argon. The reaction was left to stir at -40 °C for 30 minutes. The temperature was then allowed to raise to RT and then heated to 40 °C. Another 100 pL of 1M LiHMDS was added and the reaction left to stir at 40 °C overnight under argon (for a total of 20 h) at which point LCMS analysis showed complete conversion. The reaction mixture was taken up in DCM: MeOH, and filtered through a 45 micron filter. The solvent was evaporated under reduced pressure and the residue was purified by flash chromatography (reversed phase, MeOH in water, 30-100%) to afford 2 distinct and separable diastereomeric products: 1steluting peak (11.5 mg; LCMS: rt 1.376 min; m / z = 588.0 [M+H]+. 2ndeluting peak (13.2 mg; LCMS: rt 1.399 min; m / z 588.0 [M+H]+

[0649] Step 6: ( / W)-2-Amino-4-(6-chloro-4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1 H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 7a): the 1steluting peak from step 6 (11.2 mg, 19 pmol) was dissolved in DCM (500 pL) and TFA (199 pL, 2.60 mmol) was added. The mixture was stirred at RT for 2 h. The reaction was diluted with ACN and evaporated under reduced pressure to give diastereomer 7a (4.1 mg) as a di-TFA salt.1H NMR (DMSO-d6) 6: 9.78 (br. s., 1 H), 8.00 (s, 2 H), 7.61 (s, 1 H), 7.07 - 7.17 (m, 2 H), 4.86 (br. s., 1 H), 4.71 (br. s., 1 H), 3.67 (s, 3 H), 2.99 (br. s., 3 H), 2.29 (br. s., 1 H), 2.08 (br. s., 1 H), 1.94 (br. s., 2 H), 1.28 (dd, J = 1.0 Hz, 3 H). LCMS: m / z 488.2 [M+H]+.

[0650] (P)-2-Amino-4-(6-chloro-4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 7b): The 2ndeluting peak from step 6 (10.9 mg, 18.5 pmol) was deprotected as described above for the 1steluting peak. After removal of volatiles the residue was purified by reversed phase HPLC to provide diastereomer 7b (2.2 mg).1H NMR (DMSO-d6) 6: 8.21 (br. s, 1 H), 8.00 (s, 2 H), 7.55 (s, 1 H), 7.06 - 7.17 dd, 2 H), 4.46 (d, J=5.25 Hz, 2 H), 3.61 (s, 3 H), 2.93 - 3.05 (m, 1 H), 2.64 - 2.73 (m, 1 H), 2.54- 2.57 (m, 1 H), 2.39 (s, 3 H), 2.18- 2.35 (m, 2 H), 1-65-1.98 (m, 3 H). LCMS: m / z 488.2 [M+H]+.

[0651] EXAMPLE 8

[0652] 2-Amino-4-(6-chloro-2-((2-(dimethylamino)ethyl)(methyl)amino)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using N, N, N”-trimethylenediamine as the amine:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.87 (s, 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.55 - 3.75 (m, 2H), 3.18 (s, 3H), 2.53 (t, J = 6.5 Hz, 2H), 2.21 (s, 6H). LCMS: m / z 478.0 [M+H]+.

[0653] EXAMPLE 9 2-Amino-4-(6-chloro-4-fluoro-1-methyl-2-((3-morpholinopropyl)amino)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): The sulfone from step 4 of Example 7 (21.0 mg, 30.6 pmol) was dissolved in DMSO (500 pL) and placed in conical microwave vial. 3-Morpholinopropylamine (22.9 pL, 153 pmol) was added and the mixture heated to 150 °C in a microwave for 1 h. Only a small amount of product is formed, and it had lost its Boc protecting group. The reaction material was purified by flash chromatography (reversed phase, MeOH in water, 30-100%) affording the compounds of Example 9 as a mixture of atropisomers (3.10 mg, 20 %) as a white solid.1H NMR (MeOH-d4) δ: 8.45 (br. s., 1 H), 7.25 (s, 1 H), 7.16 (dd, J = 8.3, 5.2 Hz, 1 H), 6.97 - 7.05 (t, J = 8.3, 1 H), 3.82 - 3.94 (m, 4 H), 3.60 - 3.70 (m, 2 H), 3.59 (s, 3 H), 2.92 - 3.07 (m, 6 H), 1.96 - 2.15 (m, 2 H). LCMS: m / z 516.9 [M+H]+.

[0654] EXAMPLE 10

[0655] 2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): Prepared following the procedures of Example 7 using tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate as the amine in step 1 (LCMS: m / z = 802.2 [M+H]+). Steps 2 and 3 proceeded as expected and provided the desired 2-thiobenzimidazole intermediate:1H NMR (CDCl3) 6: 7.40 (s, 1 H), 7.38 (s, 4 H), 7.25 (dd, J = 8.8, 5.5 Hz, 1 H), 7.12 (t, J = 1.0 Hz, 1 H), 5.13 (br. s., 1 H), 4.65 (q, J = 1.0 Hz, 2 H), 2.82 (s, 6 H), 1.58 (s, 9 H), 1.48 (s, 9 H), 1.33 (s, 9 H). LCMS: m / z = 820.2 [M+H]+. Oxidation (Example 7, step 4) proceeded to provide the desired sulfone (LCMS: m / z = 852.3 [M+H]+). Steps 5 and 6 were performed as for Example 7 to provide the diastereomeric mixture of the compounds of Example 10.1H NMR (MeOH-d4) 5: 7.44 (s, 1 H), 7.13 (ddd, J = 8.3, 5.2, 3.1 Hz, 1 H), 7.00 (t, J = 8.9 Hz, 1 H), 4.89 - 5.00 (m, 1 H), 4.79 (ddd, J = 12.6, 6.5, 6.4 Hz, 1 H), 3.80 - 3.90 (m, 1 H), 3.61 - 3.71 (m, 1 H), 3.13 - 3.24 (m, 1 H), 3.01 (d, J = 5.8 Hz, 3 H), 2.71 (s, 6 H), 2.37 - 2.49 (m, 1 H), 2.14 - 2.24 (m, 1 H), 1.96 - 2.14 (m, 3 H). LCMS: m / z 555.0 [M+H]+.

[0656] EXAMPLE 11

[0657] 2-Amino-4-(6-chloro-4-fluoro-1-methyl-2-(3-morpholinopropoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared as described for Example 7 and using 4-(3-hydroxypropyl)morpholine in Step 5. The compounds of Example 11 were isolated as an atropisomeric mixture by reversed-phase chromatography.1H NMR (MeOH-d4) δ: 7.34 (s, 1H), 7.14 (dd, J = 8.3, 5.1 Hz, 1H), 6.99 (t, J = 9.1 Hz, 1H), 4.62 (t, J = 6.10 Hz, 2H), 3.71 (m, J = 3.9 Hz, 4H), 3.62 (s, 3H), 2.61 - 2.68 (m, 2H), 2.56 (br. s., 4H), 2.06 - 2.15 (m, 2H). LCMS: m / z 518.0 [M+H]+.

[0658] EXAMPLE 12A and 12B

[0659] (M)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile: Following the general procedure of Scheme F, intermediate F-4a was reacted with (S)-(1-methylpyrrolidin-2-yl)methanamine dihydrochloride in the presence of DIEA to provide the desired protected aminobenzothiazoles as a 1:1 mixture of diastereomeric atropisomers:1H NMR (MeOH-d4) δ: 8.55 (br. s., 1 H), 7.36 (td, J=8.79, 5.07 Hz, 1 H), 7.09 - 7.26 (m, 1 H), 5.07 - 5.21 (m, 2 H), 4.91 - 5.05 (m, 1 H), 4.74 (dd, J=12.19, 6.19 Hz, 1 H), 4.01 (dd, J=15.20, 2.69 Hz, 1 H), 3.69 - 3.94 (m, 1 H), 3.47 - 3.68 (m, 2 H), 2.93 - 3.09 (m, 2 H), 2.90 (s, 1 H), 2.16 - 2.38 (m, 1 H), 1.83 - 2.12 (m, 3 H), 1.49 - 1.63 (m, 9 H). LCMS: m / z 598.2 [M + H]+.

[0660] Removal of the Boc protecting group with TFA in DCM provided a diastereomeric mixture of compounds of Example 12A and 12B that were separated by reversed-phase HPLC on a biphenyl column using a MeOH in water with 0.1% FA gradient to provide the two isomerically pure diasteromers:

[0661] Example 12A (first eluting P-isomer):1H NMR (MeOH-d4) δ: 7.20 (dd, J = 8.3, 5.1 Hz, 1H), 6.91 - 7.04 (m, 1H), 5.09 - 5.18 (m, 2H), 4.92 (d, J = 12.3 Hz, 1H), 4.78 (d, J = 12.1 Hz, 1H), 4.58 (s, 1 H), 3.74 - 3.84 (m, 1H), 3.68 (br. s., 1H), 3.07 (br. s., 1H), 2.71 (br. s., 3H), 2.07 - 2.26 (m, 1H), 1.76 - 2.02 (m, 3H). LCMS: m / z 498.0 [M+ H]+.

[0662] Example 12B (second eluting / W-isomer):1H NMR (MeOH-d4) δ: 7.22 (dd, J = 8.1, 5.3 Hz, 1H), 6.99 (t, J = 8.9 Hz, 1H), 5.14 (br. s., 2H), 4.97 (d, J = 12.1 Hz, 1H), 4.76 (d, J = 12.0 Hz, 2H), 4.58 (br. s., 1H), 3.82 (br. s., 1H), 3.70 - 3.78 (m, 1H), 3.44 (br. s., 1H), 3.22 (br. s., 1H), 2.81 (br. s., 3H), 2.12 - 2.28 (m, 1H), 1.80 - 2.05 (m, 3H). LCMS: m / z 498.0 [M+H]+.

[0663] EXAMPLE 13

[0664] 2-Amino-4-(1-((1r,3S)-3-aminocyclobutyl)-6-chloro-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 7 using tert-butyl ((1r,3r)-3-aminocyclobutyl)carbamate as the amine in step 1 (LCMS: m / z = 790.2 [M+H]+). Steps 2 and 3 proceeded as expected and provided the desired 2-thiobenzimidazole intermediate: LCMS: m / z = 808.4 [M+H]+. Oxidation (Example 7, step 4) proceeded to provide the desired sulfone (LCMS: m / z = 840.4 [M+H]+). Steps 5 and 6 were performed as for Example 7 to provide the diastereomeric mixture of the compounds of Example 13.1H NMR (MeOH-4) δ: 8.45 (s, 1 H), 7.50 (s, 1 H), 7.15 (dd, J=5.13, 1.25 Hz, 1 H), 6.98 - 7.06 (m, 1 H), 5.47 (s, 1 H), 4.82 (m, 2 H), 4.11 - 4.22 (m, 1 H), 3.50 - 3.67 (m, 2 H), 3.34 - 3.41 (m, 2 H), 2.95 - 3.05 (m, 1 H), 2.90 (d, J=4.75 Hz, 3 H), 2.80 (d, J=2.50 Hz, 2 H), 2.30 - 2.43 (m, 1 H), 2.05 (m, 3 H). LCMS: m / z 543.2 [M+H]+.

[0665] EXAMPLES 14 and 17

[0666] 2-Amino-4-(6-chloro-4-fluoro-2-morpholinobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 14) and 2-amino-4-(6-chloro-4-fluoro-2-(((1-(morpholinomethyl)cyclopropyl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 17) 1:1 mixture of atropisomers:

[0667]

[0668] Step 1: 1-(Morpholine-4-carbonyl)cyclopropane-1 -carbonitrile: 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 very small drop of DMF was added followed by oxalyl chloride (507 pL, 5.85 mmol). The mixture was warmed to RT and stirred for 2 h. Toluene (4 mL) was added to the clear solution and the mixture was concentrated under reduced pressure to a colorless semi-solid which was further dried under high vac.

[0669] The waxy solid was then dissolved in THF (20.0 mL) and the solution cooled in an ice bath, morpholine (512 pL, 5.85 mmol) was added dropwise, affording a milky white mixture. DIEA (1.57 mL, 9.0 mmol) was then added, the resulting mixture was allowed to warm to RT and stirred for 90 minutes. The mixture was then concentrated to dryness. The residue was taken up in EtOAc (30 mL) and washed with 10 mL of a saturated solution of NaHCO3. The aqueous layer was extracted with EtOAc (3x20 mL). The combined organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The residue was further dried under high vac to yield 1- (morpholine-4-carbonyl)cyclopropane-1 -carbonitrile (595 mg, 73 %) as a pale yellow oil.1H NMR (CDCh) 5: 3.76 (br. s., 8H), 1.58 - 1.66 (m, 2H), 1.50 - 1.58 (m, 2H). LCMS: m / z 181.0 [M+H]+. Step 2: (1-(morpholinomethyl)cyclopropyl)methanamine dihydrochloride: the crude product 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 LAH (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 LAH (131 mg, 3.29 mmol) was added at RT then the mixture was stirred at 50 °C overnight. The reaction was then stopped, allowed too cool to RT then cooled in an ice bath. Na2SO4.10H2O (1.2 g) was added slowly and once effervescence stopped, the mixture was stirred for 1 h at RT then 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 a white foam of the desired hydroscopic product (1-(morpholinomethyl)cyclopropyl)methanamine dihydrochloride (630 mg, 79 %).1H NMR (DMSO-d6) 6: 10.97 (br. s., 1H), 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]+.

[0670] The remaining steps leading to the final compounds follow the procedures of Example 2 using (1-(morpholinomethyl)cyclopropyl)methanamine dihydrochloride (from step 2) as the amine and 9 equiv. of DIEA as the base instead of K₂CO₃. The compounds of Example 14 and Example 17 were both formed in this reaction and isolated separately as 1:1 atropisomer mixtures:

[0671] Example 14:1H NMR (DMSO-d6) 6: 8.04 (s, 2H), 7.94 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.74 (t, J = 4.3 Hz, 4H), 3.60 (t, J = 5.0 Hz, 4H). LCMS: m / z 462.9 [M+H]+.

[0672] Example 17:1H NMR (DMSO-d6) 6: 8.33 (t, J = 4.9 Hz, 1H), 8.02 (s, 2H), 7.78 (s, 1H), 7.17 (dd, J = 8.3, 5.3 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 3.58 (t, J = 4.4 Hz, 4H), 3.37 - 3.48 (m, 2H), 2.39 (br. s., 4H), 2.26 (dd, J = 20.8, 12.5 Hz, 2H), 0.50 - 0.65 (m, 2H), 0.24 - 0.39 (m, 2H). LCMS: m / z 546.0 [M+H]+.

[0673] EXAMPLE 15 2-Amino-4-(2-((R)-3-aminopyrrolidin-1-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using (R)-3-N-Boc-3-aminopyrrolidine as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 6: 8.03 (br. s., 2H), 7.91 (s, 1H), 7.14 - 7.23 (m, 1H), 7.11 (t, J = 9.3 Hz, 1H), 3.84 (br. s., 1H), 3.64 - 3.79 (m, 2H), 3.54 - 3.62 (m, 2H), 3.38 - 3.45 (m, 2H), 2.19 - 2.35 (m, 1H), 1.90 - 2.05 (m, 1H). LCMS: m / z 461.8 [M+H]+.

[0674] EXAMPLE 16

[0675] 2-Amino-4-(2-((S)-3-aminopyrrolidin-1-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using (S)-3-N-Boc-3-aminopyrrolidine as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 6: 8.03 (br. s., 2H), 7.91 (s, 1H), 7.15 - 7.22 (m, 1H), 7.11 (t, J = 9.3 Hz, 1H), 3.81 (br. s., 1H), 3.63 - 3.76 (m, 2H), 3.54 - 3.63 (m, 2H), 3.37 - 3.42 (m, 2H), 2.16 - 2.31 (m, 1H), 1.85 - 2.03 (m, 1H). LCMS: m / z 461.9 [M+H]+.

[0676] EXAMPLE 18

[0677] 2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): the procedure for the preparation of Example 10 was followed using ((2R,7aS)-2-fluorotetrahydro-1 H-pyrrolizin-7a(5H)-yl)methanol as the alcohol in Step 5. Step 6 provided the desired compound of Example 18 as a mixture of diastereomers.1H NMR (DMSO-d6) 5: 8.00 (bs, 2H), 7.41 (s, 1H), 7.05 - 7.16 (m, 2H), 5.30 (d, J = 52 Hz, 1H), 4.24 (dd, J = 10.0 Hz, 2H), 3.09 - 3.19 (m, 2H), 3.06 (s, 1 H), 2.82 - 2.89 (m, 1 H), 2.42 (s, 6H), 2.03 - 2.21 (m, 3H), 1.75 - 1.92 (m, 3H). LCMS: m / z 599.3 [M+H]+.

[0678] EXAMPLE 19

[0679] 2-Amino-4-(6-chloro-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using (R)-N, N-dimethylyrrolidin-3-amine as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.90 (s, 1H), 7.18 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.75 (br. s., 1H), 3.67 (br. s., 1H), 3.45 - 3.59 (m, 1H), 3.26 -3.31 (m, 1H), 2.91 (quin, J = 7.5 Hz, 1H), 2.21 (s, 6H), 2.15 - 2.24 (m, 1H), 1.84 - 2.00 (m, 1H). LCMS: m / z 489.9 [M+H]+. EXAMPLE 20

[0680] 2-Amino-4-(6-chloro-4-fluoro-2-((((R)-1-methylpyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using (R)-(1-methylpyrrolidine-2-yl)methanamine dihydrochloride as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.29 (t, J = 4.9 Hz, 1H), 8.02 (s, 2H), 7.77 (s, 1H), 7.17 (dd, J = 8.3, 5.4 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 3.51 - 3.66 (m, 1H), 3.20 - 3.29 (m, 1H), 2.88 - 3.04 (m, 1H), 2.35 - 2.45 (m, 1H), 2.30 (s, 3H), 2.15 (q, J = 8.8 Hz, 1 H), 1.82 - 1.95 (m, 1 H), 1.50 - 1.76 (m, 3H). LCMS: m / z 489.9 [M+ H]+.

[0681] EXAMPLE 21

[0682] 2-Amino-4-(6-chloro-4-fluoro-2-((2-(pyrrolidin-1-yl)ethyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 atropisomeric mixture): Prepared following the procedures of Example 2 using N-(2-aminoethyl)pyrrolidine (2.8 equiv.) as the amine and 2.5 equiv. of DIEA as base:1H NMR (DMSO-d6) 6: 8.42 (br. s., 1H), 8.03 (s, 2H), 7.79 (s, 1H), 7.17 (dd, J = 8.4, 5.3 Hz, 1H), 7.10 (t, J = 12, 1H), 3.49 - 3.58 (m, 2H), 2.73 (t, J = 6.1 Hz, 2H), 2.53 -2.64 (m, 4H), 1.72 (br. s., 4H). LCMS: m / z 490.0 [M+H]+.

[0683] EXAMPLE 22

[0684] 4-(2-(3,8-Diazabicyclo[3.2.1]octan-3-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 atropisomeric mixture): Prepared following the procedures of Example 2 using tert-butyl 3,8-diazabicyclo[3.2.1]octane-8-carboxlate as the amine and 2.5 equiv. of DIEA as base:1H NMR (DMSO-d6) 6: 8.04 (s, 2H), 7.90 (s, 1H), 7.16 (dd, J = 8.4, 5.5 Hz, 1H), 7.10 (t, J = 8.8, 1H), 3.51 - 3.61 (m, 4H), 3.30 (overlap of two signals, 3H), 1.58 - 1.81 (m, 4H). LCMS: m / z =488.0 [M+H]+.

[0685] EXAMPLE 23

[0686] 2 -Amino-4-(6-chloro-4- fluoro- 1-(2-hydroxyethyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 7 using 2-((tert-butyldimethylsilyl)oxy)ethan-1-amine as the amine in step 1 (LCMS: m / z = 732.3 [M+H]+). Deprotection with TFA under standard conditions allowed removal of both the silyl ether and Boc protecting group to provide the compounds of Example 23:1H NMR (MeOH-d4 5: 7.46 (s, 1 H), 7.09 - 7.19 (m, 1 H), 7.00 (t, J = 9.0 Hz, 1 H), 4.94 (m, J = 2.9 Hz, 1 H), 4.70 - 4.80 (m, 2 H), 4.19 - 4.31 (m, 2 H), 3.91 (t, J = 5.0 Hz, 1 H), 3.83 (br. s, 1 H), 3.60 - 3.71 (m, 1 H), 3.17 (m, J = 11.6, 1 H), 3.01 (d, J = 2.6 Hz, 3 H), 2.34 - 2.46 (m, 1 H), 2.00 - 2.22 (m, 3 H). LCMS: m / z 518.2 [M+H]+.

[0687] EXAMPLES 24A and 24B

[0688] (M)- and (P)-2-Amino-4-(1 -(3-aminobicyclo[1.1.1 ]pentan-1 -yl)-6-chloro-4-fluoro-2-((S)-1 -((S)- 1 -methylpyrrolidin-2-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomeric atropisomers: the procedure for the preparation of Example 10 was followed using (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol as the alcohol in Step 5. Following deprotection with TFA (Step 6), two separable diastereomeric atropisomers were isolated by reversed phase chromatography:

[0689] (P)-2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 24A; first eluting isomer):1H NMR (MeOH-d4) δ: 7.42 (s, 1H), 7.12 (dd, J = 8.3, 5.1 Hz, 1H), 6.99 (t, J = 8.90 Hz, 1H), 5.42 (dt, J = 14.3, 6.3 Hz, 1H), 3.45 - 3.57 (m, 2 H), 3.01 (d, J = 10.5 Hz, 1H), 2.85 (s, 3H), 2.59 (s, 6H), 2.28 (d, J = 7.6 Hz, 1H), 1.89 - 2.15 (m, 3H), 1.50 (d, J = 6.3 Hz, 3H). LCMS: m / z 569.2 [M+ H]+.

[0690] ( / W)-2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-fluoro-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 24B; second eluting isomer):1H NMR (MeOH-d4) δ: 7.41 (s, 1H), 7.14 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.4, 8.5 Hz, 1H), 5.40 (quin, J = 6.7 Hz, 1H), 2.79 - 2.86 (m, 1H), 2.74 (s, 2H), 2.66 (s, 3H), 2.56 (s, 6H), 2.15 - 2.24 (m, 1H), 1.89 - 2.08 (m, 3H), 1.47 (d, J = 6.3 Hz, 3H). LCMS: m / z 569.2 [M+H]+.

[0691] EXAMPLE 25

[0692] 2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-4-fluoro-2-(2-(pyrrolidin-1-yl)ethoxy)- 1 H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): the procedure for the preparation of Example 10 was followed using 1-(2-hydroxyethyl)pyrrolidine as the alcohol in Step 5.1H NMR (MeOH-d4) 5: 7.43 (s, 1 H), 7.13 (dd, J = 8.3, 5.2 Hz, 1 H), 6.96 - 7.03 (m, 1 H), 4.90 - 4.98 (m, 2 H), 3.77 (t, J = 4.8 Hz, 2 H), 3.49 (br. s., 4 H), 2.72 (s, 6 H), 2.09 - 2.15 (m, 4 H). LCMS: m / z 555.2 [M+H]+.

[0693] EXAMPLE 26

[0694] 2-Amino-4-(1-(3-aminobicyclo[1.1.1]pentan-1-yl)-6-chloro-2-(2-(dimethylamino)ethoxy)-4-fluoro-1 H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): the procedure for the preparation of Example 10 was followed using 2-(dimethylamino)ethanol as the alcohol in Step 5.1H NMR (MeOH-d4) δ: 7.42 (s, 1 H), 7.13 (dd, J = 8.4, 5.1 Hz, 1 H), 6.99 (t, J = 8.9 Hz, 1 H), 3.47 - 3.56 (m, 2 H), 2.88 (s, 6 H), 2.68 (s, 6 H). LCMS: m / z 529.2 [M+H]+.

[0695] EXAMPLE 27

[0696] 2-Amino-4-(6-chloro-4-fluoro-2-(3-(methylamino)azetidin-1-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 6: 8.03 (s, 2H), 7.90 (s, 1H), 7.18 (dd, J = 8.4, 5.5 Hz, 1H), 7.10 (t, J = 9.3 Hz, 1H), 4.29 (dt, J = 7.8, 5.0 Hz, 2H), 3.88 (dt, J = 8.6, 5.4 Hz, 2H), 3.71 (ddd, J = 12.1, 6.8, 5.4 Hz, 1H), 2.25 (s, 3H) (1 exchangeable H missing). LCMS: m / z 462.0 [M+H]+.

[0697] EXAMPLE 28

[0698] 2-Amino-4-(2-(3-amino-3-methylazetidin-1-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using tert-butyl (3-methylazetidin-3-yl)carbamate hydrochloride as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 6: 8.03 (s, 2H), 7.89 (d, J = 0.6 Hz, 1 H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 8.7 Hz, 1H), 3.96 (dd, J = 8.1, 1.6 Hz, 2H), 3.92 (t, J = 7.9 Hz, 2H), 2.36 (br. s., 2H), 1.41 (s, 3H). LCMS: m / z 462.0 [M+H]+.

[0699] EXAMPLE 29

[0700] 2-Amino-4-(2-(((1s,3s)-3-aminocyclobutyl)amino)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using tert-butyl ((1s,3s)-3-aminocyclobutyl)carbamate as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.58 (br. s., 1H), 8.03 (br. s., 2H), 7.79 (s, 1H), 7.16 (dd, J = 8.4, 5.5 Hz, 1H), 7.09 (t, J = 9.2 Hz, 1H), 3.84 (t, J = 6.1 Hz, 1 H), 3.04 (ddd, J = 15.6, 8.6, 7.1 Hz, 1H), 2.58 - 2.70 (m, 2H), 1.64 (ddt, J = 16.4, 8.1, 4.5 Hz, 2H). LCMS: m / z 462.0 [M+H]+.

[0701] EXAMPLE 30

[0702] 2-Amino-4-(6-chloro-4-fluoro-2-((((S)-5-oxopyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using (5S)-5-(aminomethyl)pyrrolidine-2-one hydrochloride as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.45 (q, J = 4.8 Hz, 1 H), 8.03 (s, 2H), 7.80 (s, 1 H), 7.73 (d, J = 1.3 Hz, 1H), 7.17 (dd, J = 8.7, 5.4 Hz, 1H), 7.10 (t, J = 9.2 Hz, 1H), 3.81 (quin, J = 5.9 Hz, 1H), 3.47 - 3.64 (m, 1H), 3.35 - 3.42 (m, 1H), 2.02 -2.27 (m, 3H), 1.72 - 1.86 (m, 1 H). LCMS: m / z 490.0 [M+ H]+.

[0703] EXAMPLE 31

[0704] 4-(2-(3,6-Diazabicyclo[3.1.1]heptan-6-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using 2-methyl-2-propanyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.17 (s, 1H), 8.05 (s, 2H), 7.93 (s, 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 9.3 Hz, 1H), 4.42 (t, J = 5.1 Hz, 2H), 3.47 - 3.55 (m, 4H), 2.93 (dd, J = 11.5, 9.5 Hz, 2H), 2.76 (q, J = 6.9 Hz, 1 H), 1.95 (d, J = 8.5 Hz, 1H). LCMS: m / z 474.0 [M+H]+.

[0705] EXAMPLE 32

[0706] 2-Amino-4-(6-chloro-2-((3-(dimethylamino)propyl)amino)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using 3-dimethylaminopropylamine as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 6: 8.38 (t, J = 5.3 Hz, 1H), 8.20 (br. s., 1H), 8.03 (s, 2H), 7.79 (s, 1H), 7.17 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 9.3 Hz, 1H), 3.40 (q, J = 6.3 Hz, 2H), 2.37 (t, J = 7.0 Hz, 2H), 2.19 (s, 6H), 1.75 (quin, J = 7.0 Hz, 2H). LCMS: m / z 478.0 [M+H]+.

[0707] EXAMPLE 33

[0708] 2-Amino-4-(6-chloro-4-fluoro-2-(3-morpholinoazetidin-1-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 1:1 mixture of atropisomers): Prepared following the procedures of Example 2 using 4-(3-azetidinyl)morpholine dihydrochloride as the amine and 6 equiv. of DIEA as base.1H NMR (DMSO-d6) 5: 8.04 (s, 2H), 7.92 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 4.21 (dd, J = 14.4, 7.9 Hz, 2H), 4.06 (dt, J = 9.0, 4.8 Hz, 2H), 3.61 (t, J = 4.1 Hz, 4H), 3.37 - 3.47 (m, 1H), 2.39 (br. s., 4H). LCMS: m / z 518.0 [M+H]+.

[0709] EXAMPLE 34

[0710] 2-Amino-4-(6-chloro-2-(3-(dimethylamino)azetidin-1-yl)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers) - Scheme B:

[0711]

[0712]

[0713] Step 2

[0714] Step 1: tert-Butyl (4-(6-chloro-3-(3-(dimethylamino)azetidine-1-carbothioamido)-2-fluoro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: intermediate B-1a (100 mg, 178 pmol) was dissolved in DCM (1.67 mL) and 1,1'-thiocarbonyldi-2(1H)-pyridone (82.7 mg, 356 pmol) was added. The reaction was left to stir at RT for 16 h. N, N-Dimethyl-3-azetidinamine dihydrochloride (95.3 mg, 534 pmol) was then added followed by DIEA (187 pL, 1.07 mmol). The mixture was left to stir at RT for 1 h. The solvent was evaporated under reduced pressure and the residue purified by flash column chromatography on silica gel in DCM (0 to 10% methanol, basic) to afford the desired thiourea (143 mg, 114 %) as a light-yellow solid. LCMS: m / z 704.2 [M+H]+. Step 2: The material from step 1 (100 mg, 1.42 mmol) was dissolved in dioxane (1.40 mL) in a 20 mL scintillation vial. Cooper (I) iodide (1.35 mg, 7.10 pmol), 1,10-phenanthroline (2.59 mg, 14.2 pmol) and Cs2CO3(92.6 mg, 2.84 mmol) were added. The solvent was degassed with argon for 5 minutes. The vial was sealed and left to stir on a hot plate at 80 °C. After 70 minutes, full conversion to desired product was observed by LCMS. The reaction was transferred to a separatory funnel with ethyl acetate and diluted with water. The aqueous layer was extracted with EtOAc 3 times. The combined organic fractions were washed with brine 2x and dried with sodium sulfate. The solvent was evaporated under reduced pressure.

[0715] SStep 3: The residue from above was suspended in DCM (2 mL) and TFA (394 pL, 5.14 mmol) was added. The reaction was left to stir at RT for 3.5 h. The solution was diluted with ACN and filtered through a 45 pm filter. The solvent was evaporated under reduced pressure and the product dissolved in 2.5 mL of DMSO for purification by flash column chromatography (reversed phase, MeOH in water with 0.1% FA, 15-100%) to provide Example 34 as a beige solid:1H NMR (MeOH-d4) δ: 7.70 (s, 1 H), 7.16 (dd, J = 8.3, 5. 1 Hz, 1 H), 7.00 (t, J = 8.9 Hz, 1 H), 4.35 - 4.44 (m, 2 H), 4.16 - 4.23 (m, 2 H), 3.75 (br. s., 1 H), 2.50 (s, 6 H). LCMS: m / z 475.9 [M+H]+. EXAMPLES 35A and 35B

[0716] (M)- and (P)-2-Amino-4-(6-chloro-4-fluoro-2-((((S)-1-(methyl-d3)pyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric atropisomers):

[0717] Preparation of (S)-1-(methyl-d3)pyrrolidine-2-carboxamide: To a cold (ice-bath) stirred mixture of L-prolinecarboxamide hydrochloride (1.00 g, 6.64 mmol) and triethylamine (7.44 mL, 53.1 mmol) in DMF (16.6 mL) was added iodomethane-d3 (2.13 mL, 33.2 mmol). The resultant reaction mixture was stirred for 5 h at ~7 °C. Solids were then filtered and rinsed with ethyl acetate. The filtrate was diluted with water (50 mL) and extracted with ethyl acetate (2 x 30 mL). The combined organic extracts were dried (Na2SO4), and concentrated to give (S)-1-(methyl-d3)pyrrolidine-2-carboxamide (140 mg, 16 %) as a white solid. The aqueous solution containing product was evaporated, and dried. The product contains triethylammonium hydrochloride. The residue was suspended in ether (20 mL), K₂CO₃ (1.5 g) was added, and the mixture stirred vigorously overnight. Solids were then filtered off, rinsed with ether and the filtrate was concentrated. The residue was purified by flash chromatography (silica, MeOH in DCM with 0.1% TEA, 0-10%) to give an additional amount of (S)-1-(methyl-d3)pyrrolidine-2-carboxamide (340 mg, 39 %) as a white solid:1H NMR (CDCl3) 5: 7.16 (br. s., 1 H), 5.46 (br. s., 1 H), 3.05 - 3.16 (m, 1 H), 2.86 (dd, J = 9.9, 5.7 Hz, 1H), 2.30 - 2.41 (m, 1H), 2.16 - 2.29 (m, 1H), 1.85 - 1.94 (m, 1H), 1.75 - 1.85 (m, 2H). LCMS: m / z 132.3 [M+H]+.

[0718] Preparation of (S)-(1-(methyl-d3)pyrrolidin-2-yl)methanamine: To a cold (ice-bath) stirred solution of (S)-1-(methyl-d3)pyrrolidine-2-carboxamide from above (100 mg, 0.762 mmol) in THF (3.25 mL) was added portion wise LAH (110 mg, 2.74 mmol) over a period of 10 min. The cooling bath was removed, and the grey suspension was stirred at RT for 2 h, and then heated at 70 °C overnight. The reaction mixture was cooled in an ice-water bath, carefully quenched with slow addition of water (115 pL) and aq. 15% NaOH solution (115 pL) and diluted with ether (10 mL). The cooling bath was removed, and the mixture stirred at RT for 10 min before filtering through a pad of Celite® that was rinsed with ether (20 mL). The combined filtrates were concentrated to give (S)-(1-(methyl-d3)pyrrolidin-2-yl)methanamine (74.0 mg, 83 %) as colorless oil:1H NMR (CDCl3) 5: 3.14 (ddd, J = 9.4, 6.9, 2.7 Hz, 1H), 2.84 (dd, J = 12.9, 3.9 Hz, 1H), 2.75 (dd, J = 12.9, 5.8 Hz, 1H), 2.24 - 2.33 (m, 2H), 2.13 (s, 2H), 1.88 - 2.00 (m, 1H), 1.61 - 1.85 (m, 3H).

[0719] The compounds of Example 35A and 35B were prepared following the procedures of Example 2 using (S)-(1-methyl-d3)pyrrolidine-2-yl)methanamine as the amine: Example 35A (first eluting / W-isomer):1H NMR (MeOH-d4) δ: 7.64 (d, J = 1.3 Hz, 1H), 7.15 (dd, J = 8.4, 5.1 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 3.68 - 3.84 (m, 2H), 3.37 - 3.46 (m, 1H), 3.22 (br. s., 1H), 2.75- 2.87 (m, 1H), 2.15- 2.27 (m, 1H), 1.81 - 2.06 (m, 3H). LCMS: m / z 493.1 [M+H]+.

[0720] Example 35B (second eluting P-isomer):1H NMR (MeOH-d4) δ: 7.65 (d, J = 1.3 Hz, 1H), 7.17 (dd, J = 8.3, 5.2 Hz, 1H), 7.01 (dd, J = 9.4, 8.4 Hz, 1H), 4.58 (s, 1H), 3.78 - 3.89 (m, 1H), 3.74 (dd, J = 12.0, 8.0 Hz, 1H), 3.38 - 3.47 (m, 1H), 2.75 - 2.90 (m, 1H), 2.14 - 2.27 (m, 1H), 1.79 -2.05 (m, 3H). LCMS: m / z 493.1 [M+H]+.

[0721] EXAMPLES 36A and 36B

[0722] (M)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-8-oxo-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (diastereomeric atropisomers):

[0723]

[0724] Example 36A (P-isomer) Example 36B ( / W-isomer) Step 1: 6-Amino-4-bromo-5-fluoroisobenzofuran-1(3H)-one: To a stirred suspension of lactone E-2a (742 mg, 2.69 mmol) in ethanol (14.3 mL) was added a solution of AcOH (3.08 mL, 53.8 mmol) in water (2.26 mL). Iron metal (751 mg, 13.4 mmol) was added in portions at RT, then the reaction was stirred for ~ 18 h at 80 °C (became soluble after heating and became darker). Celite® was added to the mixture and the resulting suspension was filtered over a celite® pad. The filtrate was concentrated under reduced pressure to afford the desired aniline (370 mg, 56 %) as an off white solid:1H NMR (DMSO-d6) 6: 5.19 (s, 2 H), 5.91 (br. s, 2 H), 7.13 (d, J = 7.3 Hz, 1 H). LCMS m / z 246.0 / 248.0 [M+H]+;

[0725] Step 2: tert-Butyl (4-(6-amino-5-fluoro-1-oxo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: In a 25-ml oven-dried microwave tube was placed the commercially available boronate (1.25 g, 3.0 mmol), the lactone from step 1 (370 mg, 1.5 mmol) and Cs2CO3(1.54 g, 4.74 mmol). THF was added under argon, and the mixture was stirred and sparged with argon for 10 min. Pd-117 (220 mg, 0.30 mmol), was added and the mixture was sparged for another 7 min, then the tube was sealed and heated at 70 °C. LCMS after 7 h showed disappearance of the bromo-limiting reagent and the appearance of a new peak corresponding to the mass of the desired product of step 2 (LCMS m / z 458.2 [M+H]+). The reaction was allowed to cool to RT, EtOAc was added and the reaction was filtered through Celite®, concentrated and loaded on silica (5 grams) and purified by chromatography (silica, EtOAc in DCM, 0-40%) to afford the desired product of step 2 (487 mg, 71 %) as a yellow solid.1H NMR (DMSO-d6) 5: 11.72 (s, 1 H), 7.49 (dd, J= 8.1, 5.4 Hz, 1 H), 7.36 (t, J = 9.1 Hz, 1 H), 7.22 (d, J = 7.4 Hz, 1 H), 5.70 (s, 2 H), 5.10 (d, J = 15.1 Hz, 1 H), 4.88 (d, J = 15.1 Hz, 1 H), 1.51 (s, 9 H). LCMS m / z 458.2 [M+H]+; SStep 3: tert-Butyl (4-(6-amino-5-fluoro-7-iodo-1-oxo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: To a solution of the aniline from step 2 (487 mg, 1.07 mmol) in ethanol (8.54 mL) was added silver sulfate (346 mg, 1.11 mmol) and iodine (282 mg, 1.11 mmol). The resulting suspension was stirred overnight at RT. After this, the solvent was evaporated, and the crude absorbed directly onto silica. The product was isolated by flash chromatography (silica, EtOAC in hexanes, 0-50%) to afford the desired iodide (522 mg, 84 %) as an orange solid:1H NMR (DMSO-d6) 5: 11.77 (s, 1 H), 7.50 (dd, J = 8.3, 5.1 Hz, 1 H), 7.37 (t, J = 8.8 Hz, 1 H), 5.73 (br. s, 2 H), 5.02 (d, J = 15.1 Hz, 1 H), 4.81 (d, J = 15.3 Hz, 1 H), 1.52 (s, 9 H). LCMS m / z 584.0 [M+H]+;

[0726] Step 4: tert-Butyl (3-cyano-7-fluoro-4-(5-fluoro-7-iodo-6-(3-(((S)-1-methylpyrrolidin-2-yl)methyl)thioureido)-1-oxo-1,3-dihydroisobenzofuran-4-yl)benzo[b]thiophen-2-yl)carbamate: A solution of the aryl iodide from sStep 3 (261 mg, 447 pmol) and 1,1'-thiocarbonyldi-2(1H)-pyridone (208 mg, 895 pmol) in DCM (2.24 mL) was stirred overnight at RT. Then, (S)-(1-methylpyrrolidin-2-yl)methanamine dihydrochloride (264 mg, 1.34 mmol) was added along with DIEA (623 pL, 3.58 mmol). The resulting solution was stirred at RT for 1 h and then concentrated under reduced pressure. The crude was purified by flash chromatography (silica, EtOAc in hexanes, 0-100%, then MeOH in DCM, 0-20%) to obtain the product as a yellow foamy solid (247 mg, 75 %): LCMS m / z 740.2 [M+H]+. Step 5: Examples 36A and 36B: The iodide from step 4 (250 mg, 169 pmol) was dissolved in DME (2.0 mL) in a 20 mL scintillation vial. Cooper (I) iodide (1.61 mg, 8.45 pmol), 1,10-phenanthroline (3.08 mg, 16.9 pmol) and Cs2CO3(110 mg, 338 pmol) were added. The mixture was degassed with argon for 5 minutes. The vial was sealed and left to stir on a hot plate at 80 °C. After 40 minutes, LCMS showed full conversion to desired product. The reaction was transferred to a separatory funnel with ethyl acetate and diluted with water. The aqueous layer was extracted with EtOAc 3 times. The combined organic fractions were washed with brine 2x and dried with sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by normal phase silica flash chromatography (silica, EtOAc in hexanes, 0-100%, then MeOH in DCM, 0-20%) to afford the Boc-protected intermediate of step 5 (52.0 mg, 50 %). The product was then dissolved in DCM (1.87 mL) and TFA (468 pL, 6.12 mmol) was added. After stirring at RT for 30 min, complete N-Boc deprotection was observed and the reaction was concentrated to dryness. The crude was dissolved in DMSO and purified by reversed phase Prep-HPLC using a biphenyl column and MeOH / Water / 0.1% FA as eluent which allowed separation of the two diastereomeric atropisomers 36A and 36B.

[0727] Example 36A (first eluted product, P-isomer):1H NMR (MeOH-d4) 5: 7.31 (dd, J = 8.3, 5.1 Hz, 1 H), 7.04 (t, J = 9.0 Hz, 1 H), 5.30 (d, J = 15.8 Hz, 1 H), 5.10 (d, J = 15.6 Hz, 1 H), 3.90 (ddd, J = 21.9, 15.0, 4.8 Hz, 2 H), 3.46 - 3.62 (m, 2 H), 3.03 (dd, J = 16.7, 7.9 Hz, 1 H), 2.96 (s, 3 H), 2.25 - 2.37 (m, 1 H), 1.90 - 2.15 (m, 3 H). LCMS m / z 512.2 [M+H]+.

[0728] Example 36B (second eluted product, / W-isomer):1H NMR (MeOH-d4) 5: 7.34 (dd, J = 8.1, 5.3 Hz, 1 H), 7.05 (t, J = 8.9 Hz, 1 H), 5.34 (d, J = 15.5 Hz, 1 H), 5.09 (d, J = 15.5 Hz, 1 H), 4.06 (dd, J = 15.1, 3.8 Hz, 1 H), 3.80 (dd, J = 15.0, 4.5 Hz, 1 H), 3.46 - 3.70 (m, 3 H), 2.96 - 3.06 (m, 4 H), 2.24 - 2.34 (m, 1 H), 1.90 - 2.14 (m, 3 H). LCMS m / z 512.2 [M+H]+.

[0729] EXAMPLE 37

[0730] 2 -Amino-4-(6-chloro-4- fluoro- 1-(2-methoxyethyl)-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): The general method of Scheme D, described in more details under Example 7 was followed using 2-methoxyethylamine in step 1:1H NMR (MeOH-d4) 5: 7.42 (s, 1H), 7.12 -7.18 (m, 1H), 6.99 (t, J = 8.9 Hz, 1H), 4.72 (dt, J = 11.3, 3.8 Hz, 1H), 4.63 (dd, J = 11.4, 6.1 Hz, 1 H), 4.22 - 4.35 (m, 2H), 3.69 - 3.77 (m, 2H), (3.31, m, 2H - under MeOD peak), 3.30 (s, 3H), 3.26 (br. s., 1H), 2.74 (d, J = 4.0 Hz, 3H), 2.16 - 2.29 (m, 1H), 1.84 - 2.03 (m, 3H). LCMS m / z 532.2 [M+H]+. EXAMPLES 38A and 38B

[0731] (M)- and (P)-2-Amino-4-(2-(3-amino-3-methylazetidin-1-yl)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile atropisomers: single atropisomers F-2a (more active (P)-isomer, second peak from separation on a Lux 5 pm cellulose-1 (OD) column as described in the synthesis of intermediates section) was converted to intermediate G-1a. The geometrically pure (P)-atropisomer of Example 38A was obtained following the procedures of Example 34 and using tert-butyl (3-methylazetidin-3-yl)carbamate hydrochloride as the amine:1H NMR (MeOH-d4) δ: 7.20 (dd, J = 8.3, 5. Hz, 4H), 6.98 (dd, J = 9.5, 8.4 Hz, 3H), 5.15 (d, J = 1.6 Hz, 7H), 4.92 (dt, J = 12.1, 2.00 Hz, 1H), 4.78 (dt, J = 12.1, 2.0 Hz, 1H), 4.02 - 4.11 (m, 4H), 1.54 (s, 3H). LCMS m / z 469.9 [M+H]+.

[0732] Starting from the less active ( / W)-atropisomer precursor of intermediate F-2a (1steluting peak on Chiralcel-OD column) and following the same procedures as for Example 38A, the less active isomer of Example 38B was obtained:1H NMR (DMSO-d6) 6:1H NMR (DMSO-d6) 6: 8.03 (s, 2H), 7.22 (dd, J = 8.3, 5.3 Hz, 1H), 7.08 (dd, J = 9.4, 8.4 Hz, 1H), 5.10 (s, 2H), 4.86 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.3 Hz, 1H), 3.88 - 4.04 (m, 4H), 2.54 (s, 1H), 1.43 (s, 3H). LCMS m / z 470.1 [M+H]+.

[0733] EXAMPLE 39

[0734] 2-Amino-4-(2-((3-aminobicyclo[1.1.1]pentan-1-yl)amino)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from intermediate G-1a following the procedures of Example 34 and using tert-butyl (3-aminobicyclo[1.1.1]pentan-1-yl)carbamate as the amine:1H NMR (MeOH-4) δ: 7.19 (dd, J = 8.4, 5.1 Hz, 1H), 6.98 (dd, J = 9.4, 8.4 Hz, 1H), 5.14 (d, J = 1.4 Hz, 2H), 4.90 (m, J = 1.90 Hz, 1H), 4.75 - 4.81 (m, 1 H), 2.33 (s, 6H). LCMS m / z 482.0 [M+H]+.

[0735] EXAMPLES 40A and 40B

[0736] ( / V?)- and (P)-2-Amino-4-(2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomeric atropisomers 40A and 40B: Prepared from intermediate G-1a following the procedures of Example 34 and using (R)-N, N-dimethylpyrrolidine-3-amine as the amine. The two diastereomeric atropisomers were separated by HPLC (reversed phase C18, MeOH in water with 0.1% NH4HCO3. Example 40A (2ndeluting P-isomer):1H NMR (MeOH-d4) δ: 7.21 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 5.17 (d, J = 1.5 Hz, 2H), 4.92 (d, J = 12.0 Hz, 1H), 4.79 (d, J = 12.0 Hz, 1H), 3.91 (dd, J = 9.8, 7.4 Hz, 1H), 3.75 - 3.85 (m, 1H), 3.56 - 3.68 (m, 1H), 3.43 - 3.52 (m, 1H), 3.07 -3.20 (m, 1H), 2.31 - 2.45 (m, 7H), 2.06 (dq, J = 12.3, 9.4 Hz, 1H). LCMS m / z 498.0 [M+H]+.

[0737] Example 40B (1steluting M-isomer):1H NMR (MeOH-d4) δ: 7.21 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (t, J = 8.9 Hz, 1H), 5.17 (s, 2H), 4.93 (d, J = 12.1 Hz, 1H), 4.79 (d, J = 12.1 Hz, 1H), 4.04 (m 1H), 3.84 (m, 1H), 3.53 - 3.71 (m, 3H), 2.67 (b.s., 6H), 2.45 - 2.58 (m, 1H), 2.13 - 2.29 (m, 1H). LCMS m / z 498.0 [M+ H]+.

[0738] EXAMPLES 41A and 41B

[0739] (M)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((((S)-pyrrolidin-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile atropisomers 41A and 41B: Prepared from intermediate G-1a following the procedures of Example 34 and using 2-(aminomethyl)-l-N-Boc-pyrrolidine as the amine. The two diastereomeric atropisomers were separated by flash chromatography on silica gel at the iodothiourea stage (step 1) and carried separately to final inhibitors 41 A and 41 B:

[0740] Example 41 A (from 1steluting iodothiourea intermediate):1H NMR (MeOH-d4) 5: 8.56 (s, 1 H), 7.21 (dd, J = 8.3, 5.2 Hz, 1H), 7.00 (dd, J = 9.5, 8.4 Hz, 1H), 5.14 (d, J = 1.5 Hz, 2H), 4.93 (d, J = 12 Hz, 1H), 4.78 (d, J = 12 Hz, 1H), 3.71 - 3.87 (m, 3H), 3.15 - 3.28 (m, 2H), 2.12 - 2.26 (m, 1H), 1.91 - 2.11 (m, 2H), 1.71 - 1.86 (m, 1H). LCMS m / z 484.0 [M+H]+.

[0741] Example 41B (from 2ndeluting iodothiourea intermediate):1H NMR (MeOH-d4) 5: 8.56 (br. s., 1H), 7.22 (dd, J = 8.3, 5.2 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 5.09 - 5.20 (m, 2H), 4.96 (d, J = 12.3 Hz, 1H), 4.77 (d, J = 12.3 Hz, 1H), 4.60 (br. s., 1H), 3.79 - 3.93 (m, 2H), 3.64 - 3.76 (m, 1H), 3.15 - 3.30 (m, 2H), 2.12 -2.25 (m, 1H), 1.90 - 2.10 (m, 2H), 1.81 (dq, J = 12.8, 8.2 Hz, 1H) LCMS m / z 484.2 [M+H]+.

[0742] EXAMPLE 42

[0743] 2-Amino-4-(2-((2-(dimethylamino)ethyl)amino)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from intermediate G-1a following the procedures of Example 34 and using N, N-dimethylethylenediamine as the amine:1H NMR (MeOH-d4) 5: 7.20 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 5.13 (d, J = 1.6 Hz, 2H), 4.91 (d, J = 12.0 Hz, 1H), 4.78 (d, J = 12.0 Hz, 1H), 4.58 (br. s., 1H), 3.68 (t, J = 6.4 Hz, 2H), 2.79 (t, J = 6.4 Hz, 2H), 2.44 (s, 6H). LCMS m / z 471.9 [M+H]+.

[0744] EXAMPLES 43A, 43B and 50

[0745] (M)- and (P)-2-Amino-4-(6-chloro-4-fluoro-1-(2-hydroxyethyl)-2-((S)-1-((S)-1-methylpyrrolidin-2-yl)ethoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile atropisomers 43A and 43B and 2-amino-4-(6-chloro-4-fluoro-2-hydroxy-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 50:

[0746]

[0747] Example 43A (M-isomer) Example 43B (P-isomer)

[0748] Step 1: tert-Butyl (4-(3-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)thioureido)-6-chloro-2-fluoro-4-iodophenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: To a solution of intermediate B-1a (1.72 g, 3.06 mmol) in DCM (20.0 mL) was added 1,1'-thiocarbonyldi-2(1H)-pyridone (823 mg, 3.37 mmol) and the solution was stirred at RT for 20 h. The reaction was monitored by LCMS analysis of aliquots quenched by addition to NH4OH. After 20 h, additional 1,1'-thiocarbonyldi-2(1H)-pyridone (320 mg, 1.38 mmol) was added and the mixture stirred at RT for 2 h. 2-[(tert-Butyldimethylsilyl)oxy]ethan-1 -amine (1.07 g, 6.12 mmol) was then added dropwise and the mixture stirred for 45 min at RT. The volatiles were then evaporated under vacuum and the crude product was adsorbed on celite®. The product was purified by flash chromatography (80 g silica, 5% to 30% EtOAc in hexanes), but the unreacted aniline could not be fully separated. The product was used as is in the next step (1.53 g with a purity of 83%: LCMS m / z 779.2 [M+H]+.

[0749] Step 2: tert-Butyl (Z)-(4-(6-chloro-2-fluoro-4-iodo-3-((2,2,3,3-tetramethyl-4-oxa-9-thia-7-aza-3-silaundecan-8-ylidene)amino)phenyl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: To a solution of the intermediate from step 1 (1.43 g, 1.83 mmol) in MeCN (30.0 mL) was added K₂CO₃ (294 mg, 2.13 mmol), followed by iodoethane (173 pL, 2.13 mmol). The reaction was stirred for 18 h at RT. Additional MeCN (10.0 mL), K₂CO₃ (294 mg, 2.13 mmol) and iodoethane (173 pL, 2.13 mmol) were added to push the reaction to completion for an additional 4 h. The volatiles were evaporated under vacuum. Then, the crude product was dissolved in EtOAc and the solids were removed by filtration through a pad of celite®. The solvent was removed under vacuum and the gummy solid product was triturated in heptane and re-evaporated to afford the desired product of step 2 (1.45 g, 93 % based on contaminating starting material). The product was used as is in the next step: LCMS m / z 807.2 [M+H]+.

[0750] SStep 3: tert-butyl (4-(1-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-6-chloro-2-(ethylthio)-4-fluoro-1 H-benzo[d]imidazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: A solution of the intermediate from step 2 (1.45 g, 1.42 mmol) in DME (15.0 mL) was degassed by bubbling Ar while stirring for 15 min, then sonicated while bubbling with Ar. To the solution was added K₂CO₃ (392 mg, 2.84 mmol), followed by 1,10-phenanthroline (51.7 mg, 284 pmol) and copper (I) iodide (27.0 mg, 142 pmol) while keeping the Ar atmosphere. The reaction mixture was heated to 80 °C and stirred for 5.5 h. Conversion had stalled between 3 h and 5.5 h, so additional copper (I) iodide (13.5 mg, 71.0 pmol) and 1,10-phenanthroline (25.8 mg, 142 pmol) were added, and the reaction was stirred for an additional 16 h at 80 °C. The volatiles were then removed under vacuum. The crude product was dissolved in EtOAc (100 mL) and washed with water (25 mL). The aqueous layer was extracted twice with EtOAc (50 mL each). The combined organic layers were washed with brine, then dried over MgSO4 and filtered through celite. The crude product was adsorbed onto celite and purified by flash chromatography (40g silica, 5% to 45% EtOAc in hexanes gradient). The product (981 mg, 81 %) was isolated as an orange solid, containing the iodo-aniline as an impurity (~15%):1H NMR (CDCl3) 5: 7.76 (br. s, 1H), 7.34 (d, J = 0.5 Hz, 1H), 7.23 - 7.26 (m, 1H), 7.12 (dd, J = 9.1, 8.4 Hz, 1H), 4.22 (dt, J = 6.5, 5.0 Hz, 2H), 3.96 (t, J = 4.9 Hz, 2H), 3.46 (q, J = 7.3 Hz, 2H), 1.57 (s, 9H), 1.49 (t, J = 7.4 Hz, 3H), 0.83 (s, 9H), -0.05 (s, 3H), -0.10 (s, 3H). LCMS m / z 679.3 [M+H]+.

[0751] Step 4: tert-Butyl (4-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)-6-chloro-2-(ethylsulfonyl)-4-fluoro-1H-benzo[d]imidazol-5-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: To a solution of the sulfide from sStep 3 (785 mg, 1.16 mmol) in DCM (11.6 mL) was added mCPBA (647 mg, 2.89 mmol) and the reaction was stirred at RT for 24 h until completion of the reaction. The solution was diluted with DCM (100 mL) and washed with sat. NaHCO3(50 mL). The aqueous layer was re-extracted twice with DCM (2 x 50 mL). The combined organic layers were washed with brine, then dried over MgSO4. The crude product was adsorbed onto celite and purified by flash chromatography (40 g silica, 5% to 30% EtOAc in hexanes). Some fractions containing an impurity were re-purified a second time by flash chromatography. The product was isolated as a light orange solid that was used directly in the next step. LCMS m / z 711.2 [M+H]+.

[0752] Step 5: In a 4-mL screw-top vial, (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1-ol (34.1 mg, 264 pmol) was dissolved in DMF (703 pL) and the atmosphere of the vial was flushed with Ar for 2 min. KOtBu (59.2 mg, 527 pmol) was added to the solution, followed by the crude sulfoxide from step 4 (75.0 mg, 105 pmol). The vial was again flushed with Ar for 1 min, then closed and heated to 70 °C for 1 h. The reaction mixture was cooled down to RT, then DMF was evaporated under vacuum.

[0753] The crude product was dissolved in DCM (500 pL) and TFA (8.07 pL, 105 pmol) was added at RT. The deprotection reaction was stirred for 4 h until completion. The solution was diluted with MeCN and fully evaporated under vacuum. The crude product was dissolved in DMSO, filtered through a 0.45 pM PTFE filter and purified by preparatory HPLC (column: Kinetex C18 100 mm x 30 mm) with a 50% to 100% B in A gradient (where A = 95% water / 5% MeOH / 0.1% formic acid; B = 5% water / 95% MeOH / 0.1% formic acid).

[0754] Example 43B (first eluting P-diastereomer):1H NMR (MeOH-d4) 5: 7.44 (s, 1H), 7.13 (dd, J = 8.3, 5.1 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 5.34 (dt, J = 14.4, 5.9 Hz, 1H), 4.22 (tdd, J = 14.9, 6.1 Hz, 2H), 3.83 - 3.96 (m, 2H), 3.45 - 3.73 (m, 2H), 3.04 - 3.19 (m, 1 H), 2.98 (s, 3H), 2.26 - 2.42 (m, 1 H), 2.01 - 2.22 (m, 2H), 1.89 - 2.01 (m, 1 H), 1.56 (d, J = 6.3 Hz, 3H). LCMS m / z 532.2 [M+H]+.

[0755] Example 43A (second eluting M-diastereomer):1H NMR (MeOH-d4) 5: 7.39 (d, J = 0.6 Hz, 1H), 7.14 (dd, J = 8.4, 5.3 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 5.25 (dt, J = 12.3, 6.3 Hz, 1H), 4.16 (td, J = 5.3, 3.0 Hz, 2H), 3.87 (t, J = 5.4 Hz, 2H), 3.09 (ddd, J = 9.4, 5.3, 3.9 Hz, 1H), 2.74 - 2.82 (m, 1H), 2.51 (s, 3H), 2.35 - 2.44 (m, 1H), 1.98 - 2.08 (m, 1H), 1.74 - 1.87 (m, 3H), 1.45 (d, J = 6.3 Hz, 3H). LCMS m / z 532.2 [M+H]+.

[0756] Example 50 (hydrolysis product):1H NMR (MeOH-d4) δ: 7.24 (d, J = 0.8 Hz, 1H), 7.14 (dd, J = 8.5, 5.1 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 4.01 (td, J = 5.4, 1.3 Hz, 2H), 3.85 (td, J = 5.3, 2.8 Hz, 2H). LCMS m / z 421.0 [M+H]+. EXAMPLE 44

[0757] 2-Amino-4-(6-chloro-4-fluoro-2-(3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (atropisomer mixture): Prepared following the procedures of Example 2 using 3-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride as the amine and 8 equiv. of DIEA as base:1H NMR (DMSO-d6) 5: 8.04 (s, 2H), 7.90 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 4.36 (d, J = 18.4 Hz, 2H), 2.62 - 2.79 (m, 2H), 2.32 (t, J = 8.9 Hz, 2H), 2.16 (s, 3H), 1.94 (s, 4H). LCMS m / z 502.2 [M+H]+.

[0758] EXAMPLE 45

[0759] 2-Amino-4-(6-chloro-4-fluoro-2-(8-methyl-3,8-diazabicyclo[3.2.1]octan-3-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (atropisomer mixture): Prepared following the procedures of Example 2 using 8-methyl-3,8-diazabicyclo[3.2.1]octane dihydrochloride as the amine and 8 equiv. of DIEA as base:1H NMR (DMSO-d6) 5: 8.04 (s, 2H), 7.90 (d, J = 1.1 Hz, 1H), 7.16 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.47 - 3.76 (m, 2H), 3.35 - 3.41 (m, 2H), 3.19 - 3.27 (m, 2H), 2.25 (s, 3H), 1.91 - 2.06 (m, 2H), 1.59 (dd, J = 13.8, 6.2 Hz, 2H). LCMS m / z 502.2 [M+H]+.

[0760] EXAMPLE 46

[0761] 4-(2-((1S,4S)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric atropisomer mixture): Prepared following the procedures of Example 2 using (1S,4S)-2-t-Boc-2,5-diazabicyclo[2.2.1]heptane as the amine and 8 equiv. of DIEA as base:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.87 (s, 1H), 7.17 (ddd, J = 8.2, 5.6, 2.2 Hz, 1H), 7.10 (dd, J = 9.5, 8.4 Hz, 1H), 4.53 (br. s., 1H), 3.72 (s, 1H), 3.59 (d, J = 8.8 Hz, 1H), 2.94 (s, 2H), 1.89 (d, J = 9.3 Hz, 1H), 1.73 (d, J = 9.3 Hz, 1H) 2H missing under water signal. LCMS m / z 474.0 [M+H]+.

[0762] EXAMPLE 47

[0763] 4-(2-((1R,4R)-2,5-Diazabicyclo[2.2.1]heptan-2-yl)-6-chloro-4-fluorobenzo[d]thiazol-5-yl)-2-amino-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric atropisomer mixture): Prepared following the procedures of Example 2 using (1S,4S)-2-t-Boc-2,5-diazabicyclo[2.2.1]heptane as the amine and 8 equiv. of DIEA as base:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.87 (s, 1H), 7.17 (ddd, J = 8.2, 5.6, 2.1 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 4.54 (br. s., 1H), 3.72 (s, 1H), 3.59 (d, J = 8.8 Hz, 1H), 2.94 (s, 2H), 1.88 (d, J = 9.1 Hz, 1H), 1.73 (d, J = 9.3 Hz, 1H) 2H missing under water signal. LCMS m / z 474.0 [M+H]+. EXAMPLE 48

[0764] 2-Amino-4-(6-chloro-2-(3-(dimethylamino)-3-(hydroxymethyl)azetidin-1-yl)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (atropisomer mixture):

[0765]

[0766] Step 1: 1 -(tert- Butyl) 3-ethyl 3-aminoazetidine-1,3-dicarboxylate: In a 50 mL flask equipped with a magnetic stir bar, 1-tert-butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (0.615 g, 2.52 mmol) was dissolved in MeOH (15.9 mL). Formaldehyde (37% aqueous solution, 1.30 mL, 17.4 mmol) was then added followed by AcOH (576 pL, 10.1 mmol). The resulting mixture was stirred at RT for 1 h then sodium cyanoborohydride (316 mg, 5.03 mmol) was carefully and slowly added (strong effervescence). The resulting reaction mixture was stirred at RT for 23 h. LCMS analysis of a sample revealed the reaction was complete. The mixture was concentrated to about 1 / 4 of its volume then diluted with water and made basic with the addition of a saturated NaHCO3solution. The mixture was then extracted 3x with and the combined organic layers were washed once with brine and dried over MgSO₄, filtered and concentrated. The resulting crude oil was purified by flash chromatography (silica, DCM in hexanes with 4% MeOH, 50-100%) to afford the desired N, N-dimethyl derivative as a colorless oil (593 mg, 87 %):1H NMR (CDCh) 6: 4.25 (q, J = 7.1 Hz, 2H), 4.10 (d, J = 8.8 Hz, 2H), 3.86 (d, J = 8.8 Hz, 2H), 2.29 (s, 6H), 1.44 (s, 9H), 1.32 (t, J = 7.1 Hz, 3H).

[0767] Step 2: 1-(tert-Butyl) 3-ethyl 3-(dimethylamino)azetidine-1,3-dicarboxylate: The ester from step 1 (590 mg, 2.17 mmol) was dissolved in THF (12.0 mL) in a 50 mLflask fitted with a reflux condenser then a 2M solution of lithium borohydride in THF (2.17 mL, 4.34 mmol) was added dropwise at RT. The resulting solution was brought to reflux and stirred for 1.5 h. LCMS analysis indicated a small amount of unreacted SM remained. The temperature of the oil bath was reduced to 45 °C and the mixture was allowed to stir for another 17 h. The starting material was completely consumed as revealed by LCMS. The mixture was allowed to cool to RT then cooled in an ice bath before quenching with ice affording a gummy white precipitate. 1 N HCI was then added dropwise (effervescence at first) until a clear, colorless solution was obtained. pH paper indicated the mixture was acidic. While still at 0 °C, a saturated solution of Na2CO3was added until a pH of about 10 was obtained as indicated by pH paper. The mixture was then extracted 3x with EtOAc. The combined organic layers were washed with brine (containing a few drops of concentrated Na2CO3) and dried over anhydrous Na2SO4. After filtration, the crude filtrate was concentrated to dryness and purified by flash chromatography (silica, EtOAc in DCM, 10%-30% then MeOH in DCM, 2-10%). to afford the desired alcohol as a thick, colorless oil which crystalized to a white solid upon standing (590 mg, 2.17 mmol):1H NMR (CDCl3) 5: 3.97 (d, J = 8.5 Hz, 2H), 3.79 (br. s., 2H), 3.59 (d, J = 7.8 Hz, 2H), 2.34 (s, 6H), 1.45 (s, 9H).

[0768] SStep 3: (3-(Dimethylamino)azetidin-3-yl)methanol, bis-TFA salt: tert-butyl 3-(dimethylamino)-3-(hydroxymethyl)azetidine-l -carboxylate from step 2 (467 mg, 2.03 mmol) was dissolved in DCM (3.00 mL) to which was added TFA (3.00 mL, 39.2 mmol) at RT. The resulting clear, colorless solution was stirred for 1.5 h at RT. The mixture was concentrated to dryness then azeotropically concentrated to dryness again from 5 mL of toluene. The residue was dried under reduced pressure affording ((3-(dimethylamino)azetidin-3-yl)methanol bis(2,2,2-trifluoroacetate)) as a colorless semi-solid (825 mg, 114 %):1H NMR (DMSO-d6) 6: 9.27 (br. s., 2H), 4.30 (d, J = 11.3 Hz, 2H), 3.95 (d, J = 11.3 Hz, 2H), 3.95 (s, 2H), 2.77 (s, 6H), 2 exchangeable H missing. LCMS m / z 131.0 [M+H]+.

[0769] Step 4: (3-(Dimethylamino)azetidin-3-yl)methanol bis(2,2,2-trifluoroacetate) (55.9 mg, 156 pmol) and intermediate A-5a (40.0 mg, 78.1 pmol) were dissolved in dry MeCN (889 pL) and DIEA (109 pL, 625 pmol) was added. The reaction was stirred at 40 °C and after 18 h LCMS indicated complete consumption of the starting material. The mixture was allowed to cool to RT then concentrated to a residue and dried under reduced pressure.

[0770] To the crude residue from above was added DCM (800 pL) and TFA (401 pL, 5.23 mmol). The resulting solution was stirred at RT for 2 h. LCMS indicated complete deprotection. The mixture was concentrated to dryness then the residue was taken up in 1 mL of DMSO and neutralized with the addition of a saturated solution of ammonium bicarbonate in 1:1 methanol and water (about 2 mL). The solution was purified by reversed phase chromatography (C18 column, MeOH in water with 0.1% NH4CO3, 50-100%) to give the compound of Example 48 as a white solid (1:1 mixture of atropisomers):1H NMR (DMSO-d6) 6: 8.04 (s, 2H), 7.91 (d, J = 0.8 Hz, 1H), 7.18 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 5.00 (t, J = 5.3 Hz, 1H), 4.02 (d, J = 8.3 Hz, 2H), 3.95 (d, J = 8.4 Hz, 2H), 3.67 (d, J = 5.3 Hz, 2H), 2.27 (s, 6H). LCMS m / z 506.2 [M+H]+.

[0771] EXAMPLE 49 2-Amino-4-(6-chloro-4-fluoro-2-((R)-3-(methylamino)pyrrolidin-1-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric atropisomer mixture): Prepared following the procedures of Example 2 using tert-butyl N-methyl-N-[(3R)-pyrrolidin-3-yl]carbamate as the amine and 8 equiv. of DIEA as base:1H NMR (DMSO-d6) 6: 8.02 (s, 2H), 7.89 (s, 1 H), 7.18 (dd, J = 8.3, 5.4 Hz, 1H), 7.10 (t, J = 8.9 Hz, 1H), 3.61 - 3.76 (m, 1H), 3.56 - 3.61 (m, 1H), 3.47 - 3.56 (m, 1H), 3.25 - 3.30 (m, 1H), 2.30 (s, 3H), 2.08 - 2.20 (m, 1H), 2.02 (br. s., 1H), 1.82 - 1.95 (m, 1H). LCMS m / z 476.2 [M+H]+.

[0772] EXAMPLES 51 A and 51B

[0773] Preparation of (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol: Lithium aluminum hydride (1M THF solution, 36.8 mL, 36.8 mmol) was slowly added at 0 °C to a solution of N-Boc-trans-4,4-difluoro-L-proline (2.73 g, 10.5 mmol) in THF (53 mL). The resulting mixture was stirred at 0 °C for 20 min and heated to 70 °C for 10 h. The reaction mixture was cooled down to 0 °C and 1 N NaOH (1.4 mL) in water (1.4 mL) and water (4.2 mL) were added. After stirring for 5 min at 0 °C and 10 min at RT, MgSO4was added. The mixture was stirred for 10 min and filtered over Celite. The solution was concentrated. The crude was use without any purification for the next step. (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol (1.41 g, 88 %) was obtained as a colorless oil.1H NMR (CDCl3) 6: 3.76 (dt, J = 11.5, 1.4 Hz, 1H), 3.35 - 3.50 (m, 2H), 2.65 - 2.80 (m, 2H), 2.19 -2.53 (m, 6H). LCMS m / z 152.3 [M+H]+.

[0774] (M)- and (P)-2-Amino-4-(6-chloro-2-(((S)-4,4-difluoro-1-methylpyrrolidin-2-yl)methoxy)-4-fluoro-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomeric atropisomers (Examples 51 A and 51 B): Prepared following the procedures of Example 43 using (S)-(4,4-difluoro-1-methylpyrrolidin-2-yl)methanol from above as the alcohol in step 5:

[0775] Example 51A (second eluting M-atropisomers):1H NMR (MeOH-4) δ: 7.41 (d, J = 0.5 Hz, 1H), 7.14 (ddd, J = 8.3, 5.2, 1.4 Hz, 1H), 6.99 (dd, J = 9.3, 8.6 Hz, 1H), 4.57 - 4.70 (m, 2H), 4.19 (qt, J = 14.9, 5.1 Hz, 2H), 3.83 - 3.94 (m, 2H), 3.40 (ddd, J = 12.5, 11.3, 4.6 Hz, 1H), 3.06 - 3.15 (m, 1H), 2.77 (ddd, J = 18.4, 14.8, 11.1 Hz, 1H), 2.50 - 2.64 (m, 1H), 2.49 (s, 3H), 2.25 - 2.43 (m, 1H). LCMS m / z 554.2 [M+H]+.

[0776] Example 51 B (first eluting P-atropisomers):1H NMR (MeOH-d4) δ: 7.26 (dd, J = 4.6, 0.8 Hz, 1H), 7.13 (ddd, J = 8.3, 5.2, 1.5 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 4.03 - 4.16 (m, 2H), 3.78 (t, J = 4.9 Hz, 2H), 3.51 - 3.60 (m, 1H), 3.43 - 3.51 (m, 1H), 3.33 - 3.37 (m, 1H), 3.23 - 3.28 (m, 1H), 2.73 (ttt, J = 9.4, 8.8, 5.1 Hz, 1H), 2.63 (ddd, J = 15.5, 6.6, 2.4 Hz, 1H), 2.33 (s, 3H), 2.25 - 2.39 (m, OH), 1.93 - 2.12 (m, 1H). LCMS m / z 554.2 [M+H]+.

[0777] EXAMPLE 52

[0778] Preparation of (S)-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methanol: To a solution of (S)-1-pyrrolidin-2-yl-methanol (1.52 g, 15.0 mmol) in MeCN (75.0 mL) was added K₂CO₃ (2.49 g, 18.0 mmol), followed by 2-bromoethoxy-t-butyldimethylsilane (3.54 mL, 16.5 mmol). The reaction was left to stir at RT for 24 h. The volatiles were evaporated under reduced pressure (max 100 mbar at 40 °C to avoid losing product). The crude product was dissolved in EtOAc and the salts were removed by filtration through celite®. The filtrate was purified by flash chromatography (40 g silica, 0% to 8% MeOH in DCM) and the product was isolated as a yellow oil (2.27 g, 58 %):1H NMR (CDCl3) 5: 3.70 (dd, J = 6.7, 5.2 Hz, 2H), 3.60 (dd, J = 10.8, 3.6 Hz, 1H), 3.36 (dd, J = 10.7, 3.4 Hz, 1H), 3.20 (dt, J = 9.3, 4.7 Hz, 1H), 2.89 (dt, J = 13.0, 6.6 Hz, 1H), 2.65 - 2.72 (m, 1H), 2.51 (dt, J = 12.8, 5.2 Hz, 1H), 2.36 (q, J = 8.3 Hz, 1H), 1.80 - 1.91 (m, 1H), 1.63 - 1.79 (m, 4H), 0.87 - 0.94 (m, 9H), 0.04 - 0.10 (m, 6H). LCMS m / z 260.2 [M+H]+.

[0779] 2-Amino-4-(6-chloro-4-fluoro-1-(2-hydroxyethyl)-2-(((S)-1-(2-hydroxyethyl)pyrrolidin-2-yl)methoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 1:1 mixture of diastereomeric atropisomers (Example 52): Prepared following the procedures of Example 43 using (S)-(1-(2-((tert-butyldimethylsilyl)oxy)ethyl)pyrrolidin-2-yl)methanol from above as the alcohol in step 5. The final mixture of atropisomers was purified by reversed-phase HPLC under basic condition:1H NMR (MeOH-d4) δ: 7.30 (s, 2H), 7.04 (dd, J = 8.3, 5.2 Hz, 2H), 6.89 (dd, J = 9.4, 8.4 Hz, 2H), 4.52 - 4.63 (m, 3H), 4.40 - 4.43 (m, 1H), 4.09 (t, J = 5.1 Hz, 4H), 3.78 (t, J = 5.3 Hz, 4H), 3.59 (td, J = 6.2, 2.2 Hz, 2H), 3.47 (ddd, J = 11.0, 4.6, 1.3 Hz, 1H), 3.40 (dd, J = 11.0, 5.8 Hz, 1H), 3.26 - 3.35 (m, 1H), 3.09 - 3.16 (m, 1H), 2.93 - 3.05 (m, 2H), 2.76 (dq, J = 13.7, 4.6 Hz, 1H), 2.57 - 2.64 (m, 1H), 2.51 (dtd, J = 12.6, 5.5, 1.3 Hz, 1H), 2.28 - 2.41 (m, 2H), 1.90 - 2.01 (m, 1 H), 1.80 - 1.89 (m, 1 H), 1.63 - 1.80 (m, 5H), 1.45 - 1.62 (m, 2H). LCMS m / z 548.2 [M+H]+.

[0780] EXAMPLE 53

[0781] 2-Amino-7-fluoro-4-(4-methyl-2-(3-(methylamino)azetidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (mixture of atropisomers):

[0782]

[0783] Step 1: 5-Methyl-6-nitro-1,3-dihydroisobenzofuran: To a solution of E-6b (489 mg, 2.45 mmol) in dioxane (12.3 mL) was added tetrakis(triphenylphosphine)palladium(0) (283 mg, 245 pmol), Cs2CO3(2.39 g, 7.35 mmol) and trimethylboroxine (346 pL, 2.45 mmol). The solution was stirred at 100 °C for 18 h. After this, the reaction was concentrated under reduced pressure and directly absorbed onto silica. The crude was purified by flash chromatography (Silica, 12 g, EtOAc in Hexanes 0-15%) to afford the desired methylated intermediate (467 mg, 106 %):1H NMR (DMSO-d6) 6: 7.96 (s, 1 H) 7.43 (s, 1 H) 5.03 (s, 4 H) 2.51 (s, 3 H).

[0784] Step 2: 4-Bromo-5-methyl-6-nitro-1,3-dihydroisobenzofuran: To a cold (-10 °C) stirred solution of the product from step 1 (467 mg, 2.61 mmol) in sulfuric acid (9.55 mL) was added 1,3-dibromo-5,5-dimethylhydantoin (768 mg, 2.63 mmol) in portions during a period of 50 min. The reaction temperature was maintained between -10 to -5 °C during the addition. After the addition was complete, the reaction mixture was stirred at the same temperature for an additional 40 min, then poured onto crushed ice (100 g) and left standing for 1 h. The precipitated product was filtered off, rinsed with water (20 mL) and dissolved in DCM. The solution was washed with brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (25 g SiO2) using a gradient of ethyl acetate in hexanes (0 to 35%) as eluent to give the desired brominated product (313 mg, 47 %):1H NMR (DMSO-d6) 6: 7.90 (s, 1 H), 5.14 - 5.19 (m, 2 H), 5.04 (t, J = 1.8 Hz, 2 H), 2.46 (s, 3 H). SStep 3: 7-Bromo-6-methyl-1,3-dihydroisobenzofuran-5-amine: To a solution of the above nitroarene (313 mg, 1.21 mmol) in EtOH (2.89 mL) - water (578 pL) was added iron metal (339 mg, 6.06 mmol) and NH4CI (324 mg, 6.06 mmol). The reaction mixture was stirred at 80 °C for 18 h. After this, celite® was added and the reaction was filtered. The filtrate was concentrated under reduced pressure to afford the desired aniline (263 mg, 95 %) as a yellow solid that was used directly in the next step:1H NMR (DMSO-d6) 6: 6.53 (s, 1 H), 5.17 (br. s, 2 H), 4.97 (br. s, 2 H), 4.82 (t, J = 2.4 Hz, 2 H), 2.13 (s, 3 H). LCMS m / z 228.0 / 230.0 [M+H]+.

[0785] Step 4: tert-Butyl (4-(6-amino-5-methyl-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: In a 25-mL oven-dried microwave tube was placed the bromoaniline from sStep 3 (263 mg, 1.15 mmol), commercially available tert-butyl (3-cyano-4-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-7-fluorobenzo[b]thiophen-2-yl)carbamate (961 mg, 2.31 mmol) and Cs2CO3(1.18 g, 3.63 mmol). THF was added under argon, and the mixture was stirred and sparged with argon for 10 min. Pd-117 (168 mg, 231 pmol), was added and the mixture was sparged for another 7 min, then the tube was sealed and heated at 70 °C. LCMS after 7 h showed disappearance of the bromo-limiting reagent and the appearance of a new peak corresponding to the desired product. The reaction was allowed to cool to RT, EtOAc was added, and the mixture was filtered through Celite®. After concentration, the residue was purified by chromatography (silica, EtOAc in DCM 0-50%) to afford the desired intermediate (148 mg, 29 %) as a yellow solid: LCMS m / z 440.2 [M+H]+.

[0786] Step 5: tert-Butyl (4-(6-amino-7-iodo-5-methyl-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: To a solution of aniline from step 4 (148 mg, 337.0 pmol) in EtOH (3.4 mL) was added iodine (89.7 mg, 354 pmol) and silver sulfate (111 mg, 354 pmol). The resulting suspension was stirred at RT for 18 h. Then, the solvent was removed under reduced pressure and the crude was absorbed onto silica and purified by flash chromatography (silica, 12 g, 0-40% EtOAc in Hexanes) to afford the desired iodide (43.0 mg, 23 %) as a brown oil that solidified on standing: LCMS m / z 564.2 [M+H]+.

[0787] Step 6: tert-Butyl (1-((7-(2-((tert-butoxycarbonyl)amino)-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-4-iodo-6-methyl-1,3-dihydroisobenzofuran-5-yl)carbamothioyl)azetidin-3-yl)(methyl)carbamate: In a 20 mL vial was added the aniline from step 5 (42.0 mg, 74.3 pmol), 1,1'-thiocarbonyldi-2(1H)-pyridone (34.5 mg, 149 pmol) and DCM (750 pL). The mixture was stirred at RT overnight. Then, 3-Boc-3-methylaminoazetidine hydrochloride (50 mg, 223 pmol) and DIEA (81.3 pL, 446 pmol) were added and the solution stirred for an additional 1.5 h. The crude was concentrated under reduced pressure and purified by flash chromatography to afford the desired thiourea (46.0 mg, 78 %) as an orange foam: LCMS m / z 794.2 [M+H]+.

[0788] Step 7: 2-Amino-7-fluoro-4-(4-methyl-2-(3-(methylamino)azetidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (Example 53): To a solution of the thiourea from step 6 (42.0 mg, 52.9 pmol) in DME (530 pL) was added 1,10-phenanthroline (1.93 mg, 10.6 pmol), copper (I) iodide (1.01 mg, 5.29 pmol) and K₂CO₃ (14.6 mg, 106 pmol). After stirring for 1 h at 80 °C, the reaction was filtered through celite® and concentrated under reduced pressure. The crude residue was dissolved in DCM (530 pL) and TFA (405 pL, 5.29 mmol) was added. The solution was stirred at RT for 4 h. Then, the solvent and excess TFA was removed under reduced pressure and the crude was dissolved in DMSO (1 mL) and treated dropwise with NH4CO3 saturated MeOH until no more effervescence was observed. The product was then isolated by reversed phase chromatography (Kinetex C18 18x100 column and 20-80% of MeOH / H2O gradient with 2% NH4CO3). Example 53 (15.0 mg, 61 %) was obtained as a white solid:1H NMR (MeOH-d4) δ: 7.09 (dd, J = 8.3, 5.3 Hz, 1H), 6.98 (dd, J = 9.5, 8.3 Hz, 1H), 5.15 (s, 2 H), 4.80 (dt, J = 11.8, 2.0 Hz, 1H), 4.69 (dt, J = 11.9, 2.1 Hz, 1H), 4.36 - 4.43 (m, 2 H), 3.95 - 4.02 (m, 2 H), 3.77 - 3.85 (m, 1 H), 2.38 (s, 3 H), 2.24 (s, 3 H). LCMS m / z 466.2 [M+H]+.

[0789] EXAMPLE 54

[0790] 2-Amino-7-fluoro-4-(4-fluoro-2-((2-hydroxyethyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from intermediate G-1a following the procedures of Example 34 and using 2-[(tert-butyldimethylsilyl)oxy]ethan-1-amine as the amine:1H NMR (MeOH-d4) δ: 7.20 (dd, J = 8.3, 5.1 Hz, 1H) 6.98 (dd, J = 9.4, 8.3 Hz, 1H) 5.13 (dd, J = 3.9, 2.0 Hz, 2H) 4.90 (dt, J=12.3, 1.8 Hz, 1 H) 4.78 (dt, J=12.1, 1.8 Hz, 1 H) 3.78 (t, J=5.5 Hz, 2 H) 3.61 (t, J=5.6 Hz, 2 H) (4 protons exchanged with D). LCMS m / z 445.0 [M+H]+.

[0791] EXAMPLE 55

[0792] 2-Amino-7-fluoro-4-(4-fluoro-1-(2-hydroxyethyl)-2-(2-morpholinoethoxy)-6,8-dihydro-1H-isobenzofuro[4,5-d]imidazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared following the procedures of Example 43 using 2-morpholinoethan-1-ol as the alcohol in step 5:1H NMR (MeOH-d4) δ: 7.19 (dd, J = 8.3, 5.2 Hz, 1H), 6.98 (dd, J = 9.5, 8.4 Hz, 1H), 5.42 - 5.52 (m, 2H), 4.89 - 4.95 (m, 1H), 4.71 - 4.83 (m, 3H), 4.15 (t, J = 5.3 Hz, 2H), 3.69 - 3.94 (m, 6H), 3.20 - 3.29 (m, 2H), 2.93 - 3.05 (m, 2H). (2Hs are hidden under the water peak). LCMS m / z 542.2 [M+H]+.

[0793] EXAMPLE 56

[0794] 2-Amino-7-fluoro-4-(4-fluoro-2-((3-methylazetidin-3-yl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from intermediate G-1a following the procedures of Example 34 and using tert-butyl 3-amino-3-methylazetidine-1 -carboxylate as the amine:1H NMR (DMSO-d6) 5: 8.79 (s, 1 H), 8.29 (br. s., 1 H), 8.03 (br. s., 1 H), 7.22 (dd, J = 8.3, 5.3 Hz, 1H), 7.08 (dd, J = 9.4, 8.4 Hz, 1H), 5.08 (br. s., 2H), 4.82 (d, J = 12.3 Hz, 1H), 4.69 (d, J = 12.3 Hz, 1H), 4.05 (d, J = 9.3 Hz, 2H), 3.66 (d, J = 9.5 Hz, 2H), 1.68 (s, 3H). LCMS m / z 470.1 [M+H]+.

[0795] EXAMPLES 57A and 57B

[0796] ( / V?)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-2-(3-(methylamino)azetidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile atropisomers: Geometrically pure (P)-atropisomers F-2a (more active isomer second peak from separation on a Lux 5 pm cellulose-1 (OD) column as described in the synthesis of intermediates section) was converted to intermediate G-1a. The geometrically pure (P)-atropisomers of Example 57A ( >97%) was obtained following the procedures of Example 34 and using 3-Boc-3-methylaminoazetidine hydrochloride as the amine:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.22 (dd, J = 8.4, 5.4 Hz, 1H), 7.08 (dd, J = 9.4, 8.4 Hz, 1H), 5.10 (s, 2H), 4.86 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.30 (td, J = 7.8, 3.3 Hz, 2H), 3.86 - 3.94 (m, 2H), 3.70 - 3.79 (m, 1H), 2.27 (s, 3H). LCMS m / z 470.1 [M+H]+.

[0797] Starting from the less active ( / W)-atropisomer precursor of intermediate F-2a (1steluting peak on a Lux 5 pm cellulose-1 (OD) column) and following the same procedures as for Example 57A, the less active (W)-isomer of Example 57B was obtained:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.22 (dd, J = 8.3, 5.3 Hz, 1H), 7.08 (dd, J = 9.4, 8.4 Hz, 1H), 5.10 (s, 2H), 4.86 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.3 Hz, 1H), 4.30 (td, J = 7.8, 3.3 Hz, 2H), 3.85 - 3.94 (m, 2H), 3.68 - 3.78 (m, 1H), 2.26 (s, 3H). LCMS m / z 470.1 [M+H]+.

[0798] EXAMPLE 58

[0799] 2-Amino-4-(6-chloro-4-fluoro-1-(2-hydroxyethyl)-2-(2-morpholinoethoxy)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile 1:1 mixture of atropisomers: Prepared following the procedures of Example 43 using 2-morpholinoethan-1-ol as the alcohol in step 5:1H NMR (MeOH-d4) δ: 7.41 (s, 1 H), 7.14 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 4.72 (t, J = 5.2 Hz, 2H), 4.19 (t, J = 5.3 Hz, 2H), 3.85 - 3.91 (m, 2H), 3.71 (t, J = 4.3 Hz, 4H), 2.93 (q, J = 5.0 Hz, 2H), 2.59 - 2.69 (m, 4H). LCMS m / z 534.2 [M+H]+.

[0800] EXAMPLE 59

[0801] 2-Amino-4-(4,6-dichloro-2-(3-(methylamino)azetidin-1-yl)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (mixture of atropisomers): Obtained following the procedure described for Example 34 but starting from intermediate B-1b and using 3-Boc-3-methylaminoazetidine hydrochloride as the amine in step 1:1H NMR (MeOH-d4) 5: 7.81 (s, 1H), 7.08 (dd, J = 8.4, 5.3 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 4.44 - 4.51 (m, 2 H), 4.12 (sxt, J = 4.6 Hz, 2H), 3.94 - 4.01 (m, 1 H), 2.51 (s, 3H). LCMS m / z 477.9 [M+ H]+.

[0802] EXAMPLE 60

[0803] 2-Amino-4-(4,6-dichloro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (diastereomeric mixture of atropisomers): Following the procedure described for Example 34 but starting from intermediate B-1b and using (S)-(1-methylpyrrolidin-2-yl)methanamine dihydrochloride as the amine in step 1:1H NMR (MeOH-d4) 5: 7.82 (d, J = 2.8 Hz, 1H), 7.11 (td, J = 8.5, 5.0 Hz, 1H), 7.01 (ddd, J = 9.5, 8.5, 2.9 Hz, 1H), 4.06 (dd, J = 45.4, 16.3 Hz, 1H), 3.54 - 3.82 (m, 3H), 3.09 - 3.16 (m, 1H) 3.05 (d, J = 14.9 Hz, 3H) 2.20 - 2.32 (m, 1H) 1.90 - 2.17 (m, 3H). LCMS m / z 506.0 [M+H]+.

[0804] EXAMPLE 61

[0805] 2-Amino-4-(2-(azetidin-3-yloxy)-6-chloro-4-fluoro-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (mixture of atropisomers): Prepared following the procedures of Example 43 using 1-Boc-3-hydroxyazetidine as the alcohol in step 5:1H NMR (MeOH-d4) δ: 7.28 (d, J = 0.8 Hz, 1H), 7.15 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 4.34 (quin, J = 6.2 Hz, 1H), 4.02 - 4.15 (m, 2H), 3.62 - 3.77 (m, 4H), 3.53 (dd, J = 9.8, 5.9 Hz, 1H), 3.44 (dd, J = 9.8, 5.8 Hz, 1H). LCMS m / z 476.2 [M+H]+.

[0806] EXAMPLE 62

[0807] 2-Amino-4-(6-chloro-4-fluoro-2-(((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methoxy)-1-(2-hydroxyethyl)-1H-benzo[d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): Preparation of ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol: Lithium aluminum hydride (1M in THF, 33.3 mL, 33.3 mmol) was added at 0 °C to a solution of N-Boc-trans-4-fluoro-L-proline (3.88 g, 16.7 mmol) in THF (41.6 mL). The resulting mixture was stirred at 0 °C for 20 min and heated to 70 °C for 10 h. After work up the desired alcohol was obtained as a lightly yellow oil (1.08 g, 98 %): ):1H NMR (DMSO-d6) 6: 4.31 (br. s., 1H), 3.31 - 3.39 (m, 1H), 3.19 (dd, J = 10.6, 6.1 Hz, 1H), 2.82 - 2.89 (m, 1H), 2.21 (s, 3H), 2.10 - 2.17 (m, 1H), 1.69 - 1.81 (m, 1H), 1.52 - 1.59 (m, 2H), 1.41 - 1.51 (m, 1H). LCMS m / z 134.0 [M+H]+.

[0808] The compound of Example 62 was prepared following the procedures of Example 43 using ((2S,4S)-4-fluoro-1-methylpyrrolidin-2-yl)methanol as the alcohol in step 5:1H NMR (MeOH-d4) 5: 7.41 (d, J = 0.6 Hz, 2H), 7.14 (ddd, J = 8.3, 5.2, 0.9 Hz, 2H), 6.99 (dd, J = 9.4, 8.4 Hz, 2H), 5.23 (app t, J = 4.9 Hz, 1H), 5.10 (app t, J = 4.9 Hz, 1H), 4.56 - 4.68 (m, 4H), 4.14 - 4.26 (m, 4H), 3.84 - 3.94 (m, 4H), 2.83 - 2.93 (m, J = 9.7, 9.7, 4.9 Hz, 2H), 2.54 - 2.63 (m, 1H), 2.49 - 2.52 (m, 6H), 2.46 - 2.54 (m, 5H), 1.95 - 2.15 (m, 2H). LCMS m / z 518.0 [M+H]+.

[0809] EXAMPLE 63

[0810] 2-Amino-7-fluoro-4-(4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dihydro-1H-isobenzofuro[4,5-d]imidazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): Prepared following the sequence described for Example 7 starting from intermediate G-1 a instead of B-1a:1H NMR (MeOH-d4) δ: 7.11 (dd, J = 8.3, 5.2 Hz, 1H), 6.90 (dd, J = 9.5, 8.4 Hz, 1H), 5.43 (d, J = 1.1 Hz, 2H), 4.80 (dt, J = 11.9, 2.1 Hz, 2H), 4.67 (dt, J = 11.9, 2.1 Hz, 2H), 4.52 (dt, J = 10.9, 3.9 Hz, 2H), 4.45 (ddd, J = 10.7, 5.6, 1.5 Hz, 1H), 3.62 (s, 3H), 3.01 - 3.09 (m, 1H), 2.74 - 2.83 (m, 1H), 2.46 (d, J = 4.5 Hz, 3H), 2.29 - 2.39 (m, 1H), 2.00 - 2.11 (m, 1 H), 1.66 - 1.84 (m, 3H). LCMS m / z 496.2 [M+H]+.

[0811] EXAMPLE 64

[0812] 2-Amino-4-(6-chloro-2-((((S)-1,2-dimethylpyrrolidin-2-yl)methyl)amino)-4-fluorobenzo[d]thiazol- 5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers):

[0813] Step 3

[0814]

[0815] Step 1: tert-Butyl (S)-2-carbamoyl-2-methylpyrrolidine-1 -carboxylate: To a cold (ice-bath) mixture of 1-(tert-butoxycarbonyl)-2-methyl-L-proline (2.00 g, 8.72 mmol) and HATU (5.03 g, 13.1 mmol) in DMF (20.0 mL) was added DIEA (4.56 mL, 26.2 mmol) over a period of 5 min. The resultant reaction mixture was stirred for 30 min and the cooling bath was removed. After stirring for an additional 20 min, the reaction mixture was cooled again in an ice-bath and aq. 28% ammonium hydroxide (1.16 mL, 17.4 mmol) was added. The resultant reaction mixture was warmed up to RT and stirred overnight. The reaction was then quenched with aq. NaHCO3solution, extracted with ethyl acetate (3 x 50 mL) and the combined organic extracts were washed with a NaHCO3solution, brine, dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, MeOH in DCM, 0-10% then reversed phase using MeOH in water, 10-100% with 0.1% FA) to give tert-butyl (S)-2-carbamoyl-2-methylpyrrolidine-1 -carboxylate (1.05 g, 53 %) as a colorless viscous oil which solidified to a white solid upon standing.1H NMR showed ~2:1 mixture of rotamers.:1H NMR (CDCl3) 5: 5.35 - 6.11 (m, 1H), 3.36 - 3.69 (m, 2H), 1.53 - 2.05 (m, 7H), 1.47 (s, 9H).1H NMR (DMSO-d6) 6: 6.96 - 7.05 (m, 1H), 6.78 - 6.90 (m, 1H), 3.48 (dt, J = 10.3, 7.0 Hz, 1H), 3.33 - 3.37 (m, 1H), 1.97 - 2.08 (m, 1H), 1.69 - 1.85 (m, 3H), 1.30 - 1.43 (m, 12H). LCMS m / z 129.1 [M-Boc+H]+.

[0816] Step 2: (S)-2-Methylpyrrolidine-2-carboxamide hydrochloride: To a cold (ice-bath) solution of tertbutyl (S)-2-carbamoyl-2-methylpyrrolidine-1-carboxylate from above (400 mg, 1.75 mmol) in MeOH (4.00 mL) was added a solution of 4N hydrochloric acid in dioxane (4.00 mL, 16.0 mmol). The mixture was stirred for 30 min, the cooling bath was removed and stirring resumed for an additional 4 h at RT until all starting material was consumed. The solvent was removed and the residue dried under high vacuum to give (S)-2-methylpyrrolidine-2-carboxamide hydrochloride (280 mg, 97 %) as a white solid:1H NMR (DMSO-d6) 6: 9.46 (br. s., 1H), 8.67 (br. s., 1H), 7.98 (s, 1H), 7.71 (s, 1H), 3.17 - 3.24 (m, 2H), 2.15 - 2.25 (m, 1H), 1.88 - 2.07 (m, 2H), 1.71 - 1.86 (m, 1H), 1.57 (s, 3H). LCMS m / z 129.1 [M+H]+.

[0817] SStep 3: (S)-1,2-Dimethylpyrrolidine-2-carboxamide: To a stirred mixture of (S)-2-methylpyrrolidine-2-carboxamide hydrochloride (280 mg, 1.70 mmol), aqueous formaldehyde solution (141 pL, 5.10 mmol), and Et3N (238 pL, 1.70 mmol) in 1,2-dichloroethane (4.0 mL) was added portion wise sodium triacetoxyborohydride (557 mg, 2.55 mmol) at RT. The resultant reaction mixture was stirred for 3 h and then diluted with DCM. MgSO4 was added, the mixture stirred for 30 min and subsequently filtered through a pad of Celite® using DCM for rinses. The filtrate was concentrated to give the crude product which was contaminated with triethylamine salts. The residue was suspended in dry ether (20 mL), K2CO3(1.5 g) was added and the resultant heterogenous mixture was stirred at RT overnight. The white suspension was then filtered through a pad of Celite®, rinsed with dry ether and the filtrate was concentrated to give (S)-1,2-dimethylpyrrolidine-2-carboxamide (200 mg, 83 %) as a white solid:1H NMR (CDCh) 6: 7.44 (br. s., 1 H), 5.50 (br. s., 1 H), 2.99 - 3.11 (m, 1H), 2.46 - 2.58 (m, 1H), 2.27 (s, 3H), 1.71 - 1.81 (m, 4H), 1.19 (s, 3H). LCMS m / z 143.3 [M+H]+.

[0818] Step 4: (S)-(1,2-Dimethylpyrrolidin-2-yl)methanamine: To a cold (ice-bath) stirred solution of (S)-1,2-dimethylpyrrolidine-2-carboxamide from above (100 mg, 0.703 mmol) in THF (3.00 mL) was added portion wise lithium aluminum hydride (101 mg, 2.53 mmol) over a period of 10 min. The cooling bath was then removed and the grey suspension was stirred at RT for 2 h and 70 °C overnight. The reaction mixture was cooled in an ice-water bath, carefully quenched with slow addition of water (110 pL) and aq. 15% NaOH solution (115 pL). The cooling bath was removed, the mixture stirred at RT and then filtered through a pad of Celite®, using ether (20 mL) for rinses. The combined filtrates were concentrated to give (S)-(1,2-dimethylpyrrolidin-2-yl)methanamine (20.0 mg, 22 %) as a colorless oil:1H NMR (CDCh) 5: 3.02 - 3.11 (m, 1H), 2.54 - 2.67 (m, 3H), 2.40 (br. s, 2H), 2.26 (s, 3H), 1.88 - 1.97 (m, 1 H), 1.68 - 1.80 (m, 2H), 1.50 (dt, J = 12.3, 7.8 Hz, 1H), 0.91 (s, 3H). LCMS m / z 129.1 [M+H]+.

[0819] Step 5: 2-Amino-4-(6-chloro-2-((((S)-1,2-dimethylpyrrolidin-2-yl)methyl)amino)-4-fluorobenzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 64 1:1 mixture of diastereomer): Prepared following the procedures of Example 2 using (S)-(1, 2-dimethylpyrrolidin-2-yl)methanamine from above as the amine and 6 equiv. of DIEA as base.1H NMR (MeOH-d4) 5: 7.56 - 7.60 (m, 1H), 7.12 - 7.18 (m, 1H), 6.96 - 7.03 (m, 1H), 3.58 - 3.66 (m, 1H), 3.41 - 3.50 (m, 1H), 3.01 - 3.12 (m, 1H), 2.69 - 2.80 (m, 1H), 2.34 - 2.43 (m, 3H), 1.95 - 2.06 (m, 1H), 1.78 - 1.89 (m, 2H), 1.62 - 1.75 (m, 1H), 1.07 - 1.13 (m, 3H). LCMS m / z 504.0 [M+H]+.

[0820] EXAMPLE 65

[0821] ( / W)-2-Amino-4-(6-chloro-4-fluoro-2-((((S)-1-(methyl-d3)pyrrolidin-2-yl)methyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (most active diastereomer): Prepared following the procedures of Example 2 using (S)-(l-(methyl-d3)pyrrolidine-2-yl-methaneamine (see Example 35) as the amine and 6 equiv. of DIEA as base. The two diastereomers were separated on a Kinetex column (150 x 21 mm) using a gradient of methanol in water (10% to 100%, 0.1% formic acid) as eluent. The most active ( / W)-isomer of Example 65 eluted first:1H NMR (MeOH-d4) δ: 7.64 (d, J = 1.3 Hz, 1H), 7.15 (dd, J = 8.4, 5.1 Hz, 1 H), 7.00 (dd, J = 9.4, 8.4 Hz, 1 H), 3.68 - 3.84 (m, 2H), 3.37 - 3.46 (m, 1 H), 3.22 (br. s., 1 H), 2.75 - 2.87 (m, 1H), 2.15 - 2.27 (m, 1H), 1.81 - 2.06 (m, 3H). LCMS m / z 493.0 [M+H]+.

[0822] EXAMPLE 66

[0823] (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((((S)-1-(methyl-d3)pyrrolidin-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (most active diastereomer): Obtained following the procedure of Example 38 starting with the most active (P)-isomer of fragment G-1a and using (S)-(1-(methyl-d3)pyrrolidine-2-yl-methaneamine (see Example 35) as the amine and 6 equiv. of DIEA as base:1H NMR (MeOH-d4) 5: 7.21 (dd, J = 8.3, 5.2 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 5.15 (d, J = 1.6 Hz, 2H), 4.95 (d, J = 12.1 Hz, 1H), 4.78 (d, J = 12.3 Hz, 1H), 4.58 (s, 1H), 3.90 - 3.99 (m, 1H), 3.78 - 3.86 (m, 1H), 3.59 (br. s., 2H), 2.24 - 2.38 (m, 1H), 1.84 - 2.05 (m, 3H). LCMS m / z 501.1 [M+H]+.

[0824] EXAMPLE 67

[0825] 2-Amino-4-(6-chloro-4-fluoro-2-((piperidin-4-ylmethyl)amino)benzo[d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (racemic atropisomers):

[0826]

[0827] Step 1: Intermediate B-1a (100 mg, 178 pmol) was dissolved in DCM (2.0 mL). 1,1"-Thiocarbonyldi-2(1H)-pyridone (72.4 mg, 312 pmol) was added and the mixture left to stir overnight (20 h) at RT. 4-Aminomethyl-1-Boc-piperidine (114 mg, 534 pmol) was added and after stirring for 30 min. the solvent was evaporated under reduced pressure. The residue was purified by flash column chromatography (silica, EtOAc in hexanes, 0-30%) to afford the expected thiourea (146 mg, 89 %) as a yellowish foam: LCMS m / z 816.2 [M-H.

[0828] Step 2: The thiourea from step 1 (130 mg, 159 pmol) was dissolved in ACN (10.0 mL). Cs2CO3(51.8 mg, 159 pmol) and 4-tert-butylbenzyl bromide (29.2 pL, 159 pmol) were added and the reaction left to stir at RT for 3 h. The reaction was transferred to a separatory funnel with EtOAc and diluted with water. The aqueous layer was extracted with EtOAc 3 times. The combined organic fractions were washed with brine 2x and dried with sodium sulfate. The solvent was evaporated under reduced pressure to provide the protected bis-Boc form of Example 67 instead of the expected S-alkylated product: LCMS m / z 688.3 [M-H.

[0829] The reaction material from above was deprotected with TFA-DCM in the usual manner and the product isolated by reversed-phase chromatography as racemic atropisomers (15 % to 100 % of B in A; A is 95% water, 5% methanol and 0.1% formic acid, B is 95% methanol, 5% water and 0.1% formic acid - Redisep C18 100 A, 5 pm). The compound of Example 67 was obtained as a white powder:1H NMR (MeOH-d4) 5: 7.58 (d, J = 1.3 Hz, 1H), 7.14 (dd, J = 8.3, 5.2 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 3.36 - 3.48 (m, 4H), 2.98 (td, J = 12.8, 2.8 Hz,

[0830] EXAMPLES 68A and 68B

[0831] ( / V?)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-1-methyl-2-(((S)-1-methylpyrrolidin-3-yl)oxy)-6,8-dihydro-1H-isobenzofuro[4,5-d]imidazol-5-yl)benzo[b]thiophene-3-carbonitrile: Prepared following the sequence described for Example 7 starting from intermediate G-1a instead of B-1a and using (S)-(+)-1-methyl-3-pyrrolidinol in step 5. Diastereomers were separated by flash column chromatography (reversed-phase) (15 % to 100 % of B in A; A is 95% water, 5% methanol and 0.1% formic acid, B is 95% methanol, 5% water and 0.1% formic acid - Redisep C18 100 A, 5 pm):

[0832] Example 68A (first eluting (M)-isomer):1H NMR (MeOH-d4) δ: 7.17 (dd, J = 8.3, 5.2 Hz, 1H), 6.97 (dd, J = 9.5, 8.4 Hz, 1H), 5.55 - 5.61 (m, 1H), 5.50 (s, 2H), 4.87 - 4.90 (m, 1H), 4.71 - 4.77 (m, 1H), 3.68 (s, 3H), 3.32 (br. s., 1H), 3.18 - 3.26 (m, 1H), 3.05 - 3.14 (m, 1H), 2.68 - 2.78 (m, 1H), 2.60 (s, 3H), 2.52 - 2.57 (m, 1 H), 2.20 - 2.30 (m, 1 H), 2.20 - 2.29 (m, 1 H). LCMS m / z 482.0 [M+H]+.

[0833] Example 68B (second eluting (P)-isomer):1H NMR (MeOH-d4) 5: 7.18 (dd, J = 8.3, 5.2 Hz, 2H), 6.98 (dd, J = 9.5, 8.3 Hz, 2H), 5.59 - 5.65 (m, 1H), 5.51 (s, 2H), 4.89 (t, J = 2.0 Hz, 1H), 4.72 -4.78 (m, 2H), 3.69 (s, 3H), 3.48 (d, J = 12.6 Hz, 1H), 3.34 - 3.40 (m, 1H), 3.19 - 3.28 (m, 1H), 2.87 - 2.96 (m, 1 H), 2.66 (s, 3H), 2.59 - 2.64 (m, 1 H), 2.26 - 2.36 (m, 1 H). LCMS m / z 482.0 [M+H]+.

[0834] EXAMPLE 69

[0835] (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((R)-3-(methylamino)pyrrolidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (most active diastereomer): obtained starting from single (P)-atropisomer F-2a (more active isomer, second peak from separation on a Lux 5 pm cellulose-1 (OD) column as described in the synthesis of intermediates section), following the procedures described for Example 38A and using tert-butyl (R)-methyl(pyrrolidin-3-yl)carbamate as the amine:1H NMR (MeOH-d4) 5: 7.21 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.4, 8.4 Hz, 1H), 5.16 (d, J = 1.6 Hz, 2H), 4.91 (d, J = 1.0 Hz, 1H), 4.78 (d, J = 1.0 Hz, 1 H), 3.80 - 3.89 (m, 1 H), 3.71 - 3.79 (m, 1 H), 3.60 - 3.70 (m, 1 H), 3.44 - 3.55 (m, 2H), 2.46 (s, 3H), 2.29 -2.41 (m, 1H), 1.97 - 2.10 (m, 1H). LCMS m / z 484.0 [M+H]+.

[0836] EXAMPLE 70

[0837] (P)-2-Amino-4-(2-(3-amino-3-methylazetidin-1-yl)-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single, more potent atropisomer):

[0838]

[0839] Example 70

[0840] Step 1: tert-Butyl (4-(6-amino-5-chloro-7-iodo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate: Single (P)-atropisomers F-2b (more active isomer, first peak from separation of racemate on a Lux 5 pm cellulose-1 (AD) column as described in the synthesis of intermediates section) was converted to intermediate G-1b: To a stirred suspension of chiral F-2b (102 mg, 222 pmol) in EtOH (1.8 mL) was added silver sulfate (76.1 mg, 244 pmol) and iodine (62 mg, 244 pmol). The resulting suspension was stirred in the dark for 1.5 h. The reaction mixture was diluted with EtOAc and quenched with aq. 10% sodium thiosulfate solution. The organic phase was separated and the aqueous layer was extracted once with EtOAc. The combined organic extracts were dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, EtOAc in hexanes, 10-60%) to give chiral G-1b (126 mg, 97 %) as a light yellow solid:1H NMR (CDCl3) 5: 7.84 (br. s., 1H), 7.14- 7.21 (m, 1H), 7.05 - 7.13 (m, 1H), 4.99 - 5.13 (m, 2H), 4.88 - 4.96 (m, 1H), 4.75 - 4.84 (m, 1H), 4.67 (br. s, 2H), 1.58 (s, 9H). LCMS m / z 582.8 [M+H]+. Step 2: tert-Butyl (4-(6-(3-((tert-butoxycarbonyl)amino)-3-methylazetidine-1-carbothioamido)-5-chloro-7-iodo-1,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (pure active atropisomer): A 5 mL vial was charged with a magnetic stir bar, chiral intermediate G-1b (60.0 mg, 102 pmol), toluene (1.46 mL) and 1,1'-thiocarbonyldi-2(1H)-pyridone (47.8 mg, 205 pmol). The vial was sealed and the reaction mixture heated in an oil bath at 80 °C for 16 h. After cooling to RT, analysis of an aliquot by LCMS showed the isothiocyanate intermediate to be a major constituent of the resulting mixture.

[0841] To the above reaction mixture was then added tert-butyl (3-methylazetidin-3-yl)carbamate hydrochloride (70.5 mg, 316 pmol) and DIEA (71.4 pL, 410 pmol). The vial was sealed once again and the mixture was stirred at RT for 1 h. Analysis of an aliquot by LCMS showed the conversion to the thiourea intermediate to be complete. The reaction mixture was purified by column chromatography (silica, EtOAc in hexanes, 0-100%) to obtain tert-butyl (4-(6-(3-((tert-butoxycarbonyl)amino)-3-methylazetidine-carbothioamido)-5-chloro-7-iodo-,3-dihydroisobenzofuran-4-yl)-3-cyano-7-fluorobenzo[b]thiophen--yl)carbamate-3 as an amorphous yellow solid.

[0842] SStep 3: The iodo intermediate from step 2, copper (I) iodide (1.90 mg, 9.98 pmol), 1,10-phenanthroline (3.40 mg, 18.8 pmol), Cs2CO3(33.4 mg, 102 pmol) and DME (5 mL) were heated in an oil bath at 70 °C for 30 minutes (LCMS showed complete conversion to the benzothiazole). The mixture was cooled to RT and solvent removed in vacuo. The resulting residue was redissolved in DCM (2 mL) and TFA (2 mL) was added, the mixture was stirred at RT for 1 h. Volatiles were removed in vacuo and the residue was dissolved in DMSO (4 mL), and purified by preparative HPLC (C18 Kinetex column, 100mm length, gradient elution: 80 / 20 to 0 / 100 A / B with A: 95% water / 5% methanol / 4g NH4CO3 per 4L and B: 5% water / 95% methanol / 4g NH4CO3 per 4L) to obtain the geometrically pure isomer of Example 70 (19.5 mg, 39 %) as a white amorphous solid:1H NMR (DMSO-d6) 6: 7.99 (s, 2H), 7.13 (dd, J = 8.4, 5.5 Hz, 1H), 7.07 (t, J = 9.4 Hz, 1H), 5.11 (s, 2H), 4.76 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 3.88 - 4.00 (m, 4H), 1.42 (s, 3H). LCMS m / z 486.0 [M+ H]+.

[0843] EXAMPLE 71

[0844] (P)-2-Amino-4-(4-chloro-2-(3-(methylamino)azetidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single, more potent (P)-atropisomer): The geometrically pure atropisomers of Example 71 was obtained from geometrically pure G-1b following the procedures of Example 70 and using tert-butyl azetidin-3-yl(methyl)carbamate hydrochloride as the amine:1H NMR (MeOH-d4) δ: 7.92 (s, 2H), 7.06 (dd, J = 8.3, 5.4 Hz, 1 H), 7.00 (t, J = 8.9 Hz, 1 H), 5.05 (s, 2H), 4.69 (d, J = 12.1 Hz, 1H), 4.55 (d, J = 12.1 Hz, 1H), 4.24 (td, J = 7.7, 4.3 Hz, 2H), 3.78 - 3.88 (m, 2H), 3.62 - 3.72 (m, 1H), 2.20 (s, 3H). LCMS m / z 486.1 [M+H]+.

[0845] EXAMPLE 72

[0846] 2-Amino-7-fluoro-4-(4-fluoro-2-((R)-3-hydroxypyrrolidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): Using the general method of Scheme I, a solution of a 1:1 mixture of atropisomers of intermediate F-4a (40.0 mg, 77 pmol) in MeCN (884 pL) was reacted with (R)-3-hydroxypyrrolidine (13.4 mg, 154 pmol) and DIEA (107 pL, 615 pmol) in a sealed vial heated to 50 °C for 1 h. The reaction mixture was then concentrated to dryness and the residue was dissolved in DCM (770 pL) and TFA (177 pL, 2.31 mmol) was added. The reaction was stirred for 30 min at RT, then concentrated to dryness. The crude was dissolved in DCM (1 mL) and DI PEA (200 pL) was added. After concentrating to dryness a second time, the residue was taken up in DMSO and formic Acid (50 pL) was added prior to reversed-phase HPLC purification using a Kinetex 8 pm C18 column and 15-100% MeOH(0.1 % formic acid) / H2O gradient to give the compounds of Example 72 (32.0 mg, 88 %) as a white powder:1H NMR (DMSO-d6) 6: 8.02 (s, 2H), 7.24 (dd, J = 8.3, 5.1 Hz, 1H), 7.08 (dd, J = 9.4, 8.5 Hz, 1H), 5.17 (dd, J = 3.5, 1.8 Hz, 1H), 5.09 - 5.13 (m, 2H), 4.87 (d, J = 12.0 Hz, 1 H), 4.68 (dt, J = 12.0, 2.0 Hz, 1 H), 4.42 - 4.48 (m, 1 H), 3.57 - 3.70 (m, 3H), 3.37 - 3.49 (m, 1 H), 2.08 - 2.18 (m, 1H), 1.92 - 2.02 (m, 1H). LCMS m / z 471.2 [M+H]+.

[0847] EXAMPLE 73

[0848] 2-Amino-7-fluoro-4-(4-fluoro-2-(((R)-2-hydroxypropyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): The procedure of Example 72 was followed using (R)-(-)-1-amino-2-propanol as the amine:1H NMR (DMSO-d6) 6: 8.34 (td, J = 5.5, 1.3 Hz, 1H), 8.02 (s, 2H), 7.21 (dd, J = 8.4, 5.4 Hz, 1H), 7.07 (dd, J = 9.5, 8.4 Hz, 1H), 5.06 (s, 2H), 4.86 (dd, J = 4.8, 2.1 Hz, 1H), 4.83 (dt, J = 11.9, 2.5 Hz, 1H), 4.67 (dt, J = 12.1, 2.1 Hz, 1H), 3.83 - 3.92 (m, 1H), 3.33 - 3.41 (m, 2H), 1.12 (dd, J = 6.1, 1.0 Hz, 3H). LCMS m / z 459.0 [M+H]+.

[0849] EXAMPLE 74

[0850] 2-Amino-7-fluoro-4-(4-fluoro-2-((R)-3-methoxypyrrolidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): The procedure of Example 72 was followed using (R)-3-methoxypyrrolidine hydrochloride as the amine:1H NMR (DMSO-d6) 6: 8.04 (s, 2H), 7.26 (dd, J = 8.3, 5.3 Hz, 1 H), 7.10 (dd, J = 9.5, 8.5 Hz, 1H), 5.14 (br. s., 2H), 4.89 (dt, J = 12.0, 2.4 Hz, 1H), 4.71 (dt, J = 12.1, 2.3 Hz, 1H), 4.14 -4.19 (m, 1 H), 4.05 (d, J = 0.8 Hz, 1H), 3.52 - 3.75 (m, 4H), 3.32 (s, 3H), 2.14 - 2.22 (m, 2H). LCMS m / z 485.2 [M+ H]+.

[0851] EXAMPLE 75

[0852] 2-Amino-7-fluoro-4-(4-fluoro-2-((S)-3-hydroxypyrrolidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): The procedure of Example 72 was followed using (S)-(-)-3-hydroxypyrrolidine as the amine:1H NMR (DMSO-d6) 5: 8.02 (s, 2H), 7.24 (dd, J = 8.1, 5.3 Hz, 1H), 7.09 (dd, J = 9.5, 8.4 Hz, 1H), 5.18 (dd, J = 3.6, 1.9 Hz, 1H), 5.12 (br. s., 2H), 4.88 (d, J = 12.3 Hz, 1H), 4.69 (dt, J = 12.0, 2.3 Hz, 1H), 4.43 - 4.49 (m, 1H), 3.57 - 3.70 (m, 3H), 3.38 - 3.50 (m, 1H), 2.08 - 2.19 (m, 1H), 1.94 - 2.03 (m, 1H). LCMS m / z 471.2 [M+H]+.

[0853] EXAMPLE 76

[0854] 2-Amino-7-fluoro-4-(4-fluoro-2-(3-hydroxy-3-methylazetidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): The procedure of Example 72 was followed using 3-methylazetidin-3-ol hydrochloride as the amine:1H NMR (DMSO-d6) 5: 8.03 (s, 2H), 7.23 (dd, J = 8.3, 5.4 Hz, 1H), 7.08 (dd, J = 9.5, 8.5 Hz, 1H), 5.89 (s, 1H), 5.10 (s, 2H), 4.86 (dt, J = 12.3, 2.6 Hz, 1H), 4.69 (dt, J = 12.1, 2.3 Hz, 1H), 4.00 - 4.10 (m, 4H), 1.48 (s, 3H). LCMS m / z 470.2 [M+H]+.

[0855] EXAMPLE 77

[0856] 2-Amino-4-(2-((2,2-difluoroethyl)amino)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomeric atropisomers): the compound of Example 77 was obtained in the same manner as described for Example 67 but using 2,2-difluoroethylamine in step 1:1H NMR (MeOH-d4 5: 7.20 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.5, 8.4 Hz, 1H), 6.12 (tt, J = 56.2, 4.0 Hz, 1H), 5.13 (d, J = 1.6 Hz, 2H), 4.88 - 4.93 (m, 1 H), 4.75 - 4.81 (m, 1 H), 3.89 (td, J = 14.9, 4.0 Hz, 2H). LCMS m / z 465.0 [M+H]+.

[0857] EXAMPLES 78A and 78B

[0858] ( / V?)- and (P)-2-Amino-4-(4-chloro-2-((((S)-1-methylpyrrolidin-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomers: the procedures outlined for Example 70 were followed starting from racemic intermediate G-1b but using (S)-(1-methylpyrrolidin-2-yl)methanamine dihydrochloride as the amine in step 1. The diastereomeric atropisomers were separated at the Boc-protected stage by reversed-phase HPLC on a Kinetex® 5pm, C18, 100A, 100 x 30.0 mm column using 0.1%w / v NH4HCO3 for A and 0.05% w / v NH4HCO3 for B gradients. The two diastereomeric carbamates were deprotected separately as usual using TFA-DCM:

[0859] Example 78A (from 1steluting carbamate; more potent (P)-isomer):1H NMR (DMSO-d6) 6: 8.33 (t, J = 4.8 Hz, 1H), 7.98 (s, 2H), 7.12 (dd, J = 8.3, 5.6 Hz, 1H), 7.07 (dd, J = 9.4, 8.4 Hz, 1H), 4.98 - 5.15 (m, 2H), 4.72 (dt, J = 12.0, 2.0 Hz, 1H), 4.60 (dt, J = 12.0, 1.8 Hz, 1H), 3.52 - 3.68 (m, 1H), 3.25 - 3.30 (m, 1H), 2.97 (ddd, J = 8.7, 6.4, 2.4 Hz, 1H), 2.38 - 2.47 (m, 1H), 2.32 (s, 3H), 2.15 (q, J = 8.6 Hz, 1 H), 1.81 - 1.97 (m, 1 H), 1.53 - 1.74 (m, 3H). LCMS m / z 514.2 [M + H]+.

[0860] Example 78B (from 2ndeluting carbamate; less potent ( / W)-isomer):1H NMR (DMSO-d6) 6: 8.33 (t, J = 4.8 Hz, 1H), 7.98 (s, 2H), 7.12 (dd, J = 8.3, 5.4 Hz, 1H), 7.07 (dd, J = 9.3, 8.4 Hz, 1H), 4.99 - 5.16 (m, 2H), 4.73 (dt, J = 12.1, 1.9 Hz, 1H), 4.60 (dt, J = 12.0, 1.9 Hz, 1H), 3.55 - 3.68 (m, 1H), 3.24 - 3.28 (m, 1H), 2.97 (ddd, J = 8.6, 6.4, 2.4 Hz, 1H), 2.38 - 2.47 (m, 1H), 2.32 (s, 3H), 2.15 (q, J = 8.5 Hz, 1 H), 1.83 - 1.97 (m, 1 H), 1.53 - 1.75 (m, 3H). LCMS m / z 514.2 [M + H]+.

[0861] EXAMPLES 79A and 79B

[0862] ( / V?)- and (P)-2-Amino-4-(4-chloro-2-((R)-3-(dimethylamino)pyrrolidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile diastereomers: the procedures outlined for Example 70 were followed starting from racemic intermediate G-1b but using (R)-N, N-dimethylpyrrolidin-3-amine as the amine in step 1. The diastereomeric atropisomers were separated at the Boc-protected stage as in Example 78, by reversed-phase HPLC on a Kinetex® 5pm, C18, 100A, 100 x 30.0 mm column using 0.1%w / v NH4HCO3 for A and 0.05% w / v NH4HCO3 for B gradients. The two diastereomeric carbamates were deprotected separately as usual using TFA-DCM:

[0863] Example 79A (from 1steluting carbamate; less potent ( / W)-isomer):1H NMR (DMSO-d6) 6: 7.98 (s, 2H), 7.14 (dd, J = 8.3, 5.4 Hz, 1H), 7.08 (dd, J = 9.5, 8.4 Hz, 1H), 5.13 (s, 2H), 4.77 (dt, J = 12.1, 2.1 Hz, 1H), 4.62 (dt, J = 12.1, 1.8 Hz, 1H), 3.92 (br. s., 1H), 3.73 (t, J = 8.0 Hz, 1H), 3.44 -3.64 (m, 3H), 2.52 (br. s., 6H), 2.35 (br. s., 1 H), 2.11 (br. s., 1 H). LCMS m / z 514.2 [M+H]+.

[0864] Example 79B (from 2ndeluting carbamate; more potent (P)-isomer):1H NMR (DMSO-d6) 6: 7.98 (s, 2H), 7.14 (dd, J = 8.3, 5.4 Hz, 1H), 7.07 (dd, J = 9.4, 8.4 Hz, 1H), 5.03 - 5.20 (m, 2H), 4.76 (dt, J = 12.1, 2.0 Hz, 1H), 4.61 (dt, J = 12.0, 2.1 Hz, 1H), 3.61 - 3.88 (m, 2H), 3.54 (q, J = 9.2 Hz, 1H), 3.28 - 3.31 (m, 1 H), 2.93 (quin, J = 7.6 Hz, 1H), 2.26 - 2.16 (m, 1H), 2.21 (s, 6H), 1.94 (dq, J = 12.1, 9.2 Hz, 1H). LCMS m / z 514.2 [M+H]+.

[0865] EXAMPLE 80

[0866] 3-Amino-1-(5-(2-amino-3-cyano-7-fluorobenzo[b]thiophen-4-yl)-6-chloro-4-fluorobenzo[d]thiazol- 2-yl)azetidine-3-carboxamide (1:1 mixture of atropisomers):

[0867] [Chemical scheme diagram - see image]

[0868]

[0869] as Example 2

[0870] - *■ Example 80

[0871] sStep 3

[0872] Step 1: tert-Butyl 3-amino-3-carbamoylazetidine-1-carboxylate: 1-tert-Butyl 3-ethyl 3-aminoazetidine-1,3-dicarboxylate (24.0 mg, 98.2 pmol) was weighed in a 4 mL vial then suspended in a 7M solution of NH3 (0.50 mL, 3.50 mmol) in methanol. The vial was capped and heated at 45 °C over 48 h. The mixture was then concentrated to dryness and further dried under reduced pressure to afford the desired carboxamide (22.0 mg, 104 %):1H NMR (DMSO-d6) 5: 7.30 (br. s., 1H), 7.18 (br. s., 1H), 4.02 (br. s., 2H), 3.53 (br. s., 2H), 1.38 (s, 2H), 1.37 (s, 9H). LCMS m / z 116.0 [M-Boc+H]+.

[0873] Step 2: 3-Aminoazetidine-3-carboxamide dihydrochloride: The carboxamide from step 1 (22.0 mg, 102 pmol) was dissolved in DCM (400 pL) then a 4M solution of hydrochloric acid in 1,4-dioxane (400 pL, 1.60 mmol) was added dropwise at RT. The mixture was stirred for 1.5 h, concentrated to dryness then further dried under reduced pressure to provide the desired azetidine as the dihydrochloride salt (18.8 mg, 98 %) as a pale yellow solid:1H NMR (DMSO-d6) 5: 9.66 (br. s., 2H), 9.08 (br. s., 3H), 8.45 (br. s., 1H), 8.11 (br. s., 1H), 4.34 (d, J = 12.1 Hz, 2H), 4.29 (d, J = 11.7 Hz, 2H). LCMS m / z 116.0 [M+H]+.

[0874] SStep 3: Prepared following the procedure of Example 2 using the azetidine from step 2 as the amine and 6 equiv. of DIEA as base. The compounds of Example 80 were obtained as a 1:1 mixture of atropisomers:1H NMR (DMSO-d6) 6: 8.04 (s, 2H), 7.91 (d, J = 1.1 Hz, 1H), 7.42 (br. s., 1H), 7.32 (br. s., 1H), 7.18 (dd, J = 8.4, 5.4 Hz, 1H), 7.10 (dd, J = 9.4, 8.3 Hz, 1H), 4.38 (dd, J = 8.1, 2.3 Hz, 2H), 3.93 (dd, J = 10.0, 8.4 Hz, 2H), 2.77 (br. s., 2H). LCMS m / z 491.0 [M+H]+.

[0875] EXAMPLE 81 2-Amino-4-(2-amino-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): 4 M HCI in dioxane (635 pL, 2.54 mmol) was added to a solution of intermediate F-3a (37.3 mg, 74.5 pmol) in MeOH (635 pL). The solution was stirred at RT for 20 h. Upon completion, the reaction was concentrated under reduced pressure and then dissolved in DMSO (2 mL), and purified by reversed phase HPLC (Kinetex C18 30x150 mm column) using 95% aq. MeOH (containing 5% water and 0.1% ammonium formate) and water (containing 5% methanol and 0.1% ammonium formate) (10-100%) to afford the atropisomer mixture of Example 81 (10.5 mg, 33 %) as a white solid.1H NMR (DMSO-d6) 6: 8.02 (s, 2H), 7.79 (s, 2H), 7.22 (dd, J = 8.4, 5.4 Hz, 1H), 7.04 - 7.10 (m, 1H), 5.06 (s, 2H), 4.84 (d, J = 12.1 Hz, 1H), 4.67 (d, J = 12.1 Hz, 1H). LCMS m / z 401.0 [M+H]+.

[0876] EXAMPLES 82A and 82B

[0877] (M)- and (P)-2-Amino-7-fluoro-4-(4-fluoro-2-(((S)-1-((S)-1-methylpyrrolidin-2-yl)ethyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile diastereomers: Prepared from intermediate F-4a following the procedure of Example 12 using (S)-1-((S)-1-methylpyrrolidin-2-yl)ethan-1 -amine as amine, which can be prepared following the procedures outlined in W02003 / 004467), and DIEA as base. The two diastereomers were separated by reversed-phase HPLC on a Kinetex-C18 column using MeOH - aqu. HCOOH gradients.

[0878] Example 82A (1steluting peak, less active ( / W)-isomer):1H NMR (MeOH-d4) 5: 7.20 (dd, J = 8.3, 5.2 Hz, 1H), 6.99 (dd, J = 9.4, 8.4 Hz, 1H), 5.14 (d, J = 1.5 Hz, 2H), 4.92 (d, J = 12.3 Hz, 1H), 4.78 (d, J = 12.1 Hz, 1H), 4.59 (br. s., 1H), 4.27 (quin, J = 6.7 Hz, 1H), 3.35 - 3.46 (m, 1H), 3.05 -3.22 (m, 1 H), 2.83 (br. s., 1 H), 2.73 (s, 3H), 2.07 - 2.22 (m, 1 H), 1.79 - 2.02 (m, 3H), 1.37 (d, J = 6.8 Hz, 3H). LCMS m / z 512.2 [M+H]+.

[0879] Example 82B (2ndeluting peak, more active (P)-isomer):1H NMR (MeOH-d4) 5: 7.22 (dd, J = 8.3, 5.2 Hz, 1H), 7.00 (dd, J = 9.4, 8.4 Hz, 1H), 5.15 (s, 2H), 4.96 (d, J = 12.3 Hz, 1H), 4.78 (d, J = 12.1 Hz, 1H), 4.59 (br. s., 1H), 4.31 (quin, J = 6.7 Hz, 1H), 3.42 (br. s., 1H), 3.03 - 3.22 (m, 1H), 2.77 - 2.88 (m, 1 H), 2.72 (s, 3H), 2.06 - 2.24 (m, 1 H), 1.78 - 2.04 (m, 3H), 1.35 (d, J = 6.6 Hz, 3H). LCMS m / z 512.2 [M+H]+.

[0880] EXAMPLE 83

[0881] 2-Amino-7-fluoro-4-(4-fluoro-2-((3aR,6aS)-tetrahydro-1H-furo[3,4-c]pyrrol-5(3H)-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from intermediate F-4a following the procedure of Example 12 using (3aR,6aS0-rel-hexahydro-1H-furo[3,4-c]pyrrole hydrochloride as the amine and DIEA as base:1H NMR (DMSO-d6) 6: 8.02 (s, 2H), 7.23 (dd, J = 8.4, 5.4 Hz, 1 H), 7.08 (dd, J = 9.6, 8.6 Hz, 1 H), 5.07 - 5.16 (m, 2H), 4.86 (dt, J = 12.0, 2.9 Hz, 1H), 4.69 (dt, J = 12.1, 2.3 Hz, 1H), 3.74 - 3.85 (m, 4H), 3.66 (dd, J = 8.8, 2.0 Hz, 2H), 3.48 (dt, J = 10.4, 2.8 Hz, 2H), 3.07 - 3.16 (m, 2H). LCMS m / z 497.2 [M+H]+.

[0882] EXAMPLES 84 and 85

[0883] (R)-2-Amino-6-chloro-4-(2-(3-(dimethylamino)pyrrolidin-1-yl)-4-fluorobenzo[d]oxazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 84) and (R)-2-amino-4-(2-(3- (dimethylamino)pyrrolidin-1-yl)-4-fluorobenzo[d]oxazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (Example 85) diastereomeric atropisomer mixtures:

[0884]

[0885] Step 1: NCS (60.1 mg, 450 pmol) was added to a suspension of J-7a (158 mg, 300 pmol) in ACN (3.0 mL). The reaction vessel was sealed, heated to 70 °C for 18 h and then cooled to RT. The solvent was removed under reduced pressure and the residue was purified by flash chromatography (silica, EtOAc in hexanes, 5-100%) to give an approximate 1:1 mixture of the deprotected chlorinated benzothiophene derivative and deprotected J-7a (100 mg). The mixture was used as such for step 2: LCMS m / z 460.0 and 426.0 [M+H]+.

[0886] Step 2: The mixture from step 1 (100 mg, 217 pmol), (R)-N, N-dimethylpyrrolidin-3-amine (33.2 pL, 261 pmol), DIEA (114 pL, 652 pmol) and DMF (2.2 mL) was heated to 70 °C for 30 min. The solvent was concentrated under reduced pressure and the residue was purified by C18 reversed-phase chromatography using an ACCQPrep HPLC system with a gradient of MeOH in water (15 to 100%, 0.1% HCOOH) as eluent to give the formate salts of the title compounds as 1:1 diastereomeric mixtures:

[0887] Example 84:1H NMR (DMSO-d6) 6: 8.09 (s, 2H), 7.33 (dd, J = 7.6, 4.3 Hz, 2H), 6.95 (dd, J = 8.1, 6.9 Hz, 1H), 3.84 (dd, J = 9.9, 7.1 Hz, 1H), 3.73 - 3.81 (m, 1H), 3.58 (td, J = 9.9, 7.2 Hz, 1H), 3.35 (dd, J = 10.1, 8.1 Hz, 1H), 2.89 (quin, J = 7.6 Hz, 1H), 2.22 (s, 6H), 2.14 - 2.20 (m, 1H), 1.82 -1.96 (m, 1 H). LCMS m / z 474.0 [M+ H]+.

[0888] Example 85:1H NMR (DMSO-d6) 6: 7.96 (s, 2H), 7.31 (d, J = 8.3 Hz, 1H), 7.12 - 7.20 (m, 1H), 7.01 - 7.10 (m, 1H), 6.91 (t, J = 7.4 Hz, 1H), 3.80 - 3.88 (m, 1H), 3.77 (t, J = 8.3 Hz, 1H), 3.52 -3.64 (m, 1H), 3.35 (t, J = 9.0 Hz, 1H), 2.88 (quin, J = 7.6 Hz, 1H), 2.21 (s, 6H), 2.12 - 2.19 (m, 2H), 1.79 - 1.97 (m, 1 H). LCMS m / z 440.0 [M + H]+.

[0889] EXAMPLE 86

[0890] 2-Amino-4-(2-((1,3-dihydroxypropan-2-yl)amino)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers):

[0891] Preparation of 2,2,3,3,9,9,10,10-octamethyl-4,8-dioxa-3,9-disilaundecan-6-amine: t-Butyldimethylsilyl chloride (6.85 g, 45.5 mmol) was added to a mixture of serinol (1.90 g, 20.9 mmol), Et3N (4.99 mL, 35.5 mmol), and 4-dimethylaminopyridine (47.6 mg, 386 pmol) in DCM (50.0 mL). The mixture was stirred at 25 °C for 18 h. The mixture was the washed with water (20 mL), the organic phase dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, EtOAc in hexanes, 0-100%). The protected amine-diol was obtained as a pale-yellow oil (2.25 g, 34 %):1H NMR (DMSO-d6) 6: 3.43 - 3.50 (m, 4H), 2.68 (quin, J = 5.5 Hz, 1H), 1.27 (brs, 2H), 0.86 (s, 18H), 0.03 (s, 12H). LCMS m / z 320.2 [M+H]+.

[0892] Following the procedure of Example 67 and using the amine from above, the compounds of Example 86 were obtained, after deprotection using 4N HCI in dioxane-MeOH, as a 1:1 mixture of atropisomers:1H NMR (DMSO-d6) 5: 8.20 (d, J = 8.0 Hz, 1H), 8.02 (s, 2H), 7.21 (dd, J = 8.4, 5.4 Hz, 1H), 7.07 (t, J = 8.9 Hz, 1H), 5.06 (brs, 2H), 4.77- 4.85 (m, 3H), 4.67 (d, J = 12.1 Hz, 1H), 3.94 (brs, 1H), 3.54 - 3.61 (m, 4H). LCMS m / z 475.1 [M+H]+.

[0893] EXAMPLE 87

[0894] 2-Amino-4-(4-chloro-2-(((1-methyl-1H-imidazol-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from racemic intermediate G-1b following the procedures of Example 70 and using (1-methyl-1H-imidazol-2-yl)methanamine dihydrochloride as the amine in step 2:1H NMR (DMSO-d6) 5: 8.86 (t, J = 5.2 Hz, 1H), 7.99 (s, 2H), 7.02 - 7.18 (m, 3H), 6.84 (s, 1H), 5.08 (s, 2H), 4.74 (d, J = 12.1 Hz, 1H), 4.55 - 4.68 (m, 3H), 3.76 (s, 3H). LCMS m / z 511.0 [M+H]+.

[0895] EXAMPLE 88 2-Amino-4-(4-chloro-2-((((S)-1,2-dimethylpyrrolidin-2-yl)methyl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single diastereomer); Prepared from chiral, more active intermediate G-1b following the procedures of Example 70 and using (S)-(1,2-dimethylpyrrolidine-2-yl)methanamine (prepared as described for Example 64) as the amine in step 2:1H NMR (MeOH-d4) δ: 7.13 (dd, J = 8.3, 5.2 Hz, 1H), 6.98 (dd, J = 9.5, 8.4 Hz, 1H), 5.14 (t, J = 2.1 Hz, 2H), 4.79 - 4.84 (m, 1H), 4.71 (dt, J = 12.0, 2.0 Hz, 1H), 3.51 - 3.61 (m, 2H), 3.06 - 3.22 (m, 1H), 2.80 (br. s., 1H), 2.44 (br. s., 3H), 2.01 - 2.12 (m, 1H), 1.81 - 1.94 (m, 2H), 1.64 - 1.78 (m, 1H), 1.14 (s, 3H). LCMS m / z 528.1 [M+H]+.

[0896] EXAMPLE 89

[0897] 2-Amino-4-(1-(2-aminothiazol-5-yl)-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dihydro-1H-isobenzofuro[4,5-d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomers): Prepared following the sequence described for Example 7 starting from intermediate G-1a instead of B-1a and using tert-butyl (5-aminothiazol-2-yl)carbamate as the amine in step 1. NaH in THF at RT was used instead of LiHMDS in step 5:1H NMR (DMSO-d6) 5: 8.01 (s, 2H), 7.38 (s, 2H), 7.14 - 7.27 (m, 2H), 7.07 (s, 1H), 4.93 (s, 2H), 4.81 (d, J = 11.0 Hz, 1H), 4.63 (d, J = 12.6 Hz, 1H), 4.39 - 4.54 (m, 2H), 2.93 (brs, 1H), 2.31 (s, 3H), 2.20 (brs, 1H), 1.91 (brs, 1H), 1.65 (brs, 4H). LCMS m / z 580.1 [M+H]+.

[0898] EXAMPLE 90

[0899] 2-Amino-4-(1-(2,2-difluoroethyl)-4-fluoro-2-(((S)-1-methylpyrrolidin-2-yl)methoxy)-6,8-dihydro-1H-isobenzofuro[4,5-d]imidazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomers): Prepared following the sequence described for Example 7 starting from intermediate G-1a instead of B-1a and using 2,2-difluoroethylamine as the amine in step 1:1H NMR (MeOH-d4) δ: 7.20 (ddd, J = 8.3, 5.3, 1.4 Hz, 1H), 6.98 (dd, J = 9.4, 8.4 Hz, 1H), 6.23 (tq, J = 54.9, 2.5 Hz, 1 H), 5.44 (s, 2H), 4.74 (dt, J = 12.0, 1.9 Hz, 2H), 4.57 - 4.62 (m, 2H), 4.34 - 4.57 (m, 3H), 3.08 - 3.13 (m, 1H), 2.77 - 2.86 (m, 1H), 2.49 - 2.52 (m, 3H), 2.38 (app. quin, J = 8.9 Hz, 1 H), 2.00 - 2.22 (m, 2H), 1.76 - 1.91 (m, 3H). LCMS m / z 546.0 [M+H]+.

[0900] EXAMPLE 91

[0901] 2-Amino-4-(2-amino-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of atropisomers): Prepared from racemic intermediate F-3b following the procedure described for Example 81:1H NMR (DMSO-d6) 5: 7.98 (s, 2H), 7.90 (s, 2H), 7.13 (dd, J = 8.3, 5.4 Hz, 1H), 7.03 - 7.09 (m, 1H), 5.08 (s, 2H), 4.70 - 4.78 (m, 1H), 4.56 - 4.64 (m, 1H). LCMS m / z 417.0 [M+H]+.

[0902] EXAMPLE 92

[0903] (P)-2-Amino-4-(4-chloro-2-(((S)-quinuclidin-3-yl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single diastereomer); Prepared from chiral, more active (P)-intermediate G-1b following the procedures of Example 70 and using (S)-(-)-3-aminoquinuclidine dihydrochloride as the amine in step 2:1H NMR (DMSO-d6) 5: 8.60 (d, J = 6.0 Hz, 1H), 7.99 (s, 2H), 7.12 (dd, J = 8.4, 5.5 Hz, 1H), 7.07 (t, J = 8.9 Hz, 1H), 5.09 (s, 2H), 4.73 (d, J = 12.0 Hz, 1H), 4.61 (d, J = 12.1 Hz, 1H), 3.92 (br. s., 1H), 2.88 (d, J = 6.5 Hz, 1H), 2.73 - 2.83 (m, 3H), 2.70 (d, J = 3.1 Hz, 1H), 2.11 (d, J = 2.9 Hz, 1H), 1.82 (br. s., 1H), 1.54 - 1.74 (m, 2H), 1.43 (d, J = 12.0 Hz, 1H), 1.23 (s, 1H). LCMS m / z 526.1 [M+H]+.

[0904] EXAMPLE 93

[0905] 2-Amino-4-(4-chloro-2-((R)-3-(dimethylamino)piperidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (1:1 mixture of diastereomers):

[0906]

[0907] Boc

[0908] sStep 3

[0909] - ► Example 93

[0910] F-4b

[0911] Step 1: tert-Butyl (R)-3-(dimethylamino)piperidine-1-carboxylate: a solution of tert-butyl (R)-3-aminopiperidine-1 -carboxylate (3.00 g, 14.98 mmol) in MeOH (50 mL) was treated with acetic acid (1.7 mL, 30 mmol) followed by 37% aqueous formaldehyde (6 mL, 61.9 mmol). After 30 min stirring, the reaction mixture was cooled to 0 - 5 °C and treated with sodium cyanoborohydride (2.35 g, 37.4 mmol) added portion-wise over 10 min. After 30 min, the cooling bath was removed and the clear mixture was stirred at RT for 6 h. The reaction mixture was concentrated under reduced pressure and partitioned between DCM (250 mL) and 10 % aqueous potassium carbonate (20 mL, pH ~ 11 - 12). The organic phase was collected and the aqueous phase was extracted again with DCM (2 x 20 mL). The combined organic extracts were dried over anhydrous MgSO4and concentrated in vacuo to give 4.0 g of a clear oil. This oil was purified by flash chromatography (silica, MeOH in DCM with 10% NH4OH, 5-7%) to give a clear oil (2.82 g, 82% yield). Bulb to bulb distillation under vacuum (2 mbar, bp 115 - 125 °C) gave the desired intermediate as a colorless oil (2.63 g, 77 % yield):1H NMR (CDCl₃) δ: 4.0 - 4.3 (br. s., 1 H), 3.96 (br. s., 1 H), 2.61 - 2.71 (m, 1 H), 2.32 (s, 6H), 2.14 (tt, J = 10.4, 3.8 Hz, 1H), 1.99 (d, J = 12.3 Hz, 1H), 1.69 - 1.80 (m, 1H), 1.62 (br. s., 1H), 1.47 (s, 9H), 1.24 - 1.41 (m, 2H). LCMS m / z 229.3 [M+H]+.

[0912] Step 2: (R)-N, N-Dimethylpiperidin-3-amine dihydrochloride: tert-butyl (R)-3-(dimethylamino)piperidine-l -carboxylate from step 1 (2.55 g, 11.17 mmol) was treated at 23 °C with 12 mL (48 mmol) of 4 M HCI in dioxane added dropwise over 10 min. After 4 h the suspension was concentrated under reduced pressure to give the bis-hydrochloride salt as a white solid. Trituration under nitrogen with ether (40 mL) followed by decantation and drying in vacuum for 18 h gave the bis hydrochloride salt (2.20 g, 98 % yield) as a hydroscopic solid:1H NMR (DMSO-d6) 5: 11.69 (br. s., 1H), 10.09 (br. s., 1H), 9.65 (br. s., 1H), 3.65 (d, J = 11.8 Hz, 1H), 3.49 - 3.56 (m, 1H), 3.19 (d, J = 12.5 Hz, 1H), 3.10 (br. t, J = 11.0 Hz, 1H), 2.72 (s, 6H), 2.17 (br. d, J = 10.4 Hz, 1 H), 1.88 - 1.98 (m, 1 H), 1.64 - 1.83 (m, 2H). LCMS m / z 129.2 [M+H]+.

[0913] Example 93 was prepared from racemic intermediate F-4b following the procedures of Example 72 and using the amine from above:1H NMR (DMSO-d6) 6: 7.99 (s, 2H), 6.97 - 7.19 (m, 2H), 5.11 (br. s., 2H), 4.74 (d, J = 12.1 Hz, 1H), 4.62 (d, J = 12.1 Hz, 1H), 4.03 (d, J = 11.8 Hz, 1H), 3.86 -3.98 (m, 1 H), 3.22-3.28 (m, 2H, overlap with water signal), 2.31 - 2.41 (m, 1 H), 2.26 (s, 6H), 1.78 - 1.96 (m, 2H), 1.45 -1.61 (m, 2H). LCMS m / z 527.9 [M+H]+.

[0914] EXAMPLE 94

[0915] (P)-2-Amino-4-(4-chloro-2-(((R)-quinuclidin-3-yl)amino)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single diastereomer): Prepared from chiral, more active (P)-intermediate G-1b following the procedures of Example 70 and using (R)-(-)-3-aminoquinuclidine dihydrochloride as the amine in step 2:1H NMR (DMSO-d6) 5: 8.58 (d, J = 6.1 Hz, 1H), 7.98 (br. s., 2H), 7.12 (dd, J = 8.0, 5.8 Hz, 1H), 7.07 (t, J = 8.1 Hz, 1H), 5.08 (br. s., 2H), 4.73 (d, J = 12.3 Hz, 1H), 4.61 (d, J = 12.4 Hz, 1H), 3.87 (br. s., 1H), 2.83 (br. s., 1H), 2.65 - 2.77 (m, 3H), 2.59 (d, J = 14.3 Hz, 1H), 2.07 (br. s., 1H), 1.80 (br. s., 1H), 1.47 - 1.74 (m, 2H), 1.37 (br. s., 1H), 1.29 (br. s., 1H), 1.23 (br. s., 1H). LCMS m / z 526.1 [M+H]+.

[0916] EXAMPLE 95

[0917] 2-Amino-4-(2-(((6-aminopyridin-2-yl)methyl)amino)-4-chloro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (racemic atropisomers): Prepared from racemic intermediate G-1b following the procedures of Example 70 and using 6-(aminomethyl)pyridine-2-amine as the amine in step 2:1H NMR (DMSO-d6) 6: 8.80 (br. s., 1 H), 7.98 (br. s., 2H), 7.35 (t, J = 7.7 Hz, 1 H), 7.10 (dd, J = 8.0, 5.8 Hz, 1H), 7.07 (t, J = 8.6 Hz, 1H), 6.54 (d, J = 7.1 Hz, 1H), 6.34 (d, J = 8.1 Hz, 1H), 5.96 (s, 2H), 5.08 (br. s., 2H), 4.73 (d, J = 12.0 Hz, 1H), 4.60 (d, J = 12.1 Hz, 1H), 4.47 (br. s., 2H). LCMS m / z 523.0 [M+H]+.

[0918] EXAMPLE 96

[0919] (P)-2-Amino-7-fluoro-4-(4-fluoro-2-(1,6-diazaspiro[3.3]heptan-6-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (single atropisomer): Prepared from chiral, more active (P)-intermediate F-4a following the procedures of Example 72 and commercially available tert-butyl 1,6-diazaspiro[3,3]hepthane-1-carboxylate oxalate (2:1) as the amine:1H NMR (DMSO-d6) 6: 8.03 (br. s., 2H), 7.22 (dd, J = 1.0 Hz, 1H), 7.07 (dd, J = 8.8 Hz, 1H), 5.09 (br. s., 2H), 4.86 (d, J = 12.5 Hz, 1H), 4.68 (d, J = 11.9 Hz, 1H), 4.27 - 4.38 (m, 2H), 4.20 (br. s., 2H). Missing 5H hidden underwater / DMSO signals. LCMS m / z 482.2 [M+H]+.

[0920] EXAMPLE 97

[0921] (P)-2-Amino-4-(2-(4-(dimethylamino)piperidin-1-yl)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single atropisomer): Prepared from chiral, more active (P)-intermediate F-4a following the procedures of Example 72 and N, N-dimethylaminopiperidine as the amine:1H NMR (DMSO-d6) 6: 8.03 (br. s., 2H), 7.19 - 7.25 (m, 1H), 7.08 (dd, J = 8.8 Hz, 1H), 5.05 - 5.15 (m, 2H), 4.85 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.0 Hz, 1H), 4.06 (d, J = 12.3 Hz, 2H), 3.24 (t, J = 12.0 Hz, 2H), 2.37 - 2.44 (m, 1H), 2.21 (s, 6H), 1.88 (d, J = 11.9 Hz, 2H), 1.45 - 1.55 (m, 2H). LCMS m / z 512.2 [M+H]+.

[0922] EXAMPLE 98

[0923] (P)-2-Amino-7-fluoro-4-(4-fluoro-2-(4-((2-hydroxyethyl)(methyl)amino)piperidin-1-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (single atropisomer): Prepared from chiral, more active (P)-intermediate F-4a following the procedures of Example 72 and 2-[methyl(piperidin-4-yl)amino]ethan-1-ol as the amine:1H NMR (DMSO-d6) 5: 8.03 (br. s., 2H), 7.22 (dd, J = 8.1, 5.5 Hz, 1H), 7.08 (dd, J = 8.9 Hz, 1H), 5.10 (br. s., 2H), 4.85 (d, J = 12.3 Hz, 1H), 4.68 (d, J = 12.1 Hz, 1H), 4.31 (t, J = 5.3 Hz, 1H), 4.09 (d, J = 11.9 Hz, 2H), 3.44 (q, J = 6.0 Hz, 2H), 3.21 (t, J = 11.7 Hz, 2H), 2.62 - 2.70 (m, 1H), 2.21 (s, 3H), 1.83 (d, J = 11.5 Hz, 2H), 1.46 - 1.58 (m, 2H). LCMS m / z 542.2 [M+H]+.

[0924] EXAMPLE 99 (P)-2-Amino-4-(2-(((1-(dimethylamino)cyclobutyl)methyl)amino)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single atropisomer):

[0925] Example 99

[0926]

[0927] 2 HCI

[0928] Step 1: 1-(Dimethylamino)cyclobutane-1-carbonitrile: A solution of KCN (1.06 g, 16.3 mmol) in water (8 mL) was added over 5 min to a stirred, cooled to 0 °C suspension of dimethylamine hydrochloride (1.33 g, 16.3 mmol) and cyclobutanone (1.14 g, 16.3 mmol). The mixture was stirred overnight at RT and then extracted with Et20 (3x15 mL). The combined organic extracts were washed with water (2x15 mL), dried over MgSO4, and then evaporated under reduced pressure to give 1-(dimethylamino)cyclobutane-1-carbonitrile (1.41 g, 70 %) as an oil used without further purification:1H NMR (CDCl₃) δ: 2.35 - 2.46 (m, 2H), 2.16 - 2.28 (m, 8H), 1.99 - 2.15 (m, 1H), 1.82 - 1.94 (m, 1H). LCMS m / z 125.0 [M+H]+.

[0929] Step 2: 1-(Aminomethyl)-N, N-dimethylcyclobutan-1-amine dihydrochloride: To a stirred suspension of LAH (977 mg, 24.5 mmol) in anhydrous THF (70 mL), under argon cooled to 0 °C, was added dropwise a solution of 1-(dimethylamino)cyclobutane-1 -carbonitrile from step 1 (1.35 g, 10.9 mmol) in anhydrous THF (35 mL) and the mixture was refluxed for 2 h. The reaction mixture was cooled to 0 °C and the excess LAH was slowly quenched using de Fieser workup procedure with a mixture of Na₂SO₄•10H₂O (2.25 g) and celite® (5 g). After stirring for 1 h, the suspension was warmed to RT and was filtered. The filter cake was washed liberally with ether, and the volume of the filtrate was reduced to 50 mL. To the filtrate was added 4N HCI in dioxane (10.9 mL, 43.5 mmol). A white precipitate immediately formed, and after 15 mins, the solvent was removed in vacuo to yield 1-(ammoniomethyl)-N, N-dimethylcyclobutan-1-aminium dichloride (1.96 g, 90 %) as a white powder. The product was used as such:1H NMR (DMSO-d6) 5: 11.22 -12.06 (br. s. 1H), 8.71 (br. s., 3H), 3.38 (br. s., 2H), 2.67 (s, 6H), 2.52 - 2.59 (m, 2H), 2.25 (t, J = 9.9 Hz, 2H), 1.69 - 1.89 (m, 2H). LCMS m / z 129.0 [M+H]+.

[0930] SStep 3: The compound of Example 99 was prepared from the chiral, more active (P)-intermediates F-2a instead of B-1a following the procedures of Example 34 and using the amine dihydrochloride from step 2 as the amine in step 1:1H NMR (DMSO-d6) 5: 8.14 (br. s., 1H), 8.02 (br. s., 2H), 7.21 (t, J = 6.5 Hz, 1H), 7.07 (t, J = 8.7 Hz, 1H), 5.06 (br. s., 2H), 4.81 (d, J = 12.1 Hz, 1H), 4.68 (d, J = 11.8 Hz, 1H), 3.59 - 3.80 (m, 2H), 2.20 (br. s., 6H), 2.05 (q, J = 9.5 Hz, 2H), 1.77 - 1.90 (m, 2H), 1.61 - 1.77 (m, 2H). LCMS m / z 512.2 [M+H]+. EXAMPLE 100

[0931] (P)-2-Amino-4-(2-((S)-3-(dimethylamino)pyrrolidin-1-yl)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single diastereomer): Prepared from chiral, more active (P)-intermediate F-4a following the procedures of Example 72 and (S)-(-)-3-(dimethylamino)pyrrolidine as the amine:1H NMR (DMSO-d6) 5: 8.03 (br. s, 2H), 7.24 (dd, J = 8.4, 5.5 Hz, 1H), 7.09 (t, J = 8.9 Hz, 1H), 5.12 (br. s., 2H), 4.87 (d, J = 12.2 Hz, 1H), 4.69 (d, J = 12.1 Hz, 1H), 3.79 (t, J = 7.9 Hz, 1H), 3.69 (t, J = 7.9 Hz, 1H), 3.53 (q, J = 8.7 Hz, 1H), 2.95 (br. s, 1H), 2.23 (br. s., 8H), 1.95 (quin, J = 9.7 Hz, 1H). LCMS m / z 498.0 [M+H]+.

[0932] EXAMPLE 101

[0933] (P)-2-Amino-4-(2-((2S,4R)-4-(dimethylamino)-2-(hydroxymethyl)pyrrolidin-1-yl)-4-fluoro-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)-7-fluorobenzo[b]thiophene-3-carbonitrile (single diastereomer): Prepared from chiral, more active (P)-intermediate F-4a following the procedures of Example 72 and [(2S,4R)-4-(dimethylamino)-2-pyrrolidinyl]methanol dihydrochloride as the amine:1H NMR (DMSO-d6) 6: 7.22 (dd, J = 8.4, 5.4 Hz, 1H), 7.08 (dd, J = 9.5, 8.4 Hz, 1H), 5.06 - 5.16 (m, 2H), 5.03 (t, J = 5.5 Hz, 1H), 4.85 (d, J = 12.1 Hz, 1H), 4.69 (d, J = 12.3 Hz, 1H), 4.08 (br. s, 1H), 3.74 (t, J = 7.9 Hz, 1H), 3.62 (t, J = 4.8 Hz, 2H), 3.04 - 3.19 (m, 1H), 2.19 (s, 7H), 1.91 - 2.04 (m, 1H). LCMS m / z 528.0 [M+H]+.

[0934] EXAMPLE 102

[0935] (P)-2-Amino-7-fluoro-4-(4-fluoro-2-((4aS,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazin-6(2H)-yl)-6,8-dihydroisobenzofuro[5,4-d]thiazol-5-yl)benzo[b]thiophene-3-carbonitrile (single diastereomer):

[0936]

[0937] Step 1: 2-(((3S,4S)-1-(tert-Butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)ammonio)ethyl sulfite: To a solution of 1-Boc-(3S,4S)-3-amino-4-hydroxypyrrolidine (800 mg, 3.96 mmol) in a mixture of ACN (6.5 mL) and 1-propanol (719 pL) in a 20 mL vial cooled to 0 °C under nitrogen was added dropwise a solution of 1,3,2-dioxathiolane 2,2-dioxide (686 pL, 4.15 mmol) in ACN (1.8 mL). After the addition, the mixture was brought to RT and left to stir for 2.25 h. A thick suspension formed, and LCMS analysis showed complete conversion of the starting material. Ether was added (30 mL) as an antisolvent, and the suspension was passed through a fritted filter. The solids were collected and dried under vacuum to afford 2-(((3S,4S)-1-(tert-butoxycarbonyl)-4-hydroxypyrrolidin-3-yl)ammonio)ethane-1 -sulfonate (1.22 g, 95 %) as a free flowing white powder:1H NMR (DMSO-d6) 6: 8.41 - 9.18 (m, 2H), 5.69 (d, J = 4.8 Hz, 1H), 4.34 (br. s., 1H), 4.01 (t, J = 5.0 Hz, 2H), 3.49 - 3.67 (m, 3H), 3.32 - 3.40 (m, 2H), 3.17 - 3.27 (m, 1H), 3.09 (dd, J = 11.3, 4.4 Hz, 1H), 1.40 (s, 9H). LCMS m / z 325.0 [M-H]’.

[0938] Step 2: tert-Butyl (4aS,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate: To a solution of the product from step 1 (1.22 g, 3.75 mmol) in a mixture of THF (8.2 mL) and isopropanol (1.68 mL) in a microwave vial was added potassium tert-butoxide (989 mg, 8.81 mmol) with stirring. The vial was capped and the solution was heated to 60 °C. After 2.5 h, LCMS analysis showed complete conversion of starting material. The flask was cooled to room temperature and water (1 mL) was added followed by celite (5 g). The suspension was passed through a fritted filter and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (silica, MeOH in DCM, 0-20%) to yield tert-butyl (4aS,7aS)-hexahydropyrrolo[3,4-b][1,4]oxazine-6(2H)-carboxylate (478 mg, 56 %) as a yellow oil.1H NMR (CDCl3) 5: 3.96 (d, J = 11.6 Hz, 1H), 3.44 - 3.77 (m, 4H), 2.81 - 3.18 (m, 5H), 1.47 (s, 9...

Claims

CLAIMS1. A compound of Formula I:wherein:X is S, O or N;R1is H, halo, OR8, C(O)OR9, substituted or unsubstituted Ci-4alkyl, or R1and R2are taken together with their adjacent carbon atoms to form an optionally substituted C4-7heterocycloalkyl; R2is selected from H, halo, CN, OR8, substituted or unsubstituted Ci-4alkyl, or R1and R2are taken together with their adjacent carbon atoms to form an optionally substituted C4-7heterocycloalkyl; R3is an optionally substituted C6-10aryl or C5-10heteroaryl;R4is H, halo (e.g. F or Cl), CN, OR8, a substituted or unsubstituted Ci-4alkyl, or a substituted or unsubstituted C3-5cycloalkyl or a C4-5heterocycloalkyl;R5is H, a substituted or unsubstituted C1-9alkyl, a substituted or unsubstituted C3-9cycloalkyl or a substituted or unsubstituted C4-9heterocycloalkyl, or R5is absent when X is S or O;L is O or NR7, preferably L being NR7when X is O;R6is independently in each occurrence a substituted or unsubstituted group selected from C1-5alkyl, C4-9cycloalkyl, C4-9heterocycloalkyl;R7is independently in each occurrence H or an optionally substituted C1-6alkyl, or R6and R7are taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl or an optionally substituted C5-9heteroaryl;or L is a carbon atom, and L and R7are taken together to form an optionally substituted C4-9heterocycloalkyl or an optionally substituted C5-9heteroaryl;R8or R9is a substituted or unsubstituted C1-5alkyl;or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

2. The compound of claim 1, wherein said compound is of Formula II:Formula IIwherein L, R1, R2, R3, R4, and R6are as defined in claim 1, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

3. The compound of claim 1, wherein said compound is of Formula III:Formula IIIwherein L, R1, R2, R3, R4, and R6are as defined in claim 1, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

4. The compound of claim 1, wherein said compound is of Formula IV:Formula IVwherein L, R1, R2, R3, R4, R5, and R6are as defined in claim 1, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

5. The compound of claim 1 or 4, wherein R5is H.

6. The compound of claim 1 or 4, wherein R5is a substituted or unsubstituted C1-6alkyl, a substituted or unsubstituted Cs-gcycloalkyl, or a substituted or unsubstituted C4- gheterocycloalkyl.

7. The compound of claim 1 or 4, wherein R5is selected from:wherein (---) represents a point of attachment between R5and N.

8. The compound of any one of claims 1, 2, and 4 to 7, wherein L is O and the compound is of Formula II-A or IV-A:wherein R1, R2, R3, R4, R5, and R6are as defined in any one of the previous claims, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

9. The compound of any one of claims 1 to 7, wherein L is NR7and the compound is of Formula II-B, III-A, or IV-B:wherein R1, R2, R3, R4, R5, R6, and R7are as defined in any one of the previous claims, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

10. The compound of any one of claims 1 to 7 and 9, wherein R7is H or an optionally substituted C1-6alkyl.

11. The compound of any one of claims 1 to 7 and 9, wherein R6and R7are taken together with their adjacent nitrogen atom to form an optionally substituted C4-9heterocycloalkyl.

12. The compound of any one of claims 1 to 10, wherein R6is selected from a substituted or unsubstituted group selected from C1-5alkyl, C4-6cycloalkyl, C4-9heterocycloalkyl.

13. The compound of claim 8, wherein L-R6is of the formula:wherein:R11and R11’ are independently in each occurrence selected from H, OH, Ci-salkoxy, halo (e.g. F), CN, and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, and / or two R11and R11’ are taken together with their adjacent carbon atom to form a carbonyl; and / or at least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group;R12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, or R12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, or at least one of R11and R11’ and one of R12and R12’ are taken togetherwith their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group;p is 0 or 1; and( — ) represents a point of attachment between L-R6and the rest of the molecule.

14. The compound of claim 9, wherein L-R6is of the formula:wherein:R7is selected from H or an optionally substituted C1-6alkyl, or R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-9heterocycloalkyl group;R11and R11’ are independently in each occurrence selected from H, OH, Ci-salkoxy, halo (e.g. F), CN, and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, and / or two R11and R11’ are taken together with their adjacent carbon atom to form a carbonyl, and / or at least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C4-9heterocycloalkyl group;R12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, or R12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, or at least one of R11and R11’ and one of R12and R12’ are taken together with their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group;p is 0 or 1; and( — ) represents a point of attachment between L-R6and the rest of the molecule.

15. The compound of claim 14, wherein:R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-9heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted Ci -salkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or - N(Ci-3alkyl)2; orat least of two R11and R11’ are taken together with their adjacent carbon atom(s) to form an optionally substituted monocyclic or polycyclic Cs-gcycloalkyl or C^heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted Ci -salkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or - N(Ci-3alkyl)2; orR12and R12’ are taken together with their adjacent nitrogen atom to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an C1- 2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2; or at least one of R11and R11’ and one of R12and R12’ are taken together with their adjacent nitrogen and carbon atoms to form an optionally substituted monocyclic or polycyclic C4- i2heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2.

16. The compound of claim 15, wherein R7and at least one of R11, R11’, R12, and R12’ are taken together with their adjacent nitrogen and carbon or nitrogen atom(s) to form an optionally substituted C4-9heterocycloalkyl group, in particular the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, C1-3alkoxyl, -NH2, -NH(C1-3alkyl), and / or -N(C1-3alkyl)2.

17. The compound of claim 15 or 16, wherein the optionally substituted C4-i2heterocycloalkyl group is an optionally substituted C5-7heterocycloalkyl group, more preferably an optionally substituted 5- to 7-membered lactam, or an optionally substituted pyrrolidine, piperidine, piperazine, or morpholine ring, in particular, the substituent is selected from a carbonyl formed by two R11and R11’ taken together, an Ci-2alkylene bridge formed by two R11’ taken together, OH, optionally substituted C1-5alkyl, and combinations thereof, the optional substituent of C1-5alkyl being preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, - NH2, -NH(Ci.3alkyl), and / or -N(Ci-3alkyl)2.

18. The compound of claim 17, wherein L-R6is selected from:wherein:p is 0 or 1;R11ais H, OH, halo (e.g. F), C1-5alkyl, preferably H or OH;R11a’ is H or C1-5alkyl, preferably H;R11band R11b’ are independently in each occurrence selected from H and C1-5alkyl optionally substituted with one or more substituents, preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2, preferably R11band R11b’ are independently H or Me;R11and R11’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, the optional substituent being preferably selected from halo (e.g. F),oxo, OH Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2, and / or two R11’ are taken together to form an Ci-2alkylene bridge; andR12and R12’ are independently in each occurrence selected from H and an optionally substituted C1-5alkyl, C4-9cycloalkyl, or C4-9heterocycloalkyl group, or R12and R12’ are taken together with the nitrogen atom bearing them to form an optionally substituted monocyclic or polycyclic C4-i2heterocycloalkyl group, the optional substituent being preferably selected from halo (e.g. F), oxo, OH Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), and / or -N(Ci-3alkyl)2.

19. The compound of claim 18, wherein R12and R12’ are independently in each occurrence selected from H, C1-5alkyl, C4-6cycloalkyl, or C4-6heterocycloalkyl group, or R12and R12’ are taken together with the nitrogen atom bearing them to form a monocyclic C4- sheterocycloalkyl group.

20. The compound of any one of claims 1 to 7, wherein L-R6is selected from:wherein (---) represents a point of attachment between L-R6and the rest of the molecule.

21. The compound of claim 20, wherein L-R6is selected from:wherein (---) represents a point of attachment between L-R6and the rest of the molecule.

22. The compound of any one of claims 1 to 21, wherein R1is H or an optionally substituted Cisalkyl, preferably H or an optionally substituted Ci-3alkyl.

23. The compound of claim 22, wherein R1is H.

24. The compound of any one of claims 1 to 23, wherein R2is H, halo, CN, OR8, or an optionally substituted Ci-3alkyl.

25. The compound of claim 24, wherein R2is H, Cl, F, CF3, or OMe, preferably Cl or CF3, more preferably Cl.

26. The compound of any one of claims 1 to 21, wherein R1and R2are taken together with their adjacent carbon atoms form an optionally substituted C4-7heterocycloalkyl.

27. The compound of claim 26, wherein R1and R2are taken together with their adjacent carbon atoms to form a C4-7heterocycloalkyl of the formula:whereinR13and R13’ are independently in each occurrence selected from H and an optionally substituted Ci-3alkyl, or two R13and R13’ on the same carbon are taken together with their adjacent carbon atom to form a carbonyl;R14and R14’ are independently in each occurrence selected from H and an optionally substituted Ci-3alkyl;or two R13and R13’ or two R14and R14’ are taken together with their adjacent carbon atom to form an optionally substituted C3-5cycloalkyl;q is an integer selected from 0 to 3, r is an integer selected from 1 to 4, wherein 1 < q + r < 4; and (===) represents a point of attachment between the cycle and the rest of the molecule.

28. The compound of claim 27, wherein r and q are such their sum equals 2 or 3.

29. The compound of claim 27 or 28, wherein r is 1.

30. The compound of claim 27 or 28, wherein r is 2.

31. The compound of any one of claims 27 to 30, wherein q is 1.

32. The compound of any one of claims 27 to 30, wherein q is 2.

33. The compound of claim 27 or 28, wherein R13, R13’, R14, and R14’ are each hydrogen atoms.

34. The compound of claim 27 or 28, wherein R13and R13’ in one instance are taken together with their adjacent carbon atom to form a carbonyl adjacent to the oxygen atom of the ring, preferably the remaining R13, R13’, R14and R14’ are each hydrogen atoms.

35. The compound of claim 26, wherein said compound is a compound of any one of Formulae ll-C, ll-D, ll-E, lll-B, IV-C, or lV-D:wherein:R3, R4, R5, R6and R7, are as defined in any one of the previous claims;or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

36. The compound of any one of claims 1 to 35, wherein R3is an optionally substituted C6-10aryl or C5-10heteroaryl.

37. The compound of claim 36, wherein R3is selected from:wherein:X5is NH, O, or S;X6, X7, and X8are each independently CH, C(R10), or N;R10is independently in each occurrence 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 Ci-5alkyl, C2.4alkynyl, Cs-ecycloalkyl, and C4-6heterocycloalkyl, each optionally substituted with one or more substituents preferably selected from halo (e.g. F), oxo, OH, Ci-3alkoxyl, -NH2, -NH(Ci-3alkyl), -N(Ci-3alkyl)2, and / or optionally substituted Ci-3alkyl;R15is independently in each occurrence selected from H or a C1-5alkyl, Cs-ecycloalkyl, C4. eheteroalkyl, or Cs-gheteroaryl group optionally substituted with one or more substituents, preferably selected from halo, oxo, CN, OH, OC1-5alkyl, NH2, N(C1-5alkyl)2, NHC(O)C1-5alkyl,C(O)H, OC(O)Ci.5alkyl, C(O)C1-5alkyl, C(O)OCi-5alkyl, CON(C1-5alkyl)2, C(O)NH2, SO2C1-5alkyl, SO2OC1-5alkyl, SO2NH2and SO2N(C1-5alkyl)2;n is an integer selected such that the total number of R10on the R3group is from 1 to 4; and - - designates a bound between R3and the rest of the compound.

38. The compound of claim 36, wherein R3is selected from:wherein X5, X6, X7, X8, R10, and n are as previously defined; andwherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration.

39. The compound of claim 36, wherein R3is selected from:wherein X5, X6, X7, X8, R10, and n are as previously defined; andwherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration.

40. The compound of claim 39, wherein R3is of the formula:wherein X5, X6, X7, X8, R10, and n are as previously defined; andwherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration.

41. The compound of any one of claims 37 to 40, wherein X5is S, X6and X7are both C(R10), X8is CH, and R10is independently in each occurrence selected from halo (e.g. F or Cl), CN, OR15, N(R15)2, and C1-5alkyl, wherein R15is independently H or a C1-5alkyl.

42. The compound of any one of claims 36 to 38, wherein R3is selected from:wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the compound.

43. The compound of claim 42, wherein R3is selected from:wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the compound.

44. The compound of claim 43, wherein R3is selected from:wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the compound.

45. The compound of claim 44, wherein R3is selected from:wherein ( — ) represents a bond serving as a point of attachment between R3and the rest of the compound; andwherein the R3group configuration is such that the compound is enriched in the atropisomer, for example at least 90%, or at least 95%, or at least 98%, having the depicted configuration.

46. The compound of any one of claims 1 to 45, wherein R4is H, halo (e.g. F or Cl), CN, OR8or a substituted or unsubstituted C3-5cycloalkyl or a C4-5heterocycloalkyl.

47. The compound of any one of claims 1 to 45, wherein R4is F, Cl, or a substituted or unsubstituted Ci-4alkyl (e.g. Me), preferably F or Cl, most preferably Cl.

48. The compound of claim 1, wherein said compound is selected from Examples 1 to 592 as defined herein, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

49. The compound of claim 48, wherein said compound is selected from Examples 12A, 38A, 40A, 41A, 52, 57A, 66, 68B, 69-71, 78A, 79B, 81, 82B, 83, 87, 88, 92-112, 114-127, 130, 132-135, 137, 138, 140-162, 164, 165, 167-191, 193-197, 199-322, 324-355, 357-396, 398- 445, 452, 455-463, 465-470, 471B, 473-504, 506-513, 515, 517-528, 531-554, and 556- 592 as defined herein, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

50. The compound of claim 48, wherein said compound is selected from Examples 12A, 40A, 79B, 100, 107, 118-120, 122, 127, 133-135, 140, 148, 149, 156, 158, 160, 169, 170, 172, 182, 188-190, 194A, 194B, 195B, 201, 203-205, 207, 208, 211, 214, 216-219, 224, 227, 228, 230-239B, 242, 245, 248-252, 255, 260, 266, 268, 270-273, 275, 276, 278, 282-286, 293, 301-305, 310, 316, 319, 327, 330, 332-334, 336-338, 340, 347, 348, 353-355, 357, 358, 360, 362, 367-371, 373-377, 379, 380, 382, 383, 384B, 385, 388-393, 398, 404, 407- 408B, 411-413, 416, 419, 424, 428, 432, 433, 436, 442, 451, 456, 466-467B, 470, 471B, 479, 480, 483, 484, 486, 488, 490, 494-496, 498, 500, 501, 503, 508, 510, 513, 519, 522, 532, 536, 540, 542, 545A, 545B, 548, 551, 556, 557, 559, 561, 563, 564, 566, 569, 572, 573, 575, 576, 581-583, 585, 586, 587 and 591 as defined herein, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

51. The compound of claim 48, wherein said compound is selected from Examples 40A, 79B, 100, 118-120, 133, 134, 140, 148, 170, 189, 205, 218, 228, 236, 242, 252, 268, 272, 303, 316, 334, 347, 368, 377, 380, 404, 407, 408B, 411, 467B, 479, 483, 488, 496, 500, 508,519, 522, 545A, 548, 557, 561, 572, 573, 576, 581-583, 586 and 587 as defined herein, or a pharmaceutically acceptable salt, prodrug, and / or solvate thereof.

52. A pharmaceutical composition comprising a compound as defined in any one of claims 1 to 51, together with a pharmaceutically acceptable carrier, diluent or excipient.

53. Use of a compound as defined in any one of claims 1 to 51 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.

54. The use of claim 53, wherein the disease or disorder is selected from a neoplasm and a developmental anomaly.

55. The use of claim 53 or 54, wherein said disease or disorder is associated with a mutated KRAS gene or an amplification of the KRAS locus.

56. The use of any one of claims 53 to 55, 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).

57. The use of any one of claims 53 to 56, wherein said disease of disorder is a neoplasm.

58. The use of claim 57, wherein said neoplasm is selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, oesophageal, 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.

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

60. 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 signalingcascade (RASopathies), or an inflammatory disease or an immune system disorder, comprising administering a compound as defined in any one of claims 1 to 51 to a subject in need thereof.

61. The method of claim 60, wherein the disease or disorder is selected from a neoplasm and a developmental anomaly.

62. The method of claim 60 or 61, wherein said disease or disorder is associated with a mutated KRAS gene or an amplification of the KRAS locus.

63. The method of any one of claims 60 to 62, 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).

64. The method of any one of claims 60 to 63, wherein said disease or disorder is a neoplasm.

65. The method of claim 64, wherein said neoplasm is selected from melanoma, thyroid carcinoma (e.g. papillary thyroid carcinoma), colorectal, oesophageal, 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.

66. The method of claim 65, wherein said neoplasm is selected from colon or colorectal cancer, lung cancer, pancreatic cancer, thyroid cancer, breast cancer and melanoma.

67. A method for inhibiting abnormal proliferation of cells, comprising contacting the cells with a compound as defined in any one of claims 1 to 51.

68. The method of claim 67, wherein said cells comprise a mutated KRAS gene or an amplification of the KRAS locus.

69. The method of claim 67 or 68, wherein said abnormal proliferation is associated with a receptor tyrosine kinase mutation or amplification (e.g. EGFR, HER2) or a mutation oramplification in a regulator of RAS downstream of the receptor (e.g. SOS1 gain of function, NF1 loss of function).

70. The method of any one of claims 67 to 69, wherein said cells are selected from melanoma cells, thyroid carcinoma cells (e.g. papillary thyroid carcinoma cells), colorectal, oesphageal, 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.

71. The method of any one of claims 67 to 70, 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.

72. The method of any one of claims 67 to 71, wherein said contacting is done in vivo.

73. The method of any one of claims 67 to 71, wherein said contacting is done ex vivo.

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