7-fluoro-5-methoxy-2,3-dihydro-[1,3]oxazino[4,5,6-de]quinazoline derivatives as ras g12d inhibitors for the treatment of cancer

Abstract

The present application relates to compounds of formula (A) that inhibit the growth of cancers that express G12D mutant Ras proteins. The molecules of the specification are thus indicated for use in the treatment of cancer that express G12D mutant Ras protein.

Description

[0001] Ras G12D Inhibitors

[0002] The present specification relates to compounds and pharmaceutically acceptable salts thereof that inhibit the growth of cancers that express G12D mutant Ras proteins. The molecules of the specification are thus indicated for use in the treatment of Ras G12D mutant cancers and for use in methods for the treatment of Ras G12D mutant cancers. The specification also relates to processes, and intermediate compounds involved in them, for preparation of compounds and to pharmaceutical compositions containing them.

[0003] The KRAS, NRAS and HRAS genes encode a set of closely related small GTPase proteins, KRas, NRas and HRas, collectively referred to herein as the Ras proteins or Ras, that share 82-90% overall sequence identity. The Ras proteins are critical components of signalling pathways that transmit signals from cell-surface receptors to regulate cellular proliferation, survival and differentiation. Ras functions as a molecular switch cycling between an inactive GDP-bound state (the OFF state) and an active GTP-bound state (the ON state). The GDP / GTP cycle of Ras is tightly regulated in cells by guanine nucleotide exchange factors (GEFs) such as Sosl and Sos2, which promote the exchange of GDP for GTP, and GTPase activating proteins (GAPs) such as NF-1 and pl20RasGAP which stimulate the intrinsic GTPase activity of Ras that hydrolyses bound GTP to GDP.

[0004] The Ras proteins are 188-189 amino acids in length and have a highly conserved / V-terminal G-domain containing the p-loop region, which binds nucleotide, and the switch I and switch II regions which are important for regulatory and effector protein interactions. The C-terminal regions of the Ras proteins are more divergent and contain elements that regulate the association of Ras with the membrane including the conserved carboxyl terminal CAXX box motif necessary for post-translational prenylation modifications. On binding to GTP the switch I and switch II regions of Ras undergo a conformational change which enables its interaction with, and activation of, effector proteins to regulate downstream signalling pathways. The best characterised effector of Ras is the serine / threonine kinase Raf which regulates the activity of the mitogen-activated protein kinase (MAPK) pathway. The PI3K pathway is another important effector pathway down-stream of Ras with the pllO catalytic subunit of the class I phosphoinositide 3-kinases interacting with Ras. Other effectors of Ras including RaIGDS, Tiaml, PLC-e and Rassfl have been have also been described (see e.g. Cox, etal. Nature Reviews Drug Discovery, 2014, 13:828-851).

[0005] RAS mutations are frequently found in cancer and approximately 30% of all human cancers have a mutation in their KRAS, NRAS or HRAS genes. Oncogenic Ras is typically, but not exclusively, associated with mutations at glycine 12, glycine 13 or glutamine 61 of Ras. These residues are located at the active site of Ras and mutations impair intrinsic and / or GAP-catalysed GTPase activity favouring theformation of GTP bound Ras that drives activation of down-stream effector pathways. KRAS is the most frequently mutated RAS gene in cancer followed by NRAS and then HRAS. There are several tumour types that exhibit a high frequency of activating mutations in KRAS including pancreatic (~90% prevalence), colorectal (~40% prevalence) and non-small cell lung cancer (~30% prevalence). KRAS mutations are also found in other cancer types including multiple myeloma, uterine cancer, bile duct cancer, stomach cancer, bladder cancer, diffuse large B cell lymphoma, rhabdomyosarcoma, cutaneous squamous cell carcinoma, cervical cancer, testicular germ cell cancer and others.

[0006] The mutation frequencies across the RAS isoforms are distinct and different. G12 mutations comprise 83% of all KRAS mutations, followed by G13 mutations (14%), while Q61 mutations are relatively rare (co 2%). Q61, meanwhile, is the predominantly mutated hotspot in NRAS, followed by G12 and G13. HRAS displays an intermediate mutation pattern, with similar mutation frequencies found across G12, G13 and Q61. In addition, the mutation frequency within one RAS isoform can exhibit significant differences between cancer types.

[0007] Recently, the first Ras targeted therapy, sotorasib, was approved by the FDA. Sotorasib forms an irreversible covalent bond with the cysteine of KRas G12C mutant to hold the protein in its inactive form (the OFF state). The approval of sotorasib is the culmination of an extensive research efforts on the development of covalent inhibitors exploiting the presence of the nucleophilic thiol of the cysteine (present in place of glycine found in wild type protein) in KRas G12C. A second RasG12C inhibitor, adagarasib, was subsequently approved in December 2022. Targeting of other Ras mutants such as Ras G12D relies predominantly on non-covalent inhibitors and is currently a very active area of research. Whilst numerous compounds targeting Ras mutants are being progressed into the clinic, no further molecules have yet been approved for therapeutic use. Delivery of molecules with the requisite activity, therapeutic window and physicochemical properties that render them suitable for therapeutic use via oral administration at a reasonably low dose remains a particular challenge in the field of cancer therapy.

[0008] As noted above, KRas G12 mutations are the most commonly occurring KRas mutations with G12D mutations observed to be prevalent in pancreatic adenocarcinoma, colorectal cancer and non-small cell lung cancer and accounting for approximately 40%, 28% and 45%, respectively, of all KRas mutations in these tumour types. KRas G12D is therefore a significant target for cancer therapy, with potential application of Ras G12D inhibitors in, for example, the treatment of colorectal cancer. Despite much activity in recent years on the development of KRas G12D inhibitors as evidenced by the entry into clinical trials of molecules such as MRTX1133, ASP3082, GFH375 and AZD0022 there is a clear need for agents that can inhibit the growth of Ras G12D mutant tumours. To date no RasG12Dinhibitor has been approved for clinical use. It is an object of the present specification to provide Ras G12D inhibitors, in particular orally bioavailable Ras G12D inhibitors, that can be used in the treatment of cancer and in particular for the treatment of Ras G12D mutant cancers.

[0009] Accordingly, in a first aspect the present specification provides a compound of Formula (A), or a pharmaceutically acceptable salt thereof,

[0010]

[0011] wherein:

[0012] Y = S or O;

[0013] Raand Rbare independently selected from Me and Et; or

[0014] Raand Rbtogether form a group selected from CH2CH2, CH2CH2CH2or CH2CH2OCH2;

[0015] R1is Me or H;

[0016] R2is Me or H;

[0017] R3is F or Me;

[0018] R4is H or F;

[0019] R5is Cl, F, CCH, CF2H or Me; and

[0020] R6is a group selected from

[0021]

[0022] wherein * indicates the site of attachment of R6to the oxygen atom.

[0023] In accordance with this first aspect, the present specification provides a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0024]

[0025] wherein:

[0026] n = 0 and X is CH2; or

[0027] n = 1 and X is O;

[0028] Y = S or O;

[0029] R1is Me or H;

[0030] R2is Me or H;

[0031] R3is F or Me;

[0032] R4is H or F;

[0033] R5is Cl, F, CCH, CF2H or Me; and

[0034] R6is a group selected from

[0035]

[0036] wherein * indicates the site of attachment of R6to the oxygen atom.

[0037] In a further aspect there is provided a compound of Formula (A), or a pharmaceutical acceptable salt thereof, for use in therapy.

[0038] In a further aspect there is provided a compound of Formula (A), or a pharmaceutical acceptable salt thereof, for use in the treatment of cancer.

[0039] In a related aspect there is provided a compound of Formula (A) for use in the treatment of cancer, wherein the cancer is a Ras G12D mutant cancer.

[0040] In a related aspect there is provided a method of treatment of cancer comprising administration of an effective amount of a compound of Formula (A), or a pharmaceutical acceptable salt thereof, to a patient in need thereof. In such aspects the cancer may be a Ras G12D mutant cancer.In a further aspect there is provided a compound of Formula (A), or a pharmaceutical acceptable salt thereof, for use in the manufacture of a medicament, for example a medicament for the treatment of cancer. In such aspects the cancer may be a Ras G12D mutant cancer.

[0041] In a further aspect there is provided a kit comprising a pharmaceutical composition comprising a compound of Formula (A), or a pharmaceutical acceptable salt thereof, and instructions for its use in the treatment of cancer. In such aspects the cancer may be a Ras G12D mutant cancer.

[0042] In a further aspect there is provided a method of treatment comprising the steps of

[0043] i) analysing a sample obtained from a patient;

[0044] ii) determining that the patient has a cancer that has a Ras G12D mutation; and iii) administering a compound of Formula (A), or a pharmaceutically acceptable salt thereof, to the patient.

[0045] In a further aspect there is provided a process for producing a compound of Formula (I), or a pharmaceutically acceptable salt thereof.

[0046] As described herein below, compounds according to the specification inhibit the proliferation of Ras G12D cancer cells in vitro. Accordingly, compounds of Formula (A) are identified as Ras G12D inhibitors, i.e. compounds that can selectively inhibit the growth of cancers with a G12D mutation in Ras protein. Advantageously, the compounds of the specification are capable of binding and inhibiting KRAS G12D in its active ON (GTP-bound) state, in addition to its inactive OFF (GDP-bound) state. Data illustrating this activity profile are provided herein below.

[0047] The overall molecular profile of compounds of Formula (A) indicate their suitability as orally bioavailable agents. This potential has already translated into preclinical models as illustrated by the data incorporated herein below. Accordingly, compounds of Formula (A) are identified herein as orally bioavailable agents for the treatment of Ras G12D cancers.

[0048] In addition to disclosing the Ras G12D inhibitory properties of the compounds of Formula (A), the present specification also relates to processes for the manufacture of said compounds, to pharmaceutical compositions containing them, to methods of treatment comprising administering the said compounds to patients, for example humans patients, in need thereof, and to the use of compounds of Formula (A) for the manufacture of medicaments, for example for use in the treatment of a patient suffering from a hyperproliferative disease such as cancer.

[0049] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure is related. Forexample, the Concise Dictionary of Biomedicine and Molecular Biology, Juo, Pei-Show, 2nd ed., 2002, CRC Press; The Dictionary of Cell and Molecular Biology, 3rd ed., 1999, Academic Press; and the Oxford Dictionary of Biochemistry and Molecular Biology, Revised, 2000, Oxford University Press, provide one of skill with a general dictionary of many of the terms used in this disclosure.

[0050] So that the present specification may be more readily understood, certain terms are explicitly defined below. In addition, definitions are set forth as appropriate throughout the present specification. Units, prefixes, and symbols are denoted in their Systeme International de Unites (SI) accepted form. Numeric ranges are inclusive of the numbers defining the range.

[0051] The term "pharmaceutical composition" refers to a preparation which is in such form as to permit the biological activity of the active ingredient, and which contains no additional components which are unacceptably toxic to a subject to which the composition would be administered. Such compositions can be sterile. A pharmaceutical composition according to the present specification will comprise a compound of Formula (A), or a pharmaceutical acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

[0052] Terms such as "treating" or "treatment" or "to treat" or "alleviating" or "to alleviate" refer to both (1) therapeutic measures that cure, slow down, lessen symptoms of, and / or halt progression of a diagnosed pathologic condition or disorder and (2) prophylactic or preventative measures that prevent and / or slow the development of a targeted pathologic condition or disorder. Thus, those in need of treatment include those already with the disorder; those prone to have the disorder; and those in whom the disorder is to be prevented. In certain aspects, a subject is successfully "treated" for cancer according to the methods of the present disclosure if the patient shows, e.g., total, partial, or transient remission of a certain type of cancer.

[0053] The term "subject" refers to any animal (e.g. a mammal), including, but not limited to humans, nonhuman primates, rodents, and the like, which is to be the recipient of a particular treatment. Typically, the terms "subject" and "patient" are used interchangeably herein in reference to a human subject. References to a compound of Formula (A) herein encompasses the free base form of the compound of Formula (A), as well as pharmaceutically acceptable salts of a compound of Formula (A). In embodiments, reference to a compound of Formula (A) refers to the free base form of the compound of Formula (A).

[0054] Compounds of Formula (A) according to the specification feature a central, tricyclic, core comprising a quinazoline motif fused through carbons -4 and -5 (C-4 & C-5) to a 1,3-oxazine ring. Incorporation of a 1,3-oxazine motif, that may also be alternatively considered as a NRCH2O tether between carbonsthat are potent Ras G12D inhibitors and that are also surprisingly stable, as has been demonstrated for example by the integrity of the ring system in in vivo DMPK studies in which the molecules have been evaluated. Furthermore, the surprising advantages derived from incorporating the 1,3-oxazine motif can be appreciated when comparing the activity of the specification with prior art compounds that feature a 7-membered ring in which the N and O atoms are separated by an ethylene group, alternative viewed as a NRCH2CH2O tether between carbons 4 and 5 of the quinazoline (as shown on the right-hand side of the figure below), as the prior art compounds exhibit greatly reduced activity as Ras G12D inhibitors, with comparative Example 26 proving 10- to 20-fold less potent as a Ras G12D inhibitor than compounds such as Examples 6 and 12 featuring the shorter NRCH2O tether.

[0055]

[0056] In addition to a group R5selected from Cl, F, CCH, CF2H or Me that is attached to C-6 of the quinazoline and a fluoro substituent at C-8, the tricyclic core of the compounds of the specification is decorated with three further groups that deliver the desired balance of high RasG12D inhibitory activity and physicochemical properties that provide for potential of therapeutic application as an orally administered dosage form. Incorporation of a Cl substituent at R5has been observed to generally deliver the best overall profile.

[0057] Of the three remaining substituents on the tricyclic core not previously discussed, the group attached to the oxygen at C-2 of the quinazoline core is selected from the substituted pyrrolizidine and pyrrolidine motifs presented below.

[0058]

[0059] It has been found that the optimal stereochemistry of these group is as presented below.

[0060]

[0061] The group attached to C-7 of the quinazoline core is a bicyclic aromatic group selected from substituted benzothiophene or benzofuran. The bond from C-7 of the quinazoline connects to C-4 of the benzothiophene or benzofuran. In compounds according to the specification, the 6,5-bicyclic aromatic group is substituted with an amine and a cyano-group at C-2 and C-3, respectively, a fluoro or methyl group at C-5 of the 6-membered ring and, optionally, a further fluoro group at C-7 of the 6-membered ring.

[0062]

[0063] The final group required to deliver the optimal overall inhibitor compound profile is a basic side chain attached via a linker to the nitrogen of the 1,3-oxazine ring. We have found that the optimal linker in this position comprises a methylene (i.e. CH? group) and a second, tertiary, carbon terminating in a NR1R2group. This second, tertiary, carbon provides optimal activity with compounds featuring unsubstituted linkers proving far less active as Ras G12D inhibitors as can be seen from the relative activities of the gem-dimethyl compound, Example 17, and the unsubstituted comparative example, Example 16, herein below. The second, tertiary, carbon may be substituted with two methyl or ethyl groups, or may be a ring atom of a cyclopropyl, cyclobutyl (see Formula (II)) or tetrahydrofuran (see Formula (III)) ring. The terminal NR1R2group is NMe?, NHMe or NHz with compounds featuring a N, N-dimethyl group generally delivering optimal activity.

[0064]

[0065] Compounds of the specification have been shown to exhibit a number of promising pharmacological properties that indicate their promise as molecules with potential application in medicine, for example in the treatment of Ras G12D mutant cancers. As noted above, small structural changes can have significant impact on the overall properties of the molecule. For example, compounds of the specification in which n = 1 and X is O have reduced basicity compared to those compounds in which n = 0 and X is CH?. Such compounds exhibit improved pharmacokinetic properties and also tend toexhibit less off-target activity. Meanwhile, compounds of the specification in which n = 0 and X is CHj have been shown to exhibit excellent selectivity in inhibiting Ras G12D relative to Ras G12V mutant cell lines and have shown greater efficacy in some models.

[0066] As the skilled person will be aware from looking at their structures, certain compounds according to the specification can exist in discrete isomeric forms and reference to a compound of the specification includes reference to all of the possible isomeric forms, albeit it will be understood that the compounds with the highest biological activity are generally preferred. By means of illustration, two isomeric forms of the same compound (see substituent attached to C-2 of the quinazoline), described herein below as Examples 10 and 11, respectively, are provided by the present disclosure. Although each compound below is drawn as a specific isomer, it will be understood that the absolute stereochemistry of the chiral centres may not have been established, and the absolute configuration of isomer 1, that is characterised in the order of its isolation and spectral properties from the isolation technique(s) described, may in actuality be the configuration shown for isomer 2. The most active compounds can nonetheless be obtained and identified by the methods provided herein.

[0067]

[0068] For convenience, when a compound has a resolved stereocentre whose absolute stereochemistry has not been definitively established or assigned, the molecule is drawn in its chiral form and a label "or 1" (or, if more than one such centre is present, "or 2", "or 3" etc) is provided at the relevant chiral centre. The uncertainty as to the absolute stereochemistry is also reflected in the compound name by an asterisk (*) added in superscript following the stereochemical designator (R or S). The R* indicates that the relevant chiral centre is provided in a single stereochemistry, albeit the centre may have R or S chirality. To illustrate, this usage is found for Example 3a, whose chemical name includes the R* annotation: Example 3a: 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1).Furthermore, when considering the structures of each of " Isomer 1" and " Isomer 2" presented above, the skilled person will be aware that rotation around the single bond linking the benzothiophene group and the quinoline is restricted due to the steric clash between the substituents on the carbon atoms adjacent to (i.e. flanking) the carbon atoms that are connected by the biaryl bond. As a result, " Isomer 1" as presented above exists in two discrete and isolable rotational isomers, also termed in the art as atropisomers. The skilled person will therefore understand that the present disclosure includes the two possible rotational isomers of " Isomer 1" and although for ease of distinguishing the two possible rotational isomers an absolute stereochemical representation can be, and is, drawn out below, the absolute configuration of Rotational isomer 1, that is characterised in the order of its isolation and spectral properties from the isolation technique(s) described, may in actuality be the configuration shown for Rotational isomer 2. In line with the comments on isomers above, it will be understood that rotational isomers of compounds of the specification with the highest biological activity are generally preferred examples according to the specification. The skilled reader will understand that where the stereochemistry is not specified in the name or drawing the disclosure, then all possible isomers and rotational isomers are disclosed.

[0069]

[0070] Rotational isomer 2

[0071] As noted above, in a first embodiment the specification provides a compound of Formula (A), or a pharmaceutically acceptable salt thereof,

[0072]

[0073] wherein:

[0074] Y = S or O;

[0075] Raand Rbare independently selected from Me and Et; orRaand Rbtogether form a group selected from CH2CH2, CH2CH2CH2 or CH2CH2OCH2;

[0076] R1is Me or H;

[0077] R2is Me or H;

[0078] R3is F or Me;

[0079] R4is H or F;

[0080] R5is Cl, F, CCH, CF2H or Me; and

[0081] R6is a group selected from

[0082]

[0083] wherein * indicates the site of attachment of R6to the oxygen atom.

[0084] In embodiments, the compound of Formula (A) is a compound of Formula (I), or a pharmaceutically acceptable salt thereof,

[0085]

[0086] wherein:

[0087] n = 0 and X is CH2: or

[0088] n = 1 and X is O;

[0089] Y = S or O;

[0090] R1is Me or H;

[0091] R2is Me or H;

[0092] R3is F or Me;

[0093] R4is H or F;

[0094] R5is Cl, F, CCH, CF2H or Me; and

[0095] R6is a group selected from

[0096]

[0097] wherein * indicates the site of attachment of R6to the oxygen atom.

[0098] In embodiments the compound of Formula (I) is a compound of Formula (la) in which Y is S.

[0099]

[0100] In embodiments the compound of Formula (I) is a compound of Formula (lb) in which Y is O.

[0101]

[0102] In embodiments the compound of Formula (I), (la) or (lb) is a compound of Formula (Ic) in which R5is Cl.

[0103]

[0104] In embodiments the compound of Formula (I), (la), (lb) or (Ic) is a compound of Formula (Id) in which R1and R2are both Me.

[0105]

[0106] In embodiments the compound of Formula (I), (la), (lb), (Ic) or (Id) is a compound of Formula (le) in which R3is F.

[0107]

[0108] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id) or (le) is a compound of Formula (If) in which R4is H.

[0109]

[0110] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If) is a compound of Formula (Ig) in which R6is selected from:

[0111]

[0112] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), or (If) is a compound of Formula (Ih) in which R6is selected from:

[0113]

[0114] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If) is a compound of Formula (li) in which R6is selected from:

[0115]

[0116] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le) or (If) is a compound of Formula (Ij) in which R6is selected from

[0117]

[0118] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li) or (Ij) is a compound of Formula (II) in which n = 0 and X is CH2

[0119]

[0120] In embodiments the compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li) or (Ij) is a compound of Formula (III) in which n = 1 and X is O.

[0121]

[0122] In embodiments the compound of Formula (III) is a compound of Formula (Illa) having the stereochemistry presented below.

[0123]

[0124] In embodiments the compound of Formula (III) is a compound of Formula (lllb) having the stereochemistry presented below.

[0125]

[0126] In embodiments the compound of Formula (A) is selected from:

[0127] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0128] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0129] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0130] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0131] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0132] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0133] 2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0134] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0135] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0136] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0137] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0138] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0139] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2)

[0140] 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1)

[0141] 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0142] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0143] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0144] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0145] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1, isomer 1);

[0146] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2, isomer 1);

[0147] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1, isomer 2);

[0148] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2, isomer 2);

[0149] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0150] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0151] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 1);

[0152] 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 2);

[0153] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0154] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0155] 2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0156] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0157] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0158] 2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0159] 2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0160] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 1);

[0161] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 2);

[0162] 2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile;

[0163] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile;

[0164] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0165] 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0166] 2-Amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile (rotational isomer 1);

[0167] 2-Amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile (rotational isomer 2);

[0168] ): 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)rnethoxy)-3-(((S)-3-(methylamino)tetrahydrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0169] ): 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3- (((S)-3-(methylamino)tetrahydrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(3-(((S)-3-aminotetrahydrofuran-3-yl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);

[0170] 2-Arnino-4-(3-(((S)-3-aminotetrahydrofuran-3-yl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0171] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1, rotational isomer 1);

[0172] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1, rotational isomer 2);

[0173] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 2, rotational isomer 1);

[0174] 2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 2, rotational isomer 2);

[0175] 2-Amino-4-(3-((l-aminocyclobutyl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1); and

[0176] 2-Amino-4-(3-((l-aminocyclobutyl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);

[0177] or a pharmaceutically acceptable thereof.

[0178] In embodiments provided herein below, it will be understood that a reference to a compound of Formula (A) or Formula (I) below also includes a reference to a compound of Formula (I), (la), (lb), (Ic), (Id), (le), (If), (Ig), (Ih), (li), (Ij), (II) or (III) as defined above.

[0179] In embodiments of the present specification there are provided compounds of Formula (A) that selectively inhibit the growth of cancers that express a G12D mutation in Ras. Compounds that selectively inhibit the growth of cancers that express a G12D mutation in Ras can be identified in in vitro assays as described hereinbelow. In embodiments, the compounds of the specification inhibit the growth of Ras G12D mutant cancers at a lower concentration than they inhibit growth of other Ras mutant cancers, for example Ras G12V mutant cancers. In embodiments, the compounds of the specification do not significantly inhibit the growth of cells expressing wild type Ras protein, for example the concentration of a compound of Formula (A) required to inhibit the growth of wild-typeRas cancer cells is typically at least 20-fold higher than that required to inhibit Ras G12D mutant cancer cells.

[0180] In embodiments of the present specification there are provided pharmaceutical compositions that comprise a compound of the Formula (A) or a pharmaceutically acceptable salt thereof, in association with a pharmaceutically acceptable excipient, optionally further comprising one or more of the other stereoisomeric forms of the compound of Formula (A) or pharmaceutically acceptable salt thereof. The present specification is intended to include all isotopes of atoms occurring in the present compounds. Isotopes will be understood to include those atoms having the same atomic number but different mass numbers. For example, isotopes of hydrogen include tritium and deuterium. Isotopes of carbon include13C and14C. Isotopically labelled compounds of Formula (A) can generally be prepared by conventional techniques known to those skilled in the art or by processes analogous to those described in the accompanying Examples using appropriate isotopically labelled reagents in place of the non-labelled reagents previously employed.

[0181] A suitable pharmaceutically acceptable salt of a compound of the Formula (A) may be, for example, an acid addition salt. A suitable pharmaceutically acceptable salt of a compound of the Formula (A) may be, for example, an acid-addition salt of a compound of the Formula (A), for example an acidaddition salt with an inorganic or organic acid. The compounds of the specification may be provided as the free compound, i.e. in the non-salified state.

[0182] A further suitable pharmaceutically acceptable salt of a compound of the Formula (A) may be, for example, a salt formed within the human or animal body after administration of a compound of the Formula (A) to said human or animal body.

[0183] The compound of Formula (A), or a pharmaceutically acceptable salt thereof, will normally be administered via the oral route though parenteral, intravenous, intramuscular, subcutaneous or in other injectable ways, buccal, rectal, vaginal, transdermal and / or nasal route and / or via inhalation, in the form of pharmaceutical preparations comprising the active ingredient or a pharmaceutically acceptable salt or solvate thereof, or a solvate of such a salt, in a pharmaceutically acceptable dosage form may be possible. Depending upon the disorder and patient to be treated and the route of administration, the compositions may be administered at varying doses, for example in an oral dose of from 0.1 mg to 2,000 mg.

[0184] The pharmaceutical formulations of the compound of Formula (A) described above may be prepared e.g. for parenteral, subcutaneous, intramuscular or intravenous administration.The pharmaceutical formulations of the compound of Formula (A) described above may conveniently be administered in unit dosage form and may be prepared by any of the methods well-known in the pharmaceutical art, for example as described in Remington's Pharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, PA., (1985).

[0185] Pharmaceutical formulations suitable for oral administration may comprise one or more physiologically compatible carriers and / or excipients and may be in solid or liquid form. Tablets and capsules may be prepared with binding agents; fillers; lubricants; and surfactants. Liquid compositions may contain conventional additives such as suspending agents; emulsifying agents; and preservatives Liquid compositions may be encapsulated in, for example, gelatin to provide a unit dosage form. Solid oral dosage forms include tablets, two-piece hard shell capsules and soft elastic gelatin (SEG) capsules. An exemplary oral composition would comprise a compound of Formula (A) and at least one pharmaceutically acceptable excipient filled into a two-piece hard shell capsule or a soft elastic gelatin (SEG) capsule.

[0186] According to a further embodiment there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use as a medicament. The medicament may be for use in the treatment of a subject, for example a warm-blooded animal, for example a human subject.

[0187] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in the production of an antiproliferative effect in a warm-blooded animal such as man.

[0188] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and / or treatment of solid tumour disease. According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for the production of an antiproliferative effect in a warm-blooded animal such as man.

[0189] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the production of an anti-proliferative effect in a warm-blooded animal such as man.

[0190] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of amedicament for use in a warm-blooded animal such as man as an anti-invasive agent in the containment and / or treatment of solid tumour disease.

[0191] According to a further embodiment, there is provided a method for producing an anti-proliferative effect in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0192] In this specification, unless otherwise stated, the phrase "effective amount" means an amount of a compound or composition which is sufficient enough to significantly and positively modify the symptoms and / or conditions to be treated (e.g., provide a positive clinical response). The effective amount of an active ingredient for use in a pharmaceutical composition will vary with the particular condition being treated, the severity of the condition, the duration of the treatment, the nature of concurrent therapy, the particular active ingredient(s) being employed, the particular pharmaceutically acceptable excipient(s) / carrier(s) utilized, and like factors within the knowledge and expertise of the attending physician. The effective amount will generally be in the range of 0.1 mg to 2,000 mg.

[0193] According to a further embodiment, there is provided a method for producing an anti-invasive effect by the containment and / or treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore. According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of cancer in a warm-blooded animal such as man.

[0194] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in the treatment of cancer in a warm-blooded animal such as man.

[0195] According to a further embodiment, there is provided a method for the treatment of cancer in a warmblooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof. According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, for use in the treatment of solid tumour disease in a warmblooded animal such as man.According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of solid tumour disease in a warm-blooded animal such as man.

[0196] According to a further embodiment, there is provided a method for the treatment of solid tumour disease in a warm-blooded animal, such as man, in need of such treatment which comprises administering to said animal an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0197] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, for use in the treatment of tumours which are sensitive to inhibition of G12D mutant Ras.

[0198] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the prevention or treatment of those tumours which are sensitive to inhibition of G12D mutant Ras. According to a further embodiment, there is provided a method for the prevention or treatment of those tumours which are sensitive to inhibition of G12D mutant Ras, which comprises administering to a patient in need thereof an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore.

[0199] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore for use in providing an inhibitory effect on G12D mutant Ras.

[0200] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore in the manufacture of a medicament for use in providing an inhibitory effect on G12D mutant Ras.

[0201] According to a further embodiment, there is also provided a method for providing an inhibitory effect on G12D mutant RAS which comprises administering an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, to a patient in need thereof.

[0202] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in providing a selective inhibitory effect on G12D mutant Ras.According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in providing a selective inhibitory effect on G12D mutant Ras.

[0203] According to a further embodiment, there is also provided a method for providing a selective inhibitory effect on G12D mutant Ras which comprises administering an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0204] In embodiments of the specification relating to the use of a compound of Formula (A) for the treatment of cancer or for the manufacture of a medicine for treatment of cancer, the G12D mutation may be present in KRas, NRas or HRas. Likewise, in embodiments of the specification relating to methods of treatment of cancer, the G12D mutation may be present in KRas, NRas or HRas. In such embodiments, the use of the compound for treatment or in a method of treatment may be indicated following analysis of a sample obtained a patient that indicates that the patient has a cancer that express Ras G12D mutant protein.

[0205] Described herein are compounds of Formula (A) that can inhibit the proliferation of cancers cells that express G12D mutant Ras protein. In cell based assays, the compounds of the present specification are shown to be potent and selective inhibitors of cells that express G12D mutant protein and the compounds of the specification may therefore be useful for the treatment of disorders mediated by KRas, NRas or HRas G12D mutations, in particular in the treatment of cancers expressing G12D mutated KRas, NRas or HRas proteins, such as a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer.

[0206] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of disorders mediated by KRas, NRas or HRas G12D mutations, for example a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer.

[0207] According to a further embodiment, there is provided a method for treating disorders mediated by KRas, NRas or HRas G12D mutations, that comprises administering an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, to a patient in need thereof, for example a patient having a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer.

[0208] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of amedicament for use in the treatment of disorders mediated by KRas, NRas or HRas G12D mutations, for example where the disorder is a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer.

[0209] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer, wherein said cancer has been identified as expressing G12D mutant Ras.

[0210] According to a further embodiment, there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, for use in the treatment of colorectal cancer, for example a colorectal cancer expressing Ras G12D.

[0211] According to a further embodiment, there is provided a method for treating a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer, for example wherein the cancer has been identified as expressing Ras G12D, which comprises administering an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore to a patient in need thereof.

[0212] According to a further embodiment, there is provided a method for treating colorectal cancer, for example a colorectal cancer expressing Ras G12D, which comprises administering an effective amount of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0213] According to a further embodiment, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of a cancer selected from colorectal, pancreatic, NSCLC, lung adenocarcinoma, ovarian, gastric and prostate cancer, for example wherein the cancer has been identified as expressing Ras G12D.

[0214] According to a further aspect of the specification, there is provided the use of a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, as defined hereinbefore, in the manufacture of a medicament for use in the treatment of colorectal cancer, for example a colorectal cancer expressing Ras G12D.

[0215] The anti-cancer treatment defined herein may be applied as a sole therapy or may involve, in addition to the compounds of the specification, conventional surgery or radiotherapy or chemotherapy.Accordingly, in one embodiment, there is provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, and an additional anti-tumour substance for the conjoint treatment of cancer. According to an embodiment of the specification there is provided a combination suitable for use in the treatment of cancer comprising a compound of the Formula (A) or a pharmaceutically acceptable salt thereof and another anti-tumour agent. In embodiments wherein the compound of Formula (A) is used in combination with a second anti-tumour agent, the compounds may be administered in a separate, simultaneous or sequential manner to achieve the optimal efficacy and tolerability.

[0216] In a further embodiment of the specification there is provided a compound of the Formula (A), or a pharmaceutically acceptable salt thereof, for use in combination with another anti-tumour agent. In a related embodiment there is provided a method of treatment comprising administering a compound of Formula (A) in combination with another anti-tumour agent to a patient in need thereof, for example a patient suffering from a cancer expressing G12D mutant Ras.

[0217] Although the compounds of the Formula (A) are primarily of value as therapeutic agents for use in warm-blooded animals (including man), they are also useful whenever it is required to inhibit G12D mutant Ras. Thus, they are useful as pharmacological standards for use in the development of new biological tests and in the search for new pharmacological agents.

[0218] Another embodiment is based on identifying a link between the G12D KRas, HRas or NRas mutation status of a patient and potential susceptibility to treatment with a compound of Formula (A). A Ras inhibitor, such as a compound of Formula (A), may then advantageously be used to treat patients with G12D KRas, HRas or NRas mutations who may be resistant to other therapies. This therefore provides opportunities, methods and tools for selecting patients for treatment with a compound of Formula (A), particularly cancer patients. The selection is based on whether the tumour cells to be treated possess wild-type or G12D mutant KRAS, HRAS or NRAS gene. The G12D KRAS, HRAS or NRAS gene status could therefore be used as a biomarker to indicate that selecting treatment with a compound of Formula (A) may be advantageous.

[0219] According to one embodiment, there is provided a method for selecting a patient for treatment with a compound of Formula (A), the method comprising providing a tumour cell-containing sample or a blood sample from a patient; determining whether the RAS gene in the patient's tumour cellcontaining sample or circulating tumour DNA (ctDNA) in the patient's blood sample encodes for wildtype (glycine at position 12) or mutant (aspartic acid at position 12) KRas, HRas or NRas protein; and selecting a patient for treatment with a compound of Formula (A) if the RAS gene in found to encode for G12D mutant Ras protein.The method may include or exclude the actual patient sample isolation step. Thus, according to one embodiment there is provided a method for selecting a patient for treatment with a compound of Formula (A), the method comprising determining whether the RAS gene in a sample previously isolated from the patient encodes for wild-type (glycine at position 12) or mutant (aspartic acid at position 12) KRas, HRas or NRas protein; and selecting a patient for treatment with a compound of Formula (A) if the RAS gene in the sample is found to encode for G12D mutant Ras.

[0220] In embodiments, the patient is selected for treatment with a compound of Formula (A) if the tumour DNA or ctDNA is identified as having a KRAS gene that encodes for G12D mutant Ras.

[0221] In embodiments, the patient is selected for treatment with a compound of Formula (A) if the tumour DNA or ctDNA is identified as having a HRAS gene that encodes for G12D mutant Ras.

[0222] In embodiments, the patient is selected for treatment with a compound of Formula (A) if the tumour DNA or ctDNA is identified as having a NRAS gene that encodes for G12D mutant Ras.

[0223] According to another embodiment, there is provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G12D mutant KRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as harbours a G12D mutant KRAS gene may be made on the basis of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G12D mutant protein, the presence of G12D mutant KRas protein, or any other suitable method to identify the genotype leading to expression of KRas G12D mutant protein.

[0224] According to another embodiment, there is provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G12D mutant HRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as harbours a G12D mutant HRAS gene may be made on the basis of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G12D mutant protein, the presence of G12D mutant HRas protein, or any other suitable method to identify the genotype leading to expression of HRas G12D mutant protein.

[0225] According to another embodiment, there is provided a compound of Formula (A), or a pharmaceutically acceptable salt thereof, for use in treating a patient with a cancer that has been identified as harbouring a G12D mutant NRAS gene, optionally wherein the identification is made on the basis of analysing a tumour biopsy or a blood sample. The identification of whether the cancer as

[0226] 1harbours a G12D mutant NRAS gene may be made on the basis of identifying the presence of a genetic mutation to the gene, the presence of mRNA encoding the G12D mutant protein, the presence of G12D mutant NRas protein, or any other suitable method to identify the genotype leading to expression of NRas G12D mutant protein.

[0227] According to another embodiment, there is provided a method of treatment of a cancerthat expresses G12D mutant KRas, HRas or NRas protein comprising administering an effective amount of a compound of Formula (A), or a pharmaceutically acceptable salt thereof, to a patient in need thereof. According to another embodiment, there is provided a pharmaceutical composition comprising a compound of Formula (A) for use in the treatment of a cancer that has been identified as harbouring a G12D mutant KRAS, HRAS or NRAS gene.

[0228] According to another embodiment, there is provided a kit comprising a pharmaceutical composition comprising a compound of Formula (A) and instructions for its use in the treatment of a cancer that has been identified as harbouring a G12D mutant KRAS, HRAS or NRAS gene.

[0229] It will be appreciated that the following examples are provided so that the nature of the invention may be fully understood. It will also be appreciated that the following examples are not intended to limit the scope of the description in any way.

[0230] Examples

[0231] The following abbreviations have been used:

[0232] CPhos 2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino)biphenyl

[0233] CPhos Pd G3 [(2-Dicyclohexylphosphino-2',6'-bis(N,N-dimethylamino) -1,1'-biphenyl)-2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate

[0234] DAST (diethylamino)sulfur trifluoride

[0235] DCM dichloromethane

[0236] d.e. diastereomeric excess

[0237] DIPEA diisopropylethylamine

[0238] DMA N,N-dimethylacetamide

[0239] DMF N,N-dimethylformamide

[0240] DMSO dimethylsulfoxide

[0241] DPPA diphenyl phosphoryl azide

[0242] e.e. enantiomeric excess

[0243] EtOAc ethyl acetate

[0244] EtOH ethanolHATU 1-[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxid hexafluorophosphate

[0245] HCCP Hexachlorocyclotriphosphazene

[0246] HCI hydrochloric acid

[0247] HPLC high performance liquid chromatography

[0248] MeCN acetonitrile

[0249] MeOH methanol

[0250] 2-MeTHF 2-Methyltetrahydrofuran

[0251] NMR nuclear magnetic resonance

[0252] IPA isopropanol

[0253] LDA lithium diisopropylamide

[0254] PE petroleum ether

[0255] pRSK / p90RSK 90 kDa ribosomal S6 kinase 1

[0256] RuPhos Pd G3 (2-Dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate

[0257] RT room temperature

[0258] scCO₂ supercritical CO₂

[0259] SPR surface plasmon resonance

[0260] TBME tert-butyl methyl ether

[0261] TEA triethylamine

[0262] TFA trifluoroacetic acid

[0263] THF tetrahydrofuran

[0264] tR retention time

[0265] XPhos Pd G3 (2-Dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)] palladium(II) methanesulfonate

[0266] Compounds are otherwise referred to by their IUPAC names or were named using PerkinElmer ChemDraw (©1998-2003 PerkinElmer Informatics, Inc., Professional 64 bit, version 22.2.0.3300).

[0267] The compounds described in this specification are further illustrated in the following Examples. The compounds were named using Chemdraw version 22.2.0.3300. These Examples are given by way of illustration only and are non-limiting. In general:

[0268] (i) operations were carried out at ambient temperature, i.e. in the range 17 to 25 °C and under an atmosphere of an inert gas such as nitrogen unless otherwise stated;(ii) evaporations were carried out by rotary evaporation or utilising Genevac equipment or Biotage vlO evaporator in vacuo and work up procedures were carried out after removal of residual solids by filtration;

[0269] (iii) flash chromatography purifications (FCC) were performed on an automated Teledyne Isco CombiFlash® Rf or Teledyne Isco CombiFlash® Companion® using prepacked RediSep Rf Gold™ Silica Columns (20-40 pm, spherical particles), GraceResolv™ Cartridges (Davisil® silica) or Silicycle cartridges (40 - 63 pm) or other conditions as specified;

[0270] (iv) C18-flash chromatography was carried out on CHEETAH ® or CHEETAH® II Flash Purification Systems or BRIX 2802 using Agela: Claricep screw-on flash C18 column 100A (20-35 pm, spherical particles) with maximum pressure 180 psi;

[0271] (v) preparative reverse phase HPLC was performed on an Agilent 1290 Infinity II Preparative system equipped with a SQ MS detector (Multimode ESI / APCI source), with a Waters CSH C18 OBD column (5 microns silica, 30 mm diameter, 100 mm length, flow rate of 50 mL / min) using decreasingly polar mixtures of water (containing 0.1— 0.3% aqueous ammonium) or water (containing 0.1% formic acid) and acetonitrile as eluents. Chiral HPLC conditions are specified for each purification below. Preparative SFC purification was performed on either a Sepiatec P100 SFC system or Waters Prep 100 SFC system equipped with QDa MS detector, using the chromatographic conditions as detailed in corresponding experimental data. Chiral SFC conditions are specified for each purification below. (vi) yields, where present, are not necessarily the maximum attainable;

[0272] (vii) in general, the structures of end products of the Formula I were confirmed by nuclear magnetic resonance (NMR) spectroscopy; NMR chemical shift values were measured on the delta scale [proton magnetic resonance spectra were determined using a Bruker Avance 500 (500 MHz) or Bruker Avance400 (400 MHz) or Bruker Avance 300 (300 MHz) instrument; measurements were taken at ambient temperature unless otherwise specified; the following abbreviations have been used: s, singlet; d, doublet; t, triplet; q, quartet; m, multiplet; dd, doublet of doublets; ddd, doublet of doublet of doublet; dt, doublet of triplets; bs, broad signal;

[0273] (viii) in general, end products of the Formula I were also characterized by mass spectrometry following liquid chromatography (LCMS or UPLC); reverse-phase C18 silica was used with a flow rate of 1 mL / min and detection was by Electrospray Mass Spectrometry and by UV absorbance recording a wavelength range of 220-320 nm. Analytical UPLC was performed on CSH C18 reverse-phase silica, using a Waters Acquity UPLC CSH C18 column with dimensions 2.1 x 50 mm and particle size 1.7 micron) Gradient analysis was employed using decreasingly polar mixtures as eluent, for example decreasingly polar mixtures of water (containing 0.1% formic acid or 0.1% ammonia) as solvent A and acetonitrile as solvent B. A typical 2 minute analytical UPLC method would employ a solvent gradientover 1.3 min, at approximately 1 mL / min, from a 97:3 mixture of solvents A and B respectively to a 3:97 mixture of solvents A and B. The reported molecular ion corresponds to the [M+H]+ unless otherwise specified; for molecules with multiple isotopic patterns (Br, Cl etc.) the reported value is the one obtained for the lowest isotope mass unless otherwise specified;

[0274] (ix) ion exchange purification was generally performed using a SCX-2 (Biotage, Propylsulfonic acid functionalized silica. Manufactured using a trifunctional silane. Non end-capped) cartridge;

[0275] (x) intermediate purity was assessed by thin layer chromatographic, mass spectral, HPLC (high performance liquid chromatography) and / or NMR analysis;

[0276] (xi) Unless otherwise stated, molecular sieves used in preparations were 4A in size;

[0277] (xii) Electrolysis was carried out in an IKA ElectraSyn 2.0 (https: / / www.ika.com / en / Products-

[0278]

[0279] ) using RuO2 / Ti electrodes.

[0280] Intermediates

[0281] tert-Butyl (5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-yl) carbamate (lnt-1)

[0282]

[0283] Step 1: Methyl 4-bromo-5-methylbenzofuran-2-carboxylate

[0284] Br

[0285]

[0286] To a solution of 2-bromo-6-fluoro-3-methylbenzaldehyde (5.00 g, 23.04 mmol) and methyl 2-hydroxyacetate (8.9 mL, 115.19 mmol) in anhydrous THF (70 mL) under nitrogen atmosphere at 0 °C was added sodium hydride (60% dispersion in mineral oil) (1.84 g, 46.08 mmol) in two portions and the resulting mixture was stirred at 70 °C for 2 hours. The reaction was cooled to RT and quenched with water and saturated NH4CI solution. The aqueous phase was extracted with EtOAc (x3) and the combined organic extracts were washed with brine. The organic phase was passed through a phase separator and the solvent was removed under reduced pressure to give the crude methyl 4-bromo-5-methylbenzofuran-2-carboxylate (7.18 g) as a yellow solid, which was used in the next step withoutfurther purification.^ NMR (500 MHz, DMSO-d6, 27 °C) 2.45 (3H, s), 3.90 (3H, s), 7.51 (1H, dd), 7.54 (1H, d), 7.67 (1H, dd).

[0287] Step 2: 4-Bromo-5-methylbenzofuran-2-carboxylic acid

[0288]

[0289] To a suspension of methyl 4-bromo-5-methylbenzofuran-2-carboxylate (6.20 g, 23.04 mmol) in THF (30 mL), MeOH (30 mL) and water (30 mL) was added LiOH (1.66 g, 69.12 mmol) at RT. The resulting suspension was stirred at RT for 2 hours. The solvent was partially removed under reduced pressure and the resulting orange suspension was acidified with 2 M HCI (aq.) (40 mL). The mixture was cooled to 0 °C for 10 min and the precipitate was collected by filtration and washed with water (x2) and heptane (x2). The resulting yellow solid was dried under vacuum at 40 °C overnight, then suspended in dry toluene (2x) and the solvent was removed under reduced pressure to afford 4-bromo-5-methylbenzofuran-2-carboxylic acid (4.78 g, 81 %) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.45 (3H, s), 7.45 (1H, d), 7.49 (1H, dd), 7.66 (1H, dd). One exchangeable proton not observed, m / z (ES-), [M-H]' = 253; 255.

[0290] Step 3: tert-Butyl (4-bromo-5-methylbenzofuran-2-yl)carbamate

[0291] Br

[0292] Boc

[0293] N'H

[0294]

[0295] 4-Bromo-5-methylbenzofuran-2-carboxylic acid (3.66 g, 14.38 mmol) was stirred in anhydrous toluene (40 mL) as a suspension at RT and under nitrogen. TEA (3.0 mL, 21.58 mmol) was added followed by DPPA (3.4 mL, 15.10 mmol) and anhydrous 2-methylpropan-2-ol (2.8 mL, 28.77 mmol) and the reaction was heated to 100 °C for 1 h behind a blast shield. The mixture was allowed to cool to RT. The reaction mixture was loaded directly onto a silica cartridge then the crude product was purified by flash silica chromatography, elution gradient 0 to 20% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl (4-bromo-5-methylbenzofuran-2-yl)carbamate (3.08 g, 66%) as a yellow solid.1H NMR (500 MHz, CDCI3, 1 °C) 1.52 - 1.62 (9H, m), 2.44 (3H, s), 6.50 (1H, s), 6.91 (1H, s), 7.00 (1H, dd), 7.14 (1H, dd). m / z (ES-), [M-H]’ = 324; 326.

[0296] Step 4: tert-Butyl (5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-vDcarbamate (lnt-1)

[0297]

[0298] tert-Butyl (4-bromo-5-methylbenzofuran-2-yl)carbamate (1.37 g, 4.20 mmol), bis(pinacolato)diboron (2.13 g, 8.40 mmol), and potassium pivalate (1.77 g, 12.60 mmol) were added to a flask and put under nitrogen atmosphere. Anhydrous 2-MeTHF (40 mL) was added and the mixture was sparged under a flow of nitrogen for 15 minutes. Bis(triphenylphosphine)palladium(ll) dichloride (0.15 g, 0.21 mmol) was added to the reaction mixture and was then degassed (4 vacuum / nitrogen cycles). The mixture was stirred at 80 °C for 5 hours. The reaction was cooled and passed through a small pad of Celite. The filter pad was washed with EtOAc (100 mL) and then concentrated in vacuo. The crude product was purified by flash silica chromatography (dry loaded), elution gradient 0 to 20% EtOAc in n-heptane. Pure fractions were evaporated to dryness to afford tert-butyl (5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-yl)carbamate (lnt-1) (1.35 g, 86%) as a beige solid.1H NMR (500 MHz, DMSO-dg, 1 °C) 1.33 (12H, s), 1.50 (9H, s), 3.17 (3H, s), 6.51 - 6.62 (1H, m), 6.91 (1H, dd), 7.33 (1H, dd). One proton not observed, m / z (ES-), [M-H]-= 372.

[0299] tert-Butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2)

[0300] it v

[0301]

[0302] lnt-2

[0303] l,l'-Bis(diphenylphosphino)ferrocenedichloropalladium (II) dichloromethane adduct (5.90 g, 7.22 mmol) was added to potassium acetate (17.72 g, 180.52 mmol), bis(pinacolato)diboron (45.80 g, 180.52 mmol) and tert-butyl (4-bromo-5-fluorobenzo[b]thiophen-2-yl)carbamate (CAS no: 2891597-49-0) (25 g, 72.21 mmol) in 1,4-dioxane (450 mL) at RT under nitrogen. The resulting mixture was stirred at 100 °C for 3 hours. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 15% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (24 g, 85%) as a white solid.1H NMR (300 MHz, DMSO-dg, 24 °C) 6 1.35 (12H, s), 1.50 (9H, s), 6.93 (1H, dd), 7.28 (1H, d), 7.90 (1H, dd), 10.83 (1H, s). m / z (ES+), [M+H]+= 394.tert-Butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3)

[0304]

[0305] lnt-3

[0306] Step 1: (3-Bromo-2,5,6-trifluorophenyl)trimethylsilane

[0307]

[0308] 2 M LDA in THF (185 mL, 369.70 mmol) was cooled to -78 °C then l-bromo-2,4,5-trifluorobenzene (CAS No: 327-52-6) (60 g, 33.3 mL, 284.39 mmol) in THF (900 mL) was added dropwise over 45 minutes under nitrogen. The resulting mixture was stirred at -78 °C for 1 hour. Trimethylchlorosilane (94 mL, 739.40 mmol) was added dropwise, and the resulting mixture was stirred at -78 °C for an extra 30 minutes, then gradually warmed to RT for 30 minutes. The mixture was poured into ice water (1 L) and extracted with EtOAc (2 x 1 L). The combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution 100% petroleum ether. Pure fractions were evaporated to dryness to afford (3-bromo-2,5,6-trifluorophenyl)trimethylsilane (80 g, 99 %) as a colourless liquid.XH NMR (300 MHz, DMSO-dg, 24 °C) 60.38 (9H, s), 7.97-8.15 (1H, m).

[0309] Step 2: 2-Bromo-3,5,6-trifluorobenzaldehyde

[0310]

[0311] 2 M LDA in THF (109 mL, 217.54 mmol) was cooled to -78 °C and then (3-bromo-2,5,6-trifluorophenyl)trimethylsilane (80 g, 197.77 mmol) in THF (800 mL) was added dropwise over 20 minutes under nitrogen. The resulting mixture was stirred at -78 °C for 1 hour. DMF (20 mL, 257.1 mmol) was added dropwise, and the mixture was stirred at -78 °C for a further 10 minutes. Acetic acid (40 mL) and water (1.2 L) were added and the mixture was gradually warmed to RT and then stirredfor 2 hours. The reaction mixture was extracted with EtOAc (2 x 1 L) and the combined organics were washed with 2 M HCI (aq.) (400 mL), water (1.2 L), and saturated brine (400 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography elution gradient 0 to 5% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford 2-bromo-3,5,6-trifluorobenzaldehyde (40 g, 85%) as a pale yellow liquid.XH NMR (300 MHz, DMSO-dg, 24 °C) 68.09-8.26 (1H, m), 10.16 (1H, s).

[0312] Step 3: Methyl 4-bromo-5,7-difluorobenzo(b]thiophene-2-carboxylate

[0313] F

[0314]

[0315] Potassium carbonate (32.4 g, 234.32 mmol) was added to 2-bromo-3,5,6-trifluorobenzaldehyde (20 g, 66.95 mmol) in DMF (200 mL) at RT under nitrogen. Methyl 2-mercaptoacetate (6.6 mL, 73.64 mmol) was then added dropwise at 0 °C under nitrogen. The resulting mixture was stirred at RT for 18 hours. The reaction mixture was poured into ice water (600 mL), the resulting precipitate was collected by filtration, washed with water (100 mL), and dried under vacuum to afford methyl 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylate (20 g, 97 %) as a yellow solid, which was used in the next step without further purification.1H NMR (300 MHz, DMSO-d6, 23 °C) 63.94 (3H, s), 7.82 (1H, t), 8.04 (1H, d).

[0316] Step 4: 4-Bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid

[0317] F

[0318]

[0319] A solution of LiOH (3.49 g, 145.88 mmol) in water (80 mL) was added to methyl 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylate (20 g, 65.14 mmol) in THF (160 mL) and MeOH (40 mL) at RT. The resulting mixture was stirred at RT for 90 minutes. The reaction mixture was acidified with 2M HCI (aq.). THF and MeOH were removed under reduced pressure. The residue was diluted with water (200 mL). The resulting precipitate was filtered and dried to afford 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid (15 g, 98%) as a yellow solid, which was used for the next step without further purification.XH NMR (300 MHz, DMSO-d6, 24 °C) 67.75 (1H, t), 7.4 (1H, d), 14.12 (1H, s). m / z (ES-), [M-H]- = 291; 293.

[0320] Step 4: tert-Butyl (4-bromo-5,7-difluorobenzo(b]thiophen-2-yl)carbamate

[0321]

[0322] TEA (3.6 mL, 25.59 mmol) was added to a suspension of 4-bromo-5,7-difluorobenzo[b]thiophene-2-carboxylic acid (5.00 g, 17.06 mmol) in toluene (50 mL) at RT and under nitrogen. DPPA (5.5 mL, 25.59 mmol) was added followed by t-BuOH (4.9 mL, 51.18 mmol) and the reaction was heated to 100 °C for 6 hours behind a blast shield. After cooling to RT, the mixture was diluted with EtOAc (200 mL) then washed with saturated brine (200 mL). The organic extract was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (5.7 g, 92%) as a yellow solid.1H NMR (300 MHz, DMSO-d6, 23 °C) 6 1.52 (9H, s), 6.85 (1H, d), 7.32 (1H, t), 11.27 (1H, s). m / z (ES-), [M-H]- = 362; 364.

[0323] Step 5: tert-Butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-vDcarbamate (lnt-3)

[0324]

[0325] Bis(diphenylphosphino)ferrocene]dichloropalladium(ll), complex with dichloromethane (0.36 g, 0.44 mmol) was added to tert-butyl (4-bromo-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (1.60 g, 4.39 mmol), bis(pinacolato)diboron (1.67 g, 6.59 mmol) and potassium acetate (1.29 g, 13.18 mmol) in dioxane (30 mL) at RT under nitrogen. The resulting mixture was stirred at 100 °C for 4 hours. After cooling to RT, the solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 40% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3) (1.2 g, 66%) as a yellow solid.1H NMR (300 MHz, DMSO-d6, 24 °C) 6 1.34 (12H, s), 1.51 (9H, s), 7.01 (1H, t), 7.36 (1H, d), 11.07 (1H, s). m / z (ES+), [M+H]+ = 412.

[0326] ( / ?*)-3-((8-Bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethyltetrahydrofuran-3-amine (lnt-4)

[0327]

[0328] ISOMER 1 ISOMER 2

[0329] lnt-4

[0330] Step 1: 5-(Benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol

[0331]

[0332] Lithium 2-methylpropan-2-olate (128.53 g, 1.61 mol) was added to 7-bromo-2,6-dichloro-5,8-difluoro-4(3H)-quinazolinone (CAS No.: 2820536-73-8) (106 g, 0.32 mol) and benzyl alcohol (34.9 mL, 0.34 mol) in MeCN (2 L) at 0 °C. The resulting mixture was stirred at 70 °C for 2 hours. The reaction mixture was slowly poured onto ice (10 L) then 12 M HCI (aq.) was added until pH reached 4. The resulting precipitate was collected by filtration, washed with water (750 mL), and dried under vacuum. The crude product was triturated with petroleum ether: EtOAc (5:1, 1 L) and the solid was collected by filtration and then dried under vacuum to give 5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (116 g, 86%) as a pale yellow solid.1H NMR (300 MHz, DMSO-dg, 23 °C) 6 4.98 (2H, s), 7.38-7.44 (3H, m), 7.56-7.62 (2H, m). One proton not observed, m / z (ES-), [M-H]’ = 415; 417; 419.

[0333] Step 2: / ? S-5-(Benzyloxy)-7-bromo-2,6-dichloro- / \ / -((3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-8-fluoroquinazolin-4-amine

[0334]

[0335] DIPEA (381 mL, 2.18 mol) was added to 5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (114 g, 0.27 mol) and HCCP (142 g, 0.41 mol) in MeCN (2.3 L) at RT. A solution of (+ / -)-3-(aminomethyl)- / V, / V-dimethyltetrahydrofuran-3-amine (CAS No: 161500-02-3) (47.20 g, 0.33 mol) in MeCN (140 mL) was added slowly after stirring the reaction for 30 minutes in an ice bath. The resulting mixture was stirred at RT for 30 minutes. The reaction mixture was poured into ice (10 L), the precipitate was collected by filtration, washed with water (1 L), and dried under vacuum. The crude product was purified by flash silica chromatography (done in two batches), elution gradient 0 to 50% DCM: EtOAc=l:l in petroleum ether. Pure fractions were evaporated to dryness. The resulting crude solid was triturated with petroleum ether: EtOAc=5:l (500 mL) at 50 °C for 2 hours. The mixture was cooled to RT then the resulting solid was collected by filtration, washed with TBME (100 mL) and dried under vacuum to give (RS)-5-(benzyloxy)-7-bromo-2,6-dichloro- / V-((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-8-fluoroquinazolin-4-amine (64 g, 43%) as a pale yellow solid.1H NMR (300 MHz, CDCU, 23 °C) 6 1.49-1.58 (1H, m), 1.83-2.10 (7H, m), 3.39 (1H, d), 3.58-3.84 (4H, m), 3.89-3.96 (1H, m), 5.1-5.27 (2H, m), 7.33-7.62 (5H, m), 8.75 (1H, s). m / z (ES+), [M+H]+ = 543; 545; 547.

[0336] Step 3: (ffS)-7-Bromo-2,6-dichloro-4-(((3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)amino)-8-

[0337]

[0338] fluoroquinazolin-5-ol

[0339]

[0340] TFA (209 mL, 2.71 mol) was added to an ice-cooled solution of (RS)-5-(benzyloxy)-7-bromo-2,6-dichloro-N-((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-8-fluoroquinazolin-4-amine (59 g, 0.11 mol) in DCM (209 mL), then trifluoromethanesulfonic acid (11.5 mL, 0.13 mol) was added slowly. The resulting mixture was stirred at RT for 1 hour. Additional trifluoromethanesulfonic acid (14.4 mL, 0.16 mol) was added dropwise to the reaction mixture. The resulting mixture was stirred at RT for an additional 1 hour. Volatiles were removed under reduced pressure. The crude product was triturated with TBME (1 L) to afford a solid. The solid was split into 3 equal batches and purified by SCX chromatography, washed with DCM then MeOH. The desired product was eluted from the columnusing 7 M NH3 / MeOH. Pure fractions were evaporated to dryness. The resulting solid was triturated with TBME (300 mL) then collected by filtration and dried under vacuum to give (RS)-7-bromo-2,6-dichloro-4-(((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoroquinazolin-5-ol (48.8 g, 96%) as a green solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.16 (m, 1H), 2.31 (dt, 1H), 2.86 (s, 6H), 3.79 (dd, 2H), 3.94 (dd, 1H), 4.01 (td, 1H), 4.05 - 4.13 (m, 2H), 12.86 (s, 1H). One proton not observed, m / z (ES+), [M+H]+ = 453; 455; 457.

[0341] Step 4: 7-Bromo-6-chloro-4-(((( / ? S)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)amino)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol

[0342]

[0343] NaH (60% dispersion in mineral oil) (24.4 g, 0.61 mol) was added to (RS)-7-bromo-2,6-dichloro-4-(((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoroquinazolin-5-ol (48 g, 0.11 mol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (CAS No: 2097518-76-6) (48.7 g, 0.31 mol) in dioxane: DMF (10:1, 2.64 L) in an ice bath. The resulting mixture was stirred at RT for 30 minutes then slowly heated to 100 °C over 30 minutes and further stirred at 100 °C for 4 hours. The mixture was poured into ice (100 mL). The reaction mixture was purified by SCX chromatography, washed with DCM then MeOH. The desired product was eluted from the column using 7 M NH3 / MeOH. Pure fractions were evaporated to dryness. The solid was triturated with TBME (1000 mL) then collected by filtration and dried under vacuum to afford 7-bromo-6-chloro-4-((((RS)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol 39.5 g, 67%) as a green solid (80% purity by LCMS). The mother liquor was evaporated and re-purified by flash C18-flash chromatography, elution gradient 2 to 50% MeCN in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 7-bromo-6-chloro-4-((((RS)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (5.20 g, 9%) as a green solid and a ~1:1 mixture of diastereomers.1H NMR (300 MHz, DMSO-dg, 24 °C) 6 1.70-1.78 (1H, m), 1.85-2.21 (6H, m), 2.32-2.40 (7H, m), 3.15-3.23 (1H, m), 3.47-3.92 (10H, m), 4.29 (2H, s), 5.46 (1H, d), 12.10 (1H, s). m / z (ES-), [M-H]- = 572; 576; 577.5: (RS)-3-((8-bromo-9-chloro-7-fluoro-5-i i-2-1 ro-lH-i

[0344] yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethyltetrahydrofuran-3-amine

[0345]

[0346] Dibromomethane (53 mL,

[0347]

[0348] to 7-bromo-6-chloro-4-((((RS)-3- (dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (44 g, 0.076 mol) and Cs2CO3(49.70 g, 0.15 mol) in DMF (440 mL). The resulting mixture was stirred at 90 °C for 80 minutes. The mixture was cooled to RT. The reaction mixture was purified by C18-flash chromatography, elution gradient 2 to 50% MeCN in water (containing 0.1% NH4HCO3). Pure fractions were evaporated and extracted with DCM (2 x 300 mL), and the combined organics were dried over Na2SO4, filtered and evaporated. The solid was triturated with TBME (300 mL) and then collected by filtration and dried under vacuum to give (RS)-3-((8-bromo- 9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethyltetrahydrofuran-3-amine (24 g, 53%) as an orange solid and a~l:l mixture of diastereomers.1H NMR (300 MHz, DMSO-dg, 24 °C) 6 1.70- 2.21 (8H, m), 2.29 (6H, s), 2.79-2.83 (1H, m), 2.96-3.21 (3H, m), 3.63-3.99 (6H, m), 4-4.24 (2H, m), 5.28 (1H, d), 5.43-5.6 (2H, m). m / z (ES+), [M+H]+ = 588; 590; 592.

[0349] Step 6: ( / ?*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-

[0350] amine (isomer 1 and 2) (isomer 1: I nt-'

[0351]

[0352] lnt-4(RS)-3-((8-Bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethyltetrahydrofuran-3-amine (22 g, 37.36 mmol) was purified by preparative chiral SFC by the following conditions: Column: CHIRALPAK IH 5*25 cm, 5 pm; Mobile Phase A: scCO2, Mobile Phase B: IPA (containing 0.1% 7M NH3-MeOH); Flow rate: 200 mL / min; Gradient (B%): isocratic 35; Column Temperature (°C): 35; Back pressure (bar): 100; Wavelength: 310 nm; RT1 (min): 4.2; RT2 (min): 6.68.

[0353] Peak 1 fractions containing the desired compound were evaporated to dryness to afford (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethyltetrahydrofuran-3-amine (lnt-4} (9.00 g, 41%) as a white solid. This desired isomer 1 was taken into the next step.1H NMR (500 MHz, DMSO, 1 °C) 1.64 - 1.92 (4H, m), 1.95 - 2.14 (4H, m), 2.29 (6H, s), 2.81 - 2.89 (1H, m), 3.03 (1H, d), 3.10 (2H, td), 3.66 - 3.73 (2H, m), 3.75 - 3.85 (2H, m), 3.89 - 3.99 (2H, m), 4.06 (1H, d), 4.16 (1H, d), 5.21 - 5.36 (1H, m), 5.51 (2H, q). m / z (ES+), [M+H]+ = 588; 590; 592.

[0354] >99% d.e. tR = 1.17, Chiral Analysis was performed under the following conditions: Column: CHIRALPAK IH-3 4.6*5 0mm, 3 µm, Mobile Phase A:scCO2; B: IPA (0.1% DEA), Gradient=10% to 50% in 2.0 min, hold 1.0 min at 50%, Flow rate = 2 mL / min, Back Pressure 1500 psi., detector = 220nm Peak 2 fractions containing the diastereomeric product were evaporated to dryness to afford (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethyltetrahydrofuran-3-amine (8.36 g, 38%) as a white solid. > 99% d.e, undesired isomer 2, tR = 1.43, Chiral Analysis was performed under the following conditions: Column: CHIRALPAK IH-3 4.6*5 0mm, 3 µm, Mobile Phase A:scCO₂; B: IPA (0.1% DEA), Gradient=10% to 50% in 2.0 min, hold 1.0 min at 50%, Flow rate = 2 mL / min, Back Pressure 1500 psi., detector = 220nm

[0355] 1H NMR (500 MHz, DMSO, 27 °C) 1.74 - 1.89 (4H, m), 1.91 - 2.15 (4H, m), 2.29 (6H, s), 2.85 (1H, d), 3.01 - 3.15 (3H, m), 3.65 - 3.73 (2H, m), 3.75 - 3.84 (2H, m), 3.93 (2H, d), 4.12 (2H, q), 5.16 - 5.37 (1H, m), 5.45 - 5.53 (2H, m). m / z (ES+), [M+H]+ = 588; 590; 592.

[0356] l-((8-Bromo-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl- [l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-5)

[0357]

[0358] Step 1: 7-Bromo-2-chloro-5,8-difluoro-6-methylquinazolin-4(3H)-one

[0359] F O

[0360]

[0361] 2 M LDA in THF (17.8 mL, 35.54 mmol) was added to anhydrous THF (65 mL) under nitrogen. The resulting mixture was cooled to -78 °C. 7-Bromo-2-chloro-5,8-difluoroquinazolin-4(3H)-one (CAS No: 2820537-81-1) (5.0 g, 16.92 mmol) in anhydrous THF (65 mL) was added and the resulting mixture was stirred at -78 °C for 1 hour, lodomethane (2.1 mL, 33.84 mmol) was then added and the resulting mixture was stirred at -78 °C for 1 hour, then at RT overnight. 2 N HCI (aq.) was added the precipitate was collected by filtration, washed with water, and dried in a vacuum oven to afford 7-bromo-2-chloro-5,8-difluoro-6-methylquinazolin-4(3H)-one (3.76 g, 72%) as an off-white solid, which was used without further purification.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.37 (3H, d), 13.55 (1H, s). m / z (ES-), [M-H]- = 307; 309; 311.

[0362] Step 2: 7-Bromo-2-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4(3H)-one

[0363]

[0364] Lithium 2-methylpropan-2-olate (4.86 g, 60.74 mmol) was added to (4-methoxyphenyl)methanol (1.68 g, 12.15 mmol) and 7-bromo-2-chloro-5,8-difluoro-6-methylquinazolin-4(3H)-one (3.76 g, 12.15 mmol) in DMA (41 mL) under nitrogen. The resulting mixture was stirred at 60 °C overnight. The reaction mixture was diluted with 1 M citric acid (400 mL), and the precipitate formed was filtered,washed with water and dried in a vacuum oven to afford 7-bromo-2-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4(3H)-one (4.67 g, 90 %) as an off-white solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.27 (3H, s), 3.77 (3H, s), 4.84 (2H, s), 6.9 - 6.99 (2H, m), 7.42 - 7.5 (2H, m). One exchangeable proton not observed, m / z (ES-), [M-H]- = 425; 427; 429.

[0365] Step 3: 7-Bromo-2-chloro- / \ / -((l-(dimethylamino)cvclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4-amine

[0366] ■Cl

[0367]

[0368] 7-Bromo-2-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4(3H)-one (4.67 g, 10.92 mmol), DIPEA (9.51 mL, 54.60 mmol) and HCCP (4.94 g, 14.20 mmol) were dissolved in MeCN (85 mL) and stirred at RT for 30 minutes. l-(Aminomethyl)- / V, / \ / -dimethylcyclobutan-l-amine (CAS No: 176445-78-6) (2.8 g, 21.84 mmol) in MeCN (17 mL) was added and the reaction was stirred at RT for 20 minutes. The reaction mixture was poured into an ice-cooled saturated NaHCO3solution and then diluted with water. The pH of the solution was checked to ensure basic. The resulting precipitate was collected by filtration, washed with water and dried in a vacuum oven at 50 °C to afford 7-bromo-2-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4-amine (9.83 g,) as a cream solid, which was used without further purification, m / z (ES+), [M+H]+ = 537; 539; 541.

[0369] Step 4: 7-Bromo-2-chloro-4-(((l-(dimethylamino)cvclobutyl)methyl)amino)-8-fluoro-6-methylquinazolin-5-ol

[0370] 'N^CI

[0371]

[0372] TFA (2.9 mL, 37.18 mmol) was added to 7-bromo-2-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-6-methylquinazolin-4-amine (2.00 g, 3.72 mmol) in DCM (35 mL). The resulting solution was stirred at RT for 1 hour. The reaction mixture was evaporated to dryness, and the crude product was redissolved in DCM and evaporated again (operation repeated 2 more times) to afford 7-bromo-2-chloro-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-6-methylquinazolin-5-ol (1.55 g, 3.72 mmol), which was used in the next step without further purification, m / z (ES+), [M+H]+ = 417; 419; 421.

[0373]

[0374] 5: l-((8-Bromo-5-chloro-7-fluoro-9-i oxazino[4,5,6-i

[0375]

[0376] -Vi m N, N-<

[0377]

[0378] i-l-amine

[0379] 'N-^CI

[0380]

[0381] Dibromomethane (2.6 mL, 37.20 mmol) was added to a suspension of 7-bromo-2-chloro-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-6-methylquinazolin-5-ol (1.55 g, 3.72 mmol) and cesium carbonate (6.06 g, 18.60 mmol) in acetonitrile (35 mL) under nitrogen and the reaction mixture stirred at 80 °C for 2.5 days. The reaction mixture was filtered through a small pad of Celite, washed with acetonitrile and evaporated to dryness. The title crude material was used in the next step without further purification, m / z (ES+), [M+H]+ = 429; 431; 433.

[0382]

[0383] 6: l-((8-Bromo-7-fluoro-5-(((2R,7aS)-2-1 ro-lH-i -9-m

[0384]

[0385] oxazino[4,5,6-delquinazolin- -yl)methyl)- / \ / , / \ / -di

[0386]

[0387] i-l-amine

[0388]

[0389]

[0390] Sodium hydride (60% dispersion in mineral oil) (0.45 g, 11.16 mmol) was added to ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (0.59 g, 3.72 mmol) in THF (40 mL) at RT under nitrogen. The resulting mixture was stirred at RT for 10 minutes. l-((8-Bromo-5-chloro-7-fluoro-9-methyl-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcyclobutan-l-amine (1.60 g, 3.72 mmol) in THF (40 mL) was added. The resulting mixture was stirred at 40 °C overnight. The reaction mixture was quenched with saturated NH4CI solution, extracted with EtOAc (100 mL), and the organic layer was washed with saturated brine, dried over MgSO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 2 M NH3 / l\ / leOH in DCM. Pure fractions were evaporated to dryness to afford 1-((8-bromo-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-[1,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)-N,N-dimethylcyclobutan-1-amine (Int-5) (0.62 g, 30%) as a dark solid.1H NMR (500 MHz, DMSO, 27°C) 1.60 - 1.68 (1H, m), 1.72 - 1.86 (6H, m), 1.92 - 2.01 (1H, m), 2.01 - 2.16 (4H, m), 2.21(6H, s), 2.28 (3H, s), 2.78 - 2.87 (1H, m), 3 - 3.04 (1H, m), 3.04 - 3.13 (2H, m), 3.84 - 3.94 (2H, m), 4.05 (1H, d), 4.12 (1H, d), 5.19 - 5.36 (1H, m), 5.42 (2H, s). m / z (ES+), [M+H]+ = 552; 554.

[0391] tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-6)

[0392] step 3

[0393]

[0394] Step 1: 7-Bromo-6-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4(3H)-one

[0395]

[0396] 7-Bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4(3H)-one (CAS no: 2939846-87-2) (20 g, 58.56 mmol) and (4-methoxyphenyl)methanol (8.0 mL, 64.41 mmol) were suspended in THF (405 mL). Sodium 2-methylbutan-2-olate (30% in 2-MeTHF) (52 mL, 128.82 mmol) was added portionwise over 10 minutes. After 1.5 hours the reaction mixture was cooled to 5 °C and quenched by dropwise addition of water (200 mL). The mixture was neutralised to pH 7 with 1 M citric acid solution (43 mL) causing a precipitate to form. The solids were collected by filtration and washed with water (200 mL). The solids were slurried with MeCN (135 mL), filtered and dried in the vacuum oven overnight at 45 °C to give 7-bromo-6-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4(3H)-one (19.2 g, 71 %) as a beige solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.52 (3H, s), 3.77 (3H, s), 4.90 (2H, s), 6.9 - 6.99 (2H, m), 7.47 - 7.54 (2H, m). One exchangeable proton not observed, m / z (ES-), [M-H]- = 457; 459; 461.Step 2: 7-Bromo-6-chloro- / V-((l-(dimethylamino)cvclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine

[0397]

[0398] 7-Bromo-6-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4(3H)-one (20.97 g, 45.62 mmol), DIPEA (40 mL, 228.08 mmol) and HCCP (20.6 g, 59.30 mmol) were suspended in MeCN (250 mL) and stirred at room temperature for 30 minutes. l-(Aminomethyl)- / V, / \ / -dimethylcyclobutan-1-amine (Cas No: 176445-78-6) (11.7 g, 91.23 mmol) in MeCN (50 mL) was added and the reaction was stirred at RT for 10 minutes. The reaction mixture was poured into an ice-cooled saturated NaHCO3solution (500 mL) and then diluted with water (300 mL). The resulting precipitate was collected by vacuum filtration, washed with water (until the filtrate ran colourless), then heptane (100 mL) and then allowed to dry on the filter pad, before collection to afford 7-bromo-6-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine (20.7 g, 80 %) as a pale yellow solid.1H NMR (500 MHz, CDCl3, 27 °C) 1.48 - 1.78 (4H, m), 2.02 (6H, s), 2.09 - 2.22 (2H, m), 2.62 (3H, s), 3.73 (2H, d), 3.83 (3H, s), 5.04 (2H, s), 6.92 (2H, d), 7.39 - 7.45 (2H, m), 8.33 (1H, s). m / z (ES+), [M+H]+ = 569; 571; 573.

[0399]

[0400] 3: 7-Bromo-6-chloro-4-i im mil m mino)-8-fluoro-2- m in-5-ol

[0401]

[0402] 7-Bromo-6-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine (6.56 g, 11.51 mmol) was dissolved in 1,4-dioxane (110 mL) and HCI (4 M in dioxane) (11.5 mL, 46.04 mmol) was added. The mixture was stirred at RT for 1 hour to afford a suspension. The precipitate was collected by filtration and washed with dioxane (50 mL). The solid was dissolved in MeOH (20 mL), filtered and the filtrate was evaporated to dryness. The crude product was dissolved in water: MeOH (40 mL, 50:50 v / v) and purified by reverse phase chromatography (C18HP Gold column), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in water)) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness under vacuum to afford 7-bromo-6-chloro-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-(methylthio)quinazolin-5-ol (3.82 g, 74 %) as a light grey-green solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.77 (1H, q), 1.89 (1H, h), 2.12 (2H, t), 2.29 (2H, q), 2.45 (3H, s), 2.72 (6H, s), 4.03 (2H, d), 12.63 (1H, s). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 449; 451; 453.

[0403] Step 4: l-((8-Bromo-9-chloro-7-fluoro-5-(methylthio)-(l,3]oxazino(4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-19)

[0404]

[0405] Chloroiodomethane (1.16 mL, 15.96 mmol) was added to a solution of 7-bromo-6-chloro-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-(methylthio)quinazolin-5-ol (3.59 g, 7.98 mmol) and cesium carbonate (7.80 g, 23.95 mmol) in DMA (39 mL) under nitrogen. The reaction was heated to 110 °C for 3 hours. The reaction mixture was cooled to RT then diluted with EtOAc (50 mL) and washed with water (5 x 50 mL) and then brine (2 x 50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford l-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine (lnt-19) (2.79 g, 76%) as a brown powder, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-dg, 1 °C) 1.57 - 1.85 (4H, m), 2.03 - 2.12 (2H, m), 2.20 (6H, s), 2.55 (3H, s), 3.92 (2H, s), 5.53 (2H, s). m / z (ES+), [M+H]+ = 461; 463; 465.

[0406] Step 5: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0407]

[0408] CPhos (0.48 g, 1.09 mmol), K2CO3 (3.01 g, 21.79 mmol) and tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (5.57 g, 14.16 mmol) were added to a flask containing l-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-19 (5.03 g, 10.89 mmol) dissolved in 1,4-dioxane (119 mL) and water (11.9 mL). Nitrogen was bubbled through the reaction mixture for 15 minutes before CPhos Pd G3 (0.88 g, 1.09 mmol) was added. The reaction mixture was cycled through vacuum and nitrogen three times. The reaction was heated to 70 °C for 1 hour and then cooled to RT. The reaction mixture was passed through a small pad of Celite eluting with DCM (60 mL). The filtrate was concentrated and passed through ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2 M NH3 / l\ / leOH and the pure fractions were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (6.96 g, 99%) as a brown foam, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.46 (9H, s), 1.61 - 1.87 (6H, m), 2.24 (6H, s), 2.56 (3H, s), 3.91 - 3.99 (2H, m), 5.60 (2H, d), 6.34 (1H, s), 7.18 - 7.25 (1H, m), 7.99 (1H, dd), 10.71 (1H, s). m / z (ES+), [M+H]+ = 648.

[0409] Step 6: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-6)

[0410] 'N^S'

[0411]

[0412] Chlorosulfonyl isocyanate (3.2 mL, 36.41 mmol) was added dropwise to a cooled solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (2.36 g, 3.64 mmol) in THF (51 mL) and DMF (6.8 mL, 87.38 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 10 minutes at -78 °C and then stirred at 0 °C for a further 30 minutes. The reaction mixture was cooled in an ice bath and quenched carefully with water (5 mL). The reaction mixture was then passed through an SCX column washing with MeOH. The desired product was eluted from the column using 2 M NH3 / MeOH and the pure fractions were evaporated to dryness. The crude product was purified by reverse phase chromatography (Interchim C18-HP Flash column), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H2O)) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-6) (0.99 g, 41%) as a cream foam.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.48 (9H, s), 1.67 (1H, d), 1.78 (1H, q), 1.90 (2H, d), 2.15 (2H, d), 2.32 (6H, s), 2.56 (3H, s), 3.92 - 4.07 (2H, m), 5.55 (1H, d), 5.61 (1H, d), 7.35 (1H, s), 8.07 (1H, s). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 673.

[0413] tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (lnt-7)

[0414] Step 1 Step 2

[0415]

[0416] Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0417]

[0418] CPhos Pd G3 (0.077 g, 0.10 mmol) and CPhos (0.042 g, 0.10 mmol) were added to a de-oxygenated solution of l-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-19) (0.44 g, 0.95 mmol), tert-butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3)(0.51 g, 1.24 mmol) and K2CO3 (0.26 g, 1.91 mmol) in 2-MeTHF (13 mL) and water (2.7 mL). The reaction mixture was then heated at 70 °C for 1.5 hours in a microwave. The reaction was passed through a SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.63 g, 0.95 mmol) as a brown solid, which was used directly in the next step without further purification, m / z (ES+), [M+H]+ = 665.2: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino methyl)-7-fluoro-5-i -2,3-

[0419]

[0420] ro-[l,3]oxazino[4,5,6-i in-8-yl)-3-cyano-5,7-diflu

[0421]

[0422] -2-

[0423]

[0424] Chlorosulfonyl isocyanate (0.83 mL, 9.50 mmol) was added dropwise to a cooled solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.63 g, 0.95 mmol) in THF (97 mL) and DMF (1.8 mL, 22.80 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 5 minutes at -78 °C then at RT for 30 minutes. The reaction mixture was cooled in an ice bath and quenched carefully with water (1 mL). The reaction mixture was then passed through an SCX column. The desired product was eluted with 2 M NH3 / l\ / leOH. The product was concentrated to afforded crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (lnt-7) (0.15 g, 23%) as a brown solid, m / z (ES+), [M+H]+ = 691.

[0425] Synthesis of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate (lnt-8)

[0426]

[0427] lnt-8

[0428] Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate

[0429]

[0430] CPhos Pd G3 (0.07 g, 0.09 mmol) and CPhos (0.04 g, 0.09 mmol) were added to a de-oxygenated solution of l-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-19) (0.40 g, 0.87 mmol), tert-butyl (5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-yl)carbamate (lnt-1) (0.36 g, 0.95 mmol) and K3PO4(0.55 g, 2.60 mmol) in 1,4-dioxane (18 mL) and water (2 mL). The reaction mixture was then heated at 75 °C for 2.5 hours. The reaction was passed through an SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness. The crude product was purified by reverse phase chromatography (Interchim C18-HP Flash column), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H2O)) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate (0.16 g, 30 %) as a cream foam.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.23 (1H, s), 1.43 (9H, d), 1.53 - 1.93 (5H, m), 2.12 (3H, s), 2.23 (6H, d), 2.55 (3H, d), 3.96 (2H, d), 5.5 - 5.66 (2H, m), 5.88 (1H, s), 7.14 (1H, d), 7.43 (1H, d), 10.73 (1H, s). m / z (ES+), [M+H]+ = 628.

[0431] Step 2: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cvano-5-methylbenzofuran-2-yl)carbamate (lnt-8)

[0432]

[0433] Chlorosulfonyl isocyanate (0.22 mL, 2.55 mmol) was added dropwise to a cooled solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate) (0.11 g, 0.25 mmol) in THF (26 mL) and DMF (0.47 mL, 6.11 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 5 minutes at -78 °C then was stirred at RT for 15 minutes. The reaction mixture was cooled in an ice bath and quenched carefully with water (1 mL). The reaction mixture was then passed through aSCX column. The desired product was eluted with 2 M NH3 / MeOH. The filtrate was concentrated to afford the crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-methylbenzofuran-2-yl)carbamate (lnt-8) (0.16 g, 0.25 mmol) as a yellow glass, which was used in the next reaction without further purification, m / z (ES+), [M+H]+ = 653.

[0434] tert-butyl (4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5- (methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-9)

[0435] lnt-9

[0436]

[0437] Isomer 1 Isomer 2 Isomer 1 Isomer 1

[0438] Step 1: ( / ? S)-7-bromo-6-chloro-N-((3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine

[0439] ""o

[0440]

[0441] 7-Bromo-6-chloro-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4(3H)-one (1.00 g, 2.18 mmol), DIPEA (1.9 mL, 10.88 mmol) and HCCP (0.98 g, 2.83 mmol) were suspended in MeCN (12 mL) and stirred at RT for 30 minutes rac-3-(aminomethyl)- / V, / V-dimethyltetrahydrofuran-3-amine (0.31 g, 2.18 mmol) in MeCN (2.3 mL) was added and the reaction was stirred at RT for 30 minutes. Additional MeCN (17 mL) was added and the reaction was stirred at RT for 30 min. An extra portion of 3-(aminomethyl)- / V, / V-dimethyltetrahydrofuran-3-amine (0.31 g, 2.18 mmol) in MeCN (3 mL) wasadded and the reaction mixture was stirred at 40 °C for 45 min. The reaction mixture was cooled to RT and then poured into an ice-cooled saturated NaHCO3solution (60 mL) and then diluted with water (50 mL). The pH of the solution was checked to ensure basic. The resulting precipitate was collected by vacuum filtration, washed with water (3 x 20 mL), heptane (3 x 20 mL) and allowed to dry on the filter pad overnight and then in the vacuum oven at 40 °C for 2.5 h to afford (RS)-7-bromo-6-chloro-N-((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine (1.30 g, 102%) as a yellow solid.1H NMR (500 MHz, CDCI3, 27 °C) 1.48 (2H, s), 1.98 (6H, s), 2.54 (3H, s), 3.34 (1H, d), 3.52 - 3.61 (1H, m), 3.64 - 3.73 (3H, m), 3.76 (3H, s), 3.8 - 3.88 (1H, m), 4.94 - 5.05 (2H, m), 6.86 (2H, d), 7.36 (2H, d), 8.35 (1H, s). m / z (ES+), [M+H]+ = 585; 587; 589.

[0442] Step 2: ( / ? S)-7-bromo-6-chloro-4-(((3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)amino)-8-fluoro-2-(methylthio)quinazolin-5-ol

[0443]

[0444] fRS^-bromo-6-chloro- / V-((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-8-fluoro-5-((4-methoxybenzyl)oxy)-2-(methylthio)quinazolin-4-amine (1.30 g, 2.21 mmol) was suspended in 1,4-dioxane (35 mL) and cooled in an ice bath. Hydrogen chloride (4 M in 1,4-dioxane) (2.2 mL, 8.84 mmol) was added. The suspension was stirred vigorously at RT for 30 minutes. The precipitate was collected by filtration and washed with 1,4-dioxane. The solid started to become sticky upon exposure to air (hygroscopic), so was transferred to a flask and stored under nitrogen. (RS)7-bromo-6-chloro-4-(((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoro-2-(methylthio)quinazolin-5-ol, HCI (1.11 g, 100%) was isolated as a yellow solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 2.16 - 2.25 (1H, m), 2.35 - 2.46 (1H, m), 2.57 (3H, s), 2.83 (6H, s), 3.63 - 4.47 (6H, m), 11.39 (1H, s). One exchangeable proton not observed, m / z ES+ [M+H]+ = 465; 467; 469.

[0445] Step 3: ( / ? S)3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethyltetrahvdrofuran-3-amine

[0446]

[0447] Dibromomethane (1.6 mL, 22.10 mmol) was added to a suspension of (RS)7-bromo-6-chloro-4-(((3-(dimethylamino)tetrahydrofuran-3-yl)methyl)amino)-8-fluoro-2-(methylthio)quinazolin-5-ol, HCI (1.11 g, 2.21 mmol) and cesium carbonate (3.60 g, 11.05 mmol) in acetonitrile (37 mL) under nitrogen and the reaction mixture was heated at 80 °C overnight. The reaction mixture was filtered whilst hot through a short pad of Celite. The pad of Celite was washed with hot acetonitrile and the filtrate was concentrated under reduced pressure to give (RS)3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dirnethyltetrahydrofuran-3-amine (0.90 g, 86 %) as a brown solid.1H NMR (500 MHz, CDCI3, 1 °C) 1.81 - 1.92 (1H, m), 2.04- 2.16 (1H, m), 2.37 (6H, s), 2.62 (3H, s), 3.80 (2H, s), 3.89 - 4.06 (4H, m), 5.40 (1H, d), 5.44 (1H, d). m / z: ES+ [M+H]+ = 477; 479; 481.

[0448] Step 4: re / -( / ?)-3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethyltetrahydrofuran-3-amine (isomer 1 and isomer 2)

[0449]

[0450] The racemic product (0.47 g, 0.98 mmol) was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 30 x 250 mm; Mobile Phase A: ScCO2; Mobile Phase B: 0.1% NH3 in MeOH, gradient used: 35% B over 10.5 minutes; Flow rate: 120.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0451] Peak 1 fractions containing the desired compound were consolidated and concentrated to give isomer 1 (0.15 g, 32 %) assigned >99% d.e., tR 2.17 min. Isomer 1 was taken into the next step. Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 μm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient: 5 to 50 %B over 1.9 min, Flow rate: 2.5 mL / min.1H NMR (500 MHz, DMSO-dg, 27 °C) 1.86 (1H, ddd), 1.98 (1H, dt), 2.29 (6H, s), 2.55 (3H, s), 3.65 (1H, d), 3.7 -3.84 (3H, m), 3.87 - 4.02 (2H, m), 5.46 - 5.57 (2H, m). m / z (ES+), [M+H]+ = 477; 479; 481. [α23.7D] = -12.1 (c. 2.06, DMSO)

[0452] Peak 2 fractions containing the desired compound were consolidated and concentrated to give undesired isomer 2 (0.14 g, 30 %) assigned >98.9% d.e. tR= 2.35 min.

[0453] 1H NMR (500 MHz, DMSO-d6, 27 °C) 1.81 - 2.05 (2H, m), 2.29 (6H, s), 2.55 (3H, s), 3.63 - 3.84 (4H, m), 3.85 - 4.05 (2H, m), 5.47 - 5.55 (2H, m). m / z (ES+), [M+H]+ = 477; 479; 481. [α23.5D] = +12.1 (c. 2.22, DMSO).

[0454] Step 5: tert-butyl (4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (methylthio)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophen-2-vhcarbamate

[0455]

[0456] CPhos Pd G3 (30.4 mg, 0.04 mmol) and CPhos (16.5 mg, 0.04 mmol) were added to a de-oxygenated solution of (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethyltetrahydrofuran-3-amine (isomer 1) (0.18 g, 0.38 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (0.15 g, 0.38 mmol) and K2CO3 (0.10 g, 0.75 mmol) in 2-MeTHF (5 mL) and water (0.5 mL). The reaction mixture was then heated at 70 °C for 1.5 hours. The reaction was concentrated then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1 M NH₃ / MeOH and the pure fractions were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5- (methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.26 g, 105%) as a cream foam. This was used without further purification, m / z (ES+), [M+H]+ = 664.

[0457] Step 6: tert-Butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-9)

[0458]

[0459] Chlorosulfonyl isocyanate (0.34 mL, 3.91 mmol) was added dropwise to a cooled solution of tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.26 g, 0.39 mmol) in THF (40 mL) and DMF (0.73 mL, 9.39 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 10 minutes at -78 °C, then was stirred at 0 °C for a further 30 minutes. The reaction mixture was cooled in an ice bath and quenched carefully with water (2 mL). This was concentrated to remove most of the solvent and then passed through an SCX column eluting the product with 2 M NH3 / MeOH. This afforded tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro- [l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-9) (0.26 g, 100%) as a brown foam, which was used in the next step without further purification, m / z (ES+), [M+H]+ = 689.

[0460] l-((8-Bromo-7,9-difluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-10)

[0461]

[0462] lnt-10

[0463] Step 1: 3-Bromo-2,4,5-trifluoro-6-iodoaniline

[0464]

[0465] 4-Methylbenzenesulfonic acid hydrate (5.05 g, 26.55 mmol) was added to 3-bromo-2,4,5-trifluoroaniline (50 g, 221.24 mmol) and l-iodopyrrolidine-2, 5-dione (59.7 g, 265.49 mmol) in MeCN (500 mL) at RT under nitrogen. The resulting mixture was stirred at RT for 16 hours. The reaction mixture was poured into saturated Na2S2O3solution (1 L) and extracted with DCM (2 x 500 mL). The combined organic extracts were dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 4% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to afford 3-bromo-2,4,5-trifluoro-6-iodoaniline (62 g, 80%) as a purple solid.1H NMR (500 MHz, DMSO-d6, 24 °C) δ 5.61 (2H, s). m / z (ES+), [M+H]+ = 352; 354.

[0466] Step 2: Ethyl 2-amino-4-bromo-3,5,6-trifluorobenzoate

[0467] F O

[0468]

[0469] Triphenylphosphine palladium chloride (9.97 g, 14.21 mmol) was added to NEt3(60 mL, 426.27 mmol) and 3-bromo-2,4,5-trifluoro-6-iodoaniline (50 g, 142.09 mmol) in EtOH (500 mL) at RT in a high pressure vessel which was then evacuated and put under a carbon monoxide atmosphere (5 atm). The resulting mixture was stirred at 80 °C for 16 hours. After cooling to RT, the solvent was removed under reduced pressure. The solid was suspended in TBME: PE (1:10) (500 mL) and stirred at RT for 30 mins. The solid was collected by filtration and dried under vacuum to afford ethyl 2-amino-4-bromo-3,5,6-trifluorobenzoate (42 g, 99%) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6, 24 °C) δ 1.30 (3H, t), 4.34 (2H, q), 6.55 (2H, s). m / z (ES+), [M+H]+ = 298; 300.

[0470] Step 3: 2-Amino-4-bromo-3,5,6-trifluorobenzoic acid

[0471]

[0472] Sodium hydroxide (56.4 g, 1.41 mol) was added to ethyl 2-amino-4-bromo-3,5,6-trifluorobenzoate (42 g, 140.91 mmol) in THF: water = 1: 1 (420 mL). The resulting mixture was stirred at 60 °C for 2 hours. THF was removed under reduced pressure. 12 M HCI (aq.) was added until the pH reached 2 then wasextracted with EtOAc (3 x 500 mL). The combined organics were dried over Na2SO4, filtered, and evaporated to afford 2-amino-4-bromo-3,5,6-trifluorobenzoic acid (35 g, 92%) as a pale yellow solid. The crude product was used in the next step directly without further purification, m / z (ES+), [M+H]+ = 268; 270.

[0473] Step 4: 2-Amino-4-bromo-3,5,6-trifluorobenzamide

[0474]

[0475] DIPEA (68 mL, 388.88 mmol) was added to HATU (73.90 g, 194.44 mmol), 2-amino-4-bromo-3,5,6-trifluorobenzoic acid (35.00 g, 129.63 mmol) and ammonium chloride (10.40 g, 194.44 mmol) in DMF (350 mL). The resulting mixture was stirred at RT for 2 hours. The reaction mixture was poured into ice water (1 L). The precipitate was collected by filtration, washed with water (200 mL), and dried under vacuum to afford 2-amino-4-bromo-3,5,6-trifluorobenzamide (25 g, 72%) as a brown solid, which was used directly in the next step directly without further purification.1H NMR (500 MHz, DMSO-dg, 24 °C) δ 5.95 (2H, s), 7.91 (2H, d). m / z (ES+), [M+H]+ = 269; 271.

[0476] Step 5: 7-Bromo-2-chloro-5,6,8-trifluoroquinazolin-4(3H)-one

[0477] F O

[0478]

[0479] Thiophosgene (12.75 mL, 167.27 mmol) was added slowly to 2-amino-4-bromo-3,5,6-trifluorobenzamide (25 g, 92.93 mmol) in 1,4-dioxane (400 mL) at RT. The mixture was stirred at RT for 1 hour then at 105 °C for 1 hour. The solvent was removed under reduced pressure. The solid was suspended in EtOAc (100 mL). The precipitate was collected by filtration, washed with EtOAc (50 mL) and dried under vacuum to afford 7-bromo-2-chloro-5,6,8-trifluoroquinazolin-4(3H)-one (15 g, 52%) as a brown solid, which was used in the next without further purification, m / z (ES+), [M+H]+ = 313; 315.

[0480] Step 6: 5-(Benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazolin-4-ol

[0481]

[0482] Lithium 2-methylpropan-2-olate (10.85 g, 135.58 mmol) was added to 7-bromo-2-chloro-5,6,8-trifluoroquinazolin-4(3H)-one (10 g, 27.12 mmol) and benzyl alcohol (4.2 mL, 40.68 mmol) in MeCN (100 mL) at RT. The resulting mixture was stirred at 80 °C for 2 hours. After cooling to RT, 12 M HCI (aq.) was added until the pH of the reaction reached 4. MeCN was removed under reduced pressure. The precipitate was filtered and the solid was suspended in EtOAc / petroleum ether = 1: 5 (100 mL). The precipitate was collected by filtration, washed with petroleum ether (50 mL), and dried under vacuum to afford 5-(benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazolin-4-ol (10 g, 92%) as a brown solid, which was used in the next step without further purification.1H NMR (300 MHz, DMSO-d6, 23 °C) δ 5.07 (2H, s), 7.34-7.42 (3H, m), 7.5-7.55 (2H, m). One exchangeable proton not seen, m / z (ES+), [M+H]+ = 401; 403.

[0483] Step 7: 5-(Benzyloxy)-7-bromo-2-chloro- / \ / -((l-(dimethylamino)cvclobutyl)methyl)-6,8-difluoroquinazolin-4-amine

[0484] N^CI

[0485]

[0486] DIPEA (10.5 mL, 59.76 mmol) was added to 5-(benzyloxy)-7-bromo-2-chloro-6,8-difluoroquinazolin-4-ol (6.00 g, 7.47 mmol) and HCCP (6.49 g, 18.68 mmol) in MeCN (80 mL) at RT over 30 minutes. Then l-(aminomethyl)- / V, / V-dimethylcyclobutan-l-amine (CAS No: 176445-78-6)(1.44 g, 11.21 mmol) was added slowly in an ice bath. The resulting mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc (100 mL), and washed with water (2 x 100 mL), and saturated brine (2 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to afford 5-(benzyloxy)-7-bromo-2-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-6,8-difluoroquinazolin-4-amine (2.40 g, 63 %) as a brown solid.XH NMR (300 MHz, DMSO-d6, 23 °C) 6 1.52-1.74 (6H, m), 2.09 (6H, s), 3.66-3.72 (2H, m), 5.33 (2H, s), 7.38-7.45 (5H, m). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 511; 513.

[0487] Step 8: 7-Bromo-4-(((l-(dimethylamino)cvclobutyl)methyl)amino)-6,8-difluoro-2-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)quinazolin-5-ol

[0488]

[0489] Cesium fluoride (5.94 g, 39.08 mmol) was added to 5-(benzyloxy)-7-bromo-2-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-6,8-difluoroquinazolin-4-amine (2.00 g, 3.91 mmol) in DMF (50 mL) at RT under nitrogen. The resulting mixture was stirred at 120 °C for 6 hours. After cooling to RT, sodium 2-methylbutan-2-olate (2.15 g, 19.54 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (1.87 g, 11.72 mmol) were added to the mixture and stirred at 80 °C for 2 hours. After cooling to RT, the reaction mixture was filtered. The filtrate was purified by C18-flash chromatography, elution gradient 60 to 100% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford 7-bromo-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-6,8-difluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (0.70 g, 33 %) as a yellow solid.1H NMR (400 MHz, DMSO-dg, 21 °C) δ 1.78-1.99 (7H, m), 2.11-2.28 (6H, m), 2.42 (6H, s), 3.06-3.2 (2H, m), 3.72-3.74 (3H, m), 4.17-4.26 (2H, m), 5.39-5.47 (1H, m), 11.90 (1H, s). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 544; 546.

[0490]

[0491] 9: l-((8-Bromo-7,9-difluoro-5-i -2-flu ro-lH-i izin-

[0492]

[0493] [l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcvclobutan-l-amine (lnt-10)

[0494]

[0495] Dibromomethane (2.24 g,

[0496]

[0497] added to 7-bromo-4-(((l- (dimethylamino)cyclobutyl)methyl)amino)-6,8-difluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (0.70 g, 1.29 mmol) and Cs2CO3(0.84 g, 2.57 mmol) in DMF (7 mL) at RT. The resulting mixture was stirred at 90 °C for 2 hours. After cooling to RT, the reaction mixture was poured into EtOAc (50 mL), washed with water (2 x 50 mL) then saturated brine (50 mL). The organic extract was dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 50 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford l-((8-bromo-7,9-difluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-10) (0.30 g, 42 %) as a brown solid.XH NMR(400 MHz, DMSO-dg, 22 °C) 6 1.6-1.87 (7H, m), 1.93-2.13 (5H, m), 2.20 (6H, s), 2.75-2.86 (1H, m), 2.98-3.03 (1H, m), 3.04-3.13 (2H, m), 3.86-3.97 (2H, m), 4.01-4.17 (2H, m), 5.18-5.36 (1H, m), 5.49 (2H, s). m / z (ES+), [M+H]+ = 556; 558.

[0498] l-((8-Bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)rnethoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)rnethyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-11)

[0499]

[0500] Step 1: 2-Amino-4-bromo-3,6-difluorobenzamide

[0501] NH2O

[0502]

[0503] DIPEA (135 mL, 773.76 mmol) was added to HATU (147 g, 386.88 mmol), 2-amino-4-bromo-3,6-difluorobenzoic acid (65.0 g, 257.92 mmol), and ammonium chloride (20.7 g, 386.88 mmol) in DMF (200 mL). The resulting mixture was stirred at RT for 1 hour. The reaction mixture was poured into ice water (800 mL). The precipitate was collected by filtration, washed with water (200 mL), and dried under vacuum to afford 2-amino-4-bromo-3,6-difluorobenzamide (46 g, 71%) as a brown solid. The product was used in the next step without further purification.1H NMR (500 MHz, DMSO-dg, 24 °C) 6 6.35 (2H, s), 6.77 (1H, dd), 7.74 (2H, d). m / z (ES), [M-H]- = 249;251.

[0504] Step 2: 7-Bromo-2-chloro-5,8-difluoroquinazolin-4(3H)-one

[0505]

[0506] Thiophosgene (21.9 mL, 286.82 mmol) was added portionwise to a stirred solution of 2-amino-4-bromo-3,6-difluorobenzamide (40.0 g, 159.34 mmol) in 1,4-dioxane (800 mL) at RT and then stirred at RT for 1 hour then at 105 °C for 1 hour. Volatiles were removed under reduced pressure. The solid was suspended in DCM / heptane (1: 10) (500 mL), then collected by filtration, washed with petroleum ether (100 mL), and dried under vacuum to afford 7-bromo-2-chloro-5,8-difluoroquinazolin-4(3H)-one (35 g, 74%) as a brown solid, which was used in the next step without further purification.XH NMR (400 MHz, DMSO-dg, 21 °C) 67.79 (1H, dd). One exchangeable proton was not observed, m / z (ES-), [M-H]- = 293;295;297.

[0507] Step 3: 5-(Benzyloxy)-7-bromo-2-chloro-8-fluoroquinazolin-4-ol

[0508] ci

[0509]

[0510] Lithium tert-butoxide (33.9 g, 423.06 mmol) was added to 7-bromo-2-chloro-5,8-difluoroquinazolin-4(3H)-one (25.0 g, 84.61 mmol), and benzyl alcohol (8.8 mL, 84.61 mmol) in MeCN (500 mL) under nitrogen. The resulting mixture was stirred at 80 °C for 2 hours. After cooling to RT, 2 M HCI (aq.) was added until the pH reached 4. Volatiles were removed under reduced pressure then water (200 mL) was added and stirred for 1 hour. The solid was collected by filtration. The filter cake was suspended in petroleum ether: EtOAc (3:1) (100 mL) and stirred for 1 hour. The solid was collected by filtration and then dried under vacuum affording the title compound (17.0 g, 52%) as a yellow solid, which was used in the next step without further purification.1H NMR (300 MHz, DMSO-d6, 24 °C) 65.24 (2H, s), 7.25-7.37 (2H, m), 7.37-7.46 (4H, m). One exchangeable proton not observed, m / z (ES-), [M-H]- = 381;383;385.

[0511] Step 4: 5-(Benzyloxy)-7-bromo-2-chloro- / \ / -((l-(dimethylamino)cvclobutyl)methyl)-8-fluoroquinazolin-4-amine

[0512]

[0513] DIPEA (46.4 mL, 265.90 mmol) was added to 5-(benzyloxy)-7-bromo-2-chloro-8-fluoroquinazolin-4-ol (17 g, 44.32 mmol) and HCCP (23.11 g, 66.48 mmol) in MeCN (300 mL) at RT over 30 minutes. Then 1-(aminomethyl)- / V, / V-dimethylcyclobutan-l-amine (CAS No: 176445-78-6) (11.36 g, 88.63 mmol) was added. The resulting mixture was stirred at RT for 1 hour. The suspension was filtered. The filter cake was washed with MeCN (50 mL) affording the title compound (7.00 g, 32%) as a pale yellow solid, which was used in the next step without further purification.1H NMR (300 MHz, DMSO-dg, 21 °C) 6 1.39-1.52 (2H, m), 1.52-1.71 (2H, m), 1.91 (6H, s), 1.96-2.06 (2H, m), 3.64 (2H, d), 5.34 (2H, s), 7.35-7.47 (4H, m), 7.48-7.54 (2H, m), 8.50 (1H, t). m / z (ES+), [M+H]+ = 493;495;497.

[0514] Step 5: 5-(Benzyloxy)-7-bromo- / V-((l-(dimethylamino)cvclobutyl)methyl)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-amine

[0515]

[0516] Sodium hydride (60% dispersion in mineral oil) (3.40 g, 85.05 mmol) was added to ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methanol (3.39 g, 21.26 mmol) in 1,4-dioxane (150 mL) and DMF (15 mL) at 0 °C under nitrogen. The mixture was stirred at RT for 30 minutes. 5-(Benzyloxy)-7-bromo-2-chloro- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoroquinazolin-4-amine (7.00 g, 14.18 mmol) was then added. The mixture was stirred at 100 °C for 1 hour. After cooling to RT, the reaction mixture was quenched with saturated NH4CI solution (200 mL) and extracted with EtOAc (3 x 200 mL). The combined organic extracts were washed with water (200 mL x 3), and saturated brine (200 mL x 3). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford 5-(benzyloxy)-7-bromo- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)quinazolin-4-amine (3.80 g, 44%) as a white solid.1H NMR (300 MHz, DMSO-d6, 22 °C) 6 1.38-1.51 (2H, m), 1.51-1.7 (2H, m), 1.7-1.87 (3H, m), 1.90 (6H, s), 1.94-2.04 (4H, m), 2.07-2.16 (1H, m), 2.73-2.88 (1H, m), 2.94-3.02 (1H, m),3.02-3.18 (2H, m), 3.60-3.66 (2H, m), 3.90-4.12 (2H, m), 5.11-5.41 (3H, m), 7.17 (1H, d), 7.34-7.47 (3H, m), 7.47-7.55 (2H, m), 8.24 (1H, t). m / z (ES+), [M+H]+ = 616; 618.

[0517] Step 6: 7-Bromo-4-(((l-(dimethylamino)cvclobutyl)methyl)amino)-8-fluoro-2-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)quinazolin-5-ol

[0518]

[0519] Trifluoromethanesulfonic acid (4.3 mL, 49.31 mmol) was added to 5-(benzyloxy)-7-bromo- / V-((l-(dimethylamino)cyclobutyl)methyl)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-4-amine (3.80 g, 6.16 mmol) in DCM (40 mL) and TFA (40 mL) at 0 °C. The resulting mixture was stirred at RT for 2 hours. Volatiles were removed under reduced pressure. Then the residue was cooled in an ice bath, diluted with water (50 mL), and saturated aq. NaOH solution was added until the pH reached 7-8. Then the mixture was extracted into EtOAc (3 x 100 mL). The combined organics were washed with water (3 x 100 mL), and saturated brine (3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated to afford the desired product (3.00 g, 92%) as a brown solid, which was used in the next step without further purification.1H NMR (400 MHz, DMSO-dg, 21 °C) 6 1.64-1.8 (3H, m), 1.8-1.97 (3H, m), 1.98-2.09 (1H, m), 2.09-2.14 (1H, m), 2.14-2.25 (3H, m), 2.27 (6H, s), 2.32-2.48 (1H, m), 2.87-2.98 (1H, m), 3.13-3.26 (3H, m), 3.74 (2H, s), 4.00-4.20 (2H, m), 5.22-5.43 (2H, m), 6.58 (1H, d), 9.59 (1H, s). m / z (ES+), [M+H]+ = 526; 528.

[0520] Step 7: l-((8-Bromo-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)-A / , A / -dimethylcyclobutan-l-amine

[0521]

[0522] Dibromomethane (9.91 g, 56.99 mmol) was added to 7-bromo-4-(((l-(dimethylamino)cyclobutyl)methyl)amino)-8-fluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (3.00 g, 5.70 mmol) and CS2CO3 (3.71 g, 11.40 mmol) in DMF (60 mL) at RT. The resulting mixture was stirred at 90 °C for 2 hours. After cooling to RT, the reaction mixture was diluted with EtOAc (300 mL), washed with water (100 mL x 3) and then saturated brine(3 x 100 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 50 to 100% MeCN in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford l-((8-bromo-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (1.70 g, 55%) as a pale yellow solid.1H NMR (300 MHz, DMSO-dg, 21 °C) 6 1.56-1.67 (1H, m), 1.67-1.87 (6H, m), 1.91-2.14 (5H, m), 2.18 (6H, s), 2.73-2.88 (1H, m), 2.95-3.11 (3H, m), 3.87 (2H, s), 4.00-4.20 (2H, m), 5.17-5.35 (1H, m), 5.39 (2H, s), 7.05 (1H, d). m / z (ES+), [M+H]+ = 538; 540.

[0523]

[0524] 8: l-((8-Bromo-7-fluoro-5-i i-2-1 ro-lH-i -9-iodo-[l,31oxazino[4,5,6-i

[0525]

[0526] i-yl)methyl)- / \ / , / \ / -dii

[0527]

[0528] i-l-amine and l-((8-bromo-7-fluoro-5-(((2R,7aS)-2-flu

[0529]

[0530] ro-lH-i

[0531]

[0532] -yl)methoxy)-9-iodo-

[0533]

[0534] oxazino[4,5,6-delquinazolin- m 1- / V-1 i-l-amine (1:1

[0535]

[0536]

[0537] NIS (1.42 g, 6.31 mmol) was added to l-((8-bromo-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcyclobutan-l-amine (1.70 g, 3.16 mmol) in cone. H2SO4(30 mL) under nitrogen. The resulting mixture was stirred at RT for 2 hours. The reaction mixture was poured into ice water. Then the pH of the mixture was adjusted to pH 7-8 by adding saturated NaHCO3solution. The mixture was diluted with EtOAc (200 mL) and washed with saturated Na2S2O3solution (100 mL x 2), water (100 mL x 3), and saturated brine (100 mL x 2). The organic layer was dried over Na2SO4, filtered and evaporated to afford an inseparable mixture of l-((8-bromo-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-iodo-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amineand l-((8-bromo-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-iodo-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / -methylcyclobutan-l-amine (1:1) (2.00 g, 96%) as a brown solid, which was used in the next step without further purification.

[0538] Mono-i:XH NMR (300 MHz, DMSO-d6, 21 °C) 6 1.58-1.86 (6H, m), 1.86-1.99 (3H, m), 1.98-2.04 (1H, m), 2.04-2.15 (2H, m), 2.20 (3H, s), 2.73-2.87 (1H, m), 2.93-3.18 (3H, m), 3.88 (2H, s),3.99-4.16 (2H, m), 5.18-5.36 (1H, m), 5.47 (2H, s). One exchangeable proton not seen, m / z (ES+), [M+H]+ = 650; 652.

[0539] Di-methyl product:1H NMR (300 MHz, DMSO-d6, 21 °C) 6 1.58-1.86 (6H, m), 1.86-1.99 (3H, m), 1.98-2.04 (1H, m), 2.04-2.15 (2H, m), 2.20 (6H, s), 2.73-2.87 (1H, m), 2.93-3.18 (3H, m), 3.88 (2H, s), 3.99-4.16 (2H, m), 5.18-5.36 (1H, m), 5.47 (2H, s). Di-methyl product: m / z (ES+), [M+H]+ = 664; 666.

[0540] Step 9: l-((8-Bromo-9-((tert-butyldimethylsilyl)ethvnyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-

[0541]

[0542] Pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcyclobutan-l-amine and l-((8-bromo-9-((tert-butyldimethylsilyl)ethvnyl)-7-fluoro-5-

[0543]

[0544] (((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V-methylcvclobutan-l-amine (1:1 mixture)

[0545] N

[0546] H

[0547] 1

[0548] Br-^r 1^N^O^"'-!, Br- / N

[0549]

[0550] Triphenylphosphine palladium chloride (0.21 g, 0.30 mmol) was added to l-((8-bromo-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-iodo-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine and l-((8-bromo-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-iodo-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V-methylcyclobutan-l-amine (1:1 mixture) (2.00 g, 3.04 mmol), tert-butyl(ethynyl)dimethylsilane (3.42 g, 24.34 mmol), NEta (4.3 mL, 30.43 mmol) and cuprous iodide (0.29 g, 1.52 mmol) in toluene (40 mL) under nitrogen. The resulting mixture was stirred at 100 °C for 2 hours. After cooling to RT, the solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. The pure fractions were evaporated to dryness to afford an inseparable mixture of l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcyclobutan-l-amine and-l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / -methylcyclobutan-l-amine (1:1) (1.70 g, 83%) as a yellow solid, which was used in the next step without further purification.

[0551] Mono-methyl product:XH NMR (300 MHz, DMSO-d6, 23 °C) 6 0.20 (6H, s), 1.01 (9H, s), 1.59-1.7 (1H, m), 1.71-1.92 (6H, m), 1.96-2.06 (3H, m), 2.07-2.16 (2H, m), 2.22 (3H, s), 2.8-2.93 (1H, m), 2.99-3.16(3H, m), 3.92 (2H, s), 4.05-4.2 (2H, m), 5.18-5.41 (1H, m), 5.52 (2H, s). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 662; 664.

[0552] Di-i: NMR (300 MHz, DMSO-d6, 23 °C) 6 0.20 (6H, s), 1.01 (9H, s), 1.59-1.7 (1H, m), 1.71-1.92 (6H, m), 1.96-2.06 (3H, m), 2.07-2.16 (2H, m), 2.22 (6H, s), 2.8-2.93 (1H, m), 2.99-3.16 (3H, m), 3.92 (2H, s), 4.05-4.2 (2H, m), 5.18-5.41 (1H, m), 5.52 (2H, s). m / z (ES+), [M+H]+ = 676; 678.

[0553]

[0554] 10: l-((8-Bromo-9-l si -7-fluoro-5-(((2R,7oS)-2-1 ro- i-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-:

[0555]

[0556] -N, N-

[0557]

[0558] i-l-amine

[0559] Br

[0560]

[0561] Formaldehyde (1.52 g, 50.77 mmol) was added to a mixture of l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine and l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / -methylcyclobutan-l-amine (1:1) (1.70 g, 2.54 mmol) in DCM (40 mL). The resulting mixture was stirred at 40 °C for 30 minutes. Then sodium triacetoxyhydroborate (3.23 g, 15.23 mmol) was added to the mixture and stirred at 40 °C for a further 1 hour. The reaction mixture was diluted with DCM (100 mL), and washed with water (50 mL x 3), and then saturated brine (50 mL x 3). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. Pure fractions were evaporated to dryness to afford l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine (1.50 g, 87 %) as a yellow solid.1H NMR (300 MHz, DMSO-d6, 22 °C) 60.20 (6H, s), 1.01 (9H, s), 1.57-1.7 (1H, m), 1.7-1.9 (6H, m), 1.95-2.02 (1H, m), 2.02-2.06 (1H, m), 2.06-2.17 (3H, m), 2.22 (6H, s), 2.77-2.92 (1H, m), 2.98-3.18 (3H, m), 3.92 (2H, s), 4.04-4.21 (2H, m), 5.19-5.37 (1H, m), 5.52 (2H, s). m / z (ES+), [M+H]+ = 676; 678.

[0562] 2-(8-Bromo-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)- / V, / V-dimethylethan-l-amine (lnt-12)

[0563]

[0564] Step 1: / V1-(5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- / V2. / V2-dimethylethane-l,2-diamine

[0565]

[0566] DIPEA (84 mL, 478.42 mmol) was added to 5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (20.0 g, 47.84 mmol) and HCCP (33.3 g, 95.68 mmol) in MeCN (200 mL) under nitrogen at RT over 30 minutes. Then A / ^A / ^dimethylethane-l^-diamine (8.43 g, 95.68 mmol) was added. The resulting mixture was stirred at RT for 1 hour. The reaction mixture was poured into water (500 mL) and extracted with DCM (2 x 500 mL). The combined organics were dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 60% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to afford / V1-(5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- / V2, / \ / 2-dimethylethane-l,2-diamine (13.0 g, 56%) as a yellow solid.1H NMR (300 MHz, DMSO-d6, 24 °C) 62.87 (6H, s), 3.52-3.57 (2H, m), 3.77-3.83 (2H, m), 4.77 (2H, s), 7.35-7.58 (5H, m). One exchangeable proton not seen, m / z (ES+), [M+H]+ = 487; 489. Step 2: 7-Bromo-2,6-dichloro-4-((2-(dimethylamino)ethyl)amino)-8-fluoroquinazolin-5-ol

[0567]

[0568] CsF (40.50 g, 266.29 mmol) was added to / V1-(5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- / V2, / V2-dimethylethane-l,2-diamine (13.0 g, 26.63 mmol) in DMF (65 mL) under nitrogen. The resulting mixture was stirred at 120 °C for 3 hours. After cooling to RT, the mixture was purified by C18-flash chromatography, elution gradient 10 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 7-bromo-2,6-dichloro-4-((2-(dimethylamino)ethyl)amino)-8-fluoroquinazolin-5-ol (6.00 g, 57%) as a brown solid.1H NMR (300 MHz, DMSO-dg, 24 °C) 6 2.89 (6H, s), 3.37 (2H, m), 3.90 (2H, m). Two exchangeable protons not observed, m / z (ES+), [M+H]+ = 397; 399.

[0569] 3: 7-Bromo-6-chloro-4-((2-(dimethylamii

[0570]

[0571] mino)-8-fluoro-2-i

[0572]

[0573] -2-

[0574]

[0575] izin-

[0576]

[0577] uinazolin-5-ol

[0578]

[0579] NaH (60% dispersion in mineral oil) (3.62 g, 90.44 mmol) was added to ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methanol (7.20 g, 45.22 mmol) in 1,4-dioxane: DMF(10:l, 60 mL) and the reaction mixture was stirred at RT for 30 minutes. 7-Bromo-2,6-dichloro-4-((2-(dimethylamino)ethyl)amino)-8-fluoroquinazolin-5-ol (6.00 g, 15.07 mmol) was added. The resulting mixture was stirred at 100 °C for 2 hours. After cooling to RT, the reaction mixture was quenched with saturated NH4CI solution (20 mL). The resulting mixture was purified by C18-flash chromatography, elution gradient 0 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 7-bromo-6-chloro-4-((2-(dimethylamino)ethyl)amino)-8-fluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (4.00 g, 51%) as a brown solid.1H NMR (300 MHz, DMSO-d6, 24 °C) 61.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.56 (6H, s), 2.91-2.94 (2H, m), 2.95-3.04 (2H, m), 3.23-3.27 (1H, m), 3.38-3.42 (2H, m), 3.62-3.67 (2H, m), 4.03-4.2 (1H, m), 5.25-5.30 (1H, m). Two exchangeable protons not observed, m / z (ES+), [M+H]+ = 520; 522.

[0580]

[0581] 4: 2-(8-Bromo-9-chloro-7-fluoro-5-i i-2-1 ro-lH-i yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)- / \ / , / \ / -dimethylethan-l-amine (lnt-12)

[0582]

[0583] Cs2CO3(5.00 g, 15.36 mmol) was added to a mixture of 7-bromo-6-chloro-4-((2- (dimethylamino)ethyl)amino)-8-fluoro-2-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)quinazolin-5-ol (4.00 g, 7.68 mmol) and dibromomethane (8.04 mL, 115.21 mmol) in DMF (40 mL). The resulting mixture was stirred at 90 °C for 2 hours. The resulting mixture was purified by C18-flash chromatography, elution gradient 0 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 2-(8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)- / \ / , / \ / -dimethylethan-l-amine (0.80 g, 20%) as a brown solid.1H NMR (300 MHz, DMSO-d6, 21 °C) 6 1.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.25 (6H, s), 2.54-2.73 (1H, m), 2.77-2.92 (1H, m), 2.94-3.06 (2H, m), 3.07-3.16 (2H, m), 3.84-3.90 (2H, m), 3.98-4.19 (2H, m), 5.25-5.30 (1H, m), 5.50 (2H, s). m / z (ES+), [M+H]+ = 532.

[0584] l-(8-Bromo-9-chloro-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)- [l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)- / V, / V,2-trimethylpropan-2-amine (lnt-13)

[0585]

[0586] lnt-13 Step 1: / V1-(5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- / \ / 2, / \ / 2,2-trimethylpropane- 1,2-diamine

[0587]

[0588] DIPEA (7.3 mL, 41.86 mmol) was added to 5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-ol (2.50 g, 5.98 mmol) and HCCP (3.12 g, 8.97 mmol) in MeCN (50 mL) under nitrogen over 30 minutes at RT. / V2, / V2,2-trimethylpropane-l,2-diamine (1.39 g, 11.96 mmol) was added. The mixture was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc (200 mL), and saturated brine (200 mL). A precipitate was formed in the organic phase, which was collected by filtration, dried under vacuum to afford / V1-(5-(benzyloxy)-7-bromo-2,6-dichloro-8-fluoroquinazolin-4-yl)- / V2, / \ / 2,2-trimethylpropane-1,2-diamine (1.10 g) as a yellow solid. The filtrate was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 20 to 30% EtOAc in petroleum ether. The pure fractions were evaporated to dryness to afford the title compound (0.90 g) as a yellow solid. A second batch was prepared in an analogous manner and combined to afford thetitle product (2.0 g, 65%) as a yellow solid, which was used in the next step without further purification.1H NMR (500 MHz, DMSO-d6, 23 °C) δ 0.94 (6H, s), 1.85 (6H, s), 3.39–3.43 (2H, m), 5.20 (2H, s), 7.35–7.39 (1H, m), 7.42–7.46 (2H, m), 7.52–7.56 (2H, m), 8.78 (1H, s). m / z (ES+), [M+H]+ = 515; 517.

[0589] 2: 7-Bromo-6-chloro-4-((2-(dim mino)-2-i mino)-8-fluoro-2-i -2- ro-lH-i izin- uinazolin-5-ol

[0590]

[0591] Cesium fluoride (5.30 g, 34.87 mmol) was added to / ^-(S-fbenzyloxyJ-y-bromo-Z^-dichloro-S-fluoroquinazolin-4-yl)- / V2, / V2,2-trimethylpropane-l,2-diamine (1.80 g, 3.49 mmol) in DMF (36 mL) at RT under nitrogen. The resulting mixture was stirred at 120 °C for 2 hours. After cooling to RT, sodium 2-methylbutan-2-olate (1.92 g, 17.43 mmol) and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (1.67 g, 10.46 mmol) were added to the mixture and the reaction stirred at 80 °C for 2 hours. After cooling to RT, the reaction mixture was purified by C18-flash chromatography, elution gradient 20 to 40% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 7-bromo-6-chloro-4-((2-(dimethylamino)-2-methylpropyl)amino)-8-fluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)quinazolin-5-ol (1.00 g, 52 %) as a green solid.1H NMR (500 MHz, DMSO-d6, 23 °C) 6 1.19-1.34 (6H, m), 1.81-2.33 (6H, m), 2.50 (6H, s), 2.58-2.78 (3H, m), 3.69-3.78 (2H, m), 4.02-4.16 (2H, m), 5.2-5.36 (2H, m), 12.57 (1H, s). One exchangeable proton was not seen, m / z (ES+), [M+H]+ = 548; 550.

[0592] 3: l-(8-Bromo-9-chloro-7-fluoro-5-i

[0593]

[0594] i-2-1 ro-lH-i

[0595]

[0596] yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)- / \ / , / \ / ,2-trimethylpropan-2-amine (lnt-13)

[0597]

[0598] Dibromomethane (6.33 g, 36.44 mmol) was added to 7-bromo-6-chloro-4-((2-(dimethylamino)-2-methylpropyl)amino)-8-fluoro-2-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)quinazolin-5-ol (1.00 g, 1.82 mmol) and cesium carbonate (1.19 g, 3.64 mmol) in DMF (36mL). The resulting mixture was stirred at 90 °C for 30 minutes. The mixture was cooled to RT. Then the mixture was purified by C18-flash chromatography, elution gradient 60 to 80% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 1-(8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-[1,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)-N,N,2-trimethylpropan-2-amine (0.64 g, 63%) as a purple solid.1H NMR (500 MHz, DMSO-d6, 23 °C) δ 0.96–1.08 (6H, m), 1.72–1.9 (3H, m), 1.94–2.12 (3H, m), 2.21 (6H, s), 2.8–2.87 (1H, m), 3–3.13 (2H, m), 3.69–3.78 (2H, m), 4.02–4.16 (2H, m), 5.2–5.36 (2H, m), 5.50 (2H, s). m / z (ES+), [M+H]+ = 560; 562.

[0599] Synthesis of l-((8-bromo-9-(difluoromethyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-14)

[0600]

[0601] lnt-14

[0602] Step 1: 7-Bromo-2-chloro- / V-{[l-(dimethylamino)cvclobutyl]methyl}-5,8-difluoroquinazolin-4-amine

[0603]

[0604] HCCP (6.72 g, 19.32 mmol) was added in one portion to a suspension of 7-bromo-2-chloro-5,8-difluoroquinazolin-4-ol (CAS No: 2820537-81-1) (5.19 g, 17.57 mmol) in acetonitrile (150 mL) at RT under nitrogen. The resulting mixture was cooled in an ice bath and DIPEA (20 mL, 114.17 mmol) was added slowly. The mixture was stirred at RT for 1 hour. l-(Dimethylamino)cyclobutanemethanamine (CAS No: 176445-78-6) (2.37 g, 18.44 mmol) in acetonitrile (20 mL) was then added to the reaction mixture and the resulting suspension was stirred to RT for 1 h. The suspension was diluted with water,filtered and the filter cake was washed with water. The solid was dissolved in DCM and passed through a phase separator cartridge. The filtrate was evaporated to dryness. The crude product was triturated with EtjO and the filtrate was evaporated to dryness to afford 7-bromo-2-chloro- / V-{[l-(dimethylamino)cyclobutyl]methyl}-5,8-difluoroquinazolin-4-amine (5.10 g, 72%) as a pale yellow solid.1H NMR (500 MHz, CDCl3, 27 °C) 1.59 (2H, ddt), 1.65 – 1.83 (2H, m), 2.20 (6H, s), 2.27 (2H, qd), 3.70 (2H, d), 7.16 (1H, dd), 7.65 (1H, d). m / z (ES+), [M+H]+ = 405.

[0605] 2: l-[(8-Bromo-5-chloro-7-1 oxazino[4,5,6-delquinazolin- - / V, / V- i-l-amine

[0606] ’N^CI

[0607]

[0608] Cesium carbonate (11.35 g, 34.83 mmol) was added to a mixture of 7-bromo-2-chloro-N-{[1-(dimethylamino)cyclobutyl]methyl}-5,8-difluoroquinazolin-4-amine (4.71 g, 11.61 mmol) and 2-(methylsulfonyl)ethan-l-ol (2.2 mL, 23.22 mmol) in DMF (50 mL) under nitrogen. The reaction mixture was heated to 100 °C for 1 hour The reaction mixture was cooled to 50 °C and chloroiodomethane (1.7 mL, 23.22 mmol) was added. The reaction mixture was heated to 80 °C for 1 hour. The mixture was then cooled to RT, diluted with water and extracted with DCM. The organic extract was passed through a phase separator cartridge and evaporated to dryness. The crude product was triturated by stirring overnight in Et? O, then filtered and the filtrate evaporated to dryness to afford l-[(8-bromo-5-chloro-7-fluoro[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl]- / V, / \ / -dimethylcyclobutan-l-amine (4.07 g, 84 %) as a red gum. m / z (ES+), [M+H]+ =415.

[0609] Step 3: l-{[8-Bromo-7-fluoro-5-{[(2R,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-vllmethoxv}[l,31oxazino[4,5,6-c / elquinazolin-3(2H)-vllmethvl}- / \ / , / \ / -dimethvlcvclobutan-l-amine

[0610]

[0611] Sodium hydride (60% dispersion in mineral oil) (0.51 g, 12.77 mmol) was added portionwise to a suspension of l-[(8-bromo-5-chloro-7-fluoro[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl]- / \ / , / \ / -dimethylcyclobutan-l-amine (3.54 g, 8.52 mmol) and ((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methanol (CAS No: 2097518-76-6) (1.49 g, 9.37 mmol) in 1,4-dioxane (50 mL) and DMF (5mL) under nitrogen in an ice bath. The mixture was stirred at RT for 1 hour. Water was added slowly to the mixture and extracted with EtOAc. The organic extract was evaporated. The residue was dissolved in DCM and passed through a phase separator cartridge. The filtrate was evaporated to dryness to afford the crude material, which was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1 M NH3 / MeOH. Fractions containing the product were evaporated to dryness. The crude was repurified by reverse phase chromatography, gradient 50% acetonitrile in water (containing 1% NH4OH (28-30% in water)) to 100% acetonitrile. Evaporation of pure fractions afforded l-{[8-bromo-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / V, / V-dimethylcyclobutan-l-amine (1.49 g, 33%) as a brown foam.1H NMR (500 MHz, CDCl3, 27 °C) 1.71 – 1.8 (2H, m), 1.82 – 1.97 (4H, m), 2.09 – 2.29 (12H, m), 2.96 (1H, td), 3.13 – 3.41 (3H, m), 3.94 (2H, dd), 4.17 – 4.29 (2H, m), 5.17 – 5.35 (3H, m), 6.80 (1H, d). m / z (ES+), [M+H]+ = 538; 540.

[0612] Step 4: 8-Bromo-3-{[l-(dimethylamino)cvclobutyl]methyl}-7-fluoro-5-{[(2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl]methoxy}-2,3-dihvdro[l,3]oxazino[4,5,6-de]quinazoline-9-carbaldehyde

[0613] Br

[0614]

[0615] Butyllithium (1.6 M in hexanes) (3.9 mL, 6.22 mmol) was added to a solution of diisopropylamine (1.0 mL, 7.22 mmol) in THF (20 mL) at -78 °C under nitrogen. The resulting solution was stirred for 30 minutes at -78 °C. A solution of l-{[8-bromo-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / \ / , / \ / -dimethylcyclobutan-l-amine (1.34 g, 2.49 mmol) in THF (10 mL) was then added dropwise. The mixture was stirred at -78 °C for 1 hour. Then / V, / V-dimethylformamide (0.96 mL, 12.44 mmol) was added and the reaction mixture was stirred at -78 °C for 15 minutes and then at 0 °C for 1 hour. The reaction mixture was quenched with saturated NH4CI solution at 0 °C and the resulting mixture was diluted with EtOAc and water. The organic layer was washed with saturated brine and then evaporated. The residue was dissolved in DCM and passed through a phase separator cartridge. Evaporation afforded the crude material, which was then triturated with Et2O. The trituration filtrate was evaporated to afford 8-bromo-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazoline-9-carbaldehyde (0.97 g, 69%) as a brown foam, m / z (ES+), [M+H]+ = 566; 568.Step 5: l-{[8-Bromo-9-(difluoromethyl)-7-fluoro-5-{[(2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin- 7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / \ / , / \ / -dimethylcyclobutan-l-amine (lnt-14)

[0616]

[0617] DAST (3.2 mL, 24.19 mmol) was added to a solution of 8-bromo-3-{[l- (dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazoline-9-carbaldehyde (1.37 g, 2.42 mmol) in DCM (30 mL) at 0 °C under nitrogen. The mixture was stirred at RT for 1 hour. Then a few microlitres of anhydrous EtOH was added and the reaction mixture was stirred at RT overnight. The reaction mixture was cautiously quenched with ice and saturated NaHCO3solution and then diluted with DCM. The organic layer was separated and dried by passing through a phase separator cartridge. The filtrate was evaporated to dryness. The crude product was purified by reverse phase chromatography, gradient 50% acetonitrile in water (containing 1% NH4OH (28-30% in water) to 100% acetonitrile. Evaporation of pure fractions afforded l-{[8-bromo-9-(difluoromethyl)-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / V, / V-dimethylcyclobutan-l-amine (lnt-14) (0.36 g, 25%) as a light brown foam, m / z (ES+), [M+H]+ = 588; 590.

[0618] Synthesis of l-{[8-bromo-9-chloro-7-fluoro-5-{[re / -(2 / ?*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl]methyl}- / V, / V-dimethylcyclobutan-l-amine (isomer 1; lnt-15 and isomer 2; lnt-16)

[0619]

[0620] isomer 1; lnt-15 isomer 2; lnt-16

[0621] Ste]3_l _l-{[8-bromo-9-chloro-7-fluoro-5-{[ / 'e / -(2 / ?*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl]methyl}- / V, / V-dimethylcyclobutan-l-amine Isomer 1 and Isomer 2

[0622]

[0623] isomer 1; lnt-15 isomer 2; lnt-16

[0624] Brine (1.25 mL), l-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-19) (0.56 g, 1.21 mmol), water (8.0 mL), 1 M HCI (aq.) (1.21 L, 1.21 mmol) were dissolved in an electrasyn tube (pH 5). The reaction was electrolysed using a RuO / Ti electrode, using 40 mA, 3.15 V to 4.2 V and 8 electron equivalents for 2 hours 45 minutes. The reaction was diluted with EtOAc (15 mL) water (10 mL). Then saturated NaHCO3solution was added to neutralise the mixture. The layers were separated and the aqueous was further extracted with EtOAc (15 mL x 2). The combined organics were passed through a phase separator and concentrated. The orange glass film was dried under vacuum overnight. The crude sulfone was used in the next step without further purification.

[0625] 2.2 M Lithium 2-methylpropan-2-olate in THF (0.83 mL, 1.82 mmol) was added to a stirred mixture of (trons)-tetrahydro-2-methoxy-lH-pyrrolizine-7a(5H)-methanol (CAS number: 2621934-70-9) (0.11 g, 0.64 mmol) and crude sulfone(0.30 g, 0.61 mmol) in MeCN (8.5 mL) under nitrogen. The resulting mixture was stirred at RT for 45 minutes. The reaction was passed through a SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford desired product (0.33 g, 46%) as a yellow glass and a mixture of diastereomers. This was separated by preparative chiral SFC using the following conditions: Column: ChiralPak IG, 5 pm, 20x250 mm; Mobile Phase A: scCO; Mobile Phase B: 0.1% NH3in MeOH, gradient used: 40 %B over 8.0 minutes; Flow rate: 80.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0626] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50% %B over 1.9 minutes Flow rate: 2.5 mL / min.

[0627] Peak 1 fractions containing the desired compound were consolidated and concentrated to give isomer 1 (lnt-15) (0.092 g, 28%) as a solid assigned >99.0%.etR = 2.29 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.68 - 1.78 (9H, m), 2.08 (4H, s), 2.21 (6H, s), 2.68 - 2.77 (2H, m), 2.96 - 3.07 (2H, m), 3.20 (3H, s), 3.98 (2H, p), 4.02 - 4.11 (2H, m), 5.52 (2H, s). m / z (ES+), [M+H]+ = 584; 586; 587.

[0628] Peak 2 fractions containing the desired compound were consolidated and concentrated to give isomer 2 (lnt-16) (0.16 g, 48%) as a solid assigned >99.0% e.e. tR = 2.73 min.1H NMR (500 MHz, DMSO-d6, 27°C) 1.68 - 1.78 (9H, m), 2.08 (4H, s), 2.21 (6H, s), 2.68 - 2.77 (2H, m), 2.96 - 3.07 (2H, m), 3.20 (3H, s), 3.98 (2H, p), 4.02 – 4.11 (2H, m), 5.52 (2H, s). m / z (ES+), [M+H]+ = 584; 586; 587.

[0629] Example la (rotational isomer 1) and lb (rotational isomer 2): 2-Amino-4-(3-((l- (dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0630]

[0631] Example 1a; Rotational isomer 1 Example 1b, Rotational isomer 2 Step 1: tert-Butyl (4-(9-((tert-butyldimethylsilyl)ethvnyl)-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0632]

[0633] XPhos Pd G3 (0.12 g, 0.14 mmol) was added to l-((8-bromo-9-((tert-butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)-N, N-dimethylcyclobutan-l-amine (lnt-11) (0.95 g, 1.40 mmol), tert-butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3) (0.87 g, 2.11 mmol) and K3PO4 (0.89 g, 4.21 mmol) in THF (20 mL) and water (5 mL) at RT. The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed with water (3 x 20 mL), and then saturated brine (3 x 20 mL). The organic layer wasdried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 60 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.76 g, 61%) as a yellow solid.1H NMR (300 MHz, DMSO-d6, 23 °C) 6 -0.14 (6H, d), 0.57 (9H, s), 1.48 (9H, s), 1.63-1.71 (1H, m), 1.76-1.88 (6H, m), 1.96-2.05 (2H, m), 2.09-2.18 (3H, m), 2.24 (6H, s), 2.77-2.88 (1H, m), 2.96-3.03 (1H, m), 3.04-3.14 (2H, m), 3.93 (2H, s), 4.05-4.2 (2H, m), 5.19-5.37 (lH,m), 5.57 (2H, s), 6.40 (1H, d), 7.28 (1H, t), 10.92 (1H, s). m / z (ES+), [M+H]+ = 881.

[0634] Step 2: tert-Butyl (4-(9-((tert-butyldimethylsilyl)ethvnyl)-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro- [l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cvano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0635]

[0636] Chlorosulfonyl isocyanate (3 mL, 34.50 mmol) was added to THF (40 mL) and cooled to -78 °C under nitrogen. To this solution, tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.76 g, 0.86 mmol) and DMF (2.7 mL, 34.50 mmol) in THF (40 mL) were added. The resulting mixture was stirred at -78 °C for 5 minutes and then stirred at RT for 1 hour. The reaction mixture was quenched with MeOH (20 mL) and the volatiles were removed under reduced pressure. Then the residue was diluted with EtOAc (100 mL) and washed sequentially with saturated NaHCO3solution (3x50 mL) and saturated brine (3 x50 mL). The organic extract was dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 60 to 100% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford the title compound (0.35 g, 45%) as a white solid (64% purity by LCMS). m / z (ES+), [M+H]+ = 907.Step 3: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-9-ethvnyl-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo(b]thiophene-3-carbonitrile

[0637]

[0638] TFA (2 mL, 25.96 mmol) was added to tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.35 g, 0.38 mmol) in DCM (4 mL) under nitrogen. The resulting mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMF (6 mL) and CsF (1.74 g, 11.42 mmol) was added under nitrogen. The mixture was stirred at RT for 16 hours. The reaction mixture was filtered through a short pad of silica gel. The filtrate was purified by C18-flash chromatography elution gradient 40% to 70% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford then repurified by preparative HPLC by the following conditions: Column: Xbridge Prep C18 OBD, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3+ 0.05% NH4OH), Mobile Phase B: ACN; Flow rate: 60 mL / min; Gradient: 46% B to 67% B in 8 min; Wave Length: 254 / 220 nm; RTl(min): 7.27. Fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (0.08 g, 30%) as a white solid.1H NMR (300 MHz, DMSO-dg, 23 °C) 61.62-1.7 (1H, m), 1.73-1.88 (6H, m), 1.96-2.06 (2H, m), 2.08-2.18 (3H, m), 2.23 (6H, s), 2.76-2.9 (1H, m), 2.97-3.15 (3H, m), 3.95 (2H, s), 4.05-4.18 (2H, m), 4.20 (1H, s), 5.17-5.4 (1H, m), 5.46-5.58 (2H, m), 7.28 (1H, t), 8.24 (2H, s). m / z (ES+), [M+H]+ = 692.

[0639] Step 4: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-9-ethvnyl-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (Examples la & lb, Rotational isomers 1 and 2)

[0640]

[0641] Example 1a; Rotational isomer 1 Example 1b, Rotational isomer 2 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (80 mg, 0.12 mmol) was purified by preparative chiral HPLC by the following conditions: Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: Hex (0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 30; Wave Length: 220 / 254 nm; RTl(min): 4.444 (rotational isomer 1); RT2(min): 6.793 (rotational isomer 2).

[0642] Peak 1 fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (21.5 mg, 27%) as a white solid assigned >99.0% e.e. (la, rotational isomer 1).1H NMR (400 MHz, DMSO-d6, 22 °C) 61.58-1.71 (1H, m), 1.72-1.87 (6H, m), 1.95-2.06 (2H, m), 2.08-2.16 (3H, m), 2.22 (6H, s), 2.77-2.87 (1H, m), 2.97-3.03 (1H, m), 3.05-3.12 (2H, m), 3.88-4 (2H, m), 4.06-4.16 (2H, m), 4.19 (1H, s), 5.21-5.34 (1H, m), 5.45-5.58 (2H, m), 7.28 (1H, t), 8.23 (2H, s). m / z (ES+), [M+H]+ = 692.

[0643] Peak 2 fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (25 mg, 31%) as a white solid assigned >99.0% e.e. (lb, rotational isomer 2).1H NMR (400 MHz, DMSO-d6, 22 °C) δ 1.59–1.7 (1H, m), 1.71–1.88 (6H, m), 1.94–2.06 (2H, m), 2.06–2.16 (3H, m), 2.22 (6H, s), 2.76–2.89 (1H, m), 3.01 (1H, s), 3.04–3.13 (2H, m), 3.94 (2H, s), 4.04–4.17 (2H, m), 4.19 (1H, s), 5.27 (1H, d), 5.43–5.59 (2H, m), 7.28 (1H, t), 8.23 (2H, s). m / z (ES+), [M+H]+ = 692.

[0644] Example 2a (rotational isomer 1) and 2b (rotational isomer 2): 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-

[0645]

[0646] Step 1: tert-Butyl (4-(9-((tert-butyldimethylsilyl)ethvnyl)-3-((l-(dimethylamino)cvclobutyl)methyl)-7- fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihvdro- [l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0647]

[0648] C Phos Pd G3 (0.06 g, 0.07 mmol) was added to C Phos (0.032 mg, 0.07 mmol), l-((8-bromo-9-((tert- butyldimethylsilyl)ethynyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)- yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine (lnt-11) (0.50 g, 0.74 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2- yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (0.44 g, 1.11 mmol) and K3PO4(0.47 g, 2.22 mmol) in THF (10 mL) and water (2.5 mL) at RT. The resulting mixture was stirred at 60 °C for 2 hours. The reaction mixture was diluted with EtOAc (50 mL) and washed sequentially with water (3x20 mL), and saturated brine (3 x 20 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 60 to 100% MeOH in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.50 g, 78%) as a pale yellow solid.1H NMR (300 MHz, DMSO-d6, 22 °C) δ -0.16 (6H, d), 0.57 (9H, s), 1.47 (9H, s), 1.63-1.71 (1H, m), 1.75-1.89 (6H, m), 1.94-2.06 (2H, m), 2.06-2.19 (3H, m), 2.24 (6H, s), 2.76-2.9 (1H, m), 2.96-3.14 (3H, m), 3.95 (2H, s), 4.05-4.21 (2H, m), 5.19-5.37(1H, m), 5.58 (2H, s), 6.37 (1H, s), 7.05-7.24 (1H, m), 7.91 (1H, dd), 10.68 (1H, s). m / z (ES+), [M+H]+ = 863.

[0649] Step 2: tert-Butyl (4-(9-((tert-butyldimethylsilyl)ethvnyl)-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro- [l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cvano-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0650]

[0651] Chlorosulfonyl isocyanate (0.5 mL, 5.56 mmol) was added to THF (24 mL) and cooled to -78 °C under nitrogen. Then tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l- (dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.48 g, 0.56 mmol) and DMF (0.4 mL, 5.56 mmol) in THF (24 mL) were added to the mixture under nitrogen. The mixture was stirred at -78 °C for 5 minutes and then stirred at RT for 1 hour. The reaction mixture was quenched with saturated NaHCO3solution (100 mL) and extracted with EtOAc (3 x 100 mL). The combined organics were washed sequentially with water (3 x 50 mL), and saturated brine (3 x 50 mL). The organic layer was dried over Na2SO4, filtered and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH in DCM. The pure fractions were evaporated to dryness to afford tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.35 g, 71%) as a pale yellow solid.

[0652] 1H NMR (400 MHz, DMSO-d6, 20 °C) δ -0.18 (6H, d), 0.54 (9H, s), 1.48 (9H, s), 1.61-1.71 (1H, m), 1.74-1.94 (6H, m), 1.98-2.07 (1H, m), 2.08-2.22 (4H, m), 2.28 (6H, s), 2.82-2.97 (1H, m), 3.07-3.22 (3H, m),3.9-4.04 (2H, m), 4.07-4.28 (2H, m), 5.19-5.37(1H, m), 5.49-5.61 (2H, m), 7.19-7.36 (1H, m), 7.88-8.1 (1H, m). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 888.

[0653] Step 3: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-9-ethvnyl-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile

[0654]

[0655] TFA (3 mL, 38.94 mmol) was added to tert-butyl (4-(9-((tert-butyldimethylsilyl)ethynyl)-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.35 g, 0.39 mmol) in DCM (8 mL) under nitrogen. The resulting mixture was stirred at RT for 2 hours. The solvent was removed under reduced pressure. The residue was dissolved in DMF (10 mL), and CsF (1.80 g, 11.82 mmol) was added under nitrogen. The resulting mixture was stirred at RT for 16 hours. The reaction mixture was filtered through a short pad of silica. The filtrate was purified by C18-flash chromatography, elution gradient 40% to 70% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.15 g, 57%) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 20 °C) δ 1.6-1.71 (1H, m), 1.71-1.89 (6H, m), 1.95-2.17 (5H, m), 2.24 (6H, s), 2.77-2.93 (1H, m), 2.98-3.19 (3H, m), 3.88-4.02 (2H, m), 4.05-4.2 (3H, m), 5.22-5.47 (1H, m), 5.49-5.59 (2H, m), 7.11 (1H, t), 7.80 (1H, dd), 7.94 (2H, s). m / z (ES+), [M+H]+ = 674.

[0656] Step 4: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-9-ethvnyl-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile (Examples 2a & 2b, Rotational isomers 1 and 2)

[0657]

[0658] Example 2a; Rotational isomer 1 Example 2b, Rotational isomer 2 The atropisomeric mixture (0.15 g, 0.22 mmol) was purified by preparative chiral HPLC by the following conditions: Column: CHIRALPAK IC, 2*25 cm, 5 pm; Mobile Phase A: HEX (0.5% 2M NH3-MeOH), Mobile Phase B: ETOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 25; Wave Length: 220 / 255 nm; RTl(min): 6.433 (rotational isomer 1); RT2(min): 11.278 (rotational isomer 2).

[0659] Peak 1 fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (45 mg, 30 %) as a white solid assigned >99% e.e. (2a, rotational isomer 1).1H NMR (400 MHz, DMSO-d6, 21 °C) δ 1.61-1.7 (1H, m), 1.7-1.89 (6H, m), 1.94-2.04 (1H, m), 2.03-2.16 (4H, m), 2.22 (6H, s), 2.76-2.88 (1H, m), 2.98-3.05 (1H, m), 3.05-3.15 (2H, m), 3.85-4.02 (2H, m), 4.04-4.18 (3H, m), 5.19-5.38 (1H, m), 5.44-5.58 (2H, m), 7.10 (1H, t), 7.80 (1H, dd), 7.93 (2H, s). m / z (ES+), [M+H]+ = 674.

[0660] Peak 2 fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (42 mg, 28%) as a white solid assigned >99.0% e.e. (2b, rotational isomer 2).1H NMR (400 MHz, DMSO-d6, 21 °C) δ 1.6-1.71 (1H, m), 1.71-1.89 (6H, m), 1.93-2.02 (1H, m), 2.02-2.16 (4H, m), 2.22 (6H, s), 2.75-2.91 (1H, m), 2.96-3.16 (3H, m), 3.94 (2H, s), 4.07 (1H, d), 4.12-4.18 (2H, m), 5.17-5.37 (1H, m), 5.46-5.57 (2H, m), 7.10 (1H, t), 7.80 (1H, dd), 7.93 (2H, s). m / z (ES+), [M+H]+ = 674.

[0661] Example 3a (rotational isomer 1) and 3b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0662]

[0663] Example 3a; Rotational Isomer 1 Example 3b; Rotational Isomer 2 Step 1: tert-Butyl (4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0664]

[0665] CPhos Pd G3 (2.47 g, 3.06 mmol) was added to (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-c / e]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethyltetrahydrofuran-3-amine (lnt-4) (9.00 g, 15.28 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (12.02 g, 30.57 mmol), K2CO3 (4.22 g, 30.57 mmol) and CPhos (1.34 g, 3.06 mmol) in 2-MeTHF (360 mL) and water (36 mL). The reaction mixture was evacuated and backfilled with nitrogen (x 3) in an ice bath. The resulting mixture was stirred at 60 °C for 2 hours. After cooling to RT, the reaction mixture was poured into saturated brine (200 mL) and extracted with EtOAc (3 x 300 mL). The combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 2 to 80% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated and extracted with DCM: MeOH (10:1, 2 x 300 mL), and the combined organics were dried over MgSO4, filtered and evaporated. The crude solid was triturated with TBME then the resultant solid was collected via filtration and dried under vacuum. The mother liquor was evaporated and repurified by preparative HPLC by the following conditions: Column: Xselect CSH Prep C18 OBD, 30*150 mm, 5 pm; Mobile Phase A: Water (containing 0.1% TFA), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 30% B to 38% B over 8 min; Wave Length: 254 / 220 nm; RTl(min): 8.53. Fractions containing the desired compound were basified with saturated NaHCO3solution, extracted with DCM: MeOH (10:1, 2 x 100 mL), and the combined organics were dried over MgSO4, filtered and evaporated to afford pale yellow solid. Two batches were combined to afford tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (7.20 g, 61%) as a pale yellow solid.XH NMR (300 MHz, DMSO-d6, 24 °C) δ 1.47 (9H, s), 1.70-2.19 (8H, m), 2.32 (6H, s), 2.79-2.87 (1H, m), 3.01-3.18 (3H, m), 3.68-3.91 (4H, m), 3.93-4.12 (3H, m), 4.15-4.20 (1H, m), 5.29 (1H, d), 5.51-5.7 (2H, m), 6.34 (1H, s), 7.19-7.25 (1H, m), 7.97-8.02 (1H, m), 10.73 (1H, s). m / z (ES+), [M+H]+ = 775.

[0666] 2: tert-Butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino

[0667]

[0668] i-3-yl)methyl)-7-fluoro-5- i-2-1 ro-lH-pyrrolizin-

[0669]

[0670] -2,3-dihydro-[l,31oxazino[4,5,6-

[0671]

[0672] in-8-yl)-3-i,-5-l

[0673]

[0674] io 1-2-’

[0675] i*N

[0676] Boc

[0677]

[0678] A solution of chlorosulfonyl isocyanate (18.89 g, 133.50 mmol) in THF (36 mL) was added dropwise to a stirred solution of tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (6.90 g, 8.90 mmol) and DMF (17.23 mL, 222.50 mmol) in THF (90 mL) at -70 °C, under nitrogen. The resulting mixture was stirred at -70 °C for 10 minutes and then allowed to warm to RT gradually. The resulting mixture was stirred at RT for 15 minutes. The reaction mixture was poured into a cooled saturated NaHCO3solution (1 L), extracted with EtOAc (2 x 1 L), and the combined organic layers were dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography (performed in two batches), elution gradient 2 to 60% MeCN in water (containing 0.1% NH4HCO3). Pure fractions were evaporated and extracted with DCM: MeOH (10:1, 2 x 700 mL). The combined organics were dried over Na2SO4, filtered and evaporated to afford tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (5.40 g, 76 %) as a yellow solid.1H NMR (500 MHz, DMSO, 1 °C) 1.48 (9H, s), 1.8 - 1.96 (2H, m), 2.02 - 2.07 (1H, m), 2.11 - 2.2 (1H, m), 2.33 (6H, d), 2.91 (1H, s), 3.06 - 3.39 (7H, m), 3.67 - 3.89 (4H, m), 3.92 - 4.08 (3H, m), 4.13 - 4.31 (2H, m), 5.26 - 5.42 (1H, m), 5.49 (1H, dd), 5.58 (1H, dd), 7.28 (1H, s), 7.99 (1H, s). m / z (ES+), [M+H]+ = 800.Step 3: 2-Amino-4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile

[0679]

[0680] TFA (25.5 mL, 331.13 mmol) was added to tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (5.30 g, 6.62 mmol) in DCM (32 mL) in an ice bath. The resulting solution was stirred at RT for 90 minutes. The mixture was then poured into an ice-cooled saturated NaHCO3solution (300 mL) slowly and then extracted with DCM: MeOH (10:1, 2 x 200 mL). The combined organics were dried over MgSO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 2 to 60% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were evaporated and extracted with DCM: MeOH (10:1, 2 x 200 mL). The combined organics were dried over MgSO4, filtered and evaporated to afford 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (3.80 g, 82%) as a yellow solid and as a mixture of atropisomers.1H NMR (300 MHz, DMSO-d6, 24 °C) δ 1.76-2.20 (8H, m), 2.31 (6H, d), 2.80-2.87 (1H, m), 2.96-3.22 (3H, m), 3.66-4.22 (8H, m), 5.29 (1H, d), 5.43-5.66 (2H, m), 7.12-7.18 (1H, m), 7.83-7.88 (1H, m), 8.00 (2H, s). m / z (ES+), [M+H]+ = 700.

[0681] Step 4: 2-Amino-4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile (Examples 3a & 3b, rotational isomers 1 and 2)

[0682]

[0683] Example 3a; Rotational Isomer 1 Example 3b; Rotational Isomer 2

[0684] 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (3.80 g, 5.43 mmol) was separated by preparative chiral SFC by the following conditions: Column: CHIRALPAK-IK, 3*25 mm, 5 pm; Mobile Phase A: scCO2, Mobile Phase B: MeOH; Flow rate: 100 mL / min; Gradient (B%): isocratic 50; Back Pressure (bar): 100; Wavelength: 220 nm; RT1 (min): 3.98; RT2 (min): 5.42.

[0685] Peak 1 fractions containing the desired compound were evaporated to dryness. The product was repurified by C18-flash chromatography, elution gradient 2 to 60% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were dried by lyophilization to afford 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (1.48 g, 39%) as a pale yellow solid assigned >99.0 % ee (3a, rotational isomer 1).1H NMR (400 MHz, DMSO-dg, 22 °C) 1.72 - 1.89 (2H, m), 1.77 - 1.84 (1H, m), 1.84 - 1.92 (1H, m), 1.98 - 2.05 (1H, m), 1.98 - 2.03 (1H, m), 2.04 - 2.20 (2H, m), 2.30 (6H, s), 2.78 - 2.88 (1H, m), 2.97 - 3.12 (2H, m), 3.14 (1H, br s), 3.69 - 3.77 (2H, m), 3.77 - 3.88 (2H, m), 3.90 - 4.06 (2H, m), 4.07 (1H, br d), 4.16 (1H, br d), 5.19 - 5.37 (1H, m), 5.47 (1H, d), 5.59 (1H, d), 7.15 (1H, t), 7.85 (1H, dd), 8.01 (2H, br s). m / z (ES+), [M+H]+ = 700. [α24.6D] = +39 (c. 1.82, MeOH).

[0686] Peak 2 fractions containing the desired compound were evaporated to dryness. The product was repurified by C18-flash chromatography, elution gradient 2 to 60% MeCN in water (containing 0.1% NH4HCO3). The pure fractions were dried by lyophilization to afford 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (1.75 g, 46%) as a pale yellow solid assigned >99.0 % ee (3b, rotational isomer 2).1H NMR (400 MHz, DMSO-d6, 27 °C) 1.75 - 2.2 (8H, m), 2.31 (6H, s), 2.79 - 3.16 (4H, m), 3.65 - 3.91 (4H, m), 3.92 - 4.06 (2H, m), 4.12 (2H, q), 5.28 (1H, d), 5.52 (2H, dd), 7.15 (1H, t), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 700.Example 4a (rotational isomer 1) and 4b (rotational isomer 2): 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0687] lnt-5

[0688]

[0689] Example 4a, rotational isomer 1 Example 4b, rotational isomer 2

[0690]

[0691] 1: tert-\ -7-fluoro-5-(((2R,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6- in-8-yl)-5,7-di iophen-2-’

[0692]

[0693] CPhos Pd G3 (0.048 g, 0.06 mmol) and CPhos (0.026 g, 0.06 mmol) were added to a de-oxygenated solution of l-((8-bromo-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethylcyclobutan-l-amine (lnt-5) (0.33 g, 0.60 mmol), tert-butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3) (0.32 g, 0.78 mmol) and K2CO3 (0.17 g, 1.20 mmol) in 2-MeTHF (8 mL) and water (1.6 mL). The reaction mixture was heated to 70 °C for 90 minutes. After cooling to RT, the reaction was passed through an SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.40 g, 89%) as a brown solid, which was used directly in the next step without further purification.1H NMR (500 MHz, DMSO, 27°C) 1.15 (2H, p), 1.47 (9H, s),1.57 - 1.72 (1H, m), 1.76 - 1.86 (4H, m), 1.99 (1H, d), 2.03 - 2.19 (4H, m), 2.24 (6H, s), 2.32 (3H, s), 2.83 (1H, q), 3.08 (3H, d), 3.86 - 3.99 (2H, m), 4.01 - 4.18 (2H, m), 5.2 - 5.36 (1H, m), 5.46 - 5.51 (2H, m), 6.31 (1H, d), 7.32 (1H, t), 10.89 (1H, s). m / z (ES+), [M+H]+ = 757.

[0694]

[0695] 2: tert-Butyl (3-cyano-4-(3-i ami m -7-fluoro-5-i

[0696]

[0697] -2- -9- -2,3-dihydro-[l,31oxazino[4,5,6- -5,7-1 io i-2-’

[0698] N N

[0699] Boc

[0700] N

[0701] N

[0702]

[0703] tert-Butyl (4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH- pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7- difluorobenzo[b]thiophen-2-yl)carbamate (0.48 g, 0.63 mmol) was dissolved in THF (10 mL) and acetonitrile (60 mL) and cooled to -10 °C in an ice salt bath. Chlorosulfonyl isocyanate (0.33 mL, 3.79 mmol) was added. The cooling bath was removed and the reaction was stirred at RT for 30 min. The reaction was cooled in an ice salt bath and DMF (2.5 mL, 31.54 mmol) was added dropwise. The cooling bath was removed and the reaction was stirred at RT for a further 30 min. The reaction was cooled in an ice salt bath and quenched with water (2 mL). The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and fractions containing the desired product were evaporated to dryness to afford the title compound (0.49 g, 0.63 g) as a brown solid. The crude product was directly used in the next step without further purification.

[0704] Step 3: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2- fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-(l,3]oxazino(4,5,6- de]quinazolin-8-yl)-5,7-difluorobenzo(b]thiophene-3-carbonitrile (Examples 4a & 4b, rotational isomers 1 and 2)

[0705]

[0706] Example 4a, rotational isomer 1 Example 4b, rotational isomer 2 TFA (2.43 mL, 31.50 mmol) was added to a solution of tert-butyl (3-cyano-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.49 g, 0.63 mmol) in DCM (9 mL). The reaction mixture was stirred at RT for 90 minutes. The reaction mixture was poured onto an SCX column, washed with MeOH / water (1:1, 100 mL), and then MeOH (50 mL). The desired product was eluted from the column using 2 M NH3 / MeOH and the pure fractions were evaporated to dryness. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% 1 M NH3 / MeOH in DCM. The pure fractions were evaporated to dryness to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (91 mg, 21%) as a brown solid.

[0707] The atropisomeric mixture (91 mg) was purified by preparative chiral SFC by the following conditions: Column: YMC SB, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient: 20%B over 12 min then 50%B over 19.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40 °C.

[0708] Peak 1 fractions containing the desired compound were consolidated and concentrated to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (11.4 mg, 13 %) as a white solid assigned >99.0 % e.e (4a, rotational isomer 1).1H NMR (500 MHz, DMSO-d6, 27 °C) 1.61 - 1.7 (1H, m), 1.81 (5H, tdd), 1.88 (3H, s), 1.93 - 2.18 (6H, m), 2.23 (6H, s), 2.82 (1H, td), 2.96 - 3.17 (3H, m), 3.85 - 4.02 (2H, m), 4.02 - 4.19 (2H, m), 5.19 - 5.36 (1H, m), 5.37 - 5.5 (2H, m), 7.27 (1H, t), 8.19 (2H, s). m / z ( ES+), [M+H]+ = 682. Peak 2 fractions containing the desired compound were consolidated and concentrated to afford 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (11.1 mg, 12 %) as a white solid assigned 94.6 % e.e. (4b,rotational isomer 2).1H NMR (500 MHz, DMSO-cfe, 27 °C) 1.61 - 1.7 (1H, m), 1.81 (5H, tdd), 1.88 (3H, s), 1.93 - 2.18 (6H, m), 2.23 (6H, s), 2.82 (1H, td), 2.96 - 3.17 (3H, m), 3.85 - 4.02 (2H, m), 4.02 - 4.19 (2H, m), 5.19 - 5.36 (1H, m), 5.37 - 5.5 (2H, m), 7.27 ( 1H, t), 8.19 (2H, s). m / z (ES+), [M+H]+ = 682.

[0709] Example 5a (rotational isomer 1) and 5b (rotational isomer 2): 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0710]

[0711] Example 5a, rotational isomer 1 Example 5b, rotational isomer 2

[0712] Step 1: tert-Butyl (4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0713]

[0714] CPhos Pd G3 (0.075 g, 0.09 mmol), CPhos (0.041 g, 0.09 mmol), K2CO3(0.26 g, 1.86 mmol) and tertbutyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (Int-2) (0.48 g, 1.21 mmol) were added to l-((8-bromo-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / \ / -dimethylcyclobutan-l-amine (lnt-5) (0.51 g, 0.93 mmol) in 1,4-dioxane (10 mL) and water (1 mL). The mixture was evacuated with nitrogen (5 cycles). The reaction mixture was heated to 70 °C for 2 hours and then cooled to RT. The reaction mixture was filtered through Celite, the Celite pad was washedwith MeOH and the filtrate was evaporated to dryness then redissolved in MeOH. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness to afford the title compound (0.68 g, 99 %) as a solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.05 - 1.26 (1H, m), 1.46 (9H, s), 1.56 - 1.7 (1H, m), 1.74 - 1.89 (6H, m), 1.99 (1H, d), 2.04 - 2.18 (4H, m), 2.25 (6H, s), 2.33 (2H, d), 2.83 (1H, q), 3 - 3.16 (3H, m), 3.87 - 3.99 (2H, m), 4.07 (1H, dd), 4.15 (1H, t), 5.2 - 5.37 (1H, m), 5.48 (2H, d), 6.28 (1H, s), 7.17 - 7.23 (1H, m), 7.92 - 7.98 (1H, m), 10.66 (1H, s). m / z (ES+), [M+H]+ = 739.

[0715]

[0716] 2: tert-l i-4-(3-((l-(dimethylami methyl)-7-fluoro-5-(((2R,7oS)-2-

[0717]

[0718] ro-lH-i izin- -9-methyl-2,3-dihydro-[l,31oxazino[4,5,6- in-8-yl)-5-1 io i-2-’

[0719] N N

[0720] Boc

[0721] N II

[0722] N^O- N

[0723]

[0724] Chlorosulfonyl isocyanate (0.8 mL, 9.22 mmol) was added dropwise to a cooled solution of tert-butyl (4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.68 g, 0.92 mmol) in THF (13 mL) and DMF (1.7 mL, 22.12 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 10 minutes at -78 °C then was stirred at 0 °C for a further 30 minutes. The reaction mixture was cooled in ice bath and quenched carefully with water (3 mL). The reaction mixture was then passed through an SCX column washing with MeOH. The desired product was eluted with 2 M NH3 / MeOH. The filtrate was evaporated to dryness to afford the crude title compound (0.60 g, 86%) as a brown solid, which was used in the next step without further purification, m / z (ES+), [M+H]+ = 764.

[0725] Step 3: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (Examples 5a & 5b, rotational isomers 1 and 2)

[0726]

[0727] Example 5a, rotational isomer 1 Example 5b, rotational isomer 2 TFA (3.1 mL, 39.53 mmol) was added to a solution of tert-butyl (3-cyano-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.60 g, 0.79 mmol) in DCM (11 mL) and the reaction mixture was stirred at RT for 90 minutes. The reaction mixture was poured onto an SCX column, washed with MeOH / water (1:1, 100 mL), and then MeOH (50 mL). The desired product was eluted from the column using 2 M NH3 / MeOH and fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative SFC by the following conditions: Column: BEH-2EP, 30x250 mm, 5 pm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient used: 15% B to 25% %B over 7 minutes; Flow rate: 100 mL / min; BPR: 100 bar; Column temperature: 40 °C. Fractions containing the desired compounds were consolidated and concentrated. The atropisomeric mixture was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 30 x 250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient used: 40 %B over 8.5 minutes; Flow rate: 60 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0728] Peak 1 fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (39.6 mg, 7%) as a white solid assigned >99.0 % e.e. (5a, rotational isomer 1).1H NMR (500 MHz, DMSO-d6, 27°C) 1.66 (1H, d), 1.73 - 1.85 (6H, m), 1.88 (3H, d), 1.95 - 2.15 (5H, m), 2.23 (6H, d), 2.83 (1H, t), 2.97 - 3.15 (3H, m), 3.84 - 4.01 (2H, m), 4.03 - 4.15 (2H, m), 5.19 - 5.35 (1H, m), 5.35 - 5.52 (2H, m), 7.08 - 7.16 (1H, m), 7.81 (1H, ddd), 7.90 (2H, s). m / z (ES+), [M+H]+ = 664.

[0729] Peak 2 fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (42.1 mg, 7%) assigned >99.0 % e.e. (5b, rotational isomer 2).1H NMR (500 MHz, DMSO_3mm, 27°C) 1.61 - 1.7 (1H, m), 1.71 - 1.86 (6H, m), 1.87 (3H, s), 1.93 - 2.18(5H, m), 2.23 (6H, s), 2.78 - 2.87 (1H, m), 2.99 - 3.15 (3H, m), 3.93 (2H, q), 4.03 - 4.15 (2H, m), 5.18 -5.36 (1H, m), 5.36 - 5.5 (2H, m), 7.07 - 7.17 (1H, m), 7.81 (1H, dd), 7.90 (2H, s). m / z (ES+), [M+H]+ = 664.

[0730] Example 6a (rotational isomer 1) and 6b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0731]

[0732] Example 6a, rotational isomer 1 Example 6b, rotational isomer 2

[0733] Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-(l,31oxazino(4,5,6-de1quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0734]

[0735] Oxone* (3.10 g, 5.05 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-6) (1.70 g, 2.53 mmol) in THF (47 mL) / water (9.5 mL) under nitrogen. The resulting solution was stirred at RT for 30 minutes. The reaction mixture was quenched with 15% sodium bisulfite solution (20 mL) and saturated sodium hydrogen carbonate solution (10 mL) and extracted with EtOAc (3 x 40 mL). The combined organics were dried over MgSO4, filtered and evaporated to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylsulfonyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate as an orange solid. This crude material was used in the next step without further purification.2.2 M Lithium 2-methylpropan-2-olate in THF (3.5 mL, 7.59 mmol) was added to a stirred mixture of ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (CAS No: 2097518-76-6) (0.48 g, 3.04 mmol) and crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylsulfonyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (1.78 g, 2.53 mmol) in acetonitrile (36 mL) under nitrogen. The resulting mixture was stirred at RT for 30 minutes. The reaction mixture was passed through an SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate as a yellow glass (1.9 g).1H NMR (500 MHz, DMSO, 27°C) 1.48 (9H, s), 1.61 - 1.73 (1H, m), 1.75 - 1.95 (6H, m), 2.04 (1H, d), 2.15 (3H, dd), 2.29 (6H, s), 2.90 (1H, s), 3.20 (4H, s), 3.93 - 4.06 (2H, m), 4.1 - 4.28 (2H, m), 5.22 - 5.43 (1H, m), 5.53 (1H, dd), 5.59 (1H, dd), 7.27 (1H, s), 7.98 (1H, s), 11.26 (1H, s). m / z (ES-), [M-H]- = 782.

[0736] Step 2: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile and 2-amino-4-(9-chloro-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cvclobutyl)methyl)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile (lnt-17)

[0737]

[0738] side product (lnt-17)

[0739] TFA (4.0 mL, 52.28 mmol) was added to a solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.82 g, 1.05 mmol) in DCM (14 mL) and the mixture was stirred at RT for 3 hours. The reaction mixture was poured onto an SCX column, washed with MeOH / water (1:1, 100 mL), and thenMeOH (50 mL). The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB, 5 pm silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing by volume 1% NH4OH (28-30% in H2O) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.47 g, 65%) as a white solid.1H NMR (500 MHz, DMSO-d6, 27°C) 1.61 - 1.71 (1H, m), 1.74 - 1.84 (5H, m), 1.99 (1H, s), 2.03 - 2.18 (4H, m), 2.23 (6H, s), 2.83 (1H, q), 3.01 - 3.15 (3H, m), 3.86 - 4.02 (2H, m), 4.05 - 4.12 (2H, m), 4.15 (1H, dd), 5.19 - 5.38 (1H, m), 5.46 - 5.61 (2H, m), 7.14 (1H, dd), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 684.

[0740] In addition, 2-amino-4-(9-chloro-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.039 g, 6%) (lnt-17) was isolated as a cream solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.69 - 1.9 (8H, m), 1.95 - 2.19 (4H, m), 2.25 (3H, s), 2.82 (1H, td), 3 - 3.13 (3H, m), 3.17 (1H, s), 3.85 - 3.96 (2H, m), 4.04 - 4.18 (2H, m), 5.17 - 5.35 (1H, m), 5.44 - 5.57 (2H, m), 7.13 (1H, dd), 7.84 (1H, dd), 7.96 (2H, s). m / z (ES+), [M+H]+ = 670.

[0741] Step 3: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (Examples 6a & 6b, rotational isomers 1 and 2)

[0742]

[0743] Example 6a, rotational isomer 1 Example 6b, rotational isomer 2 The atropisomeric mixture (0.87 g, 1.26 mmol) was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 30 x 250 mm, Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH, gradient: 40% B over 11.5 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40 °C.

[0744] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 μmMobile phase: A = Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50 B over 4.0 minutes, flow rate: 2.5 mL / min. Peak 1 fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.34 g, 39%) assigned >99.0 % e.e. (6a, rotational isomer 1), tR = 2.09 min.1H NMR (600 MHz, DMSO, 27 °C) 1.61 -1.69 (1H, m), 1.72 - 1.9 (6H, m), 1.94 - 2.17 (5H, m), 2.23 (6H, s), 2.79 - 2.86 (1H, m), 2.98 - 3.13 (3H, m), 3.93 (1H, d), 3.98 (1H, d), 4.08 (1H, d), 4.14 (1H, d), 5.2 - 5.34 (1H, m), 5.50 (1H, d), 5.57 (1H, d), 7.14 (1H, dd), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 684.

[0745] Peak 2 fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.34 g, 39%) assigned >99.0% e.e. (6b, rotational isomer 2), tR = 2.59 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.72 - 1.89 (6H, m), 1.97 - 2.17 (5H, m), 2.23 (6H, s), 2.83 (1H, q), 3.01 - 3.14 (3H, m), 3.96 (2H, s), 4.02 - 4.12 (2H, m), 4.15 (1H, d), 5.19 - 5.4 (1H, m), 5.44 - 5.65 (2H, m), 7.14 (1H, dd), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 684.

[0746] Example 7a (rotational isomer 1) and 7b (rotational isomer 2): 2-Amino-4-(9-chloro-7-fluoro-5- (((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-3-((l- (methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0747]

[0748] side product (lnt-17) Example 7b, rotational isomer 1

[0749] 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (lnt-17) (0.075 g, 0.11 mmol) was purified by preparative SFC by the following conditions: Column: ChiralPak I K, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH; gradient 50 % B over 8.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50 %B over 1.9 minutes, Flow rate: 2.5 mL / min.

[0750] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 7a (31.6 mg, 42%) as a white solid assigned >99.0% e.e. tR = 2.14 min.1H NMR (600 MHz, DMSO-d6, 27 °C) 1.75 - 1.89 (7H, m), 1.98 - 2.12 (3H, m), 2.24 (3H, s), 2.82 (1H, q), 3.01 - 3.09 (2H, m), 3.17 (3H, d), 3.82 - 3.98 (2H, m), 4.03 -4.11 (2H, m), 4.13 (1H, d), 5.19 - 5.37 (1H, m), 5.44 - 5.58 (2H, m), 7.06 - 7.2 (1H, m), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 670.

[0751] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 7b (28.2 mg, 38%) as a white solid assigned >99.0% e.e. tR = 3.09 min.1H NMR (600 MHz, DMSO-d6, 27 °C) 1.74 - 1.89 (7H, m), 1.99 - 2.13 (3H, m), 2.24 (3H, s), 2.77 - 2.87 (1H, m), 3.02 - 3.09 (2H, m), 3.17 (3H, d), 3.85 - 3.93 (2H, m), 4.02 - 4.1 (2H, m), 4.14 (1H, d), 5.2 - 5.35 (1H, m), 5.44 - 5.57 (2H, m), 7.13 (1H, t), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 670.

[0752] Example 8a (rotational isomer 1) and 8b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0753]

[0754] Example 8a; rotational isomer 1 Example 8b; rotational isomer 2Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo(b]thiophen-2-yl)carbamate

[0755] N N

[0756] Boc Cl

[0757] N

[0758]

[0759] Oxone* (1.18 g, 1.92 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.646 g, 0.96 mmol) (lnt-6) in THF (18 mL) and water (3.5 mL) under nitrogen. The resulting solution was stirred at RT for 1.5 hour. The reaction mixture was quenched with 15% sodium bisulfite solution (5 mL) and NaHCO3(10 mL), extracted with EtOAc (3 x 20 mL), the organic layer was dried over MgSO4, filtered and evaporated to afford an orange solid (650 mg) as a mixture of sulfone and sulfoxide.

[0760] 2.2 M Lithium 2-methylpropan-2-olate in THF (0.4 mL, 0.85 mmol) was added to a stirred mixture of (S)-(2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (CAS No: 2820536-99-8) (0.052 g, 0.34 mmol) and the crude product generated above (650 mg) in MeCN (5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. The reaction was passed through a SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford the crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.22 g, 0.28 mmol) as a yellow glass, which was used in the next step without further purification, m / z (ES+), [M+H]+ = 778.

[0761] Step 2: 2-amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0762]

[0763] TFA (0.22 mL, 2.80 mmol) was added to a mixture of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.22 g, 0.28 mmol) and DCM (2 mL). The resulting reaction mixture was stirred at RT for 2 hours. The reaction mixture was passed through a SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5 p silica, 30 mm diameter, 100 mm length) using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H2O) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.035 g, 19 %) as a cream solid.1H NMR (500 MHz, DMSO-dg, 27 °C) 1.62 - 1.71 (2H, m), 1.79 (5H, qt), 1.97 (1H, ddd), 2.07 - 2.15 (2H, m), 2.22 (6H, s), 2.32 - 2.39 (1H, m), 2.52 - 2.62 (2H, m), 2.99 (1H, ddd), 3.18 (1H, d), 3.5 - 3.59 (1H, m), 3.87 -4.13 (4H, m), 4.89 (2H, d), 5.45 - 5.61 (2H, m), 7.14 (1H, dd), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 678.

[0764] Step 3: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0765]

[0766] Example 8a; rotational isomer 1 Example 8b; rotational isomer 2The racemic product (30 mg, 0.044 mmol) was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 21x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH, gradient: 45% B over 9.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0767] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 μm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50% %B over 1.9 minutes, Flow rate: 2.5 mL / min.

[0768] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 8a (11.1 mg, 37%) assigned >99.0% e.e., tR = 2.26 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.68 (2H, dt), 1.72 - 1.91 (5H, m), 2.05 - 2.16 (2H, m), 2.22 (6H, s), 2.31 - 2.38 (1H, m), 2.51 - 2.54 (1H, m), 2.54 - 2.61 (2H, m), 2.99 (1H, ddd), 3.18 (1H, d), 3.47 - 3.6 (1H, m), 3.95 (2H, s), 4.03 - 4.11 (2H, m), 4.8 - 4.94 (2H, m), 5.44 - 5.66 (2H, m), 7.14 (1H, dd), 7.84 (1H, dd), 7.97 (2H, s).m / z (ES+), [M+H]+ = 678.

[0769] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 8b (8.2 mg, 28%) assigned >99.0% e.e., tR = 2.87. min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.53 - 1.72 (2H, m), 1.73 - 1.9 (5H, m), 1.97 (1H, ddd), 2.05 - 2.15 (2H, m), 2.22 (6H, s), 2.3 - 2.39 (1H, m), 2.53 - 2.61 (2H, m), 2.99 (1H, ddd), 3.14 -3.25 (1H, m), 3.49 - 3.59 (1H, m), 3.9 - 4.02 (2H, m), 4.07 (2H, q), 4.89 (2H, dd), 5.46 - 5.61 (2H, m), 7.14 (1H, dd), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 678.

[0770] Example 9a (rotational isomer 1) and 9b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4 / ?)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0771]

[0772] Example 9a; rotational isomer 1 Example 9b; rotational isomer 2 Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(methylsulfonyl)- 2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-vDcarbamate

[0773]

[0774] Oxone* (0.49 g, 0.79 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l- (dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-6) (265 mg, 0.39 mmol) in THF (8 mL) / water (1.6 mL) under nitrogen. The resulting solution was stirred at RT for 2 hours. The reaction mixture was quenched with 15% sodium bisulfite solution (5 mL) and saturated NaHCO3solution (10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSO4, filtered and evaporated to afford the crude title material (0.24 g, 86%), which was used in the next step without further purification, m / z (ES+), [M+H]+ = 705.

[0775] Step 2: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2S,4 / ?)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0776]

[0777] Lithium 2-methylpropan-2-olate (0.14 g, 1.70 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylsulfonyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.24 g, 0.34 mmol) and ((2R,4S)-4-methoxy-l-methylpyrrolidin-2-yl)methanol, HCI (Cas No:1842337-34-l) (0.12 g, 0.68 mmol) in acetonitrile (6 mL). The resulting solution was stirred at RT for 1 hour. The reaction mixture was diluted with EtOAc (10 mL) and water (10 mL), the layers were separated, and the aqueous layer was extracted with EtOAc (2 x 10 mL). The combined organic layers were washed with saturated brine (20 mL). The organic layer was dried with MgSO4, filtered and evaporated. The crude title compound (0.35 g,) was obtained as a yellow gum, which was used in the next step without further purification, m / z (ES+), [M+H]+ = 770.

[0778] Step 3: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2S,4 / ?)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0779]

[0780] Example 9a; rotational isomer 1

[0781]

[0782] TFA (0.53 mL, 6.80 mmol) was added to tert-butyl (4-(9-chloro-3-((l- (dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.26 g, 0.34 mmol) in DCM (8 mL). The resulting solution was stirred at RT for 20 hours. The reaction was incomplete and further TFA (0.53 mL, 6.80 mmol) was added to the solution and stirred at RT for 4 hours. The reaction mixture was diluted with DCM (10 mL) then quenched withsaturated NaHCO3solution (20 mL) and extracted with DCM (2 x 20 mL). The combined organic extracts were dried over MgSO4, filtered and evaporated. The crude product was purified by preparative HPLC (Waters CSH C18 OBD, 5 pm silica, 30x100 mm), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in water)) and MeCN as eluents, gradient 40 - 80% MeCN over 7 minutes; Flow rate: 50.0 mL / min. Fractions containing the desired compound were consolidated and concentrated to give the racemic product (60.4 mg). The racemic product was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient used: 50 %B over 7.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0783] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 μm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5-50 %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0784] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 9a (22.7 mg, 10%) as a white solid assigned >99.0% e.e.tR = 2.08 min.

[0785]

[0786] NMR (500 MHz, DMSO-d6, 27 °C) 1.64 - 1.95 (6H, m), 2.11 - 2.2 (2H, m), 2.23 (6H, s), 2.35 (3H, s), 2.78 (1H, tt), 3.14 - 3.22 (4H, m), 3.28 (1H, d), 3.84 - 3.93 (1H, m), 3.96 (2H, s), 4.30 (1H, dd), 4.38 (1H, dd), 5.51 (1H, d), 5.58 (1H, d), 7.14 (1H, dd), 7.85 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 670.

[0787] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 9b (20.6 mg, 9%) as a white solid assigned >99.0% e.e. tR = 2.69 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.66 (1H, d), 1.77 - 1.86 (2H, m), 1.89 (1H, dd), 2.12 (2H, d), 2.18 (1H, dd), 2.23 (6H, s), 2.35 (3H, s), 2.78 (1H, ddd), 3.19 (3H, s), 3.31 (2H, s), 3.82 - 4.04 (3H, m), 4.29 (1H, dd), 4.34 (1H, d), 4.39 (1H, dd), 5.51 (1H, d), 5.58 (1H, d), 7.15 (1H, dd), 7.85 (1H, dd), 7.98 (2H, s). m / z: ES+ [M+H]+ 670.

[0788] Example 10a (rotational isomer 1, isomer 1), 10b (rotational isomer 2, isomer 1) & 11a (rotational isomer 1, isomer 2) and lib (rotational isomer 2, isomer 2): 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2 / ?*,7oS*)-2-methoxytetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrileExample 10a (rotational isomer 1, isomer 1), and 11a (rotational isomer 2, isomer 1)

[0789]

[0790] ROTATIONAL ISOMER 1, ISOMER 1 ROTATIONAL ISOMER 2, ISOMER 1

[0791] Example 10a Example 11a

[0792] Example 10b (rotational isomer 2, isomer 1) and lib (rotational isomer 2, isomer 2):

[0793]

[0794] ROTATIONAL ISOMER 1, ISOMER 2 ROTATIONAL ISOMER 2, ISOMER 2

[0795] Example 10b Example 11b

[0796] Step 1: reZ-tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2Z?*,7aS*)-2-methoxytetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin- 8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0797]

[0798] ISOMER 1

[0799] Isomer 1 CPhos Pd G3 (12.4 mg, 0.02 mmol) and CPhos (6.7 mg, 0.02 mmol) were added to a deoxygenated solution of l-{[8-bromo-9-chloro-7-fluoro-5-{[re / -(2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / V, / \ / -dimethylcyclobutan-l-amine (lnt-15) (90 mg, 0.15 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (91 mg, 0.23 mmol) and K2CO3(42.5mg, 0.31 mmol) in 2-MeTHF (2.4 mL) and water (0.24 mL). The reaction mixture was heated to 70 °C for 3 hours. After cooling to RT, the crude was passed through an SCX column washing with MeOH (20 mL). The desired product was eluted with 2 M NH3 / MeOH and concentrated to afford the crude product (116 mg, 100%), which was used in the next step without further purification.1H NMR (500 MHz, DMSO-dg, 27 °C) 1.46 (9H, s), 1.69 - 1.92 (9H, m), 2.12 (3H, s), 2.24 (6H, s), 3.21 (3H, s), 3.95 (4H, s), 5.60 (2H, s), 6.33 (1H, s), 6.7 - 6.9 (1H, m), 7.19 - 7.26 (1H, m), 7.98 (1H, dd), 10.71 (1H, s). m / z (ES+), [M+H]+ = 771.

[0800] Isomer 2 (lnt-16) (152 mg, 0.26 mmol) was reacted in the same way as above, affording the title compound (72.2 mg, 36%) as a cream foam after the crude product was purified by reverse phase chromatography (Interchim C18-HP Flash column, 55 g), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H2O)) and MeCN as eluents.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.46 (9H, s), 1.72 - 1.86 (9H, m), 2.09 - 2.14 (3H, m), 2.24 (6H, s), 2.66 - 2.8 (2H, m), 2.92 - 3.1 (2H, m), 3.20 (3H, s), 3.95 (2H, d), 4.07 (2H, t), 5.59 (2H, s), 6.33 (1H, s), 6.82 (1H, d), 7.21 (1H, dd), 7.98 (1H, dd), 10.71 (1H, s). m / z (ES+), [M+H]+ = 771.

[0801]

[0802] 2: tert-Butyl (4-(9-chloro-3-((l-(di ami methyl)-7-fluoro-5-(((2R*,7oS*)-2-m

[0803]

[0804] ro-lH-i m -2,3-dihvdro-[l,31oxazino[4,5,6-delquinazolin- 8-yl)-3-i

[0805]

[0806] i-2-’

[0807]

[0808] ISOMER 1

[0809] Isomer 1: A solution of chlorosulfonyl isocyanate (0.020 mL, 0.23 mmol) was added dropwise to a stirred solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R*,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (116 mg, 0.15 mmol) in DCM (4 mL) and / V, / V-dimethylformamide (0.024 mL, 0.32 mmol) at 0 °C under nitrogen. The resulting solution was stirred at 0 °C for 20 minutes. The crude reaction mixture was passed through an SCX column washing with MeOH (60 mL), the product was then eluted off the column with 2 M NH3 / MeOH to afford crude tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R*,7oS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (100 mg, 77%) as a yellow oil, which was used in the next step without further purification, m / z (ES+), [M-H]+ = 797.

[0810] Isomer 2: (70 mg, 0.09 mmol) was reacted in the same way as above, affording the title compound (72 mg, 100%) as a yellow oil. m / z (ES+), [M-H]+ = 797.

[0811] Step 3: 2-amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?*,7aS*)-2-methoxytetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin- 8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0812]

[0813] ROTATIONAL ISOMER 2, ISOMER 1

[0814] Example 10a Example 11a

[0815]

[0816] ROTATIONAL ISOMER 1, ISOMER 2 ROTATIONAL ISOMER 2, ISOMER 2 Example 10b Example 11b

[0817] Isomer 1: TFA (0.48 mL, 6.28 mmol) was added to a solution of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R*,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.1 g, 0.13 mmol) in DCM (3.0 mL) was stirred at RT for 3 hours. The reaction mixture was poured onto an SCX column, washed through with MeOH / water (1:1, 100 mL), and then MeOH (50 mL). The desired product was eluted from the column using 2 M NH3 / l\ / leOH and pure fractions were evaporated to dryness. The crude product (0.104 g, 0.15 mmol) was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 21x250 mm; Mobile phase: A = scCO2, B = 0.1% NH3 in MeOH, gradient used: 40 %B over 11.5 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C. Fractions containing the desired compound were consolidated and concentrated to afford the isomers below.

[0818] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50% %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0819] Peak 1, rotational isomer 1, isomer 1: The title compound 10a (23.9 mg, 23 %) obtained as a white solid assigned 97.4% e.e. tR = 1. 1 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.62- 1.93 (10H, m), 2.12 (3H, t), 2.23 (6H, s), 2.75 (2H, s), 2.94 - 3.1 (2H, m), 3.20 (3H, s), 3.95 (2H, d), 4.04 - 4.1 (2H, m), 5.42 - 5.66 (2H, m), 7.09 - 7.19 (1H, m), 7.85 (1H, dd), 7.97 (2H, s). m / z (ES+), [M+H]+ = 696.

[0820] Peak 2, rotational isomer 2, isomer 1: The title compound 10b (23.9 mg, 23 %) obtained as a white solid assigned 98.8% e.e. tR = 2.78 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.63 - 1.9 (10H, m), 2.13 (3H, dd), 2.23 (6H, s), 2.66 - 2.8 (2H, m), 2.93 - 3.13 (2H, m), 3.20 (3H, s), 3.96 (2H, d), 4.05 - 4.1 (2H, m), 5.4 - 5.68 (2H, m), 7.14 (1H, dd), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 696.

[0821] Isomer 2: (0.072 g, 0.09 mmol) was reacted in the same way as above, affording the crude product (62.7 mg, 0.09 mmol). The crude was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 21x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH as eluents, gradient used: 40 %B over 9.2 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Columntemperature: 40.0 °C. Fractions containing the desired compound were consolidated and concentrated to give the isomers below.

[0822] Peak 1, rotational isomer 1, isomer 2: The title compound lla(15.9 mg, 25%) as a yellow solid assigned >99.0% e.e. tR = 2.29 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.64 - 1.88 (9H, m), 2.08 - 2.16 (3H, m), 2.23 (6H, s), 2.68 (1H, dd), 2.71 - 2.78 (1H, m), 2.97 (1H, dd), 3.06 (1H, dd), 3.19 (3H, s), 3.77 (1H, pd), 3.95 (2H, d), 4.06 (2H, d), 5.50 (1H, d), 5.57 (1H, d), 7.06 - 7.2 (1H, m), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES-), [M-H]- = 695.

[0823] Peak 2, rotational isomer 2, isomer 2: The title compound lib (16.9 mg, 27%) obtained as a yellow solid assigned >99.0% e.e. tR - 2.73 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.63 - 1.89 (9H, m), 2.08 - 2.17 (3H, m), 2.23 (6H, s), 2.68 (1H, dd), 2.74 (1H, q), 2.96 (1H, dt), 3.06 (1H, dd), 3.19 (3H, s), 3.77 (1H, pd), 3.91 - 4.05 (4H, m), 5.48 - 5.59 (2H, m), 7.14 (1H, dd), 7.84 (1H, dd), 7.97 (2H, s). m / z (ES-), [M-H]- = 695.

[0824] Example 12a (rotational isomer 1) and 12b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0825]

[0826] ROTATIONAL ISOMER 1 ROTATIONAL ISOMER 2

[0827] Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0828]

[0829] Oxone* (0.27 g, 0.43 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (lnt-7) (0.15 g, 0.22 mmol) in THF (4 mL) / water (0.8 mL) under nitrogen. The resulting solution was stirred at RT for 1 hour. The reaction mixture was quenched with 15% sodium bisulfite solution (5 mL) and saturated NaHCO3(10 mL) and extracted with EtOAc (3 x 20 mL). The combined organics were dried over MgSO4, filtered and evaporated. The crude material was used in the next step without further purification.

[0830] Lithium 2-methylpropan-2-olate (0.06 mL, 0.66 mmol) was added to a stirred mixture of the crude material and ((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (0.042 g, 0.26 mmol) in acetonitrile (5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. The reaction was passed through a SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.17 g, 96%) as a yellow glass, which was in the next step without further purification, m / z (ES+), [M+H]+ = 803.

[0831] Step 2: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-(l,3]oxazino(4,5,6-ce]quinazolin-8-yl)-5,7-difluorobenzo(b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0832]

[0833] ROTATIONAL ISOMER 1 ROTATIONAL ISOMER 2

[0834] TFA (0.16 mL, 2.13 mmol) was added to a mixture of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.17 g, 0.21 mmol) and DCM (2 mL) and resulting reaction mixture stirred at RT for 3 hours. The reaction mixture was passed through a SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness to afford the crude title material (0.15 g, 100%) as a yellow oil. The crude product (0.15 g) was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient 40 %B over 9.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0835] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50 %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0836] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile 12a (16.7 mg, 12%) as a white solid assigned >99.0% e.e. tR - 1.91 min.1H NMR (500 MHz, DMSO-c / 6, 27 °C) 1.62 - 1.7 (1H, m), 1.72 - 1.91 (6H, m), 1.99 (1H, d), 2.04 - 2.17 (4H, m), 2.23 (6H, s), 2.83 (1H, q), 3.02 (1H, s), 3.05 - 3.14 (2H, m), 3.89 - 4.03 (2H, m), 4.06 - 4.18 (2H, m), 5.2 - 5.36 (1H, m), 5.43 - 5.63 (2H, m), 7.32 (1H, t), 8.28 (2H, s). m / z (ES+), [M+H]+ = 702.

[0837] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (23.0 mg) with impurities (rotational isomer 2). Thus, the impure product was purified by preparative HPLC (Waters CSH C18 OBD, 5 pm silica, 30x100 mm), using decreasingly polar mixtures of 1% NH4OH (28-30% in water)) and MeCN as eluents, gradient 50 - 95% MeCN over 7 minutes. Fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile 12b (12.6 mg, 9%) as a white solid assigned >99.0% e.e. tR = 2.41 min.1H NMR (500 MHz, DMSO-c / g, 1 °C) 1.67 (1H, s), 1.81 (5H, d), 1.99 (2H, s), 2.05 - 2.17 (4H, m), 2.23 (6H, s), 2.83 (1H, s), 3.03 (1H, s), 3.10 (2H, s), 3.96 (2H, s), 4.03 - 4.19 (2H, m), 5.14 - 5.39 (1H, m), 5.45 - 5.63 (2H, m), 7.31 (1H, t), 8.28 (2H, s). m / z (ES+), [M+H]+ = 702.Example 13a (rotational isomer 1) and 13b (rotational isomer 2): 2-Amino-4-(9-chloro-3-((l- (dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile

[0838]

[0839] Step 1: tert-Butyl (4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cvano-5-methylbenzofuran-2-yl)carbamate

[0840]

[0841] Oxone* (0.31 g, 0.50 mmol) was added in one portion to tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-methylbenzofuran-2-yl)carbamate (lnt-8) (0.16 g, 0.25 mmol) in THF (4.6 mL) / water (0.9 mL) under nitrogen. The resulting solution was stirred at RT for 1.5 hours. The reaction mixture was quenched with 15% aqueous sodium bisulfite solution (5 mL) and saturated NaHCO3solution (10 mL), extracted with EtOAc (3 x 20 mL), and the organic layer was dried over MgSO4, filtered and evaporated to afford the crude material, which was used directly in the next step. Lithium 2-methylpropan-2-olate (0.34 mL, 0.75 mmol) was added to a stirred mixture of the crude material and ((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methanol (0.048 g, 0.30 mmol) in acetonitrile (5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. The reaction was passed through an SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desiredcompound were evaporated to dryness. The crude product (0.19 g, 0.25 mmol) was used in the next step without further purification.

[0842] Step 2: 2-Amino-4-(9-chloro-3-((l-(dimethylamino)cvclobutyl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomers 1 and 2)

[0843]

[0844] Example 13b ROTATIONAL ISOMER 2 TFA (0.19 mL, 2.50 mmol) was added to a mixture of tert-butyl (4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c(e]quinazolin-8-yl)-3-cyano-5-methylbenzofuran-2-yl)carbamate (0.19 g, 0.25 mmol) and DCM (2 mL) and resulting reaction mixture stirred at RT for 3 hours. The reaction mixture was passed through a SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness to afford crude (0.17 g) as a yellow oil. The crude product was purified by preparative chiral SFC by the following conditions: Column: ChiralPak I K, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B 0.1% NH3in MeOH, gradient used: 50% B over 7.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0845] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50 %B over 1.9 minutes, Flow rate: 2.5 mL / min.

[0846] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give the title compound 13a (6.1 mg, 4%) as a white solid assigned >99.0% e.e., tR = 1.96. min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.57 - 1.88 (8H, m), 1.98 (1H, s), 2.06 (3H, s), 2.08 - 2.16 (3H, m), 2.23 (6H, s), 2.82 (1H, q), 2.98 - 3.13 (3H, m), 3.87 - 4.03 (2H, m), 4.04 - 4.19 (2H, m), 5.17 - 5.37 (1H, m), 5.42 - 5.61 (2H, m), 7.05 (1H, dd), 7.33 (1H, d), 8.19 (2H, s). m / z (ES+), [M+H]+ = 664.

[0847] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give the title compound 13b (8.5 mg, 5%) as a white solid assigned >99.0% e.e. tR = 2.82 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.6 - 1.89 (8H, m), 2.07 (3H, s), 2.09 - 2.16 (3H, m), 2.24(6H, s), 2.78 - 2.86 (1H, m), 3 - 3.15 (3H, m), 3.78 (1H, td), 3.88 - 4.02 (2H, m), 4.04 - 4.18 (2H, m), 5.16 - 5.37 (1H, m), 5.45 - 5.6 (2H, m), 7.06 (1H, d), 7.34 (1H, d), 8.19 (2H, s). m / z (ES+), [M+H]+ = 664.

[0848] Example 14a (rotational isomer 1) and 14b (rotational isomer 2): 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0849]

[0850] Example 14a ROTATIONAL ISOMER 2 Example 14b ROTATIONAL ISOMER 2

[0851] Step 1: tert-Butyl (4-(9-chloro-3-(((R*)-3-(dirnethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (((S)-2-methylenetetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0852]

[0853] Saturated brine (0.5 ml), tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(methylthio)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (lnt-9) (0.22 g, 0.32 mmol), water (8 mL), 1 M HCI (aq.) (0.32 mL, 0.32 mmol) and acetone (8 mL) were dissolved in a electrasyn tube (pH 5). The reaction was electrolysed using a RuO2 / Ti electrode, using 20 mA, 1.98 V to 3.11 V and 6.95 electron equivalents for 3 hours 20 minutes. The reaction was diluted with EtOAc (15 mL) and water (10 mL). Saturated NaHCO3solution was added until the pH reached 7-8. The layers were separated and the aqueous was further extracted with EtOAc (15 mL x 2). The combined organics were passed through a phaseseparator and concentrated. The orange glass film was dried under vacuum overnight, affording the crude material (0.19 g). This was used directly in the next step without further purification.

[0854] Lithium 2-methylpropan-2-olate (0.36 mL, 0.79 mmol) was added to a stirred mixture of the crude material (0.094 g, 0.13 mmol) described above and (S)-(2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methanol (CAS No:2820536-99-8) (0.049 g, 0.32 mmol) in acetonitrile (4.5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour 30 minutes. The reaction was passed through an SCX column eluting with 2 M NH3 / MeOH. Fractions containing the desired compound were evaporated to dryness to afford the crude title compound (0.10 g, 100%), which was used directly in the next step without further purification, m / z (ES+), [M+H]+ = 794

[0855] Step 2: 2-Amino-4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5-(((S)- 2-methylenetetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo(b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0856]

[0857] Example 14a ROTATIONAL ISOMER 2 Example 14b ROTATIONAL ISOMER 2 TFA (0.2 mL, 2.57 mmol) was added to a mixture of tert-butyl (4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-ce]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.20 g, 0.26 mmol) and DCM (2 mL) and resulting reaction mixture stirred at RT for 12 hours. The reaction mixture was passed through an SCX column. The desired product was eluted from the column using 2 M NH3 / l\ / leOH and pure fractions were evaporated to dryness. The crude product was purified by preparative HPLC (Waters CSH C18 OBD, 5 pm silica, 30x100 mm), Mobile Phase A: water (containing 1% NH4OH (28-30% in water)); Mobile Phase B: MeCN, Gradient used: 50 - 95% B over 7 minutes; Flow rate: 50.0 mL / min. Fractions containing the desired compound were consolidated and concentrated to give 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (0.111 g, 40 %) as an orange solid, m / z (ES+), [M+H]+ = 694.The racemic product (0.10 g, 0.15 mmol) was purified by preparative chiral SFC by the following conditions: ChiralPak IK, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH, gradient 45 %B over 9.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0858] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scC02, B = 0.1% NH3 in methanol, Gradient used: 5-50 %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0859] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give the 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 14a (29 mg, 28%) as a white solid assigned >99.0% e.e., tR = 2.40 min.1H NMR (600 MHz, DMSO-d6, 27 °C) 1.68 (1H, dt), 1.76 - 1.83 (1H, m), 1.82 - 1.93 (2H, m), 1.94 - 2.05 (2H, m), 2.31 (6H, s), 2.36 (1H, d), 2.55 - 2.58 (1H, m), 2.58 - 2.63 (1H, m), 2.94 - 3.05 (1H, m), 3.18 (1H, d), 3.55 (1H, d), 3.65 - 3.76 (2H, m), 3.76 - 3.84 (2H, m), 3.97 (2H, s), 4 - 4.13 (2H, m), 4.85 - 4.95 (2H, m), 5.38 - 5.66 (2H, m), 7.13 (1H, t), 7.83 (1H, dd), 7.96 (2H, s). m / z (ES+), [M+H]+ = 694.

[0860] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give the 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 14b (35 mg, 34%) as a white solid assigned >99.0% e.e., tR = 2.65 min.1H NMR (600 MHz, DMSO-d6, 27 °C) 1.68 (1H, dt), 1.76 - 1.83 (1H, m), 1.82 - 1.93 (2H, m), 1.94 - 2.05 (2H, m), 2.31 (6H, s), 2.36 (1H, d), 2.55 - 2.58 (1H, m), 2.58 - 2.63 (1H, m), 2.94 - 3.05 (1H, m), 3.18 (1H, d), 3.55 (1H, d), 3.65 - 3.76 (2H, m), 3.76 - 3.84 (2H, m), 3.97 (2H, s), 4 - 4.13 (2H, m), 4.85 - 4.95 (2H, m), 5.38 - 5.66 (2H, m), 7.13 (1H, t), 7.83 (1H, dd), 7.96 (2H, s). m / z (ES+), [M+H]+ = 694.

[0861] Example 15a (rotational isomer 1) and 15b (rotational isomer 2): 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile

[0862]

[0863] Example 15a; Rotational Isomer 1 Example 15b; Rotational Isomer 2

[0864] Step 1: tert-Butyl (4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0865]

[0866] CPhos Pd G3 (41.1 mg, 0.05 mmol) and CPhos (22.2 mg, 0.05 mmol) were added to a de-oxygenated solution of (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethyltetrahydrofuran-3-amine (lnt-4) (0.30 g, 0.51 mmol), tert-butyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3) (0.21 g, 0.51 mmol) and potassium carbonate (0.14 g, 1.02 mmol) in 2-MeTHF (6.8 mL) and water (0.68 mL). The reaction mixture was then heated to 70 °C for 2 hours in a microwave. The reaction was concentrated then the crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1 M NH3 / MeOH and pure fractions were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.29 g, 73%) as a brown foam, which was used in the next step without further purification, m / z (ES+), [M+H]+ = 794.2: tert-Butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino i-3-yl)methyl)-7-fluoro-5-

[0867]

[0868] ro-lH-pyrrolizin- -2,3-dihydro-[l,31oxazino[4,5,6- in-8-yl)-3-cyano-5,7-di io i-2-’

[0869]

[0870] Chlorosulfonyl isocyanate (0.29 mL, 3.32 mmol) was added dropwise to a cooled solution of tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.26 g, 0.33 mmol) in THF (3.4 mL) and DMF (0.62 mL, 7.96 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 10 minutes at -78 °C then was stirred at -30 °C for a further 30 minutes, then a further 10 minutes at -20 °C then another 30 minutes at 0 °C. The reaction was incomplete thus the reaction was cooled to -78 °C and DMF (0.62 mL, 7.96 mmol) and chlorosulfonyl isocyanate (0.29 mL, 3.32 mmol) were added. The reaction was stirred at -78 °C for a further 10 minutes then warmed to 0 °C and stirred for 30 minutes. The reaction mixture was quenched carefully with water (1 mL). The reaction mixture was then passed through an SCX column. The desired product was eluted with 2 M NH3 / MeOH. The crude product was purified by reverse phase chromatography (Interchim C18-HP Flash column, 50 g), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H2O) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.048 g, 15%) as a colourless dry film, m / z (ES+), [M+H]+ = 819.

[0871] 3: 2-Amino-4-(9-chloro-3-(((R*)-3-(di ami i-3-yl)m -7-fluoro-5-

[0872]

[0873] i-2-1 ro-lH-i izin- -2,3-dihydro-[l,3]oxazino[4,5,6-

[0874]

[0875] in-8-yl)-5,7-di -3-carbonitrile isomer 1 and

[0876]

[0877] isomer

[0878]

[0879] Example 15a; Rotational Isomer 1 Example 15b; Rotational Isomer 2

[0880] TFA (0.05 mL, 0.59 mmol) was added to a mixture of tert-butyl (4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (48 mg, 0.06 mmol) and DCM (2 mL) and resulting reaction mixture stirred at RT for 18 hours. The reaction mixture was passed through an SCX column. The desired product was eluted from the column using 2 M NH3 / MeOH and pure fractions were evaporated to dryness to afford the crude title material (43.1 mg). The crude product was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 20x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3 in MeOH as eluents, gradient used: 35 %B over 11.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0881] Chiral Analysis was performed under the following conditions:, Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 - 50 %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0882] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give the desired product 15a (14.5 mg, 34%) as a white solid assigned >99.0% d.e., tR = 1.96 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.75 - 1.9 (4H, m), 1.96 - 2.12 (4H, m), 2.29 (6H, s), 2.82 (1H, q), 2.98 - 3.12 (3H, m), 3.69 - 3.76 (2H, m), 3.76 - 3.85 (2H, m), 3.93 (1H, d), 4.04 - 4.11 (2H, m), 4.15 (1H, d), 5.17 - 5.37 (1H, m), 5.41 - 5.63 (2H, m), 7.31 (1H, t), 8.28 (2H, s). m / z (ES+), [M+H]+ = 718.

[0883] Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give the desired product 15b (18.4 mg, 43%) as a white solid assigned >99.0% d.e., tR = 2.22 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 0.94 - 1.12 (4H, m), 1.16 - 1.34 (4H, m), 1.49 (6H, s), 2.01 (1H, q), 2.18 - 2.31 (3H, m), 2.83 - 2.95 (2H, m), 2.97 - 3.03 (2H, m), 3.09 - 3.25 (3H, m), 3.34 (1H, d), 4.31 - 4.59 (1H, m), 4.63 - 4.76 (2H, m), 6.50 (1H, t), 7.46 (2H, s). m / z (ES+), [M+H]+ = 718.Example 16a (rotational isomer 1) and 16b (rotational isomer 2): 2-Amino-4-(9-chloro-3-(2- (dimethylamino)ethyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)- 2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0884]

[0885] 1: tert-\ -(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-i

[0886]

[0887] -2-flu

[0888]

[0889] lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0890]

[0891] CPhos Pd G3 (0.24 g, 0.30 mmol) and CPhos (0.13 g, 0.30 mmol) were added to 2-(8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)- / V, / V-dimethylethan-l-amine (lnt-12) (0.80 g, 1.50 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (1.18 g, 3.00 mmol) and potassium phosphate (0.64 g, 3.00 mmol) in THF (10 mL) and water (2.5 mL) under nitrogen. The resulting mixture was stirred at 60 °C for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 30% MeOH in DCM. Pure fractions were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.50 g, 46%) as a yellow solid.

[0892] 1H NMR (300 MHz, DMSO-d6, 21 °C) 61.49 (9H, s), 1.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.25 (6H, s), 2.54-2.73 (2H, m), 2.77-2.92 (2H, m), 2.94-3.06 (1H, m), 3.07-3.16 (2H, m), 3.84-3.90 (1H, m), 3.98-4.19 (2H, m), 5.25-5.30 (1H, m), 5.56 (2H, s), 6.31 (1H, s), 7.20 (1H, t), 7.97 (1H, dd). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 719.

[0893] Step 2: tert-Butyl (4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-(l,3]oxazino(4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo(b]thiophen-2-yl)carbamate

[0894]

[0895] Chlorosulfonyl isocyanate (0.61 mL, 6.95 mmol) was added to THF (10 mL) at -78 °C under nitrogen. Then tert-butyl (4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.50 g, 0.70 mmol) and DMF (0.54 mL, 6.95 mmol) in THF (10 mL) were added to the mixture at -78 °C under nitrogen. The resulting mixture was stirred at -78 °C for 5 minutes and then stirred at 25 °C for 45 minutes. The reaction mixture was quenched with saturated NaHCO3solution (50 mL), extracted with EtOAc (3 x 50 mL), and the combined organics were dried over Na2SO4, filtered and evaporated to afford tert-butyl (4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.30 g, 58%) as a yellow solid, which was used in the next step without further purification.1H NMR (300 MHz, DMSO-d6, 21 °C) 6 1.49 (9H, s), 1.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.25 (6H, s), 2.54-2.73 (2H, m), 2.77-2.92 (1H, m), 2.95-3.07 (1H, m), 3.07-3.16 (2H, m), 3.84 (2H, m), 3.98-4.19 (2H, m), 5.24-5.32 (1H, m), 5.43-5.61 (2H, m), 7.43 (1H, t), 8.14-8.22 (1H, m). One exchangeable proton not observed, m / z (ES+), [M+H]+ = 744.

[0896] Step 3: 2-Amino-4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0897]

[0898] Example 16a; Rotational Isomer 1 Example 16b; Rotational Isomer 1 TFA (5 mL, 64.90 mmol) was added to tert-butyl (4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.30 g, 0.40 mmol) in DCM (5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. Volatiles were removed under reduced pressure. The crude product was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7 M NH3 / IVIeOH and pure fractions were evaporated to dryness to afford crude product. The crude product was purified by preparative chiral HPLC Column by the following conditions: Column: CHIRALPAK IE 2*25 cm, 5 pm; Mobile Phase A: HEX (0.5% 2 M NH3-MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 40; Wavelength: 220 / 254 nm.

[0899] Chiral Analysis was performed by Chiral HPLC, Column Name CHIRALPAK IE-3 4.6*50 mm, 3 um, Mobile Phase: Hex(0.1%DEA):(EtOH: DCM=l:l)=60:40, Flow rate = 1 ml / min

[0900] Peak 1, rotational isomer 1: fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 16a (23 mg, 9%) as a white solid assigned >99.0 % e.e. tR = 2.33 min.1H NMR (400 MHz, DMSO-d6, 21 °C) δ 1.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.25 (6H, s), 2.54-2.73 (2H, m), 2.77-2.92 (1H, m), 2.95-3.05 (1H, m), 3.07-3.16 (2H, m), 3.83-3.90 (2H, m), 3.98-4.19 (2H, m), 5.24-5.36 (1H, m), 5.43-5.61 (2H, m), 7.14 (1H, t), 7.85 (1H, dd), 8.01 (2H, s). m / z (ES+), [M+H]+ = 644.

[0901] Peak 2, rotational isomer 2: fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(9-chloro-3-(2-(dimethylamino)ethyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile 16b (26 mg, 10%) as a white solid assigned >99.0 % e.e. tR = 3.71.1H NMR (400 MHz, DMSO-d6, 21 °C) δ 1.73-1.92 (3H, m), 1.99-2.03 (1H, m), 2.03-2.1 (1H, m), 2.07-2.17 (1H, m), 2.25 (6H, s), 2.54-2.73 (2H, m), 2.77-2.92 (1H, m), 2.95-3.05 (1H, m), 3.07-3.16 (2H, m), 3.83-3.90 (2H, m), 3.98-4.19 (2H, m), 5.24-5.36 (1H, m), 5.43-5.61 (2H, m), 7.14 (1H, t), 7.85 (1H, dd), 8.01 (2H, s). m / z (ES+), [M+H]+ = 644.Example 17a (rotational isomer 1) and 17b (rotational isomer 2): 2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile

[0902]

[0903] Example 17a; Rotational Isomer 1 Example 17b; Rotational Isomer 1

[0904] Step 1: tert-Butyl (4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate

[0905]

[0906] CPhos (0.048 g, 0.11 mmol) and CPhos Pd G3 (0.089 g, 0.11 mmol) were added to l-(8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)- / V, / V,2-trimethylpropan-2-amine (lnt-13) (0.62 g, 1.11 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (0.65 g, 1.66 mmol) and K3PO4(0.70 g, 3.32 mmol) in THF (9.6 mL) and water (2.4 mL) at RT under nitrogen. The resulting mixture was stirred at 60 °C for 2 hours. After cooling to RT, the reaction mixture was poured into water (50 mL) and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and evaporated. The crude product was purified by flash silica chromatography, elution gradient 0 to 20% MeOH (containing 0.1% 7 M NH3 / MeOH) in DCM. Pure fractions were evaporated to dryness to afford tert-butyl (4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.77 g,93%) as a yellow solid.1H NMR (500 MHz, DMSO-d6, 24 °C) 6 1.02-1.09 (6H, m), 1.47 (9H, s), 1.73-1.91 (3H, m), 1.96-2.15 (3H, m), 2.24 (6H, s), 2.76-2.88 (1H, m), 3.01-3.16 (3H, m), 3.69-3.83 (2H, m), 4.02-4.19 (2H, m), 5.21-5.36 (1H, m), 5.56 (2H, s), 6.34 (1H, s), 7.22 (1H, t), 7.99 (1H, dd), 10.72 (1H, s). m / z (ES+), [M+H]+ = 747.

[0907] Step 2: tert-Butyl (4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo(b]thiophen-2-yl)carbamate

[0908]

[0909] Chlorosulfonyl isocyanate (0.25 mL, 2.81 mmol) in MeCN (4.7 mL) was added dropwise to tert-butyl (4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.70 g, 0.94 mmol) and DMF (0.73 mL, 9.37 mmol) in MeCN (14 mL) at 0 °C under nitrogen. The resulting mixture was stirred at 0 °C for 5 hours. Saturated NaHCO3solution was added until the pH of the mixture reached 8 then the aqueous phase was extracted with EtOAc (2 x 100 mL). The combined organics were dried over Na2SO4, filtered and evaporated to afford the title compound (0.63 g, 87%) as a pale yellow solid. The product was used in the next step directly without further purification, m / z (ES+), [M+H]+ = 772.

[0910] Step 3: 2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[0911]

[0912] Example 17a; Rotational Isomer 1 Example 17b; Rotational Isomer 1 TFA (2 mL, 25.96 mmol) was added to tert-butyl (4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)- 7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-3-cyano-5-fluorobenzo[b]thiophen-2-yl)carbamate (0.63 g,0.82 mmol) in DCM (10 mL) at 25 °C under nitrogen. The resulting mixture was stirred at RT for 1 hour. Volatiles were removed under reduced pressure. The crude product was purified by preparative HPLC by the following conditions: Column: Xbridge PrepC18 OBD, 30*150 mm, 5 pm; Mobile Phase A: Water (containing 10 mmol / L NH4HCO3+ 0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 47% B to 65% B in 8 min; Wave Length: 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.18 g, 33%) as a white solid. The racemic product was purified by preparative chiral HPLC by the following conditions: Column: CHIRALPAK IF 2*25 cm, 5 pm; Mobile Phase A: HEX (0.5% 2 M NH3 / MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 30; Wavelength: 220 / 254 nm.

[0913] Chiral Analysis was performed unde Chiral HPLC: Column Name: CHIRALPAK I F-3, Column Size: 4.6*50 mm, 3 urn; Mobile Phase: Hex(0.1%DEA):(EtOH: DCM=l:l)=70:30; Flow: 1 mL / min

[0914] Peak 1, rotational isomer 1: fractions containing the desired compound were evaporated to dryness to afford the title compound 17a (51.5 mg, 29 %) as a white solid assigned >99.0 % e.e., tR = 1.37 min.1H NMR (500 MHz, DMSO-d6, 24 °C) δ 1.05 (6H, s), 1.74-1.9 (3H, m), 1.98-2.15 (3H, m), 2.24 (6H, s), 2.79-2.86 (1H, m), 2.98-3.06 (1H, m), 3.05-3.15 (2H, m), 3.72-3.84 (2H, m), 4.03-4.06 (1H, m), 4.11-4.15 (1H, m), 5.21-5.35 (1H, m), 5.44-5.47 (1H, m), 5.55-5.58 (1H, m), 7.14 (1H, t), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 672.

[0915] Peak 2, rotational isomer 2: fractions containing the desired compound were evaporated to dryness to afford the title compound 17b (47.9 mg, 27%) as a white solid assigned >99.0 % e.e. tR = 2.88 min.1H NMR (500 MHz, DMSO-d6, 24 °C) 6 1.05 (6H, s), 1.75-1.87 (3H, m), 1.97-2.15 (3H, m), 2.23 (6H, s), 2.78-2.85 (1H, m), 3.01-3.03 (1H, m), 3.06-3.13 (2H, m), 3.7-3.84 (2H, m), 4.03-4.06 (1H, m), 4.11-4.15 (1H, m), 5.2-5.36 (1H, m), 5.44-5.47 (1H, m), 5.55-5.58 (1H, m), 7.14 (1H, t), 7.85 (1H, dd), 7.98 (2H, s). m / z (ES+), [M+H]+ = 672.

[0916] Example 18a (rotational isomer 1) and 18b (rotational isomer 2): 2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile

[0917]

[0918] Example 18a; Rotational Isomer 1 Example 18b; Rotational Isomer 2

[0919] Step 1: tert-Butyl (4-(3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5-(((2 / ?,7aS)-2-

[0920]

[0921] fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate

[0922]

[0923] A solution of (R*)-3-((8-bromo-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / \ / , / \ / -dimethyltetrahydrofuran-3-amine (lnt-4) (0.60 g, 1.02 mmol), tert-butyl (5-methyl-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzofuran-2-yl)carbamate (lnt-1) (0.46 g, 1.22 mmol) and potassium phosphate (0.60 g, 3.06 mmol) in 1,4-dioxane (20 mL) and water (2 mL) was degassed for 5 minutes (3 cycles of evacuation under vacuum followed by refill with nitrogen). CPhos Pd G3 (0.082 g, 0.10 mmol) and CPhos (0.044 g, 0.10 mmol) were added and the resulting solution was stirred at 70 °C for 1 h. The reaction mixture was cooled to RT. The reaction mixture was diluted with DCM and passed through a phase separator. The filtrate was concentrated. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5 p silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH3 in (28-30% in water)) and MeCN as eluents, 50% to 80% gradient. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl (4-(3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate 0.49 g, 63%) as a beige solid, m / z (ES+) [M+H]+ 755.

[0924] Step 2: 2-Amino-4-(9-chloro-3-((( / ?*)-3-(dimethylamino)tetrahvdrofuran-3-yl)methyl)-7-fluoro-5- (((2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomers 1 and 2)

[0925]

[0926] Chlorosulfonyl isocyanate (0.11 mL, 1.21 mmol) was added to THF (1.0 mL) under nitrogen in a dry ice / acetone bath. / V, / V-Dimethylformamide (0.13 mL, 1.61 mmol) was added. To this mixture was added a solution of tert-butyl (4-(3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-2-yl)carbamate 0.20 g, 0.27 mmol) in THF (3.0 mL) dropwise. The cooling bath was removed, and the mixture was stirred for 30 minutes. The reaction was poured cautiously onto saturated NaHCO3solution (20 mL). The resulting mixture was extracted with EtOAc (3 x). The combined organics were washed with brine (2 x), passed through a phase separator, and concentrated under reduced pressure. The crude mixture was further diluted with dry DCM (3.3 mL) and then HCI (6M in IPA) (4.5 mL, 26.90 mmol) was added. The resulting cloudy mixture was stirred at RT for 3.5 h. The reaction mixture was loaded directly onto a SCX column. The desired product was eluted from the column using 7 M NH3in MeOH. The crude product was purified by preparative HPLC (Waters XSelect CSH C18 ODB column, 5p silica, 30 mm diameter, 100 mm length), using decreasingly polar mixtures of water (containing 1% NH4OH (28-30% in H₂O)) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford 2-amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (18 mg) as a yellow solid. The crude product was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 21x250 mm; Mobile Phase A: scCO2; Mobile Phase B: 0.1% NH3in MeOH, gradient 40 %B over 7.6 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 μm Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50% %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0927] Peak 1, rotational isomer 1: fractions containing the desired compound were consolidated and concentrated to give the title compound 18a (6.4 mg, 4%) as a beige solid assigned >99.0% e.e. tR = 2.01 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.71 - 2.2 (9H, m), 2.30 (6H, s), 2.51 (1H, s), 2.76 - 2.89 (1H, m), 2.98 - 3.14 (3H, m), 3.67 - 3.9 (4H, m), 3.92 (1H, d), 3.97 - 4.12 (3H, m), 4.15 (1H, d), 5.16 -5.4 (1H, m), 5.39 - 5.68 (2H, m), 7.05 (1H, dd), 7.34 (1H, d), 8.19 (2H, s). m / z (ES-), [M-H]' = 678. Peak 2, rotational isomer 2: fractions containing the desired compound were consolidated and concentrated to give the tilte compound 18b (6.1 mg, 3%) as a beige solid assigned >99.0% e.e. tR = 2.35 min.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.71 - 2.24 (9H, m), 2.31 (6H, s), 2.5 - 2.54 (1H, m), 2.77 - 2.89 (1H, m), 2.97 - 3.15 (3H, m), 3.63 - 3.77 (2H, m), 3.77 - 3.89 (2H, m), 3.89 - 4.02 (2H, m), 4.02 - 4.12 (2H, m), 4.1 - 4.22 (1H, m), 5.15 - 5.41 (1H, m), 5.41 - 5.68 (2H, m), 7.05 (1H, dd), 7.34 (1H, d), 8.19 (2H, s). m / z (ES-), [M-H]' = 678.

[0928] Example 19a (rotational isomer 1) and 19b (rotational isomer 2): 2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1 and 2)

[0929]

[0930] Example 19a, rotational isomer 1 Example 19b, rotational isomer 2

[0931] Step 1: tert-Butyl (4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7,9-difluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0932]

[0933] CPhos Pd G3 (0.087 g, 0.11 mmol) and CPhos (0.047 g, 0.11 mmol) were added to l-((8-bromo-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)- / V, / V-dimethylcyclobutan-l-amine (lnt-10) (0.30 g, 0.54 mmol), tertbutyl (5,7-difluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-3) (0.42 g, 0.81 mmol) and K3PO4 (0.34 g, 1.62 mmol) in THF (8 mL) and water (2 mL) at 20 °C. The resulting mixture was stirred at 60 °C for 3 hours. The solvent was removed under reduced pressure. The crude product was purified by C18-flash chromatography, elution gradient 50 to 100% MeOH in water (0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford the title compound (0.25 g, 61%) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 21 °C) 6 1.48 (9H, s), 1.58-1.71 (1H, m), 1.73-1.88 (6H, m), 1.98-2.16 (5H, m), 2.23 (6H, s), 2.78-2.87 (1H, m), 2.96-3.14 (3H, m), 3.85-4.01 (2H, m), 4.02-4.21 (2H, m), 5.24-5.29 (1H, m), 5.55 (2H, s), 6.40 (1H, s), 7.37 (1H, t), 11.04 (1H, s). m / z (ES+), [M+H]+ = 761.

[0934] Step 2: tert-Butyl (3-cvano-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7,9-difluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate

[0935]

[0936] THF (4 mL) was cooled to -78 °C then chlorosulfonyl isocyanate (0.29 mL, 3.29 mmol) was added under nitrogen. tert-butyl (4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.25 g, 0.33 mmol) and DMF (0.25 mL, 3.29 mmol) in THF (4 mL) were added to the mixture. The resulting mixture was stirred at -78 °C for 5 minutes and then stirred at 25 °C for 1 hour. The reaction mixture was quenched with saturated NaHCO3solution (15 mL), poured into water (10 mL) then extracted with EtOAc (2 x 25 mL). The combined organics were dried over Na2SO4, filtered and evaporated. The crude product was purified by C18-flash chromatography, elution gradient 50 to 100% MeOH in water (containing 0.1% NH4HCO3). Pure fractions were evaporated to dryness to afford tert-butyl (3-cyano-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.14 g, 54%) as a yellow solid.1H NMR (400 MHz, DMSO-d6, 21 °C) 6 1.42 (9H, s), 1.58-1.71 (1H, m), 1.73-1.88 (6H, m), 1.98-2.16 (5H, m), 2.23 (6H, s), 2.78-2.87 (1H, m), 2.96-3.14 (3H, m), 3.85-4.01 (2H, m), 4.02-4.21 (2H, m), 5.24-5.29 (1H, m), 5.55 (2H, s), 7.37 (1H, t). One exchangeable proton not seen, m / z (ES+), [M+H]+ = 786.

[0937] Step 3: 2-Amino-4-(3-((l-(dimethylamino)cvclobutyl)methyl)-7,9-difluoro-5-(((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihvdro-[l,3]oxazino[4,5,6-de]quinazolin-8-

[0938]

[0939] Example 19a, rotational isomer 1 Example 19b, rotational isomer 2 TFA (0.4 mL, 5.19 mmol) was added to tert-butyl (3-cyano-4-(3-((l- (dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophen-2-yl)carbamate (0.14 g, 0.18 mmol) in DCM (1.5 mL) under nitrogen. The resulting mixture was stirred at RT for 1 hour. The solvent was removed under reduced pressure. The crude product was purified by C18-flash chromatography, elution gradient 50 to 100% MeOH in water (containing 0.1% NH4HCO3). Fractions were evaporated to dryness then what was repurified by preparative HPLC by the following conditions: Column: Xbridge Prep C18 OBD, 30*150 mm, 5 pm; Mobile Phase A: Water (10 mmol / L NH4HCO3+0.05% NH4OH), Mobile Phase B: MeCN; Flow rate: 60 mL / min; Gradient: 53% B to 70% B over 8 min; Wave Length: 254 / 220 nm. Fractions containing the desired compound were evaporated to dryness to afford the title compound (0.07 g, 57%) as a white solid.

[0940]

[0941] NMR (400 MHz, DMSO-d6, 22 °C) 6 1.6-1.7 (1H, m), 1.73-1.87 (6H, m), 1.95-2.16 (5H, m), 2.22 (6H, s), 2.76-2.91 (1H, m), 2.97-3.17 (3H, m), 3.95 (2H, s), 4.05-4.19 (2H, m), 5.19-5.39 (1H, m), 5.44-5.59 (2H, m), 7.34 (1H, t), 8.35 (2H, s). m / z (ES+), [M+H]+ = 686.

[0942] The racemic product was purified by preparative chiral HPLC by the following conditions: Column: CHIRALPAK IG, 2*25 cm, 5 pm; Mobile Phase A: HEX (0.5% 2 M NH3 / MeOH), Mobile Phase B: EtOH: DCM=1: 1; Flow rate: 20 mL / min; Gradient (B%): isocratic 30; Wave Length: 220 / 254 nm.Chiral Analysis was performed unde Chiral HPLC, Column Name: CHIRALPAK IG-3, Column Size: 4.6*50 mm, 3 urn, Mobile Phase: Hex(0.1%DEA):(EtOH: DCM=l:l)=65:35, Flow: 1 mL / min.

[0943] Peak 1, rotational isomer 1: fractions containing the desired compound were evaporated to dryness to afford the title compound 19a (25 mg, 36 %) as a white solid assigned >99.0% e.e., tR = 0.997 min.

[0944]

[0945] NMR (400 MHz, DMSO-d6, 22 °C) 6 1.6-1.7 (1H, m), 1.71-1.9 (6H, m), 1.94-2.04 (1H, m), 2.05-2.18 (4H, m), 2.23 (6H, s), 2.76-2.92 (1H, m), 2.99-3.07 (1H, m), 3.07-3.19 (2H, m), 3.9-4.03 (2H, m), 4.05-4.11 (1H, m), 4.12-4.18 (1H, m), 5.24-5.33 (1H, m), 5.48-5.56 (2H, m), 7.34 (1H, t), 8.35 (2H, s). m / z (ES+), [M+H]+ = 686.

[0946] Peak 2, rotational isomer 2: fractions containing the desired compound were evaporated to dryness to afford the title compound 19b (25 mg, 36%) as a white solid assigned >99.0% e.e.tR = 1.55 min.1H NMR (400 MHz, DMSO-d6, 22 °C) 6 1.57-1.71 (1H, m), 1.72-1.92 (6H, m), 1.94-2.17 (5H, m), 2.23 (6H, s), 2.78-2.92 (1H, m), 2.99-3.19 (3H, m), 3.84-4.02 (2H, m), 4.07-4.22 (2H, m), 5.25-5.33 (1H, m), 5.48-5.56 (2H, m), 7.34 (1H, t), 8.35 (2H, s). m / z (ES+), [M+H]+ = 686.

[0947] Example 20a (rotational isomer 1) and 20b (rotational isomer 2): 2-Amino-4-[9-(difluoromethyl)-3- {[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2 / ?,7aS)-2-fluorotetrahydro-lH-pyrrolizin- 7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene- 3-carbonitrile (rotational isomer 1 and 2)

[0948]

[0949] Example 20a, rotational isomer 1 Example 20b (rotational isomer 2)

[0950] 1: tert-Butyl {4-[9-(difluoromethyl)-3-{[l-(dimethylami

[0951]

[0952] -7-fluoro-5-

[0953]

[0954] -2-flu ro-lH-i

[0955]

[0956] methoxy 1-2,3-dihydroll, 31oxazino[4, 5,6-

[0957]

[0958] in-8-yll-5-fluoro-l-l i-2-’

[0959]

[0960] CPhos Pd G3 (0.082 g, 0.10 mmol) and CPhos (0.045 g, 0.10 mmol) were added to a de-oxygenated solution of l-{[8-bromo-9-(difluoromethyl)-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]rnethoxy}[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl]methyl}- / \ / , / \ / -dimethylcyclobutan-l-amine (lnt-14) (0.30 g, 0.51 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (0.40 g, 1.02 mmol) and K3PO4(0.33 g, 1.53 mmol) in THF (15 mL) and water (1.5 mL). The reaction mixture was heated to 60 °C for 30 minutes. The reaction mixture was cooled to room temperature, diluted with water and extracted with EtOAc. The organic layer was washed with saturated brine and concentrated in vacuo. The residue was dissolved in DCM, dried by passing through a phase separator cartridge and the filtrate was evaporated to dryness. The crude product was purified by reverse phase chromatography, gradient 60% acetonitrile in water (containing 1% NH4OH (28-30% in water)) to 100% acetonitrile. Pure fractions were combined and evaporated to a small volume of water then diluted with DCM, extracted and dried by passing through a phase separator cartridge. Evaporation afforded tert-butyl {4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophen-2-yl}carbamate (0.19 g, 48%) as an orange foam, m / z (ES+), [M+H]+ = 775.

[0961]

[0962] 2: tert-l i-4-[9-(difluoromethvl)-3-{[l-(dimethylamii

[0963]

[0964] methyl)-7-fluoro-5- {((2 / ?,7aS)-2-fluorotetrahvdro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihvdro(l,3]oxazino(4,5,6- uinazolin-8-yll-5-fluoro-l-l i-2-’

[0965]

[0966] Boc / Chlorosulfonyl isocyanate (0.35 mL, 4.01 mmol) was added dropwise to a solution of tert-butyl {4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-ce]quinazolin-8-yl]-5-fluoro-l-benzothiophen-2-yl}carbamate (0.31 g, 0.40 mmol) and DMF (0.75 mL, 9.64 mmol) in THF (10 mL) at -78 °C. The reaction mixture was stirred at -78 °C for 10 minutes and then stirred at 0 °C for 20 minutes. The reaction mixture was then quenched carefully with saturated NaHCO3solution at 0 °C and extracted with EtOAc. The organic layer was concentrated. The residue was dissolved in DCM and then purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 7 M NH3 / MeOH and combined pure fractions were evaporated to dryness to afford tert-butyl {3-cyano-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophen-2-yl}carbamate (0.31 g, 95%) as a yellow foam, m / z (ES+), [M+H]+ = 800.

[0967] Step 3: 2-Amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cvclobutyl]methyl}-7-fluoro-5- {[(2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl]methoxy}-2,3-dihvdro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile (rotational isomers 1 and 2)

[0968]

[0969] Example 20a, rotational isomer 1 Example 20b (rotational isomer 2) TFA (1.2 mL, 15.25 mmol) was added to a mixture of tert-butyl {3-cyano-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophen-2-yljcarbamate (0.31 g, 0.38 mmol) and DCM (10 mL) and the resulting reaction mixture stirred at RT for 2 hours. The reaction mixture was purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1 M NH3 / MeOH and pure fractions were evaporated to dryness. The crude material was purified by preparative chiral SFC by the following conditions: Column: ChiralPak IK, 5 pm, 20x250 mm; Mobile Phase: A = scCO2, Mobile Phase B = 0.1%NH3 in MeOH; Gradient used: 30% B over 15.0 minutes; Flow rate: 60.0 mL / min; BPR: 120 bar; Column temperature: 40.0 °C.

[0970] Chiral Analysis was performed under the following conditions: Column: ChiralPak IK, 3x100 3 pm, Mobile phase: A = scCO2, B = 0.1% NH3 in methanol, Gradient used: 5 to 50% %B over 1.9 minutes, Flow rate: 2.5 mL / min

[0971] Peak 1, rotational isomer 1: fractions were evaporated to afford 2-amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile 20a (31 mg, 12%) as a yellow gum assigned >99.0% e.e. tR = 1.89 min.1H NMR (500 MHz, CDCl3, 1 °C) 1.63 - 2.22 (18H, m), 2.90 (1H, td), 3.1 - 3.3 (3H, m), 3.68 - 3.8 (1H, m), 4.08 (1H, d), 4.14 (1H, d), 4.20 (1H, d), 5.04 - 5.29 (1H, m), 5.33 (1H, d), 5.45 (1H, d), 5.57 (2H, s), 6.46 - 6.81 (1H, m), 6.94 (1H, t), 7.45 (1H, dd). m / z (ES+), [M+H]+ = 700.

[0972] Peak 2, rotational isomer 2: fractions were evaporated to afford an impure product, which was triturated with Et2O. The solid was collected and dried under vacuum to afford 2-amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin -8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile 20b (24 mg, 9%) as a cream solid assigned >99.0% e.e. tR = 2.15 min. NMR (500 MHz, CDCl3, 1 °C) 1.52 - 2.22 (18H, m), 2.84 - 2.96 (1H, m), 3.05 - 3.23 (3H, m), 3.79 (1H, d), 4.05 (1H, d), 4.13 (1H, d), 4.21 (1H, d), 5.09 - 5.31 (1H, m), 5.29 - 5.52 (4H, m), 6.53 - 6.83 (1H, m), 6.96 (1H, t), 7.47 (1H, dd). m / z (ES+), [M+H]+ = 700.

[0973] tert-Butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin- 3(2H)-yl)methyl)tetrahydrofuran-3-yl)carbamate (lnt-18)

[0974]

[0975] lnt-18

[0976] Step 1: Butyl 3-aminotetrahvdrofuran-3-carboxylate

[0977]

[0978] To a solution of 3-aminotetrahydrofuran-3-carboxylic acid hydrochloride (CAS No: 919098-94-5) (129 g, 770 mmol), in n-BuOH (900 mL) was added SOCI2(112 mL, 1.54 mol). The mixture was stirred at 110 °C for 12 hours. The mixture was cooled to RT, then the reaction mixture was quenched by adding saturated NaHCO3solution (1 L) at 5 °C, and then extracted with EtOAc (750 mL x 2). The combined organic layers were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product butyl 3-aminotetrahydrofuran-3-carboxylate (550 g, 95%) was obtained as colourless oil, which was used in the next step without further purification.1H NMR (400 MHz, DMSO, 22 °C) 0.91 (3H, t), 1.26 - 1.46 (3H, m), 1.54 - 1.65 (2H, m), 1.93 (1H, ddd), 2.22 - 2.34 (1H, m), 2.52 (1H, p), 3.62 (1H, d), 3.79 - 3.97 (3H, m), 4.11 (2H, t).m / z (ES+), [M+H] + = 188.

[0979] Step 2: ( / ?)-3-(butoxycarbonyl)tetrahydrofuran-3-aminium ( / ?)-2-hydroxy-2-phenylacetate

[0980] NH2HO

[0981]

[0982] As described in W02008080891A2.

[0983] To a solution of butyl 3-aminotetrahydrofuran-3-carboxylate (185 g, 988 mmol) in EtOAc (2775 mL) was added (R)-2-hydroxy-2-phenylacetic acid (105 g, 692 mmol). The mixture was stirred at 75 °C for 5 hours, then cooled RT and stirred for 2 hours. The reaction mixture was filtered and the filter cake was collected affording the crude product. The solid was diluted with MeCN (3500 mL) at 75 °C and stirred for 5 hours, then the mixture was cooled down to RT. Then the mixture was filtered and the solid was collected to afford (R)-3-(butoxycarbonyl)tetrahydrofuran-3-aminium (R)-2-hydroxy-2-phenylacetate (355 g, 35%) as white solid.1H NMR (400 MHz, DMSO-d6, 22 °C) 0.89 (3H, t), 1.27 - 1.41 (2H, m), 1.52 - 1.63 (2H, m), 1.79 - 1.9 (1H, m), 2.19 - 2.3 (1H, m), 3.54 (1H, d), 3.77 - 3.96 (3H, m), 4.08 (2H, t), 4.92 (1H, s), 7.21 - 7.36 (3H, m), 7.36 - 7.45 (2H, m). Four exchangeable protons not observed.

[0984] Step 3: Butyl ( / ?)-3-((tert-butoxycarbonyl)amino)tetrahvdrofuran-3-carboxylate

[0985]

[0986] Boc

[0987] i(R)

[0988]

[0989] To a solution of (R)-3-(butoxycarbonyl)tetrahydrofuran-3-aminium (R)-2-hydroxy-2-phenylacetate (355 g, 1.05 mol) and TEA (291 mL, 2.09 mol,) in 2-MeTHF (3550 mL) was added Boc2O (274 g, 1.26 mol). The mixture was stirred at RT for 12 hours. The reaction mixture was quenched by addition of H2O (800 mL) at RT, and then extracted with 2-Me-THF (300 mLx3). The combined organic layers were washed with brine (500 mL), dried over Na2SO4, filtered and concentrated to afford the crude product butyl (R)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate (311 g) as a colourless oil, which was used into the next step without further purification, m / z (ES+), [M-100, Boc]+ = 188. Step 4: tert-Butyl (S)-(3-(hydroxymethyl)tetrahvdrofuran-3-yl)carbamate

[0990] O'z\ Boc

[0991] \ _ L- H

[0992] H

[0993]

[0994] O—

[0995] To a solution of butyl (R)-3-((tert-butoxycarbonyl)amino)tetrahydrofuran-3-carboxylate (100 g, 348 mmol) in THF (1000 mL) and EtOH (20 mL) was added 2 M LiBH4in THF (261 mL, 522 mmol) at 0 °C under nitrogen. The mixture was stirred at RT for 3 hours. The reaction mixture was quenched by addition of saturated NH4CI solution (450 mL) at 0 °C, and then extracted with EtOAc (300 mL x 3). The combined organic layers were washed with brine (400 mL), dried over Na2SO4, filtered and concentrated under reduced pressure. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in petroleum ether. Pure fractions were evaporated to dryness to afford tert-butyl (S)-(3-(hydroxymethyl)tetrahydrofuran-3-yl)carbamate (105 g, 46%) as a white solid.1H NMR (400 MHz, CDCI3, 24 °C) 1.46 (9H, s), 2.08 (2H, t), 3.7 - 3.87 (5H, m), 3.89 - 4.07 (2H, m), 5.12 (1H, s).m / z (ES+), [M-56]+= 162.1. [α20D] = -6.6 (c. 1.03, MeOH).

[0996] Step 5: tert-Butyl ( / ?)-(3-formyltetrahydrofuran-3-yl)carbamate

[0997] Boc

[0998] \ _ L- lH

[0999] o

[1000]

[1001] ^< R)

[1002] (Diacetoxyiodo)benzene (15.57 g, 48.33 mmol) was added to a mixture of tert-butyl (S)-(3-(hydroxymethyl)tetrahydrofuran-3-yl)carbamate (10.00 g, 46.03 mmol) in EtOAc (50 mL), followed by TEMPO (0.36 g, 2.30 mmol). The reaction mixture was stirred at 40 °C for 2 hours. The mixture was allowed to cool to RT, then partially concentrated. The mixture was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl (R)-(3-formyltetrahydrofuran-3-yl)carbamate (7.65 g, 77 %) as a colourless oil which crystallised upon standing.1H NMR (500 MHz, DMSO-dg, 27 °C) 1.40 (9H, s), 1.99 (1H, dt), 2.12 (1H, dt), 3.67 (1H, d), 3.77 (2H, dd), 3.99 (1H, d), 7.84 (1H, s), 9.48 (1H, s).Step 6: tert-Butyl (S)-(3-(aminomethyl)tetrahydrofuran-3-yl)carbamate

[1003] O''"''''') Boc

[1004] \ _ Z_ MH

[1005] H2N— -

[1006] To a mixture of tert-butyl (R)-(3-formyltetrahydrofuran-3-yl)carbamate (7.60 g, 35.31 mmol) in EtOH (75 mL) was added benzylamine (4.2 mL, 38.84 mmol) and the reaction mixture was stirred at RT for 18 hours. 10% Pd / C (3.76 g, 3.53 mmol) was then added and the reaction mixture was placed in a pressure vessel. The vessel was purged 3 times with hydrogen and then run at 2 bar of H2at RT for 6 hours. The mixture was filtered through celite and the solvent was removed in vacuo to afford tertbutyl (S)-(3-(aminomethyl)tetrahydrofuran-3-yl)carbamate (7.80 g, 102 %) as a colourless oi H NMR (400 MHz, DMSO-dg, 20 °C) 6 1.37 (9H, d), 1.80-1.91 (1H, m), 1.94-2.08 (1H, m), 2.60-2.80 (2H, m), 3.58 (1H, dd), 3.66-3.73 (3H, m), 6.85 (1H, brs). Two exchangeable protons not observed, m / z (ES+), [M+H]+ = 217.

[1007] Step 7: tert-Butyl (S)-(3-(((7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)amino)methyl)tetrahydrofuran-3-yl)carbamate

[1008]

[1009] To a mixture of 7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4(3H)-one (6.00 g, 17.57 mmol) in MeCN (130 mL) was added DIPEA (15.3 mL, 87.83 mmol) and then HCCP (7.94 g, 22.84 mmol) in one portion. The reaction was stirred at RT for 30 minutes. A solution of tert-butyl (S)-(3-(aminomethyl)tetrahydrofuran-3-yl)carbamate (4.56 g, 21.08 mmol) in MeCN (30 mL) was added and the reaction mixture was stirred at RT for 90 mins. The solvent was partially removed and the mixture was partitioned between EtOAc (250 mL) and water (250 mL). The organic phase was washed with water (100 mL), then brine (100 mL) and passed through a phase separating cartridge. The solvent was removed in vacuo. The crude product was purified by flash silica chromatography, elution gradient 0 to 100% EtOAc in heptane. Pure fractions were evaporated to dryness to afford tert-butyl (S)-(3-(((7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)amino)methyl)tetrahydrofuran-3-yl)carbamate (5.70 g, 60 %) as a cream solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.38 (9H, s), 1.99 -2.06 (1H, m), 2.16 (1H, dt), 2.53 (3H, s), 3.7 - 3.84 (4H, m), 3.84 - 3.96 (2H, m), 7.30 (1H, s), 7.89 (1H, s). m / z (ES+), [M+H]+ = 539; 541; 543.

[1010] Step 8: tert-Butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)carbamate (lnt-18)

[1011]

[1012] 2-(Methylsulfonyl)ethan-l-ol (1.86 g, 15 mmol) and CS2CO3 (9.78 g, 30.01 mmol) were added to a mixture of tert-butyl (S)-(3-(((7-bromo-6-chloro-5,8-difluoro-2-(methylthio)quinazolin-4-yl)amino)methyl)tetrahydrofuran-3-yl)carbamate (5.40 g, 10 mmol) in DMF (25 mL). The reaction was stirred at 50 °C for 2 hours. Chloroiodomethane (1.45 mL, 20.01 mmol) was added and the mixture was stirred at 80 °C for 2 hours. After cooling to RT, the mixture was diluted with water (150 mL) and extracted with EtOAc (2 x 150 mL). The combined organics were washed with brine (50 mL), passed through a phase separating cartridge and the solvent was removed in vacuo. The residue was triturated with MeCN (25 mL) and the resulting solid was filtered, affording the title compound (3.80 g). The mother liquor was purified by flash silica chromatography, elution gradient 0 to 50% EtOAc in heptane. Pure fractions were evaporated to dryness to afford the second batch of the title compound (0.42 g). Two batches were combined to afford tert-butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)carbamate (lnt-18) (4.22 g, 77 %) as a pale pink solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.40 (9H, s), 1.98 - 2.09 (1H, m), 2.09 - 2.17 (1H, m), 2.56 (3H, s), 3.69 - 3.86 (4H, m), 3.97 (1H, d), 4.07 (1H, d), 5.38 (2H, q), 7.26 (1H, s). m / z (ES+), [M+H]+ = 547;549;551

[1013] Example 21a (rotational isomer 1) and 21b (rotational isomer 2): 2-Amino-4-(9-chloro-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-3-(((S)-3-(methylamino)tetrahydrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomers 1 and 2)

[1014]

[1015] Example 21a; Rotational Isomer 1 Example 21b; Rotational Isomer 2 Step 1: tert-Butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin- 3(2H)-yl)methyl)tetrahvdrofuran-3-yl)(methyl)carbamate

[1016]

[1017] A solution of 1 M LDA in THF (0.4 mL, 0.37 mmol) was added dropwise to a stirred solution of tert-butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)carbamate (lnt-18) (0.10 g, 0.18 mmol) and iodomethane (0.06 mL, 0.92 mmol) in THF (1.5 mL), cooled to 5 °C, over 10 minutes under nitrogen. The resulting solution was allowed to warm to RT and stirred for 1 hour. Extra iodomethane (0.06 mL, 0.92 mmol) then 1 M LDA (0.18 mL, 0.18 mmol) was added and the mixture was stirred for a further 1 hour at RT. The mixture was diluted with saturated NH4Cl solution (10 mL) and extracted with EtOAc (20 mL). The organic extract was dried over MgSO4, filtered, and concentrated. The residue was dissolved in DCM and passed through a phase separation filter. The solution was evaporated to give tert-butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.096 g, 93 %) as a solid.1H NMR (500 MHz,DMSO-dg, 27 °C) 1.22 (9H, s), 2.16 – 2.26 (1H, m), 2.30 (1H, ddd), 2.61 (3H, s), 2.91 (3H, s), 3.67 (1H, d), 3.8 - 3.93 (2H, m), 3.96 (1H, q), 4.11 (1H, s), 4.34 (1H, s), 5.43 (2H, dt). m / z (ES+), [M+H]+ = 563; 565; 567.

[1018] Step 2: tert-Butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo(b1thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-(l,3]oxazino(4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate

[1019]

[1020] tert-Butyl (S)-(3-((8-bromo-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (95 mg, 0.17 mmol), tert-butyl (5-fluoro-4-(4,4,5,5-tetramethyl-l,3,2-dioxaborolan-2-yl)benzo[b]thiophen-2-yl)carbamate (lnt-2) (66 mg, 0.17 mmol), CPhos Pd G3 (14 mg, 0.02 mmol), CPhos, (7.4 mg, 0.02 mmol) and K2CO3 (47 mg, 0.34 mmol) were suspended in a degassed mixture of 2-MeTHF (2 mL) and water (0.2 mL). The mixture was sealed into a microwave tube. The reaction was heated to 70 °C for 2 hours in the microwave reactor. After cooling to RT, volatiles were removed under reduced pressure. The residue was dissolved in MeOH (5 mL) and purified by ion exchange chromatography, using an SCX column. The desired product was eluted from the column using 1 M NH3 in MeOH and pure fractions were evaporated to dryness to afford tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.11 g, 88 %) as a solid.1H NMR (500 MHz, DMSO-d6, 27 °C) 1.15 (9H, s), 1.45 (9H, s), 2.11 - 2.21 (1H, m), 2.23 - 2.3 (1H, m), 2.55 (3H, s), 2.89 (3H, d), 3.62 (1H, dd), 3.79 - 3.97 (3H, m), 4.14 (1H, d), 4.32 (1H, s), 5.31 - 5.51 (2H, m), 6.34 (1H, s), 7.17 - 7.23 (1H, m), 7.98 (1H, dd), 10.73 (1H, s). m / z (ES+), [M+H]+ = 750.

[1021] Step 3: tert-Butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahvdrofuran-3-yl)(methyl)carbamate

[1022]

[1023] Chlorosulfonyl isocyanate (0.73 mL, 8.38 mmol) was added dropwise to a cooled solution of tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.63 g, 0.84 mmol) in THF (12 mL) and DMF (1.6 mL, 20.12 mmol) at -78 °C under nitrogen. The reaction mixture was stirred for 15 minutes at -78 °C. The mixture was then warmed to 0 °C and then stirred for 1 hour. The reaction was quenched carefully with water (0.5 mL) and saturated NaHCO3solution (20 mL). Most of the volatiles were removed under vacuum. The residue was extracted with DCM (2 x 40 mL). The combined extracts were washed with brine (20 mL), dried over MgSO4and evaporated. The crude was absorbed onto a SCX column eluting with MeOH then 2 M NH3in MeOH. All fractions containing product were combined and then evaporated to dryness. The residue was purified by reverse phase chromatography (Interchim C18-HP Flash column), using decreasingly polar mixtures of water (containing 0.1% NH3) and MeCN as eluents. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.26 g, 39 %) as a yellow foam, m / z (ES+) [M+H]+ = 775; 777.

[1024] Step 4: tert-Butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylsulfinyl)-(l,3]oxazino(4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahvdrofuran-3-yl)(methyl)carbamate

[1025]

[1026] Oxone* (0.54 g, 0.88 mmol) was added in one portion to tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylthio)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.34 g,0.44 mmol) in a mixture of THF (8.2 mL) and water (1.6 mL) under nitrogen. The resulting solution was stirred at RT for 1.5 hours. The reaction mixture was quenched with 15% sodium bisulfite solution (10 mL) and saturated NaHCO3solution (10 mL) and extracted with EtOAc (3 x 30 mL). The combined organics were washed with brine (20 mL), dried over MgSO4, and concentrated to give crude tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylsulfinyl)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.32 g, 91 %) as a solid, m / z (ES+), [M+H]+ = 791; 763.

[1027] Step 5: tert-Butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahvdrofuran-3-yl)(methyl)carbamate

[1028]

[1029] Lithium 2-methylpropan-2-olate (0.55 mL, 1.20 mmol) was added to a stirred mixture of tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(methylsulfinyl)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.32 g, 0.40 mmol) and ((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methanol (0.077 g, 0.48 mmol) in acetonitrile (5.6 mL) under nitrogen. The resulting mixture was stirred at RT for 45 minutes. The reaction mixture was passed through a SCX2 column eluting with MeOH then 2 M NH3 in MeOH. Fractions containing the desired compound were evaporated to dryness to afford tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.35 g, 97 %) as a solid, m / z (ES+), [M+H]+ = 886; 888.

[1030] Step 6: 2-Amino-4-(9-chloro-7-fluoro-5-(((2 / ?,7oS)-2-fluorotetrahvdro-lH-pyrrolizin-7o(5H)-yl)methoxy)-3-(((S)-3-(methylamino)tetrahvdrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1 and 2)

[1031]

[1032] Example 21 a; Rotational Isomer 1 Example 21 b; Rotational Isomer 2 TFA (0.6 mL, 7.78 mmol) was added to a solution of tert-butyl ((3S)-3-((8-(2-((tert-butoxycarbonyl)amino)-3-cyano-5-fluorobenzo[b]thiophen-4-yl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-[l,3]oxazino[4,5,6-de]quinazolin-3(2H)-yl)methyl)tetrahydrofuran-3-yl)(methyl)carbamate (0.35 g, 0.39 mmol) in DCM (6.2 mL). The solution was stirred at RT for 2 hours. Extra TFA (0.6 mL, 7.78 mmol) was added and the resulting mixture was stirred for 14 hours at RT. Volatiles were evaporated to dryness. The residue was dis...

Claims

1.Claims1) A compound of Formula (A), or a pharmaceutically acceptable salt thereof,RaRbwherein:Y = S or O;Raand Rbare independently selected from Me and Et; orRaand Rbtogether form a group selected from CH2CH2, CH2CH2CH2 or CH2CH2OCH2;R1is Me or H;R2is Me or H;R3is F or Me;R4is H or F;R5is Cl, F, CCH, CF2H or Me; andR6is a group selected fromwherein * indicates the site of attachment of R6to the oxygen atom.2) A compound, or a pharmaceutically acceptable salt thereof, according to claim 1, that is a compound of Formula (I)wherein:n = 0 and X is CH2; orn = 1 and X is O;Y = S or O;R1is Me or H;R2is Me or H;R3is F or Me;R4is H or F;R5is Cl, F, CCH, CF2H or Me; andR6is a group selected fromwherein * indicates the site of attachment of R6to the oxygen atom.3) A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 or claim 2, wherein Y is S.4) A compound, or a pharmaceutically acceptable salt thereof, according to claim 1 or claim 2, wherein Y is O.5) A compound, or a pharmaceutically acceptable salt thereof, according to any preceding claim wherein R4is H.6) A compound, or a pharmaceutically acceptable salt thereof, according to any preceding claim wherein R3is F.7) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 2 to 6, wherein n = 0 and X is CH2.8) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 2 to 6, wherein n = 1 and X is O.9) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 8,Nwherein R6is a group of formula10) A compound, or a pharmaceutically acceptable salt thereof, selected from:2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-9-ethynyl-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7o(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7oS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-9-methyl-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-((l-(methylamino)cyclobutyl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2S,4R)-4-methoxy-l-methylpyrrolidin-2-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1, isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2, isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1, isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2, isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-((l-(dimethylamino)cyclobutyl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((S)-2-methylenetetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)- 2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[1,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(2-(dimethylamino)-2-methylpropyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 1);2-Amino-4-(9-chloro-3-(((R*)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)- 2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((R)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile;2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-methylbenzofuran-3-carbonitrile;2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-((l-(dimethylamino)cyclobutyl)methyl)-7,9-difluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5,7-difluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[l,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-l-benzothiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-[9-(difluoromethyl)-3-{[l-(dimethylamino)cyclobutyl]methyl}-7-fluoro-5-{[(2R,7aS)-2-fluorotetrahydro-1H-pyrrolizin-7a(5H)-yl]methoxy}-2,3-dihydro[1,3]oxazino[4,5,6-de]quinazolin-8-yl]-5-fluoro-1-benzothiophene-3-carbonitrile (rotational isomer 2);): 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-(((S)-3-(methylamino)tetrahydrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-c / e]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);): 2-Amino-4-(9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-3-(((S)-3-(methylamino)tetrahydrofuran-3-yl)methyl)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(3-(((S)-3-aminotetrahydrofuran-3-yl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1);2-Amino-4-(3-(((S)-3-aminotetrahydrofuran-3-yl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1, rotational isomer 1);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 1, rotational isomer 2);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 2, rotational isomer 1);2-Amino-4-(9-chloro-3-(((S)-3-(dimethylamino)tetrahydrofuran-3-yl)methyl)-7-fluoro-5-(((2R*,7aS*)-2-methoxytetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (isomer 2, rotational isomer 2);2-Amino-4-(3-((l-aminocyclobutyl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 1); and2-Amino-4-(3-((l-aminocyclobutyl)methyl)-9-chloro-7-fluoro-5-(((2R,7aS)-2-fluorotetrahydro-lH-pyrrolizin-7a(5H)-yl)methoxy)-2,3-dihydro-[l,3]oxazino[4,5,6-de]quinazolin-8-yl)-5-fluorobenzo[b]thiophene-3-carbonitrile (rotational isomer 2).11) A pharmaceutical composition comprising a compound, or a pharmaceutically acceptable salt thereof, according to any preceding claim, and at least one pharmaceutically acceptable excipient.12) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 10, for use as a medicine.13) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 10, for use in the treatment of cancer, for example a cancer that expresses Ras G12D mutant protein.14) A method of treatment comprising administering an effective amount of a compound according to any of claims 1 to 10, or a pharmaceutically acceptable salt thereof, to a patient, wherein the patient has been identified as having a cancer that expresses Ras G12D mutant protein.15) A compound, or a pharmaceutically acceptable salt thereof, according to any of claims 1 to 10, for use in the manufacture of a medicament, optionally wherein the medicament is for use in the treatment of a cancer that expresses Ras G12D mutant protein.16) A kit comprising a pharmaceutical composition according to claim 11 and instructions for its use in the treatment of a cancer, wherein the cancer expresses Ras G12D mutant protein.

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