WO2025163494A1 - Condensed azines for the treatment of cancer - Google Patents

Abstract

The present disclosure provides compounds and their methods of use. In particular, the compounds of the present disclosure may be useful for inhibiting RAS proteins, such as KRAS proteins. The disclosed compound may be used in the treatment of cancer and be highly selective for KRAS proteins having the G12D mutation. Alternatively or additionally, said compounds may have broad spectrum activity across a range of KRAS proteins.

Description

CONDENSED AZINES FOR THE TREATMENT OF CANCER

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to GB2401145.4 filed on January 29, 2024, and entitled “COMPOUNDS,” and GB2416725.6 filed on November 13, 2024, and entitled “COMPOUNDS,” the entire disclosures of which are expressly incorporated by reference herein.

FIELD OF INVENTION

[0002] This invention relates to compounds and their methods of use. In particular, the compounds of the present invention may be useful for inhibiting RAS proteins. More specifically, this invention relates to compounds for inhibiting a broad spectrum of KRAS proteins including mutant strains and wild-type KRAS. The compounds of the invention may therefore be used in treating conditions mediated by KRAS proteins. For example, the compounds may be used in treating cancer.

BACKGROUND

[0003] RAS (HRAS, KRAS4A and 4B, and NRAS) proteins are a group of closely related monomeric globular proteins that act as molecular switches, cycling between inactive (GDP- bound) and active (GTP-bound) states to transduce upstream cellular signals to downstream effectors to regulate a wide variety of processes, including cellular proliferation. RAS is the most frequently mutated oncogene in cancer (~30%), with KRAS the most commonly mutated isoform accounting for ~85% of RAS mutations (Hobbs et al, Journal of Cell Science (2016) 129, 1287-1292 doi:10.1242/jcs.182873).

[0004] KRAS G12D is a missense gain of function mutation that results in an amino acid substitution of the glycine (G) at codon 12 with aspartic acid and is the most prevalent accounting for ~26% of all KRAS mutations in cancer. KRAS G12D mutations are present in 36% pancreatic carcinoma patients, 13% colorectal carcinoma patients, 10% rectal carcinoma patients, 6% endometrial carcinoma patients, 4% of non-small cell lung carcinoma patients, 4% gastric carcinoma patients, 3% ovarian carcinoma patients and 2% small cell lung carcinoma patients (e.g. The AACR Project GENIE Consortium, (2017) Cancer Discovery; 7(8):818-831 . Dataset version 8). Many of these patients with G12D mutations have high unmet need with little option of efficacious targeted therapy. The mainstay of treatment for many of these patients remains chemotherapy combinations with an associated high degree of side effects and lack of efficacy.

[0005] Other KRAS missense gain of functions mutations that result in amino acid substitutions at codon 12, codon 13 and codon 61 , as well as amplification of KRAS wildtype protein also drive carcinogenesis. Alterations in KRAS are found in approximately one in seven cancers (Hoffman et al, Cancer Discovery (2022) 12, 924-937). Activating mutations in KRAS are highly prevalent in solid tumours and are predominately found in 35% lung, 45% colorectal and up to 90% pancreatic cancers. G12D, G12V and G12C are the most frequently occurring KRAS mutations and are found more than half of all KRAS driven cancers. Other KRAS mutations include KRAS G12V, KRAS G12A, KRAS G13D and KRAS Q61 H. KRAS amplifications are found in approximately 7% of cancers with KRAS alterations and are commonly occurring in ovarian carcinoma, breast carcinoma, lung adenocarcinoma, gastric adenocarcinoma, uterine cancers and esophagogastric cancers (Hoffman reviews). Pan KRAS inhibitors have the potential to treat a broader patient population including cancers harbouring KRAS mutations, KRAS wildtype amplifications and cancers driven by loss of the tumour suppressor NF1 . In addition, pan KRAS inhibitors can potentially be used to treat cancers with acquired resistance to allele specific inhibitors such as KRAS G12C inhibitors.

[0006] Due to this frequency of KRAS mutations in multiple different tumour types and the established role of KRAS as an oncogenic driver mutation in cancer, modulating the activity of KRAS is a highly attractive therapeutic goal and has been the subject of significant research efforts for greater than 30 years. However, it has proven extremely challenging to affect KRAS activity directly and research efforts have focussed on other targets in the signalling cascade that are either upstream or downstream from KRAS. Other approaches to inhibit KRAS activity have included affecting other points on the MAPK pathway (English et al., 2002; Adjei 2014; Chin et al., 2020), many of which have shown MAPK pathway inhibition to be clinically effective. Recently, mutant KRAS G12C selective inhibitors have been reported (Kettle and Cassar 2020)., which bind covalently to an allosteric pocket and have progressed into clinical trials and shown responses in selected patients.

[0007] Compounds which are capable of modulating G12D mutant KRAS are described in WO2021/041671 , WO2022/248885 and WO2022/258974. Compounds capable of modulating multiple RAS isoforms and mutants have also been described (Kessler et al. 2019), however these compounds are believed to be of limited therapeutic benefit owing to a lack of sufficient potency as well as little selectivity for KRAS over HRAS and NRAS isoforms.

[0008] An aim of the present invention is to provide alternative or improved compounds for inhibiting RAS proteins. For example, an aim of the present invention is to provide alternative or improved compounds for inhibiting KRAS proteins.

[0009] Furthermore, it is an aim of certain embodiments of this invention to provide new compounds for use in treatment of conditions modulated by RAS proteins. For example, it is an aim of certain embodiments of this invention to provide compounds for use in the treatment of cancer. Said compounds may be more selective for KRAS proteins having the G12D mutation over alternative KRAS proteins than prior art compounds. Alternatively, said compounds may have broad spectrum activity across a range of KRAS proteins.

[0010] It is an aim of certain embodiments of this invention to provide new cancer treatments. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing treatments, optionally they should have better activity.

[0011] It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity relative to prior art compounds and existing therapies.

[0012] Another aim of certain embodiments of this invention is to provide compounds having a convenient pharmacokinetic profile and a suitable duration of action following dosing. A further aim of certain embodiments of this invention is to provide compounds in which the metabolised fragment or fragments of the drug after absorption are GRAS (Generally Regarded As Safe).

[0013] Certain embodiments of the present invention satisfy some or all of the above aims.

BRIEF SUMMARY OF THE DISCLOSURE

[0014] In accordance with the present invention there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof: wherein

Z¹ is independently selected from -O- and -NR^5a-;

Z² is independently absent or is selected from -O- and -NR^5b-;

X¹ is independently selected from N and CR^3b;

R¹ is independently selected from C₀-C₃-alkylene-R^1a and C₂-C₆-alkylene-R^1b; wherein R^1a is independently selected from: a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups; R^1b is independently selected from: NR⁷R⁸, OR⁸, SR⁸, SOR⁸, SO₂R⁸ and SO(NH)R⁸; or R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups;

R² is independently C₁-C₆-alkyl, C₁-C₄-haloalkyl, C₀-C₄-alkylene-R^2a, C₁-C₄-alkylene-R^2b, C₂- C₄-alkylene-R^2c;

R^2a is independently selected from monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group; a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; and C₃-C₇-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups and any heteroaryl or phenyl R^2a group is optionally substituted with from 1 to 6 R¹¹ groups; wherein R^2b is independently selected from CONR¹²R¹² and CO₂R¹²; wherein R^2c is independently selected from NR¹²R¹³ and OR¹²; or R² and R^5b together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group; and a fused, spirofused or bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R¹⁰ groups;

R^3a and R^3b are each independently selected from: H, halo, C₁-C₄-alkyl, O-C₁-C₄-alkyl, C₁-C₄- haloalkyl, O-C₁-C₄-haloalkyl, cyclopropyl, nitro and cyano;

R⁴ is independently selected from phenyl, said phenyl being optionally fused to a C₅-C₇- cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5-, to 10-membered monocyclic or bicyclic heterocyclyl; wherein R⁴ is optionally substituted with from 1 to 4 R¹⁴ groups;

R^5a, R^5b, R⁸ and R¹² are each independently selected at each occurrence from H, C₁-C₄- haloalkyl, cyclopropyl and C₁-C₄-alkyl;

R⁶ is independently selected from H, halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl;

R^6a is independently selected from H, halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl;

R⁷ and R¹³ are each independently at each occurrence selected from H, C₁-C₄-alkyl, C₁-C₄- haloalkyl and C(O)-C₁-C₄-alkyl; or R¹² and R¹³ together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; said heterocycloalkyl group being optionally substituted with from 1 to 6 R^10a groups;

R⁹ is independently at each occurrence selected from hydroxyl, oxo, halo, cyano, NR¹²R¹³, OR¹², COR¹², CO2R¹², CONR¹²R¹³, C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl; R¹⁰ is independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², COR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R^10a is independently at each occurrence selected from oxo, halo, cyano, NR¹²R^13a, OR¹², COR¹², CO₂R¹², CONR¹²R^13a, C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R^13a, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R^13a is independently at each occurrence selected from H, C₁-C₄-alkyl, C₁-C₄-haloalkyl and C(O)-C₁-C₄-alkyl;

R¹¹ is independently selected from halo, cyano, nitro, NR¹²R¹³, OR¹², CO2R¹², CONR¹²R¹², C₁- C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R¹⁴ is independently at each occurrence selected from CF₃, hydroxyl, halo, cyano, nitro, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, phenyl and cyclopropyl; wherein any of the aforementioned alkyl, alkylene, phenyl or cycloalkyl (e.g. cyclopropyl) groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C₁-C₄-alkyl, C₁- C₄-alkyl substituted with OR^a, halo, nitro, cyano, NR^aR^b, OR^a, SR^a, CO₂R^a, C(O)R^a, CONR^aR^a; wherein R^a is independently at each occurrence selected from H, C₁-C₄-alkyl and C₁-C₄- haloalkyl; and R^b is independently at each occurrence selected from H, C₁-C₄-alkyl, C(O)- C₁- C₄-alkyl and S(O)₂-C₁-C₄-alkyl.

[0015] In an embodiment, the compound of formula (I) is a compound of formula (la): wherein R¹, R², R^3a, R⁴, R^5a, R⁶ and X¹ are as described above for compounds of formula (I).

[0016] In an embodiment, the compound of formula (I) is a compound of formula (Ila) or (lib):

wherein R¹, R², R^3a, R⁴, R^5a, R⁶, R^6a, and X¹ are as described above for compounds of formula (I).

[0017] In an embodiment, the compound of formula (I) is a compound of formula (Illa), (lllb), or (lllc): wherein R¹, R², R^3a, R⁶, R^6a, R¹⁴, X¹, Z¹ and Z² are as described above for compounds of formula (I); and x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R¹⁴ groups may be attached to either ring of the naphthyl group.

[0018] In an embodiment, the compound of formula (I) is a compound of formula (Iva) or

(IVb):

wherein R¹, R², R^3a, R^5a, R⁶, R^6a and R¹⁴ are as described above for compounds of formula (I); and x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R¹⁴ groups may be attached to either ring of the naphthyl group.

[0019] In an embodiment, the compound of formula (I) is a compound of formula (Va), (Vb), or (Vc): wherein R¹, R^3a, R⁴, R^5a, R⁶, R^6a and R¹⁰ are as described above for compounds of formula (I); and wherein R¹⁵ is independently selected from H, C₁-C₄-alkyl; wherein R¹⁶ is independently selected from H, C₁-C₄-alkyl and cyclopropyl; or wherein R¹⁵ and R¹⁶ together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R¹⁰ groups; and y is independently selected from 0, 1 , 2, 3, and 4.

[0020] In an embodiment, the compound of formula (I) is a compound of formula (Vla) or

(Vlb):

wherein R¹, R^3a, R^5a, R⁶, R^6a, R¹⁰, and R¹⁴ are as described above for compounds of formula (I); wherein R¹⁵ is independently selected from H, C₁-C₄-alkyl; wherein R¹⁶ is independently selected from H, C₁-C₄-alkyl and cyclopropyl; or wherein R¹⁵ and R¹⁶ together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R¹⁰ groups; x is independently selected from 0, 1 , 2, 3, and 4; and y is independently selected from 0, 1 , 2, 3, and 4.

[0021] In an embodiment, the compound of formula (I) is a compound of formula (Vlla) or

(Vllb): wherein R¹, R^3a, R⁴, R^5a, R⁶, R^6a and R¹⁰ are as described above for compounds of formula (I); and wherein z is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the z R¹⁰ groups may be attached to either ring of the pyrrolizidinyl group.

[0022] In an embodiment, the compound of formula (I) is a compound of formula (Vllla) or

(Vlllb):

wherein R¹, R^3a, R^5a, R⁶, R^6a, R¹⁰ and R¹⁴ are as described above for compounds of formula (I); wherein x is independently selected from 0, 1 , 2, 3, and 4; and wherein z is independently selected from 0, 1 , 2, 3, and 4.

[0023] In an embodiment, the compound of formula (I) is a compound of formula (IXa) or

(IXb): wherein R¹, R^3a, R^5a, R⁶, R^6a and R¹⁰ are as described above for compounds of formula (I); wherein z is independently selected from 0, 1 , 2, 3, and 4; and wherein

R^14a is OR¹² e.g., OH; R^14b is C₁-C₄-alkyl e.g., methyl or ethyl, or C₂-C₄-alkynyl e.g., ethynyl; and R^14c is halo e.g, F.

[0024] In an embodiment, the compound of formula (I) is a compound of formula (Xa) or

(Xb): wherein R^3a, R⁶, R^6a, R⁹, R¹⁰ and R¹⁴ are as described above for compounds of formula (I); wherein x is independently selected from 0, 1 , 2, 3, and 4; wherein n6 is independently selected from 0, 1 and 2; and wherein z is independently selected from 0, 1 , 2, 3, and 4. n6 may be 0. n6 may be 1 . n6 may be 2.

[0025] In an embodiment, the compound of formula (I) is a compound of formula (Xia) or

(Xlb):

wherein R^3a, R⁶, R^6a, R⁹, R¹⁰ and R¹⁴ are as described above for compounds of formula (I); wherein R¹² is independently at each occurrence selected from H, and C₁-C₄-alkyl, e.g., methyl; wherein x is independently selected from 0, 1 , 2, 3, and 4; wherein n7 is independently selected from 0 and 1 ; and wherein z is independently selected from 0, 1 , 2, 3, and 4. n7 may be 0.

[0026] In an embodiment, the compound of formula (I) is a compound of formula (XII): wherein X¹, R², Z², and R¹⁴ are as described above for compounds of formula (I). [0027] The following embodiments apply to compounds of any of formulae (l)-(XII). These embodiments are independent and interchangeable. Any one embodiment may be combined with any other embodiment, where chemically allowed. In other words, any of the features described in the following embodiments may (where chemically allowable) be combined with the features described in one or more other embodiments. In particular, where a compound is exemplified or illustrated in this specification, any two or more of the embodiments listed below, expressed at any level of generality, which encompass that compound may be combined to provide a further embodiment which forms part of the present disclosure.

[0028] X¹ may be N. X¹ may be CR^3b.

[0029] Z¹ may be -O-. Z¹ may be -NR^5a-.

[0030] Z² may be -O-. Z² may be -NR^5b-.

[0031] R¹ is independently C₀-C₃-alkylene-R^1a wherein R^1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0032] R¹ is independently C₀-C₃-alkylene-R^1a wherein R^1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0033] R¹ may be C₀-C₃-alkylene-R^1a. R¹ may be C₀-C₃-alkylene-R^1a wherein R^1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-R^1a wherein R^1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0034] R¹ may be C₀-C₃-alkylene-R^1a wherein R^1a is independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-R^1a wherein R^1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇- cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said hetero cyclo a Iky I ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0035] R¹ may be R^1a wherein R^1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0036] R¹ may be R^1a wherein R^1a is independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be R^1a wherein R^1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be R^1a wherein R^1a is an oxygen containing 4- to 7- membered heterocycloalkyl ring e.g. a tetrahydropyranyl ring.

[0037] R¹ is independently C₀-C₃-alkylene-R^1a wherein R^1a is independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C₃-C₇-cycloalkyl ring substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0038] R¹ may be C₀- C₃-alkylene-R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-alkylene-R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0039] R¹ may be C₀-C₃-alkylene-R^1a wherein R^1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-alkylene-R^1a wherein R^1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0040] R¹ may be C₀-C₃-alkylene-R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring wherein the ring does not comprise any nitrogen atoms; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-alkylene-R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring wherein the ring does not comprise any nitrogen atoms; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0041] R¹ may be R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be R^1a wherein R^1a is a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be R^1a wherein R^1a is a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups wherein the ring does not comprise any nitrogen atoms.

[0042] R¹ may be C₀-C₃-alkylene-R^1a wherein R^1a is a C₃-C₇-cycloalkyl ring substituted with an NR⁷R⁸ group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups. R¹ may be CH₂-alkylene-R^1a wherein R^1a is a C₃-C₇-cycloalkyl ring substituted with an NR⁷R⁸ group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0043] R¹ may be R^1a wherein R^1a is a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0044] R¹ may be R^1a wherein R^1a is a C₃-C₇-cycloalkyl ring substituted with an NR⁷R⁸ group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups.

[0045] R¹ may be R^1a wherein R^1a is phenyl optionally substituted with from 1 to 4 R⁹ groups. R¹ may be R^1a wherein R^1a is unsubstituted phenyl.

[0046] R¹ may be C₂-C₆-alkylene-R^1b. R¹ may be C₂-C₃-alkylene-R^1b. R¹ may be C³- alkylene-R^1b. R^1b may be independently selected from: NR⁷R⁸, OR⁸ and SR⁸. R^1b may be OR⁸. R^1b may be SR⁸. R^1b may be NR⁷R⁸. R⁸ may be C₁-C₄-alkyl, e.g. Me.

[0047] It may be that R¹ and R^5a are selected such that NR¹R^5a comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine. The nitrogen of said single amine is typically the N of NR¹R^5a. This is shown in the following representation, wherein the nitrogen labelled N* is the nitrogen of the single amine:

[0048] It may be that R¹ and R^5a are selected such that NR¹R^5a comprises no more than a single amine, wherein said single amine may be a secondary or tertiary amine. Compounds having no more than a single amine at this position surprisingly exhibit broad spectrum inhibition across a range of mutant KRAS forms as well as wild type KRAS rather than inhibition of the specific KRAS G12C and G12D proteins. Compounds having a single amine in this portion of the molecule typically exhibit broad spectrum inhibition of KRAS mutants including KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G13D and KRAS

Q61 H as well as wild-type KRAS. As such these compounds may be of therapeutic benefit in treating cancers bearing KRAS mutations beyond G12D and G12C, as well as cancers dependant on wild type KRAS.

[0049] It may be that R¹ and R^5a are selected such that NR¹R^5a comprises more than one amine, wherein said amines may be a primary, secondary or tertiary amine. It may be that R¹ and R^5a are selected such that NR¹R^5a comprises more than one amine, wherein said amines may be a secondary or tertiary amine. It may be that R¹ and R^5a are selected such that NR¹R^5a comprises two amines, wherein said amines may be a primary, secondary or tertiary amine. It may be that R¹ and R^5a are selected such that NR¹R^5a comprises two amines, wherein said amines may be a secondary or tertiary amine. Compounds in which R¹ and R^5a are selected such that NR¹R^5a comprises more than a single amine, e.g. two amines, typically inhibit KRAS G12D selectively.

[0050] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; and a bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; wherein the nitrogen to which R¹ and R^5a are attached is the only heteroatom in the ring system.

[0051] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; and a bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; wherein the nitrogen to which R¹ and R^5a are attached is the only nitrogen in the ring system.

[0052] It may be that R¹ and R^5a are selected such that the nitrogen of NR¹R^5a is the nitrogen of the single amine. It may be that R¹ and R^5a are selected such that NR¹R^5a is the single amine. For the avoidance of doubt, the term “amine” as used herein encompasses primary amines, e.g., methylamine; secondary amines, e.g., dimethylamine; tertiary amines, e.g., trimethylamine; cyclic amines, e.g., piperidine. For the avoidance of doubt, the term “amine” as used herein excludes amides and lactams, e.g., piperazinonyl. Furthermore, for the avoidance of doubt, the term “amine” as used herein excludes nitrogen atoms that are part of a heteroaromatic ring, e.g. the nitrogen(s) in a pyrazole, pyrrole, imidazole or triazole.

[0053] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 9- or 10-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 6- or 7- membered heterocycloalkyl ring fused to a 5-membered heteroaromatic ring. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 9-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 6- membered heterocycloalkyl ring fused to a 5-membered heteroaromatic ring. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 10-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 7- membered heterocycloalkyl ring fused to a 5- membered heteroaromatic ring.

[0054] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 9- or 10-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 6- or 7- membered heterocycloalkyl ring fused to a 5-membered heteroaromatic ring selected from pyrazole, pyrrole, imidazole or triazole. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 9-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 6- membered heterocycloalkyl ring fused to a 5-membered heteroaromatic ring selected from pyrazole, pyrrole, imidazole or triazole. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 10-membered heterocyclyl ring system, optionally substituted with from 1 to 4 R⁹ groups; said heterocyclyl group comprising a 7- membered heterocycloalkyl ring fused to a 5-membered heteroaromatic ring selected from pyrazole, pyrrole, imidazole or triazole.

[0055] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9c is selected from H and C₁-C₄-alkyl, p5 and q5 and are each selected from 0, 1 , 2 and 3; providing that the sum of p5 and q5 is 1 or greater.

[0056] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having a structure selected from: wherein r6 is selected from 0, 1 and 2.

[0057] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having a structure selected from: wherein r7 is selected from 0, 1 and 2.

[0058] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused, spirofused or bridged bicyclic 6- to 1 1 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups.

[0059] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused, spirofused or bridged bicyclic 6- to 1 1 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; wherein the ring system does not comprise a nitrogen other than the nitrogen to which R¹ and R^5a are attached. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused, spirofused or bridged bicyclic 6- to 1 1 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; wherein the ring system does not comprise an amine other than the amine NR¹R^5a.

[0060] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; and a bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups. [0061] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11- membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups.

[0062] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a 6 or 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a 6 or 7- membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups, wherein the total number of heteroatoms in the 6 or 7-membered heterocycloalkyl group is 1 or 2. The total number of heteroatoms may be 2. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a 6 or 7-membered heterocycloalkyl group, optionally substituted with 1 R⁹ group.

[0063] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form an unsubstituted monocyclic 4- to 7-membered heterocycloalkyl group. It may be that there is at least one R⁹ group and that at least one of said R⁹ groups is selected from NR¹²R¹³ and C₁-C₄-alkyl substituted with NR¹²R¹³. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9a is selected from NR¹²R¹³ and C₁-C₄-alkyl substituted with NR¹²R¹³; p1 is selected from 0, 1 , 2 and 3, q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1 , 2 and 3. R1 may be 0. R⁹ may independently at each occurrence be methyl. R^9a may be selected from NHR¹² and C₁-C₄-alkyl substituted with NHR¹².

[0064] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group comprising two nitrogen atoms in the ring, optionally substituted with from 1 to 4 R⁹ groups.

[0065] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Z⁶ is independently selected from C(O)NR^9b, NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b) and S(O)(NH); R^9b is selected from H and C₁-C₄-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1 , 2 and 3. Z⁶ may be selected from NR^9b, O, S, S(O)₂, S(O) and S(O)(NH). Z⁶ may be selected from C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b) and S(O)(NH). Z⁶ may be selected from O, S, S(O)₂, S(O) and S(O)(NH).

Z⁶ may be selected from NR^9b, O and S. Z⁶ may be selected from O and S. Z⁶ may be O.

[0066] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9b is selected from H and C₁-C₄-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1 , 2 and 3. R2 may be 0. R⁹ may independently at each occurrence be methyl. R^9b may be H. R^9b may be C₁-C₄-alkyl.

[0067] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused or spirofused bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused or spirofused bicyclic 6- to 11 -membered heterocyclyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R⁹ groups.

[0068] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a spirofused bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a spirofused bicyclic 6- to 11 -membered heterocycloalkyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9b is selected from H and C₁-C₄-alkyl; p3, p4, q3 and q4 are each independently selected from 0, 1 , 2 and 3; providing that the sum of p3, p4, q3 and q4 is from 3 to 8, the sum of p3 and q3 is 2 or greater, and the sum of p4 and q4 is 2 or greater; and r3 is selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the r3 R⁹ groups may be attached to either ring of the spirofused bicyclic ring system. r3 may be 0. R⁹ may independently at each occurrence be methyl. R^9b may be H.

[0069] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 6- to 11 -membered heterocyclyl group comprising two nitrogen atoms in the ring system, optionally substituted with from 1 to 4 R⁹ groups. It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9b is selected from H and C₁-C₄-alkyl; p5, p6, q5 and are each selected from 0, 1 , 2 and 3; providing that the sum of p3, p4, q3 and q4 is from 2 to 7, the sum of p5 and q5 is 1 or greater, and the sum of p6 and q6 is 1 or greater; and r5 is selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the r5 R⁹ groups may be attached to either ring of the fused bicyclic ring system. r5 may be 0. R⁹ may independently at each occurrence be methyl. R^9b may be H.

[0070] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a bridged bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups.

[0071] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a fused bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups. [0072] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11- membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; and a bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups, wherein the bridged bicyclic 6- to 11 -membered heterocycloalkyl group is not:

[0073] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a bridged bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups, wherein the bridged bicyclic 6- to 11 -membered heterocycloalkyl group is not:

[0074] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y¹ is independently selected from C(O)NR^9d, O and NR¹⁷; Z³ is independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂, CH₂-NR¹⁷-CH₂CH₂ and CH₂-NR¹⁷-CH₂; R¹⁷ is independently at each occurrence selected from H, C₁-C₄-haloalkyl, and C₁-C₄-alkyl; R^9d is independently selected from H and C₁-C₄-alkyl; and n1 is an integer selected from 0, 1 , 2, 3 and 4. For the absence of doubt, throughout this specification, the n1 R⁹ groups may be attached to either ring of the bridged bicyclic ring system. Z³ may be independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂, Y¹ may be independently selected from O and NR¹⁷. Y¹ may be NR¹⁷. Y¹ may be NH. n1 may be 0. R⁹ may independently at each occurrence be methyl. [0075] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y¹ is independently selected from C(O)NR^9d, O and NR¹⁷; Z⁴ is independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂, CH₂-NR¹⁷-CH₂CH₂ and CH₂-NR¹⁷-CH₂; R¹⁷ is independently at each occurrence selected from H, C₁-C₄- haloalkyl, and C₁-C₄-alkyl; R^9d is independently selected from H and C₁-C₄-alkyl; and n2 is an integer selected from 0, 1 , 2, 3 and 4. For the absence of doubt, throughout this specification, the n2 R⁹ groups may be attached to either ring of the bridged bicyclic ring system. Z⁴ may be independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂, Y¹ may be independently selected from O and NR¹⁷. Y¹ may be NR¹⁷. Y¹ may be NH. n2 may be 0. R⁹ may independently at each occurrence be methyl.

[0076] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: , wherein Y¹ is independently selected from C(O)NR^9d, O and NR¹⁷; R¹⁷is independently at each occurrence selected from H, C₁-C₄-haloalkyl, and C₁-C₄-alkyl; R^9d is independently selected from H and C₁-C₄-alkyl; and n3 is an integer selected from 0, 1 , 2, 3 and 4. For the absence of doubt, throughout this specification, the n3 R⁹ groups may be attached to either ring of the bridged bicyclic ring system. Y¹ may be independently selected from O and NR¹⁷. Y¹ may be NR¹⁷. Y¹ may be NH. n3 may be 0. R⁹ may independently at each occurrence be methyl.

[0077] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Y¹ is independently selected from C(O)NR^9d, O and NR¹⁷; Z⁵ is independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂, CH₂-NR¹⁷-CH₂CH₂ and CH₂-NR¹⁷-CH₂; R¹⁷is independently at each occurrence selected from H, C₁-C₄- haloalkyl, and C₁-C₄-alkyl; R^9d is independently selected from H and C₁-C₄-alkyl; and n5 is an integer selected from 0, 1 , 2, 3 and 4. For the absence of doubt, throughout this specification, the n5 R⁹ groups may be attached to either ring of the bridged bicyclic ring system. Z⁵ is independently selected from: CH₂, CH₂CH₂, CH₂-O-CH₂CH₂, CH₂-O-CH₂. Y¹ may be independently selected from O and NR¹⁷. Y¹ may be NR¹⁷. Y¹ may be NH. n5 may be 0. R⁹ may independently at each occurrence be methyl.

[0078] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Z⁶ is independently selected from C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b), S(O)(NH) and NR^9b; R^9b is independently at each occurrence selected from H and C₁-C₄- alkyl; and n6 is an integer selected from 0, 1 , 2, 3 and 4. n6 may be 0. Z⁶ may be selected from NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b), and S(O)(NH). Z⁶ may be selected from C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b), and S(O)(NH). Z⁶ may be selected from C(O)NR^9b, O, S, S(O)₂, S(O) and S(O)(NH). Z⁶ may be selected from O, S, S(O)₂, S(O) and S(O)(NH). Z⁶ may be selected from NR^9b, O and S. Z⁶ may be selected from O and S. Z⁶ may be O.

[0079] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein n7 is an integer selected from 0, 1 , 2 and 3.

[0080] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein n7 is an integer selected from 0, 1 , 2 and 3.

[0081] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein n8 is an integer selected from 0, 1 , 2 and 3.

[0082] n7 may be 0.

[0083] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure:

Wherein R¹² is independently at each occurrence selected from H, C₁-C₄-haloalkyl, and C₁- C₄-alkyl; and n9 is an integer selected from 0, 1 , 2 and 3. R¹² may be C₁-C₄-alkyl e.g., methyl. n9 may be 0.

[0084] It may be that, where R¹ and R^5a together with the nitrogen to which they are attached form a ring system, e.g. one of the ring systems described above, that ring system is substituted with at least one hydroxy group.

[0085] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Z⁷ is independently selected from carbon, C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b) and S(O)(NH); p7 is selected from 2 and 3, q2 is 2; and r6 is selected from 0, 1 and 2. Z⁷ may be selected from carbon, O, S, S(O)₂, S(O). Z⁷ may be carbon. Z⁷ may be selected from O and S. Z⁷ may be O. p7 may be 2. p⁷ may be 3. r6 may be 0. r6 may be 1 . Where present, R⁹ may be C₁-C₄-alkyl, e.g. methyl.

[0086] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure:

[0087] wherein Z⁸ is independently selected from a bond, carbon,

C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b) and S(O)(NH); and r7 is selected from 0, 1 and 2. Z⁸ may be a bond. Z⁸ may be carbon. Z⁸ may be selected from O and S. Z⁸ may be O. r7 may be 0.

[0088] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein r8 is an integer selected from 0, 1 and 2.

[0089] It may be that R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure:

[0090] R² may be C₀-C₄-alkylene-R^2a. R² may be CH₂-R^2a. R^2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group; wherein said R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups. R^2a may comprise at least one nitrogen in the ring system. R^2a may comprise a single nitrogen in the ring system. R^2a may be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11- membered heterocycloalkyl group; wherein said R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups and wherein R^2a comprises at least one nitrogen in the ring system. R^2a may be monocyclic 4- to 7-membered heterocycloalkyl group; wherein said R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups and wherein R^2a comprises at least one nitrogen in the ring system. R^2a may be a fused, spirofused or bridged bicyclic 6- to 11- membered heterocycloalkyl group; wherein said R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups and wherein R^2a comprises at least one nitrogen in the ring system.

[0091] R² may have the structure: is independently selected from H, C₁-C₄-alkyl; wherein

R¹⁶ is independently selected from H, C₁-C₄-alkyl and cyclopropyl; or wherein R¹⁵ and R¹⁶ together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R¹⁰ groups; and y is independently selected from 0, 1 , 2, 3, and 4. y may be selected from 0 and 1 . y may be 0. y may be 1 . R¹⁵ may be H. R¹⁶ may be C₁-C₄-alkyl.

[0092] R² may have the structure: herein z is independently selected from 0, 1 , 2, 3, and 4. z may be may be 0. z may be 1 . For example, R² may have the structure:

[0093] R² may have the structure:

, wherein R¹⁶ is independently selected from H, C₁-C₄-alkyl and ple, R² may have the structure:

[0094] R⁴ may be phenyl, said phenyl being optionally fused to a C₅-C₇-cycloalkyl ring, wherein R⁴ is optionally substituted with from 1 to 4 R¹⁴ groups. R⁴ may be phenyl, optionally substituted with from 1 to 4 R¹⁴ groups. R⁴ may be monocyclic 4- to 7-membered cycloalkyl. R⁴ may be monocyclic 4- to 7-membered heterocycloalkyl, said heterocycloalkyl being optionally fused to a C₅-C₆-heteroaryl ring. R⁴ may be a 5-membered heterocycloalkyl, e.g., thiophenyl, fused to a monocyclic 5- to 6-membered cycloalkyl, e.g., cyclohexyl. R⁴ may be substituted with from 1 to 4 R¹⁴ groups. For the avoidance of doubt, where R⁴ comprises a fused ring structure, e.g. a 5-membered heterocycloalkyl fused to a monocyclic 5- to 6- membered cycloalkyl, the 1 to 4 R¹⁴ groups may be attached to either ring. For example, the 5-membered heterocycloalkyl may be substituted with e.g., cyano and -NH₂ and the monocyclic 5- to 6-membered cycloalkyl to which it is fused may be further substituted with e.g., C₁-C₄-alkyl.

[0095] R⁴ may have the structure: wherein R^12a is independently H or C₁-C₄-alkyl; x1 is independently selected from 0, 1 , 2 and 3. R^12a may be H.

[0096] R^3a may be selected from halo, C₁-C₄-alkyl, O-C₁-C₄-alkyl, C₁-C₄-haloalkyl, O-C₁-C₄- haloalkyl, cyclopropyl, nitro and cyano. R^3a may be selected from H, halo and C₁-C₄-alkyl. R^3a may be F. R^3a may be C₁-C₄-alkyl, e.g. Me. R^3a may be H.

[0097] R^3b may be selected from halo, C₁-C₄-alkyl, O-C₁-C₄-alkyl, C₁-C₄-haloalkyl, O-C₁- C₄-haloalkyl, cyclopropyl, nitro and cyano. R^3b may be F. R^3b may be C₁-C₄-alkyl, e.g. Me. R^3b may be H.

[0098] R⁴ may be naphthyl, optionally substituted with from 1 to 4 R¹⁴ groups. R⁴ may have the structure: wherein x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R¹⁴ groups may be attached to either ring of the naphthyl group. R¹⁴ may be independently selected from CF₃, hydroxyl, OR¹², halo e.g., F; C₁-C₄-alkyl e.g., ethyl; and C₂-C₄-alkynyl e.g., ethynyl. x may be 0. x may be 1 . x may be 2. x may be 3.

[0099] R⁴ may have the structure: wherein x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R¹⁴ groups may be attached to either ring of the naphthyl group. R¹⁴ may be independently selected from CF₃, hydroxyl, OR¹², halo e.g., F; C₁-C₄-alkyl e.g., ethyl; and C₂-C₄-alkynyl e.g., ethynyl. x may be 0. x may be 1 . x may be 2. x may be 3. For example, R⁴ may have the structure:

[00100] R⁴ may have the structure: wherein R^12a is independently H or C₁-C₄-alkyl; x2 is independently selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the x2 R¹⁴ groups may be attached to either ring of the naphthyl group. R^12a may be H.

[00101] R⁴ may have the structure: wherein R^14a is OR¹² e.g., OH; R^14b is C₁-C₄-alkyl e.g., methyl or ethyl, or C₂- C₄-alkynyl e.g., ethynyl; and R^14c is halo e.g, F. For example, R⁴ may have the structure:

[00102] R⁴ may have the structure: wherein R¹⁴ is independently H, cyano, NR¹²R¹³ and C₁-C₄-alkyl. x3 is independently selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the x3 R¹⁴ groups may be attached to either ring of the heterocyclyl group. [00103] R⁴ may be 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R¹⁴ groups. R⁴ may be 9- or 10-membered bicyclic heteroaryl, optionally substituted with from 1 to 4 R¹⁴ groups.

[00104] R^5a may be H. R^5a may be C₁-C₄-alkyl, e.g. methyl.

[00105] R^5b may be H. R^5b may be C₁-C₄-alkyl, e.g. methyl.

[00106] R⁶ may be selected from halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl. R⁶ may be selected from H and C₁-C₄-alkyl. R⁶ may be selected from C₁-C₄- haloalkyl, C₁-C₄-alkyl and C₃-C₄-cycloalkyl. R⁶ may be H. R⁶ may be C₁-C₄-alkyl. R⁶ may be C₁-C₂-alkyl, e.g. methyl. R⁶ may be C₃-C₄-cycloalkyl e.g., cyclopropyl.

[00107] R^6a may be selected from halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl. R^6a may be selected from H and C₁-C₄-alkyl. R^6a may be selected from C₁-C₄- haloalkyl, C₁-C₄-alkyl and C₃-C₄-cycloalkyl. R^6a may be H. R^6a may be C₁-C₄-alkyl. R^6a may be C₁-C₂-alkyl, e.g. methyl. R^6a may be C₃-C₄-cycloalkyl e.g., cyclopropyl.

[00108] In some embodiments, R⁶ and R^6a are both H.

[00109] R⁷ may be selected from H and C₁-C₄-alkyl. R⁷ may be H. R⁷ may be C₁-C₄-alkyl, e.g. methyl.

[00110] R⁸ may be selected from H and C₁-C₄-alkyl. R⁸ may be H. R⁸ may be C₁-C₄-alkyl, e.g. methyl.

[00111] R⁹ may be independently at each occurrence selected from oxo, fluoro, cyano, NR¹²R¹³, OR¹², COR¹², C₁-C₄-alkyl, CONR¹²R¹³, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl. R⁹ may be independently at each occurrence selected from oxo, fluoro, NR¹²R¹³, OR¹², COR¹², CONR¹²R¹³; C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³ , C₁-C₄-alkyl substituted with phenyl and C₁-C₄-alkyl substituted with OR¹².

[00112] R⁹ may be independently at each occurrence selected from oxo, fluoro, cyano, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano. R⁹ may be independently at each occurrence selected from oxo, fluoro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³ and C₁-C₄-alkyl substituted with OR¹².

[00113] R⁹ may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³ provided that R¹² is not H and R¹³ is not H, OR¹², COR¹², CO₂R¹², CONR¹²R¹², C₁- C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³ provided that R¹² is not H and R¹³ is not H, C₁- C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄- alkynyl, C₁-C₄-haloalkyl and cyclopropyl.

[00114] R⁹ may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³ provided that R¹² is not H and R¹³ is not H, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³ provided that R¹² is not H and R¹³ is not H, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁- C₄-haloalkyl and cyclopropyl.

[00115] R⁹ may be independently at each occurrence selected from C₁-C₄-alkyl e.g., methyl and OR¹² e.g., OH.

[00116] R¹⁰ may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl.

[00117] R¹⁰ may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl.

[00118] R¹⁰ may be independently at each occurrence selected from oxo, fluoro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with phenyl, C₁-C₄-alkyl substituted with NR¹²R¹³ and C₁-C₄-alkyl substituted with OR¹².

[00119] R¹⁰ may be independently at each occurrence selected from oxo, fluoro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³ and C₁-C₄-alkyl substituted with OR¹². [00120] R^10a may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R^13a, C₁- C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl.

[00121] R^10a may be independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R^13a, C₁- C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄- alkynyl, C₁-C₄-haloalkyl and cyclopropyl.

[00122] R^10a may be independently at each occurrence selected from oxo, fluoro, NR¹²R^13a, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with phenyl, C₁-C₄-alkyl substituted with NR¹²R^13a and C₁-C₄-alkyl substituted with OR¹².

[00123] R^10a may be independently at each occurrence selected from oxo, fluoro, NR¹²R^13a, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R^13a and C₁-C₄-alkyl substituted with OR¹².

[00124] R^10a may be independently at each occurrence selected from halo, cyano, C₁-C₄- alkyl, C₁-C₄-haloalkyl and cyclopropyl. R^10a may be C₁-C₄-haloalkyl e.g., trifluoromethyl.

[00125] R¹¹ may be each independently at each occurrence selected from halo, cyano, nitro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C₁-C₄- haloalkyl and cyclopropyl. R¹¹ may be each independently at each occurrence selected from OR¹², monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C₁-C₄-alkyl, C₁-C₄- haloalkyl and cyclopropyl.

[00126] R¹¹ may be each independently at each occurrence selected from halo, cyano, nitro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-haloalkyl and cyclopropyl. R¹¹ may be each independently at each occurrence selected from OR¹², C₁-C₄-alkyl, C₁-C₄-haloalkyl and cyclopropyl.

[00127] It may be that R¹² is independently selected at each occurrence from H, C₁-C₄- haloalkyl, C₁-C₄-alkyl and cyclopropyl; and R¹³ is independently at each occurrence selected from H, C₁-C₄-alkyl, C₁-C₄-haloalkyl and C(O)-C₁-C₄-alkyl.

[00128] It may be that R¹² is independently selected at each occurrence from H, C₁-C₄- haloalkyl, and C₁-C₄-alkyl; and R¹³ is independently at each occurrence selected from H, C₁- C₄-alkyl, C₁-C₄-haloalkyl and C(O)-C₁-C₄-alkyl.

[00129] R¹² may independently at each occurrence be selected from H, cyclopropyl and C₁- C₄-alkyl. R¹² may be C₁-C₄-alkyl e.g., methyl. R¹² may be cyclopropyl. [00130] R¹² may independently at each occurrence be selected from H and C₁-C₄-alkyl.

[00131] R¹³ may independently at each occurrence be selected from H and C₁-C₄-alkyl.

[00132] In compounds of formula (I), it may be that R¹² and R¹³ together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R¹⁰ groups. It may be that R¹² and R¹³ together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group e.g., piperidinyl.

[00133] It may be that R¹² and R¹³ together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R^10a groups. It may be that R¹² and R¹³ together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group e.g., piperidinyl.

[00134] R^13a may be independently at each occurrence selected from H, C₁-C₄-alkyl and C(O)-C₁-C₄-alkyl. R^13a may be independently at each occurrence selected from H and C₁-C₄- alkyl.

[00135] R¹⁴ may be each independently at each occurrence selected from halo, cyano, nitro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, phenyl and cyclopropyl. R¹⁴ may be each independently at each occurrence selected from OR¹², C₁-C₄-alkyl, C₂-C₄- alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, phenyl and cyclopropyl.

[00136] R¹⁴ may be each independently at each occurrence selected from halo, cyano, nitro, NR¹²R¹³, OR¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl. R¹⁴ may be each independently at each occurrence selected from OR¹², C₁-C₄-alkyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl. R¹⁴ may be each independently at each occurrence selected from OR¹², C₁-C₄-alkyl and C₂-C₄-alkynyl. R¹⁴ may be OR¹² e.g., OH. R¹⁴ may be C₁-C₄-alkyl e.g, methyl or ethyl. R¹⁴ may be C₂-C₄-alkynyl e.g., ethynyl.

[00137] The compound of formula (I) may be selected from:

[00138] The compound of formula (I) may be selected from:

DETAILED DESCRIPTION

[00139] In an aspect of the invention there is provided the compounds of the present invention for use as a medicament.

[00140] In accordance with another aspect, the present invention provides a method of treating a condition which can be modulated by inhibition of KRAS proteins having the G12D mutation, the method comprising administering a therapeutically effective amount of a compound of the invention to a subject in need thereof.

[00141] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[00142] In an embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be, for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors.

[00143] In an aspect of the invention there is provided the compounds of the present invention for use in treating cancer. [00144] In an aspect ofthe invention there is provided a method of treating cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

[00145] In an aspect ofthe invention there is provided the use of a compound ofthe invention for manufacture of a medicament for the treatment of cancer.

[00146] The cancer may be a solid tumour or a liquid tumour. The cancer may be a carcinoma.

[00147] The cancer may be selected from cervical cancer, endometrial cancer, multiple myeloma, stomach cancer, bladder cancer, uterine cancer, esophageal squamous cell carcinoma, gastric cancer, glioblastomas, astrocytomas; retinoblastoma, osteosarcoma, chondosarcoma, Ewing’s sarcoma, rabdomysarcoma, Wilm’s tumor, basal cell carcinoma, non-small cell lung cancer, brain tumour, hormone refractory prostate cancer, prostate cancer, metastatic breast cancer, breast cancer, metastatic pancreatic cancer, pancreatic cancer, colorectal cancer, head and neck squamous cell carcinoma, cancer of the head and neck, appendix cancer, cholangiocarcinoma, cancer of unknown primary, ampulla of Vater cancer, ovarian cancer, acute myeloid leukaemia, small cell lung carcinoma, germ cell tumour, small bowel cancer, melanoma, soft tissue sarcoma, gastrointestinal stromal tumour, thyroid cancer, gastrointestinal neuroendocrine tumour, renal cell carcinoma and histiocytosis.

[00148] The cancer may be selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[00149] The cancer may have wild-type KRAS. The cancer may have a KRAS mutation. The cancer may have a KRAS mutation selected from: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12S, KRAS G13D and KRAS Q61 H. The cancer may have a KRAS G12D mutation. The cancer may have a KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[00150] The cancer may have a confirmed KRAS G12D mutation. The cancer may have a confirmed KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[00151] The subject may be human. [00152] The subject may have a cancer with a KRAS G12D mutation. The subject may have a cancer with a KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[00153] The subject may have a cancerwith a confirmed KRAS G12D mutation. The subject may have a cancer with a confirmed KRAS G12D mutation, said cancer being selected from pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non- small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[00154] The subject may have a confirmed G12D mutation in their tumour. To be confirmed, the test for G12D presence in the tumour must have >95% for analytical specificity for the detection of mutations in the KRAS gene. Such validated tests would include already commercially available tests i.e. Foundation One CDx and CARIS DNA sequencing.

[00155] As mentioned above, the invention includes a method of treating cancer. The method may comprise: a) confirming that the subject has a cancer with a G12D mutation; and b) administering to a subject in need thereof a therapeutically effective amount of a compound of the invention.

[00156] The term “halo” refers to one of the halogens, group 17 of the periodic table. In particular the term refers to fluorine, chlorine, bromine and iodine. Preferably, the term refers to fluorine or chlorine.

[00157] The term “alkyl” refers to a linear or branched hydrocarbon chain. For example, the term “C_1-6 alkyl” or “C_1-4-alkyl” refers to a linear or branched hydrocarbon chain containing 1 ,

2, 3, 4, 5, or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Where an alkyl group is indicated as being C_0-4alkyl, then it should be appreciated that this represents the possibility for the alkyl unit to be absent or 1 , 2,

3, or 4 carbon atoms in length. Alkylene groups may likewise be linear or branched and may have two places of attachment to the remainder of the molecule. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph. The alkyl and alkylene groups may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C_1-6 alkoxy.

[00158] The term “alkoxy” refers to an alkyl group which is attached to a molecule via oxygen. For example, the term “C_1-6 alkoxy” refers to an alkyl group which is attached to a molecule via oxygen. This includes moieties where the alkyl part may be linear or branched and may contain 1 , 2, 3, 4, 5, or 6 carbon atoms, for example methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Therefore, the alkoxy group may be methoxy, ethoxy, n-propoxy, iso-propoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentoxy and n-hexoxy. The alkyl part of the alkoxy group may be unsubstituted or substituted by one or more substituents. Possible substituents are described below. Substituents for the alkyl group may be halogen, e.g. fluorine, chlorine, bromine and iodine, OH, C_1-6 alkoxy.

[00159] The term “haloalkyl” refers to a hydrocarbon chain substituted with at least one halogen atom independently chosen at each occurrence, for example fluorine, chlorine, bromine and iodine. For example, the term “C_1-6 haloalkyl” refers to a linear or branched hydrocarbon chain containing 1 , 2, 3, 4, 5 or 6 carbon atoms substituted with at least one halogen. The halogen atom may be present at any position on the hydrocarbon chain. For example, C_1-6 haloalkyl may refer to chloromethyl, fluoromethyl, trifluoromethyl, chloroethyl e.g. 1-chloromethyl and 2-chloroethyl, trichloroethyl e.g. 1 ,2,2-trichloroethyl, 2,2,2- trichloroethyl, fluoroethyl e.g. 1-fluoromethyl and 2-fluoroethyl, trifluoroethyl e.g. 1 ,2,2- trifluoroethyl and 2,2,2-trifluoroethyl, chloropropyl, trichloropropyl, fluoropropyl, trifluoropropyl.

[00160] The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. For example, the term “C_2-6 alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond and having 2, 3, 4, 5 or 6 carbon atoms. The double bond(s) may be present as the E or Z isomer. The double bond may be at any possible position of the hydrocarbon chain. For example, the “C_2-6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[00161] The term “alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond. For example, the term “C_2-6 alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbon atoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the “C_2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[00162] The term “heteroalkyl” refers to a branched or linear hydrocarbon chain containing at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the term “C_1-6 heteroalkyl” refers to a branched or linear hydrocarbon chain containing 1 , 2, 3, 4, 5, or 6 carbon atoms and at least one heteroatom selected from N, O and S positioned between any carbon in the chain or at an end of the chain. For example, the hydrocarbon chain may contain one or two heteroatoms. The C_1-6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the “C_1-6 heteroalkyl” may be C_1-6 N-alkyl, C_1-6 N, N-alkyl , or C_1-6 O-alkyl. [00163] The term “cycloalkyl” refers to a saturated hydrocarbon ring system. For example, the “C_3-8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[00164] The term “cycloalkenyl” refers to an unsaturated hydrocarbon ring system containing that is not aromatic. The ring may contain more than one double bond provided that the ring system is not aromatic. For example, the “C_3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[00165] The term “heterocycloalkyl” refers to a saturated hydrocarbon ring system containing carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The “heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. For example, the “heterocycloalkyl” may be a “C_3-8 heterocycloalkyl”. The term “C_3-8 heterocycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The “C_3-8 heterocycloalkyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. A “heterocycloakyl” group may be monocyclic. A “heterocycloakyl” group may be bicyclic e.g., a fused, spirofused or bridged heterocycloalkyl ring system. For example, the “C_3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[00166] The term “heterocyclyl” refers to a saturated or unsaturated hydrocarbon ring system containing carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The “heterocyclyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. The “heterocyclyl” may be a heterocycloalkyl. The “heterocyclyl” may be a heteroaryl. The “heterocyclyl” may be a bicyclic heterocyclyl, e.g. a bicyclic heteroaryl or a bicyclic heterocycloalkyl. The “heterocyclyl” may be a heterocycloalkyl ring fused to an aryl or heteroaryl ring. The “heterocyclyl” may be a heteroaryl ring fused to an cycloalkyl or heterocycloalkyl ring. The “heterocyclyl” may be a monocyclic heterocyclyl, e.g. a monocyclic heteroaryl, a monocyclic heterocycloalkyl.

[00167] The term “heterocycloalkenyl” refers to an unsaturated hydrocarbon ring system that is not aromatic, containing carbon atoms and at least one heteroatom within the ring selected from N, O and S. For example, there may be 1 , 2 or 3 heteroatoms, optionally 1 or 2. The “heterocycloalkenyl” may be bonded to the rest of the molecule through any carbon atom or heteroatom. For example, the “heterocycloalkenyl” may be a “C_3-8 heterocycloalkenyl”. The term “C_3-8 heterocycloalkenyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 atoms at least one of the atoms being a heteroatom within the ring selected from N, O and S. The “heterocycloalkenyl” may be tetrahydropyridine, dihydropyran, dihydrofuran, pyrroline.

[00168] The term “fused” refers to a bicyclic ring system in which the two rings are attached via two atoms that are situated adjacent to each other on each ring.

[00169] The term “spirofused” refers to a bicyclic ring system in which the two rings are attached via a single atom.

[00170] The term “bridged” refers to a bicyclic ring system in which the two rings are attached via two atoms that are not situated adjacent to each other on either ring.

[00171] The term “aromatic” when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated IT system within the ring or ring system where all atoms contributing to the conjugated IT system are in the same plane.

[00172] The term “aryl” refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated IT system within a ring where all atoms contributing to the conjugated IT system are in the same plane. For example, the “aryl” may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

[00173] The term “heteroaryl” refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a conjugated IT system where all atoms contributing to the conjugated IT system are in the same plane. For example, the “heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[00174] The term “halogen” herein includes reference to F, Cl, Br and I. Halogen may be Br. Halogen may be I.

[00175] A bond terminating in a “ ” represents that the bond is connected to another atom that is not shown in the structure. A bond terminating inside a cyclic structure and not terminating at an atom of the ring structure represents that the bond may be connected to any of the atoms in the ring structure where allowed by valency.

[00176] Where a moiety is substituted, it may be substituted at any point on the moiety where chemically possible and consistent with atomic valency requirements. The moiety may be substituted by one or more substituents, e.g. 1 , 2, 3 or 4 substituents; optionally there are 1 or 2 substituents on a group. Where there are two or more substituents, the substituents may be the same or different.

[00177] Substituents are only present at positions where they are chemically possible, the person skilled in the art being able to decide (either experimentally or theoretically) without inappropriate effort which substitutions are chemically possible, and which are not.

[00178] Ortho, meta and para substitution are well understood terms in the art. For the absence of doubt, “ortho” substitution is a substitution pattern where adjacent carbons possess a substituent, whether a simple group, for example the fluoro group in the example below, or other portions of the molecule, as indicated by the bond ending in

[00179] “Meta” substitution is a substitution pattern where two substituents are on carbons one carbon removed from each other, i.e. with a single carbon atom between the substituted carbons. In other words, there is a substituent on the second atom away from the atom with another substituent. For example, the groups below are meta substituted.

[00180] “Para” substitution is a substitution pattern where two substituents are on carbons two carbons removed from each other, i.e with two carbon atoms between the substituted carbons. In other words, there is a substituent on the third atom away from the atom with another substituent. For example, the groups below are para substituted.

[00181] Throughout the description the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre or axial chirality, both (R) and (S) stereoisomers are contemplated by the invention, equally mixtures of stereoisomers or a racemic mixture are completed by the present application. Where a compound of the invention has two or more stereocentres any combination of R ) and (S) stereoisomers is contemplated. The combination of (R) and (S) stereoisomers may result in a diastereomeric mixture or a single diastereoisomer. The compounds of the invention may be present as a single stereoisomer or may be mixtures of stereoisomers, for example racemic mixtures and other enantiomeric mixtures, and diasteroemeric mixtures. Where the mixture is a mixture of enantiomers the enantiomeric excess may be any of those disclosed above. Where the compound is a single stereoisomer the compounds may still contain other diasteroisomers or enantiomers as impurities. Hence a single stereoisomer does not necessarily have an enantiomeric excess (e.e.) or diastereomeric excess (d.e.) of 100% but could have an e.e. or d.e. of about at least 85%, at least 60% or less. For example, the e.e. or d.e. may be 90% or more, 90% or more, 80% or more, 70% or more, 60% or more, 50% or more, 40% or more, 30% or more, 20% or more, or 10% or more.

[00182] The invention contemplates pharmaceutically acceptable salts of the compounds of the invention. These may include the acid addition and base salts of the compounds. These may be acid addition and base salts of the compounds. In addition, the invention contemplates solvates of the compounds. These may be hydrates or other solvated forms of the compound.

[00183] Suitable acid addition salts are formed from acids which form non-toxic salts. Examples include the acetate, aspartate, benzoate, besylate, bicarbonate/carbonate, bisulfate/sulfate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride/chloride, hydrobromide/bromide, hydroiodide/iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulfate, naphthylate, 1 ,5-naphthalenedisulfonate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate/hydrogen phosphate/dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate and trifluoroacetate salts.

[00184] Suitable base salts are formed from bases which form non-toxic salts. Examples include the aluminium, arginine, benzathine, calcium, choline, diethylamine, diolamine, glycine, lysine, magnesium, meglumine, olamine, potassium, sodium, tromethamine and zinc salts. Hemisalts of acids and bases may also be formed, for example, hemisulfate and hemicalcium salts. For a review on suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[00185] Pharmaceutically acceptable salts of compounds of formula (I) may be prepared by one or more of three methods:

(i) by reacting the compound of the invention with the desired acid or base;

(ii) by removing an acid- or base-labile protecting group from a suitable precursor of the compound of the invention or by ring-opening a suitable cyclic precursor, for example, a lactone or lactam, using the desired acid or base; or (iii) by converting one salt of the compound of the invention to another by reaction with an appropriate acid or base or by means of a suitable ion exchange column.

[00186] All three reactions are typically carried out in solution. The resulting salt may precipitate out and be collected by filtration or may be recovered by evaporation of the solvent. The degree of ionisation in the resulting salt may vary from completely ionised to almost non- ionised.

[00187] The compounds of the invention may exist in both unsolvated and solvated forms. The term 'solvate' is used herein to describe a molecular complex comprising the compound of the invention and a stoichiometric amount of one or more pharmaceutically acceptable solvent molecules, for example, ethanol. The term 'hydrate' is employed when said solvent is water.

[00188] Included within the scope of the invention are complexes such as clathrates, drug- host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and/or inorganic components which may be in stoichiometric or non-stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[00189] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[00190] The compounds of the invention include compounds of a number of formulae as herein defined, including all polymorphs and crystal habits thereof, prodrugs and isomers thereof (including optical, geometric and tautomeric isomers) as hereinafter defined and isotopically-labelled compounds of the invention.

[00191] The present invention also includes all pharmaceutically acceptable isotopically- labelled compounds of the invention wherein one or more atoms are replaced by atoms having the same atomic number, but an atomic mass or mass number different from the atomic mass or mass number most commonly found in nature.

[00192] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as ²H and ³H, carbon, such as ¹¹C, ¹³C and ¹⁴C, chlorine, such as ³⁶CI, fluorine, such as ¹⁸F, iodine, such as ¹²³l and ¹²⁵l, nitrogen, such as ¹³N and ¹⁵N, oxygen, such as ¹⁵O, ¹⁷O and ¹⁸O, phosphorus, such as ³²P, and sulphur, such as ³⁵S.

[00193] Certain isotopically-labelled compounds, for example, those incorporating a radioactive isotope, are useful in drug and/or substrate tissue distribution studies. The radioactive isotopes tritium, i.e. ³H, and carbon-14, i.e. ¹⁴C, are particularly useful for this purpose in view of their ease of incorporation and ready means of detection.

[00194] Substitution with heavier isotopes such as deuterium, i.e. ²H, may afford certain therapeutic advantages resulting from greater metabolic stability, for example, increased in vivo half-life or reduced dosage requirements, and hence may be preferred in some circumstances.

[00195] Before purification, the compounds of the present invention may exist as a mixture of enantiomers depending on the synthetic procedure used. The enantiomers can be separated by conventional techniques known in the art. Thus the invention covers individual enantiomers as well as mixtures thereof.

[00196] For some of the steps of the process of preparation of the compounds of the invention, it may be necessary to protect potential reactive functions that are not wished to react, and to cleave said protecting groups in consequence. In such a case, any compatible protecting radical can be used. In particular methods of protection and deprotection such as those described by T.W. GREENE (Protective Groups in Organic Synthesis, A. Wiley- Interscience Publication, 1981) or by P. J. Kocienski (Protecting groups, Georg Thieme Verlag, 1994), can be used. All of the above reactions and the preparations of novel starting materials used in the preceding methods are conventional and appropriate reagents and reaction conditions for their performance or preparation as well as procedures for isolating the desired products will be well-known to those skilled in the art with reference to literature precedents and the examples and preparations hereto.

[00197] Also, the compounds of the present invention as well as intermediates for the preparation thereof can be purified according to various well-known methods, such as for example crystallization or chromatography.

[00198] One or more compounds of the invention may be combined with one or more pharmaceutical agents, for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors, for the treatment of conditions modulated by the inhibition of RAS proteins, for example cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia.

[00199] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemia as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent. [00200] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, and leukemiamay involve, in addition to the compound of the invention, additional active agents. The additional active agents may be one or more active agents used to treat the condition being treated by the compound of the invention and additional active agent. The additional active agents may include one or more of the following active agents:-

(i) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluoromethoIone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

(ii) TNF inhibitors for example etanercept; monoclonal antibodies (e.g. infliximab (Remicade), adalimumab (Humira), certolizumab pegol (Cimzia), golimumab (Simponi)); fusion proteins (e.g. etanercept (Enbrel)); and 5-HT2A agonists (e.g. 2,5-dimethoxy-4- iodoamphetamine, TCB-2, lysergic acid diethylamide (LSD), lysergic acid dimethylazetidide);

(iii) anti-inflammatory drugs, for example non-steroidal anti-inflammatory drugs;

(iv) dihydrofolate reductase inhibitors/antifolates, for example methotrexate, trimethoprim, brodimoprim, tetroxoprim, iclaprim, pemetrexed, ralitrexed and pralatrexate; and

(v) immunosuppressants for example cyclosporins, tacrolimus, sirolimus pimecrolimus, angiotensin II inhibitors (e.g. Valsartan, Telmisartan, Losartan, Irbesatan, Azilsartan, Olmesartan, Candesartan, Eprosartan) and ACE inhibitors e.g. sulfhydryl- containing agents (e.g. Captopril, Zofenopril), dicarboxylate-containing agents (e.g. Enalapril, Ramipril, Quinapril, Perindopril, Lisinopril, Benazepril, Imidapril, Zofenopril, Trandolapril), phosphate-containing agents (e.g. Fosinopril), casokinins, lactokinins and lactotripeptides.

(vi) Anti-fibrotic agents for example: Pirfenidone, Nintedanib, Anti-IL-13 monoclonal antibodies (e.g. Tralokinumab, QAX576, Lebrikizumab), simtuzumab, FG-3019, lysophosphatidic acid receptor antagonists (e.g. BMS-986020, AM966), LOXL2 inhibitors, BET bromodomain inhibitors (e.g. JQ1), HDAC inhibitors (e.g. Vorinostat), thrombin inhibitors (e.g. Dabigatran), FactorXa inhibitors (e.g. Apixban, Rivaroxaban) 15PGDH inhibitors, anti- αvβ6 monoclonal antibodies (e.g. BG0001 1), Anti-CTGF monoclonal antibodies (e.g. FG- 3019), PAR1 inhibitors, Nox4 inhibitors and PAI-1 inhibitors.

(vii) CNS therapies, for example: Levodopa, Dopamine agonists, Apomorphine, Glutamate antagonist, Anticholinergics, COMT inhibitors, MAO-B inhibitors, riluzole (Rilutek), Tetrabenazine (Xenazine), haloperidol (Haldol), chlorpromazine, risperidone (Risperdal), quetiapine (Seroquel), amantadine, levetiracetam (Keppra), clonazepam (Klonopin), Donepezil (Aricept), Galantamine (Razadyne), Rivastigmine (Exelon)), Memantine (Ebixa, Axura), Aducanumab, Ocrelizumab, interferon beta-1 a (Avonex, Rebif), peginterferon beta-1 a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), natalizumab (Tysabri)

[00201] The method of treatment or the compound for use in the treatment of cancer, sarcoma, melanoma, skin cancer, haematological tumors, lymphoma, carcinoma, leukemia, and central nervous system disorders may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumor agents:

(i) antiproliferative/antineoplastic drugs and combinations thereof, such as alkylating agents (for example cis platin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, uracil mustard, bendamustin, melphalan, chlorambucil, chlormethine, busulphan, temozolamide, nitrosoureas, ifosamide, melphalan, pipobroman, triethylene-melamine, triethylenethiophoporamine, carmustine, lomustine, stroptozocin and dacarbazine); antimetabolites (for example gemcitabine and antifolates such as fluoropyrimidines like 5 fluorouracil and tegafur, raltitrexed, methotrexate, pemetrexed, cytosine arabinoside, floxuridine, cytarabine, 6-mercaptopurine, 6-thioguanine, fludarabine phosphate, pentostatine, and gemcitabine and hydroxyurea); antibiotics (for example anthracyclines like adriamycin, bleomycin, doxorubicin, daunomycin, epirubicin, idarubicin, mitomycin-C, dactinomycin and mithramycin); antimitotic agents (for example vinca alkaloids like vincristine, vinblastine, vindesine and vinorelbine and taxoids like taxol and taxotere and polokinase inhibitors); proteasome inhibitors, for example carfilzomib and bortezomib; interferon therapy; and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan, mitoxantrone and camptothecin); bleomcin, dactinomycin, daunorubicin, doxorubicin, epirubicin, idarubicin, ara-C, paclitaxel (Taxol™), nabpaclitaxel, docetaxel, mithramycin, deoxyco-formycin, mitomycin-C, L-asparaginase, interferons (especially IFN-a), etoposide, and teniposide;

(ii) cytostatic agents such as antiestrogens (for example tamoxifen, fulvestrant, toremifene, raloxifene, droloxifene and iodoxyfene), antiandrogens (for example bicalutamide, flutamide, nilutamide and cyproterone acetate), LHRH antagonists or LHRH agonists (for example goserelin, leuprorelin and buserelin), progestogens (for example megestrol acetate), aromatase inhibitors (for example as anastrozole, letrozole, vorazole and exemestane) and inhibitors of 5*-reductase such as finasteride; and navelbene, CPT-II, anastrazole, letrazole, capecitabine, reloxafme, cyclophosphamide, ifosamide, and droloxafine;

(iii) anti-invasion agents, for example dasatinib and bosutinib (SKI-606), and metalloproteinase inhibitors, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase;

(iv) inhibitors of growth factor function: for example such inhibitors include growth factor antibodies and growth factor receptor antibodies, for example the anti erbB2 antibody trastuzumab [Herceptin™], the anti-EGFR antibody panitumumab, the anti erbB1 antibody cetuximab, tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as gefitinib, erlotinib, 6- acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin-4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as lapatinib) and antibodies to costimulatory molecules such as CTLA-4, 4-IBB and PD-I, or antibodies to cytokines (IL-IO, TGF-beta); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; modulators of protein regulators of cell apoptosis (for example Bcl-2 inhibitors); inhibitors of the platelet-derived growth factor family such as imatinib and/or nilotinib (AMN107); inhibitors of serine/threonine kinases (for example Ras/Raf signalling inhibitors such as farnesyl transferase inhibitors, for example sorafenib , tipifarnib and lonafarnib), inhibitors of cell signalling through MEK and/or AKT kinases, c-kit inhibitors, abl kinase inhibitors, PI3 kinase inhibitors, Plt3 kinase inhibitors, CSF-1 R kinase inhibitors, IGF receptor, kinase inhibitors; aurora kinase inhibitors and cyclin dependent kinase inhibitors such as CDK2 and/or CDK4 inhibitors; and CCR2, CCR4 or CCR6 modulator;

(v) antiangiogenic agents such as those which inhibit the effects of vascular endothelial growth factor, for example the anti vascular endothelial cell growth factor antibody bevacizumab (A vastin™); thalidomide; lenalidomide; and for example, a VEGF receptor tyrosine kinase inhibitor such as vandetanib, vatalanib, sunitinib, axitinib and pazopanib;

(vi) gene therapy approaches, including for example approaches to replace aberrant genes such as aberrant p53 or aberrant BRCA1 or BRCA2;

(vii) immunotherapy approaches, including for example antibody therapy such as alemtuzumab, rituximab, ibritumomab tiuxetan (Zevalin®) and ofatumumab; interferons such as interferon α; interleukins such as IL-2 (aldesleukin); interleukin inhibitors for example IRAK4 inhibitors; cancer vaccines including prophylactic and treatment vaccines such as HPV vaccines, for example Gardasil, Cervarix, Oncophage and Sipuleucel-T (Provenge); gp100;dendritic cell-based vaccines (such as Ad.p53 DC); and toll-like receptor modulators for example TLR-7 or TLR-9 agonists; and

(viii) cytotoxic agents for example fludaribine (fludara), cladribine, pentostatin (NipentTM);

(ix) steroids such as corticosteroids, including glucocorticoids and mineralocorticoids, for example aclometasone, aclometasone dipropionate, aldosterone, amcinonide, beclomethasone, beclomethasone dipropionate, betamethasone, betamethasone dipropionate, betamethasone sodium phosphate, betamethasone valerate, budesonide, clobetasone, clobetasone butyrate, clobetasol propionate, cloprednol, cortisone, cortisone acetate, cortivazol, deoxycortone, desonide, desoximetasone, dexamethasone, dexamethasone sodium phosphate, dexamethasone isonicotinate, difluorocortolone, fluclorolone, flumethasone, flunisolide, fluocinolone, fluocinolone acetonide, fluocinonide, fluocortin butyl, fluorocortisone, fluorocortolone, fluocortolone caproate, fluocortolone pivalate, fluoromethoIone, fluprednidene, fluprednidene acetate, flurandrenolone, fluticasone, fluticasone propionate, halcinonide, hydrocortisone, hydrocortisone acetate, hydrocortisone butyrate, hydrocortisone aceponate, hydrocortisone buteprate, hydrocortisone valerate, icomethasone, icomethasone enbutate, meprednisone, methylprednisolone, mometasone paramethasone, mometasone furoate monohydrate, prednicarbate, prednisolone, prednisone, tixocortol, tixocortol pivalate, triamcinolone, triamcinolone acetonide, triamcinolone alcohol and their respective pharmaceutically acceptable derivatives. A combination of steroids may be used, for example a combination of two or more steroids mentioned in this paragraph;

(x) targeted therapies, for example PI3Kd inhibitors, for example idelalisib and perifosine; PD-1 , PD-L1 , PD-L2 and CTL4-A modulators, antibodies and vaccines; other IDO inhibitors (such as indoximod); anti-PD-1 monoclonal antibodies (such as MK-3475 and nivolumab); anti-PD-L1 monoclonal antibodies (such as MEDI-4736 and RG-7446); anti-PD- L2 monoclonal antibodies; and anti-CTLA-4 antibodies (such as ipilimumab);

(xii) chimeric antigen receptors, anticancer vaccines and arginase inhibitors.

[00202] Such combination treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within a therapeutically effective dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[00203] Compounds of the invention may exist in a single crystal form or in a mixture of crystal forms or they may be amorphous. Thus, compounds of the invention intended for pharmaceutical use may be administered as crystalline or amorphous products. They may be obtained, for example, as solid plugs, powders, or films by methods such as precipitation, crystallization, freeze drying, or spray drying, or evaporative drying. Microwave or radio frequency drying may be used for this purpose.

[00204] For the above-mentioned compounds of the invention the dosage administered will, of course, vary with the compound employed, the mode of administration, the treatment desired and the disorder indicated. For example, if the compound of the invention is administered orally, then the daily dosage of the compound of the invention may be in the range from 0.01 micrograms per kilogram body weight (μg/kg) to 100 milligrams per kilogram body weight (mg/kg).

[00205] A compound of the invention, or pharmaceutically acceptable salt thereof, may be used on their own but will generally be administered in the form of a pharmaceutical composition in which the compounds of the invention, or pharmaceutically acceptable salt thereof, is in association with a pharmaceutically acceptable adjuvant, diluent or carrier. Conventional procedures for the selection and preparation of suitable pharmaceutical formulations are described in, for example, "Pharmaceuticals - The Science of Dosage Form Designs", M. E. Aulton, Churchill Livingstone, 1988.

[00206] Depending on the mode of administration of the compounds of the invention, the pharmaceutical composition which is used to administer the compounds of the invention will preferably comprise from 0.05 to 99 %w (per cent by weight) compounds of the invention, more preferably from 0.05 to 80 %w compounds of the invention, still more preferably from 0.10 to 70 %w compounds of the invention, and even more preferably from 0.10 to 50 %w compounds of the invention, all percentages by weight being based on total composition. [00207] The pharmaceutical compositions may be administered topically (e.g. to the skin) in the form, e.g., of creams, gels, lotions, solutions, suspensions, or systemically, e.g. by oral administration in the form of tablets, capsules, syrups, powders or granules; or by parenteral administration in the form of a sterile solution, suspension or emulsion for injection (including intravenous, subcutaneous, intramuscular, intravascular or infusion); by rectal administration in the form of suppositories; or by inhalation in the form of an aerosol.

[00208] For oral administration the compounds of the invention may be admixed with an adjuvant or a carrier, for example, lactose, saccharose, sorbitol, mannitol; a starch, for example, potato starch, corn starch or amylopectin; a cellulose derivative; a binder, for example, gelatine or polyvinylpyrrolidone; and/or a lubricant, for example, magnesium stearate, calcium stearate, polyethylene glycol, a wax, paraffin, and the like, and then compressed into tablets. If coated tablets are required, the cores, prepared as described above, may be coated with a concentrated sugar solution which may contain, for example, gum arabic, gelatine, talcum and titanium dioxide. Alternatively, the tablet may be coated with a suitable polymer dissolved in a readily volatile organic solvent.

[00209] For the preparation of soft gelatine capsules, the compounds of the invention may be admixed with, for example, a vegetable oil or polyethylene glycol. Hard gelatine capsules may contain granules of the compound using either the above-mentioned excipients for tablets. Also, liquid or semisolid formulations of the compound of the invention may be filled into hard gelatine capsules. Liquid preparations for oral application may be in the form of syrups or suspensions, for example, solutions containing the compound of the invention, the balance being sugar and a mixture of ethanol, water, glycerol and propylene glycol. Optionally such liquid preparations may contain colouring agents, flavouring agents, sweetening agents (such as saccharine), preservative agents and/or carboxy methylcellulose as a thickening agent or other excipients known to those skilled in art.

[00210] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[00211] The size of the dose for therapeutic purposes of compounds of the invention will naturally vary according to the nature and severity of the conditions, the age and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[00212] Dosage levels, dose frequency, and treatment durations of compounds of the invention are expected to differ depending on the formulation and clinical indication, age, and co-morbid medical conditions of the patient. [00213] Throughout the description and claims of this specification, the words “comprise” and “contain” and variations of them mean “including but not limited to”, and they are not intended to (and do not) exclude other moieties, additives, components, integers or steps. Throughout the description and claims of this specification, the singular encompasses the plural unless the context otherwise requires. In particular, where the indefinite article is used, the specification is to be understood as contemplating plurality as well as singularity, unless the context requires otherwise.

[00214] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and/or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and/or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[00215] The reader's attention is directed to all papers and documents which are filed concurrently with or previous to this specification in connection with this application and which are open to public inspection with this specification, and the contents of all such papers and documents are incorporated herein by reference.

[00216] Experimental

Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. Intermediates for which synthesis is not described were prepared following procedures reported in publicly accessible scientific literature. All reactions were performed at room temperature unless otherwise stated. Compound identity and purity confirmations were performed by LCMS UV using a Waters Acquity SQ Detector 2 (ACQ-SQD2#LCA081). The diode array detector wavelength was 254 nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2μL aliquot was injected onto a guard column (0.2 μm x 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2 μm) in sequence maintained at 40 ° C. The samples were eluted at a flow rate of 0.6 mL/min with a mobile phase system composed of A (0.1% (v/v) Formic Acid in Water) and B (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes. The following methods were also used on occasions when described throughout the experimental section, gradients are detailed in Table 1. Method 3 utilised a Shimadzu 2020 series spectrometer equipped with a binary pump and diode array detector (acquisition wavelength 214 and 254 nm) and the MS was in positive and negative electrospray mode (m/z: 100-900). 2 μL Aliquot were injected onto an Agilent Poroshell 120 EC-C18 column (2.7 μm, 4.6×50 mm) maintained at 35 °C and eluted at 1 .0 ml/min using mobile phase consisting of: A: 0.05% Formic acid in water (v/v), B: 0.05% Formic acid in MeCN (v/v). Method 4 utilised an Agilent Technologies 1290 series spectrometer equipped with a binary pump and diode array detector (acquisition wavelength 214 and 254 nm) and the MS was in positive electrospray mode (m/z: 70-1000). 2 μL aliquots were injected onto an Agilent Eclipse Plus RRHD C18, (1 .8 μm, 3.0x50 mm) column maintained at 40 °C and eluted at 0.8 ml/min using mobile phase consisting of: A: 0.05% Formic acid in water (v/v), B: 0.05% Formic acid in MeCN (v/v). Methods 5 and 6 utilised a Waters Acquity H-Class QDA Detector (with PDA). The diode array detector wavelength was 254nM and the MS was in positive and negative electrospray mode (m/z: 150-800). A 2μL aliquot was injected onto a guard column (0.2μm x 2 mm filters) and UPLC column (C18, 50 x 2.1 mm, < 2μm) in sequence maintained at 40°C. The samples were eluted at a flow rate of 0.6mL/min with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and B (0.1 % (v/v) Formic Acid in MeCN) according to the gradients outlined in Table 1 below. Retention times RT are reported in minutes.

Table 1

NMR was also used to characterise final compounds. NMR spectra were obtained on a Bruker AVIII 400 Nanobay with 5mm BBFO probe. Optionally, compound Rf values on silica thin layer chromatography (TLC) plates were measured.

Compound purification was performed by flash column chromatography on silica or by preparative LCMS. LCMS purification was performed using a Waters 3100 Mass detector in positive and negative electrospray mode (m/z: 150-800) with a Waters 2489 UV/Vis detector. Samples were eluted at a flow rate of 20mL/min on a XBridge™ prep C18 5μM OBD 19x100mm column with a mobile phase system composed of A (0.1 % (v/v) Formic Acid in Water) and E3 (0.1% (v/v) Formic Acid in Acetonitrile) according to the gradient outlined in Table 2 below.

Table 2

Synthesis of intermediates

Intermediate A-1, 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane.

Intermediate Scheme 1

Step A, 3-(methoxymethoxy)naphthalene. To a suspension of 4-bromonaphthalen-2-ol (3 g, 13.45 mmol) and N,N-diisopropylethylamine (7.03 mL, 40.35 mmol) in DCM (30 mL) at 0°C was added chloromethyl methyl ether (1.53 mL, 20.17 mmol). The resulting mixture was stirred for 30 min. The reaction was then diluted with distilled water, extracted with DCM (x2), organics were combined and washed with brine (x2), dried over Na₂SO₄, filtered and the filtrate evaporated in vacuo to afford a reddish/pink oil. This was purified by flash column chromatography eluting 0-60% EtOAc in pet. ether (40 g SiO₂, dry loaded with DCM). The desired fractions were combined and evaporated in vacuo to afford a pink oil analysed as 1-bromo-3-(methoxymethoxy)naphthalene (3.2 g, 89% yield).

UPLC-MS (ES⁺, Method 1): 2.06 min, m/z 266.9, 268.9 [M+H]⁺

¹H NMR (400MHz, CDCI₃) δ/ppm: 8.19-8.15 (1H, m), 7.77-7.73 (1H, m), 7.60 (1H, d, J = 2.4Hz), 7.53- 7.46 (2H, m), 7.42-7.40 (1H, m), 5.31 (2H, s), 3.55 (3H, s).

Step B, 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (A-l). To a nitrogen purged suspension of 1-bromo-3-(methoxymethoxy)naphthalene (5.2 g, 19.4 mmol), bis(pinacolato)diboron (9.9 g, 38.9 mmol) and potassium acetate (6.7 g, 68 mmol) in toluene (50 mL) was added [1,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.4 g, 1.9 mmol). The mixture was stirred at 110°C for 2.5 hrs. The reaction mixture was then filtered over celite, washing with EtOAc and the filtrate evaporated in vacuo to afford a black oil. This was taken up in distilled water and EtOAc, extracted aqueous (x2) with EtOAc, combined organics were washed with brine, dried over Na₂SO₄, filtered and evaporated in vacuo to afford a black oil. This was purified by flash column chromatography (40 g SiO₂, dry loaded with DCM) eluting with 0-20% EtOAc in petrol ether, desired fractions were combined and evaporated in vacuo to afford waxy colourless residue. Analysed as 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (6 g, 98% yield).

UPLC-MS (ES⁺, Method 2): 2.16 min, m/z 315 [M+H]⁺

¹H NMR (400MHz, D₆-DMSO) δ/ppm: 8.56-8.59 (1H, d, J=7.1Hz), 7.86-7.89 (1H, d, 1=7.1Hz), 7.63-7.65 (1H, d, l=2.4Hz), 7.58-7.60 (1H, d, l=2.4Hz), 7.40-7.50 (2H, m), 5.31 (2H, s), 3.55 (3H, s), 1.2 (s, 12H).

Intermediate A-2, 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (A-2).

Intermediate Scheme 2

Step A, Ol-tert-butyl O-2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate. A IM solution of lithium bis(trimethylsilyl)amide (43.6mL, 43.6mmol) in THF was added to a solution of N-boc-Proline methyl ester (10g, 43.6mmol) in THF (100mL) at -78°C. Afterwards, the mixtureallowed to stir at that temperature for 30 min. 3-chloropropyl iodide (5.6mL, 52.3mmol) was added and reaction mixture was allowed to gradually warm up to 0°C. After 2 hrs in ice bath TLC (3:1 pet. ether:EtOAc) shows complete consumption of starting material (vis. with l₂). Reaction mixture was quenched with a saturated solution of aqueous ammonium chloride (50 mL), partitioned between a layer of ethyl acetate (100mL) and water (50mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (100mL), organic extracts were combined, washed with a saturated solution of brine (100mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a pale yellow oil analysed as O1-tert-butyl O2-methyl 2-(3-chloropropyl)pyrrolidine-1,2-dicarboxylate (13g, 42.5mmol, 97% yield). ¹H NMR (400M Hz, CDCI₃) δ/ppm: 3.50-3.62 (4H, m), 3.35-3.45 (2H, m), 3.19-3.23 (1H, m), 2.11-2.20 m, 1H), 1.50-2.05 (m, 6H), 1.25-1.29 (9H, d).

Step B, Methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate. Trifluoroacetic acid ( 10mL, 130.2mmol) was added to a solution of O1-tert-butyl O2-methyl 2-(3- chloropropyl)pyrrolidine-1,2-dicarboxylate (13g, 42.5mmol) in DCM (22mL). The resulting solution was allowed to stir at room temp overnight. All volatiles removed under reduced pressure and dark oil re-dissolved in DCM and evaporated again to remove TFA. The resulting dark oil was analysed as methyl 2-(3-chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate (19g, 59.4mmol, 140% yield). NMR indicates product is TFA salt and contains approximately 1 equiv. of TFA remains, used without further purification.

¹H NMR (400MHz, CDCI₃) δ/ppm: 10.20-10.45 (1H, bs), 7.70-8-02 (1H, bs), 3.91 (s, 3H), 3.45-3.70 (m, 4H), 2.45-2.55 (1H, m), 2.26-2.31 (1H, m), 2.15-2.25 (3H, m), 1.95-2.04 (2H, m), 1.55-1.65 (1H, m).

[00217] Step C, Methyl 1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate. Potassium carbonate (27g, 195.4mmol) was added to a mixture of potassium iodide (1g, 6.02mmol) and methyl 2-(3- chloropropyl)pyrrolidin-1-ium-2-carboxylate; 2,2,2-trifluoroacetate (13.5g, 42.2mmol) in methanol (200mL). The mixture was allowed to stir at 35°C for 90 mins before concentrating under reduced pressure. Then the reaction mixture was partitioned between a layer of DCM (150mL) and water (150mL). The organic layer was separated. The aqueous layer was extracted with DCM (100mL). The organic extracts were combined, washed with brine (100ml) dried (Na₂SO₄), filtered and concentrated under reduced pressure to afford methyl 1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate (6.5g, 38.4mmol, 91% yield) as a clear oil.

¹H NMR (400MHz, CDCI₃) δ/ppm: 3.73 (3H, s), 3.12-3.20 (2H, m), 2.62-2.70 (2H, m), 2.25-2.31 (2H, m), 1.78-1.85 (4H, m), 1.62-1.74 (2H, m).

Step D, 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (A-2). At 0 °C, under an N₂ atmosphere a 1M solution of lithium aluminium hydride (19.5mL, 19.5mmol) in THF was added dropwise to a solution of methyl 1,2,3,5,6,7-hexahydropyrrolizine-8-carboxylate (1.1g, 6.5mmol) in THF (10mL). The mixture was allowed to stir at that temperature for 30 mins. Maintaining temp of 0°C, inert atmosphere and using vigorous stirring, the reaction was quenched with dropwise addition of water (0.7 mL) then dropwise addition of a 15% aq. NaOH (0.7 mL) followed by more water (2ml). The mixture was allowed to stir and warm up to room temperature until the precipitated salts dispersed into a freely moving suspension, before filtering, washing the filter cake with THF (2 x 10mL). The filtrate was collected and concentrated under reduced pressure to afford 1,2,3,5,6,7-hexahydropyrrolizin-8-ylmethanol (1.0g, 7.1mmol, 100% yield) as a yellow oil. ¹H NMR (400MHz, CDCI₃) δ/ppm: 3.75-3.79 (1H, m), 3.30 (2H, s), 2.98-3.03 (2H, m), 2.59-2.65 (2H, m), 1.51-1.92 (8H, m).

Intermediate A-3, [(2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol.

Intermediate Scheme 3

Step A, Ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate. At -40°C, LiHMDS (1.34L, 1.34mol, 2.1eq) was added dropwise into a solution of ethyl 5-oxo-2- pyrrolidinecarboxylate (100g, 637mmol, 1.0eq) and 3-chloro-2-chloromethyl-1-propene (239g, 1.91mol, 3.0eq) in THF (2000mL). The mixture was allowed to warm to room temperature and stir over night. The mixture was cooled to -60°C and adjusted to pH 7 with 2M HCI, poured into water (10L), extracted with EtOAc (2L x 3), washed with brine (5L) and dried over Na₂SO₄. The filtered mixture was concentrated and purified by silica gel column (5:1 Pet.ether/EtOAc to 3:1 Pet.ether/EtOAc) to afford ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate as a colourless oil (40g, 30% yield).

¹H NMR (400MHz, CDCI₃) δ/ppm: 5.01-5.06 (2H, d), 4.16-4.30 (3H, m), 3.69-3.73 (1H, d), 3.02-3.06 (1H, d), 2.30-2.75 (4H, m), 2.07-2.16 (1H, m), 1.23-1.27 (3H, t).

Step B, Ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate. At -78°C, O₂ was bubbled through a solution of ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate (115.1g, 550mmol, 1.0eq) in DCM (1L) and MeOH (100mL) for 30 minutes. Ozone was then bubbled through the solution with stirring at -78°C until the solution became blue. O₂ was then bubbled through the solution at the same temperature for a further 30 min. Dimethyl sulfide (68.35g, l.1mol, 2.0eq) was added at -78°C and the solution was allowed to reach room temperature and stir over night. The mixture was concentrated and purified by silica gel column (5:1 Pet.ether/EtOAc to 3:1 Pet.ether/EtOAc) to give ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate (108g, 93% yield) as a colourless oil. ¹H NMR (400MHz, CDCI₃) δ/ppm: 4.20-4.24 (2H, q), 4.08-4.14 (1H, d), 3.52-3.56 (1H, d), 2.95-3.00 (2H, m), 2.81-2.86 (1H, m), 2.39-2.48 (2H, m), 2.19-2.24 (1H, m), 1.26-1.29 (3H, t).

Step C Ethyl (2S,8S)-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate. At 0°C, NaBH₄ (5.81g, 153mmol, 0.3eq) was added to a solution of ethyl 3,6-dioxo-1,2,5,7-tetrahydropyrrolizine-8- carboxylate (108g, 512mmol, 1.0eq) in EtOH (550mL) and stirred for 10 min. To the mixture was added aqueous NH₄CI (50mL) before stirring for a further 20 min at 0°C. The mixture was concentrated in vacuo and the crude was purified by silica gel column (30:1 DCM/MeOH) to afford ethyl (2S,8S)-2- hydroxy-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate as a yellow oil and apparent mixture of sterioisomers (88g, 81% yield).

LC-MS (ES⁺, Method 4): 0.40min, 214.10 [M+H]⁺ .

Step D, Ethyl (2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate. At -78°C, DAST (99.8g, 619mmol, 1.5eq) was added dropwise into a solution of rac-ethyl (2S,8S)-2-hydroxy-5-oxo-

2.3.6.7-tetrahydro-1H-pyrrolizine-8-carboxylate (88g, 413mmol, 1.0eq) in DCM (1.5L) and stirred at room temperature overnight. The mixture was cooled to 0°C before adding MeOH (60mL) and diluting with brine (2000mL). The phases were separated and the organics dried over Na₂SO₄, filtered and concentrated under reduced pressure. The crude was purified by silica gel column (8:1 to 5:1 pet. Ether/EtOAc) to give ethyl (2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H-pyrrolizine-8-carboxylate as a yellow oil (42g, 47% yield).

¹H NMR (400M Hz, CDCI₃) δ/ppm: 5.21-5.36 (1H, d), 4.20-4.47 (3H, m), 3.19-3.41 (1H, dd), 2.10-2.60 (6H, m), 1.24-1.28 (3H, t).

Step E, (6R,8S)-6-Fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3-one. At 0°C, LiBH₄ (81mL, 163mmol, 1.0eq) was added dropwise into ethyl (2R,8S)-2-fluoro-5-oxo-2,3,6,7-tetrahydro-1H- pyrrolizine-8-carboxylate (35g, 163mmol, 1.0eq) in THF (350mL) and stirred at room temperature for 2hrs. The mixture was cooled to 0°C, before adding aqueous NH₄CI (100mL) and stirring for 30 mins at 0°C, the mixture was concentrated and the crude was purified by silica gel column (30:1 DCM/MeOH) to give (6R,8S)-6-fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3-one (28g, 99% yield).

¹H NMR (400MHz, CDCI₃) δ/ppm: 5.21-5.35 (1H, d), 4.05-4.16 (1H, m), 3.51-3.55 (1H, d), 3.42-3.46 (1H, d) 2.52-3.11 (3H, m), 1.94-2.41 (5H, m).

Step F,_[(2R,8S)-2-Fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol (A-3). At 0°C, BH₃.DMS (10M, 75.1mL, 751mmol, 5.0eq) was added dropwise into rac-(6R,8S)-6-fluoro-8-(hydroxymethyl)-

2.5.6.7-tetrahydro-1H-pyrrolizin-3-one (26g, 150mmol, 1.0eq) in THF (1300mL) and stirred at room temperature overnight. The mixture was cooled to 0°C, MeOH (300mL) was added and stirring continued for lhr at 0°C. The mixture was concentrated and the crude was dissolved in MeOH (300mL) and stirred at 50°C overnight. The mixture was concentrated to give (21g, 87.9% yield) of [(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol, intermediate 21 as a colourless oil.

¹H NMR (400MHz, CDCI₃) δ/ppm: 5.11-525 (1H, d), 2.80-3.31 (6H, m), 1.74-2.11 (6H, m).

Intermediate A-4, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a] [1,4]diazepine-2 -carboxylic acid.

Intermediate Scheme 4

Step A, 2-nitro-N-prop-2-ynyl-benzenesulfonamide. A solution of propargylamine (37.28g, 676.83mmol) and N,N-diisopropylethylamine (129.81 mL, 1353.7mmol) in DCM (1.86L) was cooled to 0°C. 2-Nitrobenzenesulfonyl chloride (149.99g, 676.83mmol) was added portion- wise. The reaction mixture was then allowed to warm to room temperature and left to stir at room temperature overnight. The reaction mixture was concentrated in vacuo and the crude residue purified by flash column chromatography (SiO₂, 20-50% EtOAc/PE) to afford the desired product 2-nitro-N-prop-2-ynyl-benzenesulfonamide (151.6 g, 75% yield) as a white solid.

LC-MS (ES⁺, Method 3): 1.23min, 241.05 [M+H]⁺

Step B, N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide. 1-bromo-3- chloropropane (245.75g, 1561 mmol) was added dropwise to a stirring mixture of 2-nitro-n- prop-2-ynyl-benzenesulfonamide (50g, 208.13mmol) and cesium carbonate (169.54g, 520.33mmol) in acetone (2L). The reaction mixture was left to stir at room temperature for 5 hours. The reaction mixture was concentrated in vacuo and the crude residue partitioned between EtOAc (3L) and water (2L). The aqueous layer was twice extracted with additional EtOAC (1.5L), the combined organic layers were dried with Na₂SO₄, concentrated in vacuo and purified by flash column chromatography (SiO₂, PE/EA=2/1) to afford the desired product N-(3-chloropropyl)-2-nitro-N-prop-2-ynyl-benzenesulfonamide (43.48 g, 63% yield) as yellow solid.

LC-MS (ES⁺, Method 3): 1.70min, 317.0 [M+H]⁺

Step C, ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine- 2 -carboxylate. N,N-diisopropylethylamine (1 ,12mL, 6.4mmol) was added to a stirring solution of n-(3-chloropropyl)-2-nitro-n-prop-2-ynyl-benzenesulfonamide (2.g, 6.31 mmol) and ethyldiazoacetate (1.09mL, 9.54mmol) in benzene (6mL). The reaction mixture was irradiated in the microwave at 140°C for 1 hour. The reaction mixture was left to cool to room temperature before cesium carbonate (2.49g, 7.64mmol) and THF (2mL) were added and the reaction mixture again irradiated 140°C for 30 minutes. The reaction mixture was left to cool to room temperature and the solvents removed in vacuo. The crude residue was partitioned between water (180mL) and EtOAc (80mL). The aqueous layer was washed with additional EtOAc (150mL) and the combined organic layers washed with brine (100mL x2). The organic layer was dried over anhydrous Na₂SO₄, the solvents removed in vacuo and concentrated and purified by flash column chromatography (SiO₂, PE/EA=1/1) to afford the desired product ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1 ,7g, 61 % yield) as yellow oil.

LC-MS (ES⁺, Method 3): 1.47min, 395.05 [M+H]⁺

Step D, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a] [1,4]diazepine-2- carboxylic acid (A-4). A solution of ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylate (1.7g, 4.31 mmol) and 1 M LiOH (17.2mL, 17.24mmol) in THF (40mL) and Methanol ( 10mL) was left to stir at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and the residue acidified to pH 3 with slow addition of 1 M HCI. The resulting solid was collected via filtration to afford the desired product 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1 ,5g, 86% yield) as white solid.

LC-MS (ES⁺, Method 3): 1.10min, 367.05 [M+H]⁺

Intermediate A-5, N-ethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a] [1,4]diazepine-2- carboxamide.

Intermediate Scheme 5

Step A, N-ethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2 -carboxamide. TBTU (1.45g, 4.5mmol) and N,N-diisopropylethylamine (2.65g, 20.47mmol) were added to a stirring mixture of 5-(2-nitrophenyl)sulfonyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.5g, 4.09mmol) and ethanamine hydrochloride (330mg, 4.09mmol) at 0°C under N2. The reaction mixture was left to stir at 0°C for 15 minutes before being left to warm to room temperature and stirred for 4 hours. The reaction mixture was diluted with water (600mL) and extracted with EtOAc (200mL x3). The combined organic layers were washed with brine (200mL x2), dried over Na₂SO₄ and concentrated in vacuo to afford the crude product. The crude mixture was purified by flash column chromatography (SiO₂, DCM/MeOH=20/1) to afford the desired product N-ethyl-5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (1 ,75g, 97.8%) as a brown oil.

LC-MS (ES+, Method 4): 1.23min, 394.10 [M+H]+

Step B, N-ethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5-a][1,4]diazepine-2-carboxamide (A- 5). A mixture of N-ethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (1.75g, 4.45mmol), Thiophenol (0.98g, 8.9mmol) and cesium carbonate (2.9g, 8.9mmol) in MeCN (40mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated in vacuo and the crude residue purified by flash column chromatography (SiO₂, DCM/MeOH=10/1) to afford the desired product N-ethyl-5,6,7,8- tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (700mg, 68% yield) as a yellow solid.

LC-MS (ES+, Method 4): 0.17min, 209.15 [M+H]+

The intermediates in table 3 below were prepared by analogy with A-5 (intermediate scheme 5), replacing the amine building block ethanamine hydrochloride as described in the table entry.

Table 3 Intermediate A-9, 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane

Intermediate Scheme 6

Step A, 2-bromoethynyl(triisopropyl)silane. To a solution of N-bromosuccinimide (3.49 g, 19.6 mmol) and triisopropylsilylethyne (4.0 mL, 17.8 mmol) under N₂ in acetone (89 mL) was added silver nitrate (302 mg, 1.78 mmol). The reaction mixture was allowed to stir at room temperature for 1 h. All volatiles were removed under reduced pressure. The residue was partitioned between a layer of petrol (30 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with petrol (30 mL), organic extracts combined, washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-bromoethynyl(triisopropyl)silane (4.96 g, 19.0 mmol, 100% yield) as a clear oil.

¹H NMR (400 MHz, CDCI₃ ) δ/ppm: 1.11-1.02 (m, 21 H).

Step B, 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1 ,3-diol. Dichloro(p- cymene)ruthenium(ll) dimer (1.03 g, 1.68 mmol) was added to a nitrogen degassed suspension of 7-fluoronaphthalene-1 ,3-diol (3.00 g, 16.8 mmol), 2- bromoethynyl(triisopropyl)silane (4.62 g, 17.7 mmol) and potassium acetate (3.31 g, 33.7 mmol) in 1,4-dioxane (19.8 mL). Afterwards, the mixture was allowed to stir at 110 °C for 1 h before cooling back down to room temperature and removing all volatiles under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petrol afforded 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1 ,3-diol (4.59 g, 12.8 mmol, 76% yield) as a black oil.

UPLC-MS (ES; Method 2): 2.47 min, m/z 357.4 [M-H]’. Step C, 7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol. To a solution of 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalene-1 ,3-diol (4.59 g, 12.8 mmol) and N,N-diisopropylethylamine (4.46 mL, 25.6 mmol) in DCM (64 mL) was added bromomethyl methyl ether (0.99 mL, 12.2 mmol) at 0 °C. The mixture was allowed to stir at that temperature for 30 min then concentrated under reduced pressure and partitioned between a layer of ethyl acetate (40 mL) and water (40 mL). The organic layer was separated, aqueous layer extracted with ethyl acetate (40 mL) and organic layers combined, washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petrol afforded 7-fluoro-3-(methoxymethyloxy)-8-(2- triisopropylsilylethynyl)naphthalen-1 -ol (3.04 g, 7.55 mmol, 59% yield) as a brown oil.

¹H NMR (400 MHz, CDCI₃ ) δ/ppm: 10.30 (s, 1 H), 7.88 (dd, J = 9.1 , 5.7 Hz, 1 H), 7.42-7.34 (m, 1 H), 7.03 - 6.97 (m, 1 H), 6.77-6.71 (m, 1 H), 5.27 (s, 2H), 3.48-3.42 (m, 3H), 1.20-1.15 (m, 21 H).

Step D, [7 -fluoro-3-(methoxymethy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2- dimethylpropanoate. To a solution of 7-fluoro-3-(methoxymethyloxy)-8-{2-[tris(propan-2- yl)silyl]ethynyl}naphthalen-1-oil (3.04 g, 7.55 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.07 mmol) in DCM (15.1 mL) was added trimethyl acetyl chloride (1.1 mL, 9.07 mmol) at 0 °C. The reaction mixture was allowed to stir at 0 °C for 30 min before an extra portion of trimethyl acetyl chloride (2.2 mL, 18.1 mmol) and N,N-diisopropylethylamine (1.6 mL, 9.07 mmol) were added. The reaction mixture was stirred at 0 °C for 16 h. The reaction mixture was concentrated under reduced pressure and partitioned between ethyl acetate (40 mL) and water (40 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (40 mL). The combined organic layers were washed with a saturated solution of brine (20 mL), dried over Na₂SO₄, filtered and concentrated under reduced pressure to afford [7- fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2- dimethylpropanoate (4.88 g, 10.0 mmol, 100% yield) as a brown oil.

¹H NMR (400 MHz, CDCI₃ ) δ /ppm: 7.68 (dd, J = 9.1 , 5.5 Hz, 1 H), 7.28 (d, J = 2.4 Hz, 1 H), 7.27-7.20 (m, 1 H), 6.83 (d, J = 2.1 Hz, 1 H), 5.25 (s, 2H), 3.50 (s, 3H), 1.47 (s, 9H), 1.22-1.09 (m, 21 H).

Step E, [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate. Caesium fluoride (5.73 g, 37.8 mmol) was added to a suspension of [7-fluoro-3- (methoxymethyloxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] 2,2-dimethylpropanoate (3.68 g, 7.55 mmol) in DMF (15.1 mL). Afterwards, the mixture was allowed to stir at room temperature for 1 h before partitioning between a layer of ethyl acetate (100 mL) and water (100 mL). The organic layer was separated, aqueous layer extracted with ethyl acetate (2 x 50 mL) and organic layers combined and washed with water (2 x 50 mL), a saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petrol afforded [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (2.48 g, 7.51 mmol, 99% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 2.01 min, m/z 331 .5 [M+H]⁺.

Step F, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate. A solution of [8-ethynyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (2.48 g, 7.51 mmol) in methanol (15.0 mL) was evacuated and back-filled with nitrogen (3x). Then palladium, 10 wt. % on carbon powder, dry (240 mg, 2.25 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction was stirred at room temperature overnight. Afterwards, the mixture was passed through a pad of celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure to afford [8-ethyl-7-fluoro-3- (methoxymethyloxy)-1-naphthyl] 2,2-dimethylpropanoate (928 mg, 2.78 mmol, 37% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 2): 2.29 min, m/z 335.2 [M+H]⁺.

Step G, 8-ethyl-7-fluoro-3-(methoxymethyloxy)naphthalen-1-ol. Potassium hydroxide (467 mg, 8.33 mmol) was added to a solution of [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1- naphthyl] 2,2-dimethylpropanoate (928 mg, 2.78 mmol) in methanol (13.9 mL). Afterwards, it was allowed to stir at room temperature for 30 min. All volatiles were removed under reduced pressure and pH adjusted to pH 7 with saturated solution of ammonium chloride. Reaction mixture was partitioned between a layer of ethyl acetate (40 mL) and water (40 mL). The organic layer was separated. The aqueous layer was extracted with ethyl acetate (40 mL), organic layers combined, washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petrol afforded 8-ethyl-7- fluoro-3-(methoxymethyloxy)naphthalen-1 -ol (41 1 mg, 1.64 mmol, 59% yield) as a brown oil. UPLC-MS (ES⁺, Method 2): 1 .90 min, m/z 251 .1 [M+H]⁺.

Step H, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] trifluoromethanesulfonate. At - 40 °C, trifluoromethanesulfonic anhydride (0.41 mL, 2.46 mmol) was added to a solution of N,N-diisopropylethylamine (0.86 mL, 4.92 mmol) and 8-ethyl-7-fluoro-3- (methoxymethyloxy)naphthalen-1-ol (411 mg, 1.64 mmol) in DCM (8.2 mL). Afterwards, the mixture was allowed to stir at that temperature for 30 min. Reaction mixture was diluted with ice-water (20 mL), warmed up to room temperature and extracted with ethyl acetate (3 x 20 mL). Organic layers were combined, washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-25% ethyl acetate in petrol afforded intermediate 1-1 a, [8-ethyl-7-fluoro-3-(methoxymethyloxy)-1-naphthyl] trifluoromethanesulfonate (515 mg, 1.35 mmol, 82% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 2): 2.25 min, m/z 383.3 [M+H]⁺.

¹H NMR (400 MHz, CDCI₃) δ/ppm: 7.62 (dd, J = 9.0, 5.6 Hz, 1 H), 7.42 (d, J = 2.4 Hz, 1 H), 7.36 (d, J = 2.4 Hz, 1 H), 7.32-7.25 (m, 1 H), 5.28 (s, 2H), 3.52 (s, 3H), 3.24 (dq, J = 7.5, 2.9 Hz, 2H), 1.24 (t, J = 7.6 Hz, 3H).

Step I, 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2- dioxaborolane (A-9). Bis(pinacolato)diboron (116.91 mg, 0.46 mmol), potassium acetate (67.78 mg, 0.6 9mmol) and [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] trifluoromethanesulfonate (88 mg, 0.23 mmol) in toluene (1.1 mL) were degassed with N₂ for 5 min. [1 ,1 '-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (18.8mg, 0.02mmol) was then added and reaction mixture allowed to stir at 120°C for 1 hr. The reaction mixture was allowed to cool back down to room temperature before concentrating under reduced pressure. Purification by flash column chromatography on silica gel eluting with EtOAc in petroleum ether 0-30% afforded 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (31.9 mg, 0.09 mmol, 38% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 2): 2.21 min, m/z 361.4 [M+H]⁺

¹H NMR (400 MHz, CDCI₃ ) δ/ppm: 7.56 (dd, J = 9.0, 5.8 Hz, 1 H), 7.39 (d, J = 2.7 Hz, 1 H), 7.36 (d, J = 2.6 Hz, 1 H), 7.20 (t, J = 9.2 Hz, 1 H), 5.27 (s, 2H), 3.50 (s, 3H), 3.12 (qd, J = 7.5, 2.5 Hz, 2H), 1.44 (s, 12H), 1.29-1.24 (m, 3H).

Intermediate A-10, [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]boronic acid.

Intermediate Scheme 7

The synthesis of 7-fluoro-3-(methoxymethyloxy)-8-(2-triisopropylsilylethynyl)naphthalen-1-ol (A-9a) is described in the preparation of intermediate A-9 (intermediate scheme 6).

Step A, [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl] trifluoromethanesulfonate. A solution of 7-fluoro-3-(methoxymethyloxy)-8-(2- triisopropy lsilylethynyl)naphthalen-1-ol (A-9a) (10 g, 24.84 mmol) and N,N-diisopropylethylamine (12.98 mL, 74.52 mmol) was dissolved in dry DCM and trifluoromethanesulfonic anhydride (6.27 mL, 37.26 mmol) was added at -40°C. The mixture was stirred overnight at 40°C under N₂. The reaction mixture was diluted with ice-water(150 mL), extracted with DCM (50 mL x 3), washed with brine (100 mL), concentrated under vacuum and purified by flash column chromatography on silica gel eluting with 0-10% EtOAc in pet. ether to give [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl] trifluoromethanesulfonate as an orange liquid (12.5 g, 94% yield).

UPLC-MS (ES⁺, Method 4): 2.27 min.

Step B, [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]boronic acid (A-10). potassium acetate (16.5 g, 168.34 mmol) , tetrahydroxydiborane (15.1 g, 168.34 mmol), X-Phos (2.67 g, 5.61 mmol), X-PhosPdG2 (2.2 g, 2.81 mmol) and [7-fluoro-3-(methoxymethoxy)-8-(2- triisopropy lsilylethynyl)-1-naphthy I] trifluoromethanesulfonate (30 g, 56.11 mmol) were dissolved in ethanol (500 mL). The resulting mixture was stirred overnight at 80°C under N₂. The reaction was cooled to room temperature and concentrated in vacuo and purified flash column chromatography on silica gel eluting with 0-10% EtOAc in pet. ether to obtain [7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]boronic acid (16.8 g, 67% yield) as a brown solid.

UPLC-MS (ES⁺, Method 4): 2.48min, m/z 431.10, [M+ H]⁺

NMR (400 MHz, DMSO-d6) δ/ppm: 7.96 (s, 2H), 7.90 (dd, J = 9.1, 5.9 Hz, 1H), 7.48 - 7.38 (m, 2H), 7.19 (s, 1H), 5.31 (s, 2H), 3.42 (s, 3H), 1.17 - 1.12 (m, 21H).

Intermediate A-11 , [1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]methanol.

A-11

Intermediate Scheme 8

Step A, [1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]methanol. Sodium methoxide (0.73mL, 3.94mmol) (5.4M in MeOH) was added to a solution of [1-(iodomethyl)-2- oxabicyclo[2.1 ,1 ]hexan-4-yl]methanol (100. mg, 0.39mmol) in Methanol (1.968mL). The reaction mixture was heated to 60°C and left to stir overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). Organic layer separated and aqueous layer extracted with ethyl acetate (20 mL). Organic layers combined, washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford [1 - (methoxymethyl)-2-oxabicyclo[2.1 ,1]hexan-4-yl]methanol (36.4mg, 0.2301 mmol, 58% yield) as a yellow oil. ¹H NMR (400MHz, CDCI₃ ) δ/ppm: 3.91 (s, 2H), 3.75 (s, 2H), 3.47 (s, 2H), 3.42 (s, 3H), 1.76 - 1 .71 (m, 2H), 1 .68 - 1 .62 (m, 2H), 1 .39 (br s, 1 H).

Intermediate A-12, N,N-dimethyl-6,7,8,9-tetrsihydro-5H-[1,2,4]trjazolo[1,5-a][1,4]diazep!ne-2- carboxamide.

Intermediate Scheme 9

Step A, benzyl 3-oxo-1 ,4-diazepane-1-carboxylate. To a solution of 1,4-diazepan-2-one (1 .09g, 9.55mmol) and triethylamine (2.7mL, 19.37mmol) in DCM (24mL) at 0°C, under N₂ , was added benzyl chloroformate (1.5mL, 10.51 mmol) dropwise. The mixture was stirred at 20°C overnight. The mixture was diluted with DCM (60mL) and washed with water (20mL) and brine (20mL). The organic layer was passed through a phase separator cartridge and concentrated. The residue was purified by flash chromatography (gradient 0-20% methanol in DCM) to afford benzyl 3-oxo-1,4-diazepane-1-carboxylate (2.054g, 8.2729mmol, 86% yield) as a white solid.

UPLC-MS (ES+, Method 5): 1.44 min, m/z 249.0 [M+H]+.

¹H NMR (400MHz, CDCI₃ ) δ /ppm: 7.41 -7.28 (5H, m), 6.16-5.90 (1 H, m), 5.17 (2H, s), 4.23- 4.11 (2H, m), 3.70-3.61 (2H, m), 3.34-3.23 (2H, m), 1.95-1.84 (2H, m).

Step B, O8-benzyl O2-ethyl 5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1,5-a][1 ,4]diazepine-2,8- dicarboxylate. To a solution of benzyl 3-oxo-1,4-diazepane-1-carboxylate (1 ,05g, 4.23mmol) in anhydrous DMF (40mL) at 0°C, under N2, was added sodium hydride, (60% dispersed in mineral oil) (254. mg, 6.35mmol) and the mixture was stirred for 45 minutes. O- (diphenylphosphinyl)-hydroxylamine (1.48g, 6.35mmol) was added and the white suspension was stirred at 20oC for 3.5 hours. The mixture was filtered, and the filtrate concentrated. The residue was dissolved in ethanol (15mL) and ethyl 2-ethoxy-2-iminoacetate (1 .5mL, 10.77mmol) was added. The mixture was heated at 90°C for 18 hours. After cooling to room temperature, the mixture was concentrated, and the residue was purified twice by flash chromatography (gradient 0-8% methanol in DCM then 0-100% EtOAc in petroleum ether) to afford O8-benzyl O2-ethyl 5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1,5-a][1,4]diazepine-2,8- dicarboxylate (643mg, 1 .8672mmol, 44% yield) as a light yellow gum.

UPLC-MS (ES+, Method 5): 1.65 min, m/z 345.1 [M+H]⁺.

¹H NMR (400MHz, DMSO-d6) δ/ppm: 7.40-7.24 (5H, m), 5.06 (2H, s), 4.81-4.72 (2H, m), 4.49- 4.44 (2H, m), 4.30 (2H, q, J = 7.1 Hz), 3.76 (2H, br s), 1.95 (2H, br s), 1.29 (3H, t, J = 7.1 Hz).

Step C, 8-benzyloxycarbonyl-5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1,5-a] [1,4]diazepine-2- carboxylic acid. To a solution of O8-benzyl O2-ethyl 5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1 ,5- a][1,4]diazepine-2,8-dicarboxylate (1.21g, 3.5mmol) in THF (17mL) was added lithium hydroxide hydrate (1 :1 :1) (294.3mg, 7.01 mmol) in water (3.5mL) . The mixture was stirred at 20°C for 90 minutes and concentrated. The residue was diluted with water (10mL) and acidified to pH 2-3 with 1 N aq. HCI. The mixture was extracted with DCM (5 x 10mL). The combined organic layers were passed through a phase separator cartridge and concentrated to afford 8-benzyloxycarbonyl-5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1,5-a][1,4]diazepine-2- carboxylic acid (1 .034g, 3.2688mmol, 93% yield) as a white solid.

UPLC-MS (ES+, Method 5): 1.41 min, m/z 317.1 [M+H]⁺.

Step D, benzyl 2-(dimethylcarbamoyl)-5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1 ,5- a][1,4]diazepine-8-carboxylate. To a solution of 8-benzyloxycarbonyl-5,6,7,9-tetrahydro- [1 ,2,4]triazolo[1,5-a][1,4]diazepine-2-carboxylic acid (1.03g, 3.27mmol) and dimethylamine hydrochloride (400. mg, 4.91 mmol) in THF (22mL) were successively added propylphosphonic anhydride (3.9mL, 6.55mmol) and N,N-diisopropylethylamine (2.6mL, 14.93mmol) . The mixture was stirred at 20°C overnight. The mixture was concentrated, and the residue dissolved in EtOAc (60mL). The organic layer was washed with water (2 x 20mL) and brine (20mL), passed through a phase separator cartridge and concentrated to afford benzyl 2-(dimethylcarbamoyl)-5,6,7,9-tetrahydro-[1 ,2,4]triazolo[1,5-a][1,4]diazepine-8- carboxylate (880mg, 2.5627mmol, 78% yield) as a very thick yellow oil.

UPLC-MS (ES+, Method 5): 1.51 min, m/z 344.1 [M+H]⁺.

¹H NMR (400MHz, DMSO-d6) δ/ppm: 7.39-7.23 (5H, m), 5.06 (2H, s), 4.79-4.71 (2H, m), 4.44- 4.37 (2H, m), 3.81-3.73 (2H, m), 3.08-3.00 (3H, m), 2.96 (3H, s), 2.01-1.90 (2H, m).

Step E, N,N-dimethyl-6,7,8,9-tetrahydro-5H-[1 ,2,4]triazolo[1,5-a] [1,4]diazepine-2- carboxamide (A-35). A flask containing a solution of benzyl 2-(dimethylcarbamoyl)-5,6,7,9- tetrahydro-[1 ,2,4]triazolo[1,5-a][1,4]diazepine-8-carboxylate (880. mg, 2.56mmol) in EtOAc (25mL) was evacuated/backfilled with N₂ then Palladium , 10 wt% on carbon, 55-65% wet (546. mg, 0.26mmol) was added. The flask was then evacuated/backfilled with hydrogen and the mixture was stirred at 20°C, under a hydrogen atmosphere, overnight. The flask was evacuated/backfilled with N₂. The mixture was concentrated, and the filter cake washed with EtOAc. The filtrate was concentrated to afford N,N-dimethyl-6,7,8,9-tetrahydro-5H- [1 ,2,4]triazolo[1,5-a][1,4]diazepine-2-carboxamide (464mg, 2.2174mmol, 87% yield) as a white solid.

UPLC-MS (ES+, Method 5): 0.26 min, m/z 210.1 [M+H]⁺.

¹H NMR (400MHz, DMSO-d6) δ/ppm: 4.35-4.31 (2H, m), 3.91 (2H, s), 3.06 (3H, s), 3.06-3.02 (2H, m), 2.95 (3H, s), 2.60 (1 H, br s), 1.82-1 .75 (2H, m).

Intermediate A-13, 3-fiuoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepme-2 -carboxamide.

Intermediate Scheme 10

Step A, tert-butyl 2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepme-5- carboxylate. Propylphosphonic anhydride (6.01mL, 10.1mmol) and N,N-diisopropylethylamine (1.76mL, 10.1mmol) were added to a flask containing 5-(tert-butoxycarbonyl)-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxylic acid (568. mg, 2.02mmol) and dimethylamine hydrochloride (576.24mg, 7.07mmol) in THF (13mL). The reaction mixture was stirred at room temperature for 2.5hrs. The the volatiles were removed in vacuo. The residue was dissolved in EtOAc and washed with sat. aq. NH4CI. The aqueous layer was extracted with EtOAc (3x). The combined organic layers were passed through a phase separator and reduced in vacuo to afford tert-butyl 2- (dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (719mg, 2.3315mmol, 115.47% yield) as an orange oil.

UPLC-MS (ES+, Method 5): 1.53 min, m/z 309.1 [M+H]⁺.

¹H NMR (400MHz, DMSO-d6) δ/ppm: 6.43 (s, 1 H), 4.47 (s, 2H), 4.42 (me, 2H), 3.65 (sbr, 2H), 3.24 (s, 3H), 2.94 (s, 3H), 1.76 (sbr, 2H), 1.33 (s, 9H) ppm.

Step B, tert-butyl 2-(dimethyl cai'bamoyl)-3-flu oro-4,6,7,8-tetrahydropyrazolo[1 ,5- a][1,4]diazepine-5-carboxy!afe. N -chloromethyl-n-fluorotriethylenediammonium bis(tetrafluoroborate) - selectfluor (1838.04mg, 5.19mmol) was added to a solution of tert-butyl 2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate

(800. mg, 2.59mmol) in MeCN (13mL) and the suspension was stirred at 50°C. After 7hrs, the mixture was allowed to cool to room temperature and was concentrated in vacuo. The residue was taken up in DCM (50mL) washed with water (50mL). The aqueous layer was extracted with DCM (3x). The combined organics were passed through a phase separator and reduced in vacuo. The crude was dry loaded on celite and purified by reverse phase chromatography (C18, 25g, MeCN in H2O, +0.1 % FA each). The relevant fractions were combined and reduced in vacuo directly and co-distilled with MeOH to afford tert-butyl 2-(dimethylcarbamoyl)-3-fluoro- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate (195mg, 0.5975mmol,

23.031 % yield) as a colourless oil.

UPLC-MS (ES+, Method 5): 1.59 min, m/z 327.1 [M+H]⁺.

¹H NMR (400MHz, CDCI3) δ/ppm: 4.44 (sbr, 2H), 4.39 (me, 2H), 3.72 (sbr, 2H), 3.18 (sbr, 3H), 3.09 (s, 3H), 1.93 (me, 2H), 1.33 (s, 9H) ppm.

Step C, 3-fluoro-N,N-dimethyl -5,6 J,8-tetrahydro-4H-pyrazolo [1,5-a][1,4]diazepine-2- carboxamide. Trifluoroacetic acid (0.45mL, 5.82mmol) was added to a stirring solution o tert- butyl 2-(dimethylcarbamoyl)-3-fluoro-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5- carboxylate (190. mg, 0.58mmol) in DCM (4mL). The reaction mixture was left to stir at room temperature for 3 hrs. The reaction mixture was concentrated in vacuo and purified by SCX-2 column (2g, washing with MeOH (x3) and eluting in 1 N NH3/MeOH (x3) to afford 3-fluoro-N,N- dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (119mg, 0.5259mmol, 90.343% yield) as a yellow oil.

UPLC-MS (ES+, Method 5): 0.24 and 0.38 min, m/z 227.0 [M+H]⁺.

Intermediate A-14, [3-methyl-1-(1-methylimidazol-2-yl)azetidin-3-yl]methanol.

Intermediate Scheme 11

Step A, methyl 3-methyl-1-(1 -methylimidazol-2-yl)azetidine-3-carboxylate. To a microwave vial, a stirring mixture of methyl 3-methylazetidine-3-carboxylate hydrochloride (50. mg, 0.3mmol), 2-iodo-1-methyl-1H-imidazole (75.35mg, 0.36mmol), L-proline (90.37mg, 0.78mmol) and cesium carbonate (196.73mg, 0.6mmol) in DMF (2.00 mL) was degassed with nitrogen before the addition of copper(l) iodide (5.75mg, 0.03mmol). The vial was sealed and the reaction mixture was heated to 100°C and left to stir at that temperature overnight.The reaction mixture allowed to cool back down to room temperature and was partitioned between a layer of ethyl acetate (15 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (15 mL). The combined organic layers were washed with water (20 mL), a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with MeOH in DCM 0-6% afforded methyl 3-methyl-1-(1- methylimidazol-2-yl)azetidine-3-carboxylate (7.2mg, 0.0344mmol, 11 .398% yield) as a clear oil.

UPLC-MS (ES⁺, Method 2): 0.82 min, m/z 210.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 6.70 (d, J = 1 .5 Hz, 1 H), 6.55 (d, J = 1 .5 Hz, 1 H), 4.34 (d, J = 7.5 Hz, 2H), 3.81 (d, J = 7.6 Hz, 2H), 3.76 (s, 3H), 3.40 (s, 3H), 1.62 (s, 3H). Step B, [3-methyl-1-(1 -methyl imidazol-2-yl)azetidin-3-yl]methanol. At 0°C, lithium borohydride (O.mL, 0.08mmol) was added to a solution of methyl 3-methyl-1-(1- methylimidazol-2-yl)azetidine-3-carboxylate (11.8mg, 0.06mmol) in THF (0.56mL). Afterwards, the reaction mixture was allowed to stir at room temperature for 1 hr. The reaction mixture was quenched carefully with water and partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford [3-methyl-1-(1-methylimidazol-2-yl)azetidin-3-yl]methanol (4.4mg, 0.0243mmol, 43.051 % yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 0.45 min, m/z 182.0 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 6.62 (d, J = 1.9 Hz, 1 H), 6.35 (d, J = 2.0 Hz, 1 H), 4.40 (d, J = 7.3 Hz, 2H), 4.20 (d, J = 7.4 Hz, 2H), 3.71 (s, 2H), 3.45 (s, 3H), 1.35 (s, 3H).

Intermediate A-15, 5-ethyl-1 ,6-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)naphthalen-2-ol.

Intermediate Scheme 12

Step A, 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-ol.

Hydrogen chloride (4M in dioxane) (0.69mL, 2.78mmol) was added to a solution of 2-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (200mg, 0.56mmol) in DCM (2.78mL) and the reaction mixture was stirred at room temperature for 1 hr, then concentrated in vacuo. The crude was purified by flash column chromatography eluting EtOAc in petroleum ether 0-25%. The desired fractions were concentrated to afford 5- ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-ol (89mg, 0.282mmol, 51 % yield) as a translucent pink oil.

UPLC-MS (ES⁺, Method 5): 2.14 min, m/z 317.1 [M+H]⁺.

Step B, 5-ethyl-1 ,6-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen- 2-ol (A-23).

Selectfluor (251.43mg, 0.71 mmol) was added to a solution of 5-ethyl-6-fluoro-4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-ol (187 mg, 0.59mmol) in MeCN (3.94mL), and stirred at room temperature for 3 hrs. The mixture was diluted with EtOAc, washed with water and brine, dried with Na₂ SO₄ , filtered and concentrated. The crude was purified by flash column chromatography eluting 0-25% EtOAc in petroleum ether. The desired fractions were concentrated to afford 5-ethyl-1 ,6-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)naphthalen-2-ol (87mg, 0.2603mmol, 44% yield) as a yellow solid.

¹H NMR (400MHz, CDCI3) δ /ppm: 7.84 - 7.77 (m, 1 H), 7.43 - 7.36 (m, 1 H), 7.29 - 7.21 (m, 1 H), 5.59 (br s, 1 H), 3.17 - 3.07 (m, 2H), 1.43 (s, 12 H), 1.30 - 1.23 (t, J = 7.5 Hz, 3H).

Step C, 2-[8-ethyl-4,7-difluoro-3-(methoxymethoxy)-1-naphthyl]-4, 4, 5, 5-tetramethyl-

1 ,3,2-dioxaborolane. Chloromethyl methyl ether (0.15mL, 1.92mmol) added dropwise to a solution of 5-ethyl-1 ,6-difluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2-ol (428. mg, 1.28mmol) and N,N-diisopropylethylamine (0.45mL, 2.56mmol) in DCM (6.40mL) and the reaction mixture was stirred at room tempereature for 2 hrs. The reaction mixture was concentrated under reduced pressure and purified by flash column chromatography eluting with EtOAc in petroleum ether 0-25% to give 2-[8-ethyl-4,7-difluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (350mg, 0.9254mmol, 72.25% yield) as a yellow oil.

¹H NMR (400 MHz, CDCI3) δ /ppm: 7.95 (dd, J = 9.2, 5.8 Hz, 1 H), 7.56 (d, J = 8.7 Hz, 1 H), 7.28 (t, J = 9.3 Hz, 1 H), 5.28 (s, 2H), 3.57 (s, 3H), 3.14 (qd, J = 7.5, 2.5 Hz, 2H), 1 .44 (s, 12H), 1 .26 (t, J = 7.5 Hz, 3H).

Intermediate A-16, 6-fluoro-1-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-5-(2-triisopropylsilylethynyl)quinolin-2-one.

Intermediate Scheme 13 Step A, 4-chloro-6-fluoro-1 H-quinolin-2-one. 2,4-Dichloro-6-fluoro-quinoline (2000. mg, 9.26mmol) was dissolved in 1,4-Dioxane (18.515mL) before adding dropwise 37% hydrogen chloride (3.86mL, 46.29mmol) (cone HCI). The mixture was heated to 101 °C and stirred overnight. The reaction was cooled to room temperature, diluted with water (200 mL) and the solid precipitate collected by vacuum titration over filter paper, filter paper washed with water (2x10 mL) and solid precipitate dried under vacuum to afford 4-chloro-6-fluoro-1 H-quinolin-2- one (1717.3mg, 8.6912mmol, 94% yield) as an off-white solid.

UPLC-MS (ES+, Method 2): 1.39 min, m/z 197.9 [M+H]⁺.

Step B, 4-chloro-6-fluoro-1-(methoxymethyl)quinolin-2-one. Potassium carbonate (1801.77mg, 13.04mmol) was added to a solution of Bromomethyl methyl ether (1.06mL, 13.04mmol) and 4-chloro-6-fluoro-quinolin-2-ol (1717.3mg, 8.69mmol) in DMF (17.382mL). The reaction was heated to 70°C and stirred for 30 min. Additional Bromomethyl methyl ether (2.13mL, 26.07mmol) was added and the reaction stirred for a further 90 mins. The mixture was cooled to room temperature, diluted with water (150 mL) and solid precipitate collected by vacuum filtration over filter paper. Solid precipitate washed with water (2x10 mL) and dried under vacuum to afford 4-chloro-6-fluoro-1-(methoxymethyl)quinolin-2-one (2100.2mg, 8.6911 mmol, 100% yield) as a white solid.

UPLC-MS (ES+, Method 5): 1.63 min, m/z 241 .9 [M+H]⁺.

Step C, 6-fluoro-4-hydroxy-1-(methoxymethyl)quinolin-2-one. (2'-amino-2- biphenylyl)palladium(1 +) methanesulfonate - bis(2-methyl-2-propanyl)(2',4',6'-triisopropyl-3,6- dimethoxy-2-biphenylyl)phosphine (1 :1 :1) (111.39mg, 0.13mmol) was added to a nitrogen degassed suspension of 4-chloro-6-fluoro-1-(methoxymethyl)quinolin-2-one (2100.2mg, 8.69mmol) and Potassium hydroxide (975.24mg, 17.38mmol) in a mixture of 1,4-Dioxane (40mL) and Water (20mL). Allowed to stir at 100°C for 15 min. Allowed to cool back down to room temperature. Partitioned between a layer of ethyl acetate (40 mL) and water (40 mL). Organic layer discarded and aqueous layer acidified to ~pH2 with 2M HCI (aq). The solid precipitate was collected by vacuum filtration. The solid precipitate was washed with water (2x10mL) and dried under vacuum to afford 6-fluoro-4-hydroxy-1-(methoxymethyl)quinolin-2- one (1274.3mg, 5.7092mmol, 66% yield) as a white solid.

UPLC-MS (ES+, Method 2): 1.35 min, m/z 224.0 [M+H]⁺.

Step D, 6-fluoro-4-hydroxy-1-(methoxymethyl)-5-(2-triisopropylsilylethynyl)quinolin-2- one. Dichloro(p-cymene)ruthenium(ll) Dimer (349.63mg, 0.57mmol) was added to a nitrogen degassed suspension of 6-fluoro-4-hydroxy-1-(methoxymethyl)quinolin-2-one (1274.3mg, 5.71 mmol), 2-bromoethynyl(triisopropyl)silane (1566.23mg, 5.99mmol) and Potassium acetate (1120.63mg, 11.42mmol) in 1,4-Dioxane (11.418mL). Afterwards, allowed to stir at 110°C for 1 h. Reaction mixture allowed to cool back down to room temperature and all volatiles removed under reduced pressure. Purification by flash column chromatography (eluting in 0-60% EtOAc in Pet. Ether) to afford 6-fluoro-4-hydroxy-1-(methoxymethyl)-5-(2- triisopropylsilylethynyl)quinolin-2-one (1542.4mg, 3.8219mmol, 67% yield) as an off-white solid.

UPLC-MS (ES+, Method 2): 2.30 min, m/z 404.6 [M+H]⁺.

Step E, [6-fluoro-1-(methoxymethyl)-2-oxo-5-(2-triisopropylsilylethynyl)-4-quinolyl] trifluoromethanesulfonate. At 0°C, Trifluoromethanesulfonic anhydride (0.14mL, 0.82mmol) was added to a solution of N,N-Diisopropylethylamine (0.32mL, 1.86mmol) and 6-fluoro-4- hydroxy-1-(methoxymethyl)-5-(2-triisopropylsilylethynyl)quinolin-2-one (300. mg, 0.74mmol) in DCM (7.4337mL). The mixture was stirred at room temperature for 1 h. Additional Trifluoromethanesulfonic anhydride (0.03mL, 0.19mmol) was added. And the reaction allowed to stir at room temperature for 10 min. Reaction mixture was diluted with ice-water (20 mL) and extracted with DCM (3 x 20 mL). Organic layers were combined, filtered over a hydrophobic frit and concentrated under reduced pressure. Purification by flash column chromatography (eluting with 0-40% EtOAc in Pet. Ether) to afford [6-fluoro-1- (methoxymethyl)-2-oxo-5-(2-triisopropylsilylethynyl)-4-quinolyl] trifluoromethanesulfonate (205.9mg, 0.3844mmol, 52% yield) as a clear oil.

UPLC-MS (ES+, Method 2): 2.65 min, m/z 536.0 [M+H]⁺.

Step F, 6-fluoro-1-(methoxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(2- triisopropylsilylethynyl)quinolin-2-one (A-16). [6-fluoro-1-(methoxymethyl)-2-oxo-5-(2- triisopropylsilylethynyl)-4-quinolyl] trifluoromethanesulfonate (205.9mg, 0.38mmol), Potassium acetate (94.32mg, 0.96mmol) and Bis(pinacolato)diboron (146.42mg, 0.58mmol) in Toluene (3.8441 mL) were degassed with nitrogen and [1 ,1'- Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (31.39mg, 0.04mmol) was then added. The reaction mixture was heated to 100°C and left to stir for 90 mins. Reaction mixture allowed to cool back down to room temperature. Diluted with ethyl acetate (20 mL), filtered over a celite plug, plug washed with ethyl acetate (2x10 mL), filtrate collected and concentrated under reduced pressure. Purification by flash column chromatography (eluting with 0-40% EtOAc in petroleum ether) to afford 6-fluoro-1- (methoxymethyl)-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-5-(2- triisopropylsilylethynyl)quinolin-2-one (64.7mg, 0.1260mmol, 33% yield) as a yellow solid. UPLC-MS (ES+, Method 2): 2.65 min, m/z 514.0 [M+H]⁺.

Intermediate A-17, [1 -[[bis(trideuteriomethyl)amino]methyl]cyclopropyl]methanol. Intermediate Scheme 14

Step A, methyl 1-[bis(trideuteriomethyl)carbamoyl]cyclopropanecarboxylate. To a solution of cyclopropane-1 ,1 -dicarboxylic acid methyl ester (500. mg, 3.47mmol) in dichloromethane (3.5mL) at 0°C was added N,N-dimethylformamide (0.003mL, 0.03mmol) and oxalyl chloride (0.38mL, 4.44mmol). The reaction mixture was stirred for 3 hrs at room temperature then was evaporated in vacuo. The residue was dissolved in dichloromethane (15mL and cooled to 0°C before adding triethylamine (0.97mL, 6.94mmol) and dimethyl-d6- amine hydrochloride (303.82mg, 3.47mmol). The reaction mixture was stirred for 3 days then was diluted with dichloromethane. The organic phase was washed with brine, filtered through a phase separator and evaporated to dryness to afford methyl 1- [bis(trideuteriomethyl)carbamoyl]cyclopropanecarboxylate (518mg, 2.9228mmol, 84.25% yield) as an orange oil.

UPLC-MS (ES+, Method 5): 0.97 min, m/z 178.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 3.73 (s, 3H), 1.52 - 1.46 (m, 2H), 1.37 - 1.31 (m, 2H).

Step B, [1-[[bis(trideuteriomethyl)amino]methyl]cyclopropyl]methanol (A-17). To a solution of methyl 1-[bis(trideuteriomethyl)carbamoyl]cyclopropanecarboxylate (518. mg, 2.92mmol) in dry THF (5mL) under nitrogen at 0°C was added lithium aluminium hydride 2.4M in THF (2.68mL, 6.43mmol). The reaction mixture was stirred at room temperature for 1.5 hrs then was cooled to 0°C. One tea spoon of sodium sulfate decahydrate was carefully added and the mixture was left to stir for 30 mins. One more teaspoon of sodium sulfate decahydrate was carefully added and the reaction mixture was stirred for 10 mins. The insoluble were removed by filtration and washed with EtOAc. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (eluting with EtOAc in petroleum ether then with 20% IN NH3 methanol in dichloromethane solution) to afford [1- [[bis(trideuteriomethyl)amino]methyl]cyclopropyl]methanol (137mg, 1.013mmol, 34.66% yield) as a light yellow transparent oil.

UPLC-MS (ES+, Method 5): 0.25-0.55 min, m/z no mass [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 4.94 - 3.63 (br s, 1 H), 3.54 (s, 2H), 2.42 (s, 2H), 0.53 - 0.47 (m, 2H), 0.38 - 0.33 (m, 2H).

Intermediate A-18, [1 -[(3,3-dimethylazetidin-1-yl)methyl]cyclopropyl]methanol.

A-18

A-18 was made by analogy with A-17 (Intermediate Scheme 14), replacing dimethyl-d6-amine hydrochloride in step A with 3,3-dimethylazetidine;hydrochloride.

UPLC-MS (ES⁺, Method 5): 0.32 min, m/z 170.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ/ppm: 3.47 (s, 2H), 4.00 (s, 4H), 2.54 (s, 2H), 1.17 (s, 6H), 0.39 - 0.30 (m, 4H).

Intermediate B-1 , 7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaene-11 ,13-diol.

Intermediate Scheme 15

Step A, methyl 4-(tert-butoxycarbonylamino)pyridine-3-carboxylate. A solution of methyl 4-aminonicotinate (2 g, 13.1 mmol) and DMAP (200 mg, 1.64 mmol) in DCM (40 mL) was cooled to 0°C and triethylamine (3.66 mL, 26.3 mmol) was added followed by di-tert-butyl dicarbonate (3.16 g, 14.46 mmol). The reaction mixture was warmed to room temperature and stirred for 3 hrs. Dichloromethane was added and the reaction mixture was washed with water then brine, passed through phase separator filter paper and evaporated to dryness to afford methyl 4-(tert-butoxycarbonylamino)pyridine-3-carboxylate (3.63 g, 100% yield) as a beige solid, the crude product was used without further purification.

UPLC-MS (ES⁺, Method 5): 1.66 min, m/z 253.1 [M+H]⁺.

Step B, methyl 1-amino-4-(tert-butoxycarbonylamino)pyridin-1-ium-3- carboxylate;2,4,6-trimethylbenzenesulfonate. To a solution of methyl 4-(tert- butoxycarbonylamino)pyridine-3-carboxylate (400 mg, 1 .59 mmol) in DCM (1 mL) at 0°C was added a solution of amino 2,4,6-trimethylbenzenesulfonate (682.7 mg, 3.17 mmol) in DCM (2.5 mL). The reaction mixture was stirred at 0°C for 3 hrs then warmed to room temperature and stirred overnight. The reaction mixture was quenched with diethyl ether. The resulting precipitate was collected, washed with ether and dried to afford methyl 1-amino-4-(tert- butoxycarbonylamino)pyridin-1-ium-3-carboxylate;2,4,6-trimethylbenzenesulfonate (681 mg, 92% yield) as a white solid.

UPLC-MS (ES⁺, Method 5): 1.38 min, m/z 268.0 [M+H]⁺.

Step C, dimethyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4- dicarboxylate. Potassium carbonate (603 mg, 4.37 mmol) was added to a mixture of methyl 1 -amino-4-(tert-butoxycarbonylamino)pyridin-1-ium-3-carboxylate;2,4,6- trimethylbenzenesulfonate (681 mg, 1.46 mmol) in DMF (10 mL) at 0°C. After 5 minutes, methyl propiolate (0.14 mL, 1.6 mmol) was added, the reaction mixture was then warmed to room temperature and stirred for 2 days. The reaction mixture was poured over ice and the aqueous phase was extracted with ethyl acetate (3x). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography eluting 0-50% EtOAc in petroleum etherto afford dimethyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (203.8 mg, 40% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 2.01 min, m/z 350.1 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 9.32 (s, 1 H), 8.90 (d, J=7.66 Hz, 1 H), 8.39 (s, 1 H), 7.68 (d, J=7.63 Hz, 1 H), 3.79 (s, 3H), 3.75 (s, 3H), 1.49 (s, 9H).

Step D, dimethyl 5-(tert-butoxycarbonylamino)-7-iodo-pyrazolo[1,5-a]pyridine-3,4- dicarboxylate. To a solution of dimethyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine- 3,4-dicarboxylate (200 mg, 0.57 mmol) in THF (20 mL) was added dropwise a solution of 2,2,6,6-tetramethylpiperidinyl magnesium chloride LiCI complex (2.4 mL, 2.4 mmol) at -78 °C. after 5hrs, a solution of iodine (435 mg, 1 .72 mmol) in THF (2 mL) was added dropwise and the reaction slowly warmed to 25 °C and stirred until completion. The reaction mixture was quenched with an aqueous saturated Na₂SO₃ solution (50 mL and extracted with EtOAc (3 x 50 mL). The organic phase was then dried over Na₂SO₄, filtered and concentrated in vacuo. The material was purified via flash chromatography eluting 0-30% EtOAc in petroleum ether, like fractions were combined and concentrated to yield dimethyl 5-(tert-butoxycarbonylamino)- 7-iodo-pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (100 mg, 0.2104 mmol, 37% yield) as a white oily solid.

UPLC-MS (ES⁺, Method 5): 2.22 min, m/z 475.9 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 9.30 (s, 1 H), 8.45 (s, 1 H), 8.25 (s, 1 H), 3.78 (s, 3H), 3.76 (s, 3H), 1.49 (s, 9H).

Step E, dimethyl 5-amino-7-iodo-pyrazolo[1,5-a]pyridine-3,4-dicarboxylate. Dimethyl 5- (tert-butoxycarbonylamino)-7-iodo-pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (100 mg, 0.21 mmol) was dissolved in DCM (2 mL) and trifluoroacetic acid (2 mL, 26.12 mmol) and stirred for 2 hrs at room temperature. Concentration of the mixture under reduced pressure was followed by re-dissolution in DCM (100 mL), washing with saturated sodium bicarbonate, drying over sodium sulfate, and concentration under reduced pressure yielded dimethyl 5- amino-7-iodo-pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (83 mg, 100% yield) as a yellow oil. UPLC-MS (ES⁺, Method 5): 1.58 min, m/z 375.9 [M+H]⁺.

Step F, dimethyl 7-iodo-5-[(2,2,2-trichloroacetyl)carbamoylamino]pyrazolo[1 ,5- a]pyridine-3,4-dicarboxylate. At room temperature to a stirred solution of dimethyl 5-amino- 7-iodo-pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (60 mg, 0.15 mmol) in THF (1.5 mL) was added trichloroacetyl isocyanate (25.7 μL, 0.22 mmol) dropwise. After 90 minutes the volatiles were removed in vacuo affording dimethyl 7-iodo-5-[(2,2,2- trichloroacetyl)carbamoylamino]pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (91 .mg, 100% yield) as a off white solid. The crude product was used in the next step without purification. UPLC-MS (ES+, Method 5): 1.98 min, m/z 564.8 [M+H]⁺.

Step G, methyl 11 ,13-dihydroxy-7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1 (9),2,4,7,10,12-hexaene-3-carboxylate. 7M Ammonia in MeOH (0.16 mL, 1.14 mmol) was added to a suspension of dimethyl 7-iodo-5-[(2,2,2- trichloroacetyl)carbamoylamino]pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (128 mg, 0.23 mmol) in methanol (1 mL) at room temperature. Afterwards, the solution was heated to 60°C for 3hrs. All volatiles were removed under reduced pressure. The residue was washed with diethyl ether (10 mL), the white solid collected by filtration and dried under reduced pressure to afford methyl 1 1 ,13-dihydroxy-7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene-3-carboxylate (93 mg, 100% yield) as a white solid.

UPLC-MS (ES⁺, Method 5): 1.33 min, m/z 386.9 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 8.32 (s, 1 H), 7.34 (s, 1 H). 3.74 (s, 3H).

Step H, 7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene- 11 ,13-diol (B-1). Methyl 1 1 ,13-dihydroxy-7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene-3-carboxylate (93 mg, 0.24 mmol) was suspended in water (1 mL) and cooled to 0°C before the addition of sulfuric acid (1 mL, 18.76 mmol). The reaction was then heated to 100 °C for 2hrs, the reaction was then cooled to 0°C and adjusted to pH 2 via addition of aqueous NaOH solution (6M), solids were filtered and washed with water then dried at 50°C under vacuum, to afford 7-iodo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene-11 ,13-diol (35mg, 44.29% yield) as an off white solid.

UPLC-MS (ES⁺, Method 5): 1.28 min, m/z 328.9 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 8.04 (m, 1 H), 7.23 (s, 1 H), 7.18 (m, 1 H).

Intermediate B-2, 7-bromo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaene-11 ,13-diol.

Intermediate Scheme 16

Step A, O3-tert-butyl O4-methyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine- 3,4-dicarboxylate. Potassium carbonate (14 g, 101 mmol) was added to a mixture of methyl 1-amino-4-(tert-butoxycarbonylamino)pyridin-1-ium-3-carboxylate;4- methylbenzenesulfonate (14.87 g, 33.84 mmol) in DMF (100 mL) at 0°C. After 5 minutes, propiolic acid tert-butyl ester (5.11 mL, 37.22 mmol) was added, the reaction mixture was then warmed to room temperature and stirred for 2 days, The reaction mixture was poured over ice and the aqueous phase was extracted with EtOAc (x3). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography eluent 0-40% EtOAc in petroleum ether. Like fractions were collected, evaporated to dryness to afford O3-tert-butyl O4-methyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (6.2 g, 46 % yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 2.25 min, m/z 392.1 [M+H]⁺.

Step B, O3-tert-butyl O4-methyl 7-bromo-5-(tert-butoxycarbonylamino)pyrazolo[1,5- a]pyridine-3,4-dicarboxylate. A solution of O3-tert-butyl O4-methyl 5-(tert- butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (800 mg, 1.33 mmol) in THF (10 mL) was cooled at -78°C and 2,2,6, 6-tetramethylpiperidinyl magnesium chloride LiCI complex (5.58 mL, 5.58 mmol) was added. After 5 hours at -78°C, a solution of 1 ,2- dibromotetrachloroethane (648.92 mg, 1 .99 mmol) in THF (5 mL) was added and the reaction mixture was warmed to room temperature and stirred overnight. The reaction mixture was quenched with sat. aq. NH₄CI and extracted with ethyl acetate (3x). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography (25g column, dry loaded, eluent ethyl acetate in petroleum ether 0-15%) to afford O3-tert-butyl O4-methyl 7-bromo-5-(tert- butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (421 mg, 67% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 2.41 min, m/z 470.0/472.0 [M+H]⁺.

Step C, methyl 5-amino-7-bromo-pyrazolo[1,5-a]pyridine-4-carboxylate. O3-tert-butyl O4-methyl 7-bromo-5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3,4-dicarboxylate (421 mg, 0.9 mmol) was dissolved in trifluoroacetic acid (13.71 mL, 179.03 mmol) and heated to 60°C for 90 min, concentrated in vacuo, redissolved in EtOAc and washed with saturated aqueous sodium bicarbonate then brine, organic layers passed through phase separator and concentrated to yield methyl 5-amino-7-bromo-pyrazolo[1,5-a]pyridine-4-carboxylate (248mg, 100% yield) as a white solid.

UPLC-MS (ES⁺, Method 2): 1 .52 min, m/z 269.8/271 .8 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 7.82 (d, J=2.07 Hz, 1 H), 7.55 (b s, 2H), 7.08 (s, 1 H), 6.76 (d, J=2.08 Hz, 1 H), 3.84 (s, 3H).

Step D, methyl 7-bromo-5-[(2,2,2-trichloroacetyl)carbamoylamino]pyrazolo[1,5- a]pyridine-4-carboxylate. To a stirred solution of methyl 5-amino-7-bromo-pyrazolo[1 ,5- a]pyridine-4-carboxylate (3.88 g, 14.37 mmol) in THF (100 mL) was added trichloroacetyl isocyanate (2.4 mL, 20.11 mmol) dropwise. After 90 min the volatiles were removed in vacuo. The crude product was used in the next step without purification assuming quantitative yield. O4-ethyl O6-methyl 9-iodo-1-methyl-7-[(2,2,2- trichloroacetyl)carbamoylamino]diazonine-4,6-dicarboxylate (91 .5mg).

UPLC-MS (ES⁺, Method 5): 1.94 min, m/z 458.8 [M+H]⁺.

Step E, 7-bromo-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene- 11 ,13-diol (B-2). 7M Ammonia in MeOH (0.65 mL, 4.58 mmol) was added to a suspension of methyl 7-bromo-5-[(2,2,2-trichloroacetyl)carbamoylamino]pyrazolo[1,5-a]pyridine-4- carboxylate (420 mg, 0.92 mmol) in methanol (5 mL) at room temperature. Afterwards, heated to 60°C for 3hrs. All volatiles were removed under reduced pressure. The residue was washed with diethyl ether (10 mL) and precipitate was collected by filtration and dried under reduced pressure to afford 7-bromo-5,6, 10,12-tetrazatricyclo[7.4.0.02, 6]trideca- 1(9),2,4,7,10,12-hexaene-11 ,13-diol (251 mg, 97% yield) as a white solid.

UPLC-MS (ES⁺, Method 5): 1.15 min, m/z 282.8 [M+H]⁺.

Intermediate B-3, 7-bromo-13-chloro-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene.

Intermediate Scheme 17

Step A, tert-butyl N-(4-pyridyl)carbamate. Di-tert-butyl dicarbonate (1.27 g, 5.8 mmol) was added to a mixture of 4-aminopyridine (496 mg, 5.27 mmol) and triethylamine (0.88 mL, 6.32 mmol) in DCM (13 mL). The reaction mixture was stirred at room temperature for 1 hr and was then evaporated to dryness. The residue was purified by flash column chromatography eluting 0-10% MeOH in DCM to afford tert-butyl N-(4-pyridyl)carbamate (1.02g, 99% yield) as a white solid.

UPLC-MS (ES⁺, Method 5): 1.15 min, m/z 195.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 9.81 (s, 1 H), 8.34 (d, J = 6.2 Hz, 2H), 7.42 (d, J = 6.2 Hz, 2H), 1.49 (s, 9H).

Step B, tert-butyl N-(1-aminopyridin-1-ium-4-yl)carbamate;2,4-dinitrophenolate. To a solution of tert-butyl N-(4-pyridyl)carbamate (1 .02 g, 5.25 mmol) in MeCN (25 mL) was added O-(2,4-dinitrophenyl)hydroxylamine (1.05 g, 5.25 mmol). The reaction mixture was heated at 40 °C overnight. The reaction mixture was evaporated to dryness and the crude material was used directly in the next step.

UPLC-MS (ES⁺, Method 5): 1.11 min, m/z 210.0 [M+H-phenolate]⁺

Step C, tert-butyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3-carboxylate. Potassium carbonate (2.18 g, 15.75 mmol) was added to a solution of tert-butyl N-(1- aminopyridin-1-ium-4-yl)carbamate;2,4-dinitrophenolate (2.07 g, 5.25 mmol) in DMF (15 mL) at room temperature. Propiolic acid tert-butyl ester (1 mL, 7.28 mmol) was then added and the reaction mixture was stirred overnight. The reaction mixture was poured over ice and the aqueous phase was extracted with EtOAc (3x). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography eluting 0-50% EtOAc in petroleum ether to afford tert-butyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3-carboxylate (760 mg, 43.5% yield) as an orange solid.

UPLC-MS (ES⁺, Method 5): 2.07 min, m/z 334.0 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.00 (s, 1 H), 8.68 (d, J = 7.5 Hz, 1 H), 8.35 (s, 1 H), 8.21 (s, 1 H), 7.08 (d, J = 7.6 Hz, 1 H), 1.56 (s, 9H), 1.51 (s, 9H).

Step D, tert-butyl 7-bromo-5-(tert-butoxycarbonylamino)pyrazolo[1 ,5-a]pyridine-3- carboxylate. To a solution of tert-butyl 5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine- 3-carboxylate (500 mg, 1.5 mmol) in THF (6 mL) was added dropwise a solution of 2, 2,6,6- tetramethylpiperidinyl magnesium chloride LiCI complex (6 mL, 6 mmol) at -78°C. After 5 hrs, a solution of 1 ,2-dibromotetrachloroethane (733 mg, 2.25 mmol) in THF (5 mL) was added and the reaction slowly warmed to 25 °C and stirred overnight. The reaction mixture was quenched with aqueous saturated NH₄CI solution and extracted with DCM (x3). The organic phase was washed with brine, then passed through a phase separator and concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting 0-40% EtOAc in petroleum ether to afford tert-butyl 7-bromo-5-(tert-butoxycarbonylamino)pyrazolo[1,5- a]pyridine-3-carboxylate (374mg, 61 % yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 2.23 min, m/z 414.0 [M+H]⁺.

Step E, N-(7-bromopyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoro-acetamide. A solution of tert-butyl 7-bromo-5-(tert-butoxycarbonylamino)pyrazolo[1,5-a]pyridine-3-carboxylate (533 mg, 1 .29 mmol) in trifluoroacetic acid (5 mL, 65.29 mmol) was heated to 70°C for 48 hrs. Further trifluoroacetic acid (4 mL, 52.24 mmol) was added and the reaction was stirred overnight at 70°C. The reaction mixture was cooled down and evaporated to dryness. The residue was partitioned between DCM and aqueous Na₂CO₃ solution and extracted with DCM (x3). The organic phase was washed with brine then passed through a phase separator and evaporated to dryness to afford N-(7-bromopyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoro- acetamide (420mg, 100% yield) as a brown oil. Material was used crude without further purification.

UPLC-MS (ES⁺, Method 5): 1.66 min, m/z 309.8 [M+H]⁺.

Step F, 7-bromopyrazolo[1 ,5-a]pyridin-5-amine. A stirring solution of N-(7- bromopyrazolo[1,5-a]pyridin-5-yl)-2,2,2-trifluoro-acetamide (400 mg, 1 .3 mmol) and potassium carbonate (538 mg, 3.9 mmol) in methanol (4 mL) and water (1 mL) was stirred at room temperature over the weekend. The reaction mixture was then heated to 70°C for 3.5 hrs. The reaction was concentrated to dryness and the residue was partitioned between DCM and water. The aqueous layer was extracted with DCM (x3). The organic phase was washed with brine, passed through a phase separator and concentrated under reduced pressure. The residue was then purified by flash column chromatography eluting 0-70% EtOAc in petroleum ether to afford 7-bromopyrazolo[1,5-a]pyridin-5-amine (167 mg, 60.6% yield) as an orange solid.

UPLC-MS (ES⁺, Method 5): 1.13 min, m/z 213.9 [M+H]⁺.

Step G, ethyl N-[(7-bromopyrazolo[1 ,5-a]pyridin-5-yl)carbamothioyl]carbamate. Ethoxycarbonyl isothiocyanate (91.77 μL, 0.78 mmol) was added to a solution of 7- bromopyrazolo[1,5-a]pyridin-5-amine (165 mg, 0.78 mmol) in DCM (4 mL) and the reaction mixture was stirred at room temperature overnight. The reaction mixture was evaporated to dryness to afford ethyl N-[(7-bromopyrazolo[1,5-a]pyridin-5-yl)carbamothioyl]carbamate (265 mg, 99% yield). The material was used without further purification.

UPLC-MS (ES⁺, Method 5): 1.73 min, m/z 344.9 [M+H]⁺.

Step H, ethyl (N-Z)-N-[[(7-bromopyrazolo[1,5-a]pyridin-5-yl)amino]-ethylsulfanyl- methylene]carbamate. To a suspension of ethyl N-[(7-bromopyrazolo[1,5-a]pyridin-5- yl)carbamothioyl]carbamate (260 mg, 0.76 mmol) in acetone (4 mL) was added potassium carbonate (314.1 mg, 2.27 mmol) followed by iodoethane (60.91 μL, 0.76 mmol) . The reaction mixture was stirred at room temperature for 3 hrs and was then evaporated to dryness. The crude was dissolved in EtOAc and the organic phase was washed with water then brine, passed through phase separator and evaporated to dryness to afford ethyl (N-Z)-N-[[(7- bromopyrazolo[1,5-a]pyridin-5-yl)amino]-ethylsulfanyl-methylene]carbamate (300 mg, 100% yield) as an orange solid. The material was used without further purification.

UPLC-MS (ES⁺, Method 5): 1.88 min, m/z 373.0 [M+H]⁺.

Step I, 7-bromo-11-ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02, 6]trideca-

1(9),2,4,7,10-pentaen-13-one (B-3’). A solution of ethyl (N-Z)-N-[[(7-bromopyrazolo[1,5- a]pyridin-5-yl)amino]-ethylsulfanyl-methylene]carbamate (280 mg, 0.75 mmol) in NMP (1.5 mL) was heated to 175 °C for 50 minutes. The reaction mixture was cooled down and water was added. After stirring for 15 minutes at 0°C, the formed precipitate was collected, washed with water and dried in a vacuum oven to afford 7-bromo-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10-pentaen-13-one (230 mg, 94% yield) as a brown solid.

UPLC-MS (ES⁺, Method 5): 1.71 min, m/z 326.9 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 13.15 (s, 1 H), 8.22 (d, J = 2.1 Hz, 1 H), 7.39 (s, 1 H), 7.35 (d, J = 2.1 Hz, 1 H), 3.23 (q, J = 7.3 Hz, 2H), 1 .36 (t, J = 7.3 Hz, 3H).

Step J, 7-bromo-13-chloro-11-ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene (B-3). A suspension of 7-bromo-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-ol (230. mg, 0.71 mmol) in phosphorus oxychloride (2 mL, 21 .46 mmol) was heated to 80°C for 30 minutes. The reaction was concentrated to dryness and the residue was partitioned between DCM and aqueous Na₂CO₃. The aqueous layer was extracted with DCM (x3). The organic phase was washed with brine, passed through a phase separator and concentrated under reduced pressure to afford 7-bromo-13-chloro-11-ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene (217mg, 89% yield) as a brown solid. Material was used without further purification.

UPLC-MS (ES⁺, Method 5): 2.26 min, m/z 342.9/344.9/346.9 [M+H]⁺.

Intermediate B-4, 7-bromo-13-chloro-11-ethylsulfanyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaene.

B-4 was made by analogy with B-3 (Intermediate Scheme 17), replacing 4-aminopyridine as the starting material in step A with 3-methyl-4-aminopryridine.

UPLC-MS (ES⁺, Method 5): 2.40 min, m/z 358.8 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.13 (d, J = 2.2 Hz, 1 H), 7.63 (d, J = 2.2 Hz, 1 H), 3.28 (q, J = 7.4 Hz, 2H), 2.76 (s, 3H), 1 .49 (t, J = 7.4 Hz, 3H).

Intermediate B-4’,. 7-bromo-11-ethylsulfanyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol.

B-4’ was made by analogy with B-3’ (Intermediate Scheme 17), replacing 4-aminopyridine as the starting material in step A with 3-methyl-4-aminopryridine and stopping after step I. UPLC-MS (ES⁺, Method 2): 1 .70 min, m/z 339.0/341 .9 [M+H]⁺.

Intermediate B-5, 7-bromo-13-chloro-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene

B-5 was made by analogy with B-3 (Intermediate Scheme 17), replacing 4-aminopyridine as the starting material in step A with 3-fluoro-4-aminopyridine.

UPLC-MS (ES⁺, Method 5): 2.26 min, m/z 361/363 [M+H]⁺.

Intermediate B-5‘, 7-bromo-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9), 2, 4, 7,10-pentaen-13-one.

B-5’ was made by analogy with B-3’ (Intermediate Scheme 17), replacing 4-aminopyridine as the starting material in step A with 3-fluoro-4-aminopyridine and stopping after step I. UPLC-MS (ES⁺, Method 2): 1.63 min, m/z 343.0/344.9 [M+H]⁺.

Intermediate B-6, 7-bromo-11-ethylsulfanyl-4-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol.

B-6

B-6 was made by analogy with B-3 (Intermediate Scheme 17), replacing starting material methyl propiolate with ethyl 2-butynote in step B/C and stopping after step I.

UPLC-MS (ES⁺, Method 2): 1 .64 min, m/z 341 .0 [M+H]⁺.

Intermediate B-7, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl- 8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol.

Step A, tert-butyl N-[2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-3-methyl-4- pyridyl]carbamate. A solution of tert-Butyl (2-chloro-3-methylpyridin-4-yl)carbamate (300. mg, 1.24mmol), 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (534.33mg, 1.48mmol) and potassium carbonate (341.67mg, 2.47mmol) in 1,4-dioxane (6.1805mL) and water (2.0602mL) was degassed with nitrogen gas for 2 min. Tetrakis(triphenylphosphine)palladium(0) (285.68mg, 0.25mmol) was added and the reaction mixture was allowed to stir at 100°C overnight. The reaction mixture was cooled down to room temperature and diluted with ethyl acetate (20 mL), then filtered over a celite plug, which was washed with ethyl acetate (2x10 mL). Water was added to the filtrate and both phases were partitioned. The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was then purified by flash column chromatography on silica gel eluting with 0-50% EtOAc in petroleum ether to afford tert-butyl N-[2- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-3-methyl-4-pyridyl]carbamate (537mg,

1.219mmol, 98.618% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 1 .64 min, m/z 441 .6 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.42 (d, J = 5.7 Hz, 1 H), 8.12 (d, J = 5.7 Hz, 1 H), 7.64 (dd, J = 9.0, 5.9 Hz, 1 H), 7.43 (d, J = 2.7 Hz, 1 H), 7.22 (appt t, J = 9.3 Hz, 1 H), 7.00 (d, J = 2.7 Hz, 1 H), 6.58 (s, 1 H), 5.30 (d, J = 6.7 Hz, 1 H), 5.24 (d, J = 6.7 Hz, 1 H), 3.50 (s, 3H), 2.42-2.28 (m, 1 H), 2.20-2.08 (m, 1 H), 1.96 (s, 3H), 1.57 (s, 9H), 0.81 (t, J = 7.4 Hz, 3H).

Step B/C, methyl 5-(tert-butoxycarbonylamino)-7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1 ,5-a]pyridine-3-carboxylate. To a solution of tert-butyl N-[2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-3-methyl-4- pyridyl]carbamate (537. mg, 1.22mmol) in MeCN (6.0951 mL) was added O-(2,4- Dinitrophenyl)hydroxylamine (303.41 mg, 1 .52mmol). The reaction mixture was heated to 40°C overnight. The reaction mixture was cooled down to room temperature. Potassium carbonate (336.95mg, 2.44mmol) and methyl propiolate (0.2mL, 2.19mmol) were added. The reaction mixture allowed to stir at room temperature for 3hrs. Additional methyl propiolate (0.2mL, 2.19mmol) was added and the reaction mixture was stirred at room temperature overnight. The reaction mixture was partitioned between ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined, washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 10-60% EtOAc in petroleum ether to afford methyl 5-(tert-butoxycarbonylamino)-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1 -naphthyl]-6-methyl-pyrazolo[1,5-a]pyridine-3-carboxylate (380mg, 0.7069mmol, 57.986% yield) as an orange oil.

UPLC-MS (ES⁺, Method 2): 2.14 min, m/z 538.5 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.89 (s, 1 H), 8.21 (s, 1 H), 7.71 (dd, J = 8.9, 5.9 Hz, 1 H), 7.58 (d, J = 2.9 Hz, 1 H), 7.30-7.21 (m, 1 H), 7.09 (d, J = 2.8 Hz, 1 H), 6.60-6.53 (m, 1 H), 5.33-5.25 (m, 2H), 3.93 (s, 3H), 3.52 (s, 3H), 2.39-2.21 (m, 1 H), 2.00 (s, 3H), 1.99-1.85 (m, 1 H), 1 .59 (s, 9H), 0.55 (t, J = 7.5 Hz, 3H).

Step D, 5-amino-7-[ 8-ethyl-7-fluoro-3- naphthyl]-6-methyl-pyrazolo[1 ,5-a]pyridine-3-carboxylic acid. A suspension of methyl 5-(tert- butoxycarbonylamino)-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthyl]-6-methyl- pyrazolo[1,5-a]pyridine-3-carboxylate (330. mg, 0.61 mmol) and sodium hydroxide (122.77mg, 3.07mmol) in1,4-dioxane (8.32mL) and water (4.16mL) was heated to 100°C overnight. The reaction mixture was allowed to cool back down to room temperature and was partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was discarded, and the aqueous layer was acidified to ~pH2 with 2M HCI (aq). The aqueous layer was extracted with ethyl acetate (2 x 20 mL). The combined organic layers were washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-amino-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6- methyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (295.9mg, 0.6988mmol, 1 13.84% yield) as an orange oil.

UPLC-MS (ES⁺, Method 2): 1.67 min, m/z 424.4 [M+H]⁺.

¹H NMR (400 MHz, CDCI3 ) δ/ppm: 8.17 (s, 1H), 7.70 (dd, J = 9.1, 5.9 Hz, 1H), 7.57 (d, J = 2.7 Hz, 1H), 7.42 (s, 1H), 7.30-7.22 (m, 1H), 7.12 (d, J = 2.6 Hz, 1H), 5.35-5.25 (m, 2H), 4.30 (br s, 2H), 3.53 (s, 3H), 2.43-2.30 (m, 1H), 2.00-1.88 (m, 4H), 0.62 (t, J = 7.5 Hz, 3H).

Step E, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyn-6-methyl-pyrazolo[1,5-a]pyridin-5- amine. A suspension of 5-amino-7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl- pyrazolo[1,5-a]pyridine-3-carboxylic acid (259.93mg, 0.61mmol) in 1,2-dichlorobenzene (6.14mL) was allowed to stir at 150°C for lhr. The reaction mixture was cooled down to room temperature and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel eluting with 0-60% EtOAc in petroleum ether to afford 7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1,5-a]pyridin-5-amine (184.1 mg, 0.4852mmol, 79.04% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 1.77 min, m/z 380.5 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 7.71 -7.65 (m, 2H), 7.54 (d, J = 2.7 Hz, 1 H), 7.27-7.19 (m, 1 H), 7.16-7.12 (m, 1 H), 6.80 (s, 1 H), 6.22 (d, J = 2.2 Hz, 1 H), 5.28 (s, 2H), 3.89 (brs, 2H), 3.52 (s, 3H), 2.44-2.32 (m, 1 H), 2.00-1.88 (m, 4H), 0.57 (t, J = 7.5 Hz, 3H).

Step F, ethyl N-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1,5- a]pyridin-5-yl]carbamothioyl]carbamate. Ethoxycarbonyl isothiocyanate (57.22uL, 0.49mmol) was added to a solution of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1,5- a]pyridin-5-amine (184.1mg, 0.49mmol) in DCM (2.4259mL) and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was evaporated to dryness to afford crude ethyl N-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1,5-a]pyridin-5- yl]carbamothioyl]carbamate (247.73mg, 0.4852mmol, 100% yield) as a brown solid which was used directly in the next step.

UPLC-MS (ES⁺, Method 2): 2.01 min, m/z 511 .6 [M+H]⁺. Step G, ethyl (NZ)-N-[[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo [1 ,5-a]pyridin-5-yl]amino]-ethylsulfanyl-methylene]carbamate. To a suspension of ethyl N-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1 ,5- a]pyridin-5-yl]carbamothioyl]carbamate (247.73mg, 0.49mmol) in acetone (2.43mL) was added potassium carbonate (201 .17mg, 1.46mmol) followed by iodoethane (39.01 uL, 0.49mmol). The reaction mixture was stirred at room temperature for 3hrs. The reaction mixture was partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer extracted with ethyl acetate (20 mL). The combined organic layers were washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford ethyl (NZ)-N-[[[7- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1,5-a]pyridin-5- yl]amino]-ethylsulfanyl-methylene]carbamate (229.7mg, 0.4264mmol, 87.892% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 2.19 min, m/z 539.7 [M+H]⁺.

Step H, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-8-methyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (B-7). A solution of ethyl (NZ)-N-[[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-6-methyl-pyrazolo[1 ,5- a]pyridin-5-yl]amino]-ethylsulfanyl-methylene]carbamate (572.5mg, 1.06mmol) in DMF (10.63mL) was heated to 130°C for 1 hr. The reaction mixture was cooled down to room temperature. The reaction mixture was diluted with water (100 mL), allowed to stir at room temperature for 5 minutes and the precipitate was collected by vacuum filtration. The collected solid was washed with water (2 x 5 mL) and dried under vacuum to afford 7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (433.6mg, 0.8803mmol,

82.822% yield) as a brown solid. The filtrate was collected and extracted with ethyl acetate (2x20 mL). The organic layers were combined, washed with water (10 mL), a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11 -ethylsulfanyl-8- methyl-5,6, 10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9), 2, 4, 7, 10,12-hexaen-13-ol (64.7mg,

0.1314mmol, 12.358% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 2.06 min, m/z 493.7 [M+H]⁺.

Intermediate B-8, 11-ethylsulfanyl-8-fluoro -7-[3-(methoxymethoxy)-1-naphthyl]-

5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol

B-8 was made by analogy with B-7 (Intermediate Scheme 18), replacing starting materials tert-butyl N-(2-chloro-3-methyl-4-pyridyl)carbamate with tert-butyl N-(2-bromo-3-fluoro-4- pyridyl)carbamate and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolane with 2-(3-(2-methoxymethoxy)naphthalene-1-yl)-4,4,5,5- tetramethyl-1 ,3,2-dioxaborolane in step A.

UPLC-MS (ES⁺, Method 5): 2.14 min, m/z 497.1 [M+H]⁺.

Intermediate B-9, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl- 8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9), 2.4, 7,10,12-hexaen-13-ol.

B-9 was made by analogy with B-7 (Intermediate Scheme 18), replacing starting materials tert-butyl N-(2-chloro-3-methyl-4-pyridyl)carbamate with tert-butyl N-(-chloro-3-fluoro-4- pyridyl)carbamate in step A.

UPLC-MS (ES⁺, Method 5): 2.29 min, m/z 543.2 [M+H]⁺.

Intermediate B-10, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-11- methylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol

B-10 was made by analogy with B-7 (Intermediate Scheme 18), replacing starting materials tert-butyl N-(2-chloro-3-methyl-4-pyridyl)carbamate with tert-butyl N-(-chloro-3-fluoro-4- pyridyl)carbamate in step A, and iodoethane with iodomethane in step G.

UPLC-MS (ES⁺, Method 5): 2.02 min, m/z 483.0 [M+H]⁺. Intermediate B-11 , 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-4,8-dimethyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-ol

B-11

B-11 was made by analogy with B-7 (Intermediate Scheme 18), replacing starting material methyl propiolate with ethyl 2-butynote in step B/C.

UPLC-MS (ES⁺, Method 2): 2.20 min, m/z 539.6 [M+H]⁺.

Intermediate C-1 , 4-(7, 11 -dichloro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-y I) -1,4-oxazepane.

Intermediate Scheme 19

Step A, 4-(7, 11 -dichloro-5,6,10,12-tetrazatricyclo[7.4.0.02, 6]trideca-1(9),2,4,7,10,12- hexaen-13-yl)-1,4-oxazepane (C-1). Phosphorus oxychloride (0.91 mL, 9.75 mmol) was added to a suspension of 7-iodo-5, 6,10, 12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9), 2,4,7- tetraene-11 ,13-dione (200 mg, 0.61 mmol) in N,N-diisopropylethylamine (0.53 mL, 3.05 mmol). The reaction was heated to 90 °C overnight. The reaction was concentrated. DIPEA and toluene were added and the mixture was concentrated again. The crude was taken up in DMF (1.5 mL), N,N-diisopropylethylamine (0.42 mL, 2.44 mmol) and 1,4-oxazepane hydrochloride (92 mg, 0.67 mmol) were added. The reaction was stirred at room temperature for 2 hours. The reaction was partitioned between DCM and water. The aqueous layer was extracted with DCM (x3). The organic phase was washed with brine, passed through a phase separator and concentrated under reduced pressure. Purified by column chromatography 0- 60% EtOAc in petroleum ether 0-60%, like fractions were collected and concentrated to afford 4-(7,11 -dichloro-5,6,10,12-tetrazatricyclo[7.4.0.02, 6]trideca-1(9), 2, 4, 7, 10,12-hexaen-13-yl)- 1,4-oxazepane (171 mg, 3% yield).

UPLC-MS (ES⁺, Method 5): 1.80 min, m/z 338.0 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ/ppm: 8.31 (d, J=2.07 Hz, 1 H), 7.35 (s, 1 H), 6.98 (d, J=2.08 Hz, 1 H), 3.68-3.74 (m, 8H), 1.97-2.0 (m, 2H).

Table 4 describes intermediates that were made by analogy with C-1 (Intermediate Scheme 19), replacing 1,4-oxazepane hydrochloride with the appropriate building block and/or B-1 with the appropriate intermediate as outlined in the table.

Table 4 Intermediate D-1, 4-[7-chloro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6- methyl-1,4-oxazepan-6-ol.

Intermediate Scheme 20

Step A, 4-[7-chloro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4- oxazepan-6-ol (D-1). To a degassed mixture of anhydrous DMF (2 mL) and THF (5 mL) was added 4-(7,11-dichloro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen- 13-yl)-6-methyl-1,4-oxazepan-6-ol (654 mg, 1.07 mmol), ((2R,7aS)-2-fluorohexahydro-1 H- pyrrolizin-7a-yl)methanol (508.96 mg, 3.2 mmol), cesium carbonate (2.08 g, 6.39 mmol) and 1,4-diazabicyclo[2.2.2]octane (11.95 mg, 0.11 mmol). The reaction was stirred at 25°C overnight. The reaction was partitioned between EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc (3x). The combined organic extracts were dried and evaporated to afford a brown oil. This was purified via KP Amino coloumn (11g, 0-100% EtOAc in petroleum ether) to afford 4-[7-chloro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (82 mg, 15% yield) as a yellow transparent oil.

UPLC-MS (ES⁺, Method 5): 1.32 min, m/z 491.1 [M+H]⁺.

Table 5 describes intermediates that were made by analogy with D-1 (Intermediate Scheme 20), replacing ((2R,7aS)-2-fluorohexahydro-1 H-pyrrolizin-7a-yl)methanol with the appropriate building block and/or C-5 with the appropriate intermediate as outlined in the table.

Table 5

Intermediate D-6, 4-[7-chloro-11-[[(2R)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 1,4-oxazepane.

Intermediate Scheme 21

Step A 4-[7-chloro-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yI]-1,4-oxazepane (D-6). .A suspension of ((2R,7aS)-2-fluorohexahydro-1 H-pyrrolizin-7a-yl)methanol (88 mg, 0.56 mmol), cesium carbonate (494 mg, 1.52 mmol) and 4-(7,11-dichloro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-y I)- 1,4-oxazepane (171 mg, 0.51 mmol) in dry toluene (2 mL) was degassed with nitrogen for 5 mins. (+/-)-BINAP (37.8 mg, 0.06 mmol) and palladium (II) acetate (11.35 mg, 0.05 mmol) were then added, the mixture was then heated at 110°C for 1 hr. The mixture was diluted with EtOAc and filtered, and the filtrate concentrated. Crude residue was purified by flash chromatography 0-100% EtOAc in petroleum ether. Relevant fractions were pooled and concentrated to yield 4-[7- chloro-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yI]-1 ,4-oxazepane (55mg,

23.6% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 1 .28 min, m/z 461 .1 [M+H]⁺.

Intermediate E-1, tert-butyl 3-[7-bromo-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate Intermediate Scheme 22

Step A, tert-butyl 3-(7-bromo-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl) -3, 8- diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of 7-bromo-13-chloro-11- ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (217 mg, 0.63 mmol) and N,N-Diisopropylethylamine (330 uL, 1 .89 mmol) in DMF (3 mL) was added 8-Boc-3,8-diazabicyclo[3.2.1]octane (174 mg, 0.82 mmol). The reaction was stirred at room temperature for 1 .5 hrs. The reaction was partitioned between DCM and water. The aqueous layer was extracted with DCM (x3). The organic phase was washed with brine, passed through a phase separator and concentrated under reduced pressure. The residue was then purified by flash column chromatography eluting 0-100% EtOAc in petroleum ether to afford tert-butyl 3-(7-bromo-11-ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (330mg,100% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 2.37 min, m/z 519.0/521 .0 [M+H]⁺.

Step B, tert-butyl 3-(7-bromo-11-ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl) -3, 8- diazabicyclo[3.2.1]octane-8-carboxylate. To a solution of 4-bromo-9-chloro-7-ethylsulfanyl- 2,5-dimethyl-pyrazolo[4,3-f]quinazoline (1420 mg, 3.82 mmol) in DCM (38.3 mL) under N₂ was added m-chloroperbenzoic acid (2.175 g, 12.61 mmol). The reaction was stirred at 25°C for 2 hrs before adding further m-chloroperbenzoic acid, (328 mg, 1.91 mmol). The reaction was stirred over the weekend. The mixture was quenched with a solution of Na₂S2O₃, diluted with DCM and washed with aqueous saturated Na₂CO₃ and brine. The organic phase was passed through a phase separator and concentrated. The residue was then purified by flash column chromatography eluting 0-100% EtOAc in petroleum ether to afford tert-butyl 3-(7- bromo-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen- 13-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (216 mg, 61 % yield) as a yellow solid. UPLC-MS (ES⁺, Method 5): 1.93 min, m/z 552.9 [M+H]⁺.

Step C, tert-butyl 3-[7-bromo-11-[[(2R)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 3,8-diazabicyclo[3.2.1]octane-8-carboxylate (E-1). To a solution of ((2R,7aS)-2- fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (124 mg, 0.78 mmol) in THF (1.5 mL) under N₂ was added dropwise 1 M lithium bis(trimethylsilyl)amide in THF (0.98 mL, 0.98 mmol) at 0°C. The reaction mixture was stirred at this temperature for 20 min then tert-butyl 3-(7-bromo-11- ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (216 mg, 0.39 mmol) in THF (4 mL) was added. The reaction mixture was stirred at room temperature for 2 hrs. The mixture was quenched with water, extracted with DCM (x3), washed with brine, passed through a phase separator and evaporated. The residue was then purified by flash column chromatography eluting 0-7% MeOH in DCM to afford tert-butyl 3-[7-bromo-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (226 mg, , 93% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 1.67 min, m/z 616.2/618.1 [M+H]⁺.

Intermediate E-2, 4-[7-bromo-8-methyl-11- [[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl] -1,4-oxazepane

F

E-2 was made by anaology with tert-butyl 3-[7-bromo-11 -[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (Intermediate Scheme 22), replacing 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11 -hexaene (B-4) and 8-boc-3,8-diazabicyclo[3.2.1]octane with 1,4-oxazepane in step A.

UPLC-MS (ES⁺, Method 1): 1.30 min, m/z 519.1/521 .1 [M+H]⁺.

NMR (400 M Hz, CDCI₃) δ/ppm: 8.00 (d, J = 2.1 Hz, 1H), 6.72 (s, 1H), 5.39-5.19 (m, 1H), 4.28 (d, J = 10.3 Hz, 1H), 4.20-4.10 (m, 1H), 3.90-3.74 (m, 8H), 3.34-3.11 (m, 3H), 3.04-2.93 (m, 1H), 2.67 (s, 3H), 2.34-2.12 (m, 2H), 2.08-1.82(m, 6H).

Intermediate E-3, tert-butyl 3-[7-bromo-8-fluoro-11-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate

E-3 was made by analogy with tert-butyl 3-[7-bromo-1 1-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (E-1 ,

Intermediate Scheme 22), replacing 7-bromo-13-chloro-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-5) in step A.

UPLC-MS (ES⁺, Method 5): 1.71 min, m/z 634 [M+H]⁺.

Intermediate E-4, 5-[7-bromo-8-fluoro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a] [1,4]diazepine-2 -carboxamide

E-4 was made by analogy with tert-butyl 3-[7-bromo-1 1-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (Intermediate Scheme 22), replacing 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-5) and 8-boc-3,8-diazabicyclo[3.2.1 ]octane with N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (A-6) in step A.

UPLC-MS (ES⁺, Method 2): 1.22 min, m/z 630 [M+H]⁺. Intermediate E-5, 4-[7-bromo-8-fluoro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol

E-5 was made by analogy with tert-butyl 3-[7-bromo-1 1-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (Intermediate Scheme 22), replacing 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-5) and 8-boc-3,8-diazabicyclo[3.2.1]octane with 6-methyl-1,4-oxazepan-6-ol in step A. UPLC-MS (ES⁺, Method 2): 1.34 min, m/z 553 [M+H]⁺.

Intermediate E-6, (3R)-1-[7-bromo-8-methyll-1-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4.7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol.

E-6 was made by analogy with tert-butyl 3-[7-bromo-11 -[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (Intermediate Scheme 22), replacing 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11 -hexaene (B-4) and 8-boc-3,8-diazabicyclo[3.2.1]octane with (R)-3-methylpiperidin-3-ol hydrochloride in step A.

UPLC-MS (ES⁺, Method 2): 1.34 min, m/z 535.2 [M+H]⁺. ¹H NMR (400 MHz, CDCI₃) δ/ppm: 8.02 (d, J = 2.0 Hz, 1H), 6.76 (br s, 1H), 5.50-5.11 (m, 2H), 4.39-4.03 (m, 2H), 3.72-3.61 (m, 1H), 3.35-3.04 (m, 6H), 3.03-2.89 (m, 1H), 2.68 (s, 3H), 2.34-1.69 (m, 8H), 1.66- 1.47 (m, 2H), 1.30 (s, 3H).

Intermediate E-7, 5-[7-bromo-8-methyl-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-N,N- dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide.

E-7 was made by analogy with tert-butyl 3-[7-bromo-11 -[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (Intermediate Scheme 22), replacing 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (B-3) with 7-bromo-13-chloro-11- ethylsulfanyl-8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11 -hexaene (B-4) and 8-boc-3,8-diazabicyclo[3.2.1 ]octane with N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide (A-6) in step A.

UPLC-MS (ES⁺, Method 2): 1.28 min, m/z 628.4 [M+H]⁺.

¹H NMR (400 MHz, CDCI₃) δ/ppm: 8.02 (d, J = 2.1 Hz, 1H), 6.85 (d, J = 2.1 Hz, 1H), 6.40 (s, 1H), 5.43- 5.19 (m, 1H), 4.81-4.62 (m, 2H), 4.56-4.41 (m, 2H), 4.29-4.05 (m, 2H), 3.99-3.77 (m, 2H), 3.39-3.13 (m, 6H), 3.13-2.94 (m, 4H), 2.67 (s, 3H), 2.35-2.07 (m, 5H), 2.04-1.84 (m, 3H).

Intermediate E-8, (3R)-1-[7-bromo-11 -[[(2R,8S)-2-fiuoro-1,2,3,5,6,7- hexahydropyrrolizm-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0,02,6]trideca- 1(9), 2, 4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol.

Intermediate scheme 23

Step A, 7-bromo-13-chloro-11- ethylsulfonyl-5,6,10,12-tetrazatricyclo [7.4.0.02,6]trideca- 1(9),2, 4.7,10,12-hexaene. To a solution of 7-bromo-13-chloro-11- ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (372. mg, 0.76mmol) in DCM (12mL) was added m-chloroperbenzoic acid (653.85mg, 3.79mmol) and the mixture was stirred at room temperature for 21 hrs. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and partitioned between a layer of DCM and water/sodium bicarbonate. The organic layer was separated, the aqueous layer was extracted with DCM. The combined organic phases were filtered through phase separating filter paper and concentrated to dryness to afford 7-bromo-13-chloro-11-ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (362.9mg, 0.6763mmol, 89.243% yield) as an orange solid.

UPLC-MS (ES⁺, Method 2): 1.54 min, m/z 374.9/376.9 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.37 (m, 1.5H), 7.94 (d, J = 2.3 Hz, 0.5H), 7.90 (d, J =

2.2 Hz, 1 H), 7.78 (s, 05H) 7.59 (s, 1 H), 3.66 (q, J = 7.5 Hz, 3.5H), 1.50 (t, J = 7.5 Hz, 6.5H).

Step B, (3R}-1-(7-bromo-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl-piperidin-3-ol. To a 10mL RBF containing 7-bromo-13- chloro-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene

(100. mg, 0.27mmol) was added (R)-3-Methylpiperidin-3-ol hydrochloride (40.37mg, 0.27mmol) then the atmosphere was replaced with nitrogen. MeCN (4mL) and N,N-diisopropylethylamine (0.14mL, 0.8mmol) were added and the reaction mixture was stirred at room temperature for 4 hrs. The reaction was diluted with EtOAc and water was added then the organic layer was separated. The aqueous was extracted with EtOAc (2x) then the combined organic layers were washed with brine then passed through phase separating filter paper and concentrated. The resulting brown residue was purified by flash column chromatography eluting with MeOH in DCM 0-10% to yield (3R)-1-(7-bromo- 11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3- methyl-piperidin-3-ol (135.3mg, 0.2769mmol, 104.03% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 1 .45 min, m/z 454.1/456.1 [M+H]⁺.

¹H NMR (400 MHz, CDCI₃ ) δ/ppm: 8.20-8.21 (m, 1H), 7.41 (s, 1H), 6.97 (br s, 1H), 4.01-4.09 (m, 2H), 3.52-3.69 (m, 2H), 3.22-3.28 (m, 2H), 2.05-2.08 (m, 1H), 1.86 (d, J = 13.7 Hz, 1H), 1.62-1.69 (m, 6H), 1.47 (t, J = 7.4 Hz, 3H).

Step C, (3R)-1-[7-bromo-11-[[(2R,8S}-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,5]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (E-8). A 10 mL RBF was charged with (3R)-1-(7-bromo-11-ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl-piperidin-3-ol (135. mg,

0.3mmol), ((2R,7aS)-2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (94.61mg, 0.59mmol) and THF (3mL). The atmosphere was replaced with nitrogen then lithium bis(trimethylsilyl)amide(0.59mL, 0.59mmol) (IM in THF) was added. The reaction was stirred at room temperature for 19 hrs then 0.2 mL water was added. The reaction mixture was concentrated to give a brown residue, which was purified by flash column chromatography eluting with EtOAc in petroleum ether 20-100% to yield (3R)-1-[7-bromo-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (121.1mg, 0.1888mmol, 63.556% yield) as an brown gum.

UPLC-MS (ES⁺, Method 2): 1.27 min, m/z 519.3/521.2 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.08-8.13 (m, 1 H), 7.13 (s, 1 H), 6.72-6.87 (m, 1 H), 5.23- 5.37 (m, 1 H) 4.03-4.35 (m, 3H), 3.69-3.72 (m, 1 H), 2.97-3.33 (m, 7H), 1.56-2.29 (m, 15H), 1.25-1.29 (m, 7H).

Intermediate E-9, tert-butyl 3-[7-bromo-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl] -3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

Intermediate Scheme 24

Step A, (3R)-1-(7-bromo-11-ethylsulfanyl-4-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl-piperidin-3-ol.

HATU (145.72mg, 0.38mmol) was added to a stirring solution of 7-bromo-11-ethylsulfanyl-4- methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (100. mg,

0.29mmol), (R)-3-methylpiperidin-3-ol hydrochloride (58.11 mg, 0.38mmol), and N,N- diisopropylethylamine (0.26mL, 1.47mmol) in DMF (3.8914mL). The reaction mixture was heated to 65°C for 4 hrs. The solvent was removed in vacuo, and the residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100% to afford (3R)-1-

(7-bromo-11-ethylsulfanyl-4-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl-piperidin-3-ol (39mg, 0.0894mmol, 30.32% yield) as a yellow gum.

UPLC-MS (ES⁺, Method 2): 1.86 min, m/z 428.1 [M+H]⁺.

Step B, (3R)-1-(7-bromo-11-ethylsulfonyl-4-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl-piperidin-3-ol. m-Chloroperbenzoic acid (46.27mg, 0.27mmol) was added to a solution of (3R)-1-(7-bromo- 1 1-ethylsulfanyl-4-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl)-3-methyl-piperidin-3-ol (39. mg, 0.09mmol) in DCM (0.8937mL) and stirred at room temperature for 2 hrs. The reaction was diluted with DCM, and washed with sat. NaHCO3 (2 x 10 mL). The mixture was passed through a phase separator, and concentrated in vacuo to afford (3R)-1-(7-bromo-11-ethylsulfonyl-4-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-y l)-3-methy l-piperid in-3-ol (27mg, 0.0576mmol, 64.50% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Method 2): 1.52 min, m/z 470.2 [M+H]⁺. Step C, (3R)-1-[7-bromo-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-4-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3-methyl-piperidin-3-ol (E-9). Lithium bis(trimethylsilyl)amide (0.07mL, 0.07mmol) was added dropwise to a solution of ((2R,7aS)-2-fluorohexahydro-1H-pyrrolizin- 7a-yl)methanol (11 .93mg, 0.07mmol) and (3R)-1-(7-bromo-11-ethylsulfonyl-4-methyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3-methyl- piperidin-3-ol (27. mg, 0.06mmol) in anhydrous THF (0.58mL). The reaction was stirred at room temperature for 1.5 hrs. The reaction was concentrated in vacuo, and the crude was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100%, followed by methanol in DCM 0-5%. The desired fractions were concentrated to afford (3R)-1-[7-bromo- 1 1-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-4-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-y l]-3-methy l-pipe rid in-3-o I (26mg, 0.0487mmol, 84.55% yield) as a brown glassy solid.

UPLC-MS (ES⁺, Method 2): 1.33 min, m/z 533.4 [M+H]⁺.

E-10, 5-[7-bromo-8-methyl-11-[[rac-(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-y l]-3- fluoro-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide.

E-10 was made by analogy with (3R)-1-[7-bromo-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-4-methyl-5,6,10,12-tetrazatricyclo [7.4.0.02, 6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (E-9) (Intermediate Scheme 24), replacing 7-bromo-11- ethylsulfanyl-4-methyl-5, 6,10, 12-tetrazatricyclo[7.4.0.02, 6]trideca- 1(9),2,4,7,10,12-hexaen-13-ol (B-6) with 7-bromo-11-ethylsulfanyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (B-4’) and 8-boc-3,8- diazabicyclo[3.2.1]octane with 3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5- a][1,4]diazepine-2-carboxamide (A-13) in step A.

UPLC-MS (ES⁺, Method 5): 1 .52 min, m/z 644.1/646.1 .4 [M+H]⁺. F-1 , (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-

Intermediate Scheme 25

Step A, (3R)-1-(7-bromo-11- ethylsuifanyi-5,6,10.12-tetrazatricyclo[7.4.0.02,6]trideca - 1 (9),2,4,7,10,12-hexaen-13-yl)-3-methyl-pipendiin-3-oL The crude mixture of 7-bromo-13- chloro-11- ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (600. mg, 1 .75mmol) was taken up in DMF (7mL) ,N,N-diisopropylethylamine (1.22mL, 6.98mmol) and (R)-3-methylpiperidin-3-ol hydrochloride (291.23mg, 1.92mmol) were added. The reaction was stirred at room temperature for 90 minutes. The reaction was partitioned between EtOAc and water. The aqueous layer was extracted with EtOAc (3x) . The organic phase was washed with 10% aq. LiCI solution, passed through a phase separator and concentrated under reduced pressure to afford a brown oil. The residue was purified by flash chromatography eluting with EtOAc in petroleum ether 0-60% to afford (3R)-1-(7-bromo-11 - ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3- methyl-piperidin-3-ol (312mg, 0.7387mmol, 42.308% yield) as a yellow sticky solid.

UPLC-MS (ES⁺, Method 5): 1.94 min, m/z 422/424 [M+H]⁺.

Step B, (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfon 5y,6l-,10,12-tetrazatricycl[o7.4.0.02,6]trideca-1(9),2,4,7,i0,12-hexaen-13-yl]-3-methyl-piperidin-3-ol. A mixture of (3R)-1-(7-bromo-11-ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl)-3-methyl-piperidin-3-ol (250. mg, 0.59mmol), cesium carbonate (322.05mg, 0.99mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (233.49mg, 0.65mmol) in 1,4-dioxane (2.5mL) and water (0.5mL), was degassed with nitrogen for 5 minutes before adding cataCXium A Pd G3, Methanesulfonato(diadamantyl-n-butylphosphino)- 2'amino-1,1'-biphenyl-2-yl)palladium(II) (86.22mg, 0.12mmol). The reaction was sealed, vacuum degassed and filled with nitrogen (3x), and heated to 100°C for 1.5 hrs. The mixture was cooled to room temperature, diluted with DCM and passed through a phase separator and concentrated to dryness. The mixture was purified by column chromatography on a silica column eluting with EtOAc in petroleum ether 0-60% to afford (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl- piperidin-3-ol (271mg, 0.4707mmol, 66.272% yield) as a pale yellow gum.

UPLC-MS (ES⁺, Method 5): 2.31 min, m/z 576.2 [M+H]⁺.

Step C, (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,5]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-Ql (F-l). To a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (271. mg, 0.47mmol) in DCM (4mL) was added m-chloroperbenzoic acid (203.08mg, 1.18mmol). The reaction was stirred at 0°C for 3 hrs, allowing to warm to room temperature. Further m-chloroperbenzoic acid, (81.23mg, 0.47mmol) was added and stirring was continued for 2 hrs. The mixture was quenched with saturated aqueous sodium thiosulfate solution and diluted with further DCM and water. The layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organics were passed through a hydrophobic frit and the solvent was removed in vacuo. The mixture was again taken up in DCM (5mL) and cooled to 0°C. m-Chloroperbenzoic acid (81.23mg, 0.47mmol) was added and the mixture was stirred for 2 hrs, allowing to warm to room temperature. The mixture was quenched with saturated aqueous sodium thiosulfate solution and diluted with further DCM and water. The layers were separated, and the aqueous layer was extracted with DCM (2x). The combined organics were washed with water and brine, passed through a hydrophobic frit, and the solvent was removed in vacuo to give (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (441mg, 0.3628mmol, 77.081% yield) as a yellow-orange solid.

UPLC-MS (ES⁺, Method 5): 2.02 min, m/z 608.2 [M+H]⁺.

Table 6 describes intermediates that were made by analogy with F-1 (intermediate scheme 25), replacing 1,4-oxazepane hydrochloride with the appropriate building block and/or B-3 with the appropriate intermediate as outlined in the table.

Table 6

F-7, tert-butyl 3-[7-[8"ethyl-7-fluoro-3-(methoxymefhoxy)"1-naphthyl]"'11-ethylsulfonyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-t 3-y I] -3, 8- diazabicyclo[3.2.1]octane-8-carboxylate.

Intermediate Scheme 26

Step A, 7-bromo-13-chloro-11- ethylsulfonyl-5,6,10,12-tetrazatrtcyclo[7.4.0.02,6]trideca- 1 (9),2,4,7,10,12-hexaene. To a solution of 7-bromo-13-chloro-11 -ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (372. mg, 0.76mmol) in DCM

(12mL) was added m-chloroperbenzoic acid (653.85mg, 3.79mmol) and the mixture was stirred at room temperature for 21 hrs. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and partitioned between a layer of DCM and water/sodium bicarbonate. The organic layer was separated, the aqueous layer was extracted with DCM. The combined organic phases were filtered through phase separating filter paper and concentrated to dryness to afford 7-bromo-13-chloro-11-ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (362.9mg, 0.6763mmol, 89.243% yield) as an orange solid.

UPLC-MS (ES⁺, Method 2): 1.54 min, m/z 374.9/376.9 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 8.37 (m, 1.5H), 7.94 (d, J = 2.3 Hz, 0.5H), 7.90 (d, J =

2.2 Hz, 1 H), 7.78 (s, 05H) 7.59 (s, 1 H), 3.66 (q, J = 7.5 Hz, 3.5H), 1.50 (t, J = 7.5 Hz, 6.5H).

Step B, tert-butyl 3-(7-bromo-11-ethylsulfonyl- 5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yI) -3, 8- diazabicyclo[3.2.1]octane-3-carboxylate. To a 50 mL RBF containing 7-bromo-13-chloro- 1 1-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (211.5mg, 0.56mmol) was added 8-boc-3,8-diazabicyclo[3.2.1]octane (119.53mg, 0.56mmol) then the atmosphere was replaced with nitrogen. MeCN (8mL) and N,N-diisopropylethylamine (0.29mL, 1 .69mmol) were added and the reaction mixture was stirred at room temperature for 3 hrs. The reaction was diluted with EtOAc and water was added then the organic layer was separated. The aqueous layer was extracted with EtOAc (2x) then the combined organic layers were washed with brine then passed through phase separating filter paper and concentrated to yield tert-butyl 3-(7-bromo-11- ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl) -3 , 8- diazabicyclo[3.2.1]octane-8-carboxylate (181.8mg, 0.3132mmol, 55.623% yield) as a brown solid.

UPLC-MS (ES⁺, Method 2): 1 .80 min, m/z 551 .2/553.2 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ /ppm: 8.18-8.19 (m, 1 H), 7.39 (s, 1 H), 6.75-6.79 (m, 1 H), 4.33 (br s, 3H), 3.57 (q, J = 7.4 Hz, 2H), 3.47-3.75 (m, 2H), 1 .86-2.05 (m, 3H), 1 .50-1 .53 (m, 11 H), 1 .46 (t, J = 7.4 Hz, 4H).

Step C, tert-butyl 3-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-

5.6.10.12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (F-7). A 25 mL RBF was charged with 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (129.34mg, 0.36mmol) and cesium carbonate (212.7mg, 0.65mmol). A solution of tert-butyl 3-(7-bromo-11-ethylsulfonyl-

5.6.10.12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl)-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (180. mg, 0.33mmol) in 1,4-dioxane (4mL) was added to the vial along with water (0.5mL). The solution was degassed with nitrogen for 10 minutes then cataCXium A Pd G3, Methanesulfonato(diadamantyl-n-butylphosphino)-2'amino-1,l'-biphenyl-2-yl)palladium(ll) (23.77mg, 0.03mmol) was added and the atmosphere was replaced with nitrogen. The reaction was heated to 100°Cfor 6 hrs. The mixture was filtered through a plug of celite, which was washed through with EtOAc then concentrated. The residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-60% to yield tert-butyl 3-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13- yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (62.9mg, 0.0634mmol, 19.412% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 2): 2.12 min, m/z 705.6 [M+H]⁺.

Intermediate F-8, 4-[7-(5,6-dimethyl-1 -tetrahydropyran-2-yl-indazol-4-yl)-11- ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl] -6-methyl-1,4-oxazepan-6-ol.

Intermediate Scheme 27

Step A, 7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-11-ethylsulfanyl-8-fluoro-

5.6.10.12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol . A microwave vial was charged with 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole (93.44mg, 0.26mmol) , 7-bromo-11-ethylsulfanyl-8-fluoro-

5.6.10.12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (45. mg,

0.13mmol), cesium carbonate (85.45mg, 0.26mmol), tetrakis(triphenylphosphine)paliadium(0) (30.31 mg, 0.03mmol), 1,4-dioxane (3.2mL) and water (0.48mL). The atmosphere was replaced with nitrogen then the vial was sealed and irradiated at 140°C for 4 hrs. The reaction mixture was filtered through a plug of celite, washing through with ethyl acetate then concentrated. The crude was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100% to afford 7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-11 - ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13- ol (63.2mg, 0.1283mmol, 97.847% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 2): 1 .89/1 .91 min, m/z 493.3 [M+H]⁺.

Step B, 4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-11- ethylsulfanyl-8- fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -6- methyl-1 ,4-oxazepan-6-ol. To a solution of 7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4- yl)-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-ol (63.2mg, 0.13mmol) in DMF (1 mL) at room temperature, was added 6-methyl- 1,4-oxazepan-6-ol HCI (43.02mg, 0.26mmol) and N,N -diisopropylethylamine (0.13mL, 0.77mmol) followed by HATU (73.18mg, 0.19mmol). The reaction mixture was stirred at room temperature for 68 hrs. Additional 6-methyl-1,4-oxazepan-6-ol HCI (10.75mg, 0.06mmol) and HATU (24.39mg, 0.06mmol) were added and stirred for a further 23 hrs. The reaction mixture was diluted with EtOAc and water the phases were separated, and the aqueous phase extracted with EtOAc. The combined organic fractions were washed with brine (2x), filtered through phase separating filter paper, and concentrated under reduced pressure. The crude was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-60% to yield 4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-11-ethylsulfanyl-8-fluoro- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4- oxazepan-6-ol (39.2mg, 0.0647mmol, 50.438% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 2): 2.01/2.03/2.05 min, m/z 606.5 [M+H]⁺.

Step C, 4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl-indazol-4-yl)-11- ethylsulfonyl-8- fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -6- methyl-1 ,4-oxazepan-6-ol (F-8). To a solution of 4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl- indazol-4-yl)-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (39. mg, 0.06mmol) in DCM (2mL) was added m-chloroperbenzoic acid (33.33mg, 0.19mmol) and the mixture was stirred at room temperature for 2 hrs. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and partitioned between a layer of DCM and water/sodium bicarbonate. The organic layer was separated, the aqueous layer was extracted with DCM and the organic layers were combined. The combined organics were filtered through phase separating filter paper and concentrated to dryness to afford 4-[7-(5,6-dimethyl-1-tetrahydropyran-2-yl- indazol-4-yl)-11- ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (41 mg, 0.0643mmol, 99.853% yield) as an orange solid.

UPLC-MS (ES⁺, Method 2): 1.75 min, m/z 638.5 [M+H]⁺.

Intermediate F-9, (6S)-4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol.

F-9 was made by analogy with F-8 (Intermediate Scheme 27), replacing starting materials 7- bromo-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-ol (B-3‘) and 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole in step A with 7-bromo-1 1-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (B-5‘) and 2-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-4, 4, 5, 5-tetramethyl-1 ,3,2-dioxaborolane (A-9), then 6- methyl-1,4-oxazepan-6-ol HCI in step B with (6S)-6-methyl-1 ,4-oxazepan-6-ol;2,2,2- trifluoroacetic acid.

UPLC-MS (ES⁺, Method 2): 1.84 min, m/z 642.5 [M+H]⁺.

Intermediate F-10, (6S)-4-[7-[8-ethyl-4,7-difluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol.

F-10 was made by analogy with F-8 (Intermediate Scheme 27), replacing starting materials 7- bromo-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-ol (B-3‘) and 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole in step A with 7-bromo-1 1-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (B-5‘) and 2-[8-ethyl-4,7- difluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (A-15), then 6-methyl-1,4-oxazepan-6-ol HCI in step B with (6S)-6-methyl-1,4-oxazepan-6-ol;2,2,2- trifluoroacetic acid.

UPLC-MS (ES⁺, Method 5): 2.01 min, m/z 660.1 [M+H]⁺. Intermediate F-11, tert-butyl 3-[7-[8-ethyl-4,7-difluoro-3-(methoxymethoxy)-1-naphthyl]- 11 -ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

F-11 was made by analogy with F-8 (Intermediate Scheme 27), replacing starting materials 7- bromo-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12- hexaen-13-ol (B-3’) and 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole in step A with 7-bromo-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-ol (B-5’) and 2-[8-ethyl-4,7- difluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (A-15), then 6-methyl-1,4-oxazepan-6-ol HCI in step B with 8-boc-3,8-diazabicyclo[3.2.1]octane. UPLC-MS (ES⁺, Method 2): 2.16 min, m/z 741 .6 [M+H]⁺.

Intermediate F-12, S-[7-[8-ethyl -4,7-difluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethyl sulfonyi-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca -1(9),2,4,7,10,12- hexaen-13-yl] -N,N-dimethyl -4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide.

F-12 was made by analogy with F-8 (Intermediate Scheme 27), replacing starting materials 7- bromo-11- ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12- hexaen-13-ol (B-3’) and 5,6-dimethyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole in step A with 7-bromo-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-ol (B-5’) and 2-[8-ethyl-4,7- difluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (A-15), then 6-methyl-1,4-oxazepan-6-ol HCI in step B with N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1,5-a][1,4]diazepine-2-carboxamide.

UPLC-MS (ES⁺, Method 5): 2.03 min, m/z 737.2 [M+H]⁺.

Intermediate F-13, tert-butyl 3-[11-ethylsulfonyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-

2-yl-5-(trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate.

Intermediate Scheme 28

Step A, tert-butyl 3-(7-bromo-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl) -3, 8- diazabicyclo[3.2.1]octane-8-carboxylate. 8-Boc-3,8-diazabicyclo[3.2.1]octane (22.27 mg, 0.1mmol) was added to a solution of 7-bromo-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-ol (B-5’) (30. mg, 0.09mmol) in DMF (0.90mL) followed by N,N-diisopropylethylamine (0.08mL, 0.44mmol) and then HATU (66.48mg, 0.17mmol). The resulting solution was stirred at room temperature for 1 .5 hrs. The reaction mixture was quenched with water, the aqueous layer was extracted with EtOAc (3x). The combined organics were washed with brine, filtered through a phase separator, and concentrated under reduced pressure. The residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 5-50% to yield tert-butyl 3-(7-bromo- 11-ethylsulfanyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen- 13-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (19mg, 0.0354mmol, 40.44% yield) as a white solid.

UPLC-MS (ES⁺, Method 5): 2.40 min, m/z 537.0/539.0 [M+H]⁺. Step B, tert-butyl 3-[11 -ethylsulfanyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl-5- (trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate. 6-methyl-1- tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]boronic acid (320.5mg, 0.98mmol), tert- butyl 3-(7-bromo-11- ethylsulfanyl-8-fluoro-5, 6,10, 12-tetrazatricyclo[7.4.0.02, 6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl)-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (210. mg, 0.39mmol), SPhos Pd G3 (91.46mg, 0.12mmol) and SPhos (48.12mg, 0.12mmol) were suspended in pre-purged toluene (3.8mL). The vial was sealed, potassium carbonate in water (0.39mL, 0.78mmol) was added and the vial was purged for 10 minutes. The mixture was heated to 100°C for 3 hrs. The mixture was cooled to room temperature and directly dry-loaded to Celite for flash chromatography eluting with EtOAc in petroleum ether 0-100% to yield tert- butyl 3-[11-ethylsulfanyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl-5-

(trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (166mg, 0.2241 mmol, 57.38% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 2.62 min, m/z 741 .2 [M+H]⁺.

Step C, tert-butyl 3-[11-ethylsulfonyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl-5- (trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (F-13). To a solution of tert-butyl 3-[11-ethylsulfanyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl-5- (trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (165. mg, 0.22mmol) in DCM (2.2mL) was added m-chloroperbenzoic acid (115.3mg, 0.67mmol) at room temperature. The mixture was stirred at room temperature for 1 hr, then was quenched with aq. sat. NaHCO3. The aqueous layer was extracted with DCM (3x). The combined organics were washed with brine, passed through a phase separator and reduced in vacuo to afford tert-butyl 3-[11- ethylsulfonyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl-5-(trifluoromethyl)indazol-4-yl]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (173mg, 0.2239mmol, 100% yield) as a yellow solid. UPLC-MS (ES⁺, Method 5): 2.30 min, m/z 773.2 [M+H]⁺.

Intermediate F-14, (6S)-4-[11 -ethylsulfonyl-8-fluoro-7-[6-methyl-1-tetrahydropyran-2-yl- 5-(trifluoromethyl)indazol-4-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol.

F-14 was made by analogy with F-13 (Intermediate Scheme 28), replacing starting materials 8-boc-3,8-diazabicyclo[3.2.1]octane in step A with (6S)-6-methyl-1,4-oxazepan-6-ol;2,2,2- trifluoroacetic acid.

UPLC-MS (ES⁺, Method 5): 2.03 min, m/z 692.2 [M+H]⁺.

Intermediate F-15, 6S)-4-[7-(6-chloro-5-cyclopropyl-1-tetrahydropyran-2-yl-indazol-4- yI) -11 -ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol.

F-15 was made by analogy with F-13 (Intermediate Scheme 28), replacing starting materials 8-boc-3,8-diazabicyclo[3.2.1]octane (22.27mg, 0.1 mmol) in step A with (6S)-6-methyl-1,4- oxazepan-6-ol;2,2,2-trifluoroacetic acid and 6-methyl-1-tetrahydropyran-2-yl-5- (trifluoromethyl)indazol-4-yl]boronic acid in step B with (6-chloro-5-cyclopropyl-1- tetrahydropyran-2-yl-indazol-4-yl)boronic acid.

UPLC-MS (ES⁺, Method 5): 2.09 min, m/z 684.1/686.1 [M+H]⁺.

Intermediate F-16, N-ethyl-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide.

Intermediate Scheme 29

Step A, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol. A mixture of 2-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (115.31 mg, 0.32mmol) cesium carbonate (189.63mg, 0.58mmol), and 7-bromo-13-chloro-11- ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaene (100. mg, 0.29mmol) in 1,4-dioxane (3mL) and water (0.40mL) was degassed for 15 minutes then cataCXium A Pd G3, methanesulfonato(diadamantyl-n-butylphosphino)-2'amino-1,1'- biphenyl-2-yl)palladium(ll) (21.19mg, 0.03mmol) was added and the atmosphere was replaced with nitrogen. The reaction was heated to 100°C for 17 hrs. The reaction mixture was cooled to room temperature, diluted with EtOAc (20 mL) and water (25 mL). The phases were separated and the aqueous phase was washed with EtOAc (2 x20 mL). The combined organic fractions were dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude was purified by flash column chromatography eluting with EtOAc in petrolerum ether 0- 100% to yield 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (50mg, 0.1045mmol,

35.904% yield) as an orange solid.

UPLC-MS (ES⁺, Method 2): 2.00 min, m/z 479.3 [M+H]⁺.

Step B, N-ethyl-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yI] - 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1,4]diazepine-2-carboxamide. To a solution of 7-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (50. mg, 0.1 mmol) in DMF (1 mL) at room temperature was added N-ethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (43.52mg, 0.21 mmol) and N,N-diisopropylethylamine (0.11mL, 0.63mmol) followed byHATU (59.59mg, 0.16mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was diluted with EtOAc (50 mL) and water (50 mL), the phases were separated and the aqueous phase washed with EtOAc (20 mL). The combined organic fractions were washed with 10%w/v LiCI in water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford N-ethyl-5-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-5, 6, 10,12-tetrazatricyclo[7.4.0.02, 6]trideca-

I (9),2,4,7,10,12-hexaen-13-yl]-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2- carboxamide (70mg, 0.1047mmol, 100% yield).

UPLC-MS (ES⁺, Method 2): 2.07 min, m/z 669.8 [M+H]⁺.

Step C, N-ethyl-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (F-16). To a solution of N- ethyl-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-5, 6, 10, 12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (70. mg, 0.1 mmol) in DCM (1 mL) was added m-chloroperbenzoic acid (54.19mg, 0.31 mmol). The reaction mixture was stirred at room temperature for 1 hr. The reaction mixture was quenched by the addition of sat. aq. NaHCO3 (4mL), diluted with water (4mL) and DCM (4mL). The phases were separated and the aqueous layer was extracted with DCM (2x5mL). The combined organics were washed with sat. aq NaHCO3 (5mL), dried over Na2SO4, filtered, and concentrated under reduced pressure to give N-ethyl-5-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]- 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (69mg, 0.0985mmol, 94.07% yield).

UPLC-MS (ES⁺, Method 2): 1 .79 min, m/z 701 .5 [M+H]⁺.

Intermediate G-1, 7-bromo-13-[8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-

I I -[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaene. Intermediate Scheme 30

Step A, 7-bromo-13-(3,8-diazabicyclo[3.2.1]octan-3-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-

1 (13), 2, 4, 7, 9,11 -hexaene;dihydrochloride. A mixture of tert-butyl 3-[7-bromo-11-[[rac- (2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaen-13-y l]-3, 8- diazabicyclo[3.2.1]octane-8-carboxylate (81. mg, 0.13mmol) and hydrogen chloride in dioxane 4N (0.31 mL, 1.26mmol) in DCM (1mL) was stirred at room temperature for 4 hrs. Further hydrogen chloride in dioxane 4N (0.66mL, 2.63mmol) was added and stirring continued for 3 hrs. The mixture was concentrated in vacuo to give crude product 7-bromo-13-(3,8- diazabicyclo[3.2.1]octan-3-yl)-11-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11- hexaene;dihydrochloride (83mg, 0.1408mmol, 107.2% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 1.19 min, m/z 518.0 [M+H]⁺

Step B, 7-bromo-13-[8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-11- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaene (G-1 ). 1 -Bromo-3- methoxypropane (0.02mL, 0.15mmol) was added to a stirring solution of 7-bromo-13-(3,8- diazabicyclo[3.2.1]octan-3-yl)-11-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11- hexaene;dihydrochloride (83. mg, 0.14mmol) and potassium carbonate (77.85mg, 0.56mmol) in DMF (1.5mL). The reaction mixture was heated at 70°C for 17 hrs. Further potassium carbonate (38.93mg, 0.28mmol) and 1-bromo-3-methoxypropane (0.01 mL, 0.08mmol) were added and heating continued for 8 hrs. Further potassium carbonate (19.46mg, 0.14mmol) and 1-bromo-3-methoxypropane (0.01 mL, 0.06mmol) were added and heating continued for

2 hrs. The solvent was evaporated in vacuo . Further 1-bromo-3-methoxypropane (0.01 mL, 0.06mmol) and potassium carbonate (19.46mg, 0.14mmol) and DMF (1 ,5mL) were added and the mixture was again heated to 70°C for 8 hrs. The solvent was evaporated in vacuo. The resulting solid was purified by flash chromatography (11 g KP amino-D silica cartridge, dry loaded, 0 - 16% methanol in DCM). Product-containing fractions were combined and concentrated in vacuo to give 7-bromo-13-[8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan- 3-yl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11-hexaene (26mg, 0.0442mmol, 31.368% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 5): 1.25 min, m/z 590.1 [M+H]⁺. Intermediate G-2, 4-[7-bromo-8-methyl-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-13-yI] -1,4-oxazepane

G-2 was made by anaology with tert-butyl 7-bromo-13-[8-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-11-[[rac-(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13),2,4,7,9,11-hexaene (Intermediate Scheme 30), replacing 3-[7-bromo-11-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-

1 (13), 2, 4, 7, 9,11-hexaen-13-yl]-3,8-diazabicyclo[3.2.1]octane-8-carboxylate (E-1) with (D-5) in step A and 1-Bromo-3-methoxypropane with 1-Bromo-2-propanol in step B.

UPLC-MS (ES⁺, Method 5): 1.20 min, m/z 530.2 [M+H]⁺.

Intermediate H-1 , 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yI]-1,4-oxazepane.

Intermediate Scheme 31

Step A, 4-[7-[8-ethyl-7-f!uora-3-(methoxymethoxy)-1-naphthyn-11-ethyisulfanyi-8-methyi- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-1,4-oxazepane. N,N- Diisopropylethylamine (0.07mL, 0.4mmol), 1,4-Oxazepane hydrochloride (13.64mg, 0.1mmol) and HATU (37.7mg, 0.1mmol) were added sequentially to a solution of 7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol in NMP (0.44mL). The reaction mixture was allowed to stir at room temperature for 2hrs, then was partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The combined organic layers were washed with water (10 mL), a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-100% EtOAc in petroleum ether afforded 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfanyl-8-methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 1,4-oxazepane (24.9mg, 0.0433mmol, 65.441% yield) as an off-white solid.

UPLC-MS (ES⁺, Method 2): 2.38 min, m/z 576.8 [M+H]⁺.

¹H NMR (400 MHz, CDCI3) δ/ppm: 7.85 (d, J = 2.1 Hz, 1 H), 7.75-7.66 (m, 1 H), 7.58 (d, J = 2.7 Hz, 1 H), 7.31-7.20 (m, 2H), 6.70 (d, J = 2.1 Hz, 1 H), 5.35-5.25 (m, 2H), 3.98-3.78 (m, 8H), 3.53 (s, 3H), 3.24 (q, J = 7.3 Hz, 2H), 2.48-2.35 (m, 1 H), 2.16-2.00 (m, 6H), 1.47 (t, J = 7.3 Hz, 3H), 0.48 (t, J = 7.4 Hz, 3H).

Step B, 4-[7-[8-ethyl -7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-8- methyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl -] 1 ,4- oxazepane (H-1). At 0°C, m-chloroperbenzoic acid (24.23mg, 0.11 mmol) was added to a solution of 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-8-methyl- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-1,4-oxazepane (24.9mg, 0.04mmol) in DCM (0.43mL). The reaction mixture was allowed to stir at room temperature for 1 hr. Extra m-chloroperbenzoic acid (7.46mg, 0.04mmol) was added and the reaction mixture was stirred at room temperature for 20 minutes. The reaction mixture was quenched with a saturated solution of sodium thiosulfate and was partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was separated, the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined, washed with a saturated solution of sodium bicarbonate (2x10 mL), a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4- [7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-8-methyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]- 1,4-oxazepane (26.284mg, 0.0433mmol, 100% yield) as an off-white solid.

UPLC-MS (ES⁺, Method 2): 1.97 min, m/z 608.5 [M+H]⁺.

Table 7 describes intermediates that were made by analogy with H-1 (Intermediate Scheme 31), replacing 1,4-oxazepane hydrochloride with the appropriate building block and/or B-7 with the appropriate intermediate as outlined in the table.

Table 7 Examples

Example 1 , 5-ethyl-6-fluoro-4-[13-( 1,4-oxazepan-4-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-

1 (13), 2, 4, 7, 9,11 -hexaen-7-yl]naphthalen-2-ol.

Scheme 1

Step A, 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -1,4-oxazepane. A stirring solution of 4-[7-chloro-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]-1,4-oxazepane (55 mg, 0.12 mmol), cesium carbonate (75.14 mg, 0.23 mmol) and 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (51.6 mg, 0.14 mmol) in 1,4-dioxane (1 mL) and water (0.2 5mL) was degassed with N₂ for 5 min before adding [1 ,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (15.03 mg, 0.02 mmol). The reaction was sealed and heated to 100°C for 3hrs, cooled to room temperature, diluted with DCM and passed through a phase separator and concentrated to dryness. The residue was purified by flash column chromatography eluting 0-100% EtOAc in petroleum ether, like fractions were pooled and concentrated to afford 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)- 1 -naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]-1 ,4-oxazepane (9 mg, 11% yield) as a light brown oil.

UPLC-MS (ES⁺, Method 5): 1.78 min, m/z 659.2 [M+H]⁺.

Step B, 5-ethyl-6-fluoro-4-[13-(1,4-oxazepan-4-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(13),2,4,7,9,11-hexaen-7-yl]naphthalen-2-ol (example 1).

To 4-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1 (13),2,4,7,9,11-hexaen-13-yl]-1 ,4-oxazepane (14 mg, 0.0 2mmol) in DCM (1 mL) was added triethylsilane (0.02 mL, 0.11 mmol) and trifluoroacetic acid (0.08 mL, 1.06 mmol) and the reaction was stirred at 40°C for 4 hrs. The mixture was concentrated in vacuo and purified by reverse phase chromatography, like fractions loaded on to a SCX column washed with MeOH and eluted with 1 M NH₃ in MeOH, concentrated to yield 5-ethyl-6-fluoro-4-[13-(1,4-oxazepan- 4-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaen-7-yl]naphthalen-2-ol (3mg, 23% yield) as a white solid.

UPLC-MS (ES⁺, Method 1): 3.11 min, m/z 615.5 [M+H]⁺, 3.12 min, m/z 615.5 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ /ppm: 9.97 (s, 1 H), 7.91 (m, 1 H), 7.75-7.80 (m, 1 H), 7.29- 7.37 (m, 2H), 7.15-7.16 (m, 1 H), 7.10 (s, 1 H). 6.78-6.82 (m, 1 H), 5.23-5.36 (m, 1 H), 4.03-4.17 (m, 2H), 3.70-3.92 (m, 7H), 3.06-3.15 (m, 2H), 2.98-3.03 (m, 1 H), 2.79-2.90 (2H), 1.72-2.10 (m, 2H), 2.07 (m, 11 H), 0.47 (t, J=7.28 Hz, 3H).

Table 8 describes examples that were made by analogy with example 1 (scheme 1), replacing 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (A-9) with the appropriate boronic acid or boronate ester building block and/or D-6 with the appropriate intermediate as outlined in the table.

Table 8

Example 12, 4-[13-(3,8-diazabicyclo[3.2.1]octan-3-yl)-11-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol.

Scheme 2

Step A, tert-butyl 3-[7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -3,8- diazabicyclo[3.2.1]octane-8-carboxylate. Methanesulfonato(diadamantyl-n- butylphosphino)-2'amino-1 ,1'-biphenyl-2-yl)palladium(ll) (CataCXium A Pd G3), (53.39 mg, 0.07 mmol) was added to a nitrogen degassed suspension of cesium carbonate (239 mg, 0.73 mmol), tert-butyl 3-[7-bromo-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (226 mg, 0.37 mmol) and [7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]boronic acid (237 mg, 0.55 mmol) in 1,4-dioxane (2 mL) and water (0.5 mL). The reaction mixture was sealed and heated to 100 °C overnight. The reaction was filtered through celite, washed with EtOAc then concentrated to dryness. The residue was then purified by flash column chromatography eluting 0-7% MeOH in DCM to afford [7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]boronic acid (236 mg, crude) as a brown solid, used without further purification. UPLC-MS (ES⁺, Method 5): 2.58 min, m/z 461 .9 [M+H]⁺.

Step B, tert-butyl 3-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -3,8- diazabicyclo[3.2.1]octane-8-carboxylate. Cesium Fluoride (272 mg, 1.79 mmol) was added to a stirring solution of tert-butyl 3-[7-[7-fluoro-3-(methoxymethoxy)-8-(2- triiso propylsilylethynyI)- 1 -naphthyl]-11 -[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (330 mg, 0.36 mmol) in dry DMF (2 mL) and the reaction was stirred at room temperature for 2 hrs. The mixture was partitioned between DCM and water. The organic phase was washed with brine (x2), passed through a phase separator and concentrated under reduced pressure to afford tert-butyl 3-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1 -naphthyl]-11-[[rac-(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3,8- diazabicyclo[3.2.1]octane-8-carboxylate (313mg, crude) as a brown solid. Material was used without further purification.

UPLC-MS (ES⁺, Method 5): 1.93 min, m/z 766.3 [M+H]⁺.

Step C, 4-[13-(3,8-diazabicyclo[3.2.1]octan-3-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9), 2, 4, 7,10,12-hexaen-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (example 12).

Trifluoroacetic acid (1.37 mL, 17.89 mmol) was added to a solution of tert-butyl 3-[7-[8- ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3,8-diazabicyclo[3.2.1 ]octane-8-carboxylate (274 mg, 0.36 mmol) and triethylsilane (571 μL, 3.58 mmol) in DCM (3 mL). The reaction was stirred at room temperature for 2 hrs. The reaction mixture was concentrated under reduced pressure. The residue was purified by reverse phase chromatography eluting 10-40% MeCN in water (+0.1 % formic acid) with fractions containing product isolated by SCX. The product was then purified by flash column chromatography eluting 0-100% EtOAc in petroleum ether followed by 0-20% MeOH in DCM). The residue was again purified by reverse phase chromatography eluting 10- 30% MeCN in water (+0.1 % formic acid) with fractions containing product isolated by SCX to afford 4-[13-(3,8-diazabicyclo[3.2.1]octan-3-yl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-7-yl]-5-ethynyl-6-fluoro-naphthalen-2-ol (19mg, 0.031 mmol, 8.54% yield).

UPLC-MS (ES⁺, Method 6): 2.80 min, m/z 622.2 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.21 (s, 1 H), 7.98 (m, 1 H), 7.89-7.80 (m, 2H), 7.51- 7.31 (m, 3H), 7.32-7.21 (m, 1 H), 7.0-6.94 (m, 1 H), 6.67-6.57 (m, 1 H), 5.28 (d, J = 53.5 Hz, 1 H), 4.18-3.90 (m, 4H), 3.83-3.70 (m, 1 H), 3.60-3.39 (m, 4H), 3.18-2.97 (m, 4H), 2.92-2.75 (m, 1 H), 2.22-1 .94 (m, 4H), 1 .95-1 .71 (m, 4H).

Table 9 describes examples that were made by analogy with example 12 (scheme 2), replacing [7- fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]boronic acid (A-10) with the appropriate boronic acid or boronate ester building block and/or E-l with the appropriate intermediate as outlined in the table.

Table 9

Example 16, 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[[(2R,8S)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan- 6-ol. Scheme 3

Step A, 4-[7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan- 6-ol. A mixture of 4-[7-chloro-11-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6- methyl-1,4-oxazepan-6-ol (50. mg, 0.1 mmol) ,[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]boronic acid (44.85mg, 0.12mmol) and Caesium Carbonate (63.05mg, 0.19mmol) in 1 ,4-Dioxane (0.75mL) and Water (0.25mL) was degassed with N₂ for 5 minutes then cataCXium A Pd G3, Methanesulfonato(diadamantyl-n- butylphosphino)-2'amino-1 ,1 '-biphenyl-2-yl)palladium(ll) (14.09mg, 0.02mmol) was added. The reaction mixture was heated in a sealed vial at 100°C for 2 hours. The reaction mixture was cooled down, diluted with ethyl acetate and filtered through a pad of celite, which was washed with ethyl acetate. The filtrate was evaporated to dryness and the residue was purified by flash column chromatography (KP-amino 5g column, eluent 0-5% MeOH in DCM, dry load) to afford 4-[7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (41 mg, 0.0514mmol, 53.169% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 2): 1.86 min, m/z 797.4 [M+H]⁺

Step B, 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-11 -[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1 (9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1 ,4-oxazepan-6-ol, (example 16). Cesium Fluoride (39.07mg, 0.26mmol) was added to a solution of 4-[7-[7-fluoro-3-hydroxy-8-(2- triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6- methyl-1,4-oxazepan-6-ol (41. mg, 0.05mmol) in DMF (1 mL). The reaction mixture was stirred at room temperature overnight. The reaction mixture was diluted with DCM and the organic phase was washed with water, brine (2x) then passed through a phase separator and evaporated to dryness. The residue was purified by flash column chromatography (KP-amino 4 g column, 0-6% MeOH in DCM, wet load DCM). The residue was loaded onto a pre- equilibrated SCX-2 column (1g, washing with MeOH and eluting in 1 N NH3/MeOH) to afford 4-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (13.2mg, 0.0206mmol, 40.052% yield) as a yellow solid.

UPLC-MS (ES+, Method 1): 2.84/2.87 min, m/z 641.5 [M+H]⁺. ¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.22-10.19 (m, 1 H), 8.02-7.96 (m, 1 H), 7.89-7.85 (m, 1 H), 7.48-7.41 (m, 1 H), 7.32-7.29 (m, 1 H), 7.06 (s, 0.4H), 7.00 (s, 0.6H), 6.79 (d, J = 2.0 Hz, 0.4H), 6.72 (d, J = 2.1 Hz, 0.6H), 2.59 (br s, 0.4H), 5.30 (d, J = 53.9 Hz, 1 H), 4.97 (d, J = 2.9 Hz, 0.6H), 4.21-3.89 (m, 5H), 3.86-3.52 (m, 5H), 3.44-3.34 (m, 1 H), 3.19-2.98 (m, 3H), 2.91- 2.79 (m, 1 H), 2.23-1.95 (m, 3H), 1.92-1.73 (m, 3H), 1.08 (s, 1 H), 0.99 (s, 2H).

Table 10 describes examples that were made by analogy with example 16 (scheme 3), replacing D-1 with the appropriate intermediate as outlined in the table.

Table 10

Example 18, 5-ethyl-6-fluoro-4-[11 -[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-13-[8-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11 -hexaen-7-yl]naphthalen-2-ol.

Scheme 4

Step A, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-

1.2.3.5.6.7-hexahydropyrrolizin-8-yl]methoxy]-13-[8-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaene. A stirring solution of 7-bromo-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-13-[8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3- yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaene (26. mg, 0.04mmol), cesium carbonate (27.82mg, 0.09mmol) and 2-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (19.1 mg, 0.05mmol) in 1 ,4-dioxane (1 mL) and water (0.2mL) was degassed with nitrogen for 5 minutes before adding cataCXium A Pd G3, Methanesulfonato(diadamantyl-n-butylphosphino)-2'amino-1 , 1 '-biphenyl-2- yl)palladium(ll) (6.43mg, 0.01 mmol). The reaction was sealed, vacuum degassed and filled with nitrogen (3x), and heated to 100°C for 4 hrs. The mixture was cooled down, diluted with DCM and passed through a phase separator and concentrated to dryness. The mixture was purified by column chromatography on a KP-Amino column (5g, 5-80% EtOAc in Pet ether, wet loaded in DCM), like fractions pooled and concentrated to afford 7-[8-ethyl-7-fluoro- 3-(methoxymethoxy)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-13-[8-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaene (12mg, 0.0162mmol, 36.614% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Method 5): 1.79 min, m/z 742.3 [M+H]⁺.

Step B, 5-ethyl-6-fluoro-4-[11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-13-[8-(3-hydroxypropyl)-3,8-diazabicyclo[3.2.1]octan-3-yl]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-7-yl]naphthalen-2-ol, (example 18). Boron tribromide 1 M in methylene chloride (0.02mL, 0.02mmol)was added dropwise to a stirring solution of 5-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-[[(2R,8S)-2-fluoro-

1 .2.3.5.6.7-hexahydropyrrolizin-8-yl]methoxy]-10-[8-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]pyrazolo[5,1-a]isoquinoline (12. mg, 0.02mmol) in DCM (1 mL) at 0°C under nitrogen. The mixture was stirred for 4 hrs, allowing to warm to room temperature. Further boron tribromide 1 M in methylene chloride (0.02mL, 0.02mmol) was added and stirring continued for 18 hrs. Further boron tribromide 1 M in methylene chloride (0.02mL, 0.02mmol) was added and stirring continued for 90 minutes. The mixture was concentrated in vacuo and purified by reverse phase chromatography (5.4 g C-18 cartridge, 15 - 40% acetonitrile (+0.1 % formic acid) in water (+0.1 % formic acid)). The product-containing fractions were combined and the solvent was removed in vacuo to give 5-ethyl-6-fluoro-4-[11-[[(2R,8S)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-13-[8-(3-hydroxypropyl)-3,8- diazabicyclo[3.2.1]octan-3-yl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (13), 2, 4, 7, 9,11- hexaen-7-yl]naphthalen-2-ol (3mg, 0.0039mmol, 24.346% yield) as a pale yellow solid. UPLC-MS (ES⁺, Method 1): 2.47 min, m/z 684.5 [M+H]⁺.

¹H NMR (400 MHz, MeOD-4) δ/ppm: 7.98 (d, J=2.8 Hz, 1 H), 7.73 (dd, J=5.6, 9.2 Hz, 1 H), 7.40 (d, J=3.6 Hz, 1 H), 7.28 (t, J=9.4 Hz, 1 H), 7.19 - 7.13 (m, 2H), 6.95 - 6.87 (m, 1 H), 5.70 - 5.56 (m, 1 H), 4.76 - 4.69 (m, 2H), 4.51 - 4.35 (m, 2H), 4.27 - 4.11 (m, 2H), 4.05 - 3.89 (m, 5H), 3.80 (t, J=5.6 Hz, 2H), 3.54 - 3.47 (m, 1 H), 3.27 - 3.20 (m, 1 H), 2.85 - 2.78 (m, 1 H), 2.59 - 2.46 (m, 2H), 2.43 - 2.34 (m, 2H), 2.30 - 2.15 (m, 5H), 2.09 - 2.02 (m, 2H), 1.86 - 1.72 (m, 1 H), 0.65 (t, J=7.2 Hz, 3H).

Example 19, (3R)-1-[7-(8-ethyl-7-fluoro -3-hydroxy-1-naphthyl )-11-[(1-methylpyrrolidin -

2-yl)methoxy]-5,6,10,12-tetrazatncyclo[7.4.0.02,6]trideca -1(13),2,4,7,9,11-hexaen-13-yI] -

3-methyl-piperidin -3-ol.

Scheme 5

Step A, (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1-methylpyrrolidi-n2- yl)methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl- piperidin-3-ol. Lithium bis(trimethy lsilyl)amide (1.0 M in THF) (0.16mL, 0.16mmol) was added to a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol (100. mg, 0.08mmol) and (1-methylpyrrolidin-2-yl)methanol (19.54uL, 0.16mmol) in THF (2mL) under inert atmosphere at room temperature and the resulting solution was stirred overnight. More l-Methyl-2- pyrrolidinemethanol (19.54uL, 0.16mmol) and lithium bis(trimethylsilyl)amide (0.33mL, 0.33mmol) were added at room temperature stirring for 3.5hrs. The mixture was quenched with water (0.5mL) and concentrated. The wet residue was taken up in EtOAc, filtered through a phase separator and concentrated to afford (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1- methylpyrrolidin-2-yl)methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen- 13-yl]-3-methyl-piperidin-3-ol (51.7mg, 0.0822mmol, 99.938% yield) as a yellow crude oil.

UPLC-MS (ES⁺, Method 5): 1.80 min, m/z 629.3 [M+H]⁺.

Step B, (3R}-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[(1-methylpyrralidin-2-yl}methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol (example 19). Trifluoroacetic acid (0.31mL, 4.06mmol) was added to a solution of (3R)-1-[7-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1-methylpyrrolidin-2-yl)methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol (51. mg,

0.08mmol) and triethylsilane (0.13mL, 0.81mmol) in DCM (1.5mL). The mixture was stirred at room temperature 3.5hrs. The mixture was concentrated to dryness, taken up in MeOH and loaded onto a pre-equilibrated SCX-2 column (lg, washing with MeOH and eluting in IN NH3/MeOH). The residue was purified by flash chromatography (4g column, gradient 0-8% MeOH in DCM, dry load) and re- purified by reverse flash chromatography (5g column, gradient 10-50% MeCN in Water, acidic 0.1% FA, 80CV, celite dry load). Product containing fractions were loaded onto a pre-equilibrated SCX-2 column (lg, washing with MeOH and eluting in IN NH3/MeOH). The ammonia filtrate was evaporated to dryness to afford (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[(1-methylpyrrolidin-2- yl)methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl- piperidin-3-ol (6.6mg, 0.0113mmol, 13.916% yield) as an off-white solid.

UPLC-MS (ES⁺, Method 1): 3.26/3.28 min, m/z 585.5 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 9.98 (s, 1H), 7.95-7.88 (m, 1H), 7.79 (dd, J = 9.2, 5.9 Hz, 1H), 7.40-7.30 (m, 2H), 7.19-7.15 (m, 1H), 7.11 (s, 1H), 6.87 (br s, 1H), 4.66-4.34 (m, 2H), 4.33-4.20 (m, 1H), 4.04-3.74 (m, 1H), 3.26-3.16 (m, 1H), 3.09-2.96 (m, 1H), 2.84-2.65 (m, 1H), 2.44 (s, 3H), 2.40-2.34 (m, 1H), 2.31-2.22 (m, 1H), 2.20-2.09 (m, 1H), 2.07-1.94 (m, 2H), 1.92-1.80 (m, 1H), 1.79-1.54 (m, 7H), 1.10- 0.91 (m, 3H), 0.57-0.36 (m, 3H). Table 1 1 describes examples that were made by analogy with example 19 (scheme 5), replacing (1-methylpyrrolidin-2-yl)methanol and F-1 with the appropriate intermediates as outlined in the table.

Table 11

Example 66, (3R)-1-[7-(8-ethyl-7-fluoro -3-hydroxy-1-naphthyl)-11- [[1 -(pyrrolidin -1- ylmethyl)cyclopropynmethoxy]-5,6,10,12-tetrazatricyclo 7.4.0.02,6]trideca- 1(9), 2,4, 7,10,12-hexaen-13-yl]-3-methyl-piperidin -3-oL

Example 66

Scheme 6

Step A, (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1-

(hydroxymethyi)cyclopropyl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol. Lithium bis(trimethylsilyl)amide (1 M in THF) (O.75mL, O.75mmol) was added dropwise to a solution of (1-(Hydroxymethyl)cyclopropyl]methanol (76.3mg, 0.75mmol) in THF (2 mL) under an inert atmosphere at room temperature. The reaction mixture was stirred for 20 minutes before the addition of a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol (227. mg, 0.19mmol) in THF (2 mL). The resulting solution was stirred over the weekend. Lithium bis(tri methylsilyl )a mide (1 M in THF) (0.4 mL, 0.4 mmol) was added and the reaction stirred for another hour. The reaction mixture was quenched with water (5 mL), extracted into DCM (3 x 10 mL), washed with water (10 mL) and brine (2 x 10 mL), filtered through a phase separator, and concentrated under reduced pressure. The residue was purified by flash chromatography (0-100% EtOAc in petrol) to give (3R)-1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-11-[(1-(hydroxymethyl)cyclopropyl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-13-yl]-3-methyl-piperidin-3-ol (30mg,

0.0419mmol, 22.436% yield) as a pale yellow oil.

UPLC-MS (ES⁺, Method 5): 1 .95 min, m/z 616.3 [M+H]⁺.

Step B, 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-13-[(3R)-3-hydroxy-3-methyl-1- piperidyl]-5, 6,10, 12-tetrazatricyclo[7.4.0.02,6]trideca-1(13), 2, 4,7,9, 11-hexaen-11-yl]oxymethyl]cyclopropanecarbaldehyde. Dess Martin periodinane (21.33mg, 0.05mmol) was added to a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1- (hydroxymethyl)cyclopropyl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11- hexaen-13-yl]-3-methyl-piperidin-3-ol (30. mg, 0.04mmol) in DCM (1 mL) at room temperature and stirred for 3hrs. Further Dess Martin periodinane (21.33mg, 0.05mmol) was added and the reaction stirred for 1 hr. The reaction was quenched with an aqueous solution of Na₂S₂O₃:NaHCO₃ (1:1, 5 mL), diluted with DCM (10 mL), washed with saturated sodium bicarbonate solution (10 mL) and brine (10 mL), filtered through a phase separator, and concentrated under reduced pressure to give 1-[[7-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-13-[(3R)-3-hydroxy-3-methyl-1-piperidyl]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-11- yl]oxymethyl]cyclopropanecarbaldehyde (38mg, 0.0489mmol, 116.74% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 2.07 min, m/z 614.3 [M+H]⁺.

Step C, (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1-(pyrrolidin-1- ylmethyl)cyclopropyl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3-methyl-piperidin-3-ol. Sodium triacetoxyborohydride (31.1mg, 0.15mmol) was added to a solution of 1-[[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-13-[(3R)-3-hydroxy-3- methyl-1-piperidyl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(13),2,4,7,9,11-hexaen-11- yl]oxymethyl]cyclopropanecarbaldehyde (38. mg, 0.05mmol), pyrrolidine (6 μL, 0.07 mmol), and acetic acid (0.01mL, 0.1mmol) in DCM (1 mL) and the resulting solution was stirred for 2hrs at room temperature. The reaction was quenched with saturated aqueous sodium bicarbonate solution (2 mL), diluted with DCM (10 mL), washed with water (10 mL), and brine (10 mL), filtered through a phase separator, and concentrated under reduced pressure to give (3R)-1-[7-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-11-[(1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (27mg, 0.0339mmol, 69.323% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 1.87 min, m/z 669.3 [M+H]⁺. Step D, (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[(1-(pyrrolidin-1- ylmethyl}cyclopropyl]methoxy]-5,6,,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3-methyl-piperidin-3-ol (example 66). Trifluoroacetic acid (0.13mL, 1.7mmol) was added to a solution of (3R)-1-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[(1-(pyrrolidin- l-ylmethyl)cyclopropyl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-3-methyl-piperidin-3-ol (27. mg, 0.03mmol) and triethylsilane (0.05mL, 0.34mmol) in DCM (1 mL) and the resulting solution was stirred at room temperature overnight. The reaction mixture was concentrated under reduced pressure and the residue was purified by reverse phase chromatography (20-50% MeCN in H₂O) and a SCX-2 column (1 g) and washing with MeOH (4x) and 1 M NH₃ in MeOH (4x), which, after drying, gave (3R)-1-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-11- [(1-(pyrrolidin-1-ylmethyl)cyclopropyl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (5mg, 0.008mmol, 23.6% yield) as a yellow solid.

UPLC-MS (ES⁺, Method 1): 3.43 min, m/z 625.6 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 9.97 (s, 1 H), 7.92 - 7.90 (m, 1 H), 7.81 - 7.77 (m, 1 H), 7.38 - 7.32 (m, 2H), 7.17 - 7.15 (m, 1 H), 7.10 (s, 1 H), 6.88 (br s, 1 H), 4.32 - 4.28 (m, 2H), 2.17 - 1.80 (m, 7H), 1.70 - 1.58 (m, 9H), 1.26 - 1.22 (m, 1 H), 1.09 - 0.96 (m, 3H), 0.62 - 0.59 (m, 2H), 0.51 (t, J = 7.2 Hz, 1 H), 0.46 - 0.40 (m, 4H).

Table 12 describes examples that were made by analogy with example 66 (scheme 6), replacing F-1 , [1-(hydroxymethyl)cyclopropyl]methanol and pyrrolidine with the appropriate intermediates as outlined in the table.

Table 12

Example 92, 6-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-azaspiro[3.5]nonan-2- ol.

Scheme 7

Step A, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-8-fluoro- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol. To a solution of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfanyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-ol (200. mg, 0.4mmol) in DCM (4mL) at room temperature was added m-chloroperbenzoic acid (144. mg, 0.83mmol). The reaction mixture was stirred at room temperature for 3 hrs. More m-chloroperbenzoic acid (92. mg, 0.53mmol) was added and the reaction mixture was stirred at room temperature for 24 hrs then was diluted with dichloromethane and washed with sat. aq. NaHCO3 and brine. The organic phase was passed through a phase separator and evaporated to dryness to afford 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-ethylsulfonyl-8-fluoro-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (11 1 mg, 0.1260mmol,

31 .284% yield) as a brown oil.

UPLC-MS (ES⁺, Method 2): 1.83 min, m/z 529.3 [M+H]⁺.

Step B, 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-11-[[(2R,8S)-2- fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol. To a solution of ((2R,7aS)- 2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (66.87mg, 0.42mmol) in THF (1 mL) was added lithium bis(trimethylsilyl)amide in THF (0.42mL, 0.42mmol) at room temperature. After stirring for 20 minutes, a solution of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11- ethylsulfonyl-8-fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13- ol (111 . mg, 0.21 mmol) in THF (1 mL) was added. The reaction mixture was heated at 40°C overnight. More ((2R,7aS)-2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (33.43mg, 0.21 mmol) and lithium bis(trimethylsilyl)amide in THF (0.21 mL, 0.21 mmol) were added. The reaction mixture was heated at 40°C overnight. Water was added and the aqueous phase was extracted with ethyl acetate (3x). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100% then methanol in dichloromethane 0-20% to afford 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8- fluoro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (31 mg, 0.0522mmol,

24.866% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 1.76 min, m/z 594.2 [M+H]⁺.

Step C, 6-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-11-[[(2R,8S)-2- fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-azaspiro[3.5]nonan-2- ol. To a solution of 7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-8-fluoro-11-[[(2R,8S)- 2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-ol (31. mg, 0.05mmol) in DMF (0.50mL) at room temperature was added 6-azaspiro[3.5]nonan-2-ol (21 .mg, 0.15mmol) and N,N -diisopropylethylamine (0.05mL, 0.31 mmol). HATU (39.71 mg, 0.1 mmol) was then added and the reaction mixture was stirred at room temperature overnight. Water was added and the aqueous phase was extracted with ethyl acetate (3x). The organic phases were washed with brine, passed through phase separator filter paper and evaporated to dryness. The residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100% then methanol in dichloromethane to afford 6-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-8- fluoro- 11-[[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6- azaspiro[3.5]nonan-2-ol (14mg, 0.0195mmol, 37.399% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 1.79/1.82 min, m/z 717.3 [M+H]⁺.

Step D, 6-[7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-azaspiro[3.5]nonan-2- ol (example 92). Trifluoroacetic acid (0.04mL, 0.49mmol) and triethylsilane (0.02mL, 0.1 mmol) were added to a solution of 6-[7-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]- 8-fluoro-1 1-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-azaspiro[3.5]nonan-2-ol (14. mg, 0.02mmol) in DCM (0.20mL). The reaction mixture was stirred at room temperature for 3 hrs and was evaporated to dryness. The residue was loaded onto a SCX, washed with methanol then eluted with NH3 in methanol. The residue was purified by flash column chromatography eluting with EtOAc in petroleum ether 0-100% then methanol in dichloromethane 0-20% to afford 6-[7-(8-ethyl-7-fluoro-3-hydroxy-1 -naphthyl)-8-fluoro-11- [[rac-(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-6-azaspiro[3.5]nonan-2-ol (1 1 .9mg, 0.0177mmol, 90.567% yield) as a pale yellow solid.

UPLC-MS (ES⁺, Method 1): 3.35 and 3.43 min, m/z 718.6 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.06 (s, 1H), 7.98 (s, 1H), 7.82 (dd, J=5.9, 8.7 Hz, 1H), 7.44 (d, J=2.6 Hz, 1H), 7.37 (t, J=9.4 Hz, 1H), 7.27 (s, 1H), 6.81 (s, 1H), 5.29 (d, J=54.1 Hz, 1H), 4.93 (d, J=6.0 Hz, 0.5H), 4.82 (d, J=5.8 Hz, 0.5H), 4.23 - 4.16 (m, 1H), 4.13 - 4.06 (m, 1H), 3.93 - 3.84 (m, 1H), 3.51 - 3.47 (m, 3H), 3.15 - 3.06 (m, 2H), 3.05 - 3.05 (m, 1H), 2.87 - 2.79 (m, 1H), 2.45 - 2.40 (m, 2H), 2.19 - 2.14 (m, 1H), 2.11 - 2.06 (m, 1H), 2.04 - 2.00 (m, 2H), 1.87 - 1.72 (m, 6H), 1.67 - 1.63 (m, 2H), 1.60 - 1.54 (m, 1H), 1.46 - 1.41 (m, 1H), 1.24 - 1.22 (m, 1H), 0.55 (t, J=7.1 Hz, 3H).

Table 13 describes examples that were made by analogy with example 92 (scheme7), replacing 6-azaspiro[3.5]nonan-2-ol with the appropriate intermediate as outlined in the table.

Table 13

Example 94, 5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[[(2R,8S)-2-fluoro-

1 ,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- fetrazatricyclo[7.4.0.62,S]trideca-1(9),2,4,7,10,12-hexaen-13-yl] -N,N-dimefhyl-4, 6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2 -carboxamide.

Scheme 8

Step A, 5-[11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-N,N-dimethyl-4, 6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2 -carboxamide. To ((2R,7aS)-2- Fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (30.79mg, 0.19mmol) in anhydrous DMF (0.3mL) at 0°C under N₂, was slowly added lithium bis(trimethylsilyl)amide (1 M in THF) (161.18uL, 0.16mmol). After stirring at room temperature for 10 minutes, the solution was added to a solution of 5-[11-ethylsulfonyl-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]-5,6, 10,12-tetrazatricyclo[7.4.0.02, 6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4] diazepine- 2-carboxamide (55mg, 0.06mmol) in DMF (0.5mL) at 0°C.

The reaction mixture was left to stir at 0°C for then was poured over sat. aq. NaHCO3. The aqueous layer was extracted with EtOAc (3x). The combined organics were passed through a phase separator and reduced in vacuo to afford 5-[11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-7-[7-fluoro-3-(methoxymethoxy)-8-(2- triisopropylsilylethynyl)-1-naphthyl]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine- 2-carboxamide (48mg, 0.0403mmol, 62.437% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 2.26 min, m/z 918.4 [M+H]⁺.

Step B, 5-[7-[7-fluoro-3-hydroxy-8-(2-tr!isopropylsilyiethynyl)-1-naphthyn-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydrapyrroliziii-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepme-2- carboxamide. To a solution of 5-[7-[7-fluoro-3-(methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1- naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-N,N-dimethyl-4,6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (48. mg, 0.05mmol) in methanol (l.1mL) was added hydrogen chloride (4N in dioxane) (0.13mL, 0.52mmol). After 6hrs, the reaction mixture was poured into sat. aq. NaHCO3. The aqueous layer was extracted with EtOAC (3x). The combined organics were washed with brine, passed through a phase separator and reduced in vacuo to afford 5-[7-[7-fluoro-3-hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (43mg, 0.0492mmol, 94.098% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 2): 1.88 min, m/z 874.7 [M+H]⁺.

Step C, 5-[7-(8-ethynyl-7-fiuoro-3-hydraxy-1-naphthyl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydrapyrrol!zin-8-yl]methaxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydrapyrazolo[1,5-a][1,4] diazepine-2 -carboxamide (example 94). Cesium fluoride (29.89mg, 0.2mmol) was added to a solution of 5-[7-[7-fluoro-3- hydroxy-8-(2-triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (43. mg, 0.05mmol) in DMF (0.5mL). The reaction mixture was allowed to stir at room temperature for 6hrs, then was partitioned between a layer of EtOAc (20 mL) and water (20 mL). The organic layer was separated and the aqueous layer was extracted with ethyl acetate (20 mL). The organic layers were combined, washed with water (10 mL), brine (10 mL), dried over sodium sulfate, filtered through a phase separator and concentrated under reduced pressure. The residue was dry-loaded to Celite and subjected to reverse phase chromatography (C18, 5g, MeCN in H2O, 0-100%, with 0.1% FA). Like fractions were combined, passed through an SCX-cartride (lg) and flushed off with NH3 (IM in MeOH) to afford 5-[7-(8-ethynyl-7-fluoro-3-hydroxy-1-naphthyl)-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12- hexaen-13-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-2-carboxamide (8mg, 0.0ll1mmol, 22.657% yield) as an off-white solid.

UPLC-MS (ES⁺, Method 1): 3.06 and 3.08 min, m/z 718.6 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.20 (s, 1 H), 7.99 (dd, J = 6.0, 9.2 Hz, 1 H), 7.88 (d, J = 2.0 Hz, 1 H), 7.45 (t, J = 8.9 Hz, 1 H), 7.44 (d, J = 2.6 Hz, 1 H), 7.30 (d, J = 2.2 Hz, 1 H), 7.02 (s, 1 H), 6.80 (d, J = 2.1 Hz, 1 H), 6.50 (sbr, 1 H), 5.27 (dbr, J = 50.6 Hz, 1 H), 4.92 (d, J = 15.0 Hz, 1 H), 4.82 (d, J = 15.0 Hz, 1 H), 4.45 (me, 2H), 4.08 - 3.88 (m, 4H), 3.28 (s, 3H), 3.12 - 2.98 (m, 3H), 2.94 (s, 3H), 2.89 - 2.78 (m, 1 H), 2.14 - 1 .70 (m, 9H) ppm.

Table 13 describes examples that were made by analogy with example 94 (scheme 8), replacing F-5 with the appropriate intermediate as outlined in the table.

Table 13

Example 96, (3R)-1-[7 -(7-fluoro-3-hydroxy-8-vinyl-1-naphthyl)-11-[[(2R)-2 -fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol.

Example 96

Scheme 9

Step A, (3R)-1-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol.

Cesium fluoride (152.81 mg, 1.01 mmol) was added to a solution of (3R)-1-[7-[7-fluoro-3- (methoxymethoxy)-8-(2-triisopropylsilylethynyl)-1-naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (166. mg, 0.2mmol) in DMF (0.60mL) and the reaction mixture was left to stir at room temperature for 1 hr. Water and EtOAc were added and the layers separated. The aqueous layer was extracted with further EtOAc. The combined organic fractions were washed with brine (2x), passed through phase separating filter paper and the solvent reduced in vacuo. The residue was purified by flash chromatography (5g KP-animo column, gradient 0-3% DCM in MeOH, wet load DCM) to afford (3R)-1-[7-[8-ethynyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (136mg, 0.2034mmol, 101.08% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 5): 1.77/1.79 min, m/z 669.3 [M+H]⁺.

Step B, (3R)-1-[7-[7-fluoro-3-(methoxymethoxy)-8-vinyl-1-naphthyl]-11 -[[(2R)-2-fluoro-

1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol.

Under inert atmosphere a round bottom flask was charged (3R)-1-[7-[8-ethynyl-7-fluoro-3- (methoxymethoxy)-1 -naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3- methyl-piperidin-3-ol (136. mg, 0.2mmol), methanol (2.0486mL) and quinoline (6.58uL, 0.06mmol). The reaction mixture was subjected to 3 cycles of vacuum/nitrogen, followed by addition of palladium, 5% on calcium carbonate (424.06mg, 0.1 mmol) then 3 cycles of vacuum/nitrogen were performed followed by 3 cycles of vacuum/hydrogen gas. The reaction mixture was stirred at room temperature under hydrogen for 3 days. More palladium, 5% on calcium carbonate (212.03mg, 0.05mmol) was added then 3 cycles of vacuum/nitrogen followed by 3 cycles of vacuum/hydrogen gas were performed. The reaction mixture was stirred for 3hrs and filtered through a pad of celite which was washed with EtOAc. The filtrate was concentrated to dryness and the residue was then taken up in methanol (2mL). Palladium, 5% on calcium carbonate (424.06mg, 0.1 mmol) was added. The reaction mixture was put under hydrogen gas as previously described and stirred under hydrogen at room temperature for 20hrs. The reaction mixture was filtered through celite which was washed well with EtOAc. The filtrate was concentrated under reduced pressure and the crude residue was purified by reverse flash chromatography (20g column 15μ, gradient 10-35% AON in Water, 0.1 % FA, 55CV). Product containing fractions were loaded onto a pre-equilibrated SCX-2 column (1g, washing with MeOH and eluting in 1 N NH3/MeOH) to afford (3R)-1-[7-[7-fluoro-3- (methoxymethoxy)-8-vinyl-1-naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3- methyl-piperidin-3-ol (26mg, 0.0388mmol, 19.06% yield) as a yellow oil.

UPLC-MS (ES⁺, Method 6): 3.87 min, m/z 671 .3 [M+H]⁺.

Step C, (3R)-1-[7-(7-fluoro-3-hydroxy-8-vinyl-1-naphthyl)-11 -[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1 (9),2,4,7,10,12-hexaen-13-yl]-3-methyl-piperidin-3-ol (example 96). Trifluoroacetic acid (0.15mL, 1.94mmol) was added to a solution of (3R)-1-[7-[7-fluoro-3-(methoxymethoxy)-8- vinyl-1-naphthyl]-11-[[(2R)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methy l-pipe rid in-3-o I (26. mg, 0.04mmol) and triethylsilane (0.06mL, 0.39mmol) in DCM (0.50mL). The reaction mixture was stirred at room temperature for 3 hrs. The reaction mixture was concentrated to dryness and the product was loaded onto a pre-equilibrated SCX-2 column (washing with MeOH and eluting in 1 N NH3/MeOH). The residue was purified by flash chromatography (5g KP- amino column, gradient 0-4% MeOH in DCM) to afford (3R)-1-[7-(7-fluoro-3-hydroxy-8- vinyl-1-naphthyl)-11-[[(2R)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12- tetrazatricyclo[7.4.0.02,6]trideca-1(9),2,4,7,10,12-hexaen-13-yl]-3-methy l-pipe rid in-3-o I (17.8mg, 0.0284mmol, 73.274% yield) as a light yellow solid.

UPLC-MS (ES⁺, Method 1): 3.20 and 3.23 min, m/z 627.6 [M+H]⁺.

¹H NMR (400 MHz, DMSO-d6) δ/ppm: 10.06 (s, 1 H), 7.91 -7.80 (m, 2H), 7.42-7.32 (m 2H), 7.30-7.23 (m, 1 H), 7.04-6.99 (m, 1 H), 6.87-6.59 (m, 1 H), 5.80-5.66 (m, 1 H), 5.29 (d, J = 54.9 Hz, 1 H), 4.73-4.63 (m, 1 H), 4.62-4.43 (m ,1 H), 4.42-4.22 (m, 1 H), 4.14 (dd, J = 10.4, 1.7 Hz, 1 H), 4.4 (t, J = 9.6 Hz, 1 H), 3.64-3.41 (m, 2H), 3.17-3.07 (m, 2H), 3.06-3.00 (m, 1 H), 2.89-2.80 (m, 1 H), 2.26-1 .94 (m, 5H), 1.91 -1.53 (m, 6H), 1.12-0.91 (m, 3H).

Table 14 describes examples that were made by analogy with example 96 (scheme 9), replacing as outlined in the table.

Table 14

Chiral separation of atropisomers

The individual atropisomers of compound 43 were isolated using chiral HPLC.

Separation was conducted on a KEZHE instrument equipped with a Cellulose SZ, 30*250mm, 5 μm column. The mobile phase was Hex/EtOH/2M NH₃-MeOH (85/15/0.5) and the flow rate was 40mL/min. The column temperature was held at 25°C and components detected at 220 and 254 nm. The method run time was 11 mins. Samples were injected as solution in IPA/DCM and injection volume was 0.6 mL per run. Fractions were pooled and freeze-dried to afford both atropisomers as white solids.

Separation of compound 43 (55mg) by separation by the above method afforded (6S)-4-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (43-A) (17.3mg) and (6S)-4-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (43-B) (19.7mg).

43-A

¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.05 (s, 1 H), 7.97 (d, J = 2.2 Hz, 1 H), 7.82 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.44 (d, J = 2.7 Hz, 1 H), 7.41 - 7.34 (m, 1 H), 7.25 (2.5 Hz, 1 H), 6.85 (d, J = 2.1 Hz, 1 H), 5.29 (d, J = 54.2 Hz, 1 H), 4.96 (s, 1 H), 4.17 (d, J = 10.3 Hz, 1 H), 4.09 (d, J = 10.3 Hz, 1 H), 4.04 - 3.84 (m, 4H), 3.81 - 3.66 (m, 2H), 3.56 - 3.49 (m, 1 H), 3.43 - 3.33 (m, 1 H), 3.15 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1 H), 2.45 - 2.35 (m, 1 H), 2.19 - 1.95 (m, 3H), 1.91 - 1.69 (m, 4H), 0.97 (s, 3H), 0.52 (t, J = 7.4 Hz, 3H).

UPLC-MS (ES^+/; Method 1): 3.24 min, m/z 663.5 [M+H]⁺.

43-B

¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.05 (s, 1 H), 7.98 (d, J = 2.2 Hz, 1 H), 7.83 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.44 (d, J = 2.7 Hz, 1 H), 7.41 - 7.35 (m, 1 H), 7.23 (2.5 Hz, 1 H), 6.86 (d, J = 2.1 Hz, 1 H), 5.29 (d, J = 53.3 Hz, 1 H), 5.01 (s, 1 H), 4.19 (d, J = 10.3 Hz, 1 H), 4.12 - 4.02 (m, 2H), 3.99 - 3.74 (m, 5H), 3.49 - 3.42 (m, 2H), 3.15 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1 H), 2.45 - 2.35 (m, 1 H), 2.18 - 1 .96 (m, 3H), 1.91 - 1 .69 (m, 4H), 0.85 (s, 3H), 0.54 (t, J = 7.4 Hz, 3H). UPLC-MS (ES^+/; Method 1): 3.25 min, m/z 663.6 [M+H]⁺.

The chiral purity of 43-A and 43-B was determined by calculation of enantiomeric excess (e.e.) following analytical chiral HPLC using a Cellulose SZ 4.6 mm* 250 mm, 3 μm column, with a mobile phase of 0.1 % DEA in Hex/EtOH (85/15), flow rate 1 .67 mL/min and peak detection at 254 nm. The e.e. was determined to be >99% Scheme 11

The individual atropisomers of compound 20 were isolated using chiral HPLC.

Separation was conducted on a Gilson 281 instrument equipped with CHIRALPAK IK, 30*250mm, 5 μm column. The mobile phase was Hex/EtOH/2M NH₃-MeOH (75/25/0.5) and the flow rate was 40mL/min. The column temperature was held at 25°C and components detected at 223 and 263 nm. The method run time was 24 mins. Samples were injected as solution in EtOH/MeOH and injection volume was 1 .2 mL per run. Fractions were pooled and freeze-dried to afford both atropisomers as white solids.

Separation of compound 20 (50mg) by separation by the above method afforded (6S)-4-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1 (9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1 ,4-oxazepan-6-ol (20-A) (14.7mg) and (6S)-4-[7-(8- ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8-fluoro-11-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca- 1(9),2,4,7,10,12-hexaen-13-yl]-6-methyl-1,4-oxazepan-6-ol (20-B) (14.2mg).

20-A

¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.05 (s, 1 H), 7.92 (d, J = 2.1 Hz, 1 H), 7.82 (dd, J = 9.2, 6.0 Hz, 1 H), 7.43 (d, J = 2.6 Hz, 1 H), 7.40 - 7.33 (m, 1 H), 7.25 (d, J = 2.6 Hz, 1 H), 6.70 (d, J = 2.1 Hz, 1 H), 5.29 (d, J = 53.9 Hz, 1 H), 4.15 (d, J = 10.3 Hz, 1 H), 4.08 (d, J = 10.3 Hz, 1 H), 4.02 - 3.76 (m, 1 H), 3.56 - 3.41 (m, 4H), 3.16 - 2.97 (m, 3H), 2.88 - 2.78 (m, 1 H), 2.44 - 2.37 (m, 1 H), 2.21 - 1 .95 (m, 4H), 1 .92 - 1 .51 (m, 9H), 0.52 (t, J = 7.5 Hz, 3H).

UPLC-MS (ES^+/; Method 1): 2.66 min, m/z 644.5 [M+H]⁺.

20-B

¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.05 (s, 1 H), 7.92 (d, J = 2.1 Hz, 1 H), 7.82 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.43 (d, J = 2.6 Hz, 1 H), 7.40 - 7.33 (m, 1 H), 7.25 (d, J = 2.6 Hz, 1 H), 6.70 (d, J = 2.1 Hz, 1 H), 5.29 (d, J = 53.9 Hz, 1 H), 4.19 (d, J = 10.3 Hz, 1 H), 4.05 (d, J = 10.3 Hz, 1 H), 4.02 - 3.81 (m, 1 H), 3.55 - 3.41 (m, 4H), 3.16 - 2.98 (m, 3H), 2.88 - 2.78 (m, 1 H), 2.44 - 2.37 (m, 1 H), 2.18 - 1 .95 (m, 4H), 1 .89 - 1 .51 (m, 9H), 0.52 (t, J = 7.4 Hz, 3H).

UPLC-MS (ES^+/; Method 1): 2.66 min, m/z 644.5 [M+H]⁺.

The chiral purity of 20-A and 20-B was determined by calculation of enantiomeric excess (e.e.) following analytical chiral HPLC using a CHIRALPAK IK-3 4.6* 50 mm, 3 μm column, with a mobile phase of 0.1 % DEA in Hex/EtOH (70/30), flow rate 1 .67 mL/min and peak detection at 254 nm. The e.e. was determined to be >99%.

The individual atropisomers of compound 57 were isolated using chiral HPLC.

Separation was conducted on a Gilson 281 instrument equipped with a Cellulose SZ, 30*250mm, 5 μm column. The mobile phase was Hex/EtOH/DEA (85/15/0.5) and the flow rate was 40mL/min. The column temperature was held at 25°C and components detected at 220 and 254 nm. The method run time was 16 mins. Samples were injected as solution in EtOH/DCM and injection volume was 1 mL per run. Fractions were pooled and freeze-dried to afford both atropisomers as white solids.

Separation of compound 57 (94mg) by the above method afforded (6S)-4-[11-[[1- [(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]-6-methyl- 1,4-oxazepan-6-ol (57-A) (25.1 mg) and (6S)-4-[11-[[1-

[(dimethylamino)methyl]cyclopropyl]methoxy]-7-(8-ethyl-7-fluoro-3-hydroxy-1-naphthyl)-8- fluoro-5,6,10,12-tetrazatricyclo[7.4.0.02,6]trideca-1 (9),2,4,7,10,12-hexaen-13-yl]-6-methyl- 1,4-oxazepan-6-ol (57-B) (34.5mg). 57-A ¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.04 (s, 1 H), 7.97 (d, J = 2.2 Hz, 1 H), 7.82 (dd, J = 9.2, 6.1 Hz, 1 H), 7.44 (d, J = 2.6 Hz, 1 H), 7.41 - 7.33 (m, 1 H), 7.25 (d, J = 2.6 Hz, 1 H), 6.84 (d, J = 2.2 Hz, 1 H), 4.96 (s, 1 H), 4.33 (d, J = 10.8 Hz, 1 H), 4.28 (d, J = 10.8 Hz, 1 H), 4.06 - 3.83 (m, 4H), 3.80 - 3.66 (m, 2H), 3.57 - 3.48 (m, 1 H), 3.42 - 3.35 (m, 1 H), 2.48 - 2.26 (m, 1 H), 2.31 - 1.91 (m, 8H), 1.85 - 1 .72 (m, 1 H), 0.98 (s, 3H), 0.37 (s, 2H), 0.53 (t, J = 7.3 Hz, 3H), 0.43 (s, 2H).

UPLC-MS (ES^+/; Method 1): 3.47 min, m/z 633.5 [M+H]⁺. 57-B ¹H NMR (400 MHz, D6-DMSO) δ/ppm: 10.15 (s, 1 H), 8.00 (d, J = 2.1 Hz, 1 H), 7.83 (dd, J = 9.2, 6.0 Hz. 1 H), 7.46 (d, J = 5.6 Hz, 1 H), 7.42 - 7.34 (m, 1 H), 7.25 (d, J = 2.6 Hz, 1 H), 6.88 (d, J = 2.2 Hz, 1 H), 5.01 (s, 1 H), 4.36 (dd, J = 18.4, 11.8 Hz, 2H), 4.16 - 4.03 (m, 1 H), 3.98 - 3.76 (m, 5H), 3.54 - 3.41 (m, 2H), 3.20 - 3.14 (m, 2H), 2.85 (s, 6H), 2.46 - 2.38 (m, 1 H), 1.85 - 1.71 (m, 1 H), 0.95 - 0.74 (m, 7H), 0.55 (t, J = 7.3 Hz, 3H). UPLC-MS (ES^+/; Method 1): 3.44 min, m/z 633.6 [M+H]⁺.

The chiral purity of 57-A and 57-B was determined by calculation of enantiomeric excess (e.e.) following analytical chiral HPLC using a Cellulose SZ 4.6 mm* 250 mm, 3 μm column, with a mobile phase of 0.1 % DEA in Hex/EtOH (85/15), flow rate 1 .67 mL/min and peak detection at 254 nm. The e.e. was determined to be >99%

Biological results

HTRF Nucleotide exchange assay method

The capacity of compounds to bind KRAS G12D, other KRAS mutants and wildtype RAS isoforms was quantified using a HTRF nucleotide exchange assay. Recombinant human RAS protein (2 nM; aa1-188 KRAS WT, HRAS WT, NRAS WT, or KRAS containing the G12D, G13D or Q61 H amino acid substitutions, or4nM KRAS; aa1-188 containing the G12V, G12C, G12A or G12S amino acid substitution, an N-terminal 6xHis-tag and leader sequence), and 2nM Europium-labeled anti-6xHis antibody were mixed in assay buffer (10 mM HEPES pH 7.3, 150 mM NaCI, 5 mM MgCI₂, 0.05% BSA, 0.0025% NP-40 and 100 mM KF) with various concentrations of compound in a 384-well plate and a volume of 5 μL. After a 60-minute incubation at room temperature, 5 μl of 200 nM EDA-GTP-DY647P1 (diluted in assay buffer) was added to the plate. Following 30-minute incubation at room temperature, time-resolved fluorescence was measured on a PerkinElmer Envision plate reader. DMSO (0.3%) and unlabeled GDP (1 μM) or equivalent tool compound were used to generate the Max and Min assay signals, respectively. Data was analysed using a four-parameter logistic model to calculate IC₅₀ values, with at least two independent replicates were performed for each compound. The results are presented as IC₅₀S in Table 15 where “A” corresponds to an IC₅₀ ≤ 10 nM, “B” to an IC₅₀ >10 nM up to 100 nM, “C” is >100 nM up to 10 μM, “D” represents < 49% inhibition at 10 μM and ND = not determined:

Table 15

Claims

Claims

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

Z¹ is independently selected from -O- and -NR^5a-;

Z² is independently absent or is selected from -O- and -NR^5b-;

X¹ is independently selected from N and CR^3b;

R¹ is independently selected from C₀-C₃-alkylene-R^1a and C₂-C₆-alkylene-R^1b; wherein R^1a is independently selected from: a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a C₃-C₇-cycloalkyl ring optionally substituted with an NR⁷R⁸ group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R⁹ groups; R^1b is independently selected from: NR⁷R⁸, OR⁸, SR⁸, SOR⁸, SO₂R⁸ and SO(NH)R⁸; or R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups;

R² is independently C₁-C₆-alkyl, C₁-C₄-haloalkyl, C₀-C₄-alkylene-R^2a, C₁-C₄-alkylene-R^2b, C₂- C₄-alkylene-R^2c;

R^2a is independently selected from monocyclic 4- to 7-membered heterocycloalkyl group; a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group; a 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl group; phenyl; and C₃-C₇-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R^2a group is optionally substituted with from 1 to 6 R¹⁰ groups and any heteroaryl or phenyl R^2a group is optionally substituted with from 1 to 6 R¹¹ groups; wherein R^2b is independently selected from CONR¹²R¹² and CO₂R¹²; wherein R^2c is independently selected from NR¹²R¹³ and OR¹²; or R² and R^5b together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group; and a fused, spirofused or bridged bicyclic 6- to 1 1 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R¹⁰ groups; R^3a and R^3b are each independently selected from: H, halo, C₁-C₄-alkyl, O-C₁-C₄-alkyl, C₁-C₄- haloalkyl, O-C₁-C₄-haloalkyl, cyclopropyl, nitro and cyano;

R⁴ is independently selected from phenyl, said phenyl being optionally fused to a C₅-C₇- cycloalkyl ring; naphthyl; monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl; and 5-, to 10-membered monocyclic or bicyclic heterocyclyl; wherein R⁴ is optionally substituted with from 1 to 4 R¹⁴ groups;

R^5a, R^5b, R⁸ and R¹² are each independently selected at each occurrence from H, C₁-C₄- haloalkyl, cyclopropyl and C₁-C₄-alkyl;

R⁶ is independently selected from H, halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl;

R^6a is independently selected from H, halo, cyano, C₁-C₄-haloalkyl, C₁-C₄-alkyl and C₃-C₄- cycloalkyl;

R⁷ and R¹³ are each independently at each occurrence selected from H, C₁-C₄-alkyl, C₁-C₄- haloalkyl and C(O)-C₁-C₄-alkyl; or R¹² and R¹³ together with the nitrogen to which they are attached form a ring system selected from: monocyclic 4- to 7-membered heterocycloalkyl group; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; said heterocycloalkyl group being optionally substituted with from 1 to 6 R^10a groups;

R⁹ is independently at each occurrence selected from hydroxyl, oxo, halo, cyano, NR¹²R¹³, OR¹², COR¹², CO₂R¹², CONR¹²R¹³, C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R¹⁰ is independently at each occurrence selected from oxo, halo, cyano, NR¹²R¹³, OR¹², COR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R^10a is independently at each occurrence selected from oxo, halo, cyano, NR¹²R^13a, OR¹², COR¹², CO₂R¹², CONR¹²R^13a, C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R^13a, C₁-C₄-alkyl substituted with OR¹², C₁-C₄-alkyl substituted with cyano, C₁-C₄-alkyl substituted with phenyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl;

R^13a is independently at each occurrence selected from H, C₁-C₄-alkyl, C₁-C₄-haloalkyl and C(O)-C₁-C₄-alkyl;

R¹¹ is independently selected from halo, cyano, nitro, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁- C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄-alkyl substituted with OR¹², monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl and cyclopropyl; R¹⁴ is independently at each occurrence selected from CF₃, hydroxyl, halo, cyano, nitro, NR¹²R¹³, OR¹², CO₂R¹², CONR¹²R¹², C₁-C₄-alkyl, C₁-C₄-alkyl substituted with NR¹²R¹³, C₁-C₄- alkyl substituted with OR¹², C₂-C₄-alkenyl, C₂-C₄-alkynyl, C₁-C₄-haloalkyl, phenyl and cyclopropyl; wherein any of the aforementioned alkyl, alkylene, phenyl or cycloalkyl (e.g. cyclopropyl) groups is optionally substituted, where chemically possible, by 1 to 5 substituents which are each independently at each occurrence selected from the group consisting of: C₁-C₄-alkyl, C₁- C₄-alkyl substituted with OR^a, halo, nitro, cyano, NR^aR^b, OR^a, SR^a, CO₂R^a, C(O)R^a, CONR^aR^a; wherein R^a is independently at each occurrence selected from H, C₁-C₄-alkyl and C₁-C₄- haloalkyl; and R^b is independently at each occurrence selected from H, C₁-C₄-alkyl, C(O)-C₁- C₄-alkyl and S(O)₂-C₁-C₄-alkyl.

2. The compound of claim 1 , wherein R¹ and R^5a are selected such that NR¹R⁵ comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine.

3. The compound of claim 1 or claim 2, wherein R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 1 1 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; and a bridged bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R⁹ groups; wherein the nitrogen to which R¹ and R^5a are attached is the only nitrogen in the ring system.

4. The compound of any one of claims 1 to 3, wherein R¹ and R^5a together with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7- membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups; a fused or spirofused bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R⁹ groups.

5. The compound of claim 4, wherein R¹ and R⁵ together with the nitrogen to which they are attached form a ring system having the structure: wherein R^9a is selected from NR¹²R¹³ and C₁-C₄-alkyl substituted with NR¹²R¹³; p1 is selected from 0, 1 , 2 and 3, q1 is selected from 0, 1 and 2; and r1 is selected from 0, 1 , 2 and 3.

6. The compound of claim 4, wherein R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Z⁶ is independently selected from C(O)NR^9b, NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b) and S(O)(NH); R^9b is selected from H and C₁-C₄-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1 , 2 and 3.

7. The compound of claim 5, wherein R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein Z⁶ is independently selected from C(O)NR^9b, O, S, S(O)₂, S(O), S(O)(NR^9b), S(O)(NH) and NR^9b; R^9b is independently at each occurrence selected from H and C₁-C₄- alkyl; and n6 is an integer selected from 0, 1 , 2, 3 and 4.

8. The compound of claim 6, wherein Z⁶ may be O.

9. The compound of claim 6, wherein R¹ and R^5a together with the nitrogen to which they are attached form a ring system having the structure: wherein R¹² is independently at each occurrence selected from H, C₁-C₄-haloalkyl, and C₁- C₄-alkyl; and n9 is an integer selected from 0, 1 , 2 and 3.

10. The compound of any one of claims 1 to 9, wherein R² has the structure: wherein R¹⁵ is independently selected from H, C₁-C₄-alkyl and R¹⁶ is independently selected from H, C₁-C₄-alkyl and cyclopropyl; or wherein R¹⁵ and R¹⁶ together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R¹⁰ groups; and y is independently selected from 0, 1 , 2, 3, and 4.

1 1 . The compound of claim 10, wherein R² has the structure: wherein z is independently selected from 0, 1 , 2, 3, and 4. of any one of claims 1-9, wherein R² has the structure:

, wherein R16 is independently selected from H, C₁- C₄ -alkyl and cyclopropyl.

13. The compound of any one of claims 1 to 12, wherein X¹ is N.

14. The compound of any one of claims 1 to 13, wherein R^3a is H.

15. The compound of any one of claims 1 to 13, wherein R^3a is F.

16. The compound of any one of claims 1 to 13, wherein R^3a is methyl.

17. The compound of any one of claims 1 to 16, wherein R⁴ is phenyl, said phenyl being optionally fused to a C₅-C₇-cycloalkyl ring, wherein R⁴ is optionally substituted with from 1 to 4 R¹⁴ groups.

18. The compound of any one of claims 1 to 16, wherein R⁴ has the structure:

, wherein x is independently selected from 0, 1 , 2, 3, and 4.

19. The compound of any one of claims 1 to 16, wherein R⁴ has the structure:

20. The compound of claim 19, wherein R⁴ has the structure:

21. The compound of any one of claims 1 to 16, wherein R⁴ is 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R¹⁴ groups.

22. The compound of any one of claims 1 to 21 , wherein R⁶ is selected from H, C₁-C₄- haloalkyl, C₁-C₄-alkyl and C₃-C₄-cycloalkyl.

23. The compound of any one of claims 1 to 22, wherein R⁶ is H.

24. The compound of any one of claims 1 to 23, wherein R^6a is selected from H, C₁-C₄- haloalkyl, C₁-C₄-alkyl and C₃-C₄-cycloalkyl.

25. The compound of any one of claims 1 to 24, wherein R^6a is H.

26. The compound of claim 1 , wherein the compound of formula (I) is selected from:

27. The compound of any one of claims 1 to 26, wherein the compound is configured for medical use.

28. The compound of any one of claims 1 to 26, wherein the compound is configured to be used to treat a cancer; wherein the cancer is at least one of pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

29. The compound of claim 28, wherein the cancer has wild-type KRAS.

30. The compound of claim 28, wherein the cancer has a KRAS mutation, the KRAS mutation is one of: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRAS G12S, KRAS G13D and KRAS Q61 H.

31 . A pharmaceutical composition comprising a compound of any one of claims 1 to 26 and a pharmaceutically acceptable excipient.