Pyrazolo[4,3-f]quinazoline derivatives as modulators of g12d mutant kras useful for the treatment of cancer

Abstract

This invention relates to compounds that may be useful for inhibiting RAS proteins. More specifically, this invention relates to compounds for inhibiting a broad spectrum of KRAS mutant proteins, including KRAS G12D. 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.

Description

PYRAZOLO[4,3-F]QUINAZOLINE DERIVATIVES AS MODULATORS OF G12D MUTANT KRAS USEFUL FOR THE TREATMENT OF CANCERCROSS-REFERENCE TO RELATED APPLICATIONS

[0001] The present application claims priority to GB2307077.4, filed on May 12, 2023, and entitled “COMPOUNDS,” and GB2319678.5 filed December 20, 2023, and entitled “COMPOUNDS,” the entire disclosures of which are expressly incorporated by reference herein.FIELD OF THE 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 Q61H. 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 WG2021 / 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 inventions there is provided a compound of formula (la), or a pharmaceutically acceptable salt thereof:whereinZ1is independently selected from -O- and -NR5a-;Z2is independently absent or is selected from -O- and -NR5b-;X1is independently selected from N and CR3b;X2is selected from N, NR6, O and S;X3is selected from N and NR6;X4is CR3c;R1is independently selected from Co-Cs-alkylene-R1aand C2-C6-alkylene-R1 b; wherein R1ais independently selected from: a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups; R1 bis independently selected from: NR7R8, OR8, SR8, SOR8, SO2R8and SO(NH)R8; or R1and R5atogether 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 R9groups; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups;R2is independently Ci-Ce-alkyl, Ci-C4-haloalkyl, Co-C4-alkylene-R2a, Ci-C4-alkylene-R2b, C2- C4-alkylene-R2c;R2ais 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 Cs-Cy-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R2agroup is optionally substituted with from 1 to 6 R10groups and any heteroaryl or phenyl R2agroup is optionally substituted with from 1 to 6 R11groups; wherein R2bis independently selected from CONR12R12and CO2R12; wherein R2cis independently selected from NR12R13and OR12; or R2and R5btogether 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 R10groups;R3a, R3band R3care each independently selected from: H, halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-Ci-C4-haloalkyl, cyclopropyl, nitro and cyano;R4is 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 R4is optionally substituted with from 1 to 4 R14groups;R5a, R5b, R8and R12are each independently selected at each occurrence from H, C1-C4- haloalkyl, cyclopropyl and Ci-C4-alkyl;R6is independently selected from H, Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl;R7and R13are each independently at each occurrence selected from H, Ci-C4-alkyl, C1-C4- haloalkyl and C(O)-Ci-C4-alkyl;or R12and R13together 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 R10agroups;R9is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, CONR12R13, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4- alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10ais independently at each occurrence selected from oxo, halo, cyano, NR12R13a, OR12, COR12, CO2R12, CONR12R12, CONR12R13a, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13a, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R13ais independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl;R11is independently selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, C1- C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R14is independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, C2-C4-alkenyl, C2-C4-alkynyl, Ci-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: Ci-C4-alkyl, C1- C4-alkyl substituted with ORa, halo, nitro, cyano, NRaRb, ORa, SRa, CO2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-alkyl and Ci-C4- haloalkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci- C4-alkyl and S(O)2-Ci-C4-alkyl.

[0015] In accordance with the present inventions there is provided a compound of formula (I), or a pharmaceutically acceptable salt thereof:X2-x4D1 "Z1Y2Rl' jY|YZ2RR3a(I)Z1is independently selected from -O- and -NR5a-;Z2is independently absent or is selected from -O- and -NR5b-;X1is independently selected from N and CR3b;X2is selected from N, NR6, O and S;X3is selected from N and NR6;X4is CR3c;R1is independently selected from Co-Cs-alkylene-R1aand C2-Ce-alkylene-R1 b; wherein R1ais independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups; R1 bis independently selected from: NR7R8, OR8, SR8, SOR8, SO2R8and SO(NH)R8; or R1and R5atogether 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 R9groups; a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups;R2is independently Ci-Ce-alkyl, Ci-C4-haloalkyl, Co-C4-alkylene-R2a, Ci-C4-alkylene-R2b, C2- C4-alkylene-R2c;R2ais 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; Cs-Cy-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R2agroup is optionally substituted with from 1 to 6 R10groups and any heteroaryl or phenyl R2agroup is optionally substituted with from 1 to 6 R11groups; wherein R2bis independently selected from CONR12R12and CO2R12; wherein R2cis independently selected from NR12R13and OR12; or R2and R5btogether 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 bridgedbicyclic 6- to 11 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R10groups;R3a, R3band R3care each independently selected from: H, halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-Ci-C4-haloalkyl, cyclopropyl, nitro and cyano;R4is 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 R4is optionally substituted with from 1 to 4 R14groups;R5a, R5b, R8and R12are each independently selected at each occurrence from H, C1-C4- haloalkyl, and Ci-C4-alkyl;R6is independently selected from H, Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl;R7and R13are each independently at each occurrence selected from H, Ci-C4-alkyl, C1-C4- haloalkyl and C(O)-Ci-C4-alkyl; or R12and R13together 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 R10groups;R9and R10are each independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, C1-C4- alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R11is independently selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, C1- C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R14is independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl; wherein any of the aforementioned alkyl, alkylene 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: Ci-C4-alkyl, halo, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-alkyl and Ci-C4-haloalkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci-C4-alkyl.

[0016] In accordance with the present inventions there is provided a compound of formula (lb), or a pharmaceutically acceptable salt thereof:whereinX1is independently selected from N and CR3b;X2is selected from N, NR6, O and S;X3is selected from N and NR6;X4is CR3c;R1is independently selected from Co-Cs-alkylene-R1aand C2-C6-alkylene-R1 b; wherein R1ais independently selected from; a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups; R1 bis independently selected from: NR7R8, OR8, SR8, SOR8, SO2R8and SO(NH)R8; or R1and R5atogether 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 R9groups; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups;R2is independently Ci-Ce-alkyl, Ci-C4-haloalkyl, Co-C4-alkylene-R2a, Ci-C4-alkylene-R2b, C2- C4-alkylene-R2c;R2ais 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; Cs-Cy-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R2agroup is optionally substituted with from 1 to 6 R10groups and any heteroaryl or phenyl R2agroup is optionally substituted with from 1 to 6 R11groups; wherein R2bis independently selected from CONR12R12and CO2R12; wherein R2cis independently selected from NR12R13and OR12; or R2and R5btogether 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 R10groups;R3a, R3band R3care each independently selected from: H, halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-Ci-C4-haloalkyl, cyclopropyl, nitro and cyano;R4is 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 R4is optionally substituted with from 1 to 4 R14groups;R5a, R5b, R8and R12are each independently selected at each occurrence from H, C1-C4- haloalkyl, cyclopropyl and Ci-C4-alkyl;R6is independently selected from H, Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl;R7and R13are each independently at each occurrence selected from H, Ci-C4-alkyl, C1-C4- haloalkyl and C(O)-Ci-C4-alkyl; or R12and R13together 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 R10agroups;R9is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, CONR12R13, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, C1-C4- alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10ais independently at each occurrence selected from oxo, halo, cyano, NR12R13a, OR12, COR12, CO2R12, CONR12R12, CONR12R13a, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13a, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R13ais independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl;R11is independently selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, C1- C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R14is independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, C2-C4-alkenyl, C2-C4-alkynyl, Ci-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: Ci-C4-alkyl, C1- C4-alkyl substituted with ORa, halo, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-alkyl and C1-C4- haloalkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci- C4-alkyl and S(O)2-Ci-C4-alkyl.

[0017] For the absence of doubt, the ring comprising X2and X3is selected from pyrazole, isoxazole and isothiazole. Thus, either X2is N and X3is NR6or X3is N and X2is selected from NR6, O and S.

[0018] In an embodiment, the compound of formula (I) is a compound of formula (II):wherein R1, R2, R3a, R4, R6, X1, Z1and Z2are as described above for compounds of formula (I).

[0019] In an embodiment, the compound of formula (I) is a compound of formula (III):wherein R1, R2, R3a, R4, R6, X1, Z1and Z2are as described above for compounds of formula (I).

[0020] In an embodiment, the compound of formula (I) is a compound of formula (IV):wherein R1, R2, R3a, R4, R6, Z1and Z2are as described above for compounds of formula (I).

[0021] In an embodiment, the compound of formula (I) is a compound of formula (IVa):wherein R1, R2, R4, Z1, and Z2are as described above for compounds of formula (I).

[0022] In an embodiment, the compound of formula (I) is a compound of formula (IVb):wherein R1, R2, R4, Z1, and Z2are as described above for compounds of formula (I).

[0023] In an embodiment, the compound of formula (I) is a compound of formula (V):wherein R1, R2, R3a, R4, R6, Z1and Z2are as described above for compounds of formula (I).

[0024] In an embodiment, the compound of formula (I) is a compound of formula (Va):wherein R2, R4, Z2are as described above for compounds of formula (I).

[0025] In an embodiment, the compound of formula (I) is a compound of formula (Vb):wherein R2, R4, Z2are as described above for compounds of formula (I).

[0026] In an embodiment, the compound of formula (I) is a compound of formula (Vc):wherein R2, R4, Z2are as described above for compounds of formula (I).

[0027] In an embodiment, the compound of formula (I) is a compound of formula (Vd):wherein R2, R4, Z2are as described above for compounds of formula (I).

[0028] In an embodiment, the compound of formula (I) is a compound of formula (VI):wherein R1, R2, R3a, R14, X1, X2, X3, X4, Z1and Z2are 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 R14groups may be attached to either ring of the naphthyl group.

[0029] In an embodiment, the compound of formula (I) is a compound of formula (VII):wherein R1, R2, R3a, R5a, R14, X2, X3and X4are 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 R14groups may be attached to either ring of the naphthyl group.

[0030] In an embodiment, the compound of formula (I) is a compound of formula (VIII):wherein R1, R3a, R4, R5a, R10, X2, X3and X4are as described above for compounds of formula (I); and wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; and y is independently selected from 0, 1 , 2, 3, and 4.

[0031] In an embodiment, the compound of formula (I) is a compound of formula (IX):wherein R1, R3a, R5a, R10, R14, X2, X3and X4are as described above for compounds of formula (I); wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; x is independently selected from 0, 1 , 2, 3, and 4; and y is independently selected from 0, 1 , 2, 3, and 4.

[0032] In an embodiment, the compound of formula (I) is a compound of formula (X):wherein R1, R3a, R4, R5a, R10, X2, X3and X4are 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 R10groups may be attached to either ring of the pyrrolizidinyl group.

[0033] In an embodiment, the compound of formula (I) is a compound of formula (XI):wherein R1, R3a, R5a, R10, R14, X2, X3and X4are 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.

[0034] In an embodiment, the compound of formula (I) is a compound of formula (XII):wherein R1, R2, R3a, R6, R14, X1, Z1and Z2are 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 R14groups may be attached to either ring of the naphthyl group.

[0035] In an embodiment, the compound of formula (I) is a compound of formula (XIII):wherein R1, R2, R3a, R6, R14, X1, Z1and Z2are 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 R14groups may be attached to either ring of the naphthyl group.

[0036] In an embodiment, the compound of formula (I) is a compound of formula (XIV):and x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R14groups may be attached to either ring of the naphthyl group.

[0037] In an embodiment, the compound of formula (I) is a compound of formula (XV):and x is independently selected from 0, 1 , 2, 3, and 4. For the absence of doubt, throughout this specification, the x R14groups may be attached to either ring of the naphthyl group.

[0038] In an embodiment, the compound of formula (I) is a compound of formula (XVI):wherein R1, R3a, R4, R5a, R6andR10are as described above for compounds of formula (I); and wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; and y is independently selected from 0, 1 , 2, 3, and 4.

[0039] In an embodiment, the compound of formula (I) is a compound of formula (XVII):wherein R1, R3a, R4, R5a, R6and R10are as described above for compounds of formula (I); and wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; and y is independently selected from 0, 1 , 2, 3, and 4.

[0040] In an embodiment, the compound of formula (I) is a compound of formula (XVIII):wherein R1, R3a, R5a, R6, R10, and R14are as described above for compounds of formula (I); wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; x is independently selected from 0, 1 , 2, 3, and 4; and y is independently selected from 0, 1 , 2, 3, and 4.

[0041] In an embodiment, the compound of formula (I) is a compound of formula (XIX):wherein R1, R3a, R5a, R6, R10, and R14are as described above for compounds of formula (I); wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independentlyselected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; x is independently selected from 0, 1 , 2, 3, and 4; and y is independently selected from 0, 1 , 2, 3, and 4.

[0042] In an embodiment, the compound of formula (I) is a compound of formula (XX):wherein R1, R3a, R4, R5a, R6and R10are 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 R10groups may be attached to either ring of the pyrrolizidinyl group.

[0043] In an embodiment, the compound of formula (I) is a compound of formula (XXI):wherein R1, R3a, R4, R5a, R6and R10are 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 R10groups may be attached to either ring of the pyrrolizidinyl group.

[0044] In an embodiment, the compound of formula (I) is a compound of formula (XXII):wherein R1, R3a, R5a, R6, R10, and R14are 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.

[0045] In an embodiment, the compound of formula (I) is a compound of formula (XXIII):wherein R1, R3a, R5a, R6, R10, and R14are 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.

[0046] In an embodiment, the compound of formula (I) is a compound of formula (XXIV):wherein R1, R3a, R5a, R6, and R10are as described above for compounds of formula (I); wherein z is independently selected from 0, 1 , 2, 3, and 4; and whereinR14ais OR12e.g., OH; R14bis Ci.C4-alkyl e.g., methyl or ethyl; and R14cis halo e.g, F.

[0047] In an embodiment, the compound of formula (I) is a compound of formula (XXV):wherein R3a, R6, R10, R9and R14are as described above for compounds of formula (I); wherein x is independently selected from 0, 1 , 2, 3, and 4; wherein n10 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.

[0048] In an embodiment, the compound of formula (I) is a compound of formula (XXVI):wherein R3a, R6, R9, R10and R14are as described above for compounds of formula (I); wherein R12is independently at each occurrence selected from H, and Ci-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.

[0049] The following embodiments apply to compounds of any of formulae (l)-(XXII I) . 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.

[0050] X1may be N. X1may be CR3b.

[0051] The ring comprising X2and X3may be pyrazole, The ring comprising X2and X3may be selected from isoxazole and isothiazole. It may be that X2is N and X3is NR6. It may be that X3is N and X2is selected from NR6, O and S. It may be that X3is N and X2is NR6. It may be that X3is N and X2is selected from O and S.

[0052] Z1may be -O-. Z1may be -NR5a-.

[0053] Z2may be -O-. Z2may be -NR5b-.

[0054] R1is independently Co-Cs-alkylene-R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0055] R1is independently Co-Cs-alkylene-R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cycycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0056] R1may be Co-C3-alkylene-R1a. R1may be Co-Cs-alkylene-R1awherein R1ais independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cycycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0057] R1may be Co-Cs-alkylene-R1awherein R1ais independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a Cs-Cycycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-R1awherein R1ais independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C3- Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein saidheterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0058] R1may be R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0059] R1may be R1awherein R1ais independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais an oxygen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1 ais an oxygen containing 4- to 7- membered heterocycloalkyl ring e.g. a tetrahydropyranyl ring.

[0060] R1is independently Co-Cs-alkylene-R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cycycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0061] R1may be Co-C3-alkylene-R1a. R1may be Co-Cs-alkylene-R1awherein R1ais independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cycycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a C3-C7- cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0062] R1may be Co-C3-alkylene-R1awherein R1ais independently selected from an oxygen containing 4- to 7- membered heterocycloalkyl ring, a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-R1awherein R1ais independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a C3-C7- cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0063] R1may be R1awherein R1ais independently selected from a 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0064] R1may be R1awherein R1ais independently selected from a nitrogen containing 4- to 7- membered heterocycloalkyl ring; and a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said heterocycloalkyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais an oxygen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais an oxygen containing 4- to 7- membered heterocycloalkyl ring e.g. a tetrahydropyranyl ring.

[0065] R1may be Co-Cs-alkylene-R1awherein R1ais a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-alkylene-R1awherein R1ais a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0066] R1may be Co-Cs-alkylene-R1awherein R1ais a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-alkylene-R1awherein R1ais a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0067] R1may be Co-Cs-alkylene-R1awherein R1ais 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 R9groups. R1may be CH2-alkylene-R1awherein R1ais 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 R9groups.

[0068] R1may be R1awherein R1ais a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais a nitrogen containing 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais a 4- to 7- membered heterocycloalkyl ring; wherein said heterocycloalkyl ring is optionally substituted with from 1 to 4 R9groups wherein the ring does not comprise any nitrogen atoms.

[0069] R1may be Co-Cs-alkylene-R1awherein R1ais a Cs-Cycycloalkyl ring substituted with an NR7R8group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups. R1may be CH2-alkylene-R1awherein R1ais a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0070] R1may be R1awherein R1ais a Cs-Cy-cycloalkyl ring optionally substituted with an NR7R8group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0071] R1may be R1awherein R1ais a Cs-Cy-cycloalkyl ring substituted with an NR7R8group; wherein said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups.

[0072] R1may be R1awherein R1ais phenyl optionally substituted with from 1 to 4 R9groups. R1may be R1awherein R1ais unsubstituted phenyl.

[0073] R1may be C2-Ce-alkylene-R1 b. R1may be C2-C3-alkylene-R1 b. R1may be C3-alkylene- R1 b. R1 bmay be independently selected from: NR7R8, OR8and SR8. R1 bmay be OR8. R1 bmay be SR8. R1 bmay be NR7R8. R8may be Ci-C4-alkyl, e.g. Me.

[0074] It may be that R1and R5aare selected such that NR1R5acomprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine. It may be that R1and R5aare selected such that NR1R5acomprises no more than a single secondary or tertiary 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.

[0075] It may be that R1and R5aare selected such that NR1R5acomprises more than one amine, wherein said amines may be a primary, secondary or tertiary amine. It may be that R1and R5aare selected such that NR1R5acomprises more than one amine, wherein said amines may be a secondary or tertiary amine. It may be that R1and R5aare selected such that NR1R5acomprises two amines, wherein said amines may be a primary, secondary or tertiary amine. It may be that R1and R5aare selected such that NR1R5acomprises two amines, wherein said amines may be a secondary or tertiaryamine. Compounds in which R1and R5aare selected such that NR1R5acomprises more than a single amine, e.g. two amines, typically inhibit KRAS G12D selectively.

[0076] It may be that R1and R5atogether 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 R9groups; a fused or spirofused bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; wherein the nitrogen to which R1and R5aare attached is the only heteroatom in the ring system.

[0077] It may be that R1and R5atogether 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 R9groups; a fused or spirofused bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; wherein the nitrogen to which R1and R5aare attached is the only nitrogen in the ring system.

[0078] It may be that R1and R5aare selected such that the nitrogen of NR1R5ais the nitrogen of the single amine. It may be that R1and R5aare selected such that NR1R5ais 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.

[0079] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein R9cis selected from H and Ci-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.

[0080] It may be that R1and R5atogether 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.

[0081] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having a structure selected from:

[0082] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups.

[0083] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; wherein the ring system does not comprise a nitrogen other than the nitrogen to which R1and R5aare attached.

[0084] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused or spirofused bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups.

[0085] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused or spirofused bicyclic6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups.

[0086] It may be that R1and R5atogether with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups. It may be that R1and R5atogether with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups, wherein the total number of heteroatoms in the 6 or 7- membered group heterocycloalkyl group is 1 or 2. The total number of heteroatoms may be 2. It may be that R1and R5atogether with the nitrogen to which they are attached form a 6 or 7-membered group heterocycloalkyl group, optionally substituted with 1 R9group.

[0087] It may be that R1and R5atogether with the nitrogen to which they are attached form a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups. It may be that R1and R5atogether with the nitrogen to which they are attached form an unsubstituted monocyclic 4- to 7-membered group heterocycloalkyl group. It may be that there is at least one R9group and that at least one of said R9groups is selected from NR12R13and Ci-C4-alkyl substituted with NR12R13. It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein R9ais selected from NR12R13and Ci-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. R9may independently at each occurrence be methyl. R9amay be selected from NHR12and Ci-C4-alkyl substituted with NHR12.

[0088] It may be that R1and R5atogether with the nitrogen to which they are attached form a monocyclic 4- to 7-membered group heterocycloalkyl group comprising two nitrogen atoms in the ring, optionally substituted with from 1 to 4 R9groups.

[0089] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein Z6is independently selected from C(O)NR9b, NR9b, O, S, S(O)2, S(O), S(O)(NR9b) and S(O)(NH); R9bis selected from H and Ci-C4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1 , 2 and 3. Z6may be selected from NR9b, O, S, S(O)2, S(O) and S(O)(NH). Z6may be selected from C(O)NR9b, O, S, S(O)2, S(O), S(O)(NR9b) and S(O)(NH). Z6may be selected from O, S, S(O)2, S(O) and S(O)(NH).Z6may be selected from NR9b, O and S. Z6may be selected from O and S. Z6may be O.

[0090] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:R9bZ' RV2<0>2^AL wherein R9bis selected from H and Ci-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. R9may independently at each occurrence be methyl. R9bmay be H. R9bmay be Ci-C4-alkyl.

[0091] It may be that R1and R5atogether 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 R9groups. It may be that R1and R5atogether 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 R9groups.

[0092] It may be that R1and R5atogether 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 R9groups. It may be that R1and R5atogether 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 R9groups. It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein R9bis selected from H and Ci-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 R9groups may be attached to either ring of the spirofused bicyclic ring system. R3 may be 0. R9may independently at each occurrence be methyl. R9bmay be H.

[0093] It may be that R1and R5atogether 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 R9groups. It may be that R1and R5atogether 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 R9groups. It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein R9bis selected from H and Ci-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 R9groups may be attached to either ring of the fused bicyclic ring system. R5 may be 0. R9may independently at each occurrence be methyl. R9bmay be H.

[0094] It may be that R1and R5atogether 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 R9groups.

[0095] It may be that R1and R5atogether 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 R9groups.

[0096] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7-membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused or spirofused bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; and a bridged bicyclic 6- to 11-membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not:

[0097] It may be that R1and R5atogether 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 R9groups, wherein the bridged bicyclic 6- to 11-membered heterocycloalkyl group is not:

[0098] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:, wherein Y1is independently selected from C(O)NR9d, O and NR17; Z3is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR17-CH2CH2and CH2-NR17-CH2; R17is independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; R9dis independently selected from H and Ci-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 R9groups may be attached to either ring of the bridged bicyclic ring system. Z3may be independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, Y1may be independently selected from O and NR17. Y1may be NR17. Y1may be NH. n1 may be 0. R9may independently at each occurrence be methyl.

[0099] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:, wherein Y1is independently selected from C(O)NR9d, O and NR17; Z4is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR17-CH2CH2and CH2-NR17-CH2; R17is independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; R9dis independently selected from H and Ci-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 R9groups may be attached to either ring of the bridged bicyclic ring system. Z4may be independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, Y1may be independently selected from O and NR17. Y1may be NR17. Y1may be NH. n2 may be 0. R9may independently at each occurrence be methyl.

[0100] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:, wherein Y1is independently selected from C(O)NR9d, O and NR17; R17is independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; R9dis independently selected from H and Ci-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 R9groups may be attached to either ring of the bridged bicyclic ring system. Y1may be independently selected from O and NR17. Y1may be NR17. Y1may be NH. n3 may be 0. R9may independently at each occurrence be methyl.

[0101] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:, wherein Y1is independently selected from C(O)NR9d, O and NR17; Z5is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2, CH2-NR17-CH2CH2and CH2-NR17-CH2; R17is independently at each occurrence selected from H, Ci-C4-haloalkyl,and Ci-C4-alkyl; R9dis independently selected from H and Ci-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 R9groups may be attached to either ring of the bridged bicyclic ring system. Z5is independently selected from: CH2, CH2CH2, CH2-O-CH2CH2, CH2-O-CH2. Y1may be independently selected from O and NR17. Y1may be NR17. Y1may be NH. n5 may be 0. R9may independently at each occurrence be methyl.

[0102] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein Z6is independently selected from C(O)NR9b, O, S, S(O)2, S(O), S(O)(NR9b), S(O)(NH) and NR9b; R9bis independently at each occurrence selected from H and Ci-C4-alkyl; and n6 is an integer selected from 0, 1 , 2, 3 and 4. n6 may be 0. Z6may be selected from NR9b, O, S, S(O)2, S(O), S(O)(NR9b), and S(O)(NH). Z6may be selected from C(O)NR9b, O, S, S(O)2, S(O), S(O)(NR9b), and S(O)(NH). Z6may be selected from C(O)NR9b, O, S, S(O)2, S(O) and S(O)(NH). Z6may be selected from O, S, S(O)2, S(O) and S(O)(NH). Z6may be selected from NR9b, O and S. Z6may be selected from O and S. Z6may be O.

[0103] It may be that R1and R5atogether 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.

[0104] It may be that R1and R5atogether 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.

[0105] It may be that R1and R5atogether 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.

[0106] n7 may be 0.

[0107] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:Wherein R12is independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci- C4-alkyl; and n9 is an integer selected from 0, 1 , 2 and 3. R12may be Ci-C4-alkyl e.g., methyl. n9 may be 0.

[0108] It may be that, where R1and R5atogether 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.

[0109] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:HOZ’ (R> v- L wherein Z7is independently selected from carbon, C(O)NR9b, O, S, S(O)2, S(O), S(O)(NR9b) and S(O)(NH); p7 is selected from 2 and 3, q2 is 2; and r6 is selected from 0, 1 and 2. Z7may be selected from carbon, O, S, S(O)2, S(O). Z7may be carbon. Z7may be selected from O and S. Z7may be O. p7 may be 2. p7may be 3. r6 may be 0. r6 may be 1. Where present, R9may be Ci-C4-alkyl, e.g. methyl.

[0110] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:and 2. Z8may be a bond. Z8may be carbon. Z8may be selected from O and S. Z8may be O. r7 may be 0.

[0112] It may be that R1and R5atogether 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.

[0113] It may be that R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:

[0114] R2may be Co-C4-alkylene-R2a. R2may be CH2-R2a. R2amay be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridgedbicyclic 6- to 11-membered heterocycloalkyl group; wherein said R2agroup is optionally substituted with from 1 to 6 R10groups. R2amay comprise at least one nitrogen in the ring system. R2amay comprise a single nitrogen in the ring system. R2amay be selected from monocyclic 4- to 7-membered heterocycloalkyl group, a fused, spirofused or bridged bicyclic 6- to 11 -membered heterocycloalkyl group; wherein said R2agroup is optionally substituted with from 1 to 6 R10groups and wherein R2acomprises at least one nitrogen in the ring system. R2amay be monocyclic 4- to 7- membered heterocycloalkyl group; wherein said R2agroup is optionally substituted with from 1 to 6 R10groups and wherein R2acomprises at least one nitrogen in the ring system. R2amay be a fused, spirofused or bridged bicyclic 6- to 11-membered heterocycloalkyl group; wherein said R2agroup is optionally substituted with from 1 to 6 R10groups and wherein R2acomprises at least one nitrogen in the ring system.

[0115] R2may have the structure:, wherein R15is independently selected from H, Ci-C4-alkyl; wherein R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; 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. R15may be H. R16may be Ci-C4-alkyl.

[0116] R2may have the structure:, wherein z is independently selected from 0, 1 , 2, 3, and 4. z may be selected from 0 and 1. z may be 0. z may be 1.

[0117]

[0118] R4may be phenyl, said phenyl being optionally fused to a Cs-Cy-cycloalkyl ring, wherein R4is optionally substituted with from 1 to 4 R14groups. R4may be phenyl, optionally substituted with from 1 to 4 R14groups. R4may be monocyclic 4- to 7- membered cycloalkyl. R4may be monocyclic 4- to 7-membered heterocycloalkyl, said heterocycloalkyl being optionally fused to a Cs-Ce-heteroaryl ring. R4may be a 5- membered heterocycloalkyl, e.g., thiophenyl, fused to a monocyclic 5- to 6-membered cycloalkyl, e.g., cyclohexyl. R4may be substituted with from 1 to 4 R14groups. For theavoidance of doubt, where R4comprises a fused ring structure, e.g. a 5-membered heterocycloalkyl fused to a monocyclic 5- to 6-membered cycloalkyl, the 1 to 4 R14groups 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., Ci-C4-alkyl.

[0119] R4may have the structure:wherein R12ais independently H or Ci-C4-alkyl; x1 is independently selected from 0, 1 , 2 and 3. R12amay be H.

[0120] R3amay be selected from halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-C1-C4- haloalkyl, cyclopropyl, nitro and cyano. R3amay be selected from H, halo and C1-C4- alkyl. R3amay be F. R3amay be Ci-C4-alkyl, e.g. Me. R3amay be H.

[0121] R3bmay be selected from halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-C1-C4- haloalkyl, cyclopropyl, nitro and cyano. R3bmay be F. R3bmay be Ci-C4-alkyl, e.g. Me. R3bmay be H.

[0122] R3cmay be selected from H, halo and Ci-C4-alkyl. R3cmay be selected from H, F, Cl and CH3. R3cmay be F. R3cmay be Ci-C4-alkyl, e.g. Me. R3cmay be H.

[0123] R4may be naphthyl, optionally substituted with from 1 to 4 R14groups. R4may 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 R14groups may be attached to either ring of the naphthyl group. R14may be independently selected from OR12, halo e.g., F, and Ci-C4-alkyl e.g., ethyl, x may be 0. x may be 1. x may be 2. x may be 3.

[0124] R4may have the structure:wherein R12ais independently H or Ci-C4-alkyl; x2 is independently selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the x2 R14groups may be attached to either ring of the naphthyl group. R12amay be H.

[0125] R4may have the structure:wherein R14ais OR12e.g., OH; R14bis Ci.C4-alkyl e.g., methyl or ethyl; and R14cis halo e.g, F.

[0126] R4may havestructure:wherein R14is independently H, cyano, NR12R13and Ci-C4-alkyl. X3 is independently selected from 0, 1 , 2 and 3. For the absence of doubt, throughout this specification, the x3 R14groups may be attached to either ring of the heterocyclyl group.

[0127] R4may be 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R14groups. R4may be 9- or 10-membered bicyclic heteroaryl, optionally substituted with from 1 to 4 R14groups.

[0128] R5amay be H. R5amay be Ci-C4-alkyl, e.g. methyl.

[0129] R5bmay be H. R5bmay be Ci-C4-alkyl, e.g. methyl.

[0130] R6may be selected from Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl. R6may be Ci-C4-alkyl. R6may be Ci-C2-alkyl, e.g. methyl.

[0131] R7may be selected from H and Ci-C4-alkyl. R7may be H. R7may be Ci-C4-alkyl, e.g. methyl.

[0132] R8may be selected from H and Ci-C4-alkyl. R8may be H. R8may be Ci-C4-alkyl, e.g. methyl.

[0133] R9may be independently at each occurrence selected from oxo, fluoro, cyano, NR12R13, OR12, COR12, Ci-C4-alkyl, CONR12R13, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl. R9may be independently at each occurrence selected from oxo, fluoro, NR12R13, OR12, COR12, CONR12R13; Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with phenyl and Ci-C4-alkyl substituted with OR12.

[0134] R9may be independently at each occurrence selected from oxo, fluoro, cyano, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano. R9may be independently at each occurrence selected from oxo, fluoro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13and Ci-C4-alkyl substituted with OR12.

[0135] R9may be independently at each occurrence selected from oxo, halo, cyano, NR12R13provided that R12is not H and R13is not H, OR12, COR12, CO2R12, CONR12R12, C1-C4- alkyl, Ci-C4-alkyl substituted with NR12R13provided that R12is not H and R13is not H, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0136] R9may be independently at each occurrence selected from oxo, halo, cyano, NR12R13provided that R12is not H and R13is not H, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, C1- C4-alkyl substituted with NR12R13provided that R12is not H and R13is not H, C1-C4- alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4- alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0137] R9may be independently at each occurrence selected from Ci-C4-alkyl e.g., methyl and OR12e.g., OH.

[0138] R10may be independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0139] R10may be independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0140] R10may be independently at each occurrence selected from oxo, fluoro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with phenyl, Ci-C4-alkyl substituted with NR12R13and Ci-C4-alkyl substituted with OR12.

[0141] R10may be independently at each occurrence selected from oxo, fluoro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13and Ci-C4-alkyl substituted with OR12.

[0142] R10amay be independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13a, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0143] R10amay be independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13a, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2- C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0144] R10amay be independently at each occurrence selected from oxo, fluoro, NR12R13a, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with phenyl, Ci-C4-alkyl substituted with NR12R13aand Ci-C4-alkyl substituted with OR12.

[0145] R10amay be independently at each occurrence selected from oxo, fluoro, NR12R13a, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13aand Ci-C4-alkyl substituted with OR12.

[0146] R10amay be independently at each occurrence selected from halo, cyano, C1-C4- alkyl, Ci-C4-haloalkyl and cyclopropyl. R10amay be Ci-C4-haloalkyl e.g., trifluoromethyl.

[0147] R11may be each independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C1- C4-haloalkyl and cyclopropyl. R11may be each independently at each occurrence selected from OR12, monocyclic 4- to 7-membered cycloalkyl or heterocycloalkyl, C1- C4-alkyl, Ci-C4-haloalkyl and cyclopropyl.

[0148] R11may be each independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-haloalkyl and cyclopropyl. R11may be each independently at each occurrence selected from OR12, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl.

[0149] It may be that R12is independently selected at each occurrence from H, C1-C4- haloalkyl, Ci-C4-alkyl and cyclopropyl; and R13is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl.

[0150] It may be that R12is independently selected at each occurrence from H, C1-C4- haloalkyl, and Ci-C4-alkyl; and R13is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl.

[0151] R12may independently at each occurrence be selected from H, cyclopropyl and C1- C4-alkyl. R12may be Ci-C4-alkyl e.g., methyl. R12may be cyclopropyl.

[0152] R12may independently at each occurrence be selected from H and Ci-C4-alkyl.

[0153] R13may independently at each occurrence be selected from H and Ci-C4-alkyl.

[0154] In compounds of formula (I), it may be that R12and R13together 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 R10groups. It may be that R12and R13together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group e.g., piperidinyl.

[0155] It may be that R12and R13together 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 R10agroups. It may be that R12and R13together with the nitrogen to which they are attached form a monocyclic 4- to 7-membered heterocycloalkyl group e.g., piperidinyl.

[0156] R13amay be independently at each occurrence selected from H, Ci-C4-alkyl and C(O)-Ci-C4-alkyl. R13amay be independently at each occurrence selected from H and Ci-C4-alkyl.

[0157] R14may be each independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-haloalkyl, phenyl and cyclopropyl. R14may be each independently at each occurrence selected from OR12, Ci-C4-alkyl, Ci-C4-haloalkyl, phenyl and cyclopropyl.

[0158] R14may be each independently at each occurrence selected from halo, cyano, nitro,NR12R13, OR12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkylsubstituted with OR12, Ci-C4-haloalkyl and cyclopropyl. R14may be each independently at each occurrence selected from OR12, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl.

[0159] The compound of formula (I) may be selected from:where A is methyl, ethyl, propyl, cyclopropyl, ethenyl or ethynyl, and X is F or Cl.

[0160] The compound of formula (I) may be selected from:DETAILED DESCRIPTION

[0162] In an aspect of the invention there is provided the compounds of the present invention for use as a medicament.

[0163] 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.

[0164] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention and a pharmaceutically acceptable excipient.

[0165] 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, antitumour vaccines, cytokine therapy, or tyrosine kinase inhibitors.

[0166] In an aspect of the invention there is provided the compounds of the present invention for use in treating cancer.

[0167] In an aspect of the 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.

[0168] In an aspect of the invention there is provided the use of a compound of the invention for manufacture of a medicament for the treatment of cancer.

[0169] The cancer may be a solid tumour or a liquid tumour. The cancer may be a carcinoma.

[0170] 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.

[0171] 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.

[0172] 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 Q61H. 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.

[0173] 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-smallcell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

[0174] The subject may be human.

[0175] 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.

[0176] The subject may have a cancer with 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.

[0177] 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.

[0178] 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.

[0179] 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.

[0180] The term “alkyl” refers to a linear or branched hydrocarbon chain. For example, the term “Ci-e alkyl” or “Ci-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, isopropyl, n-butyl, sec-butyl, tert-butyl, n-pentyl and n-hexyl. Where an alkyl group is indicated as being Co-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, Ci-e alkoxy.

[0181] The term “alkoxy” refers to an alkyl group which is attached to a molecule via oxygen. For example, the term “Ci-e 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, Ci-e alkoxy.

[0182] 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 “Ci-e 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, Ci-e 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.

[0183] The term “alkenyl” refers to a branched or linear hydrocarbon chain containing at least one double bond. For example, the term “C2-6 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 “C2- 6 alkenyl” may be ethenyl, propenyl, butenyl, butadienyl, pentenyl, pentadienyl, hexenyl and hexadienyl.

[0184] The term “alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond. For example, the term “C2-6 alkynyl” refers to a branched or linear hydrocarbon chain containing at least one triple bond and having 2, 3, 4, 5 or 6 carbonatoms. The triple bond may be at any possible position of the hydrocarbon chain. For example, the “C2-6 alkynyl” may be ethynyl, propynyl, butynyl, pentynyl and hexynyl.

[0185] 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 “C1.6 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 C1.6 heteroalkyl may be bonded to the rest of the molecule through a carbon or a heteroatom. For example, the “C1.6 heteroalkyl” may be C1.6 / V-alkyl, Ci-e N, / V-alkyl, or Ci-e O-alkyl.

[0186] The term “cycloalkyl” refers to a saturated hydrocarbon ring system. For example, the “C3-8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0187] 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 “C3-8 cycloalkyl” may be cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclopentadienyl, cyclohexenyl, cyclohexadienyl, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0188] 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 “C3-8 heterocycloalkyl”. The term “C3-8 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 “C3-8 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 “C3-8 heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0189] 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.

[0190] 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 “C3-8 heterocycloalkenyl”. The term “C3-8 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.

[0191] 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.

[0192] The term “spirofused” refers to a bicyclic ring system in which the two rings are attached via a single atom.

[0193] 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.

[0194] 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 TT system within the ring or ring system where all atoms contributing to the conjugated TT system are in the same plane.

[0195] The term “aryl” refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated TT system within a ring where all atoms contributing to the conjugated TT 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.

[0196] 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 TT system where all atoms contributing to the conjugated TT system are in the same plane. For example, the “heteroaryl” may be imidazole, thiene, furane, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0197] The term “halogen” herein includes reference to F, Cl, Br and I. Halogen may be Br. Halogen may be I.

[0198] 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.

[0199] 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.

[0200] 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.

[0201] 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 “

[0202] “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.

[0203] “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.

[0204] Throughout the description the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both (F?) 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 (F?) and (S) stereoisomers is contemplated. The combination of (F?) 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.

[0205] 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.

[0206] 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.

[0207] 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).

[0208] 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.

[0209] 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.

[0210] 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.

[0211] Included within the scope of the invention are complexes such as clathrates, drughost inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also includedare 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).

[0212] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0213] 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.

[0214] 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.

[0215] Examples of isotopes suitable for inclusion in the compounds of the invention include isotopes of hydrogen, such as2H and3H, carbon, such as11C,13C and14C, chlorine, such as36CI, fluorine, such as18F, iodine, such as123l and125l, nitrogen, such as13N and15N, oxygen, such as150,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0216] 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.

[0217] 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.

[0218] 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.

[0219] 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.

[0220] 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.

[0221] 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.

[0222] 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.

[0223] 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- avp6 monoclonal antibodies (e.g. BG00011), 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-1a (Avonex, Rebif), peginterferon beta-1a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), natalizumab (Tysabri)

[0224] 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 (Avastin™); 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 a; 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.

[0225] 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.

[0226] 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.

[0227] 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 (pg / kg) to 100 milligrams per kilogram body weight (mg / kg).

[0228] 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.

[0229] 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.

[0230] 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.

[0231] 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.

[0232] 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 carboxymethylcellulose as a thickening agent or other excipients known to those skilled in art.

[0233] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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 anycombination, 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.

[0238] 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.

[0239] Experimental

[0240] 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 2pL aliquot was injected onto a guard column (0.2 pm x 2 mm filters) and LIPLC column (C18, 50 x 2.1 mm, < 2 pm) 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 pL Aliquot were injected onto an Agilent Poroshell 120 EC-C18 column (2.7 pm, 4.6x50 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 pL aliquots were injected onto an Agilent Eclipse Plus RRHD C18, (1.8 pm, 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 2pL aliquot was injected onto a guard column (0.2pm x 2 mm filters) and LIPLC column (C18, 50 x 2.1 mm, < 2pm) 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.

[0241] Table 1

[0242] 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 5pM OBD 19x100mm column 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 gradient outlined in Table 2 below.

[0243] Table 2

[0244] General Schemes

[0245] Compounds of formula (la) can be prepared using the steps described in general scheme 1 , where LG1, LG2and LG3are suitable leaving groups such as chloride (Cl), bromide (Br) or iodide (I) or alkyl sulfonyl groups eg SO2Et, or a triflate (OTf).

[0246] General Scheme 1

[0247] In step A G1 in which LG1is a halogen, for example a chloride undergoes a nucleophilic substitution reaction with an alcolhol or amine (HZ1R1) in the presence of a base, for example DIPEA in a solvent such as THF at room temperature to form G2. In step B, a second nucleophilic substitution of LG2(where LG2 may be a chloride or on SO2Et group) with an alcohol or amine (HZ2R2) can be effected using a solvent such as anhydrous THF and a base, for example NaH. In step C, G3 can undergo a transition metal catalysed cross coupling reaction, for example a Suzuki reaction (LG3 may be a bromide and R4Y a boronic acid or ester of R4) in the presence of an appropriate catalyst, for example [1 , T-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll), a base such as cesium carbonate in a solvent system such as 1 ,4-dioxane and water at elevated temperature. Additional standard deprotection steps may be required depending on the nature of the R1, R2and R4substituents installed during steps A to C. Additionally the order of the steps can be changed so that R4can be installed prior to Z1R1and Z2R2.

[0248] Intermediates of formula G1 can be prepared by the routes in general schemes 2 to 5. The starting compounds for each of these routes (described by formula G4) are commercially available or can be prepared by methods well described in the chemical literature. Intermediates of formula G1a (where X1= N, LG1= LG2= Cl and LG3= Br) can be formed according to general scheme 2 or general scheme 3.

[0249] General Scheme 2

[0250] In step A aniline G4 can be ortho-iodinated using for example, NIS in MeCN at 0°C. In step B the iodide of G5 can undergo carbonylation using a carbonyl donor such as molybdenum hexacarbonyl, a catalyst such as Pd(dppf)Ch and DBU in EtOH at 70°C. In step C the anilinic nitrogen of G6 is alkylated with trichloroacetyl isocyanate to afford G7 which in step D is treated with ammonia in MeOH at elevated temperature to cyclise and form dihydroxypyrimidine of formula G8 which can be chlorinated, for example using POC and DI PEA at reflux.

[0251] General Scheme 3

[0252] Alternatively, aniline G4 can undergo Sandmeyer isatin formation under standard conditions in steps A and B to form G10 which can be hydrolysed to a carboxylic acid of formula G11 for instance, using sodium hydroxide and sodium peroxide at room temperature in step C. Step D involves conversion of the carboxylic acid to a primary amide using an ammonia source such as ammonium chloride, a base such as DIPEA a carboxylate activating agent such as HATLI and a solvent, for instance, DMF. In step E a primary amide of formula G12 is converted to a dihydroxypyrimidine of formula G8 with a carbonyl donor, for example, GDI in a solvent such as THF at reflux. Finally chlorination of dihydroxpyrimidines of formula G8 affords compounds of formula G1a, this can be done using POC as previously described in general scheme 2.

[0253] Intermediates of formula G1 b (where X1= N, LG1= Cl, LG2= SO2Et and LG3= Br) can be formed according to the route described in general scheme 4.

[0254] General Scheme 4

[0255] In step A aniline G4 can be reacted with a isothiocyanate such as ethoxycarbonyl isothiocyanate in DCM or another suitably inert solvent to form a thiourea of formula G13. G13 can be S-alkylated to form G14 in step B using an alkylating agent such as ethyl iodide in DMF with a base such as potassium carbonate present. Cyclisation to G15 can be effected in step C by heating at elevated temperature in a high boiling solvent, this may be done using microwave irradiation to achieve a temperature of 170°C in NMP as solvent. Step D involves chlorination of the hydroxy group of G15, for example this can be done with POCh in DMF at 90°C. Finally, in step E, G16 can be converted to an intermediate of formula G1b by oxidation of the thioether linkage under suitable conditions, for instance, using a peracid such as mCPBA in DCM at room temperature.Intermediates of structure G1c (where X1= C, LG1= LG2= Cl and LG3= Br) can be formed according to the route described in general scheme 5, treating an aniline of formula G4 with malonic acid in POCh at reflux.

[0256] General Scheme 5

[0257] Synthesis of intermediatesIntermediate A-1, 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane.

[0258] Intermediate Scheme 1

[0259] Step A, 3-(methoxymethoxy)naphthalene. To a suspension of 4- bromonaphthalen-2-ol (3g, 13.45mmol) and / V, / V-diisopropylethylamine (7.03mL, 40.35mmol) in DCM (30mL) at 0°C was added chloromethyl methyl ether (1.53mL, 20.17mmol). 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 (40g SiC>2, 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 (3.2g, 11.9mmol, 89% yield).

[0260] UPLC-MS (ES+, Method 1): 2.06 min, m / z 266.9, 268.9 [M+H]+

[0261] 1H NMR (400MHz, CDC ) b / ppm: 8.19-8.15 (1 H, m), 7.77-7.73 (1 H, m), 7.60 (1 H, d, J = 2.4Hz), 7.53-7.46 (2H, m), 7.42-7.40 (1 H, m), 5.31 (2H, s), 3.55 (3H, s).

[0262] Step B, 2-[3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-1). To a nitrogen purged suspension of 1-bromo-3- (methoxymethoxy)naphthalene (5.2g, 19.4mmol), bis(pinacolato)diboron (9.9g, 38.9mmol) and potassium acetate (6.7g, 68mmol) in toluene (50mL) was added [1 ,1'bis(diphenylphosphino)ferrocene]dichloropalladium (II) (1.4g, 1.9mmol). 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 (40g SiO2, dry loaded with DCM) eluting with 0-20% EtOAc in petrolether, 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 (6g, 98% yield).

[0263] UPLC-MS (ES+, Method 2): 2.16 min, m / z 315 [M+H]+

[0264] 1H NMR (400MHz, D6-DMSO) 6 / ppm: 8.56-8.59 (1 H, d, J=7.1 Hz), 7.86-7.89 (1 H, d, J=7.1 Hz), 7.63-7.65 (1 H, d, J=2.4Hz), 7.58-7.60 (1 H, d, J=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).

[0265] Intermediate Scheme 2

[0266] Step A, 01 -tert-butyl O-2-methyl 2-(3-chloropropyl)pyrrolidine-1,2- dicarboxylate. A 1M 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 I2). 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 01-tert-butyl 02-methyl 2-(3-chloropropyl)pyrrolidine-1 ,2- dicarboxylate (13g, 42.5mmol, 97% yield).

[0267] 1H NMR (400MHz, CDCh) 5 / ppm: 3.50-3.62 (4H, m), 3.35-3.45 (2H, m), 3.19-3.23 (1 H, m), 2.11-2.20 m, 1 H), 1.50-2.05 (m, 6H), 1.25-1.29 (9H, d).

[0268] 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 01-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.

[0269] 1H NMR (400MHz, CDCh) 5 / ppm: 10.20-10.45 (1 H, bs), 7.70-8-02 (1 H, bs), 3.91 (s, 3H), 3.45-3.70 (m, 4H), 2.45-2.55 (1 H, m), 2.26-2.31 (1 H, m), 2.15-2.25 (3H, m), 1.95- 2.04 (2H, m), 1.55-1.65 (1 H, m).

[0270] 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 (Na2SC>4), 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.

[0271] 1H NMR (400MHz, CDCh) 5 / 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).

[0272] 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 precipitatedsalts 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, 7.1 mmol, 100% yield) as a yellow oil.

[0273] 1H NMR (400MHz, CDCh) 5 / ppm: 3.75-3.79 (1 H, 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.

[0274] Intermediate Scheme 3

[0275] Step A, Ethyl 6-methylene-3-oxo-1,2,5,7-tetrahydropyrrolizine-8-carboxylate.At -40°C, LiHMDS (1.34L, 1.34mol, 2.1 eq) was added dropwise into a solution of ethyl 5-oxo-2-pyrrolidinecarboxylate (100g, 637mmol, 1.0eq) and 3-chloro-2-chloromethyl- 1-propene (239g, 1.91 mol, 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).

[0276] 1H NMR (400MHz, CDCh) 5 / ppm: 5.01-5.06 (2H, d), 4.16-4.30 (3H, m), 3.69-3.73 (1 H, d), 3.02-3.06 (1 H, d), 2.30-2.75 (4H, m), 2.07-2.16 (1 H, m), 1.23-1.27 (3H, t).

[0277] 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 (1 L) 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, 1.1 mol, 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.

[0278] 1H NMR (400MHz, CDCh) b / ppm: 4.20-4.24 (2H, q), 4.08-4.14 (1 H, d), 3.52-3.56 (1 H, d), 2.95-3.00 (2H, m), 2.81-2.86 (1 H, m), 2.39-2.48 (2H, m), 2.19-2.24 (1 H, m), 1.26- 1.29 (3H, t).

[0279] Step C Ethyl (2S,8S)-2-hydroxy-5-oxo-2,3,6,7-tetrahydro-1 H-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-1 H-pyrrolizine-8-carboxylate as a yellow oil and apparent mixture of sterioisomers (88g, 81% yield).

[0280] LC-MS (ES+, Method 4): 0.40min, 214.10 [M+H]+.

[0281] 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-1 H-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-1 H-pyrrolizine-8-carboxylate as a yellow oil (42g, 47% yield).

[0282] 1H NMR (400MHz, CDCh) b / ppm: 5.21-5.36 (1 H, d), 4.20-4.47 (3H, m), 3.19-3.41 (1 H, dd), 2.10-2.60 (6H, m), 1.24-1.28 (3H, t).

[0283] Step E, (6R,8S)-6-Fluoro-8-(hydroxymethyl)-2,5,6,7-tetrahydro-1H-pyrrolizin-3- one. At 0°C, LiBH4 (81 mL, 163mmol, 1.0eq) was added dropwise into ethyl (2R,8S)- 2-fluoro-5-oxo-2,3,6,7-tetrahydro-1 H-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 mixturewas 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-1 H-pyrrolizin-3-one (28g, 99% yield).

[0284] 1H NMR (400MHz, CDCh) b / ppm: 5.21-5.35 (1 H, d), 4.05-4.16 (1 H, m), 3.51-3.55 (1 H, d), 3.42-3.46 (1 H, d) 2.52-3.11 (3H, m), 1.94-2.41 (5H, m).

[0285] 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-1 H-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 1 hr 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, 88% yield) of [(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8-yl]methanol, intermediate 21 as a colourless oil.

[0286] 1H NMR (400MHz, CDCh) 6 / ppm: 5.11-525 (1 H, d), 2.80-3.31 (6H, m), 1.74-2.11 (6H, m).Intermediate A-4, 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridine-2-amine.

[0287] Intermediate A-4 was prepared following the route described in Intermediate Scheme 4.

[0288] Intermediate Scheme 4

[0289] Step A, 6-chloro-5-iodo-4-methyl-pyridin-2-amine. To a solution of 6-chloro-4- methyl-2-pyridinamine (1.00 g, 7.01 mmol) in MeCN (16 mL) was added N- lodosuccinimide (1.89 g, 8.42 mmol). The reaction mixutre was stirred at rt for 2 h. The reaction mixture was concentrated to dryness and partitioned between DCM and brine. The organics were extracted, passed through phase separating filter paper and concentrated in vacuo. The crude material was purified by column chromatography eluting 10-100% EtOAc in pet ether. The desired fractions were combined and concentrated to dryness to provide 6-chloro-5-iodo-4-methyl-pyridin-2-amine (1.52 g, 5.66 mmol, 81% yield) as an orange solid.

[0290] UPLC-MS (ES+, Method 2): 1.76 min, m / z 268.81270.8 [M+H]+

[0291] Step B, 6-chloro-5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2- amine. To a solution of 6-chloro-5-iodo-4-methyl-pyridin-2-amine (1.50 g, 5.59 mmol) in DMF (20 mL) was added 4-methoxybenzylchloride (2.3 mL, 16.8 mmol) and sodium hydride, (60% dispersed in mineral oil) (536 mg, 22.4 mmol) and the reaction stirred at rt for 16 h. The reaction mixture was partitioned between EtOAc and water. The organics were separated and the aqueous layer was washed three times with EtOAc. The combined organic washings were washed with brine and passed through phase separating filter paper before concentrating to dryness. The crude material was then purified by column chromatography eluting 10% EtOAc in pet. ether to 100% EtOAc. The desired fractions were combined and concentrated in vacuo to provide 6-chloro- 5-iodo-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (2.83 g, 5.56 mmol, 100% yield) as a yellow solid.

[0292] UPLC-MS (ES+, Method 2): 2.59 min, m / z 509.0 [M+H]+

[0293] Step C, 6-chloro-N,N-bis[(4-methoxyphenyl)methyl]-4-methyl-5- (trifluoromethyl)pyridin-2-amine (A-4). To a solution of 6-chloro-5-iodo-N,N-bis[(4- methoxyphenyl)methyl]-4-methyl-pyridin-2-amine (1.00 g, 1.97 mmol) in DMF (10mL) was added Copper(l) iodide (749 mg, 3.93 mmol) and methyl-2,2-difluoro-2- (fluorosulfonyl)acetate (0.5 mL, 3.93 mmol) and the reaction heated to 90°C for 16 h. The reaction was diluted with EtOAc and water, the organics extracted, passed through phase separating filter paper and concentrated to dryness. The crude material was then purified by flash column chromatography eluting 0-60% EtOAc in pet. ether. The desired fractions were combined and concentrated in vacuo to provide 6-chloro-N,N- bis[(4-methoxyphenyl)methyl]-4-methyl-5-(trifluoromethyl)pyridin-2-amine (563mg, 1.2487mmol, 64% yield) as an orange oil which solidified to a white solid when left standing.

[0294] UPLC-MS (ES+, Method 2): 2.51 min, m / z 451.1 [M+H]Intermediate A-5, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid.

[0295] Intermediate Scheme 5

[0296] Step A, 2-nitro-N-prop-2-ynyl-benzenesulfonamide. A solution of propargylamine (37.28g, 676.83mmol) and N,N-diisopropylethylamine (129.81mL, 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 (SiC>2, 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.

[0297] LC-MS (ES+, Method 3): 1.23min, 241.05 [M+H]+

[0298] 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 columnchromatography (SiC>2, 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.

[0299] LC-MS (ES+, Method 3): 1.70min, 317.0 [M+H]+

[0300] 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 (80m L). 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.

[0301] LC-MS (ES+, Method 3): 1.47min, 395.05 [M+H]+

[0302] Step D, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxylic acid (A-5). A solution of ethyl 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxylate (1.7g, 4.31mmol) and 1M 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 1M 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.

[0303] LC-MS (ES+, Method 3): 1.10min, 367.05 [M+H]+Intermediate A-6, N-ethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxamide.

[0304] Intermediate Scheme 6

[0305] Step A, N-ethyl-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide. TBTLI (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 (SiC>2, 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.

[0306] LC-MS (ES+, Method 4): 1.23min, 394.10 [M+H]+

[0307] Step B, N-ethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2- carboxamide (A-6). 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 (SiC>2, 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.

[0308] LC-MS (ES+, Method 4): 0.17min, 209.15 [M+H]+

[0309] The intermediates in table 3 below were prepared by analogy with A-6 (intermediate scheme 6), replacing the amine building block ethanamine hydrochloride as described in the table entry.

[0310] Table 3Intermediate A-10, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (A-10).

[0311] Intermediate Scheme 7

[0312] Step A, tert-butyl N-(3-hydroxypropyl)-N-(1H-pyrazol-3-ylmethyl)carbamate. A stirring suspension of 1 H-pyrazole-3-carbaldehyde (1.9g, 19.77mmol) and 3-amino-1- propanol (2.27mL, 29.66mmol) in Methanol (400mL) was cooled to 0°C and stirred for 30 mins. Sodium Borohydride (1 ,5g, 39.55mmol) was added portionwise over 30 mins maintaining temperature <10°C and the mixture left to stir for 1 hour. Water (15mL) was slowly added and the mixture stirred for 40 min before portionwise addition of Di- tert-butyl dicarbonate (8.63g, 39.55mmol) and the reaction mixture left to stir for 72 hours. The reaction mixture was diluted with water and brine and extracted with EtOAc. Organic portions were combined and washed with brine and dried over Na2SO4, filtered, and concentrated to obtain the crude product as an orange oil. The crude material was purified by flash column chromatography (eluting in 0 - 100% EtOAc in Pet. Ether) to afford the desired product tert-butyl N-(3-hydroxypropyl)-N-(1 H-pyrazol- 3-ylmethyl)carbamate (1.92g, 7.5203mmol, 38% yield) as a pale yellow oil.

[0313] UPLC-MS (ES+, Method 2): 1.28 min, 254.2 [M-H]+

[0314] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 12.59 (s, 1 H), 7.62 (s, 1 H), 6.08 (s, 1 H), 4.39 (m, 1 H), 4.31 (s, 2H), 3.36 (m, 2H), 3.17 (s, 2H), 1.58 (m, 2H), 1.40 (s, 9H).

[0315] Step B, 3-[tert-butoxycarbonyl(1H-pyrazol-3-ylmethyl)amino]propyl 4- methylbenzenesulfonate. A stirring solution of tert-butyl N-(3-hydroxypropyl)-N-(1 H- pyrazol-3-ylmethyl)carbamate (1.92g, 7.52mmol) in DOM (75.203mL) was cooled to 0°C and stirred for 10 min before adding p-toluenesulfonyl chloride (1.72g, 9.02mmol) and triethylamine (1.57mL, 11.28mmol). The reaction mixture was left to stir for 4.5 hours. Additional p-toluenesulfonyl chloride (358.43mg, 1.88mmol) and triethylamine(1 ,57mL, 11.28mmol) were added and the reaction mixture was left to stir for a further hour. The reaction mixture was diluted with water (100 mL) and extracted with DCM (2 x 50mL). Organic fractions were combined, dried over Na2SO4, filtered, and concentrated to afford a brown oil. The crude material was purified by flash column chromatography (80 g, 10-80% EtAOc in pet. ether), fractions were combined and concentrated to afford 3-[tert-butoxycarbonyl(1 H-pyrazol-3-ylmethyl)amino]propyl 4- methylbenzenesulfonate (1.75g, 4.2735mmol, 57% yield) as a pale yellow solid.

[0316] UPLC-MS (ES+, Method 5): 1.88 min, 410.2 [M+H]+

[0317] 1H NMR (400 MHz, DMSO-d6) b / ppm: 8.38 (s, 1 H), 7.83 (d, 2H), 7.45 (d, 2H), 6.39 (s, 1 H), 4.37 (m, 1 H), 4.27 (s, 2H), 3.29 (s, 2H), 3.16 (s, 2H), 2.39 (s, 3H), 1.49 (s, 2H), 1.38 (s, 4H), 1.22 (s, 5H)

[0318] Step C, tert-butyl 4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5- carboxylate. A stirring solution of 3-[tert-butoxycarbonyl(1 H-pyrazol-3- ylmethyl)amino]propyl 4-methylbenzenesulfonate (1.75g, 4.27mmol) in DMF (42.735mL) was flushed with nitrogen and cooled to 0°C before adding Sodium hydride (60% dispersed in mineral oil) (512.82mg, 12.82mmol). The reaction mixture was allowed to warm to room temperature and left to stir overnight. The reaction mixture was diluted with water (30 mL) and extracted with EtOAc (3 x 15 mL). Organic fractions were combined, dried over Na2SO4, filtered and concentrated. The crude material was purified by flash column chromatography (12 g, 0-10% MeOH in DCM), like fractions were combined and concentrated to afford tert-butyl 4,6,7,8-tetrahydropyrazolo[1 ,5- a][1 ,4]diazepine-5-carboxylate (812mg, 3.4218mmol, 80% yield) as a pale yellow oil.

[0319] UPLC-MS (ES+, Method 5): 1.60 min, 238.1 [M+H]+

[0320] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.22 (s, 1 H), 6.13 (d, 1 H), 4.44 - 4.33 (m, 4H), 3.63 (s, 2H), 1.72 (s, 2H), 1.33 (s, 9H)

[0321] Step D, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (A-10). Trifluoroacetic acid (13.46mL, 175.73mmol) was added to a stirring solution of tertbutyl 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (417. mg, 1.76mmol) in DCM (20mL) and the reaction mixture left to stir at room temperature overnight. The reaction mixture was concentrated and then dissolved in methanol before loading onto an 10 g SCX cartridge. This was washed with water and methanol before eluting with 1M ammonia methanol and concentrated to afford 5, 6,7,8- tetrahydro-4H-pyrazolo[1 ,5-a][1 ,4]diazepine (210mg, 1.5307mmol, 87% yield) as a yellow oil.

[0322] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.15 (d, J = 1.72 Hz, 1 H), 6.03 (d, J = 1.72 Hz, 1 H), 4.29 - 4.26 (m, 2H), 3.76 (s, 2H), 3.01 - 2.98 (m, 2H), 1.69 - 1.64 (m, 2H). Exchangeable proton not seen.

[0323] The intermediates in table 4 below were prepared by analogy with A-10 (intermediate scheme 7), replacing 1 H-pyrazole-3-carbaldehyde with building block as described in the table entry.

[0324] Table 4Intermediate A-11, [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanol.

[0325] Intermediate Scheme 8

[0326] Step A, Methyl 1 -(pyrrolidine-1 -carbonyl)cyclopropanecarboxylate. To a solution of cyclopropane- 1 , 1-dicarboxylic acid methyl ester (400. mg, 2.78mmol) and N,N-dimethylformamide (O.mL, 0.03mmol) in DCM (1.7345mL) at 0°C was added oxalyl chloride (0.3mL, 3.55mmol). The reaction mixture was left to stir for 3 hours and reduced in vacuo to afford a yellow oil. The residue taken up in THF (1.7345mL) and cooled to 0°C before the addition of pyrrolidine (1.19mL, 2.39mmol). The mixture was left to stir at room temperature for 2 hours. The reaction mixture was taken up in EtOAc and washed with brine, organics were combined and dried under Na2SO4, filtered andthe solvents removed in vacuo to afford methyl 1 -(pyrrolidine- 1- carbonyl)cyclopropanecarboxylate (460mg, 2.3323mmol, 84% yield) as a yellow oil.

[0327] 1H NMR (400 MHz, DMSO-d6) b / ppm: 3.65 (s, 3H), 3.37 - 3.26 (m, 4H), 1.91 - 1.72 (m, 4H), 1.31 - 1.28 (m, 2H), 1.26 - 1.22 (m, 2H).

[0328] Step B, [1-(pyrrolidin-1-ylmethyl)cyclopropyl]methanol (A-11). To a solution of methyl 1-(pyrrolidine-1-carbonyl)cyclopropanecarboxylate (460. mg, 2.33mmol) in dry THF (2.0281mL) at 0°C was added Lithium Aluminium hydride 1M in THF (5.13mL, 5.13mmol). The reaction mixture was left to stir at room temperature for 2 hours. The reaction mixture was quenched on addition of 2M HCI at 0°C and the solids filtered. The filtrate was passed through a pre-equilibrated SCX-2 cartridge (2 g, washing with MeOH and eluting with 1M NHs / MeOH) and the solvents reduced in vacuo to afford [1- (pyrrolidin-1-ylmethyl)cyclopropyl]methanol (110mg, 0.7086mmol, 30% yield) as a colourless oil.

[0329] 1H NMR (400 MHz, DMSO-d6) b / ppm: 4.59 (br s, 1 H), 2.45 - 2.39 (m, 4H), 2.35 (s, 2H), 1.69 - 1.62 (m, 4H), 0.40 - 0.36 (m, 2H), 0.24 - 0.20 (m, 2H).

[0330] The intermediates in table 5 below were prepared by analogy with A-11 (intermediate scheme 8), using Cyclopropane-1 ,1 -dicarboxylic acid methyl ester and alternative amine building blocks as described in the table entry.

[0331] Table 5Intermediate A-12, Tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1- carboxylate.

[0332] Intermediate Scheme 9

[0333] Step A, Tert-butyl (2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-hydroxy- pyrrolidine-1 -carboxylate. To a solution of tert-butyl (2S,4R)-2-(hydroxymethyl)-4- hydroxy-pyrrolidine-1-carboxylate (500mg, 2.3mmol) in DCM (5mL) at 0°C was added triethylamine (0.38mL, 2.76mmol) and 4-dimethylamino pyridine, DMAP (28.12mg, 0.23mmol). The reaction mixture was stirred for 5 mins at 0°C before the addition of tert-butyl-chlorodimethylsilane (381.55mg, 2.53mmol). The reaction mixture was left to stir at room temperature overnight. The mixture was diluted with DCM and washed with sat.aq. NaHCCh. Organics were combined, dried over Na2SO4, filtered and the filtrate evaporated in vacuo to afford tert-butyl (2S,4R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-hydroxy-pyrrolidine-1 -carboxylate (763mg,2.3015mmol, 100% yield) as a colourless oil.

[0334] 1H NMR (400 MHz, CDC ) 6 / ppm: 4.55 - 4.42 (m, 1 H), 4.09 - 3.30 (m, 5H), 2.29 - 2.15 (m, 1 H), 2.11 - 1.82 (m, 1 H), 1.46 (s, 9H), 0.87 (s, 9H), 0.03 (s, 6H). Exchangeable proton not seen.

[0335] Step B, Tert-butyl (2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methoxy- pyrrolidine-1 -carboxylate. To a solution of tert-butyl (2S,4R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-hydroxy-pyrrolidine-1-carboxylate (763mg, 2.3mmol) in DMF (10mL) at 0°C was added sodium hydride, (60% dispersed in mineral oil) (119.68mg, 2.99mmol). The reaction mixture was stirred for 20 mins at 0°C before the addition of iodomethane (0.29mL, 4.6mmol). The reaction mixture was left to stir at room temperature for 2.5 hours. The reaction mixture was diluted with EtOAc, washed with sat.aq. NH4CI, organics combined and washed with water and brine. The organics were combined and dried under Na2SO4, filtered and the filtrate evaporated in vacuoto afford a yellow oil. The crude material was purified by flash column chromatography (12 g, eluting in 0-25% EtOAc in pet. ether) and the solvents removed in vacuo to afford tert-butyl (2S,4R)-2-[[tert-butyl(dimethyl)silyl]oxymethyl]-4-methoxy-pyrrolidine- 1-carboxylate (550mg, 1.5917mmol, 69% yield) as a colourless oil.

[0336] 1H NMR (400 MHz, CDCh) 5 / ppm: 4.07 - 3.83 (m, 3H), 3.73 - 3.51 (m, 2H), 3.47 - 3.34 (m, 1 H), 3.31 (s, 3H), 2.23 - 2.11 (m, 1 H), 2.09 - 1.89 (m, 1 H), 1.46 (s, 9H), 0.88 (s, 9H), 0.03 (s, 6H).

[0337] Step C, Tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1- carboxylate (A-12). To a stirring solution of tert-butyl (2S,4R)-2-[[tert- butyl(dimethyl)silyl]oxymethyl]-4-methoxy-pyrrolidine-1-carboxylate (550mg,1.59mmol) in THF (7.40mL) was added tetrabutylammonium fluoride 1.0M in THF (3.18mL, 3.18mmol). The reaction mixture was left to stir at room temperature for 1 hour. The mixture was reduced in vacuo and the crude residue purified by flash column chromatography (12 g, eluting 0-100% EtOAc in Pet. Ether) to afford the desired product tert-butyl (2S,4R)-2-(hydroxymethyl)-4-methoxy-pyrrolidine-1-carboxylate (300mg, 1.2971 mmol, 81% yield).

[0338] 1H NMR (400 MHz, CDCh) 5 / ppm: 4.99 - 4.80 (m, 1 H), 4.15 - 3.99 (m, 1 H), 3.93 - 3.77 (m, 1 H), 3.76 - 3.66 (m, 1 H), 3.65 - 3.50 (m, 2H), 3.43 - 3.33 (m, 1 H), 3.31 (s, 3H), 2.19 - 2.08 (m, 1 H), 1.64 - 1.54 (m, 1 H), 1.47 (s, 9H).Intermediate A-13, 8-bromo-6-(methoxymethoxy)tetralin-1-one.

[0339] Intermediate Scheme 10

[0340] Step A, 6-(methoxymethoxy)tetral in-1 -one. To a 0°C solution of 6-Hydroxy-1- tetralone (3000mg, 18.5mmol) and N,N-diisopropylethylamine (4.83mL, 27.75mmol) in DCM (36.994mL) was added bromomethyl methyl ether (1.81mL, 22.2mmol). Allowedto stir at that temperature for 30 min. Concentrated under reduced pressure. 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 (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6- (methoxymethoxy)tetralin-l-one (3760.8mg, 18.235mmol, 99% yield) as a brown oil.

[0341] UPLC-MS (ES+, Method 2): 1.53 min, m / z 207.2 [M+H]+.

[0342] Setp B, (E)-N-methoxy-6-(methoxymethoxy)tetralin-1 -imine. Triethylamine (7.62mL, 54.71mmol) was added to a suspension of methoxyamine hydrochloride (3807.48mg, 45.59mmol) and 6-(methoxymethoxy)tetralin-1-one (3760.8mg, 18.24mmol) in methanol (36.47mL). The reaction mixture was heated to 60 °C and left to stir overnight. Additional triethylamine (3.81 mL, 27.35mmol) and methoxyamine hydrochloride (2284.49mg, 27.35mmol) were added and the reaction again left to stir at 60°C over the weekend. Reaction mixture allowed to cool back down to room temperature and concentrated under reduced pressure. Suspended in 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 in 0-40% EtOAc in Pet. Ether) to afford (E)-N-methoxy-6- (methoxymethoxy)tetralin-l -imine (3235.1 mg, 13.75mmol, 75% yield) as a black oil.

[0343] UPLC-MS (ES+, Method 2): 2.02 min, m / z 236.4 [M+H]+.

[0344] Step C, (E)-8-bromo-N-methoxy-6-(methoxymethoxy)tetralin-1 -imine. N- Bromosuccinimide (2447.28mg, 13.75mmol) and palladium (II) acetate (308.7mg, 1.38mmol) were added sequentially to a nitrogen degassed suspension of (E)-N- methoxy-6-(methoxymethoxy)tetralin-1-imine (3235.1 mg, 13.75mmol) in acetic acid (55mL). The reaction mixture was heated to 80°C and left to stir for 30 min. Reaction mixture allowed to cool back down to room temperature, concentrated under reduced pressure and the residue basified with a saturated solution of sodium bicarbonate. Partitioned between a layer of ethyl acetate (40 mL) and water (30 mL). Organic layer separated and aqueous layer 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 to afford (E)-8-bromo-N- methoxy-6-(methoxymethoxy)tetralin-1-imine (4320mg, 13.75mmol, 100% yield) as a brown oil.

[0345] UPLC-MS (ES+, Method 2): 2.16 min, m / z 316.0 [M+H]+.

[0346] Step D, 8-bromo-6-hydroxy-tetralin-1-one. Hydrogen chloride (11.46mL, 137.5mmol) (cone) was added to a solution of (E)-8-bromo-N-methoxy-6- (methoxymethoxy)tetralin-l -imine (4320mg, 13.75mmol) in 1 ,4-dioxane (55mL). Reaction mixture allowed to stir at 100°C for 1h. Reaction mixture allowed to cool back down to room temperature, basified with a saturated solution of sodium bicarbonate and partitioned between a layer of ethyl acetate (80 mL) and water (80 mL). Organic layer was separated and the aqueous layer extracted with ethyl acetate (2x50 mL). Organic layers combined, washed with a saturated solution of brine (40 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 8-bromo- 6-hydroxy-tetralin-1-one (3314.9mg, 13.75mmol, 100% yield) as a brown oil.

[0347] UPLC-MS (ES+, Method 2): 1.39 min, m / z 242.9 [M+H]+.

[0348] Step E, 8-bromo-6-(methoxymethoxy)tetralin-1-one (A-13). To a solution of 8- bromo-6-hydroxy-tetralin-1-one (3314.9mg, 13.75mmol) and N,N-Diisopropylethylamine (4.79mL, 27.5mmol) in DOM (27.5mL) was added Bromomethyl methyl ether (1.35mL, 16.5mmol) at 0°C. The reaction mixture was allowed to stir for 30 min and concentrated under reduced pressure. The residue was partitioned between a layer of ethyl acetate (50 mL) and water (50 mL). Organic layer was separated and aqueous layer extracted with ethyl acetate (30 mL). Organic layers combined, washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude material was purified by flash column chromatography (eluting with 0-50% EtOAc in Pet. Ether) to afford 8-bromo-6-(methoxymethoxy)tetralin-1-one (1907.3mg, 6.689mmol, 49% yield) as a yellow oil.

[0349] UPLC-MS (ES+, Method 2): 1.76 min, m / z 286.9 [M+H]+.Intermediate A-14, 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin.

[0350] Intermediate Scheme 11

[0351] Step A, 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin-1-ol. Ethylmagnesium bromide (7.36mL, 7.36mmol) (1M in THF) was added to a 0°C solution of 8-bromo-6- (methoxymethoxy)tetralin-l-one (700. mg, 2.45mmol) in THF (4.9099mL). The reactionmixture was left to stir at 0°C temperature for 1 h and quenched with a saturated solution of ammonium chloride. 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. Purification by flash column chromatography (eluting 0-40% EtOAc in Pet. Ether) to afford 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin-1-ol (214.1mg, 0.6792mmol, 28% yield) as a brown oil.

[0352] UPLC-MS (ES+, Method 2): 2.08 min, m / z 298.9 [M+H]+.

[0353] Step B, 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin (A-14). Trifluoroacetic acid (0.07mL, 0.95mmol) was added to a solution of Triethylsilane (0.3mL, 1.9mmol) and 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin-1-ol (150. mg, 0.48mmol) in DCM (2.3794mL). The reaction mixture was left to stir at room temperature overnight. Basified with a saturated solution of sodium bicarbonate and 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. Purification by flash column chromatography (eluting with 0- 30% EtOAc in Pet. Ether) to afford 8-bromo-1-ethyl-6-(methoxymethoxy)tetralin (103.3mg, 0.3452mmol, 73% yield) as a clear oil.

[0354] 1H NMR (400 MHz, CDCh) b / ppm: 7.12 (d, J = 2.6 Hz, 1 H), 6.71 (d, J = 2.5 Hz, 1 H), 5.11 (s, 2H), 3.46 (s, 3H), 2.86 - 2.65 (m, 3H), 2.02 - 1.92 (m, 1 H), 1.86 - 1.54 (m, 4H), 1.41 - 1.24 (m, 1 H), 1.00 (t, J = 7.4 Hz, 3H).Intermediate A-15, (8-ethyl-7-fluoro-1 -naphthyl) trifluoromethanesulfonate.

[0355] Intermediate Scheme 12

[0356] Step A, 7-fluoronaphthalen-1-ol. A solution of 7-Fluoro-3,4-dihydronaphthalen- 1(2H)-one (500. mg, 3.05mmol) in acetic acid (10mL) was cooled to 0°C and HBr (24.64mg, 0.3mmol) added. A solution of bromine (535.36mg, 3.35mmol) in acetic acid (1 mL) was added to the mixture. The reaction mixture was warmed to room temperature and left to stir for 3h. The reaction mixture was diluted with water (100 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The residue was taken up in DMF (10mL), lithium bromide (449.64mg, 5.18mmol) and lithium carbonate (382.55mg, 5.18mmol) were added. The mixture was heated to 160°C and left to stir for 3.5hrs. The reaction mixture was diluted with water (150 mL) and extracted with EtOAc (60 mL x 3). The combined organic layers were washed with brine (200 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 7-fluoronaphthalen-1-ol (270mg, 1.665mmol, 55% yield) as a brown solid.

[0357] 1H NMR (400 MHz, DMSO-d6) b / ppm: 10.27 (s, 1 H), 7.69 (dd, J = 9.0, 5.8 Hz, 1 H), 7.78 (dd, J = 10.8, 2.5 Hz, 1 H), 7.47 - 7.42 (m, 2H), 7.37 - 7.30 (m, 1 H), 6.99 (d, J = 7.6 Hz, 1 H).

[0358] Step B, 7-fluoro-8-(2-triisopropylsilylethynyl)naphthalen-1-ol. To a stirring solution of 7-fluoronaphthalen-1-ol (270. mg, 1.67mmol) in 1 ,4-dioxane (5mL) was added potassium acetate (326.81 mg, 3.33mmol), 1-isopropyl-4-methylbenzene dimer(101.96mg, 0.17mmol) and (bromoethynyl)triisopropylsilane (0.43mL, 1.75mmol). The reaction mixture was heated to 110°C and left to stir for 2 hours. The reaction mixture was cooled to room temperature, filtered and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 7-fluoro-8-(2- triisopropylsilylethynyl)naphthalen-1-ol (470mg, 1.3721mmol, 82% yield) as a yellow oil.

[0359] 1H NMR (400 MHz, DMSO-d6) b / ppm: 10.12 (s, 1 H), 7.92 (dd, J = 9.0, 5.9 Hz, 1 H), 7.43 (d, J = 9.0 Hz, 1 H), 7.40 (d, J = 8.2 Hz, 1 H), 7.36 - 7.28 (m, 1 H), 6.97 (d, J = 7.5 Hz, 1 H), 1.23 - 1.11 (m, 21 H).

[0360] Step C, [7-fluoro-8-(2-triisopropylsilylethynyl)-1 -naphthyl] 2,2- dimethylpropanoate. To a stirring solution of 7-fluoro-8-(2- triisopropylsilylethynyl)naphthalen-1-ol (470. mg, 1.37mmol) in DCM (5mL) at 0°C was added triethylamine (416.54mg, 4.12mmol) and 4-dimethylaminopyridine (33.53mg, 0.27mmol). The reaction mixture was stirred at 0°C for 5 mins. Trimethyl acetyl chloride (0.51mL, 4.12mmol) was added, the reaction mixture warmed to room temperature and left to stir for 1h. The reaction mixture was diluted with sat. aq. NH4CI (100 mL) and extracted with EtOAc (30 mL x 4). The combined organic layers were washed with brine (200 mL x 3), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography (eluting in Pet.ether / EtOAc=5 / 1) to afford [7-fluoro-8-(2-triisopropylsilylethynyl)-1 -naphthyl] 2,2-dimethylpropanoate (560mg, 1.3126mmol, 96% yield) as a yellow solid.

[0361] 1H NMR (400 MHz, DMSO-d6) b / ppm: 8.20 (dd, J = 9.0, 5.8 Hz, 1 H), 8.00 (d, J = 8.2 Hz, 1 H), 7.69 - 7.58 (m, 2H), 7.29 (d, J = 7.60, Hz, 1 H), 1.46 (s, 9H), 1.23 - 1.11 (m, 21 H).

[0362] Step D, (8-ethynyl-7-fluoro-1 -naphthyl) 2,2-dimethylpropanoate. CsF (35.6g, 234.38mmol) was added to a stirring solution of [7-fluoro-8-(2-triisopropylsilylethynyl)- 1 -naphthyl] 2,2-dimethylpropanoate (10.g, 23.44mmol) in Methanol (100mL) and the reaction mixture left to stir at room temperature for 30 mins. The reaction mixture was diluted with water (1000 mL) and extracted with EtOAc (200 mL x 3). The combined organic layers were washed with brine (1000 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography to afford (8-ethynyl-7-fluoro-1 -naphthyl) 2,2-dimethylpropanoate (4.8g, 17.758mmol, 76% yield) as a brown oil.

[0363] 1H NMR (400 MHz, CDC ) b / ppm: 7.86 (dd, J = 9.0, 5.7 Hz, 1 H), 7.72 (d, J = 8.2 Hz, 1 H), 7.49 - 7.41 (m, 1 H), 7.34 - 7.24 (m, 1 H), 7.11 (d, J = 7.4 Hz, 1 H), 3.60 (s, 1 H), 1.47 (s, 9H).

[0364] Step E, (8-ethyl-7-fluoro-1 -naphthyl) 2,2-dimethylpropanoate. A stirring solution of (8-ethynyl-7-fluoro-1-naphthyl) 2,2-dimethylpropanoate (3.8g, 14.06mmol) in Methanol (100mL) was degassed and backfilled with nitrogen three times before Pd / C (380mg) was added. The stirring mixture was degassed and backfilled with hydrogen, the mixture warmed to 40°C and left to stir for 2 hours. The reaction mixture was cooled to room temperature before being degassed and backfilled with nitrogen then filtered through a pad of celite, washing with MeOH and the filtrate reduced in vacuo to afford the desired product (8-ethyl-7-fluoro-1 -naphthyl) 2,2-dimethylpropanoate (2.8g, 10.206mmol, 73% yield) as a brown oil.

[0365] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.94 (dd, J = 8.9, 5.9 Hz, 1 H), 7.88 (d, J = 8.1 Hz, 1 H), 7.52 - 7.41 (m, 2H), 7.15 (d, J = 7.6 Hz, 1 H), 3.12 - 3.01 (m, 2H), 1.40 (s, 9H), 1.16 (t, J = 7.5 Hz, 3H).

[0366] Step F, 8-ethyl-7-fluoro-naphthalen-1-ol. To a solution of (8-ethyl-7-fluoro-1- naphthyl) 2,2-dimethylpropanoate (950. mg, 3.46mmol) in Methanol (10mL) was added potassium hydroxide (777.2mg, 13.85mmol) and the mixture stirred at room temperature for 30 mins. The reaction mixture was diluted with water (100 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by flash column chromatography to afford 8-ethyl-7-fluoro-naphthalen-1-ol (250mg, 1.3143mmol, 38% yield) as a brown oil.

[0367] 1H NMR (400 MHz, DMSO-d6) b / ppm: 10.06 (s, 1 H), 7.72 (dd, J = 9.0, 6.0 Hz, 1 H), 7.39 - 7.21 (m, 3H), 6.92 (d, J = 7.5 Hz, 1 H), 3.40 - 3.30 (m, 2H), 1.25 (t, J = 7.3 Hz, 3H).

[0368] Step G, (8-ethyl-7-fluoro-1 -naphthyl) trifluoromethanesulfonate (A-15). N,N- Diisopropylethylamine (4.08g, 31.54mmol) was added to a stirring solution of 8-ethyl- 7-fluoro-naphthalen-1-ol (1.g, 5.26mmol) in DCM (10mL) at -40°C and the mixture stirred for 5 mins, trifluoromethanesulfonic anhydride (1.93g, 6.83mmol) was added and the mixture was stirred for 30 mins. The reaction mixture was diluted with water (100 mL) and extracted with DCM (40 mL x 3). The combined organic layers were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by flash column chromatography to afford (8-ethyl-7-fluoro-1- naphthyl) trifluoromethanesulfonate (1.5g, 4.6545mmol, 89% yield) as a brown oil.

[0369] 1H NMR (400 MHz, DMSO-d6) 5 / ppm: 8.15 (dd, J = 8.0, 1.0 Hz, 1 H), 8.09 (dd, J = 9.0, 5.9 Hz, 1 H), 7.71 (d, J = 7.7 Hz, 1 H), 7.67 - 7.58 (m, 2H), 3.26 - 3.17 (m, 2H), 1.20 (t, J = 7.5 Hz, 3H).Intermediate A-16, 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene.

[0370] Intermediate Scheme 13

[0371] Step A, 4-bromo-1-fluoro-naphthalen-2-ol. To a stirring solution of 1-Bromo-3- hydroxynaphthalene (500. mg, 2.24mmol) in MeCN (20mL) at O'C was added Selectfluor (794.06mg, 2.24mmol). The mixture was stirred at O'C to 15'C (ice bath) overnight. Additional Selectfluor (397.03mg, 1.12mmol) was added and the mixture was left to stir for 2hrs. The reaction mixture was quenched with sat. NaHCOs solution and extracted with DCMx3. The combined organic layers were filtered through a phase separator cartridge and concentrated in vacuo to afford 4-bromo-1-fluoro-naphthalen- 2-ol (540.32mg, 2.2414mmol, 100% yield) as a yellow oil.

[0372] UPLC-MS (ES-, Method 5): 2.02 min, m / z 238.9 240.9 [M-H]’.

[0373] Step B, 4-bromo-1-fluoro-2-(methoxymethoxy)naphthalene (A-16). A stirring solution of 4-bromo-1-fluoro-naphthalen-2-ol (540. mg, 1.39mmol) in DCM (12mL) was cooled to 0°C and N,N-Diisopropylethylamine (0.48mL, 2.78mmol) and Bromomethyl methyl ether (0.12mL, 1.53mmol) were added. The reaction mixture was stirred at 0°C for 2hrs. The reaction mixture was quenched with water and extracted with DCMx3. The combined organics were filtered through a phase separator cartridge and concentrated in vacuo. The crude material was purified by flash column chromatography (12g, eluting in 0-20% EtOAc in Pet. ether) to afford 4-bromo-1-fluoro- 2-(methoxymethoxy)naphthalene (189mg, 0.5635mmol, 41 % yield) as a yellow oil.

[0374] 1H NMR (400 MHz, CDC ) 5 / ppm: 8.16 - 8.11 (m, 1 H), 8.08 - 8.04 (m, 1 H), 7.75 (d, J = 7.4 Hz, 1 H), 7.60 - 7.51 (s, 2H), 5.29 (s, 2H), 3.58 (s, 3H).Intermediate A-17, [(4R)-4-[tert-butyl(dimethyl)silyl]oxy-1,2-dimethyl-pyrrolidin-2- yl]methanol.

[0375] Intermediate Scheme 14

[0376] Step A, methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-2- carboxylate. To a solution of L-4-Hydroxyproline methyl ester hydrochloride (300 mg, 2.07 mmol) in DCM (8mL) at 25°C was added Tert - butyl - chlorodimethylsilane purum (373.8 mg, 2.48 mmol) and imidazole (281.4 mg, 4.13 mmol). The mixture was stirred at 25°C for 18hrs. Reaction mixture was quenched with water and the layers separated. The aqueous layer was extracted x3 with DCM. Combined organics were washed with brine, passed through an hydrophobic frit and concentrated under reduced pressure to yield methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine-2-carboxylate (390mg, 1.50 mmol, 73% yield) as a clear oil.

[0377] 1H NMR (400MHz, CDCh) 5 / ppm: 4.41-4.34 (m, 1 H), 4.00 (t, J = 8.0 Hz, 1 H), 3.73 (s, 3H), 3.11 (dd, J = 11.5, 4.5 Hz, 1 H), 2.87-2.81 (m, 1 H), 2.10-2.02 (m, 1 H), 1.99-1.89 (m, 2H), 0.88 (s, 9H), 0.06 (s, 3H), 0.05 (s, 3H).

[0378] Step B, methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidine-2- carboxylate. To a solution of methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxypyrrolidine- 2-carboxylate (190mg, 0.73mmol) in Methanol (5mL) was added formaldehyde solution (36.5-38%) in water (0.3mL, 3.66mmol). The mixture was stirred at 25°C for 10 mins then sodium triacetoxyborohydride (232.84mg, 1.1 mmol) was added. Allowed to stir for 2hrs at 25°C. Reaction mixture was concentrated in vacuo, taken up in DCM and washed with NaHCOs saturated aqueous solution x2 and brine. The resulting organics were passed through a hydrophobic frit and reduced in vacuo to yield methyl (2S,4R)-4-[tert-butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate (132mg, 0.48mmol, 66% yield) as an orange oil.

[0379] 1H NMR (400MHz, CDCh) 5 / ppm: 4.45-4.38 (m, 1 H), 3.73 (s, 3H), 3.37 (dd, J = 9.6, 6.0 Hz, 1 H), 3.26 (t, J = 8.3 Hz, 1 H), 2.40 (s, 3H), 2.30 (dd, J = 9.6, 5.5 Hz, 1 H), 2.24- 2.12 (m, 1 H), 2.07-1.96 (m, 1 H), 0.88 (s, 9H), 0.04 (s, 3H), 0.03 (s, 3H).

[0380] Step C, methyl (4R)-4-[tert-butyl(dimethyl)silyl]oxy-1,2-dimethyl-pyrrolidine-2- carboxylate. Diisopropylamine (1.54mL, 10.97mmol) was dissolved in dry THF (30mL) and cooled to -78°C. n-Butyllithium solution (6.86mL, 10.97mmol) was added, and the mixture was stirred for 30 mins at -78°C. At -78°C, methyl (2S,4R)-4-[tert- butyl(dimethyl)silyl]oxy-1-methyl-pyrrolidine-2-carboxylate (1.5g, 5.49mmol) in THF (10mL) was added dropwise. Temperature was maintained at -78°C for 5 min before warming to 0°C. After 1 hr, lodomethane (1.02mL, 16.46mmol) was added at 0°C and reaction mixture was allowed to warm to 25°C and stir for 18hrs. The reaction mixture was quenched with a saturated aqueous solution of NH4CI. EtOAc was added and the layers separated. The aqueous layer was extracted with EtOAc x3. Organic layers were combined, dried over Na2SO4 and filtered. The filtrate was concentrated under reduced pressure. Crude residue was purified by flash chromatography (12g, dry-load onto HM-N absorbant, 0-80% EtOAc in Petroleum ether, detected using TLC). Relevant fractions were pooled and concentrated to yield methyl rac-(4R)-4-[tert- butyl(dimethyl)silyl]oxy-1,2-dimethyl-pyrrolidine-2-carboxylate (493mg, 1.7149mmol, 31 % yield) as a yellow oil.

[0381] 1H NMR (400MHz, CDCh) 6 / ppm: 4.47-4.40 (m, 0.75H), 4.40-4.34 (m, 0.25H), 3.70 (s, 1 H), 3.68 (s, 2H), 3.09 (dd, J = 9.7, 6.7 Hz, 1 H), 2.90 (dd, J = 9.4, 4.8 Hz, 0.25H), 2.77 (dd, J = 9.7, 3.5 Hz, 0.75H), 2.52 (dd, J = 13.3, 7.8 Hz, 0.75H), 2.37 (s, 1 H), 2.28 (s, 2H), 2.25 (dd, J = 13.2, 4.4 Hz, 0.25H), 2.05-1.98 (m, 0.25H), 1.70 (dd, J = 13.3, 4.6 Hz, 0.75H), 1.35 (s, 2H), 1.27 (s, 1 H), 0.87 (s, 6H), 0.86 (s, 3H), 0.04 (s, 4H), 0.02 (s, 2H).

[0382] Step D, [(4R)-4-[tert-butyl(dimethyl)silyl]oxy-1,2-dimethyl-pyrrolidin-2- yl]methanol (A-17). Lithium aluminium hydride (3.77mL, 3.77mmol) was added to a solution of methyl (4R)-4-[tert-butyl(dimethyl)silyl]oxy-1 ,2-dimethyl-pyrrolidine-2- carboxylate (493. mg, 1.71mmol) in dry THF (7mL) at 0°C. Mixture was allowed to warm to 25°C and stirred for 2hrs. The reaction mixture was quenched with MeOH, water and Rochelle's salt, and filtered. EtOAc was added and the layers were separated. The aqueous layer was extracted with EtOAc x3. Combined organics were washed with brine, passed through hydrophobic filter paper and concentrated under reduced pressure to yield [(4R)-4-[tert-butyl(dimethyl)silyl]oxy-1 ,2-dimethyl-pyrrolidin- 2-yl]methanol (285mg, 1.10mmol, 64% yield) (A-17) as an orange oil.

[0383] 1H NMR (400MHz, CDCh) 6 / ppm: 4.28-4.20 (m, 1 H), 3.27-3.20 (m, 2H), 3.14 (d, J = 10.4 Hz, 1 H), 2.54 (dd, J = 9.2, 6.6 Hz, 1 H), 2.33-2.23 (m, 1 H), 2.16 (s, 3H), 1.45 (dd, J = 13.2, 4.7 Hz, 1 H), 0.99 (s, 3H), 0.87 (s, 9H), 0.04-0.02 (m, 6H).Intermediate A-37, tert-butyl (4R)-2-(hydroxymethyl)-2-methyl-4-tetrahydropyran-2- yloxy-pyrrolidine-1 -carboxylate.

[0384] Intermediate Scheme 15

[0385] Step A, 01 -tert-butyl O2-methyl (2S,4R)-4-tetrahydropyran-2-yloxypyrrolidine- 1,2-dicarboxylate. To a solution of n-boc-trans-4-hydroxy-l-proline methyl ester (1000mg, 4.08mmol) in DCM (10mL) at 0°C was added p-toluenesulfonic acid monohydrate (77.55mg, 0.41 mmol) followed by 3,4-dihydro-2H-pyran (1.12mL, 12.23mmol). The reaction mixture was stirred at room temperature overnight, for overnight. The reaction mixture was reduced in vacuo to afford a black / brown oily residue. Crude material was purified by flash column chromatography (25g column, eluting 0-60% EtOAc in pet ether) to afford the desired product 01-tert-butyl 02-methyl (2S,4R)-4-tetrahydropyran-2-yloxypyrrolidine-1 ,2-dicarboxylate (1.056g, 3.2059mmol, 79% yield) as an yellow oil.

[0386] UPLC-MS (ES+, Method 2): 1.76 min, m / z 352.2 [M+Na]+and m / z 230.1 [M-Boc]+

[0387] Step B, 01-tert-butyl 02-methyl rac-(4R)-2-methyl-4-tetrahydropyran-2-yloxy- pyrrolidine-1 ,2-dicarboxylate. To a solution of 01-tert-butyl 02-methyl (2S,4R)-4- tetrahydropyran-2-yloxypyrrolidine-1 ,2-dicarboxylate (335. mg, 1.02mmol) in dry THF (5mL) under N2 was added lithium diisopropylamide (0.61 mL, 1.22mmol) dropwise at -78°C. The reaction mixture was stirred for 1 hour and lodomethane (0.09mL, 1.53mmol) was added dropwise. The reaction mixture was then allowed to warm to room temperature and left to stir overnight. The reaction mixture was quenched with sat. NH4CI (aq), EtOAc added and the layers separated. The aqueous layer further extracted with EtOAc (x3). The organic layers were combined, dried over Na2SO4, filtered and the solvents removed in vacuo. The crude material was purified by flash chromatography (12g, eluting in 0-50% EtOAa in Pet. Ether, ELS detector) to affordthe desired product 01 -tert-butyl 02-methyl (4R)-2-methyl-4-tetrahydropyran-2-yloxy- pyrrolidine-1 ,2-dicarboxylate (241 mg, 0.7018mmol, 69% yield) as a yellow oil.

[0388] UPLC-MS (ES+, Method 5): 2.04 min, m / z 366.3 [M+Na]+

[0389] Step C, tert-butyl (4R)-2-(hydroxymethyl)-2-methyl-4-tetrahydropyran-2-yloxy- pyrrolidine-1 -carboxylate (A-37). Lithium borohydride (38.21 mg, 1.75mmol) was added to a solution of 01-tert-butyl 02-methyl (4R)-2-methyl-4-tetrahydropyran-2- yloxy-pyrrolidine-1 ,2-dicarboxylate (241. mg, 0.7mmol) in THF (4mL) at 0 °C. The reaction mixture was allowed to warm to room temperature and left to stir overnight. The reaction mixture was quenched with MeOH and concentrated in vacuo. The crude residue was purified by flash chromatography (4g, eluting in 0-50 % EtOAa in Pet. ether) to afford the desired product tert-butyl (4R)-2-(hydroxymethyl)-2-methyl-4- tetrahydropyran-2-yloxy-pyrrolidine-1 -carboxylate (198mg, 0.6278mmol, 89.454% yield) as a colourless oil.

[0390] UPLC-MS (ES+, Method 5): 1.84 min, m / z 316.1 [M+H]+Intermediate A-31, [1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]methanol.

[0391] Intermediate Scheme 16

[0392] Step A, [1-(methoxymethyl)-2-oxabicyclo[2.1.1]hexan-4-yl]methanol (A-31).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.

[0393] 1H NMR (400MHz, CDCh) b / 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-21, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonitrile.

[0394] Intermediate Scheme 17

[0395] Step A, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide. HATLI (856.3 mg, 2.25 mmol) was added to a solution of ammonium chloride (1095.1 mg, 20.47 mmol) , N,N-Diisopropylethylamine (1.07 mL, 6.14mmol) and 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5- a][1 ,4]diazepine-2-carboxylic acid (750 mg, 2.05 mmol) in dry DMF (4.0944mL) and stirred at25 °C overnight. Further N,N-Diisopropylethylamine (0.53mL, 3.07mmol) and HATLI (311.37mg, 0.82mmol) were added and stirred at 25 °C overnight again. Mixture was acidified to pH2, diluted with water and EtOAc and the aqueous was extracted with EtOAc. Combined organics washed with brine and dried under Na2SO4, filtered, filtrate evaporated in vacuo. Residue was Suspended in EtOAc / MeOH and cream solid was filtered off and dried under vacuum affording some of the product. Filtrate was purified by flash chromatography (eluting 0-15% MeOH in EtOAc). The two batches were combined to afford the desired product 5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide (684mg, 1.872mmol, 91% yield) as a beige solid.

[0396] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 8.04-7.97 (2H, m), 7.92-7.87 (1 H, m), 7.85- 7.79 (1 H, m), 7.42 (1 H, s) 7.18 (1 H, s), 6.60 (1 H, s), 4.66 (2H, s), 4.48-4.39 (2H, m), 3.71-3.61 (2H, m), 1.97-1.87 (2H, m).

[0397] Step B, 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carbonitrile. 5-(2-nitrophenyl)sulfonyl-4, 6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide (408.5mg, 1.12mmol) was dissolved in DCM (11.2mL) and Triethylamine (0.47mL, 3.35mmol) then cooled to 0°C. Trifluoroacetic anhydride (0.31 mL, 2.24mmol) was added dropwise and stirred at 0°C for 1 hr. Diluted with DCM, washed twice with aqueous saturated NaHCO3 solution, passed through a hydrophobic filter paper and concentrated in vacuo affording 5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carbonitrile (611.5mg, 1.7605mmol, 99% yield) as a yellow / orange gum. Material was used without further purification.1H NMR (400MHz, CDCh) b / ppm: 8.04-7.99 (1 H, m), 7.77-7.64 (3H, m), 6.64 (1 H, s), 4.57 (2H, s), 4.52-4.45 (2H, m), 3.76-3.65 (2H, m), 2.15-2.05 (2H, m).

[0398] Step C, 5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine-2-carbonitrile (A- 21). To 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2- carbonitrile (611.mg, 1.76mmol) and Cesium Carbonate (1.15g, 3.52mmol) in MeCN (8.80mL) was added Thiophenol (0.36mL, 3.52mmol) and the reaction was stirred at room temperature for 90 mins in a sealed vial. The reaction was diluted with EtOAc, passed through a plug of celite, plug washed with EtOAc, the filtrate was collected and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-20% MeOH in DCM afforded 5, 6, 7, 8- tetra hydro-4 H- pyrazolo[1 ,5-a][1 ,4]diazepine-2-carbonitrile (81.4mg, 0.5018mmol, 29% yield) as a pale yellow gum.

[0399] 1H NMR (400MHz, CDCh) b / ppm: 6.46 (s, 1 H), 4.50 - 4.40 (m, 2H), 3.92 (s, 2H), 3.27- 3.17 (m, 2H), 1.93 - 1.83 (m, 2H). Exchangeable proton not seen.Intermediate A-22, 5-cyclopropyl-6-methyl-1-tetrahydropyran-2-yl-4-(4, 4,5,5- tetramethyl-1,3,2-dioxaborolan-2-yl)indazole.

[0400] Intermediate Scheme 18

[0401] Step A, 1-bromo-5-fluoro-2-iodo-3-methyl-benzene. 2-bromo-4-fluoro-6- methylaniline (4000 mg, 19.6 mmol) was stirred at 70°C with Hydrogen Chloride (6M in water) (40 mL, 240 mmol) for 30 minutes until completely dissolved. The mixture was cooled to -5 °C, and a solution of Sodium nitrite (1623 mg, 23.52 mmol) in Water (10mL) was added. The mixture was stirred for 30 minutes, then a solution of Potassium iodide (3905.1 mg, 23.52 mmol) in Water (16 mL) was added. The mixture was diluted with EtOAc (2 x 40 mL),and washed with brine (3 x 60 mL). The combined organics were dried with Na2SO4, filtered and concentrated to give a black solid. The crude was passed through a silica plug, eluting with 20% EtOAc in petroleum ether. The desired fractions were washed with aqueous saturated Na2S20s, dried and concentrated to afford 1-bromo-5-fluoro-2-iodo-3-methyl-benzene (4653 mg, 14.8 mmol, 75% yield) as a pale orange solid.

[0402] 1H NMR (400MHz, CDCh) 5 / ppm: 7.26 - 7.23 (m, 1 H), 6.97 - 6.92 (m, 1 H), 2.55 (s, 3H).

[0403] Step B, 2-bromo-6-fluoro-3-iodo-4-methyl-benzaldehyde. A solution of 1-bromo-5-fluoro-2-iodo-3-methyl-benzene (4653 mg, 14.8mmol) in anhydrous THF (17.6 mL) under N2, was cooled to -78 °C, and Lithium diisopropylamide (2M in THF / heptane / ethylbenzene) (8.87mL, 17.7 mmol) was added slowly at -78 °C, the mixture was stirred for 30 minutes. Ethyl formate (0.93mL, 16.99mmol) was then added, and stirred at -78 °C for 15 minutes. The mixture was then poured into aqueous saturated NH4CI and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered and concentrated to afford 2-bromo-6-fluoro-3-iodo-4-methyl- benzaldehyde (5066mg, 14.8 mmol, 100% yield) a pale orange solid, material was used without further purification.

[0404] 1H NMR (400MHz, CDCh) 5 / ppm: 10.19 (s, 1 H), 7.1 (d, J = 10.9 Hz, 1 H), 2.63 (s, 3H).

[0405] Step C, 4-bromo-5-iodo-6-methyl-1 H-indazole. Hydrazine hydrate (4.26mL, 87.5 mmol) was added to 2-bromo-6-fluoro-3-iodo-4-methyl-benzaldehyde (5000 mg, 14.6 mmol) in DMSO (50m L) at room temperature under N2. The mixture was heated to 120°C overnight. The reaction was cooled to room temperature and diluted with water (50 mL), then extracted with EtOAc (3 x 100 mL). The combined organics were washed twice with brine, dried with Na2SO4, filtered and concentrated to give 4-bromo-5-iodo-6-methyl-1 H-indazole (4911 mg, 14.574mmol, 100% yield) as a pale orange solid, material was used without further purification.

[0406] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 13.39 (br s, 1 H), 7.93 - 7.92 (m, 1 H), 7.58 - 7.56 (m, 1 H), 2.63 (s, 3H).

[0407] Step D, 4-bromo-5-iodo-6-methyl-1-tetrahydropyran-2-yl-indazole. p- Toluenesulfonic acid monohydrate (510.12mg, 2.96mmol) was added to 4-bromo-5- iodo-6-methyl-1 H-indazole (4991. mg, 14.8mmol) and 3,4-Dihydro-2H-pyran (2.7mL, 29.6mmol) in THF (60mL), and stirred at 50 °C overnight. The mixture reduced in volume in vacuo and diluted with EtOAc and water. The organics were washed with sat. NaHCOs x 2, and brine, dried with Na2SO4, filtered, and concentrated. The crude was purified by flash column chromatography eluting 0-15% EtOAc in petroleum ether. The desired fractions were concentrated and triturated with MeOH (10 mL). The solid was dried in vacuo to afford 4-bromo-5-iodo-6-methyl-1-tetrahydropyran-2-yl-indazole (3939mg, 9.35mmol, 63% yield) as a white solid.

[0408] UPLC-MS (ES+, Method 2): 2.21 min, m / z 421.0 [M+H]+.

[0409] Step E, 4-bromo-5-cyclopropyl-6-methyl-1-tetrahydropyran-2-yl-indazole. [1 ,1'- Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (77.58mg, 0.09mmol) was added to 4-bromo-5-iodo-6-methyl-1-tetrahydropyran-2-yl- indazole (400mg, 0.95mmol) , cesium carbonate (619.02mg, 1.9mmol) , and cyclopropylboronic acid (89.8 mg, 1.04 mmol) in 1 ,4-dioxane (5.28 mL) and water (1 .05 mL) degassed with N2. The mixture was heated to 90°C overnight. The reaction was concentrated in vacuo, and crude was purified by flash column chromatography eluting 5-30% EtOAc in petroleum ether. The desired fractions were concentrated to afford 4-bromo-5-cyclopropyl-6-methyl-1-tetrahydropyran-2-yl-indazole (214mg, 0.6383mmol, 67% yield) as a colourless oil.

[0410] UPLC-MS (ES+, Method 5): 2.36 min, m / z 335.0 [M+H]+.

[0411] Step F, 5-cyclopropyl-6-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl- 1,3,2-dioxaborolan-2-yl)indazole (A-22). [1,1'-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (52.13 mg, 0.06 mmol) was added to a solution of 4-bromo-5-cyclopropyl-6-methyl-1- tetrahydropyran-2-yl-indazole (214 mg, 0.64mmol), bis(pinacolato)diboron (243.15mg, 0.96mmol) , and potassium acetate (125.3 mg, 1.28 mmol) in 1 ,4-dioxane (4.2557mL) , degassed with N2. The mixture was heated to 100 °C overnight. The reaction was concentrated in vacuo, and the crude was purified by flash column chromatography eluting 5-50% EtOAc in petroleum ether. The desired fractions were concentrated to afford 5-cyclopropyl-6-methyl-1-tetrahydropyran-2-yl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)indazole (57 mg, 0.149mmol, 23% yield) as a colourless gum.

[0412] UPLC-MS (ES+, Method 5): 2.33 min, m / z 383.1 [M+H]+.Intermediate A-23, 5-ethyl-1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-ol.

[0413] Intermediate Scheme 19

[0414] Step A, 5-ethyl-6-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)naphthalen-2- ol.

[0415] 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) stirred at room temperature for 1 hr, then concentrated in vacuo. The crude was purified by flash column chromatography eluting 0-25% EtOAc in petroleum ether. 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.

[0416] UPLC-MS (ES+, Method 5): 2.14 min, m / z 317.1 [M+H]+.

[0417] Step B, 5-ethyl-1,6-difluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)naphthalen-2-ol (A-23).

[0418] 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 Na2SO4, 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.

[0419] 1H NMR (400MHz, CDCI3) 6 / 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).Intermediate A-24, 4-bromo-6-methyl-5-(trifluoromethyl)-1 H-indazole.

[0420] Intermediate Scheme 20

[0421] Step A, 1-bromo-5-fluoro-2-iodo-3-methyl-benzene. 2-bromo-4-fluoro-6- methylaniline (1 g, 4.9mmol) was stirred at 70°C with Hydrogen Chloride (6M in water) (10 mL, 60mmol) for 30 minutes until completely dissolved. MeCN (4mL) was added to aid solubility. The mixture was cooled to -5°C, and a solution of Sodium nitrite (405.74mg, 5.88mmol) in water (2.5mL) was added. The mixture was stirred for 30 minutes, then potassium iodide (976.3mg, 5.88mmol) as a solution in water (4mL) was added. The mixture was diluted with EtOAc (2 x 40 mL), and washed with brine (3 x 60 mL). The combined organics were dried with Na2SC>4, filtered and concentrated to give a black solid. The crude was passed through a silica plug, eluting with 20% EtOAc in petroleum ether. The desired fractions were washed with sat. Na2S20s, dried and concentrated to afford 1 -bromo- 5-fluoro-2-iodo-3-methyl-benzene (908mg,2.8833mmol, 59% yield) as a pale orange solid.

[0422] 1H NMR (400MHz, CDCh) b / ppm: 7.26 - 7.23 (m, 1 H), 6.97 - 6.92 (m, 1 H), 2.55 (s, 3H).

[0423] Step B, 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene. To a stirred solution of 1-bromo-5-fluoro-2-iodo-3-methyl-benzene (908. mg, 2.88mmol) in DMF (14.42mL) was added methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (3.3mL, 25.9mmol) and methyl-2,2-difluoro-2-(fluorosulfonyl)acetate (3.3mL, 25.95mmol). The reaction was heated to 60°C and stirred overnight. The reaction was allowed to cool to room temperature and diluted with 100 mL of water. The suspension was extracted withpetroleum ether (2 x 100 mL). The combined organic extracts were washed with brine, dried via phase separator and evaporated to afford 1 -bromo- 5-fluoro-3-methyl-2- (trifluoromethyl)benzene (369mg, 1.44mmol, 50% yield) as a pale orange oil. Material was used without further purification.

[0424] UPLC-MS (ES+, Method 5): 2.23 min.

[0425] Step C, 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde. To a stirred solution of 1-bromo-5-fluoro-3-methyl-2-(trifluoromethyl)benzene (369mg, 1.44mmol) in THF (1.9mL) under nitrogen at -65°C was added Lithium diisopropylamide (0.8mL, 1.59mmol) (2 M in THF) dropwise. The reaction was stirred for 30 mins at -65°C. N,N- Dimethylformamide (0.12mL, 1.58mmol) was then added dropwise and the reaction continued to stir at this temperature. After 2 hours the reaction was warmed to 0 °C and quenched with 1 M HCI until the solution was pH 4. The aqueous mixture was extracted with EtOAc (3x). The combined organic extracts were washed with brine, dried via phase separator and evaporated to afford 2-bromo-6-fluoro-4-methyl-3- (trifluoromethyl)benzaldehyde (251 mg, 0.881 mmol, 61% yield) as a brown oil. Material was used without further purification.

[0426] UPLC-MS (ES+, Method 5): 2.00 min.

[0427] Step D, 4-bromo-6-methyl-5-(trifluoromethyl)-1H-indazole (A-24). To a stirred solution of 2-bromo-6-fluoro-4-methyl-3-(trifluoromethyl)benzaldehyde (250mg, 0.88mmol) in THF (2mL) was added Hydrazine Hydrate (0.13mL, 2.63mmol). The reaction was stirred at 60°C for 21 hrs. The reaction was partitioned between EtOAc and water and the layers separated. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried via phase separator and evaporated to afford an orange oil. This material was purified via silica gel chromatography eluting 0-100% EtOAc in petroleum ether to afford 4-bromo-6-methyl- 5-(trifluoromethyl)-1 H-indazole (137mg, 0.491 mmol, 56% yield) as a yellow solid (A- 24).

[0428] UPLC-MS (ES+, Method 5): 1.93 min, m / z 280.8 [M+H]+.Intermediate A-25, N,N,2-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)pyrazole-3-carboxamide.

[0429] Intermediate Scheme 21

[0430] Step A, 3-bromo-N,N,1-trimethyl-pyrazole-5-carboxamide. To a stirred solution of 3-bromo-1-methyl-pyrazole-5-carboxylic acid (500mg, 2.44mmol) in DMF (10mL) at room temperature was added N,N-Diisopropylethylamine (1.27mL, 7.32mmol), N , N , N’, N’-tetramethyl-O-(benzotriazol-1 -yl)uronium tetrafluoroborate (1370.41 mg, 4.27mmol) and dimethylamine hydrochloride (298.3mg, 3.66mmol). The reaction was stirred overnight at room temperature. The reaction was partitioned between EtOAc and water and the layers separated. The aqueous was extracted with EtOAc (2x). The organic extracts were washed with water and brine, dried via phase separator and evaporated to afford 3-bromo-N,N,1-trimethyl-pyrazole-5-carboxamide (566mg, 2.439mmol, 100% yield) as an orange oil.

[0431] UPLC-MS (ES+, Method 5): 1.29 min, m / z 231.9, 233.9 [M+H]+.

[0432] 1H NMR (400MHz, CDC ) 6 / ppm: 6.34 (s, 1 H), 3.94 (s, 3H), 3.11 (s, 7H).

[0433] Step B, N,N,2-trimethyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrazole- 3-carboxamide (A-25). To a stirred solution of 3-bromo-N,N,1-trimethyl-pyrazole-5- carboxamide (570 mg, 2.46mmol) in 1,4-Dioxane (10mL) was added 1 ,1'- Bis(diphenylphosphino)ferrocene (68.08mg, 0.12mmol), Bis(pinacolato)diboron (686.06mg, 2.7mmol), Potassium acetate (723.13mg, 7.37mmol) and [1,1'- Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (100.29mg, 0.12mmol). The reaction was degassed by cycling vacuum and nitrogen three times, DMF (1mL) was added to aid solubility and the reaction was stirred overnight at 100°C. The reaction was filtered through a pad of Celite, washing with EtOAc and the filtrate evaporated to afford N,N,2-trimethyl-5-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)pyrazole-3-carboxamide (685mg, 2.4539mmol, 100% yield)

[0434] UPLC-MS (ES+, Method 5): 0.60 min, m / z 198.0 [M+H]+.Intermediate A-26, tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzothiophen-2-yl]carbamate.

[0435] Intermediate Scheme 22

[0436] Step A, tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2- dioxaborolan-2-yl)benzothiophen-2-yl]carbamate (A-26). A mixture of [1,1'- bis(diphenylphosphino)ferrocene]dichloropalladium II (59.3mg, 0.08mmol) tert-Butyl (4-bromo-3-cyano-7-fluorobenzo[b]thiophen-2-yl)carbamate (300. mg, 0.81 mmol) potassium acetate (237.94mg, 2.42mmol) bis(pinacolato)diboron (410.44mg, 1.62mmol) in DMF (8.08mL) in a sealed vial under N2 atmosphere was stirred at 90 °C overnight. Then the mixture was extracted with EtOAc for three times and the organic phase was washed with water and brine. The organic phase was dried with sodium sulfate and filtered and concentrated in vacuum to give a brown oil, which was purified by flash chromatography eluting 0 to 5 % EtOAc in Petroleum ether to give product tert-butyl N-[3-cyano-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)benzothiophen-2-yl]carbamate (408mg, 0.6535mmol, 81% yield) as a pale yellow oil.

[0437] UPLC-MS (ES+, Method 5): 2.42 min, m / z 419.0 [M+H]+.Intermediate A-27, 2-(methoxymethoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine and intermediate A-36, 2-(methoxymethyl)-5,6,7,8-tetrahydro-4H- pyrazolo[1 ,5-a][1 ,4]diazepine.

[0438] Intermediate Scheme 23

[0439] Step A, [5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepin-2-yl]methanol. Lithium borohydride (99.63mg, 4.56mmol) was added to ethyl 5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5- a][1 ,4]diazepine-2-carboxylate (1.5g, 3.8mmol) in dry THF (12.7mL) at O°C and stirred at room temperature overnight. A further portion of lithium borohydride (41.51 mg, 1.9mmol) was added and the reaction stirred for 3 hrs further at room temperature. The mixture was acidified to pH3 with 1 N HCI and extracted with EtOAc (2x). The combined organic extracts were dried via phase separator and evaporated to afford an orange oil which was purified via silica gel chromatography eluting 0-10% MeOH in DCM to afford [5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5- a][1 ,4]diazepin-2-yl]methanol (448mg, 1.27mmol, 33% yield) as an orange solid.

[0440] 1H NMR (400MHz, CDCh) b / ppm: 7.98 (d, J = 7.7 Hz, 1 H), 7.77 - 7.60 (m, 3H), 6.26 (s, 1 H), 5.32 (s, 1 H), 4.63 (s, 2H), 4.57 (s, 2H), 4.44 - 4.32 (m, 2H), 3.78 - 3.64 (m, 2H), 2.10 - 1.94 (m, 2H).

[0441] UPLC-MS (ES+, Method 5): 1.39 min, m / z 353.0 [M+H]+.

[0442] Step B, 2-(methoxymethoxymethyl)-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine. Sodium hydride (60% dispersed in mineral oil) (26.7mg, 0.67mmol) was added to a stirred solution of [5-(2-nitrophenyl)sulfonyl- 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepin-2-yl]methanol (224. mg, 0.64mmol) inTHF (3.5mL) at 0 °C. The reaction was stirred for 30 mins at 0°C. Chloromethyl methyl ether (0.05mL, 0.65mmol) was added and the reaction was stirred at room temperature overnight. A further portion of Chloromethyl methyl ether (0.02mL, 0.32mmol) was added and the reaction stirred for 2 hours at room temperature. 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 via phase separator and evaporated to afford a brown oil. This material was purified via silica gel chromatography eluting 0-80% EtOAc in petroleum ether to afford 2- (methoxymethoxymethyl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5- a][1 ,4]diazepine (168mg, 0.424mmol, 67% yield) as a brown solid.

[0443] UPLC-MS (ES+, Method 5): 1.61 min, m / z 397.0 [M+H]+.

[0444] Step C, 2-(methoxymethoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine (A-27). To 2-(methoxymethoxymethyl)-5-(2-nitrophenyl)sulfonyl- 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine (168. mg, 0.42mmol) and Cesium Carbonate (276.16mg, 0.85mmol) in MeCN (2.5mL) was added Thiophenol (0.09mL, 0.85mmol) and the reaction stirred at room temperature for 1 hr. The reaction mixture was filtered through Celite, washing with EtOAc. The filtrate was evaporated to afford a brown oil. This material was loaded on to an SCX-II Cartridge, eluting first with MeOH then with 1 M NHs / MeOH. The ammoniacal fraction was evaporated to afford 2- (methoxymethoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5-a][1 ,4]diazepine (57mg, 0.2698mmol, 64% yield) as a yellow gum. Material was used without further purification.

[0445] 1H NMR (400MHz, CDC ) b / ppm: 6.09 (s, 1 H), 4.72 (s, 2H), 4.53 (s, 2H), 4.38 - 4.34 (m, 2H), 3.88 (s, 3H), 3.42 - 3.39 (m, 3H), 3.22 - 3.15 (m, 3H), 1.87 - 1.80 (m, 3H).

[0446] Step D, 2-(methoxymethyl)-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine. To a stirring solution of [5-(2- nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepin-2-yl]methanol (220mg, 0.62mmol) in THF (6mL) under an inert atmsophere, sodium hydride, (60% dispersed in mineral oil) (24.97mg, 0.62mmol) was added at 0 °C. The reaction was left to stir for 30 minutes, lodomethane (0.04mL, 0.69mmol) was added to the flask and the ice bath removed and left to stir for 2h at 50 °C . The reaction was quenched with water and extracted with EtOAc (30mL). The organic layer was washed with water and brine (15mL each), passed through a phase separator cartridge and concentrated. The residue was purified by flash chromatography (12g column, gradient 0-100%, EtOAc in pet. ether) to afford 2-(methoxymethyl)-5-(2-nitrophenyl)sulfonyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine (144mg, 0.393mmol, 34.11% yield) as an orange solid.

[0447] UPLC-MS (ES+, Method 5): 1.56 min, m / z 367.1 [M+H]+

[0448] 1H NMR (400 MHz.CDCh) 5 7.96-7.92 (m, 1 H), 7.72-7.58 (m, 3H), 6.24 (s, 1 H), 4.56 (s, 2H), 4.42-4.33 (m, 4H), 3.72-3.65 (m, 2H), 3.38 (s, 3H). 2.06-1.97 (m, 2H).

[0449] Step E, 2-(methoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepine (A-36). To 2-(methoxymethyl)-5-(2-nitrophenyl)sulfonyl-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine (144 mg, 0.39 mmol) and cesium carbonate (256 mg, 0.79mmol) in MeCN (2.5 mL) was added thiophenol (0.08 mL, 0.79 mmol) and the reaction stirred at room temperature for 2 hours. The reaction mixture was filtered through Celite, washing with EtOAc. The filtrate was evaporated to afford a brown oil. This material was loaded on to an SCX-II cartridge, eluting first with MeOH then with 1 M NH3 / MeOH. The ammoniacal fraction was evaporated to afford 2- (methoxymethyl)-5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5-a][1 ,4]diazepine (63 mg, 0.3476 mmol, 88% yield) as an orange oil.

[0450] UPLC-MS (ES+, Method 5): 0.33 min, m / z 182.1 [M+H]+

[0451] 1H NMR (400 MHz, DMSO-d6) 5 6.01 (s, 1 H), 4.32 (s, 2H), 4.31-4.26 (m, 2H), 3.81 (s, 2H), 3.32 (s, 3H), 3.15-3.09 (m, 2H), 1.91-1.82 (m, 1 H), 1.80-1.72 (m, 2H).Intermediate A-28, N,N-dimethyl-1 -(5,6,7, 8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2-yl)methanamine.

[0452] Intermediate Scheme 24

[0453] Step A, tert-butyl 2-(dimethylcarbamoyl)-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-5-carboxylate. Propylphosphonic anhydride (9.52mL, 16. mmol) andN,N-diisopropylethylamine (3.72mL, 21.3mmol) 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 (3000mg, 10.7mmol) and dimethylamine hydrochloride (1304.36mg, 16.0 mmol) in THF (100mL). The reaction mixture was heated to 65°C and left to stir overnight. Added further dimethylamine hydrochloride (434.79mg, 5.33mmol) and N,N-Diisopropylethylamine (1.86mL, 10.66mmol), followed by propylphosphonic anhydride (6.35mL, 10.66mmol). The reaction mixture was heated to 65°C and left to stir overnight. The reaction mixture was cooled to room temperature and diluted with 500mL water. The aqueous layer was extracted with EtOAc (3x150mL). The combined organics were washed with brine (200mL), 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 (3.188g, 10.338mmol, 97% yield) as a white solid.

[0454] UPLC-MS (ES+, Method 5): 1.50 min, m / z 309.1 [M+H]+.

[0455] 1H NMR (400 MHz, DMSO-d6) b / ppm: 6.43 (s, 1 H), 4.47 (s, 2H), 4.42 (m, 2H), 3.65 (s, 2H), 3.24 (s, 3H), 2.94 (s, 3H), 1.76 (s, 2H), 1.33 (s, 9H) ppm.

[0456] Step B, tert-butyl 2-formyl-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepine-5- carboxylate. To a stirred solution of tert-butyl 2-(dimethylcarbamoyl)-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (500. mg, 1.62mmol) in THF (10mL) at 0 °C was added Lithium aluminium hydride (1.35mL, 3.24mmol) (2.4 M in THF) dropwise. The reaction was allowed to warm to RT and stirred for 30 mins. Glauber's salt was added cautiously until no more effervescence occurred, then the reaction mixture was filtered. The filtrate was evaporated to afford tert-butyl 2-formyl- 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (430mg, 1 ,6207mmol, 100% yield) as a colourless oil. Used without purification in reductive amination step.

[0457] UPLC-MS (ES+, Method 5): 1.60 min, m / z 266.0 [M+H]+.

[0458] Step C, tert-butyl 2-[(dimethylamino)methyl]-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-5-carboxylate (A-28). To a stirred solution of tert-butyl 2-formyl- 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (430. mg, 1.62mmol) in DCM (10mL) was added dimethylamine (2.43mL, 4.86mmol) (2 M in THF) and acetic acid (Glacial) (0.14mL, 2.43mmol). The reaction was stirred for 30 mins at room temperature. Sodium triacetoxyborohydride (1030.5mg, 4.86mmol) was added and the reaction was stirred for 1 hr. The reaction was quenched cautiously with saturated aqueous NaHCOs then extracted with DCM (2x). The combined organic layers were dried via phase separator and evaporated to afford a yellow oil which was purified viasilica gel chromatography eluting 0-30% MeOH in DCM to afford tert-butyl 2- [(dimethylamino)methyl]-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5- carboxylate (184mg, 0.625mmol, 39% yield) as a colourless gum.

[0459] UPLC-MS (ES+, Method 5): 1.19 min, m / z 295.1 [M+H]+.

[0460] 1H NMR (400MHz, CDCh) 5 / ppm: 6.21 (s, 1 H), 4.52 - 4.30 (m, 4H), 3.74 - 3.64 (m, 2H), 3.64 - 3.55 (m, 2H), 2.38 (s, 6H), 1.96 - 1.86 (m, 2H), 1.41 (s, 9H).

[0461] Step D, N,N-dimethyl-1 -(5,6,7, 8-tetrahydro-4H-pyrazolo[1,5-a][1,4]diazepin-2- yl)methanamine (A-28). To a stirred solution of tert-butyl 2-[(dimethylamino)methyl]- 4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (184. mg, 0.63mmol) in DCM (10mL) at room temperature was added Trifluoroacetic acid (1.2mL, 15.63mmol). The reaction was stirred for 1 hr then loaded directly on to an SCX-II Cartridge, eluting first with MeOH and then with 1 M NH3 / MeOH. The ammoniacal fraction was evaporated to afford N,N-dimethyl-1-(5,6,7,8-tetrahydro-4H-pyrazolo[1 ,5- a][1 ,4]diazepin-2-yl)methanamine (102mg, 0.525mmol, 84% yield) as a colourless oil.

[0462] 1H NMR (400MHz, CDCh) 5 / ppm: 6.04 (s, 1 H), 4.39 - 4.31 (m, 2H), 3.87 (s, 2H), 3.43 (s, 2H), 3.23 - 3.14 (m, 2H), 2.28 (s, 6H), 1.86 - 1.78 (m, 2H).Intermediate A-29, 3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide.

[0463] Intermediate Scheme 25

[0464] Step A, tert-butyl 2-(dimethylcarbamoyl)-3-fluoro-4, 6,7,8- tetrahydropyrazolo[1,5-a][1,4]diazepine-5-carboxylate. N-chloromethyl-N - fluorotriethylenediammonium bis(tetrafluoroborate) - (selectfluor) (2297.6mg, 6.49mmol) was added to a solution of tert-butyl 2-(dimethylcarbamoyl)-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (1000. mg, 3.24mmol) in MeCN (16mL) and the suspension was stirred at 50°C. The reaction mixture was stirred overnight at room temperature. The mixture was filtered and the filter cake was washed with a minimal amount of MeCN. The filtrate was concentrated in vacuo. The residue taken up in DCM (50mL) washed with H2O (50mL). The aqueous layer wasextracted with DCM. The combined organics were passed through a phase separator and reduced in vacuo. The material was purified by reverse phase chromatography (eluting 0-100% MeCN in H2O (+0.1% FA)). The relevant fractions were united and reduced in vacuo, then 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 (328mg, 1.01 mmol, 31% yield) as a red oil.

[0465] 1H NMR (400MHz, CDC ) 5 / ppm: 4.58 - 4.31 (m, 4H), 3.77 - 3.67 (m, 2H), 3.18 (s, 3H), 3.09 (s, 3H), 1.98 - 1.88 (m, 2H), 1 .43 (s, 9H).

[0466] Step B, 3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H-pyrazolo[1,5- a][1,4]diazepine-2-carboxamide (A-29). Trifluoroacetic acid (0.77mL, 10.05mmol) was added to a stirring solution of tert-butyl 2-(dimethylcarbamoyl)-3-fluoro-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-5-carboxylate (328. mg, l .mmol) in DCM (5mL). The reaction mixture was left to stir at room temperature for 2 hours. The reaction mixture was concentrated in vacuo and purified by SCX-2 column (5g, washing with MeOH (x3) and eluting in 1 N NHs / MeOH (x3)). Ammoniacal fraction was evaporated in vacuo to afford 3-fluoro-N,N-dimethyl-5,6,7,8-tetrahydro-4H- pyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide (200mg, 0.8839mmol, 88% yield) as a red oil.

[0467] UPLC-MS (ES+, Method 5): 0.31 min, m / z 227.0 [M+H]+.

[0468] Intermediate A-35,

[0469] Intermediate Scheme 26

[0470] 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 O°C,under N2, was added benzyl chloroformate (1.5mL, 10.51mmol) dropwise. The mixture was stirred at 20°C overnight. The mixture was diluted with DCM (60m L) 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.

[0471] UPLC-MS (ES+, Method 5): 1.44 min, m / z 249.0 [M+HJ+.

[0472] 1H NMR (400MHz, CDCh) b / 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).

[0473] Step B, O8-benzyl 02-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 02- 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.

[0474] UPLC-MS (ES+, Method 5): 1.65 min, m / z 345.1 [M+H]+.

[0475] 1H NMR (400MHz, DMSO-d6) b / 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).

[0476] 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 02-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.

[0477] UPLC-MS (ES+, Method 5): 1.41 min, m / z 317.1 [M+H]+.

[0478] 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.

[0479] UPLC-MS (ES+, Method 5): 1.51 min, m / z 344.1 [M+H]+.

[0480] 1H NMR (400MHz, DMSO-d6) b / 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).

[0481] 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.

[0482] UPLC-MS (ES+, Method 5): 0.26 min, m / z 210.1 [M+H]+.

[0483] 1H NMR (400MHz, DMSO-d6) b / 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-30, 2-(3-chloro-8-ethyl-7-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane.

[0484] Intermediate Scheme 27

[0485] Step A, [8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthyl] 2,2- dimethylpropanoate. To a solution of 8-ethyl-7-fluoro-3- (methoxymethoxy)naphthalen-l-ol (1000mg, 4mmol) and N,N-Diisopropylethylamine (0.84mL, 4.79mmol) in DCM (7.99mL) was added trimethyl acetyl chloride (0.59mL, 4.79mmol) at 0°C. Allowed to stir at room temperature for 2hrs. Extra N,N- Diisopropylethylamine (0.21 mL, 1.2mmol) and trimethyl acetyl chloride (0.15mL, 1.2mmol) were added. Reaction mixture stirred at room temperature overnight. Partitioned between a layer of DCM (20 mL) and water (20 mL). Organic layer separated and aqueous layer extracted with DCM (2x20 mL). Organic layers combined, filtered over hydrophobic frit and concentrated under reduced pressure to afford [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl] 2,2-dimethylpropanoate (1336.1 mg, 4mmol, 100% yield) as a brown oil.

[0486] UPLC-MS (ES+, Method 2): 2.24 min, m / z 335.2 [M+H]+.

[0487] Step B, (8-ethyl-7-fluoro-3-hydroxy-1 -naphthyl) 2,2-dimethylpropanoate.Hydrogen Chloride (4.99mL, 19.98mmol) (4N in dioxane) was added to a solution of [8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthyl] 2,2-dimethylpropanoate (1336.1 mg, 4 mmol) in DCM (7.99mL). Afterwards, allowed to stir at room temperature for 1 hr. Concentrated under reduced pressure. Material was purified by flash column chromatography eluting in 0-70% EtOAc in petroleum ether affording (8-ethyl-7-fluoro-3-hydroxy-1 -naphthyl) 2,2-dimethylpropanoate (955.2mg, 3.29mmol, 83% yield) as a brown oil.

[0488] UPLC-MS (ES+, Method 5): 2.47 min, m / z 291.0 [M+H]+.

[0489] Step C, [8-ethyl-7-fluoro-3-(trifluoromethylsulfonyloxy)-1-naphthyl] 2,2- dimethylpropanoate. At 0 °C, Trifluoromethanesulfonic anhydride (0.13mL, 0.76mmol) was added to a solution of N,N-Diisopropylethylamine (0.3mL, 1.72mmol) and (8-ethyl-7-fluoro-3-hydroxy-1-naphthyl) 2,2-dimethylpropanoate (200. mg,0.69mmol) in DCM (3.44mL). Afterwards, allowed to stir at that temperature for 15 min. Reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (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. Material was purified by flash column chromatography (eluting 0-50% EtOAc in petroleum ether) affording [8-ethyl-7-fluoro-3-(trifluoromethylsulfonyloxy)-1 -naphthyl] 2,2- dimethylpropanoate (225mg, 0.5327mmol, 78% yield) as an off-white solid.

[0490] UPLC-MS (ES+, Method 5): 2.51 min, m / z 421.0 [M+H]+.

[0491] 1H NMR (400MHz, CDCI3) b / ppm: 7.74 (dd, J = 9.0, 5.6 Hz, 1 H), 7.64 (d, J = 2.6 Hz, 1 H), 7.36 (t, J = 9.2 Hz, 1 H), 6.94 (d, J = 2.5 Hz, 1 H), 3.21-3.13 (m, 2H), 1.47 (s, 9H), 1.28-1.21 (m, 3H).

[0492] Step D, [8-ethyl-7-fluoro-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1- naphthyl] 2,2-dimethylpropanoate. A mixture of Bis(pinacolato)diboron (201.96mg, 0.8mmol), [8-ethyl-7-fluoro-3-(trifluoromethylsulfonyloxy)-1 -naphthyl] 2,2- dimethylpropanoate (225. mg, 0.53mmol) and Potassium acetate (182.99mg, 1.86mmol) in 1 ,4-Dioxane (2.6634mL) was degassed with N2 for 10 minutes then [1 ,1'-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (43.5mg, 0.05mmol) was added and the reaction mixture was heated at 100°C for 1 hr. The reaction mixture was cooled down to room temperature. Diluted with EtOAc (10 mL), filtered over a celite plug, plug washed with EtOAc (2x10 mL), filtrate collected and concentrated under reduced pressure. Material was purified by flash column chromatography eluting 0-50% EtOAc in petroleum ether affording [8- ethyl-7-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1-naphthyl] 2,2- dimethylpropanoate (206mg, 0.5146mmol, 97% yield) as an off-white solid.

[0493] UPLC-MS (ES+, Method 5): 2.64 min, m / z 401.1 [M+H]+.

[0494] Step E, (3-chloro-8-ethyl-7-fluoro-1 -naphthyl) 2,2-dimethylpropanoate. To a microwave vial, copper(ii) chloride (502.1 mg, 3.73mmol) was added to [8-ethyl-7-fluoro-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 -naphthyl] 2,2- dimethylpropanoate (498.3mg, 1.24mmol) in a mixture of MeCN (4.67 mL) and Water (1.56mL). Afterwards, the vial was sealed and allowed to stir at 90°C overnight. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of EtOAc (20 mL) and water (20 mL). Organic layer separated and aqueous layer extracted with EtOAc (2 x 10 mL). Organic layers combined, washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Material was purified by flash column chromatography eluting 0-30% EtOAc in petroleum ether affording (3-chloro-8-ethyl-7-fluoro-1 -naphthyl) 2,2- dimethylpropanoate (260.8mg, 0.8446mmol, 67% yield) as a clear oil.

[0495] UPLC-MS (ES; Method 5): 2.51 min, m / z 307.0 [M-H]'.

[0496] Step F, 3-chloro-8-ethyl-7-fluoro-naphthalen-1-ol. Potassium hydroxide (210.68mg, 3.76mmol) was added to a solution of (3-chloro-8-ethyl-7-fluoro-1- naphthyl) 2,2-dimethylpropanoate (463.8mg, 1.5mmol) in Methanol (7.5mL). Afterwards, allowed to stir at room temperature for 30 min. Acidified to ~pH2 with 2M HOI (aq). Reaction mixture partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (20 mL), organic extracts combined, washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Material was purified by flash column chromatography eluting 0-50% EtOAc in petroleum ether affording 3-chloro-8-ethyl-7-fluoro-naphthalen-1-ol (257mg, 1.41 mmol, 76% yield) as a yellow solid.

[0497] UPLC-MS (ES+, Method 5): 2.14 min, m / z 223.0 [M-H]'.

[0498] Step G, (3-chloro-8-ethyl-7-fluoro-1 -naphthyl) trifluoromethanesulfonate. At 0 °C, Trifluoromethanesulfonic anhydride (0.21 mL, 1.26mmol) was added to a solution of N,N-Diisopropylethylamine (0.5mL, 2.86mmol) and 3-chloro-8-ethyl-7-fluoro- naphthalen-1-ol (257.3mg, 1.15mmol) in DCM (5.73mL). Afterwards, allowed to stir at that temperature for 15 min. Reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (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. Material was purified by flash column chromatography eluting 0-30% EtOAc in petroleum ether affording (3-chloro-8-ethyl-7-fluoro-1-naphthyl) trifluoromethanesulfonate (253.2mg, 0.710mmol, 62% yield) as an off-white solid.

[0499] UPLC-MS (ES+, Method 5): 2.51 min, m / z 354.9 [M-2H]’.

[0500] Step H, 2-(3-chloro-8-ethyl-7-fluoro-1-naphthyl)-4,4,5,5-tetramethyl-1,3,2- dioxaborolane (A-30). A mixture of Bis(pinacolato)diboron (269.11 mg, 1 ,06mmol), (3- chloro-8-ethyl-7-fluoro-1 -naphthyl) trifluoromethanesulfonate (253.2mg, 0.71 mmol) and potassium acetate (139.32mg, 1.42mmol) in 1 ,4-Dioxane (3.55mL) was degassed with N2 for 2 min then [1 ,T-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (57.97mg, 0.07mmol) was added and the reaction mixture was heated at 80°C for 1 hr. Extra [1 ,T-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (57.97mg, 0.07mmol) was added. Reaction mixture allowed to stir at 80°C overnight. The reaction mixture was cooled down to room temperature. Diluted with EtOAc (10 mL), filtered over a celite plug, plug washed with EtOAc (2x10 mL), filtrate collected and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-30% ethyl acetate in petrol affording 2-(3-chloro-8-ethyl-7-fluoro-1-naphthyl)-4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolane (77.8mg, 0.2325mmol, 33% yield) as an off-white solid.

[0501] 1H NMR (400 MHz, CDCh) 5 / ppm: 7.81 (d, J = 2.3 Hz, 1 H), 7.59 (dd, J = 9.0, 5.8 Hz, 1 H), 7.55 (d, J = 2.2 Hz, 1 H), 7.26 (d, J = 18.4 Hz, 1 H), 3.13 (q, J = 7.5 Hz, 2H), 1.45 (s, 12H), 1.26 (t, J = 7.5 Hz, 3H).Intermediate A-34, tert-butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-

[0502] Intermediate Scheme 28

[0503] Step A, 2-(4-chloro-5-fluoro-3-pyridyl)acetonitrile. A solution of 3-Bromo-4-chloro- 5-fluoropyridine (500. mg, 2.38mmol) , 4-(4,4,5,5-Tetramethyl-1 ,3,2-dioxaborolan-2- yl)-1 ,2-oxazole (556.06mg, 2.85mmol) , and Potassium fluoride (414.15mg,7.13mmol) in Water (0.5mL) and DMS0(5mL) was sparged with nitrogen for 15 mins. [1 ,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (154.86mg, 0.24mmol) was added to the mixture then heated to 130°C using microwave irradiation for 30 mins, then cooled to rt, filtered through a pad of celite, diluted with EtOAc and purified by silica gel chromatography (12g, eluting in 50% EtOAc in Pet. Ether) the desired fractions were combined to give 2-(4-chloro-5-fluoro-3- pyridyl)acetonitrile (273mg, 1.6005mmol, 67% yield) as a brown glass.

[0504] UPLC-MS (ES+, Method 5): 1.32 min, m / z 170.9 [M+H]+

[0505] Step B, ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate. To a stirring solution of 2-(4-chloro-5-fluoro-3-pyridyl)acetonitrile (336. mg, 1.97mmol) in THF (10mL) under nitrogen at 0°C Sodium hydride, (60% dispersed in mineral oil) (118.18mg, 2.95mmol) was added portionwise and stirred for 15 mins. Ethoxycarbonyl isothiocyanate (0.26mL, 2.17mmol) was added and the mixture stirred at 0°C for 5 mins before being brought to room temperature and stirred for a further 10 mins. Copper(l) iodide (37.52mg, 0.2mmol) and L-Proline (45.36mg, 0.39mmol) were added and the reaction mixture heated to 65°C for 1 h. The reaction mixture was cooled to rt and quenched by the addition of water, and EtOAc added. The phases were separated and the aqueous phase was washed with EtOac (x2). The combined organic fractions were dried over Na2SO4, filtered and concentrated under reduced pressure. The crude material was purified by silica gel chromatography (12 g, 0-100% EtOac in pet. ether then 0-20% MeOH in EtOAc) the desired fractions were combined and concentrated under reduced pressure to give ethyl N-(3-cyano-7-fluoro- thieno[3,2-c]pyridin-2-yl)carbamate (325mg, 1.2252mmol, 62% yield) as a dark yellow powder.

[0506] UPLC-MS (ES+, Method 5): 1.65 min, m / z 265.9 [M+H]+

[0507] Step C, 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile. To a solution of ethyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (500. mg, 1.88mmol) in DMSO (4mL) at 0°C was added a solution of Sodium hydroxide (753.92mg, 18.85mmol) in Water (4mL) dropwise. The reaction mixture was stirred for 15 min, then heated to 105°C and stirred for a further 1.5 h. The reaction mixture was then cooled to rt and poured into an ice / water mix (80 mL) and stirred until all the ice had melted. The resulting suspension was filtered through a pad of celite washing with water then methanol / DCM. the organic fraction was concentrated under reduced pressure and dried in a vacuum oven to give 2-amino-7-fluoro-thieno[3,2-c]pyridine-3- carbonitrile (110mg, 0.5694mmol, 30% yield) as a yellow powder.

[0508] UPLC-MS (ES+, Method 5): 1.16 min, m / z 193.9 [M+H]+

[0509] Step D, tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate. To a solution of 2-amino-7-fluoro-thieno[3,2-c]pyridine-3-carbonitrile (175mg, 0.91 mmol) in DCM (2mL) and DMF (2mL) at 0°C was added N,N-Diisopropylethylamine (0.32mL, 1.81 mmol), 4-dimethylamino pyridine, DMAP (11.07mg, 0.09mmol) , and di-tert-butyl dicarbonate (296.53mg, 1.36mmol). The reaction mixture was warmed to room temperature and stirred for 2 h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (12g, 10- 70% EtOAc in pet. ether) the desired fractions were combined and concentrated under reduced pressure to give tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2- yl)carbamate (115mg, 0.3921 mmol, 43% yield) as yellow powder.

[0510] UPLC-MS (ES+, Method 5): 1.92 min, m / z 293.9 [M+H]+

[0511] 1H NMR (400MHz, DMSO-d6) 5 / ppm: 12.31 (1 H, s), 8.74 (1 H, s), 8.49 (1 H, s), 1.53 (9H, s)

[0512] Step E, tert-butyl N-(3-cyano-7-fluoro-5-oxido-thieno[3,2-c]pyridin-5-ium-2- yl)carbamate. m-chloroperbenzoic acid, MCPBA (703.63mg, 4.08mmol) was added to a solution of tert-butyl N-(3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (598. mg, 2.04mmol) in DCM (15mL) and the reaction mixture was stirred at room temperature for 2h. The reaction mixture was concentrated under reduced pressure and the crude material was purified by silica gel chromatography (12g, 0-6% MeOH in DCM) the desired fractions were combined and concentrated under reduced pressure to give tert-butyl N-(3-cyano-7-fluoro-5-oxido-thieno[3,2-c]pyridin-5-ium-2- yl)carbamate (507mg, 1.6391 mmol, 80% yield) as an off-white powder.

[0513] UPLC-MS (ES+, Method 5): 1.56 min, m / z 309.9 [M+H]+

[0514] 1H NMR (400MHz, DMSO-d6) 5 / ppm: 12.45 (1 H, br. s), 8.54 (1 H, dd, J = 5.4, 1.4 Hz), 8.35 (1 H, d, J = 1.4 Hz), 1.53 (9H, s)

[0515] Step F, tert-butyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2- yl)carbamate (A-34). Phosphorus oxychloride (0.09mL, l .mmol) was added to a solution of tert-butyl N-(3-cyano-7-fluoro-5-oxido-thieno[3,2-c]pyridin-5-ium-2- yl)carbamate (155mg, 0.5mmol) and DMF (0.05mL) in Toluene (5mL) and the reaction mixture was left to stir at room temperature for 2 h. The reaction was quenched by dropwise addition to sat.aq. NaHCOs (10 mL) adding solid NaHCOs as needed to maintain pH >7. The reaction vessel was rinsed with DCM (2*15 mL) adding to the aq solution. The phases were separated and the aqueous phase washed with DCM (15mL). The combined organic fractions were dried over Na2SO4, filtered, concentrated under reduced pressure. The crude material was purified by silica gel chromatography (12 g, 50-100% DCM in pet. ether) the desired fractions were combined to give tertbutyl N-(4-chloro-3-cyano-7-fluoro-thieno[3,2-c]pyridin-2-yl)carbamate (135mg, 0.4119mmol, 82% yield) as a colourless solid

[0516] UPLC-MS (ES+, Method 5): 2.10 min, m / z 327.9 [M+H]+

[0517] 1H NMR (400MHz, DMSO-d6) 6 / ppm: 12.23 (1 H, br. s), 8.34 (1 H, s), 1.54 (9H, s)Intermediate 1-1, 4-bromo-7,9-dichloro-2-methyl-pyrazolo[4,3-f]quinazoline

[0518] Intermediate 1-1 was prepared following the route in Intermediate Scheme 29 below.

[0519] Intermediate Scheme 29

[0520] Step A, 7-bromo-2-methyl-5-nitro-indazole. Potassium carbonate (2.3g, 16.53mmol) was added to 7-Bromo-5-nitro-1 H-indazole (4g, 16.53mmol) in DMF (41mL), followed by iodomethane (3.1mL, 49.58mmol). The reaction was stirred at room temperature overnight. The solvent was removed in vacuo and the crude material dissolved in EtOAc and water. The phases were separated and the aqueous was extracted with EtOAc (3 x 50mL), dried with Na2SO4, filtered and concentrated. The crude was taken up in DCM, loaded onto silica and purified by flash columnchromatography (220g SiC>2, 15-75% EtOAc in petroleum ether). The desired fractions were concentrated to afford 7-bromo-2-methyl-5-nitro-indazole (3.58g, 13.98mmol, 38% yield) as a dark orange solid.

[0521] UPLC-MS (ES+, Method 2): 1.55 min, m / z 256.0, 257.9 [M+H]+.

[0522] 1H NMR (400 MHz, CDCh) b / ppm: 8.69 (d, J = 2.0 Hz, 1 H), 8.37 (d, J = 2.0 Hz, 1 H), 8.31 (s, 1 H), 4.34 (s, 3H).

[0523] Step B, 7-bromo-2-methyl-indazol-5-amine. A solution of 7-bromo-2-methyl-5- nitro-indazole (3.58g, 13.98mmol) in ethyl acetate (93mL) was purged 3x with vacuum / N2, and platinum on carbon, 5 wt. % loading (272mg, 1.4mmol) was added. The mixture was then purged 3x with vacuum / H2and heated to 60°C overnight. The reaction was purged with N2, cooled to room temperature then filtered through a Celite pad, washing with EtOAc. The filtrate was concentrated to afford 7-bromo-2-methyl- indazol-5-amine (3.43g, 13.98mmol, 100% yield) as a brown solid.

[0524] UPLC-MS (ES+, Method 2): 0.56 min, 225.9, 227.9 [M+H]+.

[0525] 1H NMR (400 MHz, CDCh) b / ppm: 7.71 (s, 1 H), 7.07 (d, J = 1.9 Hz, 1 H), 6.72 (d, J = 1.9 Hz, 1 H), 4.18 (s, 3H), 3.60 (br s, 2H).

[0526] Step C, N-(7-bromo-2-methyl-indazol-5-yl)-2-hydroxyimino-acetamide. To a solution of sodium sulfate (38.8g, 273mmol) in water (69.887mL), was added chloral hydrate (2.76g, 16.7mmol) at room temperature. To the resulting solution was added 7-bromo-2-methyl-indazol-5-amine (3.43g, 15.2mmol) in hydrogen chloride (1M in water) (16.7mL, 16.7mmol). The mixture turned cloudy and hydroxylamine hydrochloride (3.37g, 48.6mmol) was added. The mixture was heated to 80°C for 2 hours, then returned to room temperature, filtered, and the solid collected to give N-(7- bromo-2-methyl-indazol-5-yl)-2-hydroxyimino-acetamide (3.13g, 10.5mmol, 69% yield) as a black-brown solid after drying in the vacuum oven.

[0527] UPLC-MS (ES+, Method 2): 1.16 min, m / z 296.9, 298.9 [M+H]+.

[0528] 1H NMR (400 MHz, DMSO-d6) b / ppm: 12.17 (s, 1 H), 10.20 (s, 1 H), 8.46 (s, 1 H), 8.16 (d, J = 1.7 Hz, 1 H), 7.76 (d, J = 1.6 Hz, 1 H), 7.65 (s, 1 H), 4.18 (s, 3H).

[0529] Step D, 4-bromo-2-methyl-6H-pyrrolo[3,2-e]indazole-7, 8-dione. N-(7-bromo-2- methyl-indazol-5-yl)-2-hydroxyimino-acetamide (3.13g, 10.53mmol) was dissolved in sulfuric acid (19.7mL, 368.7mmol) and heated to 60°C for 2 hours. The reaction was then cooled to room temperature and poured into ice-water. The precipitate was collected by filtration and dried in the vacuum oven, to afford 4-bromo-2-methyl-6H- pyrrolo[3,2-e]indazole-7, 8-dione (2.31g, 8.25mmol, 78% yield) as a black-purple solid.

[0530] UPLC-MS (ES+, Method 2): 1.20 min, m / z 279.9 [M+H]+.

[0531] 1H NMR (400 MHz, DMSO-d6) 5 / ppm: 10.81 (s, 1 H), 8.58 (s, 1 H), 7.25 (s, 1 H), 4.19 (s, 3H).

[0532] Step E, 5-amino-7-bromo-2-methyl-indazole-4-carboxylic acid. To a solution of 4- bromo-2-methyl-6H-pyrrolo[3,2-e]indazole-7, 8-dione (2.31g, 8.26mmol) in 1 ,4- dioxane (41.3mL) was added sodium hydroxide (19M in water) (4.35mL, 82.6mmol) at 0°C. Hydrogen peroxide solution 30 wt% in H2O (4.22mL, 41.29mmol) was added dropwise. The solution was returned to room temperature and stirred for 2 hours. The reaction was quenched with sat. Na2S20s (5 mL) and adjusted to pH 1 with 2N HCI (aq). The volatiles were removed in vacuo. The solid was extracted with n-BuOH (3 x 10mL), and the organic phase concentrated to afford 5-amino-7-bromo-2-methyl- indazole-4-carboxylic acid (1.63g, 6.04mmol, 73% yield) as a brown solid.

[0533] UPLC-MS (ES+, Method 2): 1.20 min, m / z 269.9, 271.8 [M+H]+.

[0534] 1H NMR (400 MHz, MeOD) 5 / ppm: 8.42 (s, 1 H), 7.16 (s, 1 H), 4.14 (s, 3H).

[0535] Step F, 5-amino-7-bromo-2-methyl-indazole-4-carboxamide. To a solution of 5- amino-7-bromo-2-methyl-indazole-4-carboxylic acid (1.61g, 5.96mmol), ammonium chloride (3.2g, 59.6mmol) , and N,N-Diisopropylethylamine (3.11mL,17.9mmol) in DMF (39.7mL) was added HATU (2.26g, 5.96mmol) , and stirred at room temperature for 5 hours. The solvent was removed in vacuo, and the residue suspended in water, then extracted with n-butanol (3 x 20mL). The solvent was removed in vacuo to afford 5-amino-7-bromo-2-methyl-indazole-4-carboxamide (1.07g, 3.99mmol, 67% yield) as a brown solid.

[0536] UPLC-MS (ES+, Method 2): 1.25 min, m / z 268.9, 270.9 [M+H]+.

[0537] Step G, 4-bromo-2-methyl-6H-pyrazolo[4,3-f]quinazoline-7, 9-dione. 1,1'-Carbonyldiimidazole (970.7mg, 5.99mmol) was added to a solution of 5-amino-7- bromo-2-methyl-indazole-4-carboxamide (1.07g, 3.99mmol) in THF (26.6mL) , and heated to reflux for 3 hours. The solvent was removed in vacuo, and the residue suspended in 1M HCI. The precipitate was collected by filtration to afford 4-bromo-2- methyl-6H-pyrazolo[4,3-f]quinazoline-7, 9-dione (418mg, 1.42mmol, 36% yield) as a brown solid.

[0538] UPLC-MS (ES+, Method 2): 1.07 min, m / z 294.9, 296.9 [M+H]+.

[0539] 1H NMR (400 MHz, DMSO-d6) 5 / ppm: 11.44 (s, 1 H), 11.32 (s, 1 H), 8.76 (s, 1 H), 8.19 (s, 1 H), 4.22 (s, 3H).

[0540] Step H, 4-bromo-7,9-dichloro-2-methyl-pyrazolo[4,3-f]quinazoline (1-1).Phosphorus oxychloride (1.22mL, 13.1 mmol) was added to a suspension of 4-bromo-2-methyl-6H-pyrazolo[4,3-f]quinazoline-7, 9-dione (155mg,0.53mmol) in dimethylaniline (0.33mL, 2.63mmol) , the reaction tube was sealed, and heated to 75°C overnight. The reaction was cooled to room temperature, and slowly added to an ice-cold sat. NaHCCh solution. The precipitate was collected by filtration and dried under vacuum to afford 4-bromo-7,9-dichloro-2-methyl-pyrazolo[4,3- f]quinazoline (89mg, 0.27mmol, 51% yield) as a black-green solid.

[0541] UPLC-MS (ES+, Method 2): 1.82 min, m / z 332.6 [M+H]+.Intermediate I-55, 4-bromo-7,9-dichloro-3-methyl-pyrazolo[4,3-f]quinazoline

[0542] Intermediate I-55 was prepared by analogy with 1-1 (intermediate scheme 29) above, using the other regio-isomer formed during step A.Intermediate I-49, 4-bromo-7,9-dichloro-2-cyclopropyl-pyrazolo[4,3-f]

[0543] Intermediate I-49 was prepared by analogy with 1-1 (intermediate scheme 29) above, with the following variation on Step A shown below.

[0544] Step A, 7-bromo-2-cyclopropyl-5-nitro-indazole. A solution of 7-Bromo-5-nitro- 1 H-indazole (19.2g, 79.33mmol), copper(ll) acetate (43.23g, 237.99mmol), cyclopropylboronic acid (20.44g, 237.99mmol), DMAP (38.77g, 317.32mmol) and Pyridine (25.66mL, 317.32mmol) in 1 ,4-Dioxane (800mL) was left to stir under oxygen at 100°C overnight. The mixture was diluted with water (1000 ml) and extracted with EtOAc (300 ml x 3). The combined organic phases were washed with brine, dried over sodium sulfate and concentrated under vacuum. The crude residue was purified bysilica gel chromatography (eluting with 1 / 3 EA / PE) to afford 7-bromo-2-cyclopropyl-5- nitro-indazole as a yellow solid (4.2 g, 18% yield).

[0545] LCMS (ES-API, Method 4) 0.77 min, 282.0 / 284.0 [M+H]+.Intermediate 1-52, 4-bromo-7,9-dichloro-5-fluoro-2-methyl-pyrazolo[4,3-f]quinoline

[0546] Intermediate I-52 was prepared following the route in Intermediate Scheme 30 below.

[0547] Intermediate Scheme 30

[0548] Step A, 2-bromo-3-fluoro-6-methyl-4-nitro-aniline. A stirring mixture of 5-fluoro-2- methyl-4-nitro-aniline (49g, 288. mmol) and NBS (76.8, 432mmol) in MeCN (1 L) was heated to 65°C and left to stir for 2 hours. The mixture was concentrated under vacuum and the residue poured into DCM (2L) and washed with NaOH (1 N, 1 L). The organic layers were combined and concentrated to afford 2-bromo-3-fluoro-6-methyl-4-nitro- aniline to give (60g, 240.93mmol, 84% yield) as a yellow solid.

[0549] LC-MS (ES-API, Method 4): 1.84 min, 249.0 [M+H]+.

[0550] Step B, 7-bromo-6-fluoro-5-nitro-1 H-indazole. To a stirring mixture of 2-bromo-3- fluoro-6-methyl-4-nitro-aniline (60. g, 240.93mmol) in Chloroform (600mL) was added Potassium acetate (28.37g, 289.11 mmol). The mixture was cooled to 0°C and Acetic Anhydride (68.32mL, 722.78mmol) added dropwise. The mixture was left to stir at 0°C for 1 hour after which time isopentyl nitrite (64.73mL, 481.85mmol) was added. The reaction mixture was then heated to 65°C and left to stir overnight. The reaction mixturewas cooled to room temperature and concentrated under vacuum before being treated with Na2CC>3 (aq) and extracted with DCM (600 mL x 3). The organic layers were concentrated under vacuum, poured into THF (600 mL) and NaOH (aq, 2M) added. The resulting mixture was stirred at 0°C for 2 hours. The mixture was concentrated under vacuum and the residue extracted with DCM (600 mL x 3). The organic layers were concentrated under vacuum and purified by silica gel chromatography (eluting with 3% MeOH in DCM) to afford 7-bromo-6-fluoro-5-nitro-1 H-indazole (17g, 32.69mmol, 14% yield) as a red solid.

[0551] LC-MS (ES-API, Method 4): 1.52 min, 259.9 [M+H]+.

[0552] Step C, 7-bromo-6-fluoro-2-methyl-5-nitro-indazole. To a stirring solution of 7- bromo-6-fluoro-5-nitro-1 H-indazole (5.g, 9.61 mmol) in Ethyl acetate (50mL) was added Trimethyloxonium tetrafluoroborate (1.85g, 12.5mmol) and the reaction left to stir at room temperature overnight. The reaction mixture was treated with water (60 mL) and extracted with EtOAc (60 mL x 3). The organic layers were concentrated under vacuum to afford 7-bromo-6-fluoro-2-methyl-5-nitro-indazole (5g, 9.1224mmol, 95% yield) as an orange solid.

[0553] LC-MS (ES-API, Method 4): 1.64 min, 274.0 [M+H]+.

[0554] Step D, 7-bromo-6-fluoro-2-methyl-indazol-5-amine. To a stirring mixture of 7- bromo-6-fluoro-2-methyl-5-nitro-indazole (5.0g, 9.12mmol) in Ethanol (50mL) and Water (50mL) was added Fe (2.55g, 45.61 mmol) and NH4CI (2.44g, 45.61 mmol). The mixture was heated to 80°C and left to stir for 2 hours. The mixture was filtered and extracted with EtOAc (500 mL x 3). The organic layers were concentrated under vacuum and purified by silica gel chromatography (eluting with 35% EtOAc in Pet. Ether) to afford 7-bromo-6-fluoro-2-methyl-indazol-5-amine (1.5g, 6.1458mmol, 67% yield) as a red solid.

[0555] LC-MS (ES-API, Method 4): 0.81 min, 244.0 [M+H]+.

[0556] Step E, 4-bromo-7,9-dichloro-5-fluoro-2-methyl-pyrazolo[4,3-f]quinoline (I-52).A mixture of 7-bromo-6-fluoro-2-methyl-indazol-5-amine (1 ,5g, 6.15mmol) and malonic ccid (1.28g, 12.29mmol) in POOL (20 mL) was heated to 110°C and left to stir for 3 hours. The reaction mixture was concentrated under vacuum, diluted with water (200 mL) and extracted with EtOAc (200 mL x 3). The combine organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum and purified by silica gel column (Pet.ether: EtOAc 1 :1) to afford 4-bromo-7,9-dichloro-5-fluoro-2- methyl-pyrazolo[4,3-f]quinoline (560mg, 1.6047mmol, 26% yield) as a yellow solid.

[0557] LC-MS (ES-API, Method 4) 2.36 min, 347.9 [M+H]+.Intermediate 1-72, 4-bromo-7,9-dichloro-2-(2,2,2-trifluoroethyl)pyrazolo[4,3- f]quinazoline.I-72

[0558] Intermediate Scheme 31

[0559] Step A, 7-bromo-5-nitro-2-(2,2,2-trifluoroethyl)indazole. To a stirring solution of 7-Bromo-5-nitro-1 H-indazole (3000 mg, 12.4mmol) and Cesium Carbonate (8077.18mg, 24.79mmol) in DMF (24.79mL) was added 2,2,2-Trifluoroethyl triflate (3.04mL, 21.07mmol) . It was stirred at 70 °C for 30 min. Reaction mixture allowed to cool back down to room temperature and water (200 ml) added. This was extracted with EtOAc (3 x 50ml), organic extracts combined, washed with water (2 x 50 mL), saturated solution of brine (50 mL), dried over sodium sulfate, filtered, and evaporated. It was purified by silica chromatography eluting 0-40% EtOAc in petroleum ether to give the product 7-bromo-5-nitro-2-(2,2,2-trifluoroethyl)indazole (2594.6mg,8.01 mmol, 65% yield) as a brown solid.

[0560] UPLC-MS (ES+, Method 2): 1.77 min, m / z 326.0 [M+H]+.

[0561] 1H NMR (400 MHz, CDCh) 5 / ppm: 8.73 (d, J = 1.8 Hz, 1 H), 8.51 (s, 1 H), 8.40 (dd, J = 1.9, 0.7 Hz, 1 H), 5.15 (q, J = 8.1 Hz, 2H).

[0562] Step B, 7-bromo-2-(2,2,2-trifluoroethyl)indazol-5-amine. To a suspension of 7- bromo-5-nitro-2-(2,2,2-trifluoroethyl)indazole (2594.6mg, 8.01 mmol) in Ethanol (20.016mL) / Water (6.6721 mL) were successively added ammonium chloride (1.28g, 24.02mmol) and Iron (1.34g, 24.02mmol) . The mixture was heated to 80°C and vigorously stirred for 45 min. Additional Iron (1341.5mg, 24.02mmol) was added. Reaction mixture was allowed to stir at 80°C for 1 hr. The mixture was cooled to room temperature and passed through a plug of celite. The filter cake was washed with ethyl acetate (2 x 30 mL). Filtrate collected and transferred to a separatory funnel. Water (30 mL) was added and layers partitioned. Organic layer separated and aqueous layer extracted with EtOAc (20 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 20-80% EtOAc in petroleum ether to afford 7-bromo-2-(2,2,2- trifluoroethyl)indazol-5-amine (1838.2mg, 6.2507mmol, 78% yield) as an off-white solid.

[0563] UPLC-MS (ES+, Method 5): 1.30 min, m / z 295.9 [M+H]+.

[0564] 1H NMR (400 MHz, CDCh) 5 / ppm: 7.86 (s, 1 H), 7.13 (d, J = 1.9 Hz, 1 H), 6.70 (d, J = 1.9 Hz, 1 H), 4.99 (q, J = 8.3 Hz, 2H), 3.65 (br s, 2H).

[0565] Step C, (2E)-N-[7-bromo-2-(2,2,2-trifluoroethyl)indazol-5-yl]-2-hydroxyimino- acetamide. To a suspension of Chloral hydrate (2.06g, 12.5mmol), 7-bromo-2-(2,2,2- trifluoroethyl)indazol-5-amine (1838.2mg, 6.25mmol) and Sodium sulfate (7.1g, 50.01 mmol) in a mixture of DMF (9.92mL) and Water (21.3mL) was added Hydrogen Chloride (2.82mL, 34.4mmol) (cone HCI). Reaction mixture allowed to stir at 90°C for 1hr. Hydroxylamine hydrochloride (1.52g, 21.88mmol) was added. Reaction mixture allowed to stir at 90°C for 20 min. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of EtOAc (80 mL) and water (80 mL). Organic layer separated and aqueous layer extracted with EtOAc (2x40 mL). Organic layers combined, washed with water (2x50 mL), a saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford (2E)- N-[7-bromo-2-(2,2,2-trifluoroethyl)indazol-5-yl]-2-hydroxyimino-acetamide (2.28g, 6.25mmol, 100% yield) as a brown solid.

[0566] UPLC-MS (ES+, Method 5): 1.56 min, m / z 366.9 [M+H]+.

[0567] Step D, 4-bromo-2-(2, 2, 2-trifluoroethyl)-6H-pyrrolo[3,2-e]indazole-7, 8-dione. A mixture of (2E)-N-[7-bromo-2-(2,2,2-trifluoroethyl)indazol-5-yl]-2-hydroxyimino- acetamide (2.28g, 6.25mmol) and sulfuric acid (11 ,66mL, 218.78mmol) was allowedto stir at 70°C for 3hrs. Reaction mixture allowed to cool back down to room temperature. Ice-water (100 mL) was added. Solid precipitate collected by vacuum filtration over filter paper. Paper washed with water (2x 20 mL). Solid precipitate dried under vacuum to afford 4-bromo-2-(2,2,2-trifluoroethyl)-6H-pyrrolo[3,2-e]indazole-7,8- dione (962.4mg, 2.7649mmol, 65% yield) as a brown solid.

[0568] UPLC-MS (ES+, Method 5): 1.59 min, m / z 347.9 [M+H]+.

[0569] 1H NMR (400 MHz, CDCh) b / ppm: 8.40 (s, 1 H), 7.33 (s, 1 H), 5.06 (q, J = 8.1 Hz, 2H).

[0570] Step E, 5-amino-7-bromo-2-(2,2,2-trifluoroethyl)indazole-4-carboxylic acid. To an ice-cooled suspension of 4-bromo-2-(2,2,2-trifluoroethyl)-6H-pyrrolo[3,2- e]indazole-7, 8-dione (1827.6mg, 5.25mmol) in 1 ,4-Dioxane (23.8mL) was added a solution of sodium hydroxide (2100mg, 52.51 mmol) in Water (2.50 mL). Then Hydrogen peroxide solution (30 wt% in H2O) (2.68m L, 26.25mmol) was added. Reaction mixture allowed to stir at room temperature for 30 min. Reaction mixture quenched with a saturated solution of sodium thiosulphate. Then acidified to ~pH2 with 2M HCI (aq). Partitioned between a layer of EtOAc (50 mL) and water (50 mL). Organic layer separated, aqueous layer extracted with EtOAc (2 x 20 mL) and organic layers combined. Washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 5-amino-7-bromo- 2-(2,2,2-trifluoroethyl)indazole-4-carboxylic acid (1775.1 mg, 5.25mmol, 100% yield) as a brown solid.

[0571] UPLC-MS (ES+, Method 5): 1.56 min, m / z 339.9 [M+H]+.

[0572] 1H NMR (400 MHz, CDCh) b / ppm: 8.24 (s, 1 H), 7.06 (s, 1 H), 6.27 (br s, 1 H), 5.05 (br s, 1 H), 4.97 (q, J = 9.1 Hz, 2H).

[0573] Step F, 5-amino-7-bromo-2-(2,2,2-trifluoroethyl)indazole-4-carboxamide. HATU (2395.7mg, 6.3mmol) was added to a mixture of 5-amino-7-bromo-2-(2,2,2- trifluoroethyl)indazole-4-carboxylic acid (1775.1 mg, 5.25mmol), ammonium chloride (2808.6mg, 52.5mmol) and N,N-Diisopropylethylamine (2.74mL, 15.75mmol) in DMF (15.77mL). Afterwards, allowed to stir at room temperature for 1 hr. Additional N,N- Diisopropylethylamine (2.74mL, 15.75mmol) was added. Reaction mixture allowed to stir at room temperature for 30 min. Extra N,N-Diisopropylethylamine (1.37mL, 7.88mmol) was added. Reaction mixture allowed to stir at room temperature for 15 min. Water (150 mL) was added. Solid precipitate collected by vacuum filtration. Solid washed with water (2x20 mL). Solid dried under vacuum to afford 5-amino-7-bromo-2- (2,2,2-trifluoroethyl)indazole-4-carboxamide (969.7mg, 2.88mmol, 55% yield) as a black solid.

[0574] UPLC-MS (ES+, Method 5): 1.43 min, m / z 338.9 [M+H]+.

[0575] 1H NMR (400 MHz, CDCh) 6 / ppm: 8.03 (s, 1 H), 7.08 (s, 1 H), 5.96 (br s, 1 H), 5.64 (br s, 1 H), 4.98 (q, J = 8.3 Hz, 2H).

[0576] Step G, 4-bromo-7-chloro-2-(2,2,2-trifluoroethyl)-8H-pyrazolo[4,3-f]quinazolin- 9-one. To a suspension of 5-amino-7-bromo-2-(2,2,2-trifluoroethyl)indazole-4- carboxamide (663.3mg, 1.97mmol) in 1 ,4-Dioxane (7.87mL) was added thiophosgene (0.38mL, 4.92mmol). Reaction mixture allowed to stir at 105°C for 30 min. Reaction mixture allowed to cool back down to room temperature and concentrated under reduced pressure. Residue triturated with petroleum ether (10 mL) and dried under reduced pressure to afford 4-bromo-7-chloro-2-(2,2,2-trifluoroethyl)- 8H-pyrazolo[4,3-f]quinazolin-9-one (750.7mg, 1.97mmol, 100% yield) as a brown solid.

[0577] UPLC-MS (ES+, Method 2): 1.57 min, m / z 383.0 [M+H]+.

[0578] Step H, 4-bromo-7,9-dichloro-2-(2,2,2-trifluoroethyl)pyrazolo[4,3-f]quinazoline (I-72). Phosphorus oxychloride (3.18mL, 34.1 mmol) was added to a suspension of 4- bromo-7-chloro-2-(2,2,2-trifluoroethyl)-8H-pyrazolo[4,3-f]quinazolin-9-one (650.4mg, 1.7mmol) and N,N-Diisopropylethylamine (1.19mL, 6.82mmol) . Afterwards, allowed to stir at 100°C for 1 hr. Reaction mixture allowed to cool back down to room temperature. Quenched carefully into water. Partitioned between a layer of EtOAc (50 mL) and water (50 mL). Organic layer separated and aqueous layer extracted with EtOAc (20 mL). Organic layers 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 0-60% EtOAc in petroleum ether afforded 4-bromo-7,9-dichloro-2-(2,2,2-trifluoroethyl)pyrazolo[4,3- f]quinazoline (211 mg, 0.528mmol, 31% yield) (I-72) as a brown solid.

[0579] 1H NMR (400 MHz, CDCh) b / ppm: 8.94 (s, 1 H), 8.08 (s, 1 H), 5.17 (q, J = 8.1 Hz, 2H).UPLC-MS (ES+, Method 2): 1.98 min, m / z 401.0 [M+H]+.Intermediate I-75, 4-bromo-7,9-dichloro-2,5-dimethyl-pyrazolo[4,3-f]quinazoline.

[0580] Intermediate Scheme 32

[0581] Step A, tert-butyl N-(2,5-dimethyl-4-nitro-phenyl)carbamate. A mixture of 1- bromo-2,5-dimethyl-4-nitro-benzene (50. g, 217.33mmol) tert-butylcarbamate (28.01g, 239.07mmol) X-PHOS (10.36g, 21.73mmol) Cs2CO3(106.22g, 326.mmol) and Pd(OAc)2 (2.44g, 10.87mmol) in 1 ,4-dioxane (500mL) was stirred at 100°C under N2for 2hrs. The reaction mixture was diluted with water (30 ml) and extracted with EtOAc (20 ml x 3). The combined organic phases were washed with brine (20 ml x 2), dried over sodium sulfate, concentrated under vacuum and purified by silica gel chromatography eluting with 6% EtOAc in petroleum ether to afford tert-butyl N-(2,5- dimethyl-4-nitro-phenyl)carbamate (57.9 g, 179.9 mmol, 90% yield) as a brown solid.

[0582] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 8.82 (s, 1 H), 7.86 (s, 1 H), 7.62 (s, 1 H), 2.46 (s, 3H), 2.24 (s, 3H), 1.46 (s, 9H).

[0583] Step B, 2,5-dimethyl-4-nitro-aniline. A solution of tert-butyl N-(2,5-dimethyl-4-nitro- phenyl)carbamate (55. g, 206.53mmol) in DCM (1000mL) was stirred at room temperature. To the mixture was added Trifluoroacetic acid (200. mL, 2611.75 mmol) and the reaction left to stir at room temperature for 30 min. The pH of the resultingmixture was adjusted to 8 with saturated NaHCOs solution, extracted with EtOAc (1000 mL x 3), dried over anhydrous Na2SO4 and concentrated under vacuum to afford 2,5- dimethyl-4-nitro-aniline (35g, 210.61 mmol, 100% yield) as a green solid.

[0584] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.84 (s, 1 H), 6.49 (s, 1 H), 6.29 (br s, 2H), 2.52 (s, 3H), 2.09 (s, 3H).

[0585] Step C, 2-bromo-3,6-dimethyl-4-nitro-aniline. A solution of 2,5-dimethyl-4-nitro- aniline (35. g, 210.61mmol) and NBS (41.23g, 231.68mmol) in MeCN (400mL) was stirred at 65°C under N2 for 2hrs. The mixture was diluted with water (400 ml) and extracted with EtOAc (100ml x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum to afford 2-bromo-3,6- dimethyl-4-nitro-aniline (51g, 208.1 mmol, 99% yield) as a black solid.

[0586] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.73 (s, 1 H), 6.21 (br s, 2H), 2.55 (s, 3H), 2.18 (s, 3H).

[0587] Step D, 7-bromo-6-methyl-5-nitro-1H-indazole. To a stirred solution of 2-bromo- 3,6-dimethyl-4-nitro-aniline (50. g, 204.02mmol) in acetic acid (500mL) at 0°C under N2 was added NaNO2 (28.15g, 408.03mmol) in Water (100mL) and the mixture was stirred at room temperature overnight. Water (5000mL) was then added to precipitate a brown solid and filtered. The mixture was concentrated and purified by column eluting 10% MeOH in DCM, desired fractions were combined and evaporated to afford 7-bromo-6-methyl-5-nitro-1 H-indazole (25.5g, 99.59mmol, 49% yield) as a brown solid.

[0588] 1H NMR (400 MHz, DMSO-d6) b / ppm: 13.92 (s, 1 H), 8.56 (s, 1 H), 8.45 (s, 1 H), 2.63 (s, 3H).

[0589] Step E, 7-bromo-2,6-dimethyl-5-nitro-indazole. A solution of 7-bromo-6-methyl-5- nitro-1 H-indazole (50. g, 195.27mmol) in EtOAc (1000mL) was stirred at room temperature, to the mixture was added Trimethyloxonium tetrafluoroborate (37.55g, 253.85mmol) and then the mixture was stirred at room temperature for 3hrs. The mixture was diluted with NaHCOs in water (300 mL) and extracted with EtOAc (100 mL x 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum and purified by silica gel chromatography eluting with 50% EtOAc in petroleum ether, desired fractions were combined and evaporated to afford 7-bromo-2,6-dimethyl-5-nitro-indazole(35g, 129.59 mmol, 66% yield).

[0590] 1H NMR (400 MHz, CDCI3) b / ppm: 8.27 (s, 1 H), 8.23 (s, 1 H), 4.33 (s, 3H), 2.71 (s, 3H).

[0591] Step F, 7-bromo-2,6-dimethyl-indazol-5-amine. A solution of 7-bromo-2,6- dimethyl-5-nitro-indazole (30 g, 111.1 mmol), ammonium chloride (29.71g, 555.4mmol) and Iron (31.02g, 555.37mmol) in Ethanol (300mL) and Water (150mL) was stirred at 80°C under N2 for 2hrs. The mixture was diluted with water (3000m L) and extracted with EtOAc (1000mLx 3). The combined organic phases were washed with brine, dried over sodium sulfate, concentrated under vacuum and purified by silica gel chromatography eluting with 50% EtOAc in petroleum ether, desired fractions were combined and evaporated to afford 7-bromo-2,6-dimethyl-indazol-5-amine (17g, 70.8 mmol, 64% yield).

[0592] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 8.04 (s, 1 H), 6.73 (s, 1 H), 4.80 (br s, 2H), 4.09 (s, 3H), 2.34 (s, 3H).

[0593] Step G, 7-bromo-4-iodo-2,6-dimethyl-indazol-5-amine. N-lodosuccinimide (1.03g, 4.58mmol) was added to a solution of 7-bromo-2,6-dimethyl-indazol-5-amine (1.00g, 4.16mmol) in MeCN (20.83mL) at 0 °C. Reaction mixture allowed to stir at that temperature for 15 min. Quenched with a saturated solution of sodium thiosulfate. Partitioned between a layer of EtOAc (20 mL) and water (20 mL). Organic layer separated. Aqueous layer extracted with EtOAc (20 mL). Organic layers combined, washed with water (2 x 10 mL), 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 0-60% EtOAc in petrol afforded 7-bromo-4- iodo-2,6-dimethyl-indazol-5-amine (192.5mg, 0.526mmol, 13% yield) as a brown solid.

[0594] UPLC-MS (ES+, Method 2): 1.52 min, m / z 368.0 [M+H]+.

[0595] Step H, ethyl 5-amino-7-bromo-2,6-dimethyl-indazole-4-carboxylate. 1 ,1'- Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride dichloromethane complex (42.95mg, 0.05mmol) was added to a nitrogen degassed suspension of 7-bromo-4- iodo-2,6-dimethyl-indazol-5-amine (192.5mg, 0.53mmol), Carbon monooxide - molybdenum (6:1) (138.85mg, 0.53mmol) and 1 ,8-diazabicyclo[5.4.0]undec-7-ene (0.24mL, 1.58mmol) in ethanol (5.20mL). Afterwards, allowed to stir at 70°C for 1 hr. Allowed to cool back down to room temperature, filtered over a plug of celite, plug washed with EtOAc (2x10 mL), filtrate collected and all volatiles were removed under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-60% EtOAc in petroleum ether afforded ethyl 5-amino-7-bromo-2,6-dimethyl- indazole-4-carboxylate (57.8mg, 0.1852mmol, 35% yield) as a yellow solid.

[0596] 1H NMR (400 MHz, CDCh) 6 / ppm: 8.01 (s, 1 H), 6.47 (br s, 2H), 4.42 (q, J = 7.1 Hz, 2H), 4.18 (s, 3H), 2.46 (s, 3H), 1.48 (t, J = 7.1 Hz, 3H)

[0597] UPLC-MS (ES+, Method 2): 1.58 min, m / z 313.9 [M+HJ+.

[0598] Step I, ethyl 7-bromo-2,6-dimethyl-5-[(2,2,2- trichloroacetyl)carbamoylamino]indazole-4-carboxylate. At room temperature, Trichloroacetyl isocyanate (0.03mL, 0.23mmol) was added to a solution of ethyl 5- amino-7-bromo-2,6-dimethyl-indazole-4-carboxylate (57.8mg, 0.19mmol) in THF (0.741 mL). After allowing to stir at room temperature for 10 min, all volatiles were removed under reduced pressure and the residue with triturated with diethyl ether (10 mL) for 5 min. Dried under reduced pressure to afford ethyl 7-bromo-2,6-dimethyl-5- [(2,2,2-trichloroacetyl)carbamoylamino]indazole-4-carboxylate (92.7mg, 0.185mmol, 100% yield) as an off-white solid.

[0599] UPLC-MS (ES+, Method 2): 1.78 min, m / z 501.0 [M+H]+.

[0600] Step J, 4-bromo-2,5-dimethyl-pyrazolo[4,3-f]quinazoline-7,9-diol. 7M Ammonia in MeOH (0.13mL, 0.93mmol) was added to a solution of ethyl 7-bromo-2,6-dimethyl- 5-[(2,2,2-trichloroacetyl)carbamoylamino]indazole-4-carboxylate (92.68mg,0.19mmol) in methanol (0.7406mL) at room temperature. Afterwards, allowed to stir at room temperature for 30 min. More 7M in Ammonia in MeOH (0.13mL, 0.93mmol) and Methanol (0.741 mL) were added. Reaction mixture allowed to stir at 50°C overnight. Reaction mixture allowed to cool back down to room temperature. All volatiles were removed under reduced pressure. The residue was triturated with diethyl ether (10 mL) and dried under reduced pressure to afford 4-bromo-2,5-dimethyl- pyrazolo[4,3-f]quinazoline-7,9-diol (57.24mg, 0.1852mmol, 100% yield) as a brown solid.

[0601] UPLC-MS (ES+, Method 2): 1.13 min, m / z 310.9 [M+H]+.Step K, 4-bromo-7,9-dichloro-2,5-dimethyl-pyrazolo[4,3-f]quinazoline (I-75). Phosphorus oxychloride (0.43mL, 4.63mmol) was added to a mixture of N,N-Diisopropylethylamine (0.06mL, 0.37mmol) and 4-bromo-2,5-dimethyl-pyrazolo[4,3-f]quinazoline-7,9-diol (57.24mg, 0.19mmol) . Afterwards, allowed to stir at 100°C for 2hrs. Additional phosphorus oxychloride (0.43mL, 4.63mmol) was added and reaction mixture allowed to stir at 100°C for 3hrs, room temperature for 10 days and at 100 °C for 1 hr. Reaction mixture allowed to cool back down to room temperature. Quenched carefully into water. Partitioned between a layer of EtOAc (20 mL) and water (20 mL). Organic layer separated and aqueous layer extracted with EtOAc (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 4-bromo-7,9- dichloro-2,5-dimethyl-pyrazolo[4,3-f]quinazoline (64.07mg, 0.185mmol, 100% yield) (I-75) as a brown oil.

[0602] UPLC-MS (ES+, Method 5): 2.12 min, m / z 346.9 [M+H]+.

[0603] 1H NMR (400 MHz, CDCh) 6 / ppm: 8.96 (s, 1 H), 4.47 (s, 3H), 2.93 (s, 3H).Intermediate 1-96, 4-bromo-9-chloro-7-ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3-

[0604] Intermediate Scheme 33

[0605] Step A, ethyl N-[(7-bromo-2,6-dimethyl-indazol-5-yl)carbamothioyl]carbamate.To a suspension of 7-bromo-2,6-dimethyl-indazol-5-amine (100mg, 0.42mmol) in DCM (2.60mL) was added ethoxycarbonyl isothiocyanate (0.05mL, 0.39mmol) and stirred at 25 °C for 12 hrs. Solvent was evaporated and the crude was purified by flash column chromatography (eluting in 0-100% EtOAc in pet. ether) to give ethyl N-[(7-bromo-2,6- dimethyl-indazol-5-yl)carbamothioyl]carbamate (140mg, 0.377mmol, 91% yield) as a yellow powder.

[0606] UPLC-MS (ES+, Method 5): 1.66 min, m / z 372.9 [M+H]+.

[0607] 1H NMR (400 MHz, DMSO-d6) 6 / ppm: 11.30 (s, 1 H), 11.23 (s, 1 H), 8.48 (s, 1 H), 7.63 (s, 1 H), 4.24 (t, J = 7.2 Hz, 2H), 4.19 (s, 3H), 2.34 (s, 3H), 1.28 (t, J = 7.1 Hz, 3H).

[0608] Step B, ethyl (NZ)-N-[[(7-bromo-2,6-dimethyl-indazol-5-yl)-ethyl-amino]- ethylsulfanyl-methylene]carbamate. To a solution of ethyl N-[(7-bromo-2,6- dimethyl-indazol-5-yl)carbamothioyl]carbamate (140mg, 0.38mmol) in DMF (1.89mL) under nitrogen, was added Potassium carbonate (156.35mg, 1.13mmol) portionwise, followed by dropwise addition of lodoethane (0.03mL, 0.38mmol). Reaction mixture was stirred for 1 hr at room temperature. Mixture was evaporated to give ethyl (NZ)-N- [[(7-bromo-2,6-dimethyl-indazol-5-yl)-ethyl-amino]-ethylsulfanyl-methylene]carbamate(150mg, 0.351 mmol, 93% yield) as a brown powder. Material was used without further purification.

[0609] UPLC-MS (ES+, Method 5): 2.03 min, m / z 429.1 [M+H]+.

[0610] Step C, 4-bromo-7-ethylsulfanyl-2,5-dimethyl-pyrazolo[4,3-f]quinazolin-9-ol. A solution of ethyl (NZ)-N-[[(7-bromo-2,6-dimethyl-indazol-5-yl)amino]-ethylsulfanyl- methylene]carbamate (1320mg, 3.31mmol) in NMP (16.6mL) under nitrogen was stirred for 30 minutes at 175°C in a microwave. The mixture was diluted with aqueous saturated NaHCCh and extracted with EtOAc, washed with water, dried over magnesium sulfate, filtered and evaporated to give 4-bromo-7-ethylsulfanyl-2,5- dimethyl-pyrazolo[4,3-f]quinazolin-9-ol (1120mg, 3.171mmol, 96% yield) as a brown oil. Material was used without further purification.

[0611] UPLC-MS (ES+, Method 5): 1.84 min, m / z 352.9 [M+H]+.

[0612] Step D, 4-bromo-9-chloro-7-ethylsulfanyl-2,5-dimethyl-pyrazolo[4,3- f]quinazoline. A solution of 4-bromo-7-ethylsulfanyl-2,5-dimethyl-pyrazolo[4,3- f]quinazolin-9-ol (1352mg, 3.83mmol) and phosphorus oxychloride (16.05mL, 172.23mmol) in DMF (19.2mL) was stirred at 90°C for 1 hr. The mixture was cooled down and then poured into ice cold aqueous saturated NaHCO3, extracted in DCM three times, washed with brine, dried over magnesium sulfate, filtered and evaporated to give 4-bromo-9-chloro-7-ethylsulfanyl-2,5-dimethyl-pyrazolo[4,3-f]quinazoline (920mg, 2.4752mmol, 65% yield) as a brown powder. Material was used without further purification.

[0613] UPLC-MS (ES+, Method 5): 2.34 min, m / z 372.9 [M+H]+.

[0614] Step E, 4-bromo-9-chloro-7-ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3- f]quinazoline (I-96). To a solution of 4-bromo-9-chloro-7-ethylsulfanyl-2,5-dimethyl- pyrazolo[4,3-f]quinazoline (1420. mg, 3.82mmol) in DCM (38.3mL) under N2 was added m-chloroperbenzoic acid, MCPBA (2175.7mg, 12.6mmol). The reaction was stirred at 25°C for 1 hr. The mixture was diluted with DCM and washed with aqueous saturated NaHCO3 and brine. The organics were dried over anhydrous Na2SO4, filtered and concentrated to give product 4-bromo-9-chloro-7-ethylsulfonyl-2,5-dimethyl- pyrazolo[4,3-f]quinazoline (900mg, 2.23mmol, 58% yield) as a yellow solid. Material was used without further purification.

[0615] UPLC-MS (ES+, Method 5): 1.77 min, m / z 404.9 [M+H]+.

[0616] The intermediates in table 6 below were prepared by analogy with I-96 and I96a (intermediate scheme 33), replacing with building block ethyl N-[(7-bromo-2,6- dimethyl-indazol-5-yl)carbamothioyl]carbamate as described in the table entry.Intermediate 1-138, 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-7- [[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3- f]quinazolin-9-ol.

[0618] Intermediate Scheme 34

[0619] Step A, 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl-2- methyl-pyrazolo[4,3-f]quinazolin-9-ol. A suspension of 4-bromo-9-chloro-7- ethylsulfonyl-2-methyl-pyrazolo[4,3-f]quinazoline (1.51g, 3.88mmol), 2-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (1.82g, 5.04mmol) and Cesium Carbonate (2.53g, 7.77mmol) in 1 ,4-Dioxane (32mL) I Water (6.5mL) was degassed with N2 for 5 minutes then [1 , 1'-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll) (379mg, 0.58mmol) was added and the mixture was heated at 100°C for 90 minutes. The mixture was filtered through a plug of celite and the filter cake washed with methanol. The filtrate was concentrated and the residue purified by flash chromatography (40g column, eluting int 0-20% [NH3 1 N in methanol] in DCM). Like fractions were pooled and concentrated. The residue was suspended in petroleum ether, filtered and dried to afford 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl-2-methyl-pyrazolo[4,3-f]quinazolin-9-ol (1.372g, 2.6155mmol, 67% yield) as a brown solid.

[0620] UPLC-MS (ES+, Method 5): 1.99 min, m / z 525.1 [M+H]+.

[0621] Step B, 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-7-[[(2R,8S)-2- fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3-f]quinazolin-9-ol (I- 138). To a solution of 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7- ethylsulfonyl-2-methyl-pyrazolo[4,3-f]quinazolin-9-ol (1.07g, 2.03mmol) and((2R,7aS)-2-Fluorohexahydro-1H-pyrrolizin-7a-yl)methanol (405. mg, 2.54mmol) in anhydrous THF (6.7mL) at 0°C, under N2, was slowly added sodium tert-pentoxide 30% in 2-Methyl THF (2.05mL, 5.08mmol). The mixture was warmed to room temperature and left to stir for 2 hours. The mixture was cooled to 0°C and water (30mL) was slowly added. The mixture was extracted with EtOAc (4 x 15mL). The combined organic layers were pooled, passed through a phase separator cartridge and concentrated. The residue was purified by flash chromatography (25g column, eluting in 0-5% MeOH in DCM). Like fractions were pooled and concentrated to afford 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-7-[[(2R,8S)-2-fluoro- 1,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3-f]quinazolin-9-ol (935mg, 1.5857mmol, 78% yield) as a light beige solid.

[0622] UPLC-MS (ES+, Method 5): 1.68 min, m / z 590.2 [M+H]+.Intermediate I-58, 4-(4-bromo-7-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4- f]quinazolin-9-yl)-1,4-oxazepane.

[0623] Intermediate I-58 was prepared following the route in Intermediate Scheme 35 below.

[0624] Intermediate Scheme 35

[0625] Step A, (2E)-N-(4-bromo-1H-indazol-6-yl)-2-hydroxyimino-acetamide. To a suspension of Chloral hydrate (2.39g, 14.56mmol), 4-bromo-1 H-indazol-6-amine (1544. mg, 7.28mmol) and sodium sulfate (8.27g, 58.25mmol) in a mixture of DMF (11 ,558mL) and water (24.849mL) was added hydrogen chloride (3.29m L, 40.05mmol) (cone HCI). The reaction mixture was heated to 90°C and left to stir for 1 hour. Hydroxylamine hydrochloride (1.77g, 25.48mmol) was added and the reaction mixture left to stir at 90°C for a further 30 mins. The reaction mixture was allowed to cool to room temperature, water (100 mL) added and the solid precipitate collected by vacuum filtration. The solid precipitate was washed with water (2x10 mL) and dried under vacuum to afford (2E)-N-(4-bromo-1 H-indazol-6-yl)-2-hydroxyimino-acetamide (1973.6mg, 6.9719mmol, 96% yield) as a brown solid.

[0626] UPLC-MS (ES+, Method 2): 1.29 min, m / z 282.9 / 284.9 [M+H]+.

[0627] Step B, 4-bromo-1,6-dihydropyrrolo[2,3-g]indazole-7, 8-dione. A stirring mixture of (2E)-N-(4-bromo-1 H-indazol-6-yl)-2-hydroxyimino-acetamide (1973.6mg, 6.97mmol) and sulfuric acid (13.01mL, 244.02mmol) was heated to 60°C and left to stir for 1 hour. The reaction mixture was allowed to cool room temperature, Ice-water (100 mL) added and the mixture left to stir for 5 min. The solid precipitate was collected by vacuum filtration, washed with water (2x10 mL) and dried under vacuum to afford 4-bromo-1 ,6-dihydropyrrolo[2,3-g]indazole-7, 8-dione (1563.9mg, 5.8782mmol, 84% yield) as a brown solid.

[0628] UPLC-MS (ES+, Method 2): 1.20 min, m / z 265.9 / 267.9 [M+H]+.

[0629] Step C, 6-amino-4-bromo-1 H-indazole-7-carboxylic acid. To an ice-cooled suspension of 4-bromo-1 ,6-dihydropyrrolo[2,3-g]indazole-7, 8-dione (1563.9mg, 5.88mmol) in 1 ,4-dioxane (26.592mL) was added a solution of sodium hydroxide (940.45mg, 23.51 mmol) in water (2.799mL). Then hydrogen peroxide solution 30 wt% in H2O (1.2mL, 11.76mmol) was added. The reaction mixture was allowed to warm to room temperature and left to stir for 20 min. The reaction mixture was quenched with a saturated solution of sodium thiosulphate, then acidified to ~pH2 with 2M HCI (aq) and the solid precipitate collected by vacuum filtration. Solid precipitate was washed with water (2x10 mL) and dried under vacuum to afford 6-amino-4-bromo-1 H-indazole- 7-carboxylic acid (1503.8mg, 5.8728mmol, 100% yield) as a brown solid.

[0630] UPLC-MS (ES+, Method 2): 1.29 min, m / z 255.9 / 257.9 [M+H]+.

[0631] Step D, 6-amino-4-bromo-1H-indazole-7-carboxamide. HATLI (2456.33mg, 6.46mmol) was added to a mixture of 6-amino-4-bromo-1 H-indazole-7-carboxylic acid (1503.8mg, 5.87mmol), ammonium chloride (3141.47mg, 58.73mmol) and N,N- Diisopropylethylamine (3.07mL, 17.62mmol) in DMF (29.364mL). The reaction mixture was left to stir at room temperature for 1 hour. Addtional HATLI (446.61 mg, 1.17mmol) was added and the mixture left to stir for a further 30 mins. The reaction mixture was suspended in water (100 mL) and the solid precipitate collected by vacuum filtration. Ethyl acetate (100 mL) was added and both layers partitioned. Aqueous layer extracted with ethyl acetate (50 ml). Organic layers combined, washed with water (50 mL), saturated solution of brine (50 mL), dried over sodium sulfate, filtered, combined with the solid precipitate and concentrated under reduced pressure to afford 6-amino-4- bromo-1 H-indazole-7-carboxamide (1498mg, 5.87mmol, 100% yield) as a brown solid.

[0632] UPLC-MS (ES+, Method 2): 1.21 min, m / z 254.9 / 256.9 [M+H]+.

[0633] Step E, 4-bromo-7-chloro-1,8-dihydropyrazolo[3,4-f]quinazolin-9-one. To a suspension of 6-amino-4-bromo-1 H-indazole-7-carboxamide (1498. mg, 5.87mmol) in 1 ,4-Dioxane (23.492mL) was added thiophosgene (0.95mL, 12.33mmol). The reaction mixture was heated to 105°C and left to stir for 1 hour. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The crude residue was triturated with petrol (10 mL) and dried under vacuum. The residue was again suspended in 1 ,4-Dioxane (23.492mL) and thiophosgene (0.95mL, 12.33mmol) added. The reaction mixture was heated to 105°C and left to stir for 30 mins. The reaction mixture was allowed to cool to room temperature and concentrated under vacuum. The crude residue was triturated with petrol (10mL) and dried under vacuumto afford 4-bromo-7-chloro-1 ,8-dihydropyrazolo[3,4-f]quinazolin-9-one (1759mg, 5.8729mmol, 100% yield) as a brown solid.

[0634] UPLC-MS (ES+, Method 2): 1.42 min, m / z 300.9 [M+H]+.

[0635] Step F, 4-bromo-7,9-dichloro-1H-pyrazolo[3,4-f]quinazoline. Phosphorus oxychloride (8.21mL, 88.09mmol) was added to a suspension of 4-bromo-7-chloro- 1 ,8-dihydropyrazolo[3,4-f]quinazolin-9-one (1759. mg, 5.87mmol) and N,N-Diisopropylethylamine (3.07mL, 17.62mmol). The reaction mixture was heated to 90°C and left to stir for 30 min. The mixture was allowed to cool to room temperature and quenched carefully into water. The solid precipitate was collected by vacuum filtration and washed with water (2x20 mL). Ethyl acetate (50 mL) was added to the filtrate and the organic layer separated. The aqueous layer extracted with ethyl acetate (50 mL) and organic layers combined. Combined organic layers were washed with a saturated solution of brine (10 mL), dried over sodium sulfate, filtered, combined with the solid precipitate and concentrated under vacuum to afford 4-bromo-7,9-dichloro-1 H- pyrazolo[3,4-f]quinazoline (1544.1 mg, 4.8564mmol, 83% yield) as a brown solid.

[0636] UPLC-MS (ES+, Method 2): 1.75 min, m / z 318.8 [M+H]+.

[0637] Step G, 4-(4-bromo-7-chloro-1 H-pyrazolo[3,4-f]quinazolin-9-yl)-1,4-oxazepane.At 0 °C, N,N-Diisopropylethylamine (2.54mL, 14.57mmol) was added to a solution of 1 ,4-Oxazepane hydrochloride (835.37mg, 6.07mmol) and 4-bromo-7,9-dichloro-1 H- pyrazolo[3,4-f]quinazoline (1544.1mg, 4.86mmol) in DCM (19.426mL). The reaction mixture was left to stir at room temperature for 30 min. The reaction mixture was concentrated under vacuum and purified by flash column chromatography on silica gel eluting with 0-8% MeOH in DCM to afford 4-(4-bromo-7-chloro-1 H-pyrazolo[3,4- f]quinazolin-9-yl)-1 ,4-oxazepane (702.9mg, 1.8369mmol, 38% yield) as a brown solid. 1.66 min, m / z 383.9

[0638] UPLC-MS (ES+, Method 2): 1.66 min, m / z 382.0 [M+H]+.

[0639] Step H, 4-(4-bromo-7-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4-f]quinazolin- 9-yl)-1,4-oxazepane (I-58). A suspension of 3,4-Dihydro-2H-pyran (0.12mL, 1.31 mmol), p-toluenesulfonic acid monohydrate (19.88mg, 0.1 mmol) and 4-(4-bromo- 7-chloro-1 H-pyrazolo[3,4-f]quinazolin-9-yl)-1 ,4-oxazepane (200. mg, 0.52mmol) in THF (2.1mL) was allowed to stir at room temperature overnight. Additional 3,4- Dihydro-2H-pyran (0.12mL, 1.31 mmol) and p-toluenesulfonic acid monohydrate (19.88mg, 0.1 mmol) were added and the reaction mixture was again left to stir at room temperature overnight. The reaction mixture was concentrated under vacuum and purified by flash column chromatography on silica gel eluting with 0-50% ethyl acetatein petrol to afford 4-(4-bromo-7-chloro-1-tetrahydropyran-2-yl-pyrazolo[3,4- f]quinazolin-9-yl)-1 ,4-oxazepane (118.6mg, 0.2541 mmol, 49% yield) as a yellow oil.

[0640] UPLC-MS (ES+, Method 2): 2.04 min, m / z 468.0 [M+H]+.Intermediate I-2, 4-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-1,4- oxazepane.

[0641] Intermediate Scheme 36

[0642] 4-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-1,4-oxazepane.To a solution of 4-bromo-7,9-dichloro-2-methyl-pyrazolo[4,3-f]quinazoline (112mg, 0.34mmol) and N,N-diisopropylethylamine (0.59mL, 3.37mmol) in THF (2.2mL) was added 1 ,4-oxazepane hydrochloride (51.1 mg, 0.37mmol) and stirred at room temperature for 1 hour. Further 1 ,4-oxazepane hydrochloride (51.07mg, 0.37mmol) was added and stirring continued for a further 5 hours. The solvent was removed in vacuo, and the residue loaded onto silica with DCM. The crude was purified by flash column chromatography (12g SiC>2, 5-100% EtOAc in petroleum ether). The desired fractions were concentrated to afford 4-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3- f]quinazolin-9-yl)-1 ,4-oxazepane (I-2) (50mg, 0.126mmol, 37% yield) as a yellow solid.

[0643] UPLC-MS (ES+, Method 2): 1.73 min, m / z 398.0, 400.0 [M+H]+.

[0644] The intermediates in table 7 below were prepared by analogy with I-2 (intermediate scheme 36), replacing intermediate 1-1 and building block 1 ,4-oxazepane hydrochloride as described in the table entry.

[0645] Table 7Intermediate 1-88, 4-bromo-7-chloro-9-[3-(3-methoxypropyl)-3,8- diazabicyclo[3.2.1]octan-8-yl]-2-methyl-pyrazolo[4,3-f]quinazoline.

[0646] Intermediate Scheme 37

[0647] Step A, tert-butyl 8-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)- 3,8-diazabicyclo[3.2.1]octane-3-carboxylate. N,N-Diisopropylethylamine (0.39mL, 2.26mmol) was added to a stirring solution of 4-bromo-7,9-dichloro-2-methyl- pyrazolo[4,3-f]quinazoline (250mg, 0.75mmol) (1-1) and 3-Boc-3,8- diazabicyclo[3.2.1]octane (175.9 mg, 0.828 mmol) in DCM (5 mL) and DMF (1.25 mL). The reaction mixture was left to stir at 25°C for 56 hrs. To the reaction was added water and DCM. The phases were separated. The aqueous phase was extracted with DCM (3 x 25 ml). The combined organics were dried using a phase separating filter and concentrated to afford tert-butyl 8-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3- f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (382mg, 0.752mmol, 100% yield) as a yellow solid. Material was used without further purification.

[0648] UPLC-MS (ES+, Method 5): 2.24 min, m / z 509.0 [M+H]+.

[0649] Step B, 4-bromo-7-chloro-9-(3,8-diazabicyclo[3.2.1]octan-8-yl)-2-methyl- pyrazolo[4,3-f]quinazoline (I-87). Hydrogen Chloride in 1 ,4-dioxane (2.46mL, 9.85mmol) was added to a stirring solution of tert-butyl 8-(4-bromo-7-chloro-2-methyl- pyrazolo[4,3-f]quinazolin-9-yl)-3,8-diazabicyclo[3.2.1]octane-3-carboxylate (382mg, 0.75mmol) in DCM (4.92mL). The reaction mixture was left to stir at 25°C for 56 hr. To the reaction was added water and DCM. The phases were separated. The aqueous phase was extracted with DCM (3 x 25 ml). The combined organics were dried using a phase separating filter and concentrated to afford 4-bromo-7-chloro-9-(3,8- diazabicyclo[3.2.1]octan-8-yl)-2-methyl-pyrazolo[4,3-f]quinazoline (306 mg, 0.751 mmol, 100% yield) as a yellow solid. Material was used without further purification.

[0650] UPLC-MS (ES+, Method 5): 1.44 min, m / z 409.0 [M+H]+.

[0651] Step C, 4-bromo-7-chloro-9-[3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan- 8-yl]-2-methyl-pyrazolo[4,3-f]quinazoline (I-88). 1-Bromo-3-methoxypropane (0.08mL, 0.67mmol) was added to a stirring solution of 4-bromo-7-chloro-9-(3,8- diazabicyclo[3.2.1]octan-8-yl)-2-methyl-pyrazolo[4,3-f]quinazoline (250. mg,0.61 mmol) and Potassium carbonate (254.23mg, 1.84mmol) in DMF (3.07mL). The reaction was stirred at 70 °C for 2 hrs. Solvent was evaporated to afford 4-bromo-7- chloro-9-[3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl- pyrazolo[4,3-f]quinazoline (0.28g, 0.584mmol, 95% yield) (I-88) as a yellow solid.

[0652] UPLC-MS (ES+, Method 5): 1.53 min, m / z 481.0 [M+H]+.

[0653] The intermediates in table 8 below were prepared by analogy with 1-88 (intermediate scheme 37) replacing building blocks 3-Boc-3,8-Diazabicyclo[3.2.1]octane in step A and 1-Bromo-3-methoxypropane in step C as required.Intermediate 1-91, 4-bromo-7-chloro-9-[3-[2-(methoxymethoxy)propyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]-2-methyl-pyrazolo[4,3-f]quinazoline.

[0655] Intermediate Scheme 38

[0656] Step A, 4-bromo-7-chloro-9-[3-[2-(methoxymethoxy)propyl]-3,8- diazabicyclo[3.2.1]octan-8-yl]-2-methyl-pyrazolo[4,3-f]quinazoline (1-91). To a solution of 1-[8-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-3,8- diazabicyclo[3.2.1]octan-3-yl]propan-2-ol (200 mg, 0.43mmol) in DCM (4.30mL) was added N,N-Diisopropylethylamine (0.22mL, 1 ,29mmol), the reaction was cooled to 0°C and stirred for 5 min before the addition of Chloromethyl methyl ether (0.04mL, 0.56mmol). The reaction was stirred at 25°C for 2 hrs. The mixture was extracted with DCM and water (x3) and the combined organic layer was then washed with water (x3) and brine (x1). Combined organics were dried with sodium sulfate, filtered and concentrated in vacuo to give 4-bromo-7-chloro-9-[3-[2-(methoxymethoxy)propyl]-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-pyrazolo[4,3-f]quinazoline (218mg, 0.42mmol, 100% yield) as a yellow solid, which was used in the next step directly without purification.

[0657] UPLC-MS (ES+, Method 5): 1.57 min, m / z 511.0 [M+H]+.

[0658] The intermediates in table 9 below were prepared by analogy with 1-91 (intermediate scheme 38) replacing building blocks for step A as described in the table entry.

[0659] Table 9Intermediate I-3, 4-[4-bromo-2-methyl-7-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-1,4-oxazepane.

[0660] Intermediate Scheme 39

[0661] 4-[4-bromo-2-methyl-7-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-1,4-oxazepane (I-3). Sodium hydride, (60% dispersed in mineral oil) (8.32mg, 0.21mmol) was added to a solution of ((2R,7aS)-2- fluorohexahydro-1 H-pyrrolizin-7a-yl)methanol (28.7mg, 0.18mmol) in anhydrous THF (0.5mL) , and stirred at room temperature for 45 minutes. 4-(4-Bromo-7-chloro-2- methyl-pyrazolo[4,3-f]quinazolin-9-yl)-1,4-oxazepane (I-2) (55. mg, 0.14mmol) in a solution of THF (0.4622mL) and DM F (0.5mL) was then added, and heated to 65°C overnight. The reaction was quenched with 0.1 mL water and concentrated in vacuo. The residue was loaded onto Isolute HM-N with DCM and purified by flash column chromatography (5g KP-amino functionalised silica, 5-80% EtOAc in petroleum ether). The desired fractions were concentrated to afford 4-[4-bromo-2- methyl-7-[[(2R,8S)-2-fluoro-1,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-1,4-oxazepane (I-3) (40mg, 0.077mmol, 56% yield) as a colourless gum.

[0662] UPLC-MS (ES+, Method 2): 1.28 min, m / z 519.2, 521.2 [M+H]+.

[0663] The intermediates in table 10 below were prepared by analogy with I-3 (intermediate scheme 39) replacing intermediate I-2 and building block ((2R,7aS)-2- fluorohexahydro-1 H-pyrrolizin-7a-yl)methanol as described in the table entry.

[0664] Table 10Intermediate I-62, 5-[7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2- methyl-pyrazolo[4,3-f]quinazolin-9-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide.

[0665] Intermediate Scheme 40

[0666] Step A, 5-[7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl- pyrazolo[4,3-f]quinazolin-9-yl]-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1,5- a][1,4]diazepine-2-carboxamide (I-62). A stirring mixture of 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (715.04mg, 1.98mmol), 5-(4-bromo-7-chloro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-N,N-dimethyl-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide (1.g, 1.98mmol) and Cesium Carbonate (1293.48mg, 3.97mmol) in 1 ,4-Dioxane (10mL) and Water (2mL) was degassed with nitrogen before the addition of [1 , 1 '-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll) (129.37mg, 0.2mmol). The reaction mixture was heated to 95°C and left to stir overnight. The reaction mixture was left to cool to room temperature before being passed through phase separating filter paper and the solvents reduced in vacuo to afford the crude material. The crude material was purified by flash column chromatography (eluting in 0 - 100% EtOAc in Pet. ether) to afford the desired product 5-[7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-N,N-dimethyl-4, 6,7,8- tetrahydropyrazolo[1 ,5-a][1 ,4]diazepine-2-carboxamide (1.1g, 1.1382mmol, 57% yield) as a yellow solid

[0667] UPLC-MS (ES+, Method 5): 2.05 min, m / z 657.2 [M+H]+.

[0668] The intermediates in table 11 below were prepared by analogy with I-62 (intermediate scheme 40) replacing building blocks for step A as described in the table entry.

[0669] Table 11Intermediate I-70, 7,9-dichloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2- methyl-pyrazolo[4,3-f]quinazoline.

[0670] Intermediate Scheme 41

[0671] Step A, 7,9-dichloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2- methyl-pyrazolo[4,3-f]quinazoline (I-70). A solution of 4-bromo-7,9-dichloro-2- methyl-pyrazolo[4,3-f]quinazoline (100. mg, 0.3mmol), 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (108.51 mg, 0.3mmol) and Cesium Carbonate (196.29mg, 0.6mmol) in 1 ,4-Dioxane (1.13mL) and Water (0.37mL) was degassed with nitrogen for 2 mins. [1 , 1 ‘-Bis(di-tert- butylphosphino)ferrocene]dichloropalladium(ll) (19.63mg, 0.03mmol) was added. Reaction mixture allowed to stir at 70°C for 4 hrs. Reaction mixture cooled back down to room temperature. Diluted with EtOAc (10 mL) and filtered over a plug of celite. Plug washed with EtOAc (2 x 10 mL). Filtrate collected and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-80% ethyl acetate in petroleum ether afforded 7,9-dichloro-4-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-2-methyl-pyrazolo[4,3-f]quinazoline (77.5mg,0.1597mmol, 53% yield) (I-70) as an off-white solid.

[0672] UPLC-MS (ES+, Method 5): 2.34 min, m / z 485.1 [M+H]+.

[0673] 1H NMR (400 MHz, CDCh) b / ppm: 8.77 (s, 1 H), 7.73 (s, 1 H), 7.70 (dd, J = 9.0, 5.9 Hz, 1 H), 7.53 (d, J = 2.7 Hz, 1 H), 7.29-7.23 (m, 1 H), 7.19 (d, J = 2.6 Hz, 1 H), 5.32- 5.26 (m, 2H), 4.21 (s, 3H), 3.52 (s, 3H), 2.54-2.41 (m, 1 H), 2.15-2.02 (m, 1 H), 0.65 (t, J = 7.4 Hz, 3H).Intermediate 1-71, 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2- methyl-9-(1-methylpyrazol-3-yl)pyrazolo[4,3-f]quinazoline.

[0674] Intermediate Scheme 42

[0675] Step A, 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-9-(1- methylpyrazol-3-yl)pyrazolo[4,3-f]quinazoline (1-71). A solution of 7,9-dichloro-4-[8- ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-pyrazolo[4,3-f]quinazoline (193.5mg, 0.4mmol) , 1-Methyl-3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-1 H- pyrazole (99.55mg, 0.48mmol) and Potassium carbonate (110.2mg, 0.8mmol) in 1 ,4- Dioxane (2.9902mL) and Water (0.9967mL) was degassed with nitrogen for 2 min. [1 ,1'-Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (25.98mg, 0.04mmol) was added. Reaction mixture was stirred at 70°C for 2hrs. Reaction mixture allowed to cool back down to room temperature. Partitioned between a layer of EtOAc (20 mL) and water (20 mL). Organic layer separated and aqueous layer extracted with EtOAc (20 mL). Organic layers 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 0-50% ethyl acetate in petrol afforded 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-2-methyl-9-(1-methylpyrazol-3-yl)pyrazolo[4,3-f]quinazoline (69.9mg, 0.1316mmol, 33% yield) (1-71) as an off-white solid.

[0676] 1H NMR (400 MHz, DMSO-d6) b / ppm: 7.91 (dd, J = 9.1 , 6.0 Hz, 1 H), 7.82 (s, 1 H), 7.79 (d, J = 2.0 Hz, 1 H), 7.67 (d, J = 2.7 Hz, 1 H), 7.54 (s, 1 H), 7.43 (t, J = 9.4 Hz, 1 H), 7.18 (d, J = 2.6 Hz, 1 H), 6.87 (d, J = 2.0 Hz, 1 H), 5.38-5.31 (m, 2H), 4.00 (s, 3H), 3.79 (s, 3H), 3.44 (s, 3H), 2.54-2.38 (m, 1 H), 2.14-1.98 (m, 1 H), 0.60 (t, J = 7.3 Hz, 3H).

[0677] UPLC-MS (ES+, Method 2): 2.05 min, m / z 531.4 [M+H]+.

[0678] The intermediates in table 12 below were prepared by analogy with 1-71 (intermediate scheme 42) replacing building block 1-Methyl-3-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)-1 H-pyrazole as described in the table entry.

[0679] Table 12Intermediate I-95, 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-9-[2- (methoxymethoxymethyl)-4,6,7,8-tetrahydropyrazolo[1,5-a][1,4]diazepin-5-yl]-2- methyl-pyrazolo[4,3-f]quinazoline.

[0680] Intermediate scheme 43

[0681] Step A, 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-9-[2- (methoxymethoxymethyl)-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1,4]diazepin-5-yl]-2- methyl-pyrazolo[4,3-f]quinazoline (I-95). To a stirred solution of 7,9-dichloro-4-[8-ethyl- 7-fluoro-3-(methoxymethoxy)-1-naphthyl]-2-methyl-pyrazolo[4,3-f]quinazoline(115mg, 0.24mmol) and 2-(methoxymethoxymethyl)-5,6,7,8-tetrahydro-4H- pyrazolo[1 ,5-a][1 ,4]diazepine (55.06mg, 0.26mmol) (A-27) in DCM (2mL) was added N,N-diisopropylethylamine (0.12mL, 0.71mmol). The reaction was stirred overnight at room temperature. The reaction was then stirred at 50°C for 5 hrs. The reaction was partitioned between EtOAc and DCM and the layers separated. The aqueous layer was extracted with DCM (2x). The combined organic extracts were dried via phase separator and evaporated to afford a yellow solid. This material was purified via silica gel chromatography eluting 0-100% EtOAc in petroleum ether, then 0-20% MeOH in DCM to afford 7-chloro-4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-9-[2- (methoxymethoxymethyl)-4,6,7,8-tetrahydropyrazolo[1 ,5-a][1 ,4]diazepin-5-yl]-2- methyl-pyrazolo[4,3-f]quinazoline (130mg, 0.197mmol, 83% yield) as a yellow gum.

[0682] UPLC-MS (ES+, Method 5): 2.15 min, m / z 660.2 [M+H]+.Intermediate 1-97, (3R)-1-(4-bromo-7-ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3- f]quinazolin-9-yl)-3-methyl-piperidin-3-ol.

[0683] Intermediate scheme 44

[0684] Step A, (3S)-1-(4-bromo-7-ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3-f]quinazolin- 9-yl)-3-methyl-piperidin-3-ol (I-97). N,N-Diisopropylethylamine (0.3mL, 1.71mmol) was added to a stirring solution of 4-bromo-9-chloro-7-ethylsulfonyl-2,5-dimethyl- pyrazolo[4,3-f]quinazoline (230. mg, 0.57mmol) and (R)-3-Methylpiperidin-3-ol hydrochloride (86.4mg, 0.57mmol) in DCM (2.97mL) and DMF (0.74mL). The reaction mixture was left to stir at 25°C for 4 hrs. To the reaction was added water and DCM. The phases were separated. The aqueous phase was extracted with DCM (3 x 25 ml). The combined organics were dried using a phase separating filter and concentrated to afford (3S)-1-(4-bromo-7-ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3-f]quinazolin-9-yl)-3- methyl-piperidin-3-ol (0.274g, 0.568mmol, 100% yield) as a yellow solid.

[0685] UPLC-MS (ES+, Method 5): 1.71 min, m / z 484.0 [M+H]+.

[0686] The following examples in table 13 were made by analogy with I-97 (Intermediate scheme 44) starting from the intermediate and building blocks for step A as described in the table.

[0687] Table 13Intermediate 1-118, (6S)-4-(4-bromo-7-ethylsulfonyl-5-fluoro-2-methyl-pyrazolo[4,3- f]quinazolin-9-yl)-6-methyl-1,4-oxazepan-6-ol.

[0688] Intermediate Scheme 45

[0689] Step A, (6S)-4-(4-bromo-7-ethylsulfanyl-5-fluoro-2-methyl-pyrazolo[4,3- f]quinazolin-9-yl)-6-methyl-1,4-oxazepan-6-ol. To a solution of (6S)-6-methyl-1 ,4- oxazepan-6-ol;2,2,2-trifluoroacetic acid (210.51 mg, 0.86mmol) and 4-bromo-9-chloro- 7-ethylsulfanyl-5-fluoro-2-methyl-pyrazolo[4,3-f]quinazoline (1-117a) (129. mg,0.34mmol) in DCM (1.71mL) was added N,N-Diisopropylethylamine (0.6mL, 3.43mmol) and the mixture stirred at room temperature for 30 min. Additional N,N- Diisopropylethylamine (0.3mL, 1.72mmol) was added. Allowed to stir at room temperature for 1h. 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. Purification by flash column chromatography on silica gel eluting with 0-100% ethyl acetate in petrol followed by 0-5% MeOH in DCM to afford (6S)-4-(4-bromo-7-ethylsulfanyl-5-fluoro-2- methyl-pyrazolo[4,3-f]quinazolin-9-yl)-6-methyl-1 ,4-oxazepan-6-ol (123.2mg, 0.2619mmol, 76% yield) as a brown solid.

[0690] UPLC-MS (ES+, Method 5): 1.89 min, m / z 470.0 / 472.0 [M+H]+.

[0691] Step B, (6S)-4-(4-bromo-7-ethylsulfonyl-5-fluoro-2-methyl-pyrazolo[4,3- f]quinazolin-9-yl)-6-methyl-1,4-oxazepan-6-ol. At 0 °C, m-chloroperbenzoic acid (146.75mg, 0.65mmol) was added to a solution of (6S)-4-(4-bromo-7-ethylsulfanyl-5- fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-6-methyl-1 ,4-oxazepan-6-ol (123.2mg, 0.26mmol) in DCM (2.6193mL). Afterwards, allowed to stir at room temperature for 1 h. Reaction mixture quenched with a saturated solution of sodium thiosulfate. Partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). Organic layer separated, aqueous layer extracted with ethyl acetate (20 mL) and organic layers combined. Combined organic layers 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 (6S)-4-(4-bromo-7-ethylsulfonyl-5- fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-6-methyl-1 ,4-oxazepan-6-ol (131.58mg, 0.2619mmol, 100% yield) as a clear oil.

[0692] UPLC-MS (ES+, Method 5): 1.55 min, m / z 501.9 / 503.9 [M+H]+.

[0693] The following examples in table 14 were made by analogy with 1-118 (Intermediate scheme 45) starting from the intermediate and building blocks for step A as described in the table.

[0694] Table 14Intermediate I-98, (3R)-1-[4-bromo-2,5-dimethyl-7-[[(2R,8S)-2-fluoro-1,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-3-methyl-piperidin-3- ol.

[0695] Intermediate scheme 46

[0696] Step A, (3R)-1-[4-bromo-2,5-dimethyl-7-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7- hexahydropyrrolizin-8-yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-3-methyl-piperidin-3- ol (I-98). To a solution of ((2R,7aS)-2-Fluorohexahydro-1 H-pyrrolizin-7a-yl)methanol (134.1 mg, 0.84mmol) in THF (4.05mL) under N2 was added dropwise 1 M Lithium bis(trimethylsilyl)amide in THF (0.78mL, 0.78mmol) at 0°C. The reaction mixture was stirred at this temperature for 20 mins then (3R)-1-(4-bromo-7-ethylsulfonyl-2,5- dimethyl-pyrazolo[4,3-f]quinazolin-9-yl)-3-methyl-piperidin-3-ol (250. mg, 0.52mmol) in THF (1.1337mL) was added in one portion. The reaction mixture was then stirred at 25°C overnight. The reaction was quenched with saturated aqueous NaHCCh, extracted with EtOAc, dried over magnesium sulfate, filtered and evaporated to give (3R)-1-[4-bromo-2,5-dimethyl-7-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8- yl]methoxy]pyrazolo[4,3-f]quinazolin-9-yl]-3-methyl-piperidin-3-ol (250mg, 0.457mmol, 88% yield) as a yellow oil. The material was used without further purification.

[0697] UPLC-MS (ES+, Method 5): 1.47 min, m / z 549.0 [M+H]+.

[0698] The following intermediates in table 15 were made by analogy with I-98 (Intermediate scheme 46) starting from the intermediate and building blocks for step A as described in the table.

[0699] Table 15Intermediate 1-140, 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7- ethylsulfonyl-5-fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1,4-oxazepan- 6-ol

[0700] Intermediate Scheme 47

[0701] Step A, 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfanyl-5- fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol. A solution of 4-(4-bromo-7-ethylsulfanyl-5-fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl)-6- methyl-1 ,4-oxazepan-6-ol (520.9mg, 1.11 mmol), 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (598.4mg, 1.66mmol) and Cesium Carbonate (721.66mg, 2.21 mmol) in 1 ,4-Dioxane (5.5372mL) and Water (1.8457mL) was degassed with nitrogen for 2 min. cataCXium A Pd G3, Methanesulfonato(diadamantyl-n-butylphosphino)-2'amino-1 ,T-biphenyl-2- yl)palladium(ll) (80.65mg, 0.11 mmol) was added. Reaction mixture allowed to stir at 100°C for 90 min. 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. Purification by flash column chromatography (eluting in 20-100% EtOAc in Pet. Ether) afforded 4-[4-[8-ethyl-7- fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfanyl-5-fluoro-2-methyl- pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol (457.4mg, 0.7333mmol, 66% yield) as a brown solid.

[0702] UPLC-MS (ES+, Method 2): 2.05 min, m / z 624.7 [M+H]+.

[0703] Step B, 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl-5- fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol. At 0°C, m- chloroperbenzoic acid, MCPBA (71.86mg, 0.32mmol) was added to a solution of 4-[4- [8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfanyl-5-fluoro-2-methyl- pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol (80. mg, 0.13mmol) in DCM (1.2826mL). Afterwards, allowed to stir at room temperature for 2h. Additional m- chloroperbenzoic acid, MCPBA (11.07mg, 0.06mmol) was added. Reaction mixture allowed to stir at room temperature for 15 min. Reaction mixture quenched with a saturated solution of sodium thiosulfate. Partitioned between a layer of ethyl acetate (20 mL) and water (20 mL). Organic layer separated, aqueous layer extracted with ethyl acetate (20 mL) and organic layers combined. Combined organic layers 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-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl-5- fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol (84.104mg, 0.1283mmol, 100% yield) as an off-white solid.

[0704] UPLC-MS (ES+, Method 2): 1.79 min, m / z 656.4 [M+H]+.

[0705] The following examples in table 16 were made by analogy with 1-140 (Intermediate scheme 47) starting from the intermediate and building blocks for step A as described in the table. Where the intermediate for step A is already the sulfone (e.g. I-97), step B was not required. The catalyst cataCXium A Pd G3 could be substituted for Pd(dtbpf)Ch in step A.

[0706] Table 16Intermediate 1-143, 1-[[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-fluoro-9- (6-hydroxy-6-methyl-1,4-oxazepan-4-yl)-2-methyl-pyrazolo[4,3-f]quinazolin-7- yl]oxymethyl]cyclopropanecarbaldehyde.

[0708] Step A, 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-fluoro-7-[[1- (hydroxymethyl)cyclopropyl]methoxy]-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6- methyl-1 ,4-oxazepan-6-ol. To a solution of [1-(Hydroxymethyl)cyclopropyl]methanol (54.51 mg, 0.53mmol) in THF (2mL) under N2 was added dropwise 1M Lithium bis(trimethylsilyl)amide in THF (0.53mL, 0.53mmol) at 25°C. The reaction mixture was stirred for 20 mins then 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7- ethylsulfonyl-5-fluoro-2-methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan- 6-0I (70. mg, 0.11 mmol) in THF (2mL) was added in one portion. The reaction mixture was left to stir at room temperature for 2h. The reaction mixture was quenched with water and NaHCOs(sat. aq), extracted with EtOAc (x3) and washed with brine, dried over magnesium sulfate, fitlered and evaproated to afford 4-[4-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-5-fluoro-7-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2- methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol (70.85mg,0.1067mmol, 100% yield) as a yellow oil.

[0709] UPLC-MS (ES+, Method 2): 1.77 min, m / z 664.8 [M+H]+.

[0710] Step B, 1-[[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-5-fluoro-9-(6- hydroxy-6-methyl-1 ,4-oxazepan-4-yl)-2-methyl-pyrazolo[4,3-f]quinazolin-7- yl]oxymethyl]cyclopropanecarbaldehyde. To a solution of 4-[4-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-5-fluoro-7-[[1-(hydroxymethyl)cyclopropyl]methoxy]-2- methyl-pyrazolo[4,3-f]quinazolin-9-yl]-6-methyl-1 ,4-oxazepan-6-ol (70.85mg,0.11 mmol) in DCM (3mL) was added Dess Martin periodinane (54.33mg, 0.13mmol). The reaction mixture was stirred at room temperature for 1 hour. Additional Dess Martin periodinane (90.55mg, 0.21 mmol) was added and the mixture left to stirovernight. Additional Dess Martin periodinane (90.55mg, 0.21 mmol) was added and the reaction left to stir for a further 48 hours. The reaction mixture was quenched with Na2S2C>4 (sat. aq):NaHCOs (sat. aq) (1 :1), extracted with DCM (x3) and washed with sodium bicarbonate aq and brine, dried over magnesium sulfate, fitlered and concentrated in vacuo to afford 1-[[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1- naphthyl]-5-fluoro-9-(6-hydroxy-6-methyl-1 ,4-oxazepan-4-yl)-2-methyl-pyrazolo[4,3- f]quinazolin-7-yl]oxymethyl]cyclopropanecarbaldehyde (90mg, 0.1115mmol, 104% yield) as a yellow oil.

[0711] UPLC-MS (ES+, Method 2): 2.00 min, m / z 662.3 [M+H]+.Intermediate 1-111, 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1 -naphthyl]-7-ethylsulfonyl- 2,5-dimethyl-pyrazolo[4,3-f]quinazolin-9-ol.

[0712] Intermediate Scheme 49

[0713] Step A, 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl- 2,5-dimethyl-pyrazolo[4,3-f]quinazolin-9-ol. A solution of 2-[8-ethyl-7-fluoro-3- (methoxymethoxy)-1-naphthyl]-4,4,5,5-tetramethyl-1 ,3,2-dioxaborolane (358.71 mg, 1.mmol), 4-bromo-7-[[(2R,8S)-2-fluoro-1 ,2,3,5,6,7-hexahydropyrrolizin-8-yl]methoxy]- 9-[3-(3-methoxypropyl)-3,8-diazabicyclo[3.2.1]octan-8-yl]-2-methyl-pyrazolo[4,3- f]quinazoline (500. mg, 0.83mmol) and cesium carbonate (540.74mg, 1.66mmol) in 1 ,4- Dioxane (6.9878mL) and Water (1.3102mL) was degassed with nitrogen and [1,1'- Bis(di-tert-butylphosphino)ferrocene]dichloropalladium(ll) (54.08mg, 0.08mmol) added. The reaction mixture was heated to 100°C for 30 minutes. The reaction mixture was cooled to room temperature then filtered through a phase separator cartridge, washing with MeOH. The filtrate was concentrated under reduced to afford the desired product 4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7-ethylsulfonyl-2,5- dimethyl-pyrazolo[4,3-f]quinazolin-9-ol (134mg, 0.25mmol, 100% yield) as an oil.

[0714] UPLC-MS (ES+, Method 5): 2.01 min, m / z 539.1 [M+H]+.Intermediate 1-112, 4-[4-[8-ethyl-7-fluoro-3-(methoxymethoxy)-1-naphthyl]-7- ethylsulfonyl-2,5-dimethyl-pyrazolo[4,3-...

Claims

CLAIMS1. A compound of formula (I), or a pharmaceutically acceptable salt thereof:Z1is independently selected from -O- and -NR5a-;Z2is independently absent or is selected from -O- and -NR5b-;X1is independently selected from N and CR3b;X2is selected from N, NR6, O and S;X3is selected from N and NR6;X4is CR3c;R1is independently selected from Co-Cs-alkylene-R1aand C2-Ce-alkylene-R1 b; wherein R1ais independently selected from: a 4- to 7- membered heterocycloalkyl ring; a phenyl ring; and a Cs-Cycycloalkyl ring optionally substituted with an NR7R8group; wherein said heterocycloalkyl ring, said phenyl ring or said cycloalkyl ring is optionally substituted with from 1 to 4 R9groups; R1 bis independently selected from: NR7R8, OR8, SR8, SOR8, SO2R8and SO(NH)R8; or R1and R5atogether 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 R9groups; and a fused, spirofused or bridged bicyclic 6- to 11-membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups;R2is independently Ci-Ce-alkyl, Ci-C4-haloalkyl, Co-C4-alkylene-R2a, Ci-C4-alkylene-R2b, C2- C4-alkylene-R2c;R2ais 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 Cs-Cy-cycloalkyl; wherein any heterocycloalkyl or cycloalkyl R2agroup is optionally substituted with from 1 to 6 R10groups and any heteroaryl or phenyl R2agroup is optionally substituted with from 1 to 6 R11groups; wherein R2bis independently selected from CONR12R12and CO2R12; wherein R2cis independently selected from NR12R13and OR12; or R2and R5btogether 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 bridgedbicyclic 6- to 11 -membered heterocycloalkyl group, said heterocycloalkyl group being optionally substituted with from 1 to 6 R10groups;R3a, R3band R3care each independently selected from: H, halo, Ci-C4-alkyl, O-Ci-C4-alkyl, Ci-C4-haloalkyl, O-Ci-C4-haloalkyl, cyclopropyl, nitro and cyano;R4is 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 R4is optionally substituted with from 1 to 4 R14groups;R5a, R5b, R8and R12are each independently selected at each occurrence from H, C1-C4- haloalkyl, cyclopropyl and Ci-C4-alkyl;R6is independently selected from H, Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl;R7and R13are each independently at each occurrence selected from H, Ci-C4-alkyl, C1-C4- haloalkyl and C(O)-Ci-C4-alkyl; or R12and R13together 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 R10agroups; R9is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, CONR12R13, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10is independently at each occurrence selected from oxo, halo, cyano, NR12R13, OR12, COR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R10ais independently at each occurrence selected from oxo, halo, cyano, NR12R13a, OR12, COR12, CO2R12, CONR12R12, CONR12R13a, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13a, Ci-C4-alkyl substituted with OR12, Ci-C4-alkyl substituted with cyano, Ci-C4-alkyl substituted with phenyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R13ais independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci-C4-alkyl;R11is independently selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, C1- C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, monocyclic 4-to 7-membered cycloalkyl or heterocycloalkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R14is independently at each occurrence selected from halo, cyano, nitro, NR12R13, OR12, CO2R12, CONR12R12, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR12R13, Ci-C4-alkyl substituted with OR12, C2-C4-alkenyl, C2-C4-alkynyl, Ci-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: Ci-C4-alkyl, C1- C4-alkyl substituted with ORa, halo, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-alkyl and C1-C4- haloalkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci- C4-alkyl and S(O)2-Ci-C4-alkyl.

2. A compound of claim 1 , wherein R1and R5aare selected such that NR1R5comprises no more than a single amine, wherein said single amine may be a primary, secondary or tertiary amine.

3. A compound of claim 1 or claim 2, wherein R1and R5atogether 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 R9groups; a fused or spirofused bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; and a bridged bicyclic 6- to 11 -membered heterocyclyl group, optionally substituted with from 1 to 4 R9groups; wherein the nitrogen to which R1and R5aare attached is the only nitrogen in the ring system.

4. A compound of any one of claims 1 to 3, wherein R1and R5atogether with the nitrogen to which they are attached form a ring system selected from: a monocyclic 4- to 7- membered group heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups; a fused or spirofused bicyclic 6- to 11 -membered heterocycloalkyl group, optionally substituted with from 1 to 4 R9groups.

5. A compound of claim 4, wherein R1and R5together with the nitrogen to which they are attached form a ring system having the structure:wherein R9ais selected from NR12R13and Ci-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. A compound of claim 4, wherein R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein Z6is independently selected from C(O)NR9b, NR9b, O, S, S(O)2, S(O), S(O)(NR9b) and S(O)(NH); R9bis selected from H and Ci-C4-alkyl; p2 is selected from 2 and 3, q2 is 2; and r2 is selected from 0, 1 , 2 and 3.

7. A compound of claim 5, wherein R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein Z6is independently selected from C(O)NR9b, O, S, S(O)2, S(O), S(O)(NR9b), S(O)(NH) and NR9b; R9bis 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. A compound of claim 6, wherein Z6may be O.

9. A compound of claim 6, wherein R1and R5atogether with the nitrogen to which they are attached form a ring system having the structure:wherein R12is independently at each occurrence selected from H, Ci-C4-haloalkyl, and C1- C4-alkyl; and n9 is an integer selected from 0, 1 , 2 and 3.

10. A compound of any one of claims 1 to 9, wherein R2has the structure:, wherein R15is independently selected from H, Ci-C4-alkyl and R16is independently selected from H, Ci-C4-alkyl and cyclopropyl; or wherein R15and R16together with the atoms to which they are attached form a 5- or 6-membered heterocycloalkyl ring, optionally substituted with 1 or 2 R10groups; and y is independently selected from 0, 1 , 2, 3, and 4.

11. A compound of claim 10, wherein R2has the structure:, wherein z is independently selected from 0, 1 , 2, 3, and 4.

12. A compound of any one of claims 1 to 11 , wherein X1is N.

13. A compound of any one of claims 1 to 12, wherein X2is N and X3is NR6.

14. A compound of any one of claims 1 to 12, wherein X3is N and X2is NR6.

15. A compound of claim 13 or claim 14, wherein R6is selected from Ci-C4-haloalkyl, Ci-C4-alkyl and C3-C4-cycloalkyl.

16. A compound of any one of claims 1 to 15, wherein R3cis H.

17. A compound of any one of claims 1 to 15, wherein R3ais H.

18. A compound of any one of claims 1 to 15, wherein R3ais F.

19. A compound of any one of claims 1 to 15, wherein R3ais methyl.

20. A compound of any one of claims 1 to 19, wherein R4is phenyl, said phenyl being optionally fused to a Cs-Cy-cycloalkyl ring, wherein R4is optionally substituted with from 1 to 4 R14groups.21 . A compound of any one of claims 1 to 19, wherein R4has the structure:wherein x is independently selected from 0, 1 , 2, 3, and 4.

22. A compound of claim 21 , wherein R4has the structure:independently H or Ci-C4-alkyl; x2 is independently selected from 0, 1, 2 and 3.

23. A compound of any one of claims 1-22 having the structure:

24. A compound of any one of claims 1-23 having the structure:

26. A compound of any one of claims 1-25 having the structure:

27. A compound of any one of claims 1-26 having the structure28. A compound of any one of claims 1 to 27, wherein R4is 5-, 6-, 9- or 10-membered monocyclic or bicyclic heteroaryl, optionally substituted with from 1 to 4 R14groups.

29. A compound of any one of claims 1 to 28, wherein the compound of formula (I) is selected from:

30. A compound of any one of claims 1 to 29 for medical use.

31. A compound of any one of claims 1 to 30 for use in treating cancer; optionally wherein the cancer is selected from: pancreatic carcinoma, colorectal carcinoma, rectal carcinoma, endometrial carcinoma, non-small cell lung carcinoma, gastric carcinoma, ovarian carcinoma and small cell lung carcinoma.

32. A compound for use of claim 31 , wherein the subject being treated has a cancer having wild-type KRAS.

33. A compound for use of claim 32, wherein the subject being treated has a cancer having a KRAS mutation selected from: KRAS G12D, KRAS G12C, KRAS G12V, KRAS G12A, KRAS G12D, KRAS G12S, KRAS G13D and KRAS Q61H.

34. A pharmaceutical composition comprising a compound of any one of claims 1 to 29 and a pharmaceutically acceptable excipient.

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