Modulators of rho-associated protein kinase

Abstract

This invention relates to novel triazole compounds and pharmaceutical compositions comprising the novel triazole compounds. More specifically, the invention relates to triazole compounds useful as modulators of Rho-associated protein kinase (ROCK), for example ROCK1 and / or ROCK2 inhibitors. This invention also relates to uses of the triazole compounds and methods of treatment employing the triazole compounds.

Description

Modulators of Rho-associated Protein Kinase

[0001] This invention relates to novel compounds and pharmaceutical compositions comprising the novel compounds. More specifically, the invention relates to compounds useful as modulators of Rho- associated protein kinase (ROCK), for example ROCK1 and / or ROCK2 inhibitors. This invention also relates to processes for preparing the compounds, uses of the compounds and methods of treatment employing the compounds. The compounds of the invention may therefore be used in treating ROCK- mediated diseases.BACKGROUND

[0002] Rho-associated coiled-coil Kinase (ROCK) is a member of the AGC family of serine / threonine kinases that are involved in many aspects of cellular signalling [Lock et al 2012], Highly conserved in mammalian species, two isoforms of ROCK are known to exist ROCK1 and ROCK2. They share 65% homology in their amino acid sequence and 92% homology in their kinase domain. In addition, they contain a long coiled-coil domain, a PH domain and a Rho binding domain, suggesting they are activated by Rho GTPases such as RhoA that link several classes of cell surface receptor to internal kinase signalling. ROCK1 and ROCK2 have been shown to bind to and phosphorylate a large number of substrate proteins involved in processes such as migration, pro- fibrotic cytokine production, cell adhesion and proliferation, but the most studied are those associated with actin cytoskeleton rearrangements [Surma et a / 2014], The best characterized ROCK substrate is the Myosin Phosphatase Target Subunit 1 (MYPT1), a regulatory subunit of myosin phosphatase. MYPT1 counteracts the activity of Myosin Light Chain (MLC) kinase and thus decreases the contraction of smooth muscle cells. ROCK phosphorylates and deactivates MYPT1 and that in turn leads to MLC kinase phosphorylation, activation and actomyosin contraction [Feng et al 1999; Velasco et al 2002], When administered systemically pan-ROCK inhibitors induce vasodilation, hyperaemia and hypotension, limiting their use as therapeutic agents in the context of fibrosis and most other diseases [Kast et al 2007], ROCK is also known to phosphorylate LIM-kinases (LIMK1 and LIMK2) which in turn phosphorylate cofilin leading to increased cellular actin filaments [Maekawa et al 1999], Many additional substrates have been identified, some of which have been suggested to be more specifically phosphorylated by either ROCK1 or ROCK2. [Hartmann et al 2015], ROCK isoforms are differentially expressed in different tissues with ROCK1 predominant in the kidney, liver, lungs, and testis, while ROCK2 is predominantly expressed in the brain and muscle tissues [Nakagawa et al 1996], Isoform expression can also alter during disease, with ROCK2 often increasing in expression in comparison to ROCK1 ; taken together all these data strongly suggest that ROCK1 and ROCK2 have both overlapping and distinct functions in homeostasis and disease.

[0003] Both ROCK1 and ROCK2 are involved in numerous pro-fibrotic processes with pan-ROCK inhibitors able to strongly suppress TGFp stimulated myofibroblast activation, chemokine driven fibroblast migration and EMT in response to profibrotic mediators such as Lysophosphatidic acid (LPA) and endothelin [Sakai et al 2016], The specific role of each ROCK isoform in disease is largely unknown at present although both independent and redundant roles have been suggested. Studies using haplozygous knockout mice (ROCK2+Z-) where one allele of ROCK2 has been removed(reducing the expression of ROCK2) have shown that multiple aspects of disease can be attenuated. Knipe et al demonstrated that both ROCK1 + / - mice and ROCK2+ / - mice were protected in the bleomycin induced lung fibrosis model of IPF. A more recent study looked at both ROCK2+ / - mice and ROCK2 haplozygous mice, with one allele of ROCK2 mutated to a kinase activity dead configuration, thereby reducing signalling but not expression of ROCK2 [Wei et al 2020], In both models the knockout mice showed remarkable protection from weight gain when fed a high fat diet, with some resistance to obesity induced type 2 diabetes and liver steatosis. The results mirrored work carried out by Soliman et al 2016 that also showed that ROCK2+ / - mice were protected from type 2 diabetes insulin resistance when fed a high fat diet. An earlier study also looking at ROCK2 in the context of poor nutrition demonstrated a role for ROCK2 in atherosclerosis. Mice deficient in Low Density Lipoprotein receptor (LDLr- / -) develop atherosclerosis when fed a high cholesterol diet. Bone marrow specific deletion of ROCK2 in these mice led to dramatic reduction in atherosclerotic lesions and reduced inflammatory cytokines in macrophages, suggesting ROCK2 may play a significant role in macrophage derived fatty foam cell formation that is a key pathogenic driver in atherosclerosis [Zhou et al 2012], ROCK2 may also play a role in the often-fatal thrombosis observed in atherosclerosis. LDLr- / - mice with platelet specific knockout of ROCK2 showed a significant reduction in circulating blood clots when fed a high cholesterol diet [Sladojevic et al 2017], Furthertissue specific knockouts of ROCK2 have also shown protection in models of human disease. Deletion of ROCK2 in cardiac specific fibroblasts reduced both cardiac hypertrophy and fibrosis and improved heart function in an angiotensin II infusion model of heart failure [Shimizu et al 2017], Similar protection was also observed in the same model when ROCK2 was specifically deleted in cardiomyocytes [Okamoto et al 2013], Taken together the knockout data shows that ROCK2 is not only involved in fibrosis but also in a number of the deleterious processes that lead to fibrosis and tissue remodelling making ROCK2 a nodal point for disease progression.

[0004] ROCK also plays a significant role in pathologies of the central nervous system (CNS). For example, ROCK-signalling has been demonstrated to be elevated in the serum, spleen, brain and spinal cord of Multiple Sclerosis (MS) patients compared to healthy individuals. Dysregulation of autophagy contributes to the development of misfolded tau aggregates in early Alzheimer's disease (AD). When inhibited, ROCK2, which is expressed in excitatory neurons, can induce autophagy pathways and inhibition of ROCK2 could be a therapeutic approach for AD.

[0005] Furthermore, it is an aim of certain embodiments of this invention to provide new treatments, for example treatments for diabetes, inflammation, Alzheimer’s, hypertension, muscular dystrophies, fibrosis, cancer, pathologies of the central nervous system and other conditions associated with ROCK1 and / or ROCK2. In particular, it is an aim of certain embodiments of this invention to provide compounds which have comparable activity to existing ROCK therapies.

[0006] It is an aim of certain embodiments of this invention to provide compounds which exhibit reduced cytotoxicity or increased solubility relative to prior art compounds and existing therapies.

[0007] 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 aimof 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).

[0008] Certain embodiments of the present invention satisfy some or all of the above aims.BRIEF SUMMARY OF THE DISCLOSURE

[0009] The present invention provides a compound of formula (I) or a pharmaceutically acceptable salt thereof:Z1is independently selected from -CR6R6-CR6R6-, -CR6=CR6-, -N=CR6a- and -CR6a=N-;X1and X2are each independently selected from carbon and nitrogen; wherein at least one of X1and X2is carbon;L1is selected from -O- and -NR7-;R1is independently selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R3is independently selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Co-C3-alkylene-R3a, C2-C4-alkyl substituted with NR8R9, C2-C4-alkyl substituted with SR8and C2-C4-alkyl substituted with OR10; wherein R3ais independently at each occurrence selected from cyclopropyl and azetidinyl, said cyclopropyl and azetidinyl groups being optionally substituted with from 1 to 4 R11groups;R4and R12are each independently at each occurrence selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R5is independently selected from H, CONR8R8, phenyl optionally substituted with a single R13group and / or from 1 to 3 R12groups, and 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups;R6is independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, cyclopropyl; or where two R6groups are attached tothe same carbon atom, the two R6groups and the carbon atom to which they are attached may together form a C3-C6 cycloalkyl ring; or where two R6groups are attached to adjacent carbon atoms, the two R6groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring;R6ais independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R7and R8are each independently at each occurrence selected from H, Ci-C4-alkyl and C1-C4- haloalkyl;R9is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci- C4-alkyl; or R8and R9, together with the nitrogen atom to which they are attached together form a 5- to 8-membered heterocycloalkyl group optionally substituted with from 0 to 4 R11cgroups;R10is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and C1-C4- haloalkyl;R11is independently at each occurrence selected from =O, halo, nitro, cyano, NR8R9, OR14, SR8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R11cis independently selected from =O, halo , nitro, cyano, NR8R9a, OR14, SR8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R9ais independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2- Ci-C4-alkyl;R13is independently selected from Cs-Ce-cycloalkyl, 3- to 6-membered-heterocycloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10; wherein where R13is cycloalkyl or heterocycloalkyl, R13is optionally substituted with from 1 to 4 R11groups;R14is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci- C4-alkyl; and m is an integer selected from 0, 1 , 2, 3 and 4; p is an integer selected from 0, 1 , 2 and 3; 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: oxo, fluoro, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci- C4-alkyl and S(O)2-Ci-C4-alkyl.

[0010] In an embodiment, the present invention provides a compound of formula (la) and pharmaceutically acceptable salts thereof:Z1is independently selected from -CR6R6-CR6R6-, -CR6=CR6-, -N=CR6a- and -CR6a=N-;X1and X2are each independently selected from carbon and nitrogen; wherein at least one of X1and X2is carbon;L1is selected from -O- and -NR7-;R1is independently selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R3is independently selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Co-C3-alkylene-R3a, C2-C4-alkyl substituted with NR8R9, C2-C4-alkyl substituted with SR8and C2-C4-alkyl substituted with OR10; wherein R3ais independently at each occurrence selected from cyclopropyl and azetidinyl, said cyclopropyl and azetidinyl groups being optionally substituted with from 1 to 4 R11groups;R4and R12are each independently at each occurrence selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R5is independently selected from H, CONR8R8, phenyl optionally substituted with a single R13group and / or from 1 to 3 R12groups, and 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups;R6is independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, cyclopropyl; or where two R6groups are attached to the same carbon atom, the two R6groups and the carbon atom to which they are attached may together form a C3-C6 cycloalkyl ring; or where two R6groups are attached to adjacent carbon atoms, the two R6groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring;R6ais independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R7and R8are each independently at each occurrence selected from H, Ci-C4-alkyl and C1-C4- haloalkyl;R9is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci- C4-alkyl; or R8and R9, together with the nitrogen atom to which they are attached together form a 5- to 8-membered heterocycloalkyl group optionally substituted with from 0 to 4 R11groups;R10is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and C1-C4- haloalkyl;R11is independently at each occurrence selected from =O, halo, nitro, cyano, NR8R9, OR14, SR8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R13is independently selected from Cs-Ce-cycloalkyl, 3- to 6-membered-heterocycloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10; wherein where R13is cycloalkyl or heterocycloalkyl, R13is optionally substituted with from 1 to 4 R11groups;R14is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci- C4-alkyl; and m is an integer selected from 0, 1 , 2, 3 and 4; p is an integer selected from 0, 1 , 2 and 3; 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: oxo, fluoro, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; and Rbis independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci- C4-alkyl and S(O)2-Ci-C4-alkyl.

[0011] In an embodiment, the compound of formula (I) or (la) is a compound of formula (II):wherein X1, X2, L1, Z1, R3, R4, R5and m are as described above for compounds of formula (I) or (la), and wherein R2is selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl.

[0012] In an embodiment, the compound of formula (I) or (la) is a compound of formula (III):wherein Z1, R2, R3, R4, R5and m are as described above for compounds of formula (I) or (la) and formula (II).

[0013] In an embodiment, the compound of formula (I) or (la) is a compound of formula (IV):wherein Z1, R2, R3, R4, R5and m are as described above for compounds of formula (I) or (la) and formula (II).

[0014] In an embodiment, the compound of formula (I) or (la) is a compound of formula (V):(la) and formula (II); and wherein R1ais selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SO2NR8R8, SO2R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci- C4-alkyl substituted with OR10, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0015] In an embodiment, the compound of formula (I) or (la) is a compound of formula (VI):wherein X1, X2, R2, R3, R4, R5, R6, R7and m are as described above for compounds of formula (I) or (la) and formula (II) and R1ais selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SC>2NR8R8, SO2R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0016] In an embodiment, the compound of formula (I) or (la) is a compound of formula (V):formula (II); and R1ais selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SC>2NR8R8, SO2R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0017] In an embodiment, the compound of formula (I) or (la) is a compound of formula (VI):wherein R2, R3, R4, R5, R6, R7and m are as described above for compounds of formula (I) or (la) and formula (II); and R1ais selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SC>2NR8R8, SO2R8,CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0018] In an embodiment, the compound of formula (I) or (la) is a compound of formula (VII):wherein R2, R3, R4, R5, R6and m are as described above for compounds of formula (I) or (la).

[0019] In an embodiment, the compound of formula (I) or (la) is a compound of formula (VIII):wherein R2, R3, R4, R5, R6, R7and m are as described above for compounds of formula (I) or (la) and formula (II); and R1ais selected from H, halo, nitro, cyano, NR8R9, OR10, SR8, SC>2NR8R8, SO2R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl.

[0020] In an embodiment, the compound of formula (I) or (la) is a compound of formula (IX):wherein R2, R3, R4, R5, R6and m are as described above for compounds of formula (I) or (la) and formula (II).

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

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

[0023] The following embodiments apply to compounds of any of formulae (l)-(XI) and (la). 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.

[0024] It may be that X1and X2are each carbon. It may be that X1is carbon and X2is nitrogen. It may be that X1is nitrogen and X2is carbon. It may be that X1is CR4aand X2is nitrogen; wherein R4ais independently selected from halo, nitro, cyano, OR10, Ci-C4-alkyl and Ci-C4-haloalkyl and cyclopropyl. It may be that X1is nitrogen and X2is CR4a; wherein R4ais independently selected from halo, nitro, cyano, OR10, Ci-C4-alkyl and Ci-C4-haloalkyl and cyclopropyl.

[0025] L1may be -O-. L1may be -NR7-.

[0026] p may be 0. p may be selected from 0 and 1 . p may be selected from 1 and 2. p may be 1 .

[0027] It may be that R1is independently at each occurrence selected from halo, nitro, cyano, OR10, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl.

[0028] It may be that R1is independently selected from halo, nitro, cyano, OR10, Ci-C4-alkyl and Ci-C4-haloalkyl and cyclopropyl. It may be that R1is independently selected from H, fluoro, C1-C3- alkyl, Ci-Cs-fluoroalkyl and cyclopropyl.

[0029] It may be that R2is independently selected from H, halo, nitro, cyano, OR10, Ci-C4-alkyl, C1- C4-haloalkyl and cyclopropyl. It may be that R2is independently selected from H, fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R2is H. It may be that R2is independently selected from fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R2is independently halo, e.g. fluoro. It may be that R2is independently Ci-Cs-alkyl, e.g. methyl.

[0030] R3may be independently selected from Ci-C4-alkyl and cyclopropyl. R3may be Ci-C4-alkyl, e.g. methyl or ethyl.

[0031] m may be 0. m may be selected from 1 and 2. m may be 1 .

[0032] R4may be independently at each occurrence selected from halo, nitro, cyano, OR10, C1-C4- alkyl, Ci-C4-haloalkyl, CR8R8NR8R9, CR8R8OR8, and cyclopropyl. R4may be independently at each occurrence selected from halo, nitro, cyano, OR10, Ci-C4-alkyl, Ci-C4-haloalkyl, CR8R8NR8R9, CR8R8OR8, and cyclopropyl. It may be that R4is independently at each occurence selected from fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R4is independently at each occurrence selected from fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R4is independently at each occurrence halo, e.g. fluoro. It may be that R4is independently at each occurrence Ci-Cs-alkyl, e.g. methyl.

[0033] It may be that m is 1 and R4is Ci-Cs-alkyl, e.g. methyl. The single R4group may be ortho to the R5group. Alternatively, the single R4group may be meta to the R5group.

[0034] R5may be independently selected from CONR8R8, phenyl optionally substituted with a single R13group and / or from 1 to 3 R12groups, and 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterOocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be H.

[0035] R5may be independently 5- or 6- membered monocyclic heterocyclyl, wherein said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is substituted with a single R13group and / or from 1 to 3 R12groups. R5may be independently 5- or 6- membered monocyclic heterocyclyl, wherein said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ringor partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be independently 5- or 6- membered monocyclic heteroaryl, optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be independently 5- membered monocyclic heteroaryl, optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be independently 6- membered monocyclic heteroaryl, optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be independently 5- membered monocyclic heteroaryl, optionally substituted with a single R13group and / or from 1 to 3 R12groups. The R5group may comprise a nitrogen in the ring system. R5may selected from imidazole and pyridine, optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be imidazole, optionally substituted with a single R13group and / or from 1 to 3 R12groups. R5may be pyridine, optionally substituted with a single R13group and / or from 1 to 3 R12groups.

[0036] R5may be independently selected from 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is substituted with a single R13group and / or from 1 to 3 R12groups. R5is independently selected from 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups.

[0037] R5may be independently selected from 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with from 1 to 4 R11groups and wherein any unsaturated ring is substituted with from 1 to 3 R12groups. R5may be independently selected from 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with from 1 to 3 R12groups.

[0038] R5may be independently 5- or 6- membered monocyclic heterocyclyl, wherein said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with from 1 to 4 R11groups and wherein any unsaturated ring is substituted with from 1 to 3 R12groups. R5may be independently 5- or 6- membered monocyclic heterocyclyl, wherein said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with from 1 to 3 R12groups. R5may be independently 5- or 6- membered monocyclic heteroaryl, optionally substituted with from 1 to 3 R12groups. R5may be independently 5- membered monocyclic heteroaryl,optionally substituted with from 1 to 3 R12groups. R5may be independently 6- membered monocyclic heteroaryl, optionally substituted with from 1 to 3 R12groups. R5may be independently 5- membered monocyclic heteroaryl, optionally substituted with from 1 to 3 R12groups. The R5group may comprise a nitrogen in the ring system. R5may selected from imidazole and pyridine, optionally substituted with from 1 to 3 R12groups. R5may be imidazole, optionally substituted with from 1 to 3 R12groups. R5may be pyridine, optionally substituted with from 1 to 3 R12groups.

[0039] R5may be unsubstituted phenyl. R5may be phenyl substituted with a single R13group and / or from 1 to 3 R12groups. R5may be phenyl substituted with R13group. R5may be phenyl substituted with cyclopropyl.

[0040] R5may have the structure:wherein x1 is an integer independently selected from 0, 1 and 2. x1 may be 0.

[0041] R5may have the structure:wherein x2 is an integer independently selected from 0 and 1 ; and R12ais independently selected from: H and Ci-C4-alkyl. x2 may be 0. R12amay be Ci-C4-alkyl, e.g. methyl.

[0042] R5may have the structure:wherein R12bis independently selected from halo, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl; and x1 is an integer independently selected from 0, 1 and 2. x1 may be 0. R12bmay be selected from Ci-C4-cycloalkyl and cyclopropyl.

[0043] R5may have the structure:are each independently selected from H, halo, C1-C4- alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, CR8R8NR8R9, CR8R8OR8and cyclopropyl; and R12ais independently selected from: H, Ci-C4-alkyl and cyclopropyl. R12amay be Ci-C4-alkyl, e.g.methyl. R12dmay be H. R12dmay be selected from Ci-C4-cycloalkyl and cyclopropyl. R12cmay be H. R12cmay be selected from Ci-C4-cycloalkyl and cyclopropyl.

[0044] R5may have the structure:wherein R12bis independently selected from halo, Ci-C4-alkyl, C2-C4-alkenyl,C2-C4-alkynyl, Ci-C4-haloalkyl, CR8R8NR8R9, CR8R8OR8and cyclopropyl; and wherein R12fand R12eare each independently selected from H, halo, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, C1-C4- haloalkyl and cyclopropyl. R12fmay be H. R12emay be H. R12emay be selected from Ci-C4-cycloalkyl and cyclopropyl. R12bmay be selected from Ci-C4-cycloalkyl and cyclopropyl. 5 may have the structure:12gwherein R129is independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl. R129may be Ci-C4-haloalkyl e.g. trifluoroethyl. 5 may have the structure:2gwherein R129is independently selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl. R129may be Ci-C4-haloalkyl e.g. trifluoroethyl.

[0047] R5may have the structure:wherein y is an integer independently selected from 0 and 1 ; and x3 is an integer independently selected from 0, 1 , 2 and 3. x3 may be 0. x3 may be 1 . y may be 0. y may be1.

[0048] R5may have the structure:wherein y is an integer independently selected from 0 and 1 ; and x3 is an integer independently selected from 0, 1 , 2 and 3. x3 may be 0. x3 may be 1 . y may be 0. y may be 1 .

[0049] R5may have the structure:wherein y is an integer independently selected from 0 and 1 ; and x3 is an integer independently selected from 0, 1 , 2 and 3. x3 may be 0. x3 may be 1 . y may be 0. y may be 1 .

[0050] R5may have the structure:wherein x4 is an integer independently selected from 0, 1 and 2. x4 may be 0. x4 may be 1 .

[0051] R5may have the structure:wherein x4 is an integer independently selected from 0, 1 and 2. x4 may be 0. x4 may be 1 . may have the structure:

[0053] R5may have the structure:

[0054] R5may have the structure:, wherein R11ais selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl. R11amay be Ci-C4-alkyl, e.g. methyl. R11amay be Ci-C4-haloalkyl.

[0055] R5may have the structure:, wherein R11bis selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl. R11bmay be Ci-C4-haloalkyl, e.g. trifluoroethyl or trifluoropropyl.

[0056] R5may have the structure:wherein y is an integer independently selected from 0 and 1 ; and x3 is an integer independently selected from 0, 1 , 2 and 3. x3 may be 0. x3 may be 1. y may be 0. y may be 1. R13may be cyclopropyl.

[0057] R5may have the structure:wherein R12his selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and cyclopropyl. R12hmay be cyclopropyl.

[0058] R12may be independently at each occurrence selected from halo, nitro, cyano, OR10, Ci- C4-alkyl and Ci-C4-haloalkyl and cyclopropyl. It may be that R12is independently at each occurence selected from fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R12is independently at each occurrence selected from fluoro, Ci-Cs-alkyl, Ci-Cs-fluoroalkyl and cyclopropyl. It may be that R12is independently at each occurrence selected from Ci-Cs-alkyl, e.g. methyl, and cyclopropyl. It may be that R12is independently at each occurrence halo, e.g. fluoro. It may be that R12is independently at each occurrence Ci-Cs-alkyl, e.g. methyl.

[0059] R5may comprise an R13group. R13may be Cs-Ce-cycloalkyl. R13may be CR8R8NR8R9. R13may be CR8R8OR8. R13may be 3- to 6-membered-heterocycloalkyl. R13may be C3-C4-cycloalkyl. R13may be 4-membered-heterocycloalkyl. R13may be selected from oxetane, azetidine, cyclopropyl and cyclobutyl. R13may be cyclopropyl. R5may comprise a cyclopropyl.

[0060] Illustrative R5groups include:

[0061] Further illustrative R5groups include:

[0062] Further illustrative R5groups include:

[0063] Further illustrative R5groups include:

[0064] It may be that no more than two R6groups are a group other than H. It may be that the two R6groups and the carbon atom to which they are attached together form a C3-C6 cycloalkyl ring. Itmay be that the two R6groups and the carbon atom to which they are attached together form a cyclopropyl ring.

[0065] R6may be independently at each occurrence selected from H, fluoro, Ci-C4-alkyl and cyclopropyl. R6may be independently at each occurrence selected from H and Ci-C4-alkyl. R6may at each occurence be H. R6may at each occurrence be Ci-C4-alkyl, e.g. Me. It may be that a single R6group is H and a single R6group is Ci-C4-alkyl, e.g. Me.

[0066] R7may be H. R7may be Ci-C4-alkyl, e.g. methyl.

[0067] Z1may be -CR6R6-CR6R6-. Z1may be -CaH2-CR6R6- wherein Cais the carbon atom attached to the NH group in the ring comprising Z1. R6may be independently at each occurrence selected from H, fluoro, Ci-C4-alkyl and cyclopropyl. R6may be independently at each occurrence selected from H, fluoro and Ci-C4-alkyl. Z1may be -CH2-CH2-. Z1may be -CaH2-CMe2-. Z1may be -CaH2-CF2-. Z1may be -CaH2-CMe-.

[0068] Z1may be -CR6=CR6-. Z1may be -CaH=CR6- wherein Cais the carbon atom attached to the NH group in the ring comprising Z1. R6may be independently at each occurrence selected from H, fluoro, Ci-C4-alkyl and cyclopropyl. R6may be independently at each occurrence selected from H, fluoro and Ci-C4-alkyl. Z1may be -CaH=CF-.

[0069] Z1may be independently selected from -CR6a=N- and -N=CR6a-. Z1may be -CR6a=N-. Z1may be -N=CR6a-.

[0070] R6ais independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl. R6amay be selected from H and Ci-C4-alkyl e.g., methyl. R6amay be H.

[0071] Z1may be -CbH=CR6a- wherein Cbis the carbon atom attached to the NH group in the ring comprising Z1. R6amay be independently at each occurrence selected from H, Ci-C4-alkyl and cyclopropyl. R6amay be independently at each occurrence selected from H and Ci-C4-alkyl. Z1may be -CbH=N-.

[0072] Z1may be -Na=CR6a- wherein Nais the nitrogen atom attached to the NH group in the ring comprising Z1. R6amay be independently at each occurrence selected from H, Ci-C4-alkyl and cyclopropyl. R6amay be independently at each occurrence selected from H and Ci-C4-alkyl. Z1may be -CH=Na-.

[0073] The compound of formula (I) may be selected from:

[0074] The invention may be defined according to any one of the following clauses:1 . A compound of formula (la) and pharmaceutically acceptable salts thereof:X1and X2are each independently selected from carbon and nitrogen; wherein at least one of X1and X2is carbon;L1is selected from -O- and -NR7-;R1is independently selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R3is independently selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Co-C3-alkylene-R3a, C2-C4-alkyl substituted with NR8R9, C2-C4-alkyl substituted with SR8and C2-C4-alkyl substituted with OR10; wherein R3ais independently at each occurrence selected from cyclopropyl and azetidinyl, said cyclopropyl and azetidinyl groups being optionally substituted with from 1 to 4 R11groups;R4and R12are each independently at each occurrence selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R5is independently selected from H, CONR8R8, phenyl optionally substituted with a single R13group and / or from 1 to 3 R12groups, and 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups;R6is independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, cyclopropyl; or where two R6groups are attached to the same carbon atom, the two R6groups and the carbon atom to which they are attached may together form a C3-C6 cycloalkyl ring; or where two R6groups are attached to adjacent carbon atoms, the two R6groups and the carbon atoms to which they are attached may together form a C3-C6 cycloalkyl ring;R6ais independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R7and R8are each independently at each occurrence selected from H, Ci-C4-alkyl and Ci-C4-haloalkyl;R9is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2-Ci- C4-alkyl; or R8and R9, together with the nitrogen atom to which they are attached together form a 5- to 8-membered heterocycloalkyl group optionally substituted with from 0 to 4 R11groups;R10is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and C1-C4- haloalkyl;R11is independently at each occurrence selected from =O, halo, nitro, cyano, NR8R9, OR14, SR8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R13is independently selected from Cs-Ce-cycloalkyl, 3- to 6-membered-heterocycloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10; wherein where R13is cycloalkyl or heterocycloalkyl, R13is optionally substituted with from 1 to 4 R11groups;R14is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci- C4-alkyl; and m is an integer selected from 0, 1 , 2, 3 and 4; p is an integer selected from 0, 1 , 2 and 3; 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: oxo, fluoro, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; 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 p is selected from 0 and 1 .3. A compound of claim 1 or claim 2, wherein L1is -NR7-.4. A compound of claim 3, wherein R7is H.5. A compound of any one of claims 1 to 4, wherein R3is independently selected from C1-C4- alkyl and cyclopropyl.6. A compound of any one of claims 1 to 5, wherein m is 1 .7. A compound of claim 6, wherein R4is selected from Ci-Cs-alkyl and cyclopropyl.8. A compound of any one of claims 1 to 7, wherein R5is imidazole, optionally substituted with a single R13group and / or from 1 to 3 R12groups.9. A compound of any one of claims 1 to 7, wherein R5is pyridine, optionally substituted with a single R13group and / or from 1 to 3 R12groups.10. A compound of claim 9, wherein R5has the structure:wherein x4 is an integer independently selected from 0, 1 and 2.11. A compound of claim 9, wherein R5has the structurewherein x4 is an integer independently selected from 0, 1 and 2.12. A compound of any one of claims 1 to 11 , wherein Z1is -CR6R6-CR6R6-.13. A compound of any one of claims 1 to 11 , wherein Z1-CR6=CR6-.14. A compound of any one of claims 1 to 13, wherein R6is independently at each occurrence selected from H and Ci-C4-alkyl.15. A compound of any one of claims 1 to 13, wherein two R6groups are attached to the same carbon atom and the two R6groups and the carbon atom to which they are attached together form a C3-C6 cycloalkyl ring.16. A compound of any one of claims 1 to 13, wherein two R6groups are attached to adjacent carbon atoms and the two R6groups and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl ring.17. A compound of any one of claims 1 to 16, wherein X1and X2are each carbon.18. A pharmaceutical formulation comprising a compound of any one of claims 1 to 17 and a pharmaceutically acceptable excipient.19. A compound of any one of claims 1 to 17 for use as a medicament.20. A compound of any one of claims 1 to 17 for use in treating a a disease or disorder selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0075] In an embodiment there is provided compounds of the present invention having a ROCK2 binding affinity within category +++ or ++++ as defined elsewhere herein. In an embodiment there is provided compounds of the present invention having a ROCK2 binding affinity IC50 value of < 3 pM. In an embodiment there is provided compounds of the present invention having a ROCK2 binding affinity IC50 value of < 0.3 pM. Optionally, the binding activity is determined using the assay for ROCK2 inhibition defined in the examples.

[0076] In an aspect of the invention there is provided the compounds of the present invention, or a pharmaceutically acceptable salt thereof, for use as a medicament.

[0077] In accordance with another aspect, the present invention provides a pharmaceutical formulation comprising a compound of the present invention, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

[0078] In an embodiment, the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be, for example anti-inflammatory agents, anti-fibrotic agents, chemotherapeutics, anti-cancer agents, immunosuppressants, anti-tumour vaccines, cytokine therapy, or tyrosine kinase inhibitors.

[0079] In accordance with another aspect, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a condition which is modulated by ROCK1 and / or ROCK2. Usually conditions that are modulated by ROCKs (please note that ROCKs refer to either or both of ROCK1 and ROCK2) are conditions that would be treated by the inhibition of ROCKs using a compound of the present invention. A compound of any formula disclosed herein may be for use in the treatment of a condition treatable by the inhibition of ROCKs. As discussed above, ROCK signalling is instrumental in a number of conditions.

[0080] In another aspect of the invention, there is provided a compound of the present invention, or a pharmaceutically acceptable salt thereof, for use in the treatment of a disease or disorder selected from: fibrotic diseases, auto-immune, muscular dystrophy, inflammatory conditions, central nervous system disorders, or cancer.

[0081] In an aspect of the invention there is provided a method of treating a disease or disorder which is modulated by ROCK1 and / or ROCK2 wherein the method comprises administering a therapeutic amount of a compound of the invention, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0082] The method of treatment may be a method of treating a condition treatable by the inhibition of ROCK1 and / or ROCK2.

[0083] The invention also provides a method of treating a disease or disorder selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer, wherein the method comprises administering a therapeutic amount of a compound of any formula disclosed herein, or a pharmaceutically acceptable salt thereof, to a patient in need thereof.

[0084] The disease or disorder may be selected from: Sarcoidosis, sclerosis, primary biliary sclerosis, sclerosing cholangitis, dermatitis, atopic dermatitis, Still's disease, chronic obstructive pulmonary disease, Guillain-Barre disease, Graves' disease, Addison's disease, Raynaud's phenomenon, or autoimmune hepatitis. Arthritis, rheumatoid arthritis, psoriatic arthritis, osteoarthritis, degenerative arthritis, polymyalgia rheumatic, ankylosing spondylitis, reactive arthritis, gout, pseudogout, inflammatory joint disease, systemic lupus erythematosus, polymyositis, and fibromyalgia. Additional types of arthritis include Achilles tendinitis, achondroplasia, acromegalic arthropathy, adhesive capsulitis, adult onset Still's disease, anserine bursitis, avascular necrosis, Behcet's syndrome, bicipital tendinitis, Blount's disease, brucellar spondylitis, bursitis, calcaneal bursitis, calcium pyrophosphate dihydrate deposition disease (CPPD), crystal deposition disease, Caplan's syndrome, carpal tunnel syndrome, chondrocalcinosis, chondromalacia patellae, chronic synovitis, chronic recurrent multifocal osteomyelitis, Churg-Strauss syndrome, Cogan's syndrome,corticosteroid-induced osteoporosis, costosternal syndrome, CREST syndrome, cryoglobulinemia, degenerative joint disease, dermatomyositis, diabetic finger sclerosis, diffuse idiopathic skeletal hyperostosis (DISH), discitis, discoid lupus erythematosus, drug-induced lupus, Duchenne's muscular dystrophy, Dupuytren's contracture, Ehlers-Danlos syndrome, enteropathic arthritis, epicondylitis, erosive inflammatory osteoarthritis, exercise-induced compartment syndrome, Fabry's disease, familial Mediterranean fever, Farber's lipogranulomatosis, Felty's syndrome, Fifth's disease, flat feet, foreign body synovitis, Freiberg's disease, fungal arthritis, Gaucher' s disease, giant cell arteritis, gonococcal arthritis, Goodpasture's syndrome, granulomatous arteritis, hemarthrosis, hemochromatosis, Henoch-Schonlein purpura, Hepatitis B surface antigen disease, hip dysplasia, Hurler syndrome, hypermobility syndrome, hypersensitivity vasculitis, hypertrophic osteoarthropathy, immune complex disease, impingement syndrome, Jaccoud's arthropathy, juvenile ankylosing spondylitis, juvenile dermatomyositis, juvenile rheumatoid arthritis, Kawasaki disease, Kienbock's disease, Legg-Calve-Perthes disease, Lesch-Nyhan syndrome, linear scleroderma, lipoid dermatoarthritis, Lofgren's syndrome, Lyme disease, malignant synovioma, Marfan's syndrome, medial plica syndrome, metastatic carcinomatous arthritis, mixed connective tissue disease (MCTD), mixed cryoglobulinemia, mucopolysaccharidosis, multicentric reticulohistiocytosis, multiple epiphyseal dysplasia, mycoplasmal arthritis, myofascial pain syndrome, neonatal lupus, neuropathic arthropathy, nodular panniculitis, ochronosis, olecranon bursitis, Osgood-Schlatter's disease, osteoarthritis, osteochondromatosis, osteogenesis imperfecta, osteomalacia, osteomyelitis, osteonecrosis, osteoporosis, overlap syndrome, pachydermoperiostosis Paget's disease of bone, palindromic rheumatism, patellofemoral pain syndrome, Pellegrini-Stieda syndrome, pigmented villonodular synovitis, piriformis syndrome, plantar fasciitis, polyarteritis nodos, Polymyalgia rheumatic, polymyositis, popliteal cysts, posterior tibial tendinitis, Pott's disease, prepatellar bursitis, prosthetic joint infection, pseudoxanthoma elasticum, psoriatic arthritis, Raynaud's phenomenon, reactive arthritis / Reiter's syndrome, reflex sympathetic dystrophy syndrome, relapsing polychondritis, retrocalcaneal bursitis, rheumatic fever, rheumatoid vasculitis, rotator cuff tendinitis, sacroiliitis, salmonella osteomyelitis, sarcoidosis, saturnine gout, Scheuermann's osteochondritis, scleroderma, septic arthritis, seronegative arthritis, shigella arthritis, shoulder-hand syndrome, sickle cell arthropathy, Sjogren's syndrome, slipped capital femoral epiphysis, spinal stenosis, spondylolysis, staphylococcus arthritis, Stickler syndrome, subacute cutaneous lupus, Sweet's syndrome, Sydenham's chorea, syphilitic arthritis, systemic lupus erythematosus (SLE), Takayasu's arteritis, tarsal tunnel syndrome, tennis elbow, Tietse's syndrome, transient osteoporosis, traumatic arthritis, trochanteric bursitis, tuberculosis arthritis, arthritis of Ulcerative colitis, undifferentiated connective tissue syndrome (UCTS), urticarial vasculitis, viral arthritis, Wegener's granulomatosis, Whipple's disease, Wilson's disease, yersinial arthritis and conditions involving vascularization and / or inflammation, include atherosclerosis, rheumatoid arthritis (RA), hemangiomas, angiofibromas, and psoriasis. Other non-limiting examples of angiogenic disease are retinopathy of prematurity (retrolental fibroplastic), corneal graft rejection, corneal neovascularization related to complications of refractive surgery, corneal neovascularization related to contact lens complications, corneal neovascularization related to pterygium and recurrent pterygium , corneal ulcer disease, and nonspecific ocular surface disease, insulin-dependent diabetes mellitus, multiple sclerosis, myastheniagravis, Chrorfs disease, autoimmune nephritis, primary biliary cirrhosis, acute pancreatitis, allograph rejection, allergic inflammation, contact dermatitis and delayed hypersensitivity reactions, inflammatory bowel disease, septic shock, osteoporosis, osteoarthritis, cognition defects induced by neuronal inflammation, Osier- Weber syndrome, restinosis, and fungal, parasitic and viral infections, including cytomegalo viral infections.

[0085] Any of the conditions disclosed above as being treatable by ROCK1 and / or ROCK2 inhibition may be treated by a compound of the invention, or may be treated in a method comprising administering a compound of the invention, or may be treated by a medicament manufactured through the use of a compound of the present invention.

[0086] In embodiments, the disease or disorder may be selected from: Idiopathic Pulmonary Fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; Nonalcoholic Steatohepatitis (NASH); Nonalcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney, glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren’s syndrome, asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE, cGVHD, inflammatory bowel disease, stenosis of the bowel, disorders involving neuronal degeneration or physical injury to neural tissue, Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), multiple sclerosis, liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma, wherein the method comprises administering a therapeutic amount of a compound of any formula disclosed herein, to a patient in need thereof.

[0087] In certain embodiments, the disease or disorder is selected from: Idiopathic Pulmonary Fibrosis (IPF); systemic sclerosis (SSC); interstitial lung disease (ILD); type 1 and type 2 diabetes; diabetic nephropathy; Nonalcoholic Steatohepatitis (NASH); Nonalcoholic fatty liver disease (NAFLD); hypertension, atherosclerosis, restenosis, stroke, heart failure, coronary vasospasm, cerebral vasospasm, peripheral circulatory disorder, peripheral artery occlusive disease, ischemia / reperfusion injury, pulmonary hypertension and angina, and erectile dysfunction, fibroid lung, fibroid liver and fibroid kidney.

[0088] In certain embodiments the disease or disorder is selected from: glaucoma, ocular hypertension, retinopathy, rheumatoid arthritis, psoriasis, psoriatic arthritis, Sjogren’s syndrome,asthma, adult respiratory distress syndrome, chronic obstructive pulmonary disease (COPD), SLE and cGVHD, inflammatory bowel disease and stenosis of the bowel.

[0089] In certain embodiments, compounds of the invention are for use in the treatment of or are used in a method of treatment of central nervous system disorders. Such disorders may involve neuronal degeneration or physical injury to neural tissue, including without limitation, Huntington's disease, Parkinson's Disease, Alzheimer's, Amyotrophic lateral sclerosis (ALS), or multiple sclerosis.

[0090] In certain embodiments compounds of the invention, or pharmaceutically acceptable salts thereof, are for use in the treatment of or are used in a method of treatment of cancer. Examples include but are not limited to: liver cancer, bladder cancer, hepatoma, squamous carcinoma of the lung, non-small cell lung cancer, adenocarcinoma of the lung, small-cell lung cancer, , various types of head and neck cancer, breast cancer, colon cancer, colorectal cancer, cancer of the peritoneum, hepatocellular cancer, gastrointestinal cancer, esophageal cancer, endometrial or uterine carcinoma, salivary gland carcinoma, squamous cell cancer, pituitary cancer, astrocytoma, soft tissue sarcoma, pancreatic cancer, glioblastoma, cervical cancer, ovarian cancer, kidney cancer, liver cancer, prostate cancer, vulval cancer, thyroid cancer, hepatic carcinoma, brain cancer, endometrial cancer, testis cancer, cholangiocarcinoma, gallbladder carcinoma, gastric cancer and melanoma.

[0091] In another aspect of the invention there is provided a pharmaceutical composition, wherein the composition comprises a compound of the invention, or a pharmaceutically acceptable salt thereof, and pharmaceutically acceptable excipients.

[0092] In an embodiment the pharmaceutical composition may be a combination product comprising an additional pharmaceutically active agent. The additional pharmaceutically active agent may be one disclosed elsewhere herein.

[0093] In an aspect of the present invention there is provided the use of a compound of the invention, or a pharmaceutically acceptable salt thereof, in the manufacture of a medicament for use in the treatment of any condition disclosed herein.DETAILED DESCRIPTION

[0094] Given below are definitions of terms used in this application. Any term not defined herein takes the normal meaning as the skilled person would understand the term.

[0095] 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 chlorine or fluorine.

[0096] The term “alkyl” refers to a linear or branched hydrocarbon chain. For example, the term “Ci- 6 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, / so-propyl, n-butyl, sec-butyl, te / Y-butyl, n-pentyl and n-hexyl. Alkyl groups may be unsubstituted or may be substituted by one or more substituents. “Alkylene” groups may likewise be linear or branched and is divalent, i.e. it attached at two positions to other portions of the molecule. For example, Ci-Cs-alkylene may refer to methylene, ethylene or propylene. Alkylene groups may be unsubstituted or may be substituted by one or more substituents. For theabsence of doubt, the term “Co-alkylene” refers to a group in which an alkylene chain is absent. For example, “Co-alkylene-R3a” refers to an R3a. Furthermore, an alkylene group may, for example, correspond to one of those alkyl groups listed in this paragraph.

[0097] 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. The term “fluoroalkyl” refers to a hydrocarbon chain substituted with at least one fluorine atom..

[0098] 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.

[0099] 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 carbon atoms. 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.

[0100] 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, C1-6 N, / V-alkyl, or C1-6 O-alkyl.

[0101] The term “heterocycle” refers to a saturated, unsaturated or aromatic ring system containing at least one heteroatom selected from N, O or S. A “heterocyclic” system may contain 1 , 2, 3 or 4 heteroatoms, for example 1 or 2. A “heterocyclic” system may be monocyclic or a fused polycyclic ring system, for example, bicyclic or tricyclic. A “heterocyclic” moiety may contain from 3 to 14 carbon atoms, for example, 3 to 8 carbon atoms in a monocyclic system and 7 to 14 carbon atoms in apolycyclic system. “Heterocyclic” encompasses heterocycloalkyl moieties, heterocycloalkenyl moieties and heteroaryl moieties. For example, the heterocyclic group may be: oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran. Heteroaryl includes groups such as pyridones and N-alkyl-pyridones.

[0102] The term “C3-8 cycloalkyl” refers to a saturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms. For example, the “C3-8 cycloalkyl” may be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl and cyclooctyl.

[0103] The term “C3-8 cycloalkenyl” refers to an unsaturated hydrocarbon ring system containing 3, 4, 5, 6, 7 or 8 carbon atoms 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, cyclohexadienly, cycloheptenyl, cycloheptadiene, cyclooctenyl and cycloatadienyl.

[0104] 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. The “heterocycloalkyl” may have one or more, e.g. one or two, bonds to the rest of the molecule: these bonds may be through any of the atoms in the ring. 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 atoms at least one of the atoms being a heteroatom within the ring selected from N, O and S. The “heterocycloalkyl” may be oxirane, aziridine, azetidine, oxetane, tetrahydrofuran, pyrrolidine, imidazolidine, succinimide, pyrazolidine, oxazolidine, isoxazolidine, thiazolidine, isothiazolidine, piperidine, morpholine, thiomorpholine, piperazine, and tetrahydropyran.

[0105] The term “aromatic” when applied to a substituent as a whole means a single ring or polycyclic ring system with 4n + 2 electrons in a conjugated IT system within the ring or ring system where all atoms contributing to the conjugated IT system are in the same plane.

[0106] The term “aryl” refers to an aromatic hydrocarbon ring system. The ring system has 4n +2 electrons in a conjugated IT system within a ring where all atoms contributing to the conjugated IT system are in the same plane. For example, the “aryl” may be phenyl and naphthyl. The aryl system itself may be substituted with other groups.

[0107] The term “heteroaryl” refers to an aromatic hydrocarbon ring system with at least one heteroatom within a single ring or within a fused ring system, selected from O, N and S. The ring or ring system has 4n +2 electrons in a conjugated IT system where all atoms contributing to the conjugated IT system are in the same plane. For example, the “heteroaryl” may be imidazole, oxazole,isoxazole, thiazole, isothiazole, thiene, furan, thianthrene, pyrrole, benzimidazole, pyrazole, pyrazine, pyridine, pyrimidine and indole.

[0108] A bond terminating in a “ -rJ~r” 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.

[0109] A bond drawn as a solid line and a dotted line represents a bond which can be either a single bond or a double bond, where chemically possible. For example, the bond drawn below could be a single bond or a double bond.

[0110] 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.

[0111] 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.

[0112] 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 “ ■rJ~r”.

[0113] “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.

[0114] “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.

[0115] Throughout the description the disclosure of a compound also encompasses pharmaceutically acceptable salts, solvates and stereoisomers thereof. Where a compound has a stereocentre, both ( / ?) 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 ( / ?) and (S) stereoisomers is contemplated. The combination of ( / ?) 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.

[0116] 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.

[0117] 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.

[0118] 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 reviewon suitable salts, see "Handbook of Pharmaceutical Salts: Properties, Selection, and Use" by Stahl and Wermuth (Wiley-VCH, Weinheim, Germany, 2002).

[0119] 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.

[0120] 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.

[0121] 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.

[0122] Included within the scope of the invention are complexes such as clathrates, drug-host inclusion complexes wherein, in contrast to the aforementioned solvates, the drug and host are present in stoichiometric or non-stoichiometric amounts. Also included are complexes of the drug containing two or more organic and / or inorganic components which may be in stoichiometric or non- stoichiometric amounts. The resulting complexes may be ionised, partially ionised, or non- ionised. For a review of such complexes, see J Pharm Sci, 64 (8), 1269-1288 by Haleblian (August 1975).

[0123] Hereinafter all references to compounds of any formula include references to salts, solvates and complexes thereof and to solvates and complexes of salts thereof.

[0124] The compounds of the invention include compounds of a number of formula 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.

[0125] 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.

[0126] 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 as15O,17O and18O, phosphorus, such as32P, and sulphur, such as35S.

[0127] 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.

[0128] 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.

[0129] 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.

[0130] 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.

[0131] 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.

[0132] 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 ROCK, for example fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

[0133] The method of treatment or the compound for use in the treatment of fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer as defined hereinbefore may be applied as a sole therapy or be a combination therapy with an additional active agent.

[0134] The method of treatment or the compound for use in the treatment of fibrotic diseases, autoimmune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders diseases may 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-1 a (Avonex, Rebif), peginterferon beta-1 a (Plegridy), teriflunomide (Aubagio), fingolimod (Gilenya), mitoxantrone (Novantrone), dimethyl fumarate (Tecfidera), natalizumab (Tysabri)

[0135] 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 5a- 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- / V-(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 (Nipent™);(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, fluocinoloneacetonide, 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.

[0136] 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.

[0137] 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.

[0138] 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).

[0139] 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.

[0140] 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, morepreferably 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.

[0141] 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.

[0142] 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.

[0143] 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.

[0144] For intravenous (parenteral) administration the compounds of the invention may be administered as a sterile aqueous or oily solution.

[0145] 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.

[0146] 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.

[0147] Throughout the description, clauses 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 thedescription 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.

[0148] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.

[0149] 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.

[0150] The compounds of the invention may be prepared according to or analogously to the General Schemes 1 and 2 and Examples 1 to 132.EXAMPLES AND SYNTHESISAs used herein the following terms have the meanings given: “Ac” refers to acetyl; “ADP” refers to adenosine diphosphate; “ATP” refers to adenosine triphosphate; “Boc” refers to te / Y-butoxycarbonyl; “dba” refers to dibenzylideneacetone; “d” refers to doublet; “DCE” refers to 1 ,2-dichloroethane; “DCM” refers to dichloromethane; “DIPEA” refers to / V, / V-Diisopropylethylamine; “DMAP” refers to 4- (dimethylamino)pyridine; “DMF” refers to / V, / V-dimethylformamide; “DMSO” refers to dimethylsulfoxide; “dppf refers to 1 ,T-b / s(diphenylphosphino)ferrocene; “DTT” refers to dithiothreitol; “EDC” refers to / V-(3-dimethylaminopropyl)- / V-ethylcarbodiimide; “EDTA” refers to ethylenediamine tetra-acetic acid; “ES-API” refers to atmospheric pressure ionization electrospray; “ESI” refers to electrospray ionization; “Et” refers to ethyl; “EtOAc” refers to ethyl acetate; “HATU” refers to 1- [b / s(dimethylamino)methylene]-1 / 7-1 ,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate; “HEPES” refers to (4-(2-hydroxyethyl)-1 -piperazineethanesulfonic acid); “HOBt” refers to 1- hydroxybenzotriazole hydrate; “HPLC” refers to high performance liquid chromatography; “IPA” refers to 2-propanol; “ ’ refers to coupling constant; “LCMS” or “LC-MS” refers to liquid chromatography / mass spectrometry; LiHMDS” refers to lithium b / s(trimethylsilyl)amide; “m” refers to multiplet; “Me” refers to methyl; “MIM” refers to monoisotopic mass; “min” refers to min; “MS” refers to mass spectrometry; “NMR” refers to nuclear magnetic resonance; “Pet. Ether” refers to Pet. Ether; “PG” refers to protecting group; “PTSA” refers to p-toluenesulfonic acid monohydrate; “q” refers to quartet; “quint” refers to quintet; “Rf” refers to Retention factor; “RT” refers to retention time,; “r.t.” refers to room temperature; “s” refers to singlet; “SCX” refers to strong cation exchange; “SEM” refersto 2-(trimethylsilyl)ethoxymethyl; “t” refers to triplet; “TBME” refers to te / Y-butyl methyl ether; “TEA” refers to triethylamine; “TFA” refers to trifluoroacetic acid; “TFE” refers to trifluoroethanol; “THF” refers to tetrahydrofuran; “THP” refers to tetrahydropyran; “TLC” refers to thin layer chromatography; “TMS” refers to tetramethylsilane; “UPLC” refers to ultra-performance liquid chromatography; “UV” refers to ultraviolet; “XantPhos” refers to 4,5-bis(diphenylphosphino)-9,9-dimethylxanthene; and “XPhos” refers to 2-dicyclohexylphosphino-2',4',6'-triisopropylbiphenyl.Solvents, reagents and starting materials were purchased from commercial vendors and used as received unless otherwise described. All reactions were performed at r.t. 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 2 pL aliquot was injected onto a guard column (0.2 pm x 2 mm filters) and UPLC 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 the below. Retention times RT are reported in min.Compound identity confirmations were also performed by LCMS UV using the following:Method C: LC: Agilent Technologies 1290 series ; Binary Pump ; Diode Array DetectorColumn: Agilent Eclipse Plus RRHD C18, 1.8pm, 3.0x50 mm ; Column Temperature: 40°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 3.0 min ; Flow Rate: 1.0mL / min ; Gradient:MS: G6120A, Quadrupole LC / MS ; Ion Source: ESI ; Signal: positive ; TIC: 70~1000 m / z; Fragmentor: 60 ; Threshold: 5 ; Gain: 1 ; Drying gas flow: 10 L / min ; Nebulizer pressure: 35 psiMethod D: LC: Agilent Technologies 1290 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Eclipse Plus RRHD C18, 1.8pm, 3.0x50 mm ; Column Temperature: 40°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 3.0 min ; Flow Rate: 1.0 mL / min ; Gradient:MS: G6120A, Quadrupole LC / MS ; Ion Source: ESI ; Signal: positive ; TIC: 70~1000 m / z Fragmentor: 60 ; Threshold: 5 ; Gain: 1 ; Drying gas flow: 10 L / min ; Nebulizer pressure: 35 psiMethod E: LC: Agilent Technologies 1290 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Eclipse Plus RRHD C18, 1.8pm, 3.0x50 mm ; Column Temperature: 40°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 3.0 min ; Flow Rate: 1 .OmL / min ; Gradient:MS: G6120A, Quadrupole LC / MS ; Ion Source: ESI ; Signal: positive ; TIC: 70~1000 m / z; Fragmentor: 60 ; Threshold: 5 ; Gain: 1 ; Drying gas flow: 10 L / min ; Nebulizer pressure: 35 psiMethod F: LC: Shimadzu 2020 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm ; Column Temperature: 35°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN(v / v) ; Run time: 5.0 min ; Flow rate: 1.0 mL / min ; Gradient:MS: Ion Source: ESI ; Signal: positive and negative ; TIC: 100~900 m / z ; Fragmentor: 60; Threshold: 5 ; Gain: 1 ; Drying gas: 20 L / min ; Nebulizing Gas: 1.5 L / minMethod G: LC: Shimadzu 2020 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm ; Column Temperature: 35°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN(v / v); Run time: 5.0 min; Flow rate: 1.0 mL / min ; Gradient:MS: Ion Source: ESI ; Signal: positive and negative ; TIC: 100~900 m / z ; Fragmentor: 60Threshold: 5 ; Gain: 1 ; Drying gas: 20 L / min ; Nebulizing Gas: 1.5 L / minMethod H: LC: Shimadzu LC-20XR series ; Binary Pump ; Diode Array Detector ; Column: Waters ACQUITY UPLC HSS C18, 1.8 pm, 3.0x50 mm ; Column Temperature: 25°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN (v / v); Run time: 3.0 min ; Flow Rate: 0.5 mL / min ; Gradient:MS: 2020, Quadrupole LC / MS, Ion Source: API-ESI ; TIC: 100~900 m / z ; Drying gas flow: 15 L / min ; Nebulizer pressure: 1 ,5L / min ; Drying gas temperature: 250°C ; Vcap: 4500V.Method I: LC: Shimadzu 2020 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm ; Column Temperature: 35°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN(v / v) ; Run time: 5.0 min ; Flow rate: 1.0 mL / min ; Gradient:MS: Ion Source: ESI ; Signal: positive and negative ; TIC: 100~900 m / z ; Fragmentor: 60 ;Threshold: 5 ; Gain: 1 ; Drying gas: 20 L / min ; Nebulizing Gas: 1.5 L / minMethod J: LC: Shimadzu LC-20XR series ; Binary Pump ; Diode Array Detector ; Column: Waters ACQUITY UPLC HSS C18, 1 .8 pm, 3.0x50 mm ; Column temperature: 25°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 3.0 min ; Flow Rate: 0.6 mL / min ; Gradient:MS: 2020, Quadrupole LC / MS ; Ion Source: API-ESI ; TIC: 100~900 m / z; Drying gas flow: 15 L / min; Nebulizer pressure: 1 ,5L / min ; Drying gas temperature: 250°C ; Vcap: 4500VMethod K: LC: Shimadzu LC-20XR series ; Binary Pump ; Diode Array Detector ; Column: Waters ACQUITY UPLC HSS C18, 1.8 pm, 3.0x50 mm column ; Column temperature: 25°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 3.0min ; Flow Rate: 0.6 mL / min ; Gradient:MS: 2020, Quadrupole LC / MS ; Ion Source: API-ESI ; TIC: 100~900 m / z ; Drying gas flow: 15 L / min; Nebulizer pressure: 1 ,5L / min ; Drying gas temperature: 250°C ; Vcap: 4500VMethod L: LC: Agilent Technologies 1290 series; Binary Pump; Diode Array Detector; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm; Column Temperature: 35°C ; Acquisition wavelength: 214 nm, 254 nm ; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v) ; Run time: 5.0 min ; Flow rate: 1.0 mL / min ; Gradient:MS: G6120A, Quadrupole LC / MS ; Ion Source: ESI ; Signal: positive and negative ; TIC: 70~1000 m / z ; Fragmentor: 60 ; Threshold: 5 ; Gain: 1 ; Drying gas flow: 10 L / min ; Nebulizer pressure: 35 psiMethod M: LC: Agilent Technologies 1290 series ; Binary Pump ; Diode Array Detector ; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm; Column Temperature: 35°C; Acquisition wavelength: 214 nm, 254 nm; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v); Run time: 5.0 min; Flow rate: 1.0 mL / min; Gradient:MS: G6120A, Quadrupole LC / MS; Ion Source: ESI; Signal: positive and negative; TIC: 70~1000 m / z; Fragmentor: 60; Threshold: 5; Gain: 1 ; Drying gas flow: 10 L / min; Nebulizer pressure: 35 psiMethod N: LC: Agilent Technologies 1290 series; Binary Pump; Diode Array Detector; Column: Agilent Poroshell 120 EC- C18, 2.7 pm, 4.6x50 mm; Column Temperature: 35°C; Acquisition wavelength: 214 nm, 254 nm; Mobile Phase: A: 0.05% Formate in water (v / v), B: 0.05% Formate in ACN(v / v); Run time: 5.0 min; Flow rate: 1.0 mL / min; Gradient:MS: G6120A, Quadrupole LC / MS; Ion Source: ESI; Signal: positive; TIC: 70~1000 m / z; Fragmentor: 60; Threshold: 5; Gain: 1 ; Drying gas flow: 10 L / min; Nebulizer pressure: 35 psiMethod O: LC: Shimadzu LC-20XR series; Binary Pump; Diode Array Detector; Column: Waters ACQUITY UPLC HSS C18, 1.8 pm, 3.0x50 mm column; Column temperature: 25°C; Acquisition wavelength: 214 nm, 254 nm; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v); Run time: 3.0 min ; Flow Rate: 0.6 mL / min; Gradient:MS: 2020, Quadrupole LC / MS; Ion Source: API-ESI ; TIC: 100~900 m / z; Drying gas flow: 15 L / min; Nebulizer pressure: 1 ,5L / min; Drying gas temperature: 250 °C; Vcap: 4500V.Method P: LC: Shimadzu LC-20AD series; Binary Pump; Diode Array Detector; Column: Waters Sunfire, 3.5 pm, 4.6x50 mm column; Column temperature: 25°C; Acquisition wavelength: 214 nm, 254 nm; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v); Run time: 5.0 min ; Flow Rate: 1 mL / min ; Gradient:MS: 2020, Quadrupole LC / MS; Ion Source: API-ESI; TIC: 100~900 m / z ; Drying gas flow: 15 L / min, Nebulizer pressure: 1 ,5L / min; Drying gas temperature: 250 °C; Vcap: 4500V.Method Q: LC: Shimadzu LC-20AD series; Binary Pump; Diode Array Detector; Column: Waters Sunfire, 3.5 pm, 4.6x50 mm column; Column temperature: 25°C; Acquisition wavelength: 214 nm, 254 nm; Mobile phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in MeCN (v / v); Run time: 5.0 min; Flow Rate: 1 mL / min; Gradient:MS: 2020, Quadrupole LC / MS; Ion Source: API-ESI; TIC: 100~900 m / z; Drying gas flow: 15 L / min; Nebulizer pressure: 1 ,5L / min; Drying gas temperature: 250 °C; Vcap: 4500V.Method R: LC: Agilent Technologies 1290 series; Binary Pump; Diode Array Detector; Column: Agilent EclipsePlus RRHD C18, 1 ,8pm, 3.0x50 mm ; Column temperature: 25°C; Acquisition wavelength: 214 nm, 254 nm; Mobile phase: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN (v / v); Flow Rate: 0.8 mL / min; Gradient:MS: G6120A, Quadrupole LC / MS, Ion Source: API-ES; TIC: 70~1000 m / z; Fragmentor: 70; Drying gas flow: 12 L / min; Nebulizer pressure: 36 psi; Drying gas temperature: 350°C; Vcap: 3000V. Method S: LC: Shimadzu 2020 series; Binary Pump; Diode Array Detector; Column: AgilentPoroshell 120 EC- C18, 2.7 pm, 4.6x50 mm; Column Temperature: 35°C; Acquisition wavelength:214 nm, 254 nm; Mobile Phase: A: 0.05% Formic acid in water (v / v), B: 0.05% Formic acid in ACN(v / v); Run time: 5.0 min ; Flow rate: 1.0 mL / min; Gradient:MS: Ion Source: ESI; Signal: positive / negative ; TIC: 100~900 m / z ; Fragmentor: 60 ; Threshold: 5 ; Gain: 1 ; Drying gas: 20 L / min ; Nebulizing Gas: 1.5 L / minNMR was also used to characterise final compounds.1H NMR spectra were obtained at r.t., unless otherwise stated, on a Bruker AVI 500 with either a 5 mm Dual or 5 mm QNP probe with Z gradients, a Bruker DRX500 with a 5 mm QNP probe with Z gradients or a Bruker AVIII 400 Nanobay with 5 mm BBFO probe. Chemical shifts are reported in ppm and referenced to either TMS (0.00 ppm), DMSO- de (2.50 ppm), CDCh (7.26 ppm) or MeOD-d4 (3.31 ppm). NH or OH signals that exchange with deuterated solvent are not reported. 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 20 mL / min on a XBridge™ prep C18 5 pM OBD 19 x 100 mm 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 the table below.Compound identity confirmations were also performed by analytical Supercritical Fluid Chromatography (SFC) using a Waters UPC2 analytical SFC (SFC-H). A 10 pL aliquot was injected onto an HPLC column (Cellulose-2, 150x4.6mm I.D., 3 pm) at RT which was controlled at 35° C. The samples were eluted at a flow rate of 2.0 mL / min with a mobile phase system composed of A for CO2 and B for methanol (0.05% DEA, V / V) eluting under isocratic elution (50% phase B).Compound purification was also performed by preparative Supercritical Fluid Chromatography (SFC). SFC purification was performed using a MG II preparative SFC(SFC-13). Samples were eluted at a flow rate of 80 mL / min on a Cellulose-2, 250x30mm I.D., 10 pm particle size with a mobile phase system composed of A for CC>2 and B for Methanol (0.1 % NH3H2O) under isocratic elution (50% phase B).General Scheme 15 General Scheme 3General Method for the synthesis of intermediates 1 and 2:Intermediate 1 : 3,5-dibromo-1 -methyl-1 ,2,4-triazoleTo a solution of 3, 5-dibromo-1 / 7-1 ,2,4-triazole (10.0 g, 44.1 mmol) in DMF (75 mL) and potassium carbonate (12.2 g, 88.2 mmol, 2.0 eq.) was added iodomethane (3.02 mL, 48.5 mmol, 1.1 eq.) in one portion. This gave rise to a strong exotherm from 17 °C to 38 °C after one minute. The reaction mixture was stirred overnight, diluted with 150 mL of EtOAc and then filtered to remove most of the inorganics. The solvent was removed under reduced pressure and the resultant yellow oily solid was partitioned between EtOAc (250 mL) and water (100 mL) and the aqueous washed with EtOAc (150 mL). Thecombined organics were washed with washed with brine (50 mL), dried over magnesium sulfate, filtered and the solvent removed in vacuo to give 3,5-dibromo-1-methyl-1 ,2,4-triazole (6.20 g, 25.8 mmol, 58% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1 .79 min, m / z 241 .7 [M+H]+.1H NMR (400 MHz, DMSO-de) 6 3.83 (3H) ppm.Intermediate 2: 3,5-dibromo-1 -ethyl-1 ,2,4-triazoleFollowing the procedure described for intermediate 1 , a solution of 3,5-dibromo-1 / 7-1 ,2,4-triazole (60.0 g, 267 mmol, 1.0 eq.), iodoethane (45.4 g, 294 mmol, 1.1 eq.) and K2CO3 (73.2 g, 533 mmol, 2.0 eq.) in DMF (216 mL) gave after work-up 3,5-dibromo-1 -ethyl-1 ,2,4-triazole (59.0 g, 231 mmol, 88%). LC-MS (ES-API, Method N): 1.58 min, m / z, 254.1 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 4.18 (q, J = 7.2 Hz, 2H), 1.36 (t, J = 7.2 Hz, 3H) ppm.Procedure for the synthesis of intermdiates 3-13Analytical data of intermediates 3-13 are given in Table 1.Intermediate 3: 6-aminosDirof2,3-dihvdroisoguinoline-4,1 '-cvclopropanel-l -oneStep 1 : methyl 4-bromo-2-(cyanomethyl)benzoateTo a solution of methyl 4-bromo-2-(bromomethyl)benzoate (180 g, 584 mmol) and K2CO3 (209 g, 2100 mmol) in MeCN (500 mL) at 0 °C was added TMSCN (291 g, 2104 mmol). The reaction mixture was stirred at 50 °C under a N2 atmosphere overnight. The reaction mixture was allowed to cool back down to r.t. and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 2% EtOAc in petrol afford methyl 4-bromo-2-(cyanomethyl)benzoate (107 g, 421 mmol, 72% yield). LC-MS (ES-API, Method C): 1.40 min, m / z 254.0 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 7.89 (d, J = 8.4 Hz, 1 H), 7.82 (d, J = 1 .6 Hz, 1 H), 7.73 (dd, J = 8.4, 1 .8 Hz, 1 H), 4.26 (s, 2H), 3.87 (s, 3H).Step 2: methyl 4-bromo-2-(1-cyanocyclopropyl)benzoateA mixture of methyl 4-bromo-2-(cyanomethyl)benzoate (7.80 g, 30.7 mmol), 1 ,2-dibromoethane (2.90 mL, 33.8 mmol) and NaH (1 .60 g, 67.5 mmol) in DMF (157 mL) was stirred at r.t. under N2 atmosphere for 16 h. The mixture was diluted with saturated solution of ammonium chloride and extracted with EtOAc (x 3). The organic extracts were combined, washed with a saturated solution of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel elution with 10% EtOAc in petrol afforded methyl 4-bromo-2-(1- cyanocyclopropyl)benzoate (7.40 g, 26.4 mmol, 86% yield). LC-MS (ES-API, Method F): 2.84 min,m / z 282.1 [M+2]+.1H NMR (400 MHz, DMSO-cfe) 6 7.83 (d, J = 1 .9 Hz, 1 H), 7.81 (d, J = 8.3 Hz, 1 H), 7.74 (dd, J = 8.4, 2.0 Hz, 1 H), 3.90 (s, 3H), 1.71 - 1 .63 (m, 2H), 1 .44 - 1 .37 (m, 2H) ppm.Step 3: 6-bromospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-1-oneA mixture of methyl 4-bromo-2-(1-cyanocyclopropyl)benzoate (3.50 g, 12.5 mmol), C0CI2 6H2O (8.85 g, 37.5 mmol) and NaBH4 (2.37 g, 62.5 mmol) in MeOH (140 mL) was stirred at 50 °C under a N2 atmosphere overnight. The reaction mixture was cooled to r.t.. The reaction mixture was quenched carefully with water and then extracted with EtOAc (3x). The organic extracts were combined, dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 2% MeOH in DCM afforded 6-bromospiro[2,3- dihydroisoquinoline-4,1 '-cyclopropane]-1-one (3.15 g, 12.5 mmol, quantitative yield).LC-MS(ES-API, Method C): 0.632 min, m / z, 252 / 254 [M+H]+ / [M+2]+.Step 4: te / Y-butyl / V-(1-oxospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-6-yl)carbamateA round bottom flask was charged with 6-bromospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-1- one (2.05 g, 8.10 mmol), te / Y-butylcarbamate (1.91 g, 16.3 mmol), caesium carbonate (7.95 g, 24.4 mmol), XantPhos (941 mg, 1.63 mmol) and anhydrous 1 ,4-dioxane (15.2 mL). The mixture was degassed with N2 for 5 minutes, then Pd2(dba)3 (183 mg, 0.81 mmol) was added. The reaction was stirred at 100°C for 3 h. After cooling to r.t., the mixture was concentrated under reduced pressure. The crude material was purified by flash column chromatography on silica gel eluting with 5% MeOH in DCM to afford te / Y-butyl / V-(1-oxospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-6- yl)carbamate (1.76 g, 6.10 mmol, 75% yield). LC-MS (ES-API, Method D): 1.80 min, m / z 289.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.52 (s, 1 H), 7.82 - 7.77 (m, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.35 (dd, J = 8.5, 1.8 Hz, 1 H), 7.09 (d, J = 1.7 Hz, 1 H), 3.19 (d, J = 2.5 Hz, 2H), 1.47 (s, 9H), 0.99 - 0.94 (m, 2H), 0.91 - 0.85 (m, 2H) ppm.Step 5: 6-aminospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-1-oneTo a solution of te / Y-butyl (1 '-oxo-2',3'-dihydro-1 ' / 7-spiro[cyclopropane-1 ,4'-isoquinolin]-6'- yl)carbamate (1.61 g, 5.58 mmol) in MeOH (3 mL) was added hydrogen chloride (4.0 M in 1 ,4- dioxane) (9 mL, 36.0 mmol). The reaction mixture was stirred at r.t. for 16 h. The mixture was basified to pH 8 with a saturated solution of NaHCOs (100 mL) and extracted with a 3:1 mixture of CHCh / IPA (3 x 50 mL). The combined organic extracts were washed with a saturated solution of brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 6-aminospiro[2,3- dihydroisoquinoline-4,1 '-cyclopropane]-1-one (1.05 g, 5.58 mmol, quantitative yield).Intermediate 4: 6-bromo-4-methyl-3,4-dihydro-2H-isoquinolin-1 -oneStep 1 : methyl 4-bromo-2-(1-cyanoethyl)benzoateA mixture of methyl 4-bromo-2-(cyanomethyl)benzoate (106 g, 419 mmol), methyl iodide (47.4 g, 334 mmol) and NaHMDS (61.2g, 334 mmol) in THF (1 L) was stirred at r.t. under a N2 atmosphere for 16h. The solution was carefully quenched with MeOH at 0 °C and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 2-7% EtOAc in petrol afforded methyl 4-bromo-2-(1-cyanoethyl)benzoate (98.0 g, 366 mmol, 88% yield). LC-MS (ES-API, Method D): 2.43 min, m / z 267.9 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 7.87 - 7.80 (m, 2H), 7.72 (dd, J = 8.4, 2.0 Hz, 1 H), 4.95 (q, J = 7.1 Hz, 1 H), 3.86 (s, 3H), 1 .59 (d, J = 7.2 Hz, 3H) ppm. Step 2: 6-bromo-4-methyl-3,4-dihydro-2H-isoquinolin-1-oneFollowing procedure (Int 3 step 3), methyl 4-bromo-2-(1-cyanoethyl)benzoate (98.0 g, 367 mmol) afforded 6-bromo-4-methyl-3,4-dihydro-2H-isoquinolin-1-one (87.8 g, 366 mmol, quantitative yield)1H NMR (400 MHz, DMSO-cfe) 6 7.86 - 7.81 (m, 2H), 7.72 (dd, J = 8.4, 2.0 Hz, 1 H), 4.95 (q, J = 7.1 Hz, 1 H), 3.86 (s, 3H), 1.59 (d, J = 7.1 Hz, 3H) ppm.Step 3: tert-butyl / V-(4-methyl-1-oxo-3,4-dihydro-2 / 7-isoquinolin-6-yl)carbamateA mixture of methyl 6-bromo-4-methyl-3,4-dihydroisoquinolin-1 (2 / 7)-one (54.0 g, 225 mmol), tert- butyl carbamate (52.7 g, 450 mmol), Pd(OAc)2 (5.05 g, 22.5 mmol), Xantphos (26.0 g, 45.0 mmol) and CS2CO3 (220 g, 675 mmol) in toluene (400 mL) was stirred at 110 °C under a N2 atmosphere for 16 h. The reaction mixture was then cooled to r.t. and 4 L of water was added. The mixture was extracted with EtOAc (300 mL x 3). The combined organic extracts were washed with a saturated solution of brine, dried over Na2SO4, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 1-2% MeOH in DCM afforded tert-butyl N- (4-methyl-1 -oxo-3, 4-dihydro-2 / 7-isoquinolin-6-yl)carbamate (43.7 g, 174 mmol, quantitative yield) as a brown solid. LC-MS (ES-API, Method D): 1.68 min, m / z 277.1 [M+H]+.1H NMR (400 MHz, DMSO- cfe) 6 9.46 (s, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 7.54 (s, 1 H), 7.47 (s, 1 H), 7.36 (d, J = 8.5 Hz, 1 H), 3.47 - 3.39 (m, 1 H), 3.13 - 3.03 (m, 1 H), 3.03 - 2.92 (m, 1 H), 1.49 (s, 9H), 1.22 (d, J = 6.8 Hz, 3H) ppm. Step 4: 6-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-oneTo a solution of te / Y-butyl (4-methyl-1-oxo-1 ,2,3,4-tetrahydroisoquinolin-6-yl)carbamate (46.0 g, 166 mmol) was added HCI in dioxane (120 mL) and MeOH (40 mL). The reaction mixture was stirred at r.t. for 16 h. The pH was then adjusted to pH 9 with saturated solution of sodium bicarbonate and the mixture was extracted with EtOAc (4 x 200 mL). The combined organic extracts were washed with H2O (1.20 L), saturated solution of brine (700 mL), dried with Na2SO4, filtered and concentrated under reduced pressure to afford 15.0 g of crude material. Trituration with EtOAc (75 mL) and drying under vacuum afforded 6-amino-4-methyl-3,4-dihydro-2 / 7-isoquinolin-1-one (9.40 g, 53.3 mmol, 32% yield).Intermediate 5: 6-amino-3,4-dihydro-2H-isoquinolin-1-oneStep 1 : tert-butyl / V-(1 -oxo-3, 4-dihydro-2 / 7-isoquinolin-6-yl)carbamateA round bottom flask was charged with 6-bromo-3,4-dihydro-1 (2 / 7)-isoquinolinone (515 mg, 2.28 mmol), te / Y-butylcarbamate (334 mg, 2.85 mmol), caesium carbonate (1.48 g, 4.56 mmol), XantPhos (132 mg, 0.230 mmol) and anhydrous 1 ,4-dioxane (15.2 mL). The mixture was degassed with N2 for 5 minutes, then Pd2(dba)3 (104 mg, 0.110 mmol) was added. The reaction was stirred at 100°C for 3 h. After cooling to r.t., the mixture was filtered through a plug of Celite and washed with MeOH. The filtrate was concentrated under reduced pressure to afford te / Y-butyl / V-(1-oxo-3,4-dihydro-2H- isoquinolin-6-yl)carbamate (498 mg, 1.90 mmol, 83% yield) as a light brown solid.UPLC-MS (ES+, Method A): 1 .56 min m / z 263.1 [M+H]+Step 2: 6-amino-3,4-dihydro-2 / 7-isoquinolin-1-oneTo a solution ofte / Y-butyl / V-(1-oxo-3,4-dihydro-2H-isoquinolin-6-yl)carbamate (498 mg, 1.90 mmol) in 1 ,4-dioxane (13.6 mL) was added hydrogen chloride (4.0 M in 1 ,4-dioxane) (5.70 mL, 22.8 mmol) and the mixture was heated at 40 °C for 23 h. The reaction mixture was then cooled to r.t.. The crude product was taken up in MeOH and purified with a SCX column (SCX-2, 2 x MeOH wash, 2 x 1 M NH3 in MeOH). Further purification by flash column chromatography on silica gel eluting with 0-10% MeOH in DCM afforded 6-amino-3,4-dihydro-2 / 7-isoquinolin-1 -one (79.9 mg, 0.490 mmol, 26% yield) as a brown solid.Intermediate 6: 6-amino-4,4-dimethyl-2,3-dihydroisoquinolin-1 -oneStep 1 : 2-bromo-4-nitro-benzoic acidA solution of lithium hydroxide (460 mg, 19.2 mmol) in Water (9.6 mL) was added to a solution of methyl 2-bromo-4-nitrobenzoate (2.00 g, 7.69 mmol) in THF (28.8 mL). The mixture was stirred at r.t. for 16 h and then partitioned between EtOAc (100 mL) and water (50 mL). The organic layer was separated. The aqueous layer was acidified to ~pH 1 with 2 M HCI (aq) and was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with a saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 2-bromo-4- nitro-benzoic acid (1 .74 g, 7.05 mmol, 92% yield) as an off-white solid.1H NMR (400 MHz, CDCI3) 5 8.59 (d, J = 2.2 Hz, 1 H), 8.28 (dd, J = 8.6, 2.2 Hz, 1 H), 8.13 (d, J = 8.6 Hz, 1 H) ppm.Step 2: 2-bromo- / V-(2-methylallyl)-4-nitro-benzamideTo a suspension of 2-methallylamine (0.22 mL, 2.44 mmol), / V, / V-diisopropylethylamine (0.71 mL, 4.06 mmol) and 2-bromo-4-nitro-benzoic acid (500 mg, 2.03 mmol) in THF (10.2 mL) was addedpropylphosphonic anhydride (1 .8 mL, 3.05 mmol) (50 wt% in EtOAc) and the resulting solution was stirred at r.t. for 1 h. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc (100 mL). The organic layer was washed with water (50 mL), a saturated solution of sodium bicarbonate (2 x 50 mL) and a saturated solution of brine (50 mL), dried over Na2SO4, filtered over a silica plug and concentrated under reduced pressure to afford 2-bromo- / V-(2-methylallyl)-4-nitro- benzamide (591 mg, 1.98 mmol, 97% yield) as an off-white solid. UPLC-MS (ES+, Method A): 1.75 min, m / z 300.9 [M+2]+.1H NMR (400 MHz, CDCb) 6 8.50 (d, J = 2.2 Hz, 1 H), 8.25 (dd, J = 8.4, 2.2 Hz, 1 H), 7.73 (d, J = 8.4 Hz, 1 H), 6.06 (s, 1 H), 5.03 - 4.94 (m, 2H), 4.08 (d, J = 6.0 Hz, 2H), 1 .87 (s, 3H) ppm.Step 3: tert-butyl / V-(2-bromo-4-nitro-benzoyl)- / V-(2-methylallyl)carbamateTo a suspension of 2-bromo- / V-(2-methylallyl)-4-nitro-benzamide (0.22 mL, 1.64 mmol) and di-tert- butyl dicarbonate (537 mg, 2.46 mmol) in DCM (6.6 mL) was added DMAP (20.0 mg, 0.160 mmol) and the resulting solution was stirred at r.t. for 90 min. The reaction mixture was then partitioned between EtOAc (50 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (20 mL). The organic extracts were combined, washed with water (20 mL), 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 0-100% EtOAc in petrol afforded te / Y-butyl / V-(2-bromo-4-nitro-benzoyl)- / V-(2-methylallyl)carbamate (653 mg, 1 .64 mmol, quantitative yield) as a clear oil. UPLC-MS (ES+, Method A): 2.14 min, m / z 400.9 [M+2]+1H NMR (400 MHz, CDCb) 6 8.46 (d, J = 2.1 Hz, 1 H), 8.25 (dd, J = 8.4, 2.2 Hz, 1 H), 7.43 (d, J = 8.4 Hz, 1 H), 4.98 - 4.87 (m, 2H), 4.44 (s, 2H), 1 .86 (s, 3H), 1 .30 (s, 9H) ppm.Step 4: te / Y-butyl 4,4-dimethyl-6-nitro-1-oxo-3 / 7-isoquinoline-2-carboxylatePalladium (II) acetate (32.3 mg, 0.140 mmol) was added to a nitrogen degassed suspension of sodium formate (98.0 mg, 1.44 mmol), sodium acetate (236 mg, 2.88 mmol), tetrabutylammonium bromide (464 mg, 1.44 mmol) and te / Y-butyl / V-(2-bromo-4-nitro-benzoyl)- / V-(2-methylallyl)carbamate (575 mg, 1.44 mmol) in DMF (7.2mL). The reaction mixture was stirred at 70 °C for 16 h, cooled to r.t. and partitioned between EtOAc (100 mL) and water (100 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The organic extracts were combined, washed with water (2 x 50 mL), saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford te / Y-butyl 4,4-dimethyl-6-nitro-1-oxo-3 / 7- isoquinoline-2-carboxylate (461 mg, 1.49 mmol, quantitative yield) as a clear oil. UPLC-MS (ES+, Method A): 2.04 min, m / z 343.0 [M+Na]+.1H NMR (400 MHz, CDCb) 6 8.36 (dd, J = 8.3, 0.6 Hz, 1 H), 8.23 - 8.16 (m, 2H), 3.83 (s, 2H), 1 .61 (s, 9H), 1 .45 (s, 6H) ppmStep 5: te / Y-butyl 6-amino-4,4-dimethyl-1-oxo-3 / 7-isoquinoline-2-carboxylateA suspension of te / Y-butyl 4,4-dimethyl-6-nitro-1-oxo-3 / 7-isoquinoline-2-carboxylate (461 mg, 1.44 mmol) in MeOH (7.2 mL) and dry 10 wt.% Palladium on carbon powder (48.3 mg, 0.45 mmol) was subjected to 3x vacuum then nitrogen cycles then 3x vacuum / hydrogen purges. The reaction mixture was stirred at r.t. for 2 h under a hydrogen atmosphere. The reaction mixture was filtered through celite, which was rinsed with MeOH. The filtrate was concentrated under reduced pressure to afford te / Y-butyl 6-amino-4,4-dimethyl-1-oxo-3 / 7-isoquinoline-2-carboxylate (393 mg, 1.35 mmol, 94% yield) as a yellow gum. UPLC-MS (ES+, Method A): 1 .78 min, m / z 291 .2 [M+H]+1H NMR (400 MHz, CDCb) 6 8.01 (d, J = 8.5 Hz, 1 H), 6.61 (dd, J = 8.5, 2.2 Hz, 1 H), 6.54 (d, J = 2.2 Hz, 1 H), 3.72 (s, 2H), 1.60 (s, 9H), 1.32 (s, 6H) ppm.Step 6: 6-amino-4,4-dimethyl-2,3-dihydroisoquinolin-1-oneTrifluoroacetic acid (0.45 mL, 5.90 mmol) was added to a solution of te / Y-butyl 6-amino-4,4-dimethyl- 1-oxo-3 / 7-isoquinoline-2-carboxylate (343 mg, 1.18 mmol) in DCM (2.4 mL). #The reaction mixture was stirred at r.t. for 15 min, basified with sodium bicarbonate to ~pH 10. EtOAc (30 mL) was added and the layers separated. The organic layer was washed with saturated solution of sodium bicarbonate (20 mL), saturated solution of brine (2 x 10 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-amino-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (185 mg, 0.97 mmol, 83% yield) as a yellow solid.Intermediate 7: 6-hydroxy-4,4-dimethyl-2,3-dihydroisoquinolin-1 -oneStep 1 : 2-bromo-4-methoxy- / V-(2-methylallyl)benzamideTo a suspension of 2-methallylamine (0.95 mL, 10.4 mmol), N,N-diisopropylethylamine (3.02 mL, 17.3 mmol) and 2-Bromo-4-methoxybenzoic acid (2.00 g, 8.66 mmol) in THF (34.6 mL) was added propylphosphonic anhydride (7.73 mL, 13.0 mmol) (50 wt% in EtOAc) and the resulting solution was stirred at 25°C overnight. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc (150 mL). The organic layer was washed with water (50 mL), a saturated solution of sodium bicarbonate (2 x 50 mL) and a saturated solution of brine (50 mL), dried over Na2SO4, filtered and concentrated under reduced pressure to afford 2-bromo-4-methoxy-N-(2- methylallyl)benzamide (1.77 g, 6.22 mmol, 71.9% yield) as an off-white solid.UPLC-MS (ES+, Method A): 1.53 min, m / z 285.9 [M+2]+.1H NMR (400 MHz, CDCI3) 6 7.63 (d, J = 8.6 Hz, 1 H), 7.14 (d, J = 2.5 Hz, 1 H), 6.91 (dd, J = 8.6, 2.5 Hz, 1 H), 6.21 (s, 1 H), 5.02 - 4.90 (m, 2H), 4.07 - 4.01 (m, 2H), 3.85 (s, 3H), 1 .85 (s, 3H) ppm.Step 2: tert-butyl / V-(2-bromo-4-methoxy-benzoyl)- / V-(2-methylallyl)carbamateTo a suspension of 2-bromo-4-methoxy-N-(2-methylallyl)benzamide (0.22 mL, 6.22 mmol) and Di- tert-butyl dicarbonate (2.04 g, 9.34 mmol) in DCM (24.9 mL) was added 4-dimethylamino pyridine, DMAP (76 mg, 0.62 mmol) and the resulting solution was stirred at room temperature for 2h. Extra 4- dimethylamino pyridine, DMAP (76 mg, 0.62 mmol) was added and reaction mixture allowed to stir at room temperature for 15 min. More Di-tert-butyl dicarbonate (2.04 g, 9.34 mmol) was added and reaction mixture was allowed to stir at room temperature for 15 min. All volatiles removed under reduced pressure. Purification by flash column chromatography on silica gel eluting 20-100% EtOAc in petrol afforded tert-butyl N-(2-bromo-4-methoxy-benzoyl)-N-(2-methylallyl)carbamate (2.30 g, 5.99mmol, 96.3% yield) as a clear oil. UPLC-MS (ES+, Method A): 2.05 min, m / z 329.9 [M-tBu+2]+1H NMR (400 MHz, CDCI3) 6 7.23 (d, J = 8.6 Hz, 1 H), 7.09 (d, J = 2.5 Hz, 1 H), 6.87 (dd, J = 8.6, 2.5 Hz, 1 H), 4.92 - 4.85 (m, 2H), 4.38 (s, 2H), 3.82 (s, 3H), 1 .82 (s, 3H), 1 .24 (s, 9H) ppm.Step 3: te / Y-butyl 6-methoxy-4,4-dimethyl-1-oxo-3 / 7-isoquinoline-2-carboxylatePalladium (II) acetate (135 mg, 0.600 mmol) was added to a nitrogen degassed suspension of Sodium formate (408 mg, 5.99 mmol), Sodium acetate (983 mg, 12.0 mmol), Tetrabutylammonium bromide (1.93 g, 5.99 mmol) and tert-butyl N-(2-bromo-4-methoxy-benzoyl)-N-(2-methylallyl)carbamate (2.30 g, 5.99 mmol) in DMF (30 mL). The reaction mixture was stirred at 70°C overnight. Extra Palladium (II) acetate (135 mg, 0.600 mmol) was added and reaction mixture was stirred at 70°C for 2h 30 min. Reaction mixture allowed to cool back down to room temperature and all volatiles removed under reduced pressure. Then the reaction mixture was partitioned between a layer of EtOAc (100 mL) and water (50 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 50mL). The combined organic extracts were washed with water (2 x 50mL), saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 0-30% EtOAc in petrol afforded tert-butyl 6-methoxy-4,4-dimethyl-1-oxo-3H-isoquinoline-2-carboxylate (296 mg, 0.97 mmol, 16.2% yield) as a clear oil. UPLC-MS (ES+, Method A): 1.87 min, m / z 250.2 [M+H]+.1H NMR (400 MHz, CDCh) 6 8.14 (d, J = 8.7 Hz, 1 H), 6.84 (dd, J = 8.7, 2.5 Hz, 1 H), 6.78 (d, J = 2.5 Hz, 1 H), 3.87 (s, 3H), 3.74 (s, 2H), 1 .58 (s, 9H), 1 .33 (s, 6H) ppm.Step 4: 6-hydroxy-4,4-dimethyl-2,3-dihydroisoquinolin-1-oneAt -78 °C, boron tribromide (2.1 mL, 2.13 mmol) (1 M in DCM) was added to a solution of te / Y-butyl 6- methoxy-4,4-dimethyl-1-oxo-3 / 7-isoquinoline-2-carboxylate (296 mg, 0.97 mmol) in DCM (1.9 mL). The mixture was stirred at -78°C for 30 min and then r.t. for 1 h. Extra boron tribromide (2.13 mL, 2.13 mmol) (1 M in DCM) was added at r.t. and the reaction mixture was stirred for another 16 h. The mixture was carefully basified with a saturated solution of sodium bicarbonate and partitioned between EtOAc (20 mL) and water (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 20 mL). The combined organic extracts were 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 20-100% EtOAc in petrol afforded 6-hydroxy-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (149 mg, 0.78 mmol, 81 % yield) as a white solid.Step 1 : 6-bromo-4-chloro-2H-isoquinolin-1-oneTo a solution of 6-bromoisoquinolin-1 (2H)-one (1.00 g, 4.46 mmol) in DMA (24 mL) was added NCS (717 mg, 5.37 mmol). The reaction mixture was stirred at 50 °C for 1 h under nitrogen. The mixture was cooled to r.t. diluted with water (300 mL) and extracted with EtOAc (90 mL x 3). The combined organic extracts were washed with brine (300 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting in 50% EtOAc in petrol to afford 6-bromo-4-chloro-2H-isoquinolin-1-one (900 mg, 3.48 mmol, 78%). LC-MS (ES- API, Method C): 1.135 min, m / z 258.0 / 260.0 [M+H]+Step 2: te / Y-butyl N-(4-chloro-1-oxo-2H-isoquinolin-6-yl)carbamateTo a solution of 6-bromo-4-chloroisoquinolin-1 (2H)-one (100 mg, 3.71 mmol), te / Y-butylcarbamate (50 mg, 4.09 mmol), CS2CO3 (380 mg, 11.1 mmol) in toluene (6 mL) was degassed with nitrogen. Pd(OAc)2 (8.74 mg, 0.400 mmol) and xant-phos (45.0 mg, 0.740 mmol) were added and the solution was stirred at 110 °C for 16h. The reaction mixture was cooled to RT and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting in (0-5% MeOH in DCM) to afford give te / Y-butyl N-(4-chloro-1-oxo-2H-isoquinolin-6-yl)carbamate (550 mg, 1.87 mmol, 60.3% yield). LC-MS (ES-API, Method J):0.567 min, m / z 295.05 [M+H]+Step 3: 6-amino-4-chloro-2H-isoquinolin-1-oneTo a solution of tert-butyl (4-chloro-1-oxo-1 ,2-dihydroisoquinolin-6-yl)carbamate (460 mg, 1.56 mmol) in MeOH (4.6 mL) was added HCI in dioxane (13.8 mL) and the reaction mixture was stirred at RT for 16h. The reaction mixture was diluted with water (100 mL) and extracted with EtOAc (40 mL x 3). The combined organic extracts were washed with brine (100 mL), dried over Na2SO4 and concentrated in vacuo to afford 6-amino-4-chloro-2H-isoquinolin-1-one (110 mg, 0.57 mmol, 36.2%).Intermediate 9: 6-amino-4,4,7-trimethyl-2,3-dihydroisoquinolin-1 -oneStep 1 : 6-amino-7-bromo-4,4-dimethyl-2,3-dihydroisoquinolin-1-one / V-Bromosuccinimide (468 mg, 2.63 mmol) was added to an ice cooled solution of 6-amino-4,4- dimethyl-2,3-dihydroisoquinolin-1-one (500 mg, 2.63 mmol) in DMF (5.3 mL). The mixture was stirred at r.t. for 15 min. Water (50 mL) was added and the mixture stirred for a further 10 min. The precipitate was collected by vacuum filtration, washed with water (2 x 10 mL) and air dried under vacuum to afford 6-amino-7-bromo-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (525 mg, 1.95 mmol, 74% yield) as a brown solid. UPLC-MS (ES+, Method A): 1 .26 min, m / z 271 .2 [M+2]+.1H NMR (400 MHz, DMSO- d6) 6 7.75 (s, 1 H), 7.62 (s, 1 H), 6.73 (s, 1 H), 5.89 (s, 2H), 3.08 (d, J = 2.9 Hz, 2H), 1.19 (s, 6H) ppm. Step 2: 6-amino-4,4,7-trimethyl-2,3-dihydroisoquinolin-1-one[1 ,1 '-B / s(di-te / Y-butylphosphino)ferrocene]dichloropalladium(ll) (127 mg, 0.200 mmol) was added to a fully nitrogen degassed mixture of 2,4,6-trimethylboroxin (0.55 mL, 3.90 mmol), potassium phosphate tribasic (828 mg, 3.90 mmol), 6-amino-7-bromo-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (525 mg, 1 .95 mmol), 1 ,4-dioxane (6 mL) and water (2 mL) at r.t. The reaction mixture was heated to 85 °C for 1 h. The reaction mixture was cooled back down to r.t. and concentrated under reduced pressure.Purification by flash column chromatography on silica gel eluting with 0-8% MeOH in DCM afforded 6-amino-4,4,7-trimethyl-2,3-dihydroisoquinolin-1-one (396mg, 1 .94mmol, 99%yield) as a brown solid.Intermediate 10: 6-amino-7-fluoro-4,4-dimethvl-2,3-dihvdroisoquinolin-1 -oneStep 1 : 2-bromo-5-fluoro-N-(2-methylallyl)-4-nitro-benzamideTo a suspension of 2-methallylamine (0.41 mL, 4.55 mmol), N,N-diisopropylethylamine (1.32 mL, 7.58 mmol) and 2-Bromo-5-fluoro-4-nitrobenzoic acid (1 .00 g, 3.79 mmol) in THF (15 mL) was added propylphosphonic anhydride (3.4 mL, 5.68 mmol) (50 wt% in EtOAc) and the resulting solution was stirred at 25°C for 1 h. The mixture was concentrated under reduced pressure and the residue dissolved in EtOAc (100 mL). The organic layer was washed with water (50 mL), a saturated solution of sodium bicarbonate (2 x 50 mL), saturated solution of brine (50 mL), dried over Na2SO4, filtered through a silica plug and concentrated under reduced pressure to afford 2-bromo-5-fluoro-N-(2- methylallyl)-4-nitro-benzamide (1.02 g, 3.22 mmol, 85.0% yield) as an off-white solid. UPLC-MS (ES+, Method A): 1.57 min, m / z 318.8 [M+2]+(92%).1H NMR (400 MHz, CDCb): 7.54 (dd, J = 7.1 , 3.0 Hz, 1 H), 7.43 (dd, J = 7.4, 3.0 Hz, 1 H), 5.93 (s, 1 H), 5.02 - 4.91 (m, 2H), 4.04 (d, J = 6.1 Hz, 2H), 1.84 (s, 3H)Step 2: te / Y-butyl N-(2-bromo-5-fluoro-4-nitro-benzoyl)-N-(2-methylallyl)carbamateTo a suspension of 2-bromo-5-fluoro-N-(2-methylallyl)-4-nitro-benzamide (0.22 mL, 3.22 mmol) and Di-tert-butyl dicarbonate (1.05 g, 4.83 mmol) in DCM (13 mL) was added 4-dimethylamino pyridine, DMAP (39 mg, 0.32 mmol) and the resulting solution was stirred at r.t. for 1 h. Then the reaction mixture was partitioned between a layer of EtOAc (50 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (20 mL). The organic extracts were combined. Washed with a water (20 mL), 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 0-60% EtOAc in petrol afforded tert-butyl N-(2-bromo-5-fluoro- 4-nitro-benzoyl)-N-(2-methylallyl)carbamate (1.31 g, 3.14 mmol, 97.5% yield) as a clear oil. UPLC-MS (ES+, , Method A): 2.05 min, m / z 418.9 [M+H]+(90%).1H NMR (400 MHz, CDCb): 7.53 (dd, J = 7.3, 2.9 Hz, 1 H), 7.18 (dd, J = 7.3, 2.9 Hz, 1 H), 5.00 - 4.83 (m, 2H), 4.42 (s, 2H), 1 .85 - 1 .80 (m, 3H), 1.29 (s, 9H)Step 3: te / Y-butyl 7-fluoro-4,4-dimethyl-6-nitro-1-oxo-3H-isoquinoline-2-carboxylatePalladium (II) acetate (70 mg, 0.310 mmol) was added to a nitrogen degassed suspension of Sodium formate (214 mg, 3.14 mmol), Sodium acetate (515 mg, 6.28 mmol), Tetrabutylammonium bromide (1.01 g, 3.14 mmol) and tert-butyl N-(2-bromo-5-fluoro-4-nitro-benzoyl)-N-(2-methylallyl)carbamate (1.31 g, 3.14 mmol) in DMF (16 mL). The reaction was stirred at 70 °C for 24h. Reaction mixture allowed to cool back down to room temperature, EtOAc (100 mL) and water (100 mL) were added. The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic extracts were washed with water (2 x 50 mL), saturated solution of brine (50 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford tert-butyl 7- fluoro-4,4-dimethyl-6-nitro-1-oxo-3H-isoquinoline-2-carboxylate (1 .06 g, 3.14 mmol, quanitative yield) as an orange gum. UPLC-MS (ES+, Method A): 1.96 min, m / z 361.1 [M+Na]+(86%).1H NMR (400 MHz, CDCb): 8.09 (dd, J = 8.4, 2.9 Hz, 1 H), 7.39 (dd, J = 7.0, 2.9 Hz, 1 H), 3.71 (s, 2H), 1 .59 (s, 9H), 1.43 (s, 6H)Step 4: te / Y-butyl 6-amino-7-fluoro-4,4-dimethyl-1-oxo-3H-isoquinoline-2-carboxylateA solution of tert-butyl 7-fluoro-4,4-dimethyl-6-nitro-1-oxo-3H-isoquinoline-2-carboxylate (1 .06 g, 3.14 mmol) in Methanol (16 mL) was evacuated and back-filled with nitrogen (3x). Then Palladium, 10 wt. % on carbon powder, dry (105 mg, 0.99 mmol) was added and the mixture was evacuated and backfilled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction was stirred at r.t. overnight. The mixture was passed through a pad of celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure to afford tert-butyl 6- amino-7-fluoro-4,4-dimethyl-1-oxo-3H-isoquinoline-2-carboxylate (968 mg, 3.14 mmol, quantitative yield) as a yellow gum. UPLC-MS (ES+, Method A): 1 .74 min, m / z 309.0 [M+H]+(78 %).1H NMR (400 MHz, CDCb): 7.48 - 7.38 (m, 1 H), 6.69 - 6.60 (m, 1 H), 3.70 (s, 2H), 1 .58 (s, 9H), 1 .45 (s, 6H) - NH2 not observedStep 5: 6-amino-7-fluoro-4,4-dimethyl-2,3-dihydroisoquinolin-1 -oneTrifluoroacetic acid (1.20 mL, 15.7 mmol) was added to a solution of tert-butyl 6-amino-7-fluoro-4,4- dimethyl-1-oxo-3H-isoquinoline-2-carboxylate (968 mg, 3.14 mmol) in DCM (6.3 mL) and stirred at room temperature for 15 min. The reaction mixture was basified with sodium bicarbonate to ~pH10. EtOAc (30 mL) was added. The aqueous layer was separated. Organic layer was washed with a saturated solution of sodium bicarbonate (20 mL), saturated solution of brine (20mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 6-amino-7-fluoro-4,4- dimethyl-2,3-dihydroisoquinolin-1-one (654 mg, 3.14 mmol, quantitative yield) as an orange gum. Intermediate-oneStep 1 : methyl 2-[(E)-2-(dimethylamino)vinyl]-4-nitro-benzoate te / Y-butoxybis(dimethylamino)methane (1.59 mL, 7.69 mmol) was added to Methyl 2-Methyl-4- nitrobenzoate (1.00 g, 5.12 mmol). Reaction mixture allowed to stir at 140°C for 2h. Extra tert- butoxybis(dimethylamino)methane (1.06 mL, 5.12 mmol) was added and the reaction mixture was allowed to stir at 140 °C for 30 min. The reaction mixture was cooled to room temperature. 14 mL (6:1) of Petro l / EtOAc was added and reaction mixture was allowed to stir at r.t. overnight. The liquid was decanted and the flask was dried under reduced pressure to afford methyl 2-[(E)-2- (dimethylamino)vinyl]-4-nitro-benzoate (885 mg, 3.54 mmol, 69% yield) as a black gum.1H NMR (400 MHz, CDCb): 8.22 (d, J = 2.2 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.67 (dd, J = 8.7, 2.3 Hz, 1 H), 7.03 (d, J = 13.6 Hz, 1 H), 6.12 (d, J = 13.6 Hz, 1 H), 3.91 (s, 3H), 2.94 (s, 6H) Step 2: 6-nitro-2H-isoquinolin-1-oneAqueous ammonia (3.49 mL, 31.4 mmol) was added to a suspension of methyl 2-[(E)-2- (dimethylamino)vinyl]-4-nitro-benzoate (785 mg, 3.14 mmol) in 1-Butanol (3.1 mL) and stirred at 100 °C for 45 min. The reaction mixture was cooled to room temperature. All volatiles removed under reduced pressure to afford 6-nitro-2H-isoquinolin-1-one (597 mg, 3.14 mmol, 100% yield) as a brown solid. UPLC-MS (ES+, Method A): 1.67 min, m / z 190.9 [M+H]+(84%).1H NMR (400 MHz, CDCb): 8.55 (d, J = 8.8 Hz, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.24 (dd, J = 8.7, 2.1 Hz, 1 H), 7.22 (d, J = 7.2 Hz, 1 H), 6.65 (d, J = 7.3 Hz, 1 H)Step 3: 4-fluoro-3-methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1 -one n-chloromethyl-n-fluorotriethylenediammonium bis(tetrafluoroborate) - selectfluor (1 .48 g, 4.17 mmol) was added to 6-nitro-2H-isoquinolin-1-one (634 mg, 3.33 mmol) in a mixture of MeCN (8.3 mL) and Methanol (8.3 mL) and stirred at 80 °C for 1 h. The reaction mixture was cooled to room temperature and all volatiles removed under reduced pressure to afford 4-fluoro-3-methoxy-6-nitro-3,4-dihydro- 2H-isoquinolin-1-one (801 mg, 3.33 mmol, 100% yield) as a brown solid. UPLC-MS (ES+, Method A): 1.74 min, m / z 240.9 [M+H]+(39%)Step 4: 4-fluoro-6-nitro-2H-isoquinolin-1-one4N Hydrogen Chloride in dioxane (2.49 mL, 9.96 mmol) was added to a suspension of 4-fluoro-3- methoxy-6-nitro-3,4-dihydro-2H-isoquinolin-1-one (801 mg, 3.33 mmol) in MeCN (10.1 mL) and stirred at 65 °C for 2h. The reaction mixture was cooled to r.t.. All volatiles removed under reduced pressure. The residue was basified with a saturated solution of sodium bicarbonate. The mixture waspartitioned between a layer of EtOAc (50 mL) and water (20 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4-fluoro-6-nitro-2H-isoquinolin-1-one (476 mg, 2.28 mmol, 68.5% yield) as a brown solid. UPLC-MS (ES+, Method A): 1.92 min, m / z 208.9 [M+H]+(32%).1H NMR (400 MHz, DMSO-de): 11 .61 (s, 1 H), 8.48-8.43 (m, 2H), 8.34 (dd, J = 8.8, 2.2 Hz, 1 H), 7.67 - 7.62 (m, 1 H) Step 5: 6-amino-4-fluoro-2H-isoquinolin-1-oneA solution of 4-fluoro-6-nitro-2H-isoquinolin-1-one (476 mg, 2.28 mmol) in Methanol (11.4 mL) was evacuated and back-filled with nitrogen (3x). Then Palladium, 10 wt. % on carbon powder, dry (49 mg, 0.460 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction was stirred at room temperature for 2h. Extra Palladium, 10 wt. % on carbon powder, dry (49 mg, 0.460 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction was stirred at r.t. overnight. Extra Palladium, 10 wt. % on carbon powder, dry (49 mg, 0.460 mmol) was added and the hydrogen balloon was refilled and the reaction mixture was stirred at r.t. for 6h. Afterwards, the mixture was passed through a pad of celite, which was washed with MeOH. The filtrate was concentrated under reduced pressure to afford 6-amino-4-fluoro-2H-isoquinolin-1-one (391 mg, 2.19 mmol, 96% yield) as a brown gum.Intermediate 12: 6-amino-4,4-difluoro-2,3-dihydroisoquinolin-1 -oneStep 1 : methyl 2-[E-2-(dimethylamino)vinyl]-4-nitro-benzoateA mixture of te / Y-butoxybis(dimethylamino)methane (21.2 mL, 102 mmol) and methyl 2-methyl-4- nitrobenzoate (5.00 g, 25.6 mmol) was heated at 140 °C for 6 h and then cooled to r.t. All volatiles were removed under reduced pressure. 21 mL of 6:1 Petrol / EtOAc was added and the reaction mixture was allowed to stand at 0°C for 30 min. The liquid was decanted and the flask was concentrated under reduced pressure to afford methyl 2-[(E)-2-(dimethylamino)vinyl]-4-nitro- benzoate (5.18 g, 20.7 mmol, 81 % yield) as a black solid.1H NMR (400 MHz, CDCb) 6 8.22 (d, J = 2.2 Hz, 1 H), 7.88 (d, J = 8.7 Hz, 1 H), 7.67 (dd, J = 8.7, 2.3 Hz, 1 H), 7.03 (d, J = 13.6 Hz, 1 H), 6.12 (d, J = 13.6 Hz, 1 H), 3.91 (s, 3H), 2.94 (s, 6H) ppm.Step 2: 6-nitro-2 / 7-isoquinolin-1-oneAqueous ammonia (18.4 mL, 207 mmol) was added to a suspension of methyl 2-[(E)-2- (dimethylamino)vinyl]-4-nitro-benzoate (5.18 g, 20.7 mmol) in IPA (10.4 mL). The mixture was stirred at 100 °C for 45 min and cooled to r.t. All volatiles were removed under reduced pressure to afford 6- nitro-2 / 7-isoquinolin-1-one (3.94 g, 20.7 mmol, quantitative yield) as a brown solid. UPLC-MS (ES+, Method A): 1.24 min, m / z 190.9 [M+H]+.1H NMR (400 MHz, CDCb) 6 8.55 (d, J = 8.8 Hz, 1 H), 8.43 (d, J = 2.2 Hz, 1 H), 8.24 (dd, J= 8.7, 2.1 Hz, 1 H), 7.22 (d, J=7.2 Hz, 1 H), 6.65 (d, J = 7.3 Hz, 1 H) ppm. Step 3: 4-fluoro-3-methoxy-6-nitro-3,4-dihydro-2 / 7-isoquinolin-1 -oneFollowing the procedure described for intermediate 11 step 3, 6-nitro-2 / 7-isoquinolin-1-one (3.00 g, 15.8 mmol) afforded 4-fluoro-3-methoxy-6-nitro-3,4-dihydro-2 / 7-isoquinolin-1-one (3.79 g, 15.8 mmol, quantitative yield) as a brown solid. UPLC-MS (ES+, Method A): 1 .30 min, m / z 240.9 [M+H]+Step 4: 4-fluoro-6-nitro-2 / 7-isoquinolin-1-oneFollowing the procedure described for intermediate 11 step 4, 4-fluoro-3-methoxy-6-nitro-3,4-dihydro- 2 / 7-isoquinolin-1-one (3.79 g, 15.8 mmol) afforded 4-fluoro-6-nitro-2 / 7-isoquinolin-1-one (2.90 g, 13.9 mmol, 88% yield) as a brown solid. UPLC-MS (ES+, Method A): 1 .32 min, m / z 208.9 [M+H]+1H NMR (400 MHz, DMSO-d6) 6 11.61 (s, 1 H), 8.48 - 8.43 (m, 2H), 8.34 (dd, J = 8.8, 2.2 Hz, 1 H), 7.70 - 7.60 (m, 1 H) ppm.Step 5: 4,4-difluoro-3-hydroxy-6-nitro-2,3-dihydroisoquinolin-1 -one n-Chloromethyl-n-fluorotriethylenediammonium bis(tetrafluoroborate) (selectfluor) (4.04 g, 11.4 mmol) was added to 4-fluoro-6-nitro-2H-isoquinolin-1-one (1.90 g, 9.13 mmol) in a mixture of MeCN (33 mL) and water (3.3 mL). The reaction mixture was stirred 60 °C for 30 min then cooled to r.t. and all volatiles removed under reduced pressure. The residue was partitioned between EtOAc (30 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were washed with a saturated solution of brine (20 mL), dried over sodium sulfate, filtered and concentrated under reduced pressure to afford 4,4-difluoro-3- hydroxy-6-nitro-2,3-dihydroisoquinolin-1-one (1.48 g, 6.08 mmol, 66.6% yield) as a brown solid. UPLC-MS (ES+, Method A): 1 .27 min, m / z 244.9 [M+H]+. H NMR (400 MHz, DMSO-d6) 6 9.52 - 9.44 (m, 1 H), 8.56 - 8.50 (m, 1 H), 8.49 - 8.40 (m, 1 H), 8.24 (d, J = 8.5 Hz, 1 H), 7.26 (d, J = 5.6 Hz, 1 H), 5.22 - 5.13 (m, 1 H) ppm.Step 6: 4,4-difluoro-6-nitro-2,3-dihydroisoquinolin-1-oneMethanesulfonic acid (1 .33 mL, 20.5 mmol) was added to a suspension of 4,4-difluoro-3-hydroxy-6- nitro-2,3-dihydroisoquinolin-1-one (500 mg, 2.05 mmol) in DCM (5.1 mL). Triethylsilane (0.65 mL, 4.10 mmol) was added to the solution and reaction mixture was stirred at 40°C for 2h.Triethylsilane (0.65 mL, 4.10 mmol) was added and the reaction mixture was stirred at 40°C for 1 h. Triethylsilane (0.65mL, 4.10 mmol) was added and the reaction mixture stirred at 40°C for 1 h. Triethylsilane (0.65mL, 4.10 mmol) was added and reaction mixture was stirred at 40 °C for 2h. Reaction mixture was cooled to room temperature. The mixture was carefully basified with a saturated solution of sodium bicarbonate. Then the reaction mixture was partitioned between a layer of EtOAc (30 mL) and water (30 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (30 mL). The combined organic extracts were 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 30-70% EtOAc in petrol afforded 4,4-difluoro-6-nitro-2,3-dihydroisoquinolin-1 -one (152 mg, 0.67 mmol, 32.5% yield) as an orange solid. UPLC-MS (ES+, Method A): 1 .35 min, m / z 228.9 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.83 (s, 1 H), 8.54 (dd, J = 8.5, 2.2 Hz, 1 H), 8.45 - 8.42 (m, 1 H), 8.26 (d, J = 8.5 Hz, 1 H), 4.04 (dt, J = 13.4, 2.9 Hz, 2H) ppm. Step 7: 6-amino-4,4-difluoro-2,3-dihydroisoquinolin-1-oneA solution of 4,4-difluoro-6-nitro-2,3-dihydroisoquinolin-1-one (152 mg, 0.67 mmol) in Methanol (3.3 mL) was evacuated and back-filled with nitrogen (3x). Then Palladium, 10 wt. % on carbon powder, dry (14.2 mg, 0.13 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction was stirred at r.t. overnight. The mixture was passed through a pad of celite, washing with MeOH. The filtrate was concentrated under reduced pressure to afford 6-amino-4,4-difluoro-2,3-dihydroisoquinolin-1- one (132 mg, 0.67 mmol, quantitative yield) as a brown gum.Intermediate 13: 6-amino-5-methyl-2H-isoquinolin-1-oneStep 1 : 6-amino-2H-isoquinolin-1-oneA solution of 6-n itroisoq u inolin- 1 (2H)-one (15.0 g) in IPA (30 mL) was evacuated and back-filled with nitrogen (3x). Pd / C (1.50 g, 78.9 mmol) was added and the mixture was evacuated and back-filled with nitrogen (3x). Then the mixture was evacuated and back-filled with hydrogen (2x). The reaction mixture stirred at r.t.. The reaction was filtered and concentrated to afford the 6-amino-2H-isoquinolin- 1-one (10.0 g, 62.4 mmol, 79.2% yield). LC-MS (ES-API, Method C): 0.73 min, m / z 161 .1 [M+H]+1H NMR (400MHz, DMSO-d6) 6 10.60 (s, 1 H), 7.83 (d, J = 8.7 Hz, 1 H), 6.97-6.92 (m, 1 H), 6.69 (dd, J = 8.7, 2.1 Hz, 1 H), 6.52 (d, J = 2.1 Hz, 1 H), 6.20 (d, J = 7.1 Hz, 1 H), 5.84 (s, 2H) ppm Step 2: 6-amino-5-bromo-2H-isoquinolin-1-oneTo a solution of 6-aminoisoquinolin-1 (2H)-one (2.30 g, 14.4 mmol) in DMF (100 mL) was added NBS (1.28 g, 7.18 mmol) and the reaction mixture was stirred for 1 h at r.t. Water (1 L) was added to the reaction mixture and the mixture was extracted with EtOAc (200 mL x4). The combined organic extracts were washed with brine (2x), dried with sodium sulfate, filtered and concentrated in vacuo to afford 6-amino-5-bromo-2 / 7-isoquinolin-1-one (quantitative yield). LC-MS (ES+, Method C): 0.67 min, m / z 240.9 [M+H]+.1H NMR (400 MHz, DMSO-de) 11 .13 (s, 1 H), 7.97 (d, J = 8.7 Hz, 1 H), 7.29 - 7.23 (m, 1 H), 7.02 (d, J = 8.7 Hz, 1 H), 6.60 (d, J = 7.4 Hz, 1 H), 6.26 (s, 2H)Step 3: 6-amino-5-methyl-2H-isoquinolin-1-oneA solution of 6-amino-5-bromoisoquinolin-1 (2H)-one (2.00 g, 8.40 mmol) and 2,4,6-trimethyl- 1 ,3,5,2,4,6-trioxatriborinane(45%) (4.20 g, 16.8 mmol.) and K3PO4 (3.55 g, 16.8 mmol), in 1 ,4-dioxane (30 mL) and H2O (10 mL) was degassed wih nitrogen. Pd(dppf)Cl2 (600 mg, 0.800 mmol) was added and the mixture was stirred at 80°C overnight. The reaction mixture was cooled to room temperature,concentrated in vacuo and purified by flash column chromatography on silica gel (DCM:MeOH=40:1) to afford 6-amino-5-methyl-2H-isoquinolin-1-one (700 mg, 4.02 mmol, 48% yield).Procedures for the synthesis of intermediates 14-30 General proceduresGeneral procedure A: To a solution of 6-amino-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (1 eq) and 3,5-dibromo-1-ethyl-1 ,2,4-triazole (1.0-1 .2 eq) in dry DMF (0.03-0.5M) was added sodium bis(trimethylsilyl)amide 2M in THF (3.0-3.2 eq) The mixture was stirred at -30- RT r.t. for 0.5-16h. Then the reaction mixture was partitioned between a layer of ethyl acetate (100 mL) and water (50 mL). The organic layer was separated. The aqueous layer was extracted with EtOAc (2 x 50 mL). The organic extracts were combined. Washed with water (2 x 50 mL), saturated solution of brine (50mL), dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel to afford the desired product.80-100 °C, O / NGeneral Procedure B: K2CO3 (1.3 eq) was added to a stirred solution of 3,5-dibromo-1-ethyl-1 ,2,4- triazole (1.1 eq) and 6-hydroxy-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (1 eq) in DMF (0.5M). Reaction mixture was to stirred at 80-100 °C overnight. The reaction was cooled to RT and water (20 mL) was added. The solid precipitate was collected by vacuum filtration. Washed with water (2 x 20 mL) and EtOAc (20 mL). The residue was purified by flash column chromatography on silica gel to afford the desired product.Intermediate 14: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]spiro[2,3-dihydroisoquinoline- 4,1'-cyclopropane]-1 -oneFollowing general procedure A, 6-aminospiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-1-one (300 mg, 1.60 mmol), 3,5-dibromo-1-ethyl-1 / 7-1 ,2,4-triazole (426 mg, 1.70 mmol), and NaHMDS (876 mg, 4.70 mmol) in DMF (60 mL) was stirred at -30 °C over half an hour, and at r.t. under N2 overnight. After extraction afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]spiro[2,3-dihydroisoquinoline- 4,1 '-cyclopropane]-1-one(quantitative yield).Intermediate 15: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4,4-dimethyl-2,3- dihydroisoquinolin-1 -oneFollowing general procedure A: 6-amino-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (900 mg, 4.73 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (1.27 g, 4.97 mmol), Sodium bis(trimethylsilyl)amide 2M in THF (7.10 mL, 14.2 mmol) in DMF (9.5 mL) was stirred at 0 °C under N2 for 15 min then r.t. for 30min. Purification by flash column chromatography on silica gel eluting in 0-100% EtOAc in petrol then 0-6% MeOH in DCM followed by a MeOH trit (5 mL) afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol- 3-yl)amino]-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (773 mg, 2.12 mmol, 44.9% yield) as an off- white solid.Intermediate 16: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)oxy]-4,4-dimethyl-2,3- dihydroisoquinolin-1 -oneFollowing general procedure B: K2CO3 (140 mg, 1.02 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (219 mg, 0.86 mmol) and 6-hydroxy-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (149 mg, 0.78 mmol) in DMF (1 .6 mL) was stirred at 80 °C overnight. Purification by flash column chromatography on silica gel eluting with 20-100% EtOAc in petrol followed by 0-10% MeOH in DCM afforded 6-[(5-bromo-2- ethyl-1 ,2,4-triazol-3-yl)oxy]-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (150 mg, 0.41 mmol, 52.5% yield) as an off-white solid.Intermediate 17: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4-methyl-3,4-dihydro-2H- isoquinolin-1 -oneFollowing general procedure A: 6-amino-4-methyl-3,4-dihydro-2H-isoquinolin-1-one (500 mg, 2.84 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (723 mg, 2.84 mmol), Sodium bis(trimethylsilyl)amide 2M in THF (5 mL, 8.50 mmol) in DMF (5 mL) was stirred at 0 °C under N2 for 15 min then r.t. for 30min. Purification by flash column chromatography on silica gel eluting in 0-5% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4-methyl-3,4-dihydro-2H-isoquinolin-1-one (917 mg, 2.62 mmol, 92.3% yield).Intermediate 18: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-3,4-dihydro-2H-isoquinolin-1 - oneFollowing general procedure A: 6-amino-3,4-dihydro-2H-isoquinolin-1-one (400 mg, 2.47 mmol), 3,5- dibromo-1-ethyl-1 ,2,4-triazole (629 mg, 2.47 mmol), Sodium bis(trimethylsilyl)amide 2M (3.70 mL, 7.40 mmol) in DMF (5 mL) was stirred at -20 °C under N2 for 15 min then r.t. for 16h. Purification by flash column chromatography on silica gel eluting in 0-2% MeOH in DCM afforded 6-[(5-bromo-2- ethyl-1 ,2,4-triazol-3-yl)amino]-3,4-dihydro-2H-isoquinolin-1-one (600 mg, 1.78 mmol, 72.4% yield).Intermediate 19: 6-[(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]-3,4-dihydro-2H-isoquinolin-1 - oneFollowing general procedure A: 6-amino-3,4-dihydro-2H-isoquinolin-1-one (4.40g, 27.1 mmol), 3,5- dibromo-1-methyl-1 ,2,4-triazole (6.53g, 27.1 mmol), Sodium bis(trimethylsilyl)amide 2M (40mL, 80mmol) in DMF (40 mL) was stirred at -20 °C for 2h. Purification by flash column chromatography on silica gel eluting in 0-10% MeOH in DCM afforded 6-[(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]- 3,4-dihydro-2H-isoquinolin-1-one (5.00g, 15.5mmol, 57.2.% yield).Intermediate 20: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4-chloro-2H-isoquinolin-1-oneFollowing general procedure A: 6-amino-4-chloro-2H-isoquinolin-1-one (86 mg, 0.440 mmol), 3,5- dibromo-1-ethyl-1 ,2,4-triazole (112 mg, 0.440 mmol), Sodium bis(trimethylsilyl)amide 2M (0.70 mL, 1 .32 mmol) in DMF (5 mL) was stirred at -20 °C under N2 for 30 min then r.t. for 16h . Purification by flash column chromatography on silica gel eluting in 0-5% MeOH in DCM afforded 6-[(5-bromo-2- ethyl-1 ,2,4-triazol-3-yl)amino]-4-chloro-2H-isoquinolin-1 -one (90 mg, 0.24 mmol, 55.6% yield).Intermediate 21 : 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-2H-isoquinolin-1 -oneFollowing general procedure A: 6-Aminoisoquinolin-1 (2H)-one (500 mg, 3.12 mmol), 3,5-dibromo-1- ethyl-1 ,2,4-triazole (796 mg, 3.12 mmol), Sodium bis(trimethylsilyl)amide 2M (4.70 mL, 9.40 mmol) in DMF (5 mL) was stirred at -20 °C 2h. Purification by flash column chromatography on silica gel eluting in (DCM / MeOH=70 / 1 ~30 / 1) afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-2H-isoquinolin-1- one (700 mg, 2.09 mmol, 67% yield) as a yellow solid.Intermediate 22: 6-[(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]-2H-isoquinolin-1 -oneFollowing general procedure A: 6-Aminoisoquinolin-1 (2H)-one (6.00 g, 37.5 mmol), 3,5-dibromo-1- ethyl-1 ,2,4-triazole (6.02 g, 37.5 mmol), Sodium bis(trimethylsilyl)amide 2M (56 mL, 112 mmol) in DMF (80 mL) was stirred at -20 °C under N2 for 2h. Purification by flash column chromatography eluting in 0-10% MeOH in DCM afforded 6-[(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]-2H- isoquinolin-1-one (6.70 g, 20.9 mmol, 56% yield).Intermediate 23: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)oxy]-2H-isoquinolin-1 -oneFollowing general procedure B: K2CO3 (111 mg, 0.810 mmol), 3,5-dibromo-1-methyl-1 ,2,4-triazole (174 mg, 0.680 mmol) and 6-Hydroxyisoquinolin-1 (2H)-one (100 mg, 0.620 mmol) in DMF (1 .24 mL) was stirred at 80 °C overnight. Purification by flash column chromatography on silica gel eluting with 20-100% EtOAc in petrol followed by 0-10% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol- 3-yl)oxy]-2H-isoquinolin-1-one (148 mg, 0.440 mmol, 71 % yield) as an off-white solid.Intermediate 24: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4,4,7-trimethyl-2,3- dihydroisoquinolin-1 -oneFollowing general procedure A: 6-amino-4,4,7-trimethyl-2,3-dihydroisoquinolin-1-one (198 mg, 0.970 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (259 mg, 1.02 mmol), Sodium bis(trimethylsilyl)amide 2Min THF (1.45 mL, 2.91 mmol) in DMF (1.94 mL) was stirred at 0 °C under N2 for 15 min then r.t. for 15min. Purification by flash column chromatography on silica gel eluting in 0-8% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4,4,7-trimethyl-2,3-dihydroisoquinolin-1-one (262 mg, 0.690 mmol, 71.3% yield) as a brown solid.Intermediate 25: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-7-fluoro-4,4-dimethyl-2,3- dihydroisoquinolin-1 -oneFollowing general procedure A: 6-amino-7-fluoro-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (350 mg, 1.68 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (450 mg, 1.76 mmol), Sodium bis(trimethylsilyl)amide 2M in THF (2.5mL, 5.04 mmol) in DMF (1.9 mL) was stirred at 0°C under N2 for 15 min then r.t. for 2h. Purification by flash column chromatography on silica gel eluting in 0-100% EtOAc in petrol then 0-6% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-7-fluoro-4,4-dimethyl-2,3- dihydroisoquinolin-1-one (297 mg, 0.780 mmol, 46.3% yield) as a brown solid.Intermediate 26: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4-fluoro-2H-isoquinolin-1 -oneFollowing general procedure A: 6-amino-4-fluoro-2 / 7-isoquinolin-1-one (167 mg, 0.940 mmol), 3,5- dibromo-1-ethyl-1 ,2,4-triazole (251 mg, 0.980 mmol), Sodium b / s(trimethylsilyl)amide 2 M in THF (1.40 mL, 7.40 mmol) in DMF (5 mL) was stirred at r.t. for 1 h. Purification by flash column chromatography on silica gel eluting in 0-8% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4- triazol-3-yl)amino]-4-fluoro-2H-isoquinolin-1-one (86.5 mg, 0.250 mmol, 26% yield) as a yellow solid.Intermediate 27: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-4,4-difluoro-2,3- dihydroisoquinolin-1 -oneFollowing general procedure A: 6-amino-4,4-difluoro-2,3-dihydroisoquinolin-1-one (137 mg, 0.69 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (185 mg, 0.72 mmol), Sodium b / s(trimethylsilyl)amide 2M (1.03 mL, 2.07 mmol) in DMF (1.4 mL) was stirred at r.t. for 30min. Purification by flash column chromatography on silica gel eluting in 40-100% EtOAc in petrol afforded 6-[(5-bromo-2-ethyl-1 ,2,4- triazol-3-yl)amino]-4,4-difluoro-2,3-dihydroisoquinolin-1-one (99.1 mg, 0.270 mmol, 39% yield) as a yellow solid.Intermediate 28: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)oxy]-3,4-dihydro-2H-isoquinolin-1 -oneFollowing general procedure B: K2CO3 (127 mg, 0.920 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (198 mg, 0.780 mmol) and 6-hydroxy-3,4-dihydro-2H-isoquinolin-1-one (115 mg, 0.700 mmol) in DMF (1.56 mL) was stirred at 80°C for 22h. Purification by flash column chromatography on silica gel eluting in 0-7% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)oxy]-3,4-dihydro-2H- isoquinolin-1-one (128 mg, 0.380 mmol, 53.8% yield) as a white solid.Intermediate 29: 6-[(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]-4,4-dimethyl-2,3- dihydroisoquinolin-1 -oneFollowing general procedure A: 6-amino-4,4-dimethyl-3,4-dihydroisoquinolin-1 (2H)-one (300 mg, 1.58 mmol), 3,5-dibromo-1-ethyl-1 ,2,4-triazole (456 mg, 1.89 mmol), sodium b / s(trimethylsilyl)amide (868 mg, 4.73 mmol) in DMF (10 mL) was stirred at -20°C under N2 for 30 min then r.t. for 16h. Purification by flash column chromatography on silica gel eluting in 0-5% MeOH in DCM afforded 6- [(5-bromo-2-methyl-1 ,2,4-triazol-3-yl)amino]-4,4-dimethyl-2,3-dihydroisoquinolin-1-one (400 mg, 1.14 mmol, 72% yield).Intermediate 30: 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-5-methyl-2H-isoquinolin-1 -oneFollowing general procedure A: 6-amino-5-methyl-2H-isoquinolin-1-one (700 mg, 4.02 mmol), 3,5- dibromo-1-ethyl-1 ,2,4-triazole (1 .23 g, 4.82 mmol), sodium b / s(trimethylsilyl)amide 2M (6.00 mL, 12.1 mmol) in DMF (14 mL) was stirred r.t. for 16h. Purification by flash column chromatography on silica gel eluting in 0-3% MeOH in DCM afforded 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]-5-methyl-2 / 7- isoquinolin-1-one (170 mg, 0.490 mmol, 12% yield).Compounds prepared in a similar manner to that set out above are given in the table below:Table 2General method for the synthesis of Intermediates 31-36A method for preparing Intermediates 31 and 36 is given below. Further intermediates that were prepared in a similar manner from commercially available bromopyridines are given in Table 3. Intermediate 31 : 5-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl) pyridine1 ,4-dioxane, 90 °C, overnightStep 1 : 4-(5-methylpyridin-2-yl)phenolA solution of 2-bromo-5-methylpyridine (3.00 g, 17.4 mmol), (4-hydroxyphenyl)boronic acid (2.89 g, 20.9mmol), Pd(dppf)Cl2.DCM (1 .42 g, 1 .74 mmol) and K2CO3 (3.62 g, 26.1 mmol) in 1 ,4-dioxane / H2Q (90 mL / 10 mL) was stirred at 100 °C under N2 atmosphere overnight. The mixture was cooled to room temperature and then concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 50% EtOAc in petrol to give 4-(5-methylpyridin-2-yl)phenol (1.44 g, 45% yield) as an off-white solid. LC-MS (ES-API, Method C): 0.40 min, m / z 185.1 [M+H]+1H NMR (400 MHz, DMSO-cfe) 6 9.67 (s, 1 H), 8.44 (s, 1 H), 7.91 (d, J = 9.4 Hz, 2H), 7.74 (d, J = 7.8 Hz, 1 H), 7.63 (dd, J = 2.1 , 8.0 Hz, 1 H), 6.86 (d, J = 8.6 Hz, 2H), 2.33 (s, 3H) ppm.Step 2: 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonateTo a mixture of 4-(5-methylpyridin-2-yl)phenol (1.34 g, 7.20 mmol) and triethylamine (2.20 g, 21.6 mmol) in DCM (30 mL) was added trifluoromethanesulfonic anhydride (3.10 g, 11 .0 mmol) slowly at 0 °C. The resulting mixture was stirred at 0 °C for 0.5h and then stirred at r.t. under N2 atmosphere overnight. The mixture was diluted with water (100 mL) and extracted with DCM (20 mL x 3). The combined organic layers were washed with brine (80 mL), dried over Na2SC>4 and concentrated in vacuo. The residue was purified by column chromatography on silica gel, eluting with 25% EtOAc in petrol to afford 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonate (1.94 g, 85% yield) as a brown oil. LC-MS (ES-API, Method C): 2.00 min, m / z 318.1 [M+H]+.1H NMR (400 MHz, DMSO-d6) 68.55 (s, 1 H), 8.25 (d, J = 9.0 Hz, 2H), 7.95 (d, J = 8.2 Hz, 1 H), 7.76 (dd, J = 8.0, 1 .8 Hz, 1 H), 7.61 (d, J = 8.9 Hz, 2H), 2.37 (s, 3H) ppm.Step 3: 5-methyl-2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyridineA mixture of 4-(5-methylpyridin-2-yl)phenyl trifluoromethanesulfonate (1.70 g, 5.40 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (2.72 g, 10.7 mmol), Pd(dppf)Cl2DCM (438 mg, 0.540 mmol) and potassium acetate (1.58 g, 16.2 mmol) in 1 ,4-dioxane (7 mL) was stirred at 90°C under N2 atmosphere overnight. The mixture was concentrated in vacuo, and the crude was purified by column chromatography on silica gel, eluting with 25% EtOAc in petrol to give 5-methyl- 2-(4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl)pyridine (1.80 g, assume quantitative) as a brown solid. LC-MS (ES-API, Method C): 1.70 min, m / z 296.2 [M+H]+1H NMR (400 MHz, DMSO-cfe) 6 8.51 (d, J = 1 .6 Hz, 1 H), 8.07 (d, J = 8.4 Hz, 2H), 7.88 (d, J = 8.0 Hz, 1 H), 7.77 (d, J = 8.0 Hz, 2H), 7.71-7.69 (m, 1 H), 2.34 (s, 3H), 1.31 (s, 12H) ppm.Intermediate 34: 2-cyclopropyl-5-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]pyridineStep 1 : 5-bromo-2-cyclopropyl-pyridineUnder a N2 atmosphere, a solution of 2,5-dibromopyridine (50.0 g, 211 mmol), cyclopropylmagnesium bromide (500 mL, 1 M in THF), Zinc chloride (1 L, 0.5M in THF) and tetrakis(triphenylphosphine)palladium(0) (14.6 g, 12.7 mmol) was stirred at r.t. for 16h. A saturated solution of ammonium chloride (400 mL) was added. The mixture was partitioned between EtOAc (200 mL) and water (600 mL). The layers were separated and the aqueous layer was extracted with EtOAc (2 x 200 mL). The combined organic layers were washed with a saturated solution of brine (2 L), dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting with 100% petrol afforded 5-bromo-2-cyclopropyl- pyridine (23.0 g, 116 mmol, 55% yield) as a yellow oil. LC-MS (ES-API, Method D): 1.36 min, m / z 244.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 8.49 (d, J = 2.2 Hz, 1 H), 7.85 (dd, J = 8.4, 2.3 Hz, 1 H), 7.29 (d, J = 8.4 Hz, 1 H), 2.15 - 2.04 (m, 1 H), 1.02 - 0.83 (m, 4H) ppm.Step 2: 4-(6-cyclopropyl-3-pyridyl)-3-methyl-phenolA solution of 5-bromo-2-cyclopropylpyridine (8.30 g, 41.9 mmol), 4-hydroxy-2-methylphenylboronic acid (7.64 g, 50.3 mmol), K2CO3 (8.69 g, 62.9 mmol) and Pd(dppf)Cl2’DCM (3.42 g, 4.19 mmol) in 1 ,4-dioxane / H2Q (65 mL / 7.2 mL) was stirred at 100°C under a N2 atmosphere for 16h. The mixturewas cooled to r.t. and then concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting (Petrol / EtOAc 50:1 to 10:1) afforded 4-(6-cyclopropyl-3- pyridyl)-3-methyl-phenol (6.68 g, 29.7 mmol, 71 % yield). LC-MS (ES-API, Method D) 0.57 min, m / z 226.2 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 9.43 (s, 1 H), 8.30 (d, J =1 .7 Hz, 1 H), 7.55 (dd, J = 8.0, 2.2 Hz, 1 H), 7.30 (d, J = 8.0 Hz, 1 H), 7.00 (d, J = 8.2 Hz, 1 H), 6.73 - 6.61 (m, 2H), 2.19 - 2.06 (m, 4H), 0.99 - 0.88 (m, 4H) ppm.Step 3: [4-(6-cyclopropyl-3-pyridyl)-3-methyl-phenyl] trifluoromethanesulfonateTo a mixture of 4-(6-cyclopropyl-3-pyridyl)-3-methyl-phenol (6.58 g, 29.2 mmol) and triethylamine (8.90 g, 87.6 mmol) in dry DCM (60 mL) was added trifluoromethanesulfonic anhydride (12.4 g, 43.8 mmol) slowly at 0 °C. The resulting mixture was stirred at r.t. under N2 atmosphere for 16h. The mixture was diluted with water (7 L) and extracted with DCM (3 x 80 mL). The organic layers were combined and concentrated under reduced pressure. Purification by flash column chromatography on silica gel, eluting (DCM / MeOH 1 :0 to 40:1) afforded [4-(6-cyclopropyl-3-pyridyl)-3-methyl-phenyl] trifluoromethanesulfonate (8.34 g, 23.3 mmol, 80% yield) as a clear oil.LC-MS (ES-API, Method D): 2.71 min, m / z 358.1 [M+H]+Step 4: 2-cyclopropyl-5-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]pyridineA mixture of [4-(6-cyclopropyl-3-pyridyl)-3-methyl-phenyl] trifluoromethanesulfonate (8.34 g, 2.34 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (11.9 g, 46.7 mmol), Pd(dppf)Cl2’DCM (2.90 g, 2.33 mmol) and potassium acetate (6.87 g, 70.0 mmol) in 1 ,4-dioxane (80 mL) was stirred at 90°C under a N2 atmosphere for 16h. The mixture was cooled back down to r.t. and concentrated under reduced pressure. Purification by flash column chromatography on silica gel eluting in 10% EtOAc in petrol afforded 2-cyclopropyl-5-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]pyridine (3.90 g, 11.6 mmol, 50% yield) as a white solid. LC-MS (ES-API, Method D): 2.71 min, m / z 336.3 [M+H]+.1H NMR (400 MHz, DMSO-cfe) 6 8.36 (d, J = 1.9 Hz, 1 H), 7.67 - 7.59 (m, 2H), 7.55 (d, J = 7.5 Hz, 1 H), 7.36 (d, J = 8.0 Hz, 1 H), 7.21 (d, J = 7.6 Hz, 1 H), 2.24 (s, 3H), 2.20 - 2.10 (m, 1 H), 1 .30 (s, 12H), 1.01 - 0.92 (m, 4H) ppm.Compounds prepared in a similar manner to that set out above are given below in Table 3.able 3General method for the synthesis of Intermediates 37-43Methods for preparing Intermediates 37-40 and 43 are given below. Further intermediates that were prepared in a similar manner from commercially available starting materials are given in Table 4.Intermediate 40: 4-cyclopropyl-1 -[2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]imidazoleStep 1 : 2-(4-bromo-2-fluoro-anilino)-1-cyclopropyl-ethanoneTo a solution of 4-bromo-2-fluoroaniline(3.00 g, 15.8 mmol) in EtOH (60 mL) were added 2-bromo-1- cyclopropylethan-1-one (2.83 g, 17.4 mmol), LiBr (2.06 g, 23.7 mmol) and NaHCOs (2.65 g, 31.6 mmol), the mixture was stirred at 80 °C under nitrogen overnight. The mixture was concentrated and purified by flash column chromatography on silica gel eluting in 10% EtOAc in petrol to afford 2-(4- bromo-2-fluoro-anilino)-1-cyclopropyl-ethanone (2.78 g, 10.2 mmol, 65% yield). LCMS (ES-API, Method C): 1 .62 min, m / z 272.0 1274.0 [M+H]+ / [M+2]+Step 2: / V-(4-bromo-2-fluoro-phenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamideTo a solution of 2-((4-bromo-2-fluorophenyl)amino)-1-cyclopropylethan-1-one (2.72 g, 10.0 mmol) in formic acid (21 mL) was added acetic anhydride (7 mL), the mixture was stirred at r.t. overnight. The mixture was concentrated and adjusted to pH 9 with NaHCOs and extracted with EtOAc, washed with brine and dried over Na2SO4 and concentrated to give / V-(4-bromo-2-fluoro-phenyl)- / V-(2-cyclopropyl- 2-oxo-ethyl)formamide (2.74 g, 9.13 mmol, 91 % yield). LCMS (ES-API, Method C): 1.22 min, m / z 300.0 I 302.0 [M+H]+Z [M+2]+Step 3: 1-(4-bromo-2-fluoro-phenyl)-4-cyclopropyl-imidazoleTo a solution of / V-(4-bromo-2-fluorophenyl)- / V-(2-cyclopropyl-2-oxoethyl)formamide (2.56 g, 8.50 mmol) in acetic acid (64 mL) was added NH+OAc (3.29 g, 42.5 mmol), the mixture was stirred at 130 °C under nitrogen overnight. The mixture was concentrated and adjusted to pH 9 with NaHCOs and extracted with EtOAc, washed with brine and dried over Na2SO4, concentrated and purified by flash column chromatography on silica gel eluting in 5% MeOH in DCM to give 1-(4-bromo-2-fluoro- phenyl)-4-cyclopropyl-imidazole (0.95 g, 3.38 mmol, 40% yield). LCMS (ES-API, Method C): 0.40 min, m / z 281 .0 1 283.0 [M+H]+ / [M+2]+Step 4: 4-cyclopropyl-1 -[2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazoleTo a solution of 1-(4-bromo-2-fluorophenyl)-4-cyclopropyl-1 H-imidazole (900 mg, 3.20 mmol) in THF (50 mL) were added 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1 ,3,2-dioxaborolane) (1.63 g, 6.40 mmol), Pd2dba3 (360 mg, 0.320 mmol) and XPhos (378 mg, 0.640 mmol) and KOAc (1 .08 g, 9.60 mmol), the mixture was stirred at 75 °C under nitrogen overnight. The mixture was concentrated and purified by reverse phase chromatography (30% MeCN in water) to give 4-cyclopropyl-1-[2-fluoro-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole (0.63 g, 1 .92 mmol, 60% yield). LCMS (ES-API,Method D): 0.29 min, m / z 247.1 [M+H]+boronic acidIntermediate 37: 4-methyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazoleStep 1 : 1-(4-bromoanilino)propan-2-oneKI (1.59 g, 9.60 mmol) and K2CO3 (1.45 g, 10.5 mmol) were added to a solution of 4-bromoaniline (1 .50 g, 8.70 mmol) in DMF (17.4 mL) under N2, and the reaction mixture was stirred for 5 minutes at 20 °C before chloroacetone (1 .56 mL, 19.6 mmol) was added. The reaction mixture was then stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo and the residue partitioned between EtOAc and water. The two phases were separated, and the water was re-extracted with EtOAc. The organic extracts were combined, washed with brine and filtered through phase separating filter paper. The crude material was purified by flash column chromatography silica gel eluting in 0-60% EtOAc in petrol to afford 1-(4-bromoanilino)propan-2-one (701 mg, 3.07 mmol, 35% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1 .62 min, m / z 227.9 1 229.8 [M+H]+ / [M+2]+.1H NMR (400 MHz, CDCh) 6 7.30 - 7.22 (m, 2H), 6.50 - 6.44 (m, 2H), 4.61 (br s, 1 H), 3.97 (d, J = 4.4 Hz, 2H), 2.26 (s, 3H) ppm. Step 2: / V-acetonyl- / V-(4-bromophenyl)formamideFormic acid (2.5mL, 66.4mmol) and acetic anhydride (6.30 mL, 66.4 mmol) were heated at 60 °C for 15 minutes. The solution was then cooled to 0 °C and 1-(4-bromoanilino)propan-2-one (0.13 mL, 3.07 mmol) was added. The mixture was heated at 60°C for 1 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between EtOAc and sat. aq. NaHCOs solution added. The two phases were separated and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separating filter paper and concentrated in vacuo to afford / V-acetonyl- / V-(4-bromophenyl)formamide (676 mg, 2.64 mmol, 86% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1 ,43min, m / z 255.91257.8 [M+H]+Z [M+2]+.1H NMR (400 MHz, CDCh) 6 8.46 (s, 1 H), 7.57-7.50 (m, 2H), 7.10-7.02 (m,2H), 4.52 (s,2H), 2.22 (s, 3H) ppm Step 3: 1-(4-bromophenyl)-4-methyl-imidazoleTEA (0.37 mL, 2.64 mmol) and NH4OAC (2.04 g, 26.4 mmol) were successively added to a suspension of / V-acetonyl- / V-(4-bromophenyl)formamide (676 mg, 2.64 mmol) in 1-butanol (13 mL). The vial was sealed, and the mixture irradiated at 150 °C for 45 min. The reaction mixture was cooled to r.t. and then concentrated in vacuo. The residue was partitioned between EtOAc and water. The two phases were separated, and the aqueous phase re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separating filter paper and then concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting in 0-100% EtOAc in petrol to afford 1-(4-bromophenyl)-4-methyl-imidazole (351 mg, 1 .48 mmol, 56% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.12 min, m / z 236.9 / 238.8 [M+H]+ / [M+2]+.1H NMR (400MHz, CDCb) 6 7.76 (d, J = 1 .3 Hz, 1 H), 7.62 - 7.56 (m, 2H), 7.27 - 7.21 (m, 2H), 6.98 - 6.96 (m, 1 H), 2.29 (d, J = 1.0 Hz, 3H) ppmStep 4: 4-methyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole 1-(4-Bromophenyl)-4-methyl-imidazole (351 mg, 1.48 mmol), bis(pinacolato)diboron (564 mg, 2.22 mmol) and KOAc (436 mg, 4.44 mmol) were combined in 1 ,4-dioxane (15 mL). The reaction mixture was degassed with N2 then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) chloride DCM complex (60.0 mg, 0.07 mmol) was added. The reaction mixture was heated at 100 °C overnight. After cooling to r.t., the reaction mixture was filtered through celite and washed with EtOAc. The filtrate was concentrated in vacuo and the crude material was purified by flash column chromatography on silica eluting in 0-100% EtOAc in petrol to afford 4-methyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]imidazole (189 mg, 0.660 mmol, 45% yield) as a brown oil. UPLC-MS (ES+, Method A): 1 .36 min, m / z 284.9 [M+H]+.1H NMR (400 MHz, CDCb) 6 7.92 - 7.86 (m, 2H), 7.81 (d, J = 1.4 Hz, 1 H), 7.39 - 7.32 (m, 2H), 7.05 - 7.04 (m, 1 H), 2.30 (d, J = 1.0 Hz, 3H), 1.36 (s, 12H) ppm.Intermediate 38: 4-cyclopropyl-1 -[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]imidazoleStep 1 : 2-(4-bromo-2-methyl-anilino)-1-cyclopropyl-ethanoneK2CO3 (446 mg, 3.20 mmol) and KI (491 mg, 3.00 mmol) were added to a solution of 4-bromo-2- methylaniline (500 mg, 2.70 mmol) in DMF (5.0 mL) under N2, and the reaction mixture was stirred for 5 minutes at 20 °C before 2-bromo-1 -cyclopropylethanone (0.59 mL, 6.05 mmol) was added. The reaction mixture was then stirred at 20 °C for 1 h. The reaction mixture was concentrated in vacuo.The residue was partitioned between EtOAc and water. The two phases were separated, and the water was re-extracted with EtOAc. The organic extracts were combined, washed with brine and filtered through phase separating filter paper. The crude material was purified by flash column chromatography on silica gel eluting in 0-60% EtOAc in petrol to afford 2-(4-bromo-2-methyl-anilino)- 1-cyclopropyl-ethanone (405 mg, 1.50 mmol, 56% yield) as a brown oil. UPLC-MS (ES+, Method A): 1 .90 min, m / z 267.9 1 269.9 [M+H]+ / [M+2]+.1H NMR (400 MHz, CDCb) 6 7.21 (dd, J = 8.3, 2.5 Hz, 1 H), 7.18 - 7.16 (m, 1 H), 6.36 (d, J = 8.4Hz, 1 H), 4.60 (br s, 1 H), 4.17 (s, 2H), 2.17 (s, 3H), 2.05 - 1.98 (m, 1 H), 1.20 - 1.15 (m, 2H), 1.05 - 0.99 (m, 2H) ppm.Step 2: / V-(4-bromo-2-methyl-phenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamideFormic acid (1.23 mL, 32.6 mmol) and acetic anhydride (3.1 mL, 32.6 mmol) were heated at 60 °C for 15 minutes. The solution was then cooled to 0 °C and 2-(4-bromo-2-methyl-anilino)-1-cyclopropyl- ethanone (0.13 mL, 1.51 mmol) was added. The mixture was heated at 60 °C for 1 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between EtOAc and sat. aq. NaHCOs solution. The two phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separating filter paper and concentrated in vacuo to afford / V-(4-bromo-2-methyl-phenyl)- / V-(2- cyclopropyl-2-oxo-ethyl)formamide (423 mg, 1 .43 mmol, 95% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1.67 min, m / z 295.9 I 297.9 [M+H]+ / [M+2]+.1H NMR (400 MHz, CDCb) 6 8.18 (s, 1 H), 7.44 (d, J = 2.0 Hz, 1 H), 7.38 - 7.34 (m, 1 H), 7.23 (d, J = 8.4 Hz, 1 H), 4.58 (s, 2H), 2.29 (s, 3H), 1 .97 - 1.90 (m, 1 H), 1.13 - 1.08 (m, 2H), 0.99-0.93 (m, 2H) ppm.Step 3: 1-(4-bromo-2-methylphenyl)-4-cyclopropyl-imidazoleTEA (0.2mL, 1 .43mmol) and NH+OAc (1 .10 g, 14.3 mmol) were successively added to a suspension of / V-(4-bromo-2-methyl-phenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamide (423 mg, 1.43 mmol) in 1- butanol (7 mL). The vial was sealed, and the mixture irradiated at 150 °C for 45 min. The reaction mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between EtOAc and water. The two phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, filtered through phase separating filter paper and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting in 0 - 50% EtOAc in petrol (to afford 1-(4-bromo-2-methyl-phenyl)-4-cyclopropyl-imidazole (129 mg, 0.470 mmol, 33% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1 .32 min, m / z 277.0 I 278.9 [M+H]+Z [M+2]+.1H NMR (400 MHz, CDCb) 6 7.47 (d, J = 2.0 Hz, 1 H), 7.42 - 7.38 (m, 2H), 7.07 (d, J = 8.3 Hz, 1 H), 6.75 (d, J = 1 .3 Hz, 1 H), 2.18 (s, 3H), 1 .94 - 1.86 (m, 1 H), 0.92 - 0.85 (m, 2H), 0.84 - 0.79 (m, 2H) ppm.Step 4: 4-cyclopropyl-1 -[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole 1-(4-Bromophenyl)-4-cyclopropyl-imidazole (129 mg, 0.470 mmol), bis(pinacolato)diboron (196 mg, 0.770 mmol) and KOAc (151 mg, 1.54 mmol) were combined in 1 ,4-dioxane (5 mL). The reaction mixture was degassed with N2 then [1 ,1 '-bis(diphenylphosphino)ferrocene]palladium(ll) chloride DCM complex (21 .0 mg, 0.0300 mmol) was added. The reaction mixture was heated at 100 °C overnight. Cooled to r.t. and the reaction mixture was filtered through celite and washed through with EtOAc. The filtrate was concentrated in vacuo. The crude material was purified by flash column chromatography silica eluting in 0-100% EtOAc in petrol to afford 4-cyclopropyl-1-[2-methyl-4- (4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole (quantitative yield) as a brown oil. UPLC-MS (ES+, Method A): 1.52 min, m / z 325.0 [M+H]+.1H NMR (400 MHz, CDCb) 6 7.76 (d, J = 1 .4 Hz, 1 H), 7.70 (d, J = 7.8 Hz, 1 H), 7.44 (d, J = 1 .4 Hz, 1 H), 7.20 (d, J = 7.8 Hz, 1 H), 6.79 (d, J=1 .3 Hz, 1 H), 2.23 (s, 3H), 1 .94 - 1 .87 (m, 1 H), 1 .36 (s, 12H), 0.91 - 0.85 (m, 2H), 0.84-0.80 (m, 2H) ppm.Intermediate 39: 4-cyclopropyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]imidazoleStep 1 : 2-(4-bromoanilino)-1-cyclopropyl-ethanoneKI (3.40g, 20.5mmol) and K2CO3 (3.09 g, 22.4 mmol) were added to a solution of 4-bromoaniline (3.2 g, 18.7 mmol) in DMF (34 mL). The reaction was stirred for 5 minutes at 20 °C, under N2 before 2- bromo-1 -cyclopropylethanone (4.1 mL, 41.9 mmol) was added. The reaction mixture was stirred at 20°C for 1 h. The reaction mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water.and the two phases were separated. The aqueous layer was re-extracted with EtOAc. The organic extracts were combined, washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. The crude material was purified by flash column chromatography on silica gel eluting in 0 - 60% EtOAc in petrol to afford 2-(4-bromoanilino)-1-cyclopropyl-ethanone (4.28 g, 16.8 mmol, 90% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1 .80 min, m / z 253.9 1255.9 [M+H]+ / [M+2]+.1H NMR (400 MHz, CDCh) 6 7.27 (d, J = 8.9 Hz, 2H), 6.49 (d, J = 8.9 Hz, 2H), 4.67 (s, 1 H), 4.13 (s, 2H), 2.03 - 1.96 (m, 1 H), 1 .18 - 1 .13 (m, 2H), 1.03 - 0.98 (m, 2H) ppm.Step 2: / V-(4-bromophenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamideFormic acid (13.7 mL, 364 mmol) and acetic anhydride (34 mL, 364 mmol) were heated at 60 °C for 15 minutes. The solution was then cooled to 0 °C and 2-(4-bromoanilino)-1-cyclopropyl-ethanone (4.28 g, 16.8 mmol) was added. The mixture was heated at 60 °C for 1 h. The reaction mixture was cooled to r.t. and concentrated in vacuo. The residue was partitioned between EtOAc and sat. aq. NaHCOs solution. The two phases were separated, and the aqueous phase was re-extracted with EtOAc. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated in vacuo to afford / V-(4-bromophenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamide (4.75 g, 16.8 mmol, 99% yield) as a yellow oil. UPLC-MS (ES+, Method A): 1 .57 min, m / z 281 .9 / 283.9 [M+H]+I [M+2]+.1H NMR (400 MHz, CDCh) 6 8.47 (s, 1 H), 7.51 (d, J = 8.8 Hz, 2H), 7.06 (d, J = 8.8 Hz, 2H), 4.70 (s, 2H), 2.02 - 1.94 (m, 1 H), 1 .15 - 1 .10 (m, 2H), 1.01 - 0.95 (m, 2H) ppm.Step 3: 1-(4-bromophenyl)-4-cyclopropyl-imidazole / V-(4-bromophenyl)- / V-(2-cyclopropyl-2-oxo-ethyl)formamide (4.75 g, 16.8 mmol) in 1 -butanol (40 mL), triethylamine (2.35 mL, 16.9 mmol) and NH4OAC (13.0 g, 168 mmol) were split into 4 equal portions each and added to 4 microwave vials. The vials were sealed and the mixture irradiated at 150 °C for 1 .5 h. The reaction mixtures were combined and concentrated in vacuo. The residue was partitioned between EtOAc and water. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The crude material was purified by flash column chromatography on silica gel eluting in 0 - 50% EtOAc in petrol (to afford 1-(4-bromophenyl)-4-cyclopropyl-imidazole (2.35 g, 8.93 mmol, 53% yield) as a yellow solid. UPLC-MS (ES+, Method A): 1.21 min, m / z 262.9 / 264.9 [M+H]+ / [M+2]+.1H NMR (400 MHz, CDCh) 6 7.71 (d, J = 1 .2 Hz, 1 H), 7.58 (d, J = 8.8 Hz, 2H), 7.26 (d, J = 8.8 Hz, 2H), 7.00 (d, 1 H, J = 1 ,2Hz, 1 H), 1 .96 - 1 .88 (m, 1 H), 0.94 - 0.81 (m, 4H) ppm.Step 4: 4-cyclopropyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole 1-(4-Bromophenyl)-4-cyclopropyl-imidazole (2.35 g, 8.90 mmol), bis(pinacolato)diboron (2.49 g, 9.80 mmol) and KOAc (1.75 g, 17.9 mmol) were combined in 1 ,4-dioxane (50 mL) and the mixture was degassed with N2 for 10 min. [1 ,1 '-Bis(diphenylphosphino)ferrocene]Palladium(ll) chloride DCM complex (729 mg, 0.890 mmol) was added and the reaction mixture was heated at 90 °C for 2 h. The mixture was cooled to r.t. filtered through celite washed with EtOAc. The filtrate was concentrated in vacuo and the residue purified by flash column chromatography (silica) eluting with EtOAc in Pet. Ether (0-100%) to afford 4-cyclopropyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole (1 .80 g, 5.80 mmol, 65% yield) as a colourless oil. UPLC-MS (ES+, Method A): 1 .45 min, m / z 311 .0 [M+H]+.1H NMR (400 MHz, CDCI3) 6 7.89 (d, J= 8.4Hz, 2H), 7.84 - 7.82 (m, 1 H), 7.35 (d, J = 8.4Hz, 2H), 7.06 - 7.05 (m, 1 H), 1.96 - 1.89 (m, 1 H), 1.36 (s, 12H), 0.93 - 0.82 (m, 4H) ppm.Intermediate 43: 2,4-dimethyl-1 -[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2- yl)phenyl]imidazoleStep 1 Step 2Step 1 : 1-(4-bromophenyl)-2,4-dimethyl-imidazoleCui (606 mg, 3.18 mmol) and (+ / -)-trans-1 ,2-diaminocyclohexane (727 mg, 6.40 mmol) were added to 1-bromo-4-iodobenzene (3.00 g, 10.6 mmol), 2,5-dimethyl-1 H-imidazole (2.04 g, 21.2 mmol) and CS2CO3 (10.4 g, 31.8 mmol) in diethylene glycol dimethyl ether (10 mL). The mixture was degassed with N2 for 10 minutes. The vial was then sealed and heated at 150 °C for 18 h. The mixture was coled to r.t. and extracted with EtOAc. The combined organic extracts were dried over Na2SC>4, filtered, concentrated in vacuo and purified by flash column chromatography on silica gel eluting in 2% MeOH in DCM to afford 1-(4-bromophenyl)-2,4-dimethyl-imidazole (470 mg, 1.87 mmol, 17% yield) as an orange oil. LCMS (ES-API, Method C): 0.30 min, m / z 251 .0 1253.0 [M+H]+ / [M+2]+Step 2: 2,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazolePd2dba3 (157 mg, 0.170 mmol) and XPhos (163 mg, 0.340 mmol) were added to a solution of 1-(4- bromophenyl)-2,4-dimethyl-1 H-imidazole (430 mg, 1.70 mmol), 4,4,5,5-tetramethyl-2-(3,3,4,4- tetramethylborolan-1-yl)-1 ,3,2-dioxaborolane (870 mg, 3.40 mmol) and KOAc (504 mg, 5.10 mmol) in THF (10 mL) The mixture was heated to 75 °C for 18 h under N2. The mixture was cooled to r.t., filtered and concentrated in vacuo and purified by reverse phase column eluting in 0-30% MeCN in water) to afford 2,4-dimethyl-1-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole (300 mg, 1.00 mmol, 59% yield). LCMS (ES-API, Method D): 1.12 min, m / z 299.1 [M+H]+Compounds prepared in a similar manner to that set out above are given below in Table 4.Table 4General method for the synthesis of Intermediates 44-46A method for preparing Intermediate 44 is given below. Further intermediates that were prepared in a similar manner from commercially available bromophenols are given in Table 5. Intermediate 44: 2-cyclopropyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2- yl)phenyl]imidazoleStep 1 Step 2Step 3Step 1 : 4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenolTo a solution of 4-bromo-2-cyclopropyl-1-methyl-1 / 7-imidazole (20.0 g, 100 mmol) in 1 ,4-dioxane (470 mL) and water (53 mL) were added (4-hydroxyphenyl)boronic acid (17.8 g, 0.120 mol), Pd(dppf)Cl2CH2Cl2 (8.13 g, 0.010 mol) and K2CO3 (20.6 g, 150 mmol), the mixture was stirred at 100 °C under nitrogen overnight. The mixture was concentrated and purified by column chromatography eluting in 50% EtOAc in petrol to afford 4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenol (19.9 g, 92.7 mmol, 93% yield). LCMS (ES-API, Method C): 0.32 min, m / z 215.2 [M+H]+1H NMR (400 MHz, DMSO-d6) 6 9.27 (s, 1 H), 7.48 (d, J = 8.5 Hz, 2H), 7.26 (s, 1 H), 6.73 (d, J = 8.7 Hz, 2H), 3.67 (s, 3H), 2.01 - 1 .94 (m, 1 H), 0.96 - 0.85 (m, 4H) ppm.Step 2: [4-(2-cyclopropyl-1-methyl-imidazol-4-yl)phenyl] trifluoro methanesulfonateTo a solution of 4-(2-cyclopropyl-1-methyl-1 H-imidazol-4-yl)phenol (19.9 g, 92.7 mmol) in DCM was added trifluoromethanesulfonic anhydride (23.4 mL, 139 mmol) and triethylamine (38.6 mL, 278 mmol) at 0 °C and then at room temperature overnight. The mixture was concentrated and purified by flash column chromatography eluting in 25% EtOAc in petrol to give [4-(2-cyclopropyl-1-methyl- imidazol-4-yl)phenyl] trifluoromethanesulfonate (13.0 g, 37.5 mmol, 41 %). LCMS (ES-API, Method D): 1 .23 min, m / z 347.0 [M+H]+.1H NMR (400 MHz, DMSO-d6) 6 7.82 (d, J= 9.0 Hz, 2H), 7.60 (s, 1 H), 7.43 (d, J = 8.9 Hz, 2H), 3.71 (s, 3H), 2.04-1 .96 (m, 1 H), 0.98-0.93 (m, 2H), 0.91 - 0.86 (m, 2H) ppm. Step 3: 2-cyclopropyl-1-methyl-4-[4-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazoleTo a solution of 4-(2-cyclopropyl-1-methyl-1 / 7-imidazol-4-yl)phenyl trifluoromethanesulfonate (13.6 g, 39.2 mmol) in dioxane (90 mL) were added b / s(pinacolato)diboron (19.9 g, 78.3 mmol), Pd(dppf)Cl2CH2Cl2 (3.20 g, 3.90 mmol) and KOAc (1 1.5 g, 117 mmol), the mixture was stirred at 90 °C under nitrogen overnight. The mixture was concentrated and purified by flash column chromatography eluting in (petrol / EtOAc 2:1) to afford 2-cyclopropyl-1-methyl-4-[4-(4, 4,5,5- tetramethyl-1 ,3,2-dioxaborolan-2-yl)phenyl]imidazole (17.8 g, 54.9 mmol, 100%).Table 5General method for the synthesis of Intermediates 47-49A method for preparing Intermediate 47 is given below. Further intermediates that were prepared in a similar manner from commercially available starting materials are given in Table 6.Intermediate 47: 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)-N-(2,2,2- trifluoroethyl)benzamideStep 1 : Propylphosphonic anhydride 50% solution in EtOAc (1 .8 mL, 3.02 mmol) was added dropwise to a stirred solution of 3-(4,4,5,5-tetramethyl-1 ,3,2-dioxaborolan-2-yl)benzoic acid (0.50 g, 2.02 mmol), / V, / V-diisopropylethylamine (1.05 mL, 6.05 mmol) and trifluoroethylamine (0.24 mL, 3.02 mmol) at room temperature and was stirred for 16h. The reaction was quenched with EtOAc (15 mL) and saturated sodium bicarbonate solution (15 mL). The two phases were separated and the organic layer was washed with 3 x 10 mL of saturated brine, passed through a phase separator, and concentrated in vacuo. The crude product was triturated and slurried in 10 mL of Pet. Ether. The solid was collected and dried by vacuum filtration to afford 3-(4,4,5,5-tetramethyl- 1 ,3,2-dioxaborolan-2-yl)- / V-(2,2,2-trifluoroethyl)benzamide (658 mg, 1.98 mmol, 98% yield) as a white powder.Table 6General Method for the synthesis final compounds 1-62Example 1 : 6-[[5-[4-(4-cyclopropylimidazol-1 -yl)-3-methyl-phenyl]-2-ethyl-1 ,2,4-triazol-3- yl]amino]spiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]-1-oneA mixture of 6-[(5-bromo-2-ethyl-1 ,2,4-triazol-3-yl)amino]spiro[2,3-dihydroisoquinoline-4,1 '- cyclopropane]-1-one (100 mg, 0.3 mmol), 4-cyclopropyl-1-[2-methyl-4-(4,4,5,5-tetramethyl-1 ,3,2- dioxaborolan-2-yl)phenyl]imidazole (107 mg, 0.35 mmol), potassium carbonate (192 mg ,1 .5 mmol) and Pd(dppf)Cl2 DCM (22.5 mg, 0.03 mmol) in degassed dioxane (8 mL) and water (2 mL) was stirred at 110 °C under nitrogen overnight. The reaction was cooled, diluted with water (10 mL) and extracted with ethyl acetate (3 x 20mL). The combined organic phases were dried over sodium sulfate, filtered, and evaporated. The residue was purified by prep-HPLC to yield 6-[[5-[4-(4-cyclopropylimidazol-1- yl)-3-fluoro-phenyl]-2-ethyl-1 ,2,4-triazol-3-yl]amino]spiro[2,3-dihydroisoquinoline-4,1 '-cyclopropane]- 1-one (4.3 mg, 0.009 mmol, 3% yield) as a white soild. LC-MS (ES+, Method L): 2.31 min, m / z 480.20 [M+H]+. 1 H NMR (400 MHz, DMSO-d) 6 9.27 (s, 1 H), 7.97 (s, 1 H), 7.88 (d, J = 8.3 Hz, 1 H), 7.84 (d,J = 8.5 Hz, 1 H), 7.77 (s, 1 H), 7.68 (s, 1 H), 7.62 (d, J = 8.6 Hz, 1 H), 7.41 (s, 1 H), 7.36 (d, J = 8.1 Hz,1 H), 7.17 (s, 1 H), 4.21 (q, J = 7.2 Hz, 2H), 3.23 (s, 2H), 2.25 (s, 3H), 1.38 (t, J = 7.1 Hz, 3H), 1.01 (d,J = 12.9 Hz, 4H), 0.80 (d, J = 8.1 Hz, 2H), 0.71 (d, J = 5.1 Hz, 2H) ppm.The following 61 examples were made by the same general method:able 7: Example CompoundsROCK2 Binding Activity:Assay for ROCK2 inhibition was performed using the protein construct N-terminal 6His-tagged ROCK2 catalytic domain 11-552 (Dundee University, UK). Protein was purified from a baculovirus expression system. Long S6 peptide (KEAKEKRQEQIAKRRRLSSLRASTSKSGGSQK) was used as substrate. Kinase reactions were carried out in 15 pL volume in a 96-well plate (black, half area) using 1 .25 nM constitutively active ROCK2 kinase, 100 pM long S6 peptide, 20 pM ATP and test compound in DMSO (or DMSO only for controls). The final concentration of DMSO was <1 %. Assay buffer was 50 mM HEPES pH 7.5 supplemented with 0.2 mM EDTA, 10 mM magnesium acetate, 0.01 % Tween-20, 1 mM DTT and 0.01 % BSA. Test compounds were pre-incubated with ROCK2 kinase for 1 h before addition of ATP and long S6 peptide. After incubation for a further 1 h, the amount of ADP produced was measured using ADP-Glo Kinase Assay (Promega) as per manufacturer’s instructions. The luminescence was measured on a PHERAstar FS (BMG Labtech). The concentration of test compound required to inhibit ADP production by 50% (the IC50) was calculated using a four-parameter logistic function with software by Dotmatics.Table 8 shows the ROCK2 or ROCK1 binding activity, as determined by the assay described above, for certain compounds of the formula, categorised based on the ROCK2 or ROCK1 IC50 value of the compound as “+”, “++”, “+++” and “++++”. The category “+” refers to compounds with a ROCK2 or ROCK1 IC50 value of > 10 pM. The category “++” refers to compounds with a ROCK2 or ROCK1 IC50 value of 10 to 3 pM. The category “+++” refers to compounds with a ROCK1 or ROCK2 IC50 value of 3 to 0.3 pM. The category “++++” refers to compounds with a ROCK1 or ROCK2 IC50 value of <0.3pM.

[0151] 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.

[0152] Features, integers, characteristics, compounds, chemical moieties or groups described in conjunction with a particular aspect, embodiment or example of the invention are to be understood to be applicable to any other aspect, embodiment or example described herein unless incompatible therewith. All of the features disclosed in this specification (including any accompanying claims, abstract and drawings), and / or all of the steps of any method or process so disclosed, may be combined in any combination, except combinations where at least some of such features and / or steps are mutually exclusive. The invention is not restricted to the details of any foregoing embodiments. The invention extends to any novel one, or any novel combination, of the features disclosed in this specification (including any accompanying claims, abstract and drawings), or to any novel one, or any novel combination, of the steps of any method or process so disclosed.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.

Claims

CLAIMS1. A compound of formula (I) or a pharmaceutically acceptable salt thereof:X1and X2are each independently selected from carbon and nitrogen; wherein at least one of X1and X2is carbon;L1is selected from -O- and -NR7-;R1is independently selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R3is independently selected from Ci-C4-alkyl, Ci-C4-haloalkyl, Co-C3-alkylene-R3a, C2-C4-alkyl substituted with NR8R9, C2-C4-alkyl substituted with SR8and C2-C4-alkyl substituted with OR10; wherein R3ais independently at each occurrence selected from cyclopropyl and azetidinyl, said cyclopropyl and azetidinyl groups being optionally substituted with from 1 to 4 R11groups;R4and R12are each independently at each occurrence selected from halo, nitro, cyano, NR8R9, OR10, SR8, SO2R8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl substituted with NR8R9, C1- C4-alkyl substituted with OR10, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R5is independently selected from H, CONR8R8, phenyl optionally substituted with a single R13group and / or from 1 to 3 R12groups, and 4- to 10- membered heterocyclyl, wherein said heterocyclyl group may be monocyclic or bicyclic and wherein any given ring of said heterocyclyl group may be saturated, unsaturated or partially unsaturated; wherein any saturated ring or partially unsaturated ring is optionally substituted with a single R13group and / or from 1 to 4 R11groups and wherein any unsaturated ring is optionally substituted with a single R13group and / or from 1 to 3 R12groups;R6is independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, cyclopropyl; or where two R6groups are attached to the same carbon atom, the two R6groups and the carbon atom to which they are attached may together form a C3-C6 cycloalkyl ring; or where two R6groups are attached to adjacent carbonatoms, the two R6groups and the carbon atoms to which they are attached may together form a C3- Ce cycloalkyl ring;R6ais independently at each occurrence selected from H, halo, Ci-C4-alkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10, and cyclopropyl;R7and R8are each independently at each occurrence selected from H, Ci-C4-alkyl and C1-C4- haloalkyl;R9is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2- Ci-C4-alkyl; or R8and R9, together with the nitrogen atom to which they are attached together form a 5- to 8-membered heterocycloalkyl group optionally substituted with from 0 to 4 R11cgroups;R10is independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and C1-C4- haloalkyl;R11is independently at each occurrence selected from =O, halo, nitro, cyano, NR8R9, OR14, SR8, SO2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R11cis independently selected from =O, halo , nitro, cyano, NR8R9a, OR14, SR8, SC>2NR8R8, CO2R8, C(O)R8, CONR8R8, Ci-C4-alkyl, C2-C4-alkenyl, C2-C4-alkynyl, Ci-C4-haloalkyl and cyclopropyl;R9ais independently at each occurrence selected from H, Ci-C4-alkyl, C(O)-Ci-C4-alkyl and S(O)2- Ci-C4-alkyl;R13is independently selected from Cs-Ce-cycloalkyl, 3- to 6-membered-heterocycloalkyl, Ci-C4-alkyl substituted with NR8R9, Ci-C4-alkyl substituted with OR10; wherein where R13is cycloalkyl or heterocycloalkyl, R13is optionally substituted with from 1 to 4 R11groups;R14is independently at each occurrence selected from H, Ci-C4-alkyl, Ci-C4-haloalkyl and C(O)-Ci- C4-alkyl; and m is an integer selected from 0, 1 , 2, 3 and 4; p is an integer selected from 0, 1 , 2 and 3; 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: oxo, fluoro, nitro, cyano, NRaRb, ORa, SRa, CC>2Ra, C(O)Ra, CONRaRa; wherein Rais independently at each occurrence selected from H, Ci-C4-haloalkyl, and Ci-C4-alkyl; 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 p is selected from 0 and 1 .

3. A compound of claim 1 or claim 2, wherein L1is -NR7-.

4. A compound of claim 3, wherein R7is H.

5. A compound of any one of claims 1 to 4, wherein R3is independently selected from C1-C4- alkyl and cyclopropyl.

6. A compound of any one of claims 1 to 5, wherein m is 1 .

7. A compound of claim 6, wherein R4is selected from Ci-Cs-alkyl and cyclopropyl.

8. A compound of any one of claims 1 to 7, wherein R5is imidazole, optionally substituted with a single R13group and / or from 1 to 3 R12groups.

9. A compound of any one of claims 1 to 7, wherein R5is pyridine, optionally substituted with a single R13group and / or from 1 to 3 R12groups.

10. A compound of claim 9, wherein R5has the structure:wherein x4 is an integer independently selected from 0, 1 and 2.

11. A compound of claim 9, wherein R5has the structurewherein x4 is an integer independently selected from 0, 1 and 2.

12. A compound of any one of claims 1 to 11 , wherein Z1is -CR6R6-CR6R6-.

13. A compound of any one of claims 1 to 11 , wherein Z1-CR6=CR6-.

14. A compound of any one of claims 1 to 13, wherein R6is independently at each occurrence selected from H and Ci-C4-alkyl.

15. A compound of any one of claims 1 to 13, wherein two R6groups are attached to the same carbon atom and the two R6groups and the carbon atom to which they are attached together form a C3-C6 cycloalkyl ring.

16. A compound of any one of claims 1 to 13, wherein two R6groups are attached to adjacent carbon atoms and the two R6groups and the carbon atoms to which they are attached together form a C3-C6 cycloalkyl ring.

17. A compound of any one of claims 1 to 16, wherein X1and X2are each carbon.

18. A compound of claim 1 wherein the compound of formula (I) is selected from:19. A pharmaceutical formulation comprising a compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable excipient.

20. A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use as a medicament. 21 . A compound of any one of claims 1 to 18, or a pharmaceutically acceptable salt thereof, for use in treating a a disease or disorder selected from: fibrotic diseases, auto-immune, inflammatory-fibrotic conditions, inflammatory conditions, central nervous system disorders, or cancer.

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