Decahydroquinolines as DNA polymerase theta inhibitors

Abstract

The present invention relates to compounds of the Formula (I), and pharmaceutically salts thereof, wherein R1, R2, R3, R4, A1 and R6 are each as defined herein. The compounds of the present invention inhibit Polθ. The novel therapeutic compounds are therefore useful for the treatment and / or prevention of diseases and conditions in which Polθ activity is implicated, such as, for example but not limited to, the treatment and / or prevention of cancer. The present invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds defined herein, to processes for synthesising these compounds and to their use for the treatment of diseases and / or conditions in which Polθ activity is implicated.

Description

DECAHYDROQUINOLINES AS DNA POLYMERASE THETA INHIBITORSINTRODUCTION

[0001] The present invention relates to novel therapeutic compounds. More specifically, the present invention relates to novel therapeutic compounds that inhibit PolQ. The novel therapeutic compounds are therefore useful for the treatment and / or prevention of diseases and conditions in which PolQ activity is implicated, such as, for example but not limited to, the treatment and / or prevention of cancer. The present invention also relates to pharmaceutical compositions comprising the novel therapeutic compounds defined herein, to processes for synthesising these compounds and to their use for the treatment of diseases and / or conditions in which PolQ activity is implicated.BACKGROUND OF THE INVENTION

[0002] The Maintenance of genome integrity is of upmost importance for cell survival since genomic aberration is a major cause of disease, notably cancer1. The genome is continuously challenged by a various types of DNA damage, amongst which double strand breaks (DSBs) are considered the most toxic as they are a source of dramatic genomic rearrangements if not repaired or repaired inaccurately2.

[0003] DNA polymerase theta (Polθ, encoded by POLQ) is a multifunctional enzyme comprising a C-terminal DNA polymerase domain, an N-terminal ATPase / helicase domain and a less structured central domain with protein interaction partner binding function3. Both enzymatic functions have been shown to have mechanistic activity in DNA repair processes. The helicase domain disrupts Rad51 nucleofilament formation, removes RPA from single stranded DNA and stimulates ssDNA annealing. The polymerase domain extends single stranded DNA ends to close ssDNA gaps.

[0004] Polθ expression is largely absent in normal cells, but expression has been shown to be upregulated in multiple cancers and increased expression correlates with poor prognosis4,5,6. In normal mammalian cells, Homologous Recombination (HR) and Non- Homologous End Joining (NHEJ) are the two major pathways for repairing DSBs faithfully. Other alternative pathways referred to as Alternative-NHEJ (ALT-NHEJ) are also involved in DSB repair, mostly in the absence of HR and NHEJ, as back-up pathways7,4,8. The most characterised ALT-NHEJ pathway is Micro-Homology End Joining (MMEJ), which relies on micro-homologies flanking the breaks to repair the lesion. In doing so, MMEJ inherentlyleads to deletions and therefore contributes genomic instability9 10. Polθ is a prominent actor in MME J which has been shown to process and anneal the single strand DNA ends, as well as to synthesise DNA to complete the repair11’12’13.

[0005] DNA Damage Response (DDR) deficiency, such as loss of HR, results in genomic instability and is often associated with cancer. However, DDR deficient cancers can become critically dependent on back-up DNA repair pathways, which present an Achilles heel that can be targeted to eliminate cancer cells. For example, PARP1 inhibitors are selectively lethal in cancer cells deficient in components of HR (e.g. ATM, BARD1 , PALB2, BRCA1 , BRCA2 etc.)14.

[0006] Likewise, selective lethality is observed when PolQ functions are abrogated in the context of HR and NHEJ deficiencies. MMEJ is infrequently used when HR and NHEJ are available15but becomes necessary when the canonical pathways are impaired during carcinogenesis, rendering these cancer cells specifically dependant on Polθ4,6.

[0007] PARP inhibitors are used in the treatment for HR deficient cancers but inherent or acquired drug resistance is a significant limitation. Two of the most frequent mechanisms of resistance to PARPi, could be counteracted by inhibition of Polθ:(i) The main mechanism of resistance observed in clinical samples, is the reactivation of HR through reversion of the mutation that caused the HR deficiency17. A significant proportion of such reversion mutations are thought to be acquired through the action of PolQ in MMEJ18 19.(ii) Restoration of HR activity in BRCA1 deficient cancer through loss of SHLD / 53BP1 complex has been shown to lead to PARP inhibitor resistance20’21’22 23. PolQ inhibitors are anticipated to be useful in treating such tumours24and deficiency in both the SHLD / 53BP1 complex and BRCA1 is demonstrated to result in vulnerability to PolQ inhibition2526.

[0008] In addition to the synthetic lethality observed in HR and NHEJ deficient cancer, PolQ loss has been reported to sensitise cancer cells to many standard of care agents. Depletion of PolQ leads to potentiation of various chemotherapies, such as topo-isomerase1 / 2 inhibitors27hydroxyurea, platinum agents28, bleomycin, as well as irradiation2930. Furthermore, loss of PolQ was also shown to enhance effects of DNA repair targeted inhibitors: e.g. PARP31, ATM27, ATR32and DNAPK32.

[0009] Considering the numerous evidence of sensitisation to DNA repair associated therapies, PolQ is a promising target for combination with already established standard of care agents.

[0010] There is therefore a need for new and improved agents capable of targeting PolQ and inhibiting its activity. The present invention was devised with the foregoing in mind. References1. Helleday T., et al, Nat Rev Genet. (2014); 15:585-982. Ceccaldi R., et al, Trends Cell Biol. (2016); 26:52-643. Seki M. et al., Nucleic Acids Res., (2003); 31:6117-264. Ceccaldi R., et al., Nature (2015); 518:258-625. Lemee F., et al,. PNAS (2010); 107:13390-56. Higgins G.S., et al., Oncotarget (2010) ; 1:175-847. Kabotyanski E.B., et al, Nucleic Acids Res. (1998); 26:5333-428. Ahrabi S., et al, Nucleic Acids Res. (2016); 44:5743-579. McVey M., et al., Trends Genet. (2008); 24:529-3810. Sfeir A., et al, Biochem Sci. (2015); 40:701-14)11. Chan S.H., et al., PLoS Genet. (2010); 6:e100100512. Wyatt D.W., et al, Mol Cell. (2016); 63:662-67313. Black S.J., et al., Nat Commun. (2019); 10:442314. Audeh M.W., et al., Lancet (2010); 376 (9737):245-5115. Truong W., et al., PNAS (2013); 110:7720-772516. Mateos-Gomez P.A., et al., Nature (2015); 518:254-5717. Noordermeer S.M., et al., Trends Cell Biol. (2019); 29:820-83418. Edwards S.L., et al., Nature (2008); 451(7182):1111-519. Lukashchuk N., et al., J Clin Oncol (2022) 40(16_suppl): 5559-5559)20. Jaspers J.E., et al., Cancer Discov. (2013); 3(1):6821. Pettitt S.J., et al., Nat Commun. (2018); 9:1849;22 Noordermeer S.M., et al., Nature (2018) 560:11723. Nacson J., et al, Cell Rep. (2018); 25(5):1384)24. Higgins G., et al, Science (2018); 359(6381):1217-121825. Zatreanu D., et al, Nat Commun. (2021); 12(1):363626. Feng W., et al, Nat Commun. (2019); 10(1):428627. Wang Zl et al., J Biol Chem. 2019 Mar 15; 294(11): 3909-391928. Dai CH et al., Oncotarget. 2016; 7(40):65157-6517029. Yousefzadeh MJ et al., PLoS Genet. 2014 Oct 2; 10(10):e100465430. Higgins G et al. Cancer Res. 2010 Apr 1 ;70(7):2984-9331. Schrempf et al., Trends Cancer. 2021;7(2):98-11132. Kumar RJ et al., NAR Cancer. 2020 Dec; 2(4): zcaa038SUMMARY OF THE INVENTION

[0011] In one aspect, the present invention provides a compound of Formula I as defined herein, and / or a pharmaceutically acceptable salt, hydrate or solvate thereof.

[0012] In another aspect, the present invention provides a pharmaceutical composition which comprises a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and one or more pharmaceutically acceptable excipients.

[0013] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0014] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which PolQ activity is implicated.

[0015] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of PolQ.

[0016] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer or benign neoplasms.

[0017] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.

[0018] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which PolQ activity is implicated.

[0019] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition associated with aberrant activity of PolQ.

[0020] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer or benign neoplasms.

[0021] In another aspect, the present invention the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a cancer.

[0022] In another aspect, the present invention provides a method of treating a disease or condition in which PolQ activity is implicated, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0023] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of PolQ, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0024] In another aspect, the present invention provides a method of treating cancer or benign neoplasms, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0025] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0026] In another aspect, the present invention provides a combination treatment comprising a compound of Formula I, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, with one or more additional therapeutic agents.

[0027] In another aspect, the present invention provides processes for preparing compounds of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined herein, with one or more additional therapeutic agents.

[0028] In a further aspect, the present invention provides the use of a compound of Formula I or a salt, hydrate or solvate thereof, for CRISPR gene editing in vitro or in vivo.

[0029] In another aspect, the present invention provides the use of a compound of Formula I or a salt, hydrate or solvate thereof, for increasing the efficiency of CRISPR gene editing in vitro or in vivo.

[0030] In another aspect, the present invention provides a compound of Formula I, or a salt, hydrate or solvate thereof, for use in CRISPR gene editing in vivo.

[0031] In another aspect, the present invention provides a compound of Formula I, or a salt, hydrate or solvate thereof, for use in increasing the efficiency of CRISPR gene editing in vivo.

[0032] Preferred, suitable, and optional features of any one particular aspect of the present invention are also preferred, suitable, and optional features of any other aspect.DETAILED DESCRIPTION OF THE INVENTIONDefinitions

[0033] Unless otherwise stated, the following terms used in the specification and claims have the following meanings set out below.

[0034] It is to be appreciated that references to “treating” or “treatment” include prophylaxis as well as the alleviation of established symptoms of a condition. “Treating” or “treatment” of a state, disorder or condition therefore includes: (1) preventing or delaying the appearance of clinical symptoms of the state, disorder or condition developing in a human that may be afflicted with or predisposed to the state, disorder or condition but does not yet experience or display clinical or subclinical symptoms of the state, disorder or condition, (2) inhibiting the state, disorder or condition, i.e., arresting, reducing or delaying the development of the disease or a relapse thereof (in case of maintenance treatment) or at least one clinical or subclinical symptom thereof, or (3) relieving or attenuating the disease, i.e., causing regression of the state, disorder or condition or at least one of its clinical or subclinical symptoms.

[0035] A “therapeutically effective amount” means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The "therapeutically effective amount" will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.

[0036] References to “PolQ” refer to DNA polymerase theta (encoded by POLQ).

[0037] The compounds and intermediates described herein may be named according to either the IUPAC (International Union for Pure and Applied Chemistry) or CAS (Chemical Abstracts Service) nomenclature systems. It should be understood that unless expressly stated to the contrary, the terms “compounds of Formula I”, “compounds of the invention” and the more general term “compounds” refer to and include any and all compounds described by and / or with reference to Formula I herein. It should also be understood that these terms encompasses all stereoisomers, i.e. cis and trans isomers, as well as optical isomers, i.e. R and S enantiomers, of such compounds, in substantially pure form and / or any mixtures of the foregoing in any ratio. This understanding extends to pharmaceutical compositions andmethods of treatment that employ or comprise one or more compounds of the Formula I , either by themselves or in combination with additional agents.

[0038] Unless specified otherwise, atoms are referred to herein by their chemical symbol as appearing in the IUPAC periodic table of the Elements. For example, “C” refers to a carbon atom.

[0039] The term "(m-nC)" or "(m-nC) group" used alone or as a prefix, refers to any group having m to n carbon atoms.

[0040] In this specification the term “alkyl” includes both straight and branched chain alkyl groups. References to individual alkyl groups such as “propyl” are specific for the straight chain version only and references to individual branched chain alkyl groups such as “isopropyl” are specific for the branched chain version only. For Example, “(1-6C)alkyl” includes (1- 4C)alkyl, (1-3C)alkyl, propyl, isopropyl and f-butyl. A similar convention applies to other radicals, for example “phenyl(1-6C)alkyl” includes phenyl(1-4C)alkyl, benzyl, 1-phenylethyl and 2-phenylethyl.

[0041] An “alkylene” group is an alkyl group that is positioned between and serves to connect two other chemical groups. Thus, “(1-6C)alkylene” means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, for example, methylene, ethylene, propylene, 2- methylpropylene, pentylene, and the like.

[0042] “(3-6C)cycloalkyl” means a hydrocarbon ring containing from 3 to 6 carbon atoms, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl or bicyclo[2.2.1]heptyl.

[0043] The term “halo” or “halogeno” refers to fluoro, chloro, bromo and iodo.

[0044] As used herein by themselves or in conjunction with another term or terms, “haloalkyl” and “haloalkyl group” refer to alkyl groups in which one or more hydrogen atoms are replaced by halogen atoms. Representative examples include, but are not limited to, -CF3, -CHF2, -CH2F, -CF2CF3, -CHFCF3, and -CH2CF3. Suitably, a haloalkyl group is selected from -CHF2 and -CF3, suitably -CF3.

[0045] As used herein by themselves or in conjunction with another term or terms, “haloalkoxy” and “haloalkoxy group” refer to alkoxy groups (i.e. O-alkyl groups) in which one or more hydrogen atoms are replaced by halogen atoms. Representative examples include, but are not limited to, -OCF3, -OCHF2, -OCH2F, and -OCF2CF3. Suitably, a haloalkyoxy group is selected from -OCHF2 and -OCF3, suitably -OCF3.

[0046] The term “heterocyclyl”, “heterocyclic” or “heterocycle” means a non-aromatic saturated or partially saturated monocyclic, fused, bridged, or spiro bicyclic heterocyclic ring system(s). Monocyclic heterocyclic rings contain from about 3 to 12 (suitably from 3 to 7) ring atoms, with from 1 to 5 (suitably 1 , 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur in the ring. Bicyclic heterocycles contain from 7 to 17 member atoms, suitably 7 to 12 member atoms, in the ring. Bicyclic heterocyclic(s) rings may be fused, spiro, or bridged ring systems. Examples of heterocyclic groups include cyclic ethers such as, but not limited to, oxiranyl, oxetanyl, tetrahydrofuranyl, dioxanyl, and substituted cyclic ethers. Heterocycles containing nitrogen include, for example, azetidinyl, pyrrolidinyl, piperidinyl, piperazinyl, tetrahydrotriazinyl, tetrahydropyrazolyl, and the like. Typical sulfur containing heterocycles include tetrahydrothienyl, dihydro-1 , 3-dithiol, tetrahydro-2 / 7-thiopyran, and hexahydrothiepine. Other heterocycles include dihydrooxathiolyl, tetrahydrooxazolyl, tetrahydro-oxadiazolyl, tetrahydrodioxazolyl, tetrahydrooxathiazolyl, hexahydrotriazinyl, tetrahydrooxazinyl, morpholinyl, thiomorpholinyl, tetrahydropyrimidinyl, dioxolinyl, octahydrobenzofuranyl, octahydrobenzimidazolyl, and octahydrobenzothiazolyl. For heterocycles containing sulfur, the oxidized sulfur heterocycles containing SO or SO2 groups are also included. Examples include the sulfoxide and sulfone forms of tetrahydrothienyl and thiomorpholinyl such as, but not limited to, tetrahydrothiene 1 ,1 -dioxide and thiomorpholinyl 1 ,1 -dioxide. A suitable value for a heterocyclyl group which bears 1 or 2 oxo (=0) or thioxo (=S) substituents is, for example, 2-oxopyrrolidinyl, 2-thioxopyrrolidinyl, 2-oxoimidazolidinyl, 2-thioxoimidazolidinyl, 2-oxopiperidinyl, 2,5-dioxopyrrolidinyl, 2,5-dioxoimidazolidinyl or 2,6- dioxopiperidinyl. Particular heterocyclyl groups are saturated monocyclic 3 to 7 membered heterocyclyls containing 1 , 2 or 3 heteroatoms selected from nitrogen, oxygen or sulfur, for example azetidinyl, tetrahydrofuranyl, tetrahydropyranyl, pyrrolidinyl, morpholinyl, tetrahydrothienyl, tetrahydrothienyl 1 ,1-dioxide, thiomorpholinyl, thiomorpholinyl 1 ,1-dioxide, piperidinyl, homopiperidinyl, piperazinyl or homopiperazinyl. As the skilled person would appreciate, any heterocycle may be linked to another group via any suitable atom, such as via a carbon or nitrogen atom. However, reference herein to piperidino or morpholino refers to a piperidin-1-yl or morpholin-4-yl ring that is linked via the ring nitrogen.

[0047] By “bridged ring systems” is meant ring systems in which two rings share more than two atoms, see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages 131-133, 1992. Examples of bridged heterocyclyl ring systems include, aza-bicyclo[2.2.1]heptane, 2-oxa-5-azabicyclo[2.2.1]heptane, aza-bicyclo[2.2.2]octane, aza- bicyclo[3.2.1]octane and quinuclidine.

[0048] By “spiro bicyclic ring systems” we mean that the two ring systems share one commonspiro carbon atom, i.e. the heterocyclic ring is linked to a further carbocyclic or heterocyclic ring through a single common spiro carbon atom. Examples of spiro ring systems include 6- azaspiro[3.4]octane, 2-oxa-6-azaspiro[3.4]octane, 2-azaspiro[3.3]heptanes, 2-oxa-6- azaspiro[3.3]heptanes, 7-oxa-2-azaspiro[3.5]nonane, 6-oxa-2-azaspiro[3.4]octane, 2-oxa-7- azaspiro[3.5]nonane and 2-oxa-6-azaspiro[3.5]nonane.

[0049] The term “heteroaryl” or “heteroaromatic” means an aromatic mono-, bi-, or polycyclic ring incorporating one or more (for example 14, particularly 1, 2 or 3) heteroatoms selected from nitrogen, oxygen or sulfur. The term heteroaryl includes both monovalent species and divalent species. Examples of heteroaryl groups are monocyclic and bicyclic groups containing from five to twelve ring members, and more usually from five to ten ring members. The heteroaryl group can be, for example, a 5- or 6-membered monocyclic ring or a 9- or 10- membered bicyclic ring, for example a bicyclic structure formed from fused five and six membered rings or two fused six membered rings. Each ring may contain up to about four heteroatoms typically selected from nitrogen, sulfur and oxygen. Typically, the heteroaryl ring will contain up to 3 heteroatoms, more usually up to 2, for example a single heteroatom. In one embodiment, the heteroaryl ring contains at least one ring nitrogen atom. The nitrogen atoms in the heteroaryl rings can be basic, as in the case of an imidazole or pyridine, or essentially non-basic as in the case of an indole or pyrrole nitrogen. In general, the number of basic nitrogen atoms present in the heteroaryl group, including any amino group substituents of the ring, will be less than five.

[0050] Examples of heteroaryl include furyl, pyrrolyl, thienyl, oxazolyl, isoxazolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl, oxadiazolyl, thiadiazolyl, triazolyl, tetrazolyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, 1 ,3,5-triazenyl, benzofuranyl, indolyl, isoindolyl, benzothienyl, benzoxazolyl, benzimidazolyl, benzothiazolyl, benzothiazolyl, indazolyl, purinyl, benzofurazanyl, quinolyl, isoquinolyl, quinazolinyl, quinoxalinyl, cinnolinyl, pteridinyl, naphthyridinyl, carbazolyl, phenazinyl, benzisoquinolinyl, pyridopyrazinyl, thieno[2,3b]-furanyl-, 2H-furo[3,2b]-pyranyl-, 5H-pyrido[2,3-d]-ooxazinyl-,1 H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2, 1 b]thiazoly I , -imidazo[1 , 2b] [ 1 , 2 , 4]-triazi ny I . “Heteroaryl” also covers partially aromatic bi- or polycyclic ring systems wherein at least one ring is an aromatic ring and one or more of the other ring(s) is a nonaromatic, saturated or partially saturated ring, provided at least one ring contains one or more heteroatoms selected from nitrogen, oxygen or -sulfur-. Examples of partially aromatic heteroaryl groups include for example, tetrahydroisoquinolinyl, tetrahydroquinolinyl, 2-oxo-1 ,2,3,4-tetrahydroquinolinyl, dihydrobenzthienyl, dihydrobenzfuranyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,3]dioxolyl,2,2-dioxo-1 ,3-dihydro-2-benzothienyl, 4,5,6,7-tetrahydrobenzofuranyl, indolinyl,1.2.3.4-tetrahydro-1 , 8-naphthyridinyl , 1 ,2,3,4-tetrahydropyrido[2,3-b]pyrazinyl,3.4-dihydro-2 / 7-pyrido[3,2-b][1 ,4]oxazinyl and 6,8-dihydro-5H-[1 ,2,4]triazolo[4,3-a]pyrazinyl.

[0051] Examples of five membered heteroaryl groups include but are not limited to pyrrolyl, furanyl, thienyl, imidazolyl, furazanyl, oxazolyl, oxadiazolyl, oxatriazolyl, isoxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl and tetrazolyl groups.

[0052] Examples of six membered heteroaryl groups include but are not limited to pyridyl, pyrazinyl, pyridazinyl, pyrimidinyl and triazinyl.

[0053] A bicyclic heteroaryl group may be, for example, a group selected from: a benzene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyridine ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a pyrimidine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrrole ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a pyrazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a pyrazine ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an imidazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an oxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isoxazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; an isothiazole ring fused to a 5- or 6-membered ring containing 1 or 2 ring heteroatoms; a thiophene ring fused to a 5- or 6-membered ring containing 1, 2 or 3 ring heteroatoms; a furan ring fused to a 5- or 6-membered ring containing 1 , 2 or 3 ring heteroatoms; a cyclohexyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1, 2 or 3 ring heteroatoms; and a cyclopentyl ring fused to a 5- or 6-membered heteroaromatic ring containing 1 , 2 or 3 ring heteroatoms.

[0054] Particular examples of bicyclic heteroaryl groups containing a six membered ring fused to a five membered ring include but are not limited to benzfuranyl, benzthiophenyl, benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzisothiazolyl,isobenzofuranyl, indolyl, isoindolyl, indolizinyl, indolinyl, isoindolinyl, purinyl (e.g., adeninyl, guaninyl), indazolyl, benzodioxolyl and pyrazolopyridinyl groups.

[0055] Particular examples of bicyclic heteroaryl groups containing two fused six membered rings include but are not limited to quinolinyl, isoquinolinyl, chromanyl, thiochromanyl, chromenyl, isochromenyl, chromanyl, isochromanyl, benzodioxanyl, quinolizinyl, benzoxazinyl, benzodiazinyl, pyridopyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, phthalazinyl, naphthyridinyl and pteridinyl groups.

[0056] The term “aryl” means a cyclic or polycyclic aromatic ring having from 5 to 12 carbon atoms. The term aryl includes both monovalent species and divalent species. Examples of aryl groups include, but are not limited to, phenyl, biphenyl, naphthyl and the like. In particular embodiment, an aryl is phenyl.

[0057] This specification also makes use of several composite terms to describe groups comprising more than one functionality. Such terms will be understood by a person skilled in the art. For example heterocyclyl(m-nC)alkyl comprises (m-nC)alkyl substituted by heterocyclyl.

[0058] The term “aryl(1-2C)alkyl” means an aryl group covalently attached to a (1-2C)alkylene group, both of which are defined herein. Examples of aryl-(1-2C)alkyl groups include benzyl, phenylethyl, and the like.

[0059] “Heteroaryl(1-3C)alkyl” means a heteroaryl group covalently attached to a (1- 3C)alkylene group, both of which are defined herein. Examples of heteroaryl-alkyl groups include pyridin-3-ylmethyl, 2-(benzofuran-2-yl)ethyl, and the like.

[0060] “Heterocyclyl(1-2C)alkyl” means a heterocyclyl group covalently attached to a (1- 2C)alkylene group, both of which are defined herein.

[0061] “(3-6C)cycloalkyl-(1-2C)alkyl” means a (3-6C)cycloalkyl group covalently attached to a (1-2C)alkylene group, both of which are defined herein.

[0062] The term "optionally substituted" refers to either groups, structures, or molecules that are substituted and those that are not substituted. The term “wherein a / any CH, CH2, CH3 group or heteroatom (i.e. NH) within a R1group is optionally substituted” suitably means that (any) one of the hydrogen radicals of the R1group is substituted by a relevant stipulated group.

[0063] Where optional substituents are chosen from “one or more” groups it is to be understood that this definition includes all substituents being chosen from one of the specified groups or the substituents being chosen from two or more of the specified groups.

[0064] A wavy bond is used herein to show a point of attachment.

[0065] The phrase “compound of the invention” means those compounds which are disclosed herein, both generically and specifically.

[0066] As used herein by itself or in conjunction with another term or terms, “pharmaceutically acceptable” refers to materials that are generally chemically and / or physically compatible with other ingredients (such as, for example, with reference to a formulation), and / or are generally physiologically compatible with the recipient (such as, for example, a subject) thereof.

[0067] As used herein by themselves or in conjunction with another term or terms, “subject(s)” and “patient(s)”, suitably refer to mammals, in particular humans.Compounds of the invention

[0068] In a first aspect, the present invention relates to a compound, or pharmaceutically acceptable salt thereof, having the structural formula I shown below:wherein: R1 and R2are each independently selected from hydrogen, fluoro or methyl;R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, (1-4C)alkoxy, phenyl, (3-6C)cycloalkyl, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl, wherein a phenyl, (3-6C)cycloalkyl, heterocyclyl ring, or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino;Xi is NR3c, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)p- (where p is 0, 1 or 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl,-[CH2]o-[(3-6C)cycloalkyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino;R3Cis hydrogen or (1 -6C)alkyl optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino;R4 is selected from hydrogen, F, Cl, (1-3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl optionally substituted by halo or hydroxy or R4aand R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino;or R4 is a group-X2-L2-X3-R4C wherein:X2 is absent, -O- or -NH-;L2 is (1-4C)alkylene;X3is NR4d, -NR4d-C(O)-, -C(O)-NR4d-, -NR4d-O-C(O)-, -NR4dS(O)P- or-S(O)P- (where p is 0, 1 or 2), where R4dis hydrogen or (1 -2C)alkyl ; andR4C is hydrogen or (1 -6C)alkyl;A1 is N or CRs wherein Rs is selected from hydrogen, F, Cl, (1-3C)alkyl or (1-3C)alkoxy; andRs is selected from hydrogen, F, Cl, (1 -3C)alkyl or (1-3C)alkoxy.

[0069] Particular compounds of the invention include, for example, compounds of the formula I, or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of R1, R2, R3, R4, A1 and Rs have any of the meanings defined hereinbefore or are as defined in any one of paragraphs (1) to (22) hereinafter:-(1) R1 and R2 are independently selected from hydrogen or fluoro;(2) R1 and R2 are both hydrogen;(3) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl, wherein a heterocyclyl ring or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl or amino;Xi is NR3c, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)p- (where p is 0, 1 or 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl,-[CH2]o-[(3-6C)cycloalkyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy;R3Cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(4) R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3bis selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl],and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3cis hydrogen or (1 -4C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(5) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);Rsb is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy; and and a phenyl, 5 or 6-membered heteroaryl, or 4 to 8- membered heterocyclyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1-2C)alkoxy.(6) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3Cis hydrogen or (1-6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(7) R4 is selected from hydrogen, F, Cl, (1-3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl orR4aand R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl; or R4 is a group-X2- L2-X3- R4Cwherein:X2is absent, -O- or -NH-; l_2is (1-4C)alkylene;X3is NR4d, -NR4d-C(O)-, -C(O)-NR4d-, -NR4d-O-C(O)-, -NR4dS(O)P- or-S(O)P- (where p is 0, 1 or 2), where R4dis hydrogen or (1 -2C)alkyl ; andR4C is hydrogen or (1 -6C)alkyl.(8) R4 is selected from hydrogen, F, Cl, (1-3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl orR4a and R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl(9) R4 is selected from hydrogen, F, Cl, (1 -2C)alkyl or (1-2C)alkoxy.(10) R4 is selected from hydrogen, F, Cl, methoxy, methyl or ethyl.(11) A1 is N or CR5, wherein R5 is selected from hydrogen, F, Cl, (1-3C)alkyl or (1- 3C)alkoxy.(12) A1 is N or CR5, wherein R5 is hydrogen.(13) Re is selected from hydrogen, F, Cl, (1-2C)alkyl or (1-2C)alkoxy.(14) Re is selected from hydrogen, F, Cl, methyl or methoxy.(15) R3 is a group of the formula:-[CH2]n-R3a or-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3, 4 or 5;R3ais cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl, wherein a heterocyclyl ring or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl or amino;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)p- (where p is 0, 1 or 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl, -[CH2]o-[(3-6C)cycloalkyl], and wherein:o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(16) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3, 4 or 5;R3ais cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);Rsb is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3cis hydrogen or (1 -4C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(17) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3 or 4;R3ais cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy; and a phenyl, 5 or 6-membered heteroaryl, or 4 to 8-membered heterocyclyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy;R3Cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1-2C)alkoxy.(18) R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 0, 1 , 2, 3 or 4;R3ais cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein:o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3cis hydrogen or (1-6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(19) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl, wherein a heterocyclyl ring or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl or amino;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3cS(O)p- or -S(O)p- (where p is 0, 1 or 2);Rsb is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl, -[CH2]o-[(3-6C)cycloalkyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(20) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);Rsb is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3cis hydrogen or (1 -4C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.(21) R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3bis selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy; and a phenyl, 5 or 6-membered heteroaryl, or 4 to 8-membered heterocyclyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1-2C)alkoxy.(22) R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3bis selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3Cis hydrogen or (1-6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

[0070] Suitably, in the compounds of formula I, R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above. Most suitably, R1 and R2 are as defined in paragraph (2) above.

[0071] Suitably, in the compounds of formula I, R3 is as defined hereinbefore or is as defined in any one of paragraphs (3) to (6) above. More suitably, R3 is as defined in paragraph (5) or (6) above. Most suitably, R3 is as defined in paragraph (6) above.

[0072] Suitably, in the compounds of formula I, R3 is as defined in paragraph (15) above. More suitably, R3 is as defined in paragraph (16) above. Even more suitably, R3 is as defined in paragraph (17) above. Most suitably, R3 is as defined in paragraph (18) above.

[0073] Suitably, in the compounds of formula I, R3 is as defined in paragraph (19) above. More suitably, R3 is as defined in paragraph (20) above. Even more suitably, R3 is as defined in paragraph (21) above. Most suitably, R3 is as defined in paragraph (21) above.

[0074] Suitably, in the compounds of formula I, R4 is as defined hereinbefore or is as defined in any one of paragraphs (7) to (10) above. More suitably, R4 is as defined in paragraph (9) or (10) above. Most suitably, R4 is as defined in paragraph (10) above.

[0075] Suitably, in the compounds of formula I, A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above. Most suitably, A1 is as defined in paragraph (12) above.

[0076] Suitably, in the compounds of formula I, Re is as defined hereinbefore or as defined in paragraph (13) or (14) above. Most suitably, Re is as defined in paragraph (14) above.

[0077] Suitably, in the compounds of formula I, R3 is not hydrogen.

[0078] Suitably, in the compounds of formula I, Rsa is not hydrogen.

[0079] Suitably, in the compounds of formula I, n is not 0.

[0080] Suitably, in the compounds of formula I, when n is 0, Rsa is not hydrogen.

[0081] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have one of the structural formulae la, lb, Ic, Id, le, If or Ig shown below:wherein R1, R2, R3, R4, A1 and Re are as defined in any one of paragraphs (1) to (22) above.

[0082] In a particular group of compounds of the invention, the compounds have the structural formula la shown above.

[0083] In a particular group of compounds of the invention, the compounds have the structural formula lb shown above.

[0084] In a particular group of compounds of the invention, the compounds have the structural formula Ic shown above.

[0085] In a particular group of compounds of the invention, the compounds have the structural formula Id shown above.

[0086] In a particular group of compounds of the invention, the compounds have the structural formula le shown above.

[0087] In a particular group of compounds of the invention, the compounds have the structural formula If shown above.

[0088] In a particular group of compounds of the invention, the compounds have the structural formula Ig shown above.

[0089] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined hereinbefore or is as defined in any one of paragraphs (3) to (6) above;R4 is as defined hereinbefore or is as defined in any one of paragraphs (7) to (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0090] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined in paragraph (5) or (6) above;R4 is as defined in paragraph (9) or (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0091] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (6) above;R4 is as defined in paragraph (10) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0092] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined hereinbefore or is as defined in paragraph (15) above;R4 is as defined hereinbefore or is as defined in any one of paragraphs (7) to (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0093] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (1) above;R3 is as defined in paragraph (15) above;R4 is as defined in paragraph (7) above;Ai is as defined in paragraph (11) above; andRe is as defined in paragraph (13) above.

[0094] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (15) above;R4 is as defined in paragraph (8) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0095] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined in paragraph (16) above;R4 is as defined in paragraph (9) or (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0096] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (1) above;R3 is as defined in paragraph (16) above;R4 is as defined in paragraph (9) above;A1 is as defined in paragraph (11) above; andRe is as defined in paragraph (13) above.

[0097] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (16) above;R4 is as defined in paragraph (10) above;Ai is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0098] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (17) above;R4 is as defined in paragraph (10) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0099] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (18) above;R4 is as defined in paragraph (10) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0100] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined hereinbefore or is as defined in paragraph (19) above;R4 is as defined hereinbefore or is as defined in any one of paragraphs (7) to (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0101] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (1) above;R3 is as defined in paragraph (19) above;R4 is as defined in paragraph (7) above;Ai is as defined in paragraph (11) above; andRe is as defined in paragraph (13) above.

[0102] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (19) above;R4 is as defined in paragraph (8) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0103] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined hereinbefore or as defined in paragraph (1) or (2) above;R3 is as defined in paragraph (20) above;R4 is as defined in paragraph (9) or (10) above;A1 is as defined hereinbefore or as defined in paragraph (11) or (12) above; andRe is as defined hereinbefore or as defined in paragraph (13) or (14) above.

[0104] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (1) above;R3 is as defined in paragraph (20) above;R4 is as defined in paragraph (9) above;A1 is as defined in paragraph (11) above; andRe is as defined in paragraph (13) above.

[0105] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (20) above;R4 is as defined in paragraph (10) above;Ai is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0106] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (21) above;R4 is as defined in paragraph (10) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0107] A particular group of compounds have any one of the formulae la to Ig above, wherein R1, R2, R3, R4, A1 and Re have the following definitions:R1 and R2 are as defined in paragraph (2) above;R3 is as defined in paragraph (22) above;R4 is as defined in paragraph (10) above;A1 is as defined in paragraph (12) above; andRe is as defined in paragraph (14) above.

[0108] Particular compounds of the present invention include any of the compounds described in the example section of the present application, or a pharmaceutically acceptable salt thereof, and, in particular, any of the following:(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-(azetidin-3-yl)-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}ethan-1-one;1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-(azetidin-3-yl)-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}ethan-1-one;(2S)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-methanesulfonylpropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(dimethylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(1H-imidazol-5-yl)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-hydroxybutan-1-one;(3R)-4-[(4aR,8aS)-decahydroquinolin-1-yl]-3-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-oxobutanenitrile;(3R)-4-[(4aR,8aS)-decahydroquinolin-1-yl]-3-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-oxobutanamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-5-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}pentan-1-one;(2R)-1-[(4aRS,8aSR)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;N-[(2R)-3-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-oxopropyl]oxetane-3-carboxamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-[bis(2-hydroxyethyl)amino]-2-{cyclopropyl[(2,4-dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(oxetan-3-yl)amino]propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(2,2-difluoroethyl)amino]propan-1-one;N-[(2R)-3-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-oxopropyl]methanesulfonamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-({2-oxaspiro[3.3]heptan-6-yl}amino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(2-hydroxyethyl)amino]propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-4-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-[(2,2-difluoroethyl)amino]butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-(dimethylamino)butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-(methylamino)butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-6-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}hexan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{[(4- chlorophenyl)methyl](cyclopropyl)amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-4-amino-2-{[(4- chlorophenyl)methyl](cyclopropyl)amino}butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4-ethylphenyl)methyl]amino}- 3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- difluorophenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4- methoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-[benzyl(methyl)amino]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aS,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2- methylphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{[(4- cyclopropoxyphenyl)methyl](cyclopropyl)amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,6-dimethoxypyridin-3- yl)methyl]amino}-3-hydroxypropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4- methoxyphenyl)methyl]amino}-3-hydroxypropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}-3-hydroxypropan-1-one; tert-butyl N-{2-[2-({[(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-hydroxy-1-oxopropan-2- yl](cyclopropyl)amino}methyl)-5-methoxyphenoxy]ethyl}carbamate;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-[cyclopropyl({[4-methoxy-2-(morpholin-4- yl)phenyl]methyl})amino]-3-hydroxypropan-1-one;"(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-one;(2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-one; or a pharmaceutically acceptable salt thereof.

[0109] Though the present invention may relate to any compound or particular group of compounds defined herein by way of optional, preferred or suitable features, or otherwise in terms of particular embodiments, the present invention may also relate to any compound or particular group of compounds that specifically excludes said optional, preferred or suitable features or particular embodiments.

[0110] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein.Salts and Solvates

[0111] The compounds (including final products and intermediates) described herein may be isolated and used per se or may be isolated in the form of a salt, suitably pharmaceutically acceptable salts. It should be understood that the terms “salt(s)” and “salt form(s)” used by themselves or in conjunction with another term or terms encompasses all inorganic and organic salts, including industrially acceptable salts, as defined herein, and pharmaceutically acceptable salts, as defined herein, unless otherwise specified. As usedherein, industrially acceptable salts are salts that are generally suitable for manufacturing and / or processing (including purification) as well as for shipping and storage, but may not be salts that are typically administered for clinical or therapeutic use. Industrially acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more.

[0112] Pharmaceutically acceptable salts, as used herein, are salts that are generally chemically and / or physically compatible with the other ingredients comprising a formulation, and / or are generally physiologically compatible with the recipient thereof. Pharmaceutically acceptable salts may be prepared on a laboratory scale, i.e. multi-gram or smaller, or on a larger scale, i.e. up to and including a kilogram or more. It should be understood that pharmaceutically acceptable salts are not limited to salts that are typically administered or approved by the FDA or equivalent foreign regulatory body for clinical or therapeutic use in humans. A practitioner of ordinary skill will readily appreciate that some salts are both industrially acceptable as well as pharmaceutically acceptable salts. It should be understood that all such salts, including mixed salt forms, are within the scope of the application.

[0113] In one embodiment, the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.

[0114] A suitable pharmaceutically acceptable salt of a compound of the invention is, for example, an acid addition salt of a compound of the invention which is sufficiently basic, for example, an acid-addition salt with, for example, an inorganic or organic acid, for example hydrochloric, hydrobromic, sulfuric, phosphoric, trifluoroacetic, formic, citric or maleic acid. -In addition a suitable pharmaceutically acceptable salt of a compound of the invention which is sufficiently acidic is an alkali metal salt, for example a sodium or potassium salt, an alkaline earth metal salt, for example a calcium or magnesium salt, an ammonium salt or a salt with an organic base which affords a physiologically acceptable- cation, for example a salt with methylamine, dimethylamine, trimethylamine, piperidine, morpholine or tris-(2-hydroxyethyl)amine.

[0115] In general, salts of the present application can be prepared in situ during the isolation and / or purification of a compound (including intermediates), or by separately reacting the compound (or intermediate) with a suitable organic or inorganic acid or base (as appropriate) and isolating the salt thus formed. The degree of ionisation in the salt may vary from completely ionised to almost non-ionised. In practice, the various salts may be precipitated (with or without the addition of one or more co-solvents and / or anti-solvents) and collected by filtration or the salts may be recovered by evaporation of solvent(s). Salts of the presentapplication may also be formed via a “salt switch” or ion exchange / double displacement reaction, i.e. reaction in which one ion is replaced (wholly or in part) with another ion having the same charge. One skilled in the art will appreciate that the salts may be prepared and / or isolated using a single method or a combination of methods.

[0116] Representative salts include, but are not limited to, acetate, aspartate, benzoate, besylate, bicarbonate / carbonate, bisulphate / sulphate, borate, camsylate, citrate, edisylate, esylate, formate, fumarate, gluceptate, gluconate, glucuronate, hexafluorophosphate, hibenzate, hydrochloride / chloride, hydrobromide / bromide, hydroiodide / iodide, isethionate, lactate, malate, maleate, malonate, mesylate, methylsulphate, naphthylate, 2-napsylate, nicotinate, nitrate, orotate, oxalate, palmitate, pamoate, phosphate / hydrogen phosphate / dihydrogen phosphate, saccharate, stearate, succinate, tartrate, tosylate, trifluoroacetate and the like. Other examples of representative salts include alkali or alkaline earth metal cations such as, but not limited to, sodium, lithium, potassium, calcium, magnesium, and the like, as well as non-toxic ammonium, quaternary ammonium and amine cations including, but not limited to, ammonium, tetramethylammonium, tetraethylammonium, lysine, arginine, benzathine, choline, tromethamine, diolamine, glycine, meglumine, olamine and the like.

[0117] Certain compounds of the Formula I and sub-formulae thereof may exist in solvated as well as unsolvated forms such as, for example, hydrated forms. It is to be understood that the invention encompasses all such solvated forms that possess the biological activity described herein.Polymorphs

[0118] It is also to be understood that certain compounds of the Formula I and sub-formulae thereof may exhibit polymorphism, and that the invention encompasses all such forms that possess the biological activity described herein.N-oxides

[0119] Compounds of the Formula I and sub-formulae thereof containing an amine function may also form N-oxides. A reference herein to a compound of the Formula I and sub-formulae thereof that contains an amine function also includes the N-oxide. Where a compound contains several amine functions, one or more than one nitrogen atom may be oxidised to form an N-oxide. Particular examples of N-oxides are the N-oxides of a tertiary amine or a nitrogen atom of a nitrogen-containing heterocycle. N-Oxides can be formed by treatment of the corresponding amine with an oxidizing agent such as, but not limited to, hydrogen peroxideor a per-acid (e.g. a peroxycarboxylic acid), see for example Advanced Organic Chemistry, by Jerry March, 4thEdition, Wiley Interscience, pages. More particularly, N-oxides can be made by the procedure of L. W. Deady (Syn. Comm. 1977, 7, 509-514) in which the amine compound is reacted with m-chloroperoxybenzoic acid (mCPBA), for example, in an inert solvent such as, but not limited to, dichloromethane.Tautomers

[0120] Compounds of the Formula I and sub-formulae thereof may exist in a number of different tautomeric forms and references to compounds of the Formula I and sub-formulae thereof include all such forms. For the avoidance of doubt, where a compound can exist in one of several tautomeric forms, and only one is specifically described or shown, all others are nevertheless embraced by Formula I and sub-formulae thereof. Examples of tautomeric forms include keto-, enol-, and enolate-forms, as in, for example, the following tautomeric pairs: keto / enol (illustrated below), pyrimidone / hydroxypyrimidine, imine / enamine, amide / imino alcohol, amidine / amidine, nitroso / oxime, thioketone / enethiol, and nitro / aci-nitro.keto enol enolateIsomers

[0121] Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed “isomers”. Isomers that differ in the arrangement of their atoms in space are termed “stereoisomers”. Stereoisomers that are not mirror images of one another are termed “diastereomers” and those that are nonsuperimposable mirror images of each other are termed “enantiomers”. When a compound has an asymmetric center, for example, it is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R and Ssequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (- )isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0122] Certain compounds of Formula I and sub-formulae thereof may have one or more asymmetric centres and therefore can exist in a number of stereoisomeric configurations. Consequently, such compounds can be synthesized and / or isolated as mixtures of enantiomers and / or as individual (pure) enantiomers, and, in the case of two or more asymmetric centres, single diastereomers and / or mixtures of diastereomers. It should be understood that the present application includes all such enantiomers and diastereomers and mixtures thereof in all ratios.Isotopes

[0123] The compounds of the present invention are described herein using structural formulas that do not specifically recite the mass numbers or the isotope ratios of the constituent atoms. As such it is intended that the present application includes compounds in which the constituent atoms are present in any ratio of isotope forms. For example, carbon atoms may be present in any ratio of12C,13C, and14C; hydrogen atoms may be present in any ratio of1H,2H, and3H; etc. Preferably, the constituent atoms in the compounds of the present invention are present in their naturally occurring ratios of isotope forms.Prodrugs and Metabolites

[0124] The compounds of Formula I and sub-formulae thereof may be administered in the form of a pro-drug which is broken down in the human or animal body to release a compound of the invention. A pro-drug may be used to alter the physical properties and / or the pharmacokinetic properties of a compound of the invention. A pro-drug can be formed when the compound of the invention contains a suitable group or substituent to which a propertymodifying group can be attached. Examples of pro-drugs include in vivo cleavable ester derivatives that may be formed at a carboxy group or a hydroxy group in a compound of the Formula I and in-vivo cleavable amide derivatives that may be formed at a carboxy group or an amino group in a compound of the Formula I and sub-formulae thereof.

[0125] Accordingly, the present invention includes those compounds of the Formula I and sub-formulae thereof as defined hereinbefore when made available by organic synthesis and when made available within the human or animal body by way of cleavage of a pro-drug thereof. Accordingly, the present invention includes those compounds of the Formula I that are produced by organic synthetic means and also such compounds that are produced in the human or animal body by way of metabolism of a precursor compound, that is a compound of the Formula I and sub-formulae thereof may be a synthetically-produced compound or a metabolically-produced compound.

[0126] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof is one that is based on reasonable medical judgement as being suitable for administration to the human or animal body without undesirable pharmacological activities and without undue toxicity.

[0127] Various forms of pro-drug have been described, for example in the following documents :- a) Methods in Enzymology, Vol. 42, p. 309-396, edited by K. Widder, et al. (Academic Press, 1985); b) Design of Pro-drugs, edited by H. Bundgaard, (Elsevier, 1985); c) A Textbook of Drug Design and Development, edited by Krogsgaard-Larsen and H. Bundgaard, Chapter 5 “Design and Application of Pro-drugs”, by H. Bundgaard p. 113-191 (1991); d) H. Bundgaard, Advanced Drug Delivery Reviews, 8, 1-38 (1992); e) H. Bundgaard, et al., Journal of Pharmaceutical Sciences, 77, 285 (1988); f) N. Kakeya, et al., Chem. Pharm. Bull., 32, 692 (1984); g) T. Higuchi and V. Stella, “Pro-Drugs as Novel Delivery Systems”, A.C.S. Symposium Series, Volume 14; and h) E. Roche (editor), “Bioreversible Carriers in Drug Design”, Pergamon Press, 1987.

[0128] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable ester thereof. An in vivo cleavable ester of a compound of the Formula I containing a carboxy group is, for example, a pharmaceutically acceptable ester which is cleaved in the human or animal body to produce the parent acid. Suitable pharmaceutically acceptable esters for carboxy include Ci-ealkyl esters such as, but not limited to, methyl, ethyl and tertbutyl, C1-6alkoxymethyl esters such as, but not limited to, methoxymethyl esters, Ci- ealkanoyloxymethyl esters such as, but not limited to, pivaloyloxymethyl esters, 3-phthalidyl esters, Cs-scycloalkylcarbonyloxy- Ci-ealkyl esters such as, but not limited to, cyclopentylcarbonyloxymethyl and 1 -cyclohexylcarbonyloxyethyl esters, 2-oxo-1,3- dioxolenylmethyl esters such as, but not limited to, 5-methyl-2-oxo-1,3-dioxolen-4-ylmethyl esters and Ci-ealkoxycarbonyloxy- Ci-ealkyl esters such as, but not limited to, methoxycarbonyloxymethyl and 1 -methoxycarbonyloxyethyl esters.

[0129] A suitable pharmaceutically acceptable pro-drug of a compound of the FormulaI and sub-formulae thereof that possesses a hydroxy group is, for example, an in vivo cleavable ester or ether thereof. An in vivo cleavable ester or ether of a compound of the Formula I and sub-formulae thereof containing a hydroxy group is, for example, a pharmaceutically acceptable ester or ether which is cleaved in the human or animal body to produce the parent hydroxy compound. Suitable pharmaceutically acceptable ester forming groups for a hydroxy group include inorganic esters such as, but not limited to, phosphate esters (including phosphoramidic cyclic esters). Further suitable pharmaceutically acceptable ester forming groups for a hydroxy group include Ci-walkanoyl groups such as, but not limited to, acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, Ci- walkoxycarbonyl groups such as, but not limited to, ethoxycarbonyl, / V, / V -(Ci-6)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, / V-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4-(Ci-4alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include a-acyloxyalkyl groups such as, but not limited to, acetoxymethyl and pivaloyloxymethyl groups.

[0130] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses a carboxy group is, for example, an in vivo cleavable amide thereof, for example an amide formed with an amine such as, but not limited to, ammonia, a Ci-4alkylamine such as, but not limited to, methylamine, a (Ci-4alkyl)2amine such as, but not limited to, dimethylamine, / V-ethyl- / V-methylamine or diethylamine, a Ci- 4alkoxy- C2-4alkylamine such as, but not limited to, 2-methoxyethylamine, a phenyl-Ci- 4alkylamine such as, but not limited to, benzylamine and amino acids such as, but not limited to, glycine or an ester thereof.

[0131] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I and sub-formulae thereof that possesses an amino group is, for example, an in vivo cleavable amide derivative thereof. Suitable pharmaceutically acceptable amides from an amino group include, for example an amide formed with Ci-walkanoyl groups such as, but not limited to, an acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N- alkylaminomethyl, / V, / V-dialkylaminomethyl, morpholinomethyl, piperazin-1 -ylmethyl and 4- (Ci-4alkyl)piperazin-1 -ylmethyl.

[0132] The in vivo effects of a compound of the Formula I and sub-formulae thereof may be exerted in part by one or more metabolites that are formed within the human or animalbody after administration of a compound of the Formula I and sub-formulae thereof. As stated hereinbefore, the in vivo effects of a compound of the Formula I and sub-formulae thereof may also be exerted by way of metabolism of a precursor compound (a pro-drug).Pharmaceutical Compositions

[0133] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in association with a pharmaceutically acceptable diluent or carrier.

[0134] The compositions of the invention may be in a form suitable for oral use (for example as tablets, lozenges, hard or soft capsules, aqueous or oily suspensions, emulsions, dispersible powders or granules, syrups or elixirs), for topical use (for example as creams, ointments, gels, or aqueous or oily solutions or suspensions), for administration by inhalation (for example as a finely divided powder or a liquid aerosol), for administration by insufflation (for example as a finely divided powder) or for parenteral administration (for example as a sterile aqueous or oily solution for intravenous, subcutaneous, intramuscular, intraperitoneal or intramuscular dosing or as a suppository for rectal dosing).

[0135] The compositions of the invention may be obtained by conventional procedures using conventional pharmaceutical excipients, well known in the art. Thus, compositions intended for oral use may contain, for example, one or more colouring, sweetening, flavouring and / or preservative agents.

[0136] An effective amount of a compound of the present invention for use in therapy is an amount sufficient to treat or prevent a proliferative condition referred to herein, slow its progression and / or reduce the symptoms associated with the condition.

[0137] The amount of active ingredient that is combined with one or more excipients to produce a single dosage form will necessarily vary depending upon the individual treated and the particular route of administration. For example, a formulation intended for oral administration to humans will generally contain, for example, from 0.5 mg to 1.5 g of active agent (more suitably from 0.5 to 600 mg, for example from 1 to 200 mg) compounded with an appropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0138] The size of the dose for therapeutic or prophylactic purposes of a compound of the Formula I will naturally vary according to the nature and severity of the conditions, the age andsex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0139] It is to be noted that dosages and dosing regimens may vary with the type and severity of the condition to be alleviated, and may include the administration of single or multiple doses, i.e. QD (once daily), BID (twice daily), etc., over a particular period of time (days or hours). It is to be further understood that for any particular subject or patient, specific dosage regimens may need to be adjusted over time according to the individual need and the professional judgment of the person administering or supervising the administration of the pharmaceutical compositions. For example, doses may be adjusted based on pharmacokinetic or pharmacodynamic parameters, which may include clinical effects such as toxic effects and / or laboratory values. Thus, the present application encompasses intrapatient dose-escalation as determined by the person skilled in the art. Procedures and processes for determining the appropriate dosage(s) and dosing regimen(s) are well-known in the relevant art and would readily be ascertained by the skilled artisan. As such, one of ordinary skill would readily appreciate and recognize that the dosage ranges set forth herein are exemplary only and are not intended to limit the scope or practice of the pharmaceutical compositions described herein.

[0140] In using a compound of the invention for therapeutic or prophylactic purposes it will generally be administered so that a daily dose in the range, for example, 0.1 mg / kg to 75 mg / kg body weight is received, given if required in divided doses. In general lower doses will be administered when a parenteral route is employed. Thus, for example, for intravenous or intraperitoneal administration, a dose in the range, for example, 0.1 mg / kg to 30 mg / kg body weight will generally be used. Similarly, for administration by inhalation, a dose in the range, for example, 0.05 mg / kg to 25 mg / kg body weight will be used.

[0141] For the compounds of the present invention, oral administration is particularly suitable. The compounds of the present invention may be formulated as a tablet, capsule or solution for oral administration. Suitably, the compound of the present invention is formulated in a unit dosage form (e.g. a tablet or capsule) for oral administration. Typically, unit dosage forms will contain about 0.5 mg to 1.5 g of a compound of this invention.Synthesis

[0142] The compounds of the present invention can be prepared by any suitable technique known in the art. Particular methods for forming compounds of formula I defined herein are shown in the accompanying example section.

[0143] In the description of the synthetic methods described herein and in any referenced synthetic methods that are used to prepare the starting materials, it is to be understood that all proposed reaction conditions, including choice of solvent, reaction atmosphere, reaction temperature, duration of the experiment and workup procedures, can be selected by a person skilled in the art.

[0144] It is understood by one skilled in the art of organic synthesis that the functionality present on various portions of the molecule must be compatible with the reagents and reaction conditions utilised.

[0145] It will be appreciated that during the synthesis of the compounds of the invention in the processes defined herein, or during the synthesis of certain starting materials, it may be desirable to protect certain substituent groups to prevent their undesired reaction. The skilled chemist will appreciate when such protection is required, and how such protecting groups may be put in place, and later removed.

[0146] For Examples of protecting groups see one of the many general texts on the subject, for example, ‘Protective Groups in Organic Synthesis’ by Theodora Green (publisher: John Wiley & Sons). Protecting groups may be removed by any convenient method described in the literature or known to the skilled chemist as appropriate for the removal of the protecting group in question, such methods being chosen so as to effect removal of the protecting group with the minimum disturbance of groups elsewhere in the molecule.

[0147] Thus, if reactants include, for example, groups such as amino, carboxy or hydroxy it may be desirable to protect the group in some of the reactions mentioned herein.

[0148] By way of example, a suitable protecting group for an amino or alkylamino group is, for example, an acyl group, for example an alkanoyl group such as, but not limited to, acetyl, an alkoxycarbonyl group, for example a methoxycarbonyl, ethoxycarbonyl or tbutoxycarbonyl group, an arylmethoxycarbonyl group, for example benzyloxycarbonyl, or an aroyl group, for example benzoyl. The deprotection conditions for the above protecting groups necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or alkoxycarbonyl group or an aroyl group may be removed by, for example, hydrolysis with a suitable base such as, but not limited to, an alkali metal hydroxide, for example lithium or sodium hydroxide. Alternatively an acyl group such as a terfbutoxycarbonyl group may be removed, for example, by treatment with a suitable acid as hydrochloric, sulfuric or phosphoric acid or trifluoroacetic acid and an arylmethoxycarbonyl group such as a benzyloxycarbonyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon, or by treatment with a Lewis acid for example boron tris(trifluoroacetate). A suitablealternative protecting group for a primary amino group is, for example, a phthaloyl group which may be removed by treatment with an alkylamine, for example dimethylaminopropylamine, or with hydrazine.

[0149] A suitable protecting group for a hydroxy group is, for example, an acyl group, for example an alkanoyl group such as acetyl, an aroyl group, for example benzoyl, or an arylmethyl group, for example benzyl. The deprotection conditions for the above protecting groups will necessarily vary with the choice of protecting group. Thus, for example, an acyl group such as an alkanoyl or an aroyl group may be removed, for example, by hydrolysis with a suitable base such as an alkali metal hydroxide, for example lithium, sodium hydroxide or ammonia. Alternatively, an arylmethyl group such as a benzyl group may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0150] A suitable protecting group for a carboxy group is, for example, an esterifying group, for example a methyl or an ethyl group which may be removed, for example, by hydrolysis with a base such as sodium hydroxide, or for example a t-butyl group which may be removed, for example, by treatment with an acid, for example an organic acid such as trifluoroacetic acid, or for example a benzyl group which may be removed, for example, by hydrogenation over a catalyst such as palladium on carbon.

[0151] Resins may also be used as a protecting group.

[0152] The methodology employed to synthesise a compound of formula (I) will vary depending on the nature of R1, R2, R3, R4, A1 and Re and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying example section.

[0153] Once a compound of formula (I) has been synthesised by any one of the processes defined herein, the processes may then further comprise one or more of the additional steps of:(i) removing any residual protecting groups present;(ii) converting the compound formula (I) into another compound of formula (I);(iii) forming a pharmaceutically acceptable salt, hydrate or solvate of the compound of formula I; and / or(iv) forming a prodrug of the compound of formula I.

[0154] An example of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of R1, R2, R3, R4, A1 and Re may be further reacted to change the nature of the group and provide an alternative compound of formula (I).

[0155] The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art.Therapeutic Uses and Applications

[0156] The compounds of the present invention are potent inhibitors of PolQ. Data showing the PolQ inhibition for the exemplified compounds is presented in the accompanying example section.

[0157] Accordingly, the compounds of formula I are useful for the treatment and / or prevention of diseases and conditions in which PolQ activity is implicated, such as, for example, but not limited to, the treatment and / or prevention of cancer and / or benign neoplasms.

[0158] In one aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in therapy.

[0159] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a disease or condition in which PolQ activity is implicated.

[0160] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition in which PolQ activity is implicated.

[0161] In another aspect, the present invention provides a method of treating a disease or condition in which PolQ activity is implicated, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0162] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or apharmaceutical composition as defined herein, for use in the treatment of a disease or condition associated with aberrant activity of PolQ.

[0163] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a disease or condition associated with aberrant activity of PolQ.

[0164] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of PolQ, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0165] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of cancer or benign neoplasms.

[0166] In another aspect, the present invention provides the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of cancer or benign neoplasms.

[0167] In another aspect, the present invention provides a method of treating a cancer or a benign neoplasm, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0168] A benign neoplasm may be, for example, hemangiomas, hepatocellular adenoma, cavernous haemangioma, focal nodular hyperplasia, acoustic neuromas, neurofibroma, bile duct adenoma, bile duct cystanoma, fibroma, lipomas, leiomyomas, mesotheliomas, teratomas, myxomas, nodular regenerative hyperplasia, trachomas, pyogenic granulomas, moles, uterine fibroids, thyroid adenomas, adrenocortical adenomas or pituitary adenomas. The benign neoplasm may be endometrial implants or a keratocystic odontogenic tumor.

[0169] In another aspect, the present invention provides a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein, for use in the treatment of a cancer.

[0170] In another aspect, the present invention the use of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in the manufacture of a medicament for use in the treatment of a cancer.

[0171] In another aspect, the present invention provides a method of treating cancer, said method comprising administering to a subject in need thereof an effective amount of a compound of Formula I as defined herein, or a pharmaceutically acceptable salt, hydrate or solvate thereof, or a pharmaceutical composition as defined herein.

[0172] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be for use in the treatment of a homologous recombination (HR) deficient cancer.

[0173] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be for used in the treatment of cancer characterized by a reduction or absence of the components of Homologous Recombination (HR).

[0174] For this reason, the compounds of the present invention may be used in the treatment of cancers characterized by a reduction or absence of one or more of ATM, BARD1 , PALB2, BRCA1 and BRCA2, the absence of one or more of the ATM, BARD1 , PALB2, BRCA1 and BRCA2 genes, or a reduced function of ATM, BARD1 , PALB2, BRCA1 and BRCA2 protein.

[0175] In a particular aspect of the invention, the compounds of the present invention, or pharmaceutically acceptable salts thereof, may be for used in the treatment of cancer characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, or a reduced function of BRCA protein.

[0176] In a further aspect, the present invention relates to compounds of the present invention, or pharmaceutically acceptable salts thereof, for use in the treatment of cancers that are resistant to PARP inhibitor treatment.

[0177] The compounds of the present invention may be useful for the treatment of the adult population. The compounds of the present invention may also be useful for the treatment of the paediatric population.

[0178] As a consequence of their inhibition of PolQ, the compounds of the present invention will be useful in providing a means of disabling the ability of cells to perform MMEJ. It is therefore anticipated that the compounds may prove useful in treating or preventing proliferative disorders such as cancers. In addition, the compounds of the invention may be useful in the treatment of diseases in which there is a disorder associated with cell accumulation.

[0179] In one embodiment, the compounds of the present invention are suitably lethal in BRCA1 and BRCA2 deficient primary and secondary solid tumours, including breast, ovarian, prostate and pancreas. In a further embodiment, the compounds of the present invention are suitably lethal in a variety of primary and secondary solid tumours which are HRD by mechanisms other than BRCA deficiency, such as those with promoter hypermethylation. In these tumours where no DSB repair pathway may be fully down regulated the compound of the present invention may be given along with another DDR modulator such as a PARP inhibitor, a DNA-PK inhibitor, an ATR inhibitor, an ATM inhibitor, a wee1 inhibitor or a CHK1 inhibitor.

[0180] In a further embodiment, the compounds of the present invention are suitably lethal in primary and secondary breast, ovarian, prostate and pancreatic tumours retaining BRCA1 deficiency but which, following or not following exposure to PARP inhibitor medication, are resistant to PARP inhibitor treatment.

[0181] In a further embodiment, the compounds of the present invention suitably increase the objective response rate (ORR), including the complete response rate (CRR), will delay the onset of PARP inhibitor resistance, will increase the time to relapse and disease free survival (DFS), and will increase the overall survival (OS) of homologous recombination deficiency (HRD, BRCA1 / 2 deficient and other HRD mechanisms) primary and secondary tumours (breast, ovarian, prostate and pancreas) when given with PARP inhibitor treatment programmes.

[0182] In a further embodiment, the compounds of the present invention suitably show synthetic sickness and / or synthetic lethality in a variety of tumours with loss of ATM activity (ATM+) particularly in the context of WT p53. T umour types will include around 10% of all solid tumours including gastric, lung, breast, and CRC, along with CLL. Co-medicating with another DDR modifier, such as a DNA-PK inhibitor, PARP inhibitor or ATR inhibitor, may further enhance such activity. PolQ inhibitors will resensitise CLL to classical chemotherapy and chemo-immunotherapy where drug resistance has emerged. Thus, according to a further embodiment, the pharmaceutical composition of the present invention additionally comprises a DNA-PK inhibitor, PARP inhibitor, or ATR inhibitor.

[0183] In a further embodiment, the compounds of the present invention suitably show synthetic sickness and / or synthetic lethality in a variety of tumours deficient in the DNA double strand break repair process of non-homologous end-joining (NHEJ-D). Tumour types will include approximately 2-10% of all solid tumours including prostate, pancreatic, cervical, breast, lung, bladder and oesophageal. Co-medicating with another DDR modifier, such as aPARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor, may further enhance such activity. PolQ inhibitors will further sensitise NHEJD cancer cells to DNA double strand breaks (DSB) inducing chemotherapies and to ionising radiation based therapies. Thus, according to a further embodiment, the pharmaceutical composition of the present invention additionally comprises a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor.

[0184] In a further embodiment, the compounds of the present invention suitably reduce the DNA replication stress response during the chemotherapy of HR proficient tumours such as ovarian, NSCL and breast tumours over-expressing PolQ. This will increase the ORR to treatment and increase OS. Such effects are particularly likely with cytarabine (Ara-C) and hydroxyurea used in a wide variety of leukemias including CML, and the management of squamous cell carcinomas.

[0185] In a further embodiment, the compounds of the present invention suitably selectively sensitise solid tumours to radiotherapy, including EBRT and brachytherapy, with little or no sensitisation of normal tissues. In a fractionated curative-intent setting this will increase loco- regional control driving increased survival. This will be particularly evident in the management of non-small cell lung cancer (NSCLC), squamous cell carcinoma of head and neck (SCCH&N), rectal cancer, prostate cancer and pancreatic cancer. In a further embodiment, the compounds of the present invention suitably show synthetic sickness and / or synthetic lethality in PTEN deleted tumours such as CaP, with or without comedication with a PARP inhibitor. Furthermore, such tumours will exhibit exquisite sensitivity to radiotherapy both by dint of the PTEN deletion as well as the PolQ inhibitor induced radiosensitivity.

[0186] In a further embodiment, the compounds of the present invention suitably suppress TLS polymerase activity, sensitising primary and secondary solid tumours (e.g. breast, lung, ovarian, CRC) to drugs (e.g. cisplatin, mitomycin and cyclophosphamide) as well as reducing the acquisition of drug-induced mutations implicated in tumour resistance leading to prolongation of remission and increased TTR.

[0187] In a further embodiment, the compounds of the present invention suitably resensitise BCR- ABL-positive CML which is has developed imatinib resistance, as well as other solid tumours with elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

[0188] In a further embodiment, the compounds of the present invention suitably show synthetic sickness and / or synthetic lethality in aromatase inhibitor resistant ER primary andsecondary breast cancers, again showing elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

[0189] According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours characterised by a deficiency in homologous recombination (HRD).

[0190] It will be appreciated that references herein to “deficiency in homologous recombination (HRD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.

[0191] In one embodiment, said homologous recombination genes are selected from any of: ATM, ATR, BRCA1 , BRCA2, BARD1 , RAD51C, RAD50, CHEK1 , CHEK2, FANCA, FANCB, FANCC, FANCD2, FANCE, FANCF, FANCG, FANCI, FANCL, FANCM, PALB2 (FANCN), FANCP (BTBD12), ERCC4 (FANCQ), PTEN, CDK12, MRE11 , NBS1 , NBN, CLASPIN, BLM, WRN, SMARCA2, SMARCA4, LIG1 , RPA1 , RPA2, BRIP1 and PTEN.

[0192] It will be appreciated that references herein to “non-homologous end-joining deficiency (NHEJD)” refer to any genetic variation which results in a deficiency or loss of function of the resultant homologous recombination gene. Examples of said genetic variation include mutations (e.g. point mutations), substitutions, deletions, single nucleotide polymorphisms (SNPs), haplotypes, chromosome abnormalities, Copy Number Variation (CNV), epigenetics, DNA inversions, reduction in expression and mis-localisation.

[0193] In one embodiment, said non-homologous end-joining genes are selected from any one or more of: LIG4, NHEJ1 , POLL, POLM, PRKDC, XRCC4, XRCC5, XRCC6, and DCLRE1C.

[0194] According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours which overexpress PolQ.

[0195] According to a further aspect of the invention there is a provided a compound of formula (I) as defined herein for use in the treatment of tumours which have elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

[0196] The cancer may be non-metastatic or metastatic and which may be a solid tumour or a haematological (“liquid”) cancer. The cancer may, for example, be selected from:(1) Carcinoma, including for example tumours derived from stratified squamous epithelia (squamous cell carcinomas) and tumours arising within organs or glands (adenocarcinomas). Examples include breast, colon, lung, prostate, ovary, esophageal carcinoma (including, but not limited to, esophageal adenocarcinoma and squamous cell carcinoma), basal-like breast carcinoma, basal cell carcinoma (a form of skin cancer), squamous cell carcinoma (various tissues), head and neck carcinoma (including, but not limited to, squamous cell carcinomas), stomach carcinoma (including, but not limited to, stomach adenocarcinoma, gastrointestinal stromal tumor), signet ring cell carcinoma, bladder carcinoma (including transitional cell carcinoma (a malignant neoplasm of the bladder)), bronchogenic carcinoma, colorectal carcinoma (including, but not limited to, colon carcinoma and rectal carcinoma), anal carcinoma, gastric carcinoma, lung carcinoma (including but not limited to small cell carcinoma (SCLC) and non-small cell carcinoma of the lung (NSCLC), lung adenocarcinoma, squamous cell carcinoma, large cell carcinoma, bronchioloalveolar carcinoma, and mesothelioma), neuroendocrine tumors (including but not limited to carcinoids of the gastrointestinal tract, breast, and other organs), adrenocortical carcinoma, thyroid carcinoma, pancreatic carcinoma (including, but not limited to, pancreatic ductal adenocarcinoma, pancreatic adenocarcinoma, acinar cell carcinoma, intraductal papillary mucinous neoplasm with invasive carcinoma, mucinous cystic neoplasm with invasive carcinoma, islet cell carcinoma and neuroendocrine tumors), breast carcinoma (including, but not limited to, ductal carcinoma, lobular carcinoma, inflammatory breast cancer, clear cell carcinoma, mucinous carcinoma), ovarian carcinoma (including, but not limited to, ovarian epithelial carcinoma or surface epithelial-stromal tumor including serous tumor, endometrioid tumor and mucinous cystadenocarcinoma, sex-cord- stromal tumor), liver and bile duct carcinoma (including, but not limited to, hepatocellular carcinoma, cholangiocarcinoma and hemangioma), prostate carcinoma, adenocarcinoma, brain tumours (including, but not limited to glioma, glioblastoma and medulloblastoma), germ cell tumors, sweat gland carcinoma, sebaceous gland carcinoma, papillary carcinoma, papillary adenocarcinoma, cystadenocarcinoma, kidney carcinoma (including, but not limited to, renal cell carcinoma, clear cell carcinoma and Wilm's tumor), medullary carcinoma, ductal carcinoma in situ or bile duct carcinoma, choriocarcinoma, seminoma, embryonal carcinoma, cervical carcinoma, uterine carcinoma (including, but not limited to, endometrial adenocarcinoma, uterine papillary serous carcinoma, uterine clear-cell carcinoma, uterine sarcomas and leiomyosarcomas, mixed mullerian tumors), testicular carcinoma, osteogenic carcinoma, epithelial carcinoma, sarcomatoid carcinoma, nasopharyngeal carcinoma, laryngeal carcinoma; oral and oropharyngeal squamous carcinoma;(2) Sarcomas, including: osteosarcoma and osteogenic sarcoma (bone); chondrosarcoma (cartilage); leiomyosarcoma (smooth muscle); rhabdomyosarcoma (skeletal muscle); mesothelial sarcoma and mesothelioma (membranous lining of body cavities); fibrosarcoma (fibrous tissue); angiosarcoma and hemangioendothelioma (blood vessels); liposarcoma (adipose tissue); glioma and astrocytoma (neurogenic connective tissue found in the brain); myxosarcoma (primitive embryonic connective tissue); chordoma, endotheliosarcoma, lymphangiosarcoma, lymphangioendotheliosarcoma, synovioma, Ewing's sarcoma, mesenchymous and mixed mesodermal tumor (mixed connective tissue types) and other soft tissue sarcomas;(3) Myeloma and multiple myeloma;(4) Hematopoietic tumours, including: myelogenous and granulocytic leukemia (malignancy of the myeloid and granulocytic white blood cell series); lymphatic, lymphocytic, and lymphoblastic leukemia (malignancy of the lymphoid and lymphocytic blood cell series); polycythemia vera and erythremia (malignancy of various blood cell products, but with red cells predominating); myelofibrosis.(5) Lymphomas, including: Hodgkin and Non-Hodgkin lymphomas;(6) Solid tumors of the nervous system including medulloblastoma, craniopharyngioma, ependymoma, pinealoma, hemangioblastoma, acoustic neuroma, oligodendroglioma, meningioma, neuroblastoma and schwannoma;(7) Melanoma, uveal melanoma and retinoblastoma; and(8) Mixed Types, including, e.g., adenosquamous carcinoma, mixed mesodermal tumor, carcinosarcoma or teratocarcinoma.

[0197] Further examples of cancers (and their benign counterparts) which may be treated (or inhibited) include, but are not limited to tumours of epithelial origin (adenomas and carcinomas of various types including adenocarcinomas, squamous carcinomas, transitional cell carcinomas and other carcinomas) such as carcinomas of the bladder and urinary tract, breast, gastrointestinal tract (including the esophagus, stomach (gastric), small intestine, colon, rectum and anus), liver (hepatocellular carcinoma), gall bladder and biliary system, exocrine pancreas, kidney, lung (for example adenocarcinomas, small cell lung carcinomas, non-small cell lung carcinomas, bronchioalveolar carcinomas and mesotheliomas), head and neck (for example cancers of the tongue, buccal cavity, larynx, pharynx, nasopharynx, tonsil, salivary glands, nasal cavity and paranasal sinuses), ovary, fallopian tubes, peritoneum, vagina, vulva, penis, cervix, myometrium, endometrium, thyroid (for example thyroid follicularcarcinoma), adrenal, prostate, skin and adnexae (for example melanoma, basal cell carcinoma, squamous cell carcinoma, keratoacanthoma, dysplastic naevus); haematological malignancies (i.e. leukemias, lymphomas) and premalignant haematological disorders and disorders of borderline malignancy including haematological malignancies and related conditions of lymphoid lineage (for example acute lymphocytic leukemia [ALL], chronic lymphocytic leukemia [CLL], B-cell lymphomas such as diffuse large B-cell lymphoma [DLBCL], follicular lymphoma, Burkitt’s lymphoma, mantle cell lymphoma, MALT lymphoma, T-cell lymphomas and leukaemias, natural killer [NK] cell lymphomas, Hodgkin’s lymphomas, hairy cell leukaemia, monoclonal gammopathy of uncertain significance, plasmacytoma, multiple myeloma, and post-transplant lymphoproliferative disorders), and haematological malignancies and related conditions of myeloid lineage (for example acute myelogenous leukemia [AML], chronic myelogenous leukemia [CML], chronic myelomonocytic leukemia [CMML], hypereosinophilic syndrome, myeloproliferative disorders such as polycythaemia vera, essential thrombocythaemia and primary myelofibrosis, myeloproliferative syndrome, myelodysplastic syndrome, and promyelocytic leukemia); tumours of mesenchymal origin, for example sarcomas of soft tissue, bone or cartilage such as osteosarcomas, fibrosarcomas, chondrosarcomas, rhabdomyosarcomas, leiomyosarcomas, liposarcomas, angiosarcomas, Kaposi’s sarcoma, Ewing’s sarcoma, synovial sarcomas, epithelioid sarcomas, gastrointestinal stromal tumours, benign and malignant histiocytomas, and dermatofibrosarcoma protuberans; tumours of the central or peripheral nervous system (for example astrocytomas, gliomas and glioblastomas, meningiomas, ependymomas, pineal tumours and schwannomas); endocrine tumours (for example pituitary tumours, adrenal tumours, islet cell tumours, parathyroid tumours, carcinoid tumours and medullary carcinoma of the thyroid); ocular and adnexal tumours (for example retinoblastoma); germ cell and trophoblastic tumours (for example teratomas, seminomas, dysgerminomas, hydatidiform moles and choriocarcinomas); and paediatric and embryonal tumours (for example medulloblastoma, neuroblastoma, Wilms tumour, and primitive neuroectodermal tumours); or syndromes, congenital or otherwise, which leave the patient susceptible to malignancy (for example Xeroderma Pigmentosum).

[0198] Particular examples of cancers that can be targeted with the compounds of the present invention include, but are not limited to lymphoma, prostate cancer, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, prostate cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophagealcancer, and pancreatic cancer. More particularly, the cancers may be one or more of the following breast cancer, ovary cancer, pancreatic cancer, prostate cancer, lung cancer and / or colorectal cancer.

[0199] Many diseases are characterized by persistent and unregulated angiogenesis. Chronic proliferative diseases are often accompanied by profound angiogenesis, which can contribute to or maintain an inflammatory and / or proliferative state, or which leads to tissue destruction through the invasive proliferation of blood vessels. Tumour growth and metastasis have been found to be angiogenesis-dependent. Compounds of the invention may therefore be useful in preventing and disrupting initiation of tumour angiogenesis. In particular, the compounds of the invention may be useful in the treatment of metastasis and metastatic cancers.

[0200] Metastasis or metastatic disease is the spread of a disease from one organ or part to another non-adjacent organ or part. The cancers which can be treated by the compounds of the invention include primary tumours (i.e. cancer cells at the originating site), local invasion (cancer cells which penetrate and infiltrate surrounding normal tissues in the local area), and metastatic (or secondary) tumours ie. tumours that have formed from malignant cells which have circulated through the bloodstream (haematogenous spread) or via lymphatics or across body cavities (trans-coelomic) to other sites and tissues in the body.

[0201] Particular cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.

[0202] The compounds may also be useful in the treatment of tumour growth, pathogenesis, resistance to chemo- and radio-therapy by sensitising cells to chemotherapy and as an anti-metastatic agent.Routes of Administration

[0203] The compounds of the invention or pharmaceutical compositions comprising these compounds may be administered to a subject by any convenient route of administration, whether systemically / peripherally or topically (i.e., at the site of desired action).

[0204] Routes of administration include, but are not limited to, oral (e.g. by ingestion); buccal; sublingual; transdermal (e.g. by a patch, plaster, etc.); transmucosal (e.g. by a patch, plaster, etc.); intranasal (e.g. by nasal spray); ocular (e.g. by eye drops, eye ointment etc.); pulmonary (e.g. by inhalation or insufflation therapy, for example via an aerosol, for example by the nose or mouth); rectal (e.g. by suppository or enema); vaginal (e.g. by pessary); parental, forexample by injection, including subcutaneous, intradermal, intramuscular, intravenous, intraarterial, intracardiac, intrathecal, intraspinal, intracapsular, subcapsular, intraorbital, intraperitoneal, intratracheal, subcuticular, intraarticular, subarachnoid, and intrasternal; by implant of a depot or reservoir dosage form, for example subcutaneously or intramuscularly.

[0205] The compounds of the present invention are particularly suitable for oral administration.Combination Therapies

[0206] The compounds of the invention and salts, solvates thereof defined hereinbefore may be applied as a sole therapy or may involve, in addition to the compound of the invention, one or more additional therapeutic agents, e.g. an anti-tumour agent.

[0207] In the context of cancer treatment, in addition to the compound of the invention, therapy may additionally involve conventional surgery, radiotherapy and / or chemotherapy. Such chemotherapy may include one or more of the following categories of anti-tumour agents:- other antiproliferative / antineoplastic drugs and combinations thereof, as used in medical oncology, such as, but not limited to, alkylating agents (for example cisplatin, oxaliplatin, carboplatin, cyclophosphamide, nitrogen mustard, melphalan, chlorambucil, busulphan, temozolamide and nitrosoureas); antimetabolites (for example gemcitabine and antifolates such as, but not limited to, fluoropyrimidines like 5-fluorouracil and tegafur, raltitrexed, methotrexate, cytosine arabinoside, and hydroxyurea); antitumour 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); and topoisomerase inhibitors (for example epipodophyllotoxins like etoposide and teniposide, amsacrine, topotecan and camptothecin); cytostatic agents such as, but not limited to, antioestrogens (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, but not limited to, finasteride; anti-invasion agents [for example c-Src kinase family inhibitors like 4-(6-chloro-2,3- methylenedioxyanilino)-7-[2-(4-methylpiperazin-1-yl)ethoxy]-5-tetrahydropyran-4-yloxyquinazoline (AZD0530; International Patent Application WO 01 / 94341), / \ / -(2-chloro-6- methylphenyl)-2-{6-[4-(2-hydroxyethyl)piperazin-1-yl]-2-methylpyrimidin-4-ylamino}thiazole- 5-carboxamide (dasatinib, BMS-354825; J. Med. Chem., 2004, 47, 6658-6661) and bosutinib (SKI-606), and metalloproteinase inhibitors like marimastat, inhibitors of urokinase plasminogen activator receptor function or antibodies to Heparanase]; 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 [Erbitux, C225] and any growth factor or growth factor receptor antibodies disclosed by Stern et al. (Critical reviews in oncology / haematology, 2005, Vol. 54, pp11-29); such inhibitors also include tyrosine kinase inhibitors, for example inhibitors of the epidermal growth factor family (for example EGFR family tyrosine kinase inhibitors such as, but not limited to, / V-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), / V-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido- / V-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin- 4-amine (Cl 1033), erbB2 tyrosine kinase inhibitors such as, but not limited to, lapatinib); inhibitors of the hepatocyte growth factor family; inhibitors of the insulin growth factor family; inhibitors of the platelet-derived growth factor family such as, but not limited to, imatinib and / or nilotinib (AM N 107); inhibitors of serine / threonine kinases (for example Ras / Raf signalling inhibitors such as, but not limited to, farnesyl transferase inhibitors, for example sorafenib (BAY 43-9006), tipifarnib (R115777) and lonafarnib (SCH66336)), 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 (insulin-like growth factor) kinase inhibitors; aurora kinase inhibitors (for example AZD1152, PH739358, VX-680, MLN8054, R763, MP235, MP529, VX-528 AND AX39459) and cyclin dependent kinase inhibitors such as, but not limited to, CDK2 and / or CDK4 inhibitors; antiangiogenic agents such as, but not limited to, those which inhibit the effects of vascular endothelial growth factor, [for example the anti-vascular endothelial cell growth factor antibody bevacizumab (Avastin™) and for example, a VEGF receptor tyrosine kinase inhibitor such as, but not limited to, vandetanib (ZD6474), vatalanib (PTK787), sunitinib (SU11248), axitinib (AG-013736), pazopanib (GW 786034) and 4-(4-fluoro-2-methylindol-5-yloxy)-6- methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (AZD2171 ; Example 240 within WO 00 / 47212), compounds such as, but not limited to, those disclosed in International Patent Applications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compoundsthat work by other mechanisms (for example linomide, inhibitors of integrin avp3 function and angiostatin)]; vascular damaging agents such as, but not limited to, Combretastatin A4 and compounds disclosed in International Patent Applications WO 99 / 02166, WO 00 / 40529, WO 00 / 41669,WO 01 / 92224, WO 02 / 04434 and WO 02 / 08213; an endothelin receptor antagonist, for example zibotentan (ZD4054) or atrasentan; antisense therapies, for example those which are directed to the targets listed above, such as, but not limited to, ISIS 2503, an anti-ras antisense; gene therapy approaches, including for example approaches to replace aberrant genes such as, but not limited to, aberrant p53 or aberrant BRCA1 or BRCA2, GDEPT (gene-directed enzyme pro-drug therapy) approaches such as, but not limited to, those using cytosine deaminase, thymidine kinase or a bacterial nitroreductase enzyme and approaches to increase patient tolerance to chemotherapy or radiotherapy such as multi-drug resistance gene therapy; and immunotherapy approaches, including for example ex-vivo and in-vivo approaches to increase the immunogenicity of patient tumour cells, such as, but not limited to, transfection with cytokines such as interleukin 2, interleukin 4 or granulocyte-macrophage colony stimulating factor, approaches to decrease T-cell anergy, approaches using transfected immune cells such as, but not limited to, cytokine-transfected dendritic cells, approaches using cytokine-transfected tumour cell lines and approaches using anti-idiotypic antibodies.

[0208] In a particular embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, conventional surgery or radiotherapy or chemotherapy.

[0209] In a further embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, standard chemotherapy for the cancer concerned and / or therapy with a DNA damage repair inhibitors (e.g. PARP, ATM, ATR, WEE1 , CHK1 , USP1 and DNAPK inhibitors).

[0210] In a further embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, therapy with a PARP inhibitor.

[0211] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Suchcombination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0212] According to this aspect of the invention there is provided a combination for use in the treatment of a cancer (for example a cancer involving a solid tumour) comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and another anti-tumour agent.

[0213] According to this aspect of the invention there is provided a combination for use in the treatment of a proliferative condition, such as, but not limited to, cancer (for example a cancer involving a solid tumour), comprising a compound of the invention as defined hereinbefore, or a pharmaceutically acceptable salt, hydrate or solvate thereof, and any one of the anti-tumour agents listed herein above.

[0214] In a further aspect of the invention there is provided a compound of the invention or a pharmaceutically acceptable salt, hydrate or solvate thereof, for use in the treatment of cancer in combination with another anti-tumour agent, optionally selected from one listed herein above.

[0215] Herein, where the term “combination” is used it is to be understood that this refers to simultaneous, separate or sequential administration. In one aspect of the invention “combination” refers to simultaneous administration. In another aspect of the invention “combination” refers to separate administration. In a further aspect of the invention “combination” refers to sequential administration. Where the administration is sequential or separate, the delay in administering the second component should not be such as to lose the beneficial effect of the combination. In one embodiment, a combination refers to a combination product.

[0216] According to a further aspect of the invention there is provided a pharmaceutical composition which comprises a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in combination with an anti-tumour agent (optionally selected from one listed herein above), in association with a pharmaceutically acceptable diluent or carrier.Biological Activity

[0217] The biological assay described in the example section (Biological Assay 1) may be used to measure the pharmacological effects of the compounds of the present invention.

[0218] Although the pharmacological properties of the compounds of formula I vary with structural change, as expected, the compounds of the invention were found to be active in the assays described in Biological Assay 1. In general, the compounds of the invention demonstrate an IC50 of 5000 nM or less in the assay described in Biological Assay 1 , with preferred compounds of the invention demonstrating an IC50 of 100 nM or less and the most preferred compounds of the invention demonstrating an IC50 of 30 nM or less.Additional applications

[0219] The compounds of the present invention are also potentially useful agents for increasing the efficiency and robustness of CRISPR gene editing in vitro and in vivo.

[0220] In this regard, homologous recombination (HR) is primordial to ensure the correct modification of the DNA (insertion of DNA in the genome, base mutation, etc). Consistent with the hypothesis that TMEJ competes with HR for the access to resected DNA breaks (Mateos-Gomez P.A., et al., (2017), Nat. Struct. Mol. Biol. (2017) 24(12): 1116-1123), it has been shown that loss of PolQ leads to an increase of HR on CRISPR induced breaks and improves the fidelity and frequency of the genome modification (Mara K., et al., New Phyto. (2019); 222(3): 1380-1391 ; Zelenski A.N., et al., Nat. Commun., (2017); 8(1):66). Therefore, a PolQ inhibitor can be used to increase efficiency and robustness of CRISPR genome editing in vitro, and potentially in vivo (Schimmel J. et al., Cell Rep. (2023) 42: 112019).

[0221] For this reason, a role for the loss of PolQ enhancing the efficacy of CRISPR mediated gene editing has been described in WO 2017 / 062754. Thus, the compounds of the invention are likely to be useful in enhancing the efficiency of CRISPR based editing methodologies and / or CRISPR based editing therapeutics. Furthermore, compound mediated PolQ inhibition is likely to reduce the frequency of random integration events and thus provide a route to ameliorate any safety concerns of CRISPR mediated technology. Thus, according to a further aspect of the invention, there is provided the use of a compound of formula (I) as defined herein in a CRISPR based editing methodology and / or CRISPR based editing therapeutics, such as the enhancement of efficiency of CRISPR based editing methodology and / or CRISPR based editing therapeutics.

[0222] For this reason, in a further aspect, the present invention provides the use of a compound of the invention (i.e. a compound of formula I or any sub-formulae thereof) or a salt, hydrate or solvate thereof, for CRISPR gene editing in vitro or in vivo.

[0223] In another aspect, the present invention provides the use of a compound of the invention (i.e. a compound of formula I or any sub-formulae thereof), or a salt, hydrate or solvate thereof, for increasing the efficiency of CRISPR gene editing in vitro or in vivo.

[0224] In another aspect, the present invention provides a compound of the invention (i.e. a compound of formula I or any sub-formulae thereof), or a salt, hydrate or solvate thereof, for use in CRISPR gene editing in vivo.

[0225] In another aspect, the present invention provides a compound of the invention (i.e. a compound of formula I or any sub-formulae thereof), or a salt, hydrate or solvate thereof, for use in increasing the efficiency of CRISPR gene editing in vivo.EXAMPLES

[0226] The invention will now be illustrated, but not limited, by reference to the specific embodiments described in the following examples. Compounds are named using conventional IIIPAC nomenclature, or as named by the chemical supplier.

[0227] The following synthetic procedures are provided for illustration of the methods used; for a given preparation or step the precursor used may not necessarily derive from the individual batch synthesized according to the step in the description given.General Conditions:Mass spectra were run on LC-MS systems using electrospray ionization. These were run using either a Waters Acquity H-Class LIPLC with PDA and QDa mass detection, an Acquity LIPLC (binary pump / PDA detector) + ZQ Mass Spectrometer or Acquity i- Class (quaternary pump / PDA detector) + Quattro Micro Mass Spectrometer, a Waters Acquity uPLC system with Waters PDA and ELS detectors or a Shimadzu LC-MS- 2010EV system or a Waters Quattro Premier XE or a SQD2; ionization mode, electrospray positive or negative. [M+H]+refers to mono-isotopic molecular weights.NMR spectra were run on either a Bruker Avance III HD 500 MHz NMR spectrometer or a Bruker Avance III HD 400 MHz NMR spectrometer. Spectra were recorded at 298K and and chemical shifts are quoted in ppm using residual undeuterated solvent as the internal reference.The following examples are intended to illustrate the invention and are not to be construed as being limitations thereon. Temperatures are given in degrees centigrade.If not mentioned otherwise, all evaporations are performed in vacuo, preferably between about 15 mm Hg and 375 mmHg (20 - 500 mbar). The structure of finalproducts, intermediates and starting materials is confirmed by standard analytical methods, e.g., microanalysis and spectroscopic characteristics, MS and NMR. Abbreviations used are those conventional in the art. If not defined, the terms have their generally accepted meanings.Abbreviations br broadCelite® Celite® filter materialCHCI3 chloroform d doublet dd doublet of doubletsDCE 1,2-dichloroethaneDCM dichloromethaneDI PEA diisopropylethylamineDMF A / ,A / -dimethylformamideDMSO dimethyl sulfoxideEtOAc ethyl acetateEtOH EthanolHATU 1-[Bis(dimethylamino)methylene]-1 H-1 ,2,3-triazolo[4,5-b]pyridinium 3- oxide hexafluorophosphateHCI hydrogen chlorideHPLC high pressure liquid chromatographyI PA isopropyl alcoholLC-MS liquid chromatography and mass spectrometryMeOH methanolMeCN acetonitrileMgSO4 magnesium sulfateMS mass spectrometry m multipletmin(s) minute(s) ml_ milliliter(s) m / z mass to charge ratioNa2SO4 sodium sulfateNMP A / -methyl-2-pyrrolidoneNMR nuclear magnetic resonanceRt retention time s singlet t tripletTBME methyl tert-butyl etherTBTU 2- (1 H-benzotriazol-1-yl)-1 ,1 ,3,3-tetramethyluronoium hexafluorophosphateTFA trifluoroacetic acidTHF tetrahydrofuran

[0228] Referring to the examples that follow, compounds of the preferred embodiments were synthesized using the methods described herein, or other methods, which are known in the art.

[0229] The various starting materials, intermediates, and compounds of the preferred embodiments may be isolated and purified, where appropriate, using conventional techniques such as precipitation, filtration, crystallization, evaporation, distillation, and chromatography. Unless otherwise stated, all starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt-forming procedures.

[0230] The LCMS conditions are as follows: Method A Column: Kinetex Core- Shell C18 50 x 2.1 mm, 5 pm column protected by Phenomenex “Security Guard” column; column temp: 40 °C; eluents: A: 0.1% formic acid in water, B: 0.1% formic acid in MeCN; flow rate: 1.2 mL / min; gradient: 0 - 1.20 mins 5-100% B, 1.20 - 1.30 mins 100% B, 1.30 - 1.31 mins 100-5% B. Method B Column: Phenomenex Kinetex Core-Shell C850 x2.1 mm, 5 pm column protected by Phenomenex “Security Guard” column; column temp: 40 °C; eluents: A: 0.1% formic acid in water, B: 0.1% formic acid in MeCN; flowrate: 1.2 mL / min; gradient: 0 - 1.83 mins 5-100% B, 1.83 - 2.25 mins 100% B, 2.25 - 2.26 mins 100-5% B. Method C Column: Waters Atlantis dC18, 100 x 2.1 mm, 3 pm column; column temp: 40 °C; eluents: A: 0.1% formic acid in water, B: 0.1 % formic acid in MeCN; flow rate: 0.6 mL / min; gradient: 0 - 5.00 mins 5-100% B, 5.00 - 5.40 mins 100% B, 5.40 - 5.42 mins 100-5% B. Method D Column: Phenomenex Kinetex-XB C18, 100 x 2.1 mm, 1.7 pm column; column temp: 40 °C; eluents: A: 0.1 % formic acid in water, B: 0.1 % formic acid in MeCN; flow rate: 0.6 mL / min; gradient: 0 - 5.30 mins 5-100% B, 5.30 - 5.80 mins 100% B, 5.80 - 5.82 mins 100-5% B. Method E Column: Phenomenex Gemini NX C18 column (2.0 mm x 50 mm, 3 pm; column temp: 40 °C; eluents: A: 2 mM ammonium bicarbonate modified to pH 10 with ammonium hydroxide, B: MeCN; flow rate: 1.0 mL / min; gradient: 0 - 1.80 mins 1-100% B, 1.80 - 2.10 mins 100% B, 2.10 - 2.30 mins 100-1 % B. Method F Column: Phenomenex Gemini C18 2.0 mm x 100 mm, 3 pm column; column temp: 40 °C; eluents: A: 2 mM ammonium bicarbonate modified to pH10 with ammonium hydroxide, B: MeCN; flow rate: 0.6 mL / min; gradient: 0 - 5.50 mins 5- 100% B, 5.50 - 5.90 mins 100% B, 5.90 - 5.92 mins 100-5% B. Method G Column: Waters UPLC® BEHTMC18, 2.1 mm x 100 mm, 1.7 pm column; column temp: 40 °C; eluents: A: 2 mM ammonium bicarbonate modified to pH10 with ammonium hydroxide, B: MeCN; flow rate: 0.6 mL / min; gradient: 0 - 5.30 mins 5-100% B, 5.30 - 5.80 mins 100% B, 5.80 - 5.82 mins 100-5% B.

[0231] Preparative HPLC conditions are as follows: Method 1 Purifications were performed on a Gilson LC system using a Waters SunfireTM C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 1.90 min then a gradient of 10 - 95% B over 14.10 min and held for 2.0 min, where A = 0.1 % formic acid in water and B = 0.1 % formic acid in acetonitrile. A second gradient of 95 - 10% B was then applied over 0.20 min and held for a further 1.25 min. UV spectra were recorded at 215 nm. Method 2 Purifications were performed on a Gilson LC system using a Waters SunfireTM C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 1.90 min then a gradient of 30 - 95% B over 9.60 min and held for 1.97 min, where A = 0.1% formic acid in water and B = 0.1% formic acid in acetonitrile. A second gradient of 95 - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm. Method 3 Purifications were performed on a Gilson LC system using using a Waters XbridgeTM C18 column (30 mm x 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 10% B for 2.00 min then a radient of 10 - 95% B over 14.00 min and held for 2.00 min, where A = 0.2% ammonium hydroxide inwater and B = acetonitrile. A second gradient of 95 - 10% B was then applied over 0.20 min and held for 1.25 min. UV spectra were recorded at 215 nm. Method 4 Purifications were performed on a Gilson LC system using a Waters XbridgeTM C18 column (30 mm * 100 mm, 5 pm; temperature: room temperature), with an injection volume of 1500 μL at a flow rate of 40 mL / min at 30% B for 2.00 min then a gradient of 30 - 95% B over 9.50 min and held for 1.97 min, where A = 0.2% ammonium hydroxide in water and B = acetonitrile. A second gradient of 95 - 30% B was then applied over 0.33 min and held for 1.65 min. UV spectra were recorded at 215 nm.SYNTHESISExample 1(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-(azetidin-3-yl)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]ethenoneStep 1 : tert-Butyl 3-(1-amino-2-methoxy-2-oxo-ethyl)azetidine-1 -carboxylateA stirred suspension of 10% palladium on carbon (0.84 g, 0.793 mmol) in EtOH (80 mL) was treated with tert-butyl 3-(1-{[(benzyloxy)carbonyl]amino}-2-methoxy-2-oxoethyl)azetidine-1- carboxylate (3.00 g, 7.93 mmol). The reaction mixture was stirred under an atmosphere of hydrogen at room temperature overnight. The resulting mixture was filtered through Celite® and washed through with EtOH (50 mL). The filtrate was concentrated in vacuo to afford the title compound as a yellow oil.1H NMR (500 MHz, CDCI3) δ 4.04 - 3.93 (m, 2H), 3.88 - 3.75(m, 2H), 3.72 (s, 3H), 3.61 - 3.51 (m, 1 H), 2.76 - 2.64 (m, 1 H), 1.43 (s, 9H). NH2protons not observed. LC-MS (Method A): Rt 0.76 mins; MS m / z 267 [M+Na]+.Step 2: tert-Butyl 3-[1-[(2,4-dimethoxyphenyl)methylamino]-2-methoxy-2-oxo-ethyl]azetidine-1 -carboxylateTo a solution of sodium triacetoxyborohydride (2.97 g, 14.0 mmol) and tert-butyl 3-(1-amino- 2-methoxy-2-oxo-ethyl)azetidine-1-carboxylate (step 1) (90%, 1.90 g, 7.00 mmol) in anhydrous THF (40 mL) was added acetic acid (130 μL) followed by 2,4- dimethoxybenzaldehyde (1.28 g, 7.70 mmol) portion-wise at 0 °C and the mixture stirred at room temperature overnight. The reaction was quenched with water (50 mL) and the product extracted with EtOAc (3 x 20 mL). The combined organic extracts were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with a gradient of 18-100% TBME in heptane to afford the title compound as a colourless oil.1H NMR (400 MHz, CDCI3) δ 7.17 - 7.01 (m, 1 H), 6.46 - 6.36 (m, 2H), 4.16 - 4.08 (m, 1 H), 3.99 - 3.86 (m, 2H), 3.81 - 3.78 (m, 6H), 3.77 - 3.67 (m, 4H), 3.66 - 3.60 (m, 3H), 3.37 - 3.30 (m, 1 H), 2.73 - 2.55 (m, 1 H), 1.46 - 1.38 (m, 9H). LC- MS (Method A): Rt 0.95 mins; MS m / z 395.2 [M+H]+.Step 3: tert-Butyl 3-[1-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-2-methoxy-2-oxo- ethyl]azetidine-1 -carboxylateTo a solution of terf-butyl 3-[1-[(2,4-dimethoxyphenyl)methylamino]-2-methoxy-2-oxo- ethyl]azetidine-1 -carboxylate (step 2) (81%, 3.02 g, 6.20 mmol) in anhydrous DCE (40 mL) was added sodium cyanoborohydride (0.45 mL, 8.06 mmol) and acetic acid (0.2 mL) followed by [(1-ethoxycyclopropyl)oxy](trimethyl)silane (2.5 mL, 12.4 mmol) and the reaction mixture was stirred at 70 °C for 12 h. The resulting mixture was diluted with saturated aqueous sodium bicarbonate (80 mL) and extracted with DCM (3 x 50 mL). The combined organic extracts were washed with brine (50 mL), dried over Na2SC>4 and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with a gradient of 0-60% EtOAc in heptane to afford the title compound as a colourless oil.1H NMR (500 MHz, CDCI3) δ 7.12 - 7.00 (m, 1 H), 6.45 - 6.36 (m, 2H), 3.96 - 3.90 (m, 1 H), 3.86 - 3.82 (m, 1H), 3.81 - 3.78 (m, 3H), 3.77 - 3.69 (m, 7H), 3.60 - 3.53 (m, 1 H), 3.48 - 3.44 (m, 1 H), 3.03 - 2.90 (m, 1 H), 2.35 - 2.22 (m, 1 H), 1.43 - 1.36 (m, 9H), 1.30 - 1.21 (m, 2H), 0.47 - 0.38 (m, 2H), 0.35 - 0.16 (m, 2H). LC-MS (Method A): Rt 1.43 mins; MS m / z 435.3 [M+H]+.Step 4: 2-(1-ferf-Butoxycarbonylazetidin-3-yl)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl] amino]acetic acidTo a solution of terf-butyl 3-[1-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-2-methoxy- 2-oxo-ethyl]azetidine-1-carboxylate (step 3) (94%, 1.10 g, 2.38 mmol) in THF (12.5 mL), MeOH (6 mL) and water (6 mL) was added lithium hydroxide monohydrate (0.15 g, 3.57 mmol) and reaction mixture was then left to stir at room temperature overnight. The volatiles were removed in vacuo and the resulting aqueous mixture was diluted with water (40 mL) then acidified to pH 4 by dropwise addition of 1M HCI. The product was extracted with DCM (3 x 15 mL) and the combined organic extracts were passed through a phase separator and concentrated in vacuo to afford the title compound as a colourless oil.1H NMR (500 MHz, CDCI3) δ 7.08 (d, J = 8.0 Hz, 1 H), 6.47 - 6.43 (m, 2H), 4.22 - 4.15 (m, 1 H), 4.14 - 4.07 (m, 1H), 4.03 - 3.94 (m, 3H), 3.84 - 3.79 (m, 7H), 3.68 - 3.59 (m, 1H), 3.27 - 3.16 (m, 1 H), 1.98 - 1.89 (m, 1 H), 1.45 (s, 9H), 0.62 - 0.32 (m, 4H). The carboxylic acid proton not observed. LC-MS (Method A): Rt 1.04 mins; MS m / z 443.2 [M+Na]+.Step 5: terf-Butyl 3-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-2-oxo-ethyl]azetidine-1-carboxylateTo a solution of 2-(1-terf-butoxycarbonylazetidin-3-yl)-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]acetic acid (step 4) (70%, 850 mg, 1.41 mmol) and (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (236 mg, 1.70 mmol) in anhydrous DMF (8 mL) was added DI PEA (366 mg, 2.83 mmol) followed by HATLI (646 mg, 1.70 mmol) and the reaction mixture was allowed to stir at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with a gradient of 50-100% MeCN in water (+ 0.1% formic acid). The product fractions were neutralised using saturated aqueous sodium bicarbonate solution and extracted with DCM (2 x 30 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the title compound as a colourless oil.1H NMR (500 MHz, CDCI3) δ 7.11 - 7.06 (m, 1 H), 6.42 - 6.35 (m, 2H), 4.06 - 3.89 (m, 4H), 3.89 - 3.68 (m, 8H), 3.71 - 3.55 (m, 2H), 3.48 - 3.27 (m, 3H), 3.25 - 3.15 (m, 1H), 2.16 - 2.05 (m, 2H), 1.73 - 1.66 (m, 3H), 1.60 - 1.56 (m, 2H), 1.53 - 1.48 (m, 1 H), 1.46 - 1.40 (m, 10H), 1.31 - 1.20 (m, 1H), 1.20 - 0.95 (m, 3H), 0.41 - 0.29 (m, 2H), 0.24 - 0.08 (m, 2H). LC-MS (Method A): Rt 1.35 mins; MS m / z 542.4 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-(azetidin-3-yl)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]ethenoneTo a solution of terf-butyl 3-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]- 1-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-2-oxo-ethyl]azetidine-1-carboxylate (step 5) (140 mg, 0.258 mmol) in DCM (2 mL) was added TFA (59 μL, 0.775 mmol) and the reaction mixture was stirred at room temperature for 2 h. The reaction was then quenched with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with a gradient of 10-60% MeCN in water (+ 0.1% formic acid). The product fractions were neutralised with saturated aqueous sodium bicarbonate solution and extracted with DCM (~20 mL). The organic portion was dried over Na2SC>4 and concentrated in vacuo to afford the title compound as a white solid.1H NMR (500 MHz, CDCI3) δ 7.12 - 7.05 (m, 1 H), 6.44 - 6.33 (m, 2H), 4.05 - 3.96 (m, 1 H), 3.96 - 3.88 (m, 1 H), 3.88 - 3.52 (m, 12H), 3.48 - 3.26 (m, 2H), 3.19 - 2.95 (m, 1 H), 2.12 - 2.03 (m, 2H), 1.73 - 1.66 (m, 4H), 1.58 - 1.19 (m, 6H), 1.17 - 0.96 (m, 3H), 0.47 - 0.25 (m, 2H), 0.25 - 0.09 (m, 2H). LC-MS (Method D): Rt 2.60 mins; MS m / z 442.4 [M+H]+.Example 21-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-(69zetidine-3-yl)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]ethanoneStep 1 : terf-Butyl 3-[2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-2-oxo-ethyl]azetidine-1-carboxylateTo a solution of 2-(1-terf-butoxycarbonylazetidin-3-yl)-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]acetic acid (Example 1 , step 4) (94%, 501 mg, 1.12 mmol) and (4aR,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (171 mg, 1.23 mmol) in anhydrous DMF (6 mL) was added DIPEA (289 mg, 2.24 mmol) followed by HATLI (511 mg, 1.34 mmol) and the reaction mixture was allowed to stir at room temperature for 2 h. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-70% TBME in heptane to afford the title compound as a colourless oil and as a 53:47 mixture of diastereomers.1H NMR (500 MHz, CDCI3) δ 7.12 - 7.00 (m, 1H), 6.46 - 6.33 (m, 2H), 4.08 - 3.80 (m, 5H), 3.80 - 3.74 (m, 6H), 3.68 - 3.56 (m, 1 H), 3.55 - 3.45 (m, 1 H), 3.43 - 3.16 (m, 3H), 2.19 - 1.95 (m, 2H), 1.85 - 1.67 (m, 5H), 1.45 - 1.42 (m, 9H), 1.35 - 1.21 (m, 5H), 0.91 - 0.82 (m, 3H), 0.45 - 0.29 (m, 2H), 0.25 - 0.11 (m, 2H). LC-MS (Method A): Rt 1.36 mins (52%) and 1.49 mins (46%); MS m / z 542.5 [M+H]+.Step 2: 1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-(azetidin-3-yl)-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]ethanoneterf-Butyl 3-[2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-2-oxo-ethyl]azetidine-1-carboxylate (step 1) (100%, 518 mg, 0.956 mmol) was dissolved in 4M HCI in 1 ,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 3 h. The resulting mixture was then diluted with saturated aqueous sodium bicarbonate solution (20 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-30% MeOH in EtOAc to afford the title compound as a white solid and as a 60:40 mixture of diastereomers.1H NMR (500 MHz, CDCI3) δ 8.46 (s, 1H), 6.96 - 6.77 (m, 1H), 6.30 - 6.18 (m, 2H), 4.00 - 3.71 (m, 4H), 3.71 - 3.56 (m, 7H), 3.56 - 2.85 (m, 6H), 2.04 - 1.65 (m, 2H), 1.63 - 1.51 (m, 4H), 1.46 - 0.78 (m, 8H), 0.29 - -0.17 (m, 4H). LC-MS (Method D): Rt 2.51 mins (55%) and 2.57 mins (37%); MS m / z 442.4 [M+H]+.Example 31-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-methylsulfonyl-propan-1-oneStep 1 : Methyl (2S)-2-amino-3-methylsulfanyl-propanoateTo a solution of D-cysteine methyl ester hydrochloride (1:1) (2.0 g, 11.7 mmol) in MeOH (75 mL) was added sodium ethoxide (95%, 3.8 mL, 46.6 mmol) and iodomethane (1.82 g, 12.8 mmol) and the reaction mixture was stirred at room temperature for 1 h 15 mins. The resulting mixture was diluted with EtOAc and washed twice with water. The organic portion was dried over MgSO4 and concentrated in vacuo to afford the title compound as a yellow oil.1H NMR (400 MHz, CDCI3) δ 3.84 - 3.78 (m, 1H), 3.77 (s, 3H), 2.96 (dd, J = 13.8, 4.7 Hz, 1H), 2.85 (dd, J = 13.7, 7.3 Hz, 1 H), 2.14 (s, 3H), 1.31 - 1.21 (m, 2H).Step 2: Methyl (2S)-2-[(2,4-dimethoxyphenyl)methylamino]-3-methylsulfanyl-propanoateA mixture of methyl (2S)-2-amino-3-methylsulfanyl-propanoate (step 1) (90%, 556 mg, 3.35 mmol) and DCE (20 mL) was treated with sodium triacetoxyborohydride (769 mg, 3.63 mmol) followed by acetic acid (0.05 mL) and the solution was heated at 65 °C for 2 h. The resulting mixture was cooled to 0 °C and quenched by the slow addition of water (5 mL). Thesolution was diluted with DCM (20 mL) and the organics were separated, dried overMgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-10% MeOH in EtOAc. Further purification was achieved by chromatography on silica eluting with a gradient of 0-10% MeOH in TBME to afford the title compound as a pale-yellow oil.1H NMR (400 MHz, CDCI3) δ 7.20 - 7.08 (m, 1H), 6.50 - 6.36 (m, 2H), 4.61 (s, 1 H), 3.84 (s, 1 H), 3.82 - 3.75 (m, 6H), 3.72 - 3.65 (m, 3H), 3.48 - 3.38 (m, 1 H), 3.00 - 2.58 (m, 2H), 2.02 (s, 3H). NH proton not observed. LC-MS (Method A): Rt 0.87 mins; MS m / z 300.2 [M+ H]+.Step 3: Methyl (2S)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-methylsulfanyl- propanoateA solution of methyl (2S)-2-[(2,4-dimethoxyphenyl)methylamino]-3-methylsulfanyl- propanoate (step 2) (95%, 276 mg, 0.875 mmol) in anhydrous DCE (4 mL) was treated with [(1-ethoxycyclopropyl)oxy](trimethyl)silane (153 mg, 0.875 mmol), acetic acid (110 μL) and sodium cyanoborohydride (110 mg, 1.75 mmol) and the solution was heated at 65 °C for 18 h. The resulting mixture was cooled to room temperature and diluted with DCM (20 mL) and saturated aqueous sodium bicarbonate solution (5 mL). The organic portion was separated, washed with water (2 x 5 mL), dried overMgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-10% MeOH in TBME to afford the title compound as a colourless gum.1H NMR (400 MHz, CDCI3) δ 7.22 (d, J = 8.0 Hz, 1 H), 6.46 - 6.37 (m, 2H), 3.87 (d, J = 14.3 Hz, 1 H), 3.80 (s, 3H), 3.78 (s, 3H), 3.74 (s, 3H), 3.64 (dd, J = 8.9, 6.0 Hz, 1H), 2.99 - 2.70 (m, 2H), 2.25 - 2.13 (m, 1H), 2.01 (s, 3H), 1.28 - 1.23 (m, 1 H), 0.46 - 0.32 (m, 4H). LC-MS (Method A): Rt 1.36 mins; MS m / z 340.2 [M+H]+.Step 4: 2-[Cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-methylsulfanyl- propanoic acidMethyl (2S)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-methylsulfanyl- propanoate (step 3) (150 mg, 0.442 mmol) was added to a solution of 2M NaOH (0.44 mL, 0.884 mmol) in MeOH (2 mL) and the reaction mixture was heated at 50 °C for 1 h. The resulting solution was cooled to 0 °C and neutralised by the addition of 2M HCI (0.5 mL). The mixture was diluted with DCM (20 mL) and the organics were separated, washed with water (2 x 5 mL), dried over MgS aOn4d concentrated in vacuo to afford the title compound as a pale-yellow oil. LC-MS (Method A): Rt 1.00 mins; MS m / z 326.1 [M+H]+.Step 5: 1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-methylsulfanyl-propan-1-oneTo a solution of 2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-methylsulfanyl- propanoic acid (step 4) (81%, 198 mg, 0.492 mmol) in DMF (1.16 mL) was added (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (68 mg, 0.492 mmol). HATLI (280 mg, 0.738 mmol) and DIPEA (0.13 mL, 0.738 mmol) were added. The reaction mixture was stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc (20 mL). The organics were washed with water (3 x 5 mL), dried over MgSO an4d concentrated in vacuo. Purification by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) followed by further purification by chromatography on silica eluting with a gradient of 0-100% TBME in heptane. The product fractions were concentrated in vacuo, taken up in MeCN:water and freeze-dried to afford the title compound as a pale-yellow gum and as a 52:48 mixture of diastereomers.1H NMR (400 MHz, CDCI3) δ 7.16 - 7.07 (m, 1H), 6.45 - 6.36 (m, 2H), 3.86 - 3.70 (m, 9H), 3.65 - 3.57 (m, 1 H), 3.41 - 3.23 (m, 2H), 2.97 - 2.75 (m, 2H), 2.24 - 2.00 (m, 5H), 1.75 - 1.61 (m, 4H), 1.54 - 1.39 (m, 4H), 1.28 - 1.17 (m,2H), 1.12 - 0.99 (m, 2H), 0.47 - 0.20 (m, 4H). LC-MS (Method F): Rt 5.88 min (48%) and 5.98 mins (44%); MS m / z 447.3 [M+H]+.Step 6: 1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-methylsulfonyl-propan-1-one1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-methylsulfanyl-propan-1-one (step 5) (92%, 62 mg, 0.128 mmol) in a mixture of MeOH:MeCN:water (1:1:2, 3 mL) was treated with potassium peroxymonosulfate (78 mg, 0.512 mmol) and reaction mixture was stirred at room temperature for 2 h. The organics were extracted with EtOAc (10 mL), washed with water (5 mL) and separated. The organics were concentrated in vacuo and the crude material was purified by preparative HPLC (Method 2). The product fractions were concentrated in vacuo and freeze-dried overnight to afford the title compound as a white solid as a single diastereomer.1H NMR (400 MHz, CDCI3) δ 7.18 - 7.11 (m, 1H), 6.47 - 6.37 (m, 2H), 4.33 (dd, J = 13.9, 10.1 Hz, 1H), 4.09 - 4.00 (m, 1H), 3.83 - 3.78 (m, 7H), 3.36 (d, J = 14.0 Hz, 1H), 3.26 - 3.17 (m, 1H), 2.89 (s, 3H), 2.87 - 2.80 (m, 1H), 2.77 - 2.62 (m, 1 H), 2.13 - 2.02 (m, 1 H), 1.88 - 1.80 (m, 1 H), 1.73 - 1.60 (m, 4H), 1.45 - 1.32 (m, 4H), 1.10 - 0.94 (m, 4H), 0.91 - 0.79 (m, 1 H), 0.54 - 0.24 (m, 4H). LC-MS (Method D): Rt 4.22 mins; MS m / z 479.3 [M+H]+.Example 4(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : tert-Butyl / V-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-(benzyloxycarbonylamino)-3-oxo-propyl]carbamateTo an ice-cooled (0 °C) solution of DIPEA (15 mL, 88.7 mmol), / \ / -[(benzyloxy)carbonyl]-3- [(terf-butoxycarbonyl)amino]-D-alanine (25.00 g, 73.9 mmol) and HATLI (33.71 g, 88.7 mmol) in DCM (400 mL) was added portion-wise (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (100%, 11.32 g, 81.3 mmol). The reaction mixture was allowed to warm to room temperature and stirred for 2.5 h. The resulting mixture was diluted with water (200 mL), stirred for 10 mins and extracted with DCM (3 x 150 mL). The combined organic extracts were dried overMgSO4 and concentrated in vacuo to yield a crude yellow oil. The crude material was purified by chromatography on silica eluting with a gradient of 0-100% TBME in heptane to afford the title compound as a colourless glass.1H NMR (400 MHz, CDCI3) δ 7.45 - 7.28 (m, 5H), 6.02 - 5.81 (m, 1 H), 5.18 - 5.06 (m, 2H), 5.04 - 4.94 (m, 1 H), 4.70 (s, 1 H), 3.68 - 3.18 (m, 4H), 2.16 - 2.00 (m, 1 H), 1.86 - 1.67 (m, 4H), 1.65 - 1.51 (m, 2H), 1.43 (s, 9H), 1.34 - 1.22 (m, 2H), 1.17 - 1.04 (m, 2H), 0.97 - 0.77 (m, 3H). LC-MS (Method A): Rt 1.36 mins; MS m / z 482.3 [M+Na]+.Step 2: tert-Butyl / V-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- amino-3-oxo-propyl]carbamate10% Palladium on carbon (4.56 g, 4.29 mmol) was added to a stirred solution of tert-butyl / V- [(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-(benzyloxycarbonylamino)-3-oxo-propyl]carbamate (step 1) (99%, 19.90 g, 42.9 mmol) in EtOH (300 mL). The reaction mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 4 h. The resulting mixture was filtered through Celite® and washed through with MeOH (100 mL). The filtrate was concentrated in vacuo to afford the title compound as a colourless glass.1H NMR (400 MHz, CDCI3) δ 5.18 (br s, 1H), 3.83 - 3.68 (m, 1 H), 3.48 (s, 1 H), 3.41 - 3.32 (m, 2H), 3.20 (br s, 1 H), 3.03 - 2.86 (m, 1 H), 2.04 (br s, 1 H), 1.88 - 1.68 (m, 6H), 1.65 - 1.58 (m, 3H), 1.44 (s, 9H), 1.34 - 1.02 (m, 5H). LC-MS (Method A): Rt 0.99 mins; MS m / z 326.2 [M+H]+.Step 3: tert-Butvl / V-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-oxo-propyl]carbamateterf-Butyl N -[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-amino-3-oxo- propyl]carbamate (step 2) (99%, 13.57 g, 41.3 mmol), 2,4-dimethoxybenzaldehyde (6.86 g, 41.3 mmol), sodium borohydride (1.87 g, 49.5 mmol) and MgSO4 (9.94 g, 82.6 mmol) were suspended in DCM (200 mL) and stirred at room temperature overnight. The resulting mixture was filtered and concentrated in vacuo. The residue was taken up in MeOH (200 mL), triethylamine (32 mL, 0.227 mol) was added and the mixture stirred at room temperature for 1 h. The resulting mixture was quenched with water (200 mL) and extracted with DCM (3 x 150 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to afford the title compound as a pale-yellow gum. LC- MS (Method E): Rt 1.95 mins; MS m / z 476.3 [M+H]+.Step 4: terf-Butyl / \ / -[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-oxo-propyl]carbamateSodium cyanoborohydride (3.91 g, 62.3 mmol) was added to a solution of tert-butyl A / -[(2R)- 3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-oxo-propyl]carbamate (step 3) (83%, 20.05 g, 35.0 mmol), [(1-ethoxycyclopropyl)oxy](trimethyl)silane (21 mL, 0.105 mol) and acetic acid (9 mL) in anhydrous DCE (250 mL) and the mixture was stirred under nitrogen at 65 °C overnight. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (200 mL) and extracted with DCM (3 x 200 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to afford the title compound as a yellow gum. LC-MS (Method E): Rt 2.35 mins; MS m / z 516.5 [M+H]+.Step 5:tert-Butyl / V-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-oxo-propyl]- / \ / -methyl-carbamateTo an ice-cooled (0 °C) solution of tert-butyl / \ / -[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-oxo- propyl]carbamate (step 4) (78%, 22.00 g, 33.3 mmol) in anhydrous DMF (200 mL) was added sodium hydride (60%, 1.33 g, 33.3 mmol) and the reaction mixture was allowed to warm to room temperature and stirred for 1 h. The mixture was re-cooled to 0 °C and treated dropwise with iodomethane (2.1 mL, 33.3 mmol). The mixture was allowed to warm to room temperature, stirred for 3 days and then re-cooled to 0 °C. Water (150 mL) was added whilst stirring and the mixture was extracted with DCM (3 x 100 mL). The organics were combined, dried over MgSO4 and concentrated in vacuo to yield a crude yellow gum. The crude material was purified by chromatography on silica eluting with a gradient of 0-100% TBME inheptane to afford the title compound as a colourless glass. LC-MS (Method B): Rt 1.50 mins; MS m / z 530.5 [M+ H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneTo a flask containing 4M HCI in 1,4-dioxane (15 mL, 60.0 mmol) was added tert-butyl N- [(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-oxo-propyl]-N-methyl-carbamate (step 5) (99%, 5.20 g, 9.7 mmol) in anhydrous 1 ,4-dioxane (25 mL) and the reaction was stirred until a clear solution was obtained. Further 4M HCI in 1,4-dioxane (12 mL, 48.6 mmol) was added and the reaction was stirred at room temperature overnight. Additional 4M HCI in 1,4-dioxane (ca. 3 mL, 12 mmol) was added and the solution was stirred for 2 h at room temperature. The reaction was concentrated in vacuo and diluted with EtOAc (100 mL). The solution was basified to pH 10 with saturated aqueous potassium carbonate solution and washed with water (10 mL) and brine (10 mL). The organic layer was dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 15% MeOH in EtOAc. The product fractions were concentrated in vacuo and further purification by C18 reverse phase chromatography eluting with a gradient of 40-45% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) afforded the title compound as a colourless solid.1H NMR (400 MHz, CDCI3) δ 7.22 - 7.08 (m, 1 H), 6.50 - 6.33 (m, 2H), 3.98 - 3.86 (m, 1H), 3.84 - 3.73 (m, 8H), 3.39 - 3.13 (m, 3H), 3.02 - 2.79 (m, 2H), 2.49 (s, 3H), 2.26 - 1.99 (m, 3H), 1.73 - 1.64 (m, 3H), 1.56 - 1.36 (m, 4H), 1.32 - 0.96 (m, 5H), 0.51 - 0.10 (m, 4H). LC- MS (Method D): Rt 2.48 mins; MS m / z 430.4 [M+H]+.Example 5(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(dimethylamino)propan-1-oneStep 1 : (4aR.8aS)-1.2.3.4.4a.5.6.7.8.8a-Decahvdroguinoline(2{R},3{R})-2,3-Dihydroxybutanedioic acid (53.9 g, 0.359 mol) and rac-(4aR,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (50.0 g, 0.359 mol) were suspended in MeOH (175 mL) and heated to dissolution. Diethyl ether (175 mL) was added and the mixture left to stand at room temperature overnight. 76.9 g of crystals were obtained by vacuum filtration. Recrystallisation from MeOH (3 mL / g)-diethyl ether (2.5 mL / g) and standing overnight at room temperature a further three times gave 25.8 g of the hydrogen L-tartrate salt of l-trans- decahydroquinoline as a white powder. The salt was suspended in a mixture of diethyl ether (200 mL) and 1M NaOH (150 mL) and stirred vigorously until two clear immiscible layers were observed. The layers were separated, and the aqueous layer was extracted with diethyl ether (40 mL). Further 1M NaOH was added (3 x 25 mL) and the aqueous extracted with diethyl ether (25 mL). The combined organic extracts were dried over MgSO4 and left to concentrate in an evaporating dish overnight to yield the title compound as colourless crystals.1H NMR (500 MHz, CDCI3) δ 3.12 - 2.96 (m, 1 H), 2.76 - 2.47 (m, 1H), 2.16 - 2.00 (m, 1 H), 1.78 - 1.69 (m, 1 H), 1.69 - 1.58 (m, 4H), 1.57 - 1.43 (m, 2H), 1.38 - 1.11 (m, 3H), 1.08 - 0.90 (m, 3H). NH proton not observed.Step 2: terf-Butyl / \ / -[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-[(dimethylamino)methyl]-2-oxo-ethyl]carbamateTo a stirred solution of (2R)-2-(terf-butoxycarbonylamino)-3-(dimethylamino)propanoic acid (400 mg, 1.72 mmol), / V-ethyl- / V-isopropyl-propan-2-amine (301 μL, 1.72 mmol) and HATLI (1.31 g, 3.44 mmol) in DCM (6 mL) at room temperature was added (4aR,8aS)- 1 ,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (step 1) (100%, 288 mg, 2.07 mmol) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (5 mL) and extracted with DCM (3 x 5 mL). The organic extracts were passed through a phase separator and concentrated in vacuo to yield a crude yellow oil. The crude material was purified by C18 reverse phase chromatography eluting with a gradient of 10- 100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) to afford the title compound as a pale-yellow oil.1H NMR (500 MHz, CDCI3) δ 5.35 (s, 1 H), 4.65 - 4.50 (m, 1 H), 3.79 - 3.11 (m, 2H), 2.59 - 2.45 (m, 2H), 2.26 (s, 6H), 2.16 - 2.03 (m, 1 H), 1.96 - 1.65 (m, 7H), 1.62 - 1.54 (m, 2H), 1 .42 (s, 9H), 1 .33 - 0.97 (m, 4H). LC-MS (Method E): Rt 1.73 mins; MS m / z 354.4 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3- (dimethylamino)propan-l-onetert-Butyl / V-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [(dimethylamino)methyl]-2-oxo-ethyl]carbamate (step 2) (100%, 317 mg, 0.897 mmol) was stirred in 4M HCI in 1 ,4-dioxane (3.0 mL, 12.0 mmol) at room temperature for 1 h. The solvent was removed in vacuo. The resulting off-white solid was taken up in saturated aqueous sodium carbonate solution (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as an orange oil.1H NMR (400 MHz, CDCI3) δ 3.77- 3.62 (m, 1 H), 3.41 - 3.26 (m, 1 H), 3.21 - 3.02 (m, 1 H), 2.38 - 2.27 (m, 2H), 2.26 (s, 6H), 2.11 - 1.99 (m, 1 H), 1 .87 (s, 3H), 1.83 - 1 .52 (m, 7H), 1 .49 - 1.36 (m, 1 H), 1.34 - 1.21 (m, 2H), 1 .20 - 1.00 (m, 2H). LC-MS (Method E): Rt 1.37 mins; MS m / z 254.3 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-(dimethylamino)propan-1-oneTo a stirred solution of 2,4-dimethoxybenzaldehyde (38 mg, 0.229 mmol) in anhydrous MeOH (1 mL) was added (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- amino-3-(dimethylamino)propan-1-one (step 3) (98%, 71 mg, 0.274 mmol) and the reaction mixture was heated at 50 °C for 1 h. The mixture was cooled to 0 °C and sodium borohydride (10 mg, 0.274 mmol) was added portion-wise at 0 °C. The resulting mixture was heated at 50 °C for 30 mins and then allowed to cool to room temperature. Water (2 mL) was added and the mixture was extracted with DCM (3 x 3 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 2) to yield the title compound as a colourless gum.1H NMR (400 MHz, CDCI3) δ 7.23 - 7.11 (m, 1 H), 6.49 - 6.24 (m, 2H), 3.78 (s, 6H), 3.72 - 3.65 (m, 1 H), 3.64 - 3.52 (m, 2H), 3.40 (s, 1H), 3.10 (s, 1H), 2.58 - 2.45 (m, 1 H), 2.41 - 2.31 (m, 1 H), 2.23 (s, 6H), 1.77- 1.68 (m, 6H), 1.66 - 1.49 (m, 4H), 1.36 - 1.01 (m, 5H). LC-MS (Method E): Rt 1.91 mins; MS m / z 404.4 [M+H]+.Step 5: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(dimethylamino)propan-1-oneTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-(dimethylamino)propan-1-one (step 4) (100%, 55 mg, 0.136 mmol) in DCE (1 mL) was added sodium carbonate (29 mg, 0.273 mmol), copper(ll) acetate (25 mg, 0.136 mmol), 2,2’-bipyridine (21 mg, 0.136 mmol) and cyclopropylboronic acid (15 mg, 0.177 mmol) and the reaction mixture was stirred vigorously at 70 °C for 4 h. The resulting mixture was allowed to cool to room temperature. The mixture was diluted withwater (3 mL) and extracted with DCM (3 x 5 mL). The combined organics were passed through a phase separator. The solvent was removed in vacuo and purification by C18 reverse phase chromatography eluting with a gradient of 10-45% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) yielded a yellow gum. The material was further purified by chromatography on silica eluting with a gradient of 0-60% EtOAc in heptane to afford the title compound as a colourless gum.1H NMR (500 MHz, CDCI3) δ 7.22 - 7.02 (m, 1H), 6.48 - 6.17 (m, 2H), 3.90 - 3.72 (m, 8H), 3.67 - 3.60 (m, 1H), 3.39 - 3.09 (m, 3H), 2.96 - 2.80 (m, 1H), 2.73 - 2.61 (m, 1H), 2.27 (s, 6H), 2.21 - 2.07 (m, 2H), 1.58 - 1.35 (m, 5H), 1.30 - 1.18 (m, 3H), 1.17 - 0.80 (m, 4H), 0.40 - 0.32 (m, 2H), 0.33 - 0.24 (m, 1H), 0.23 - 0.15 (m, 1 H). LC-MS (Method D): Rt 2.71 mins; MS m / z 444.3 [M+H]+.Example 6(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(1H-imidazol-5-yl)propan-1-oneStep 1 : terf-Butyl / \ / -[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-(1 H-imidazol-5-ylmethyl)-2-oxo-ethyl]carbamateTo a stirred solution of / V-ethyl- / V-isopropyl-propan-2-amine (0.63 mL, 3.59 mmol), HATLI (2.05 g, 5.39 mmol) and (4aR,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (Example 5, step 1) (100%, 0.50 g, 3.59 mmol) in DCM (10 mL) was added (2R)-2-(terf- butoxycarbonylamino)-3-(1H-imidazol-5-yl)propanoic acid (917 mg, 3.59 mmol) and the reaction mixture was stirred at room temperature for 1 h. Water (10 mL) was added and the mixture was extracted with DCM (3 x 15 mL), separating the organics using a phase separator. The organics were concentrated in vacuo and purification of the crude material byC18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) afforded the title compound as a colourless solid.1H NMR (400 MHz, CDCI3) δ 7.53 (s, 1 H), 6.82 (s, 1 H), 5.52 (d, J = 8.0 Hz, 1 H), 4.73 (d, J = 6.0 Hz, 1 H), 3.59 - 3.26 (m, 1 H), 3.12 - 2.83 (m, 3H), 2.06 - 2.02 (m, 1 H), 1.84 - 1.46 (m, 8H), 1.42 (s, 9H), 1.39 (s, 1 H), 1.33 - 1.19 (m, 2H), 1.15 - 0.93 (m, 3H). LC-MS (Method A): Rt 0.92 mins; MS m / z 377.8 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-(1 H- imidazol-5-yl)propan- 1 -oneterf-Butyl / V-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-(1 H-imidazol- 5-ylmethyl)-2-oxo-ethyl]carbamate (step 1) (87%, 641 mg, 1.48 mmol) was stirred in 4M HCI in 1 ,4-dioxane (6.0 mL, 24.0 mmol) at room temperature for 1 h. The resulting mixture was concentrated in vacuo. The resulting white solid was taken up in saturated aqueous sodium carbonate solution and extracted with EtOAc (3 x 10 mL) and IPA:CHCl3 (1 :1 ; 10 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a colourless oil. LC-MS (Method E): Rt 1.21 mins; MS m / z 277.4 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-(1 H-imidazol-5-yl)propan-1-oneTo a stirred solution of 2,4-dimethoxybenzaldehyde (110 mg, 0.662 mmol) in anhydrous MeOH (3 mL) was added (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- amino-3-(1 H-imidazol-5-yl)propan-1-one (step 2) (88%, 249 mg, 0.794 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 1 h. The mixture was cooled to 0 °C and sodium borohydride (30 mg, 0.794 mmol) was added portion-wise at 0°C. The resulting mixture was stirred at room temperature for 2 h. Water (2 mL) was added and the organics extracted with DCM (3x3 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound as a colourless gum.1H NMR (500 MHz, CDCI3) δ 11.31 (s, 1H), 7.48 (s, 1H), 7.09 (d, J= 8.2 Hz, 1H), 6.79 (s, 1 H), 6.49 (d, J = 2.2 Hz, 1 H), 6.42 (dd, J = 8.2, 2.4 Hz, 1 H), 3.90 (s, 3H), 3.80 (s, 3H), 3.71 - 3.64 (m, 1H), 3.59-3.51 (m, 2H), 3.45-3.11 (m, 2H), 2.81 -2.73 (m, 1H), 2.73-2.57 (m, 1H), 2.19-2.06 (m, 1H), 1.82-1.53 (m, 9H), 1.50- 1.39 (m, 1H), 1.38-1.23 (m, 2H), 1.17 -1.04 (m, 2H). LC-MS (Method E): Rt 1.50 mins; MS m / z 427.3 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(1H-imidazol-5-yl)propan-1-oneTo a sealed tube containing (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-2-[(2,4-dimethoxyphenyl)methylamino]-3-(1H-imidazol-5-yl)propan-1-one (step 3) (100%, 132 mg, 0.309 mmol) was added anhydrous DCE (2 mL), [(1- ethoxycyclopropyl)oxy](trimethyl)silane (124 μL, 0.619 mmol), acetic acid (13 μL) and sodium cyanoborohydride (29 mg, 0.464 mmol). The reaction mixture was heated at 65 °C overnight and then allowed to cool to room temperature. DCM (3 mL) and saturated aqueous sodium bicarbonate solution (5 mL) were added and the mixture was stirred vigorously for 5 mins. The organics were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 4) followed by further purification by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) to afford the title compound as a colourless gum.1H NMR (500 MHz, CDCI3) δ 7.44 (s, 1 H), 7.11 - 6.99 (m, 1 H), 6.82 (s, 1 H), 6.57 - 6.23 (m, 2H), 3.93-3.83 (m, 2H), 3.81 -3.76 (m, 6H), 3.50-3.35 (m, 2H), 3.31 -3.24 (m, 1H), 3.12 -3.06 (m, 1H), 2.89-2.81 (m, 1H), 2.64-2.54 (m, 1H), 2.15-2.00 (m, 2H), 1.76-1.63 (m, 4H), 1.57- 1.32 (m, 5H), 1.28-1.16 (m, 1H), 1.13-0.90 (m, 3H), 0.54-0.46 (m, 2H), 0.39 - 0.33 (m, 1 H), 0.31 - 0.24 (m, 1 H). LC-MS (Method D): Rt 2.53 mins; MS m / z 467.4 [M+H]+.Example 7(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-hydroxy-butan-1-oneStep 1 : (2R)-2-(terf-Butoxycarbonylamino)-4-ftert-butyl(diphenyl)silyl1oxy-butanoic acidA solution of (2R)-2-{[(tert-butoxy)carbonyl]amino}-4-hydroxybutanoic acid (1.00 g, 4.56 mmol) in anhydrous DMF (5 mL) was treated with imidazole (807 mg, 11.9 mmol) followed by terf-butyl-chloro-diphenyl-silane (3.13 g, 11.4 mmol) and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with EtOAc (40 mL) and washed with water (3 x 10 mL). The organics were dried over Na2SO4,and concentrated in vacuo. The intermediate was suspended in MeOH (9 mL) and water (5 mL). Potassium carbonate (1.58 g, 11.4 mmol) was added and the reaction stirred at room temperature for 2 h. MeOH was removed in vacuo and the aqueous was acidified to pH 1 with 10% citric acid. The aqueous layer was extracted with DCM (3 x 50 mL) and the combined organic extracts were dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 0-100% TBME in heptane to afford the title compound as a pale-yellow oil.1H NMR (500 MHz, CDCI3) δ 7.76 - 7.60 (m, 4H), 7.52 - 7.35 (m, 6H), 5.98 (d, J = 6.4 Hz, 1 H), 4.50 - 4.38 (m, 1 H), 3.88 - 3.68 (m, 2H), 2.20 - 1 .96 (m, 2H), 1.45 (s, 9H), 1.06 (s, 9H). The carboxylic acid proton not observed. LC-MS (Method A): Rt 1.54 mins; MS m / z 480.4 [M+H]+.Step 2: tert-Butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1- carbonyl]-3-[terf-butyl(diphenyl)silyl]oxy-propyl]carbamateA mixture of HATU (698 mg, 1.84 mmol), (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (426 mg, 3.06 mmol) and (2R)-2-(fe / t-butoxycarbonylamino)-4-[fe / t- butyl(diphenyl)silyl]oxy-butanoic acid (step 1) (700 mg, 1.53 mmol) in DMF (15 mL) was treated with DIPEA (0.32 mL, 1.84 mmol) and the solution was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo and the residue was taken up in EtOAc (25 mL). The mixture was washed with water (2 x 10 mL), saturated brine solution (5 mL), dried over MgSO an4d concentrated in vacuo. The crude material was purified by chromatography on silica eluting with 40% EtOAc in heptane to afford the title compound as a pale-yellow oil.1H NMR (500 MHz, CDCI3) δ 7.78 - 7.30 (m, 10H), 5.37 (br.s, 1 H), 4.91 - 4.69 (m, 1 H), 3.86 - 3.58 (m, 3H), 3.51 - 3.07 (m, 2H), 2.18 - 2.05 (m, 1 H), 1.97 - 1.82 (m, 2H), 1.74 - 1.50 (m, 9H), 1.43 (s, 9H), 1.33 - 1.23 (m, 2H), 1.20 - 1.11 (m, 1 H), 1.05 (s, 9H). LC-MS (Method B): Rt 2.25 mins; MS m / z 601.5 [M+Na]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-4-[terf- butyl(diphenyl)silyl]oxy-butan-1-oneThe title compound was prepared from tert-butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinoline-1-carbonyl]-3-[terf-butyl(diphenyl)silyl]oxy-propyl]carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 2, step 2. LC-MS (Method B): Rt 1.44 mins; MS m / z 479.9 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-[terf- butyl(diphenyl)silyl]oxy-2-[(2,4-dimethoxyphenyl)methylamino]butan-1-oneTo a flask containing (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2- amino-4-[terf-butyl(diphenyl)silyl]oxy-butan-1-one (step 3) (56%, 590 mg, 0.690 mmol) was added sodium triacetoxyborohydride (205 mg, 0.966 mmol), anhydrous DCE (6 mL), acetic acid (0.2 mL) and 2,4-dimethoxybenzaldehyde (115 mg, 0.690 mmol) and the solution was heated at 65 °C for 2 h. The resulting mixture was cooled to room temperature, treated dropwise with water (1 mL) and stirred for 5 mins. The mixture was concentrated in vacuo and the residue was taken up in EtOAc (20 mL). The organics were washed with water (2 x 5 mL), saturated brine solution (10 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting in 80% TBME in heptane to afford the title compound as a colourless clear oil.1H NMR (400 MHz, CDCI3) δ 7.70 - 7.62 (m, 4H), 7.48 - 7.34 (m, 7H), 7.28 - 7.23 (m, 1 H), 6.50 - 6.39 (m, 2H), 4.06 - 3.94 (m, 2H), 3.80 (s, 3H), 3.79 (s, 3H), 3.76 - 3.68 (m, 3H), 3.56 (d, J = 13.1 Hz, 1 H), 3.49 - 3.04 (m, 2H), 2.12 - 2.02 (m, 1H), 1.77 - 1.68 (m, 6H), 1.37 - 1.28 (m, 2H), 1.21 - 0.97 (m, 14H), 0.96 - 0.84 (m, 1 H). LC-MS (Method A): Rt 1.33 mins; MS m / z 629.3 [M+H]+.Step 5: (2R)-1-f(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-auinolin-1-yl1-4-ftert- butyl(diphenyl)silyl]oxy-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-oneThe title compound was prepared from 2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-4-[terf-butyl(diphenyl)silyl]oxy-2-[(2,4-dimethoxyphenyl)methylamino]butan-1- one (step 4) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.LC-MS (Method B): Rt 1.92 mins; MS m / z 669.6 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-hydroxy-butan-1-one(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-[terf- butyl(diphenyl)silyl]oxy-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-one (step 5) (216 mg, 0.323 mmol) in THF (3 mL) under nitrogen was treated with tetrabutylammonium fluoride in THF (0.17 mL, 0.646 mmol) and the solution was stirred at room temperature overnight. The reaction was quenched by the addition of saturated aqueous potassium carbonate solution (3 mL) and the solution was diluted with EtOAc (20 mL). The organic layer was separated, washed with water (3 x 3 mL), brine (3 mL) dried over MgSC>4 and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound a white solid.1H NMR (400 MHz, CDCI3) δ 7.14 - 7.00 (m, 1 H), 6.49 - 6.34 (m, 2H), 3.80 (s, 3H), 3.79 - 3.77 (m, 2H), 3.76 (s, 3H), 3.60 - 3.42 (m, 2H), 3.28 (td, J = 10.9, 2.8 Hz, 1 H), 3.06 (br.s, 1H), 2.74 (td, J = 13.0, 12.6, 5.6 Hz, 1 H), 2.52 - 2.35 (m, 1 H), 2.24 - 2.00 (m, 4H), 1.71 - 1.63 (m, 3H), 1.56 - 1.34 (m, 5H), 1.31 - 1.18 (m, 2H), 1.16 - 0.94 (m, 3H), 0.52 - 0.38 (m, 2H), 0.38 - 0.18 (m, 2H). LC-MS (Method D): Rt 2.29 mins; MS m / z 431.4 [M+H]+.Example 8(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-oxo-butanenitrileStep 1 : terf-Butyl / \ / -[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- (cyanomethyl)-2-oxo-ethyl]carbamateTo a stirred solution of (2R)-2-(terf-butoxycarbonylamino)-3-cyano-propanoic acid (1.00 g, 4.67 mmol), DIPEA (815 μL, 4.67 mmol), and HATU (3.55 g, 9.34 mmol) in DCM (20 mL) and DMF (2.5 mL) at room temperature was added (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) (650 mg, 4.67 mmol) and the reaction mixture was stirred at room temperature overnight. Water (20 mL) was added and the mixture was extracted with DCM (3 x 30 mL). The combined organics were passed through a phase separator and concentrated in vacuo. Purification of the crude material by C18 reverse phase chromatography eluting with a gradient of 10-45% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) afforded the title compound as an off-white solid.1H NMR (500MHz, CDCI3) δ 5.60 - 5.44 (m, 1 H), 4.93 - 4.77 (m, 1 H), 3.47 - 3.34 (m, 1 H), 3.34 - 3.11 (m, 1 H), 2.77 - 2.67 (m, 2H), 2.19 - 2.05 (m, 1 H), 1.87 - 1.56 (m, 9H), 1.44 (s, 9H), 1 .36 - 0.97 (m, 4H). LC-MS (Method B): Rt 1 .48 mins; MS m / z 280.2 [M-‘Butyl+H]+.Step 2a: (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-4-oxo- butanenitrile andStep 2b: (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-4-oxo- butanamideA solution of tert-butyl / V-[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- (cyanomethyl)-2-oxo-ethyl]carbamate (step 1) (1.50 g, 4.47 mmol) in DCM (20 mL) was treated with 4M HCI in 1,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo and the residue dissolved in EtOAc (10 mL), basified with saturated aqueous sodium bicarbonate solution (5 mL) and extracted with EtOAc (2 x 10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. Purification by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) to afford (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-4-oxo- butanenitrile. LC-MS (Method A): Rt 0.85 mins; MS m / z 236.2 [M+H]+.The aqueous portion was concentrated in vacuo and purified by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) to afford (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- amino-4-oxo-butanamide. LC-MS (Method A): Rt 0.77 mins; MS m / z 254.2 [M+H]+.Step 3: (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[(2,4- dimethoxyphenyl)methylamino]-4-oxo-butanenitrileTo a stirred solution of 2,4-dimethoxybenzaldehyde (34 mg, 0.204 mmol) in anhydrousMeOH (2 mL) was added (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-4-oxo-butanenitrile (step 2a) (48 mg, 0.204 mmol) and the mixture was stirred at room temperature for 1 h. The resulting mixture was cooled to 0 °C, sodium borohydride (9 mg, 0.245 mmol) was added portion-wise and the mixture was stirred at room temperature under nitrogen overnight. The resulting mixture was concentrated in vacuo and the crude product was purified by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1 ammonia) in water (+ 0.1% ammonia) to afford the title compound. LC-MS (Method A): Rt 1.05 mins; MS m / z 386.2 [M+H]+.Step 4: (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-oxo-butanenitrileThe title compound was prepared from (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[(2,4-dimethoxyphenyl)methylamino]-4-oxo-butanenitrile (step 3) and cyclopropylboronic acid analogously to Example 5, step 5.1H NMR (500 MHz, CDCI3) δ 7.08 (d, J = 8.0 Hz, 1 H), 6.47 - 6.40 (m, 2H), 3.86 - 3.73 (m, 9H), 3.28 - 3.21 (m, 2H), 2.89 - 2.78 (m, 1 H), 2.78 - 2.68 (m, 2H), 2.23 - 2.16 (m, 1 H), 1.89 - 1.82 (m, 1 H), 1.74 - 1.61 (m, 4H), 1.46 - 1.36 (m, 3H), 1.29 - 1.17 (m, 2H), 1.12 - 0.95 (m, 3H), 0.57 - 0.47 (m, 2H), 0.39 - 0.26 (m, 2H). LC-MS (Method G): Rt 4.59 mins; MS m / z 426.5 [M+H]+.Example 9(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-oxo-butanamideStep 1 : (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[(2,4- dimethoxyphenyl)methylamino]-4-oxo-butanamideThe title compound was prepared from (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-amino-4-oxo-butanamide (Example 8, step 2b) and 2,4- dimethoxybenzaldehyde analogously to Example 5, step 4.1H NMR (500 MHz, CDCI3) δ 8.50 (s, 1 H), 7.08 (d, J = 8.2 Hz, 1 H), 6.52 - 6.32 (m, 2H), 5.26 (s, 1 H), 3.85 - 3.74 (m, 6H), 3.72-3.58 (m, 2H), 3.59-3.47 (m, 1H), 3.47-3.11 (m, 2H), 2.45-2.30 (m, 1H), 2.30- 2.18 (m, 1H), 2.03 (s, 1H), 1.90- 1.52 (m, 9H), 1.52-1.36 (m, 1H), 1.36-1.20 (m, 2H), 1.20 - 0.99 (m, 2H). LC-MS (Method A): Rt 0.94 mins; MS m / z 404.7 [M+H]+.Step 2: (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo-butanamideThe title compound was prepared from (3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[(2,4-dimethoxyphenyl)methylamino]-4-oxo-butanamide (step 1) and [(1- ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (400 MHz, CDCI3) δ 7.17 (d, J= 8.1 Hz, 1H), 6.48 (br s, 1H), 6.46-6.37 (m, 2H), 5.12 (br s, 1H), 3.90 - 3.82 (m, 2H), 3.79 (s, 3H), 3.76 (s, 3H), 3.73 - 3.65 (m, 1H), 3.31 - 3.13 (m, 2H), 2.99 -2.88 (m, 1H), 2.76-2.57 (m, 2H), 2.14-2.04 (m, 1H), 2.00-1.90 (m, 1H), 1.74-1.62 (m, 4H), 1.53- 1.45 (m, 1H), 1.45-1.33 (m, 3H), 1.29- 1.15 (m, 1H), 1.12-0.92 (m, 3H), 0.49 - 0.43 (m, 2H), 0.41 - 0.32 (m, 1H), 0.31 - 0.21 (m, 1H). LC-MS (Method D): Rt 2.48 mins; MS m / z 444.3 [M+H]+.Example 10(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-5-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]pentan-1-oneStep 1 : (2R)-2-(tert-Butoxvcarbonvlamino)-5-( 1 ,3-dioxoisoindolin-2-yl)pentanoic acidTo a solution of (2R)-5-amino-2-((tert-butoxycarbonyl)amino)pentanoic acid(1.00 g, 4.31 mmol) and 2-benzofuran-1 , 3-dione (638 mg, 4.31 mmol) in anhydrous toluene (10 mL) was added triethylamine (0.60 mL, 4.31 mmol) and the reaction mixture was stirred at 110 °C overnight. The resulting mixture was concentrated in vacuo and purification by C18 reverse phase chromatography eluting with a gradient of 10-90% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) afforded the title compound as a pale orange solid. LC-MS (Method A): Rt 1.07 mins; MS m / z 361.1 [M-H]’.Step 2: terf-Butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1- carbonyl]-4-(1 ,3-dioxoisoindolin-2-yl)butyl]carbamateTo a stirred solution of (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (Example 5, step 1) (1.03 g, 7.40 mmol), / V-ethyl- / V-isopropyl-propan-2-amine (1.3 mL, 7.40 mmol) and HATU (5.63 g, 14.8 mmol) in DCM (3 mL) and anhydrous DMF (3 mL) was added (2R)-2-(terf- butoxycarbonylamino)-5-(1 ,3-dioxoisoindolin-2-yl)pentanoic acid (step 1) (2.68 g, 7.40 mmol)and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with water (20 mL) and extracted with DCM (3 x 20 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0-100% TBME in heptane afforded the title compound as a pale-yellow gum.1H NMR (500 MHz, CDCI3) δ 7.88 - 7.78 (m, 2H), 7.78 - 7.61 (m, 2H), 5.50 - 5.36 (m, 1 H), 4.63 - 4.51 (m, 1 H), 3.75 - 3.64 (m, 2H), 3.61 - 3.15 (m, 2H), 2.12 - 2.02 (m, 1 H), 1.88 - 1.51 (m, 9H), 1.48 - 1.35 (m, 10H), 1.34 - 1.19 (m, 3H), 1.19 - 1.00 (m, 3H), 0.92 - 0.80 (m, 1 H). LC-MS (Method A): Rt 1.39 mins; MS m / z 484.3 [M + H]+.Step 3: 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-amino-5-oxo- pentyl]isoindoline-1 ,3-dione hydrochlorideterf-Butyl A / -[( 1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1-carbonyl]-4-(1 ,3- dioxoisoindolin-2-yl)butyl]carbamate (step 2) (1.12 g, 2.32 mmol) was dissolved in 4M HCI in 1 ,4-dioxane (10 mL) and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to afford the title compound as a white glassy solid. LC-MS (Method A): Rt 0.86 mins; MS m / z 384.7 [M+H]+.Step 4: 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-[(2,4- dimethoxyphenyl)methylamino]-5-oxo-pentyl]isoindoline-1 , 3-dioneTo a flask containing 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-4- amino-5-oxo-pentyl]isoindoline-1, 3-dione hydrochloride (step 3) (973 mg, 2.23 mmol) was added sodium triacetoxyborohydride (851 mg, 4.02 mmol), anhydrous DCE (16 mL) and acetic acid (400 μL). 2,4-Dimethoxybenzaldehyde (371 mg, 2.23 mmol) was added, and the reaction mixture was heated at 65 °C for 2 h. The resulting mixture was allowed to cool to room temperature and water (15 mL) was added. The mixture was concentrated in vacuo and the residue was taken up in EtOAc (10 mL). The organics were washed with water (2 x 5 mL), saturated brine solution (5 mL), dried over MgSO4and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-100% TBME in heptane to afford the title compound as a pale-yellow gum.1H NMR (500 MHz, CDCI3) δ 7.86 - 7.79 (m, 2H), 7.74 - 7.66 (m, 2H), 7.20 (d, J = 8.0 Hz, 1 H), 6.45 - 6.35 (m, 2H), 5.30 (s, 2H), 3.77 (d, J = 1.5 Hz, 6H), 3.71 - 3.58 (m, 3H), 3.56 - 3.36 (m, 3H), 3.28 - 3.01 (m, 1 H), 2.18 - 1.93 (m, 1 H), 1.86 - 1.47 (m, 10H), 1.47 - 1.35 (m, 1H), 1.35 - 0.79 (m, 5H). LC-MS (Method B): Rt 1.23 mins; MS m / z 534.4 [M+H]+.Step 5: 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-5-oxo-pentyl]isoindoline-1 , 3-dioneTo a sealed tube containing 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-4-[(2,4-dimethoxyphenyl)methylamino]-5-oxo-pentyl]isoindoline-1 , 3-dione (step 4) (630 mg, 1.18 mmol) was added anhydrous DCE (10 mL), [(1-ethoxycyclopropyl)oxy](trimethyl)silane (712 μL, 3.54 mmol), acetic acid (250 μL) and sodium cyanoborohydride (111 mg, 1.77 mmol). The reaction mixture was heated at 65 °C for 4 h and then allowed to cool to room temperature. The resulting mixture was taken up in DCM (10 mL) and the organics washed with saturated aqueous sodium bicarbonate solution (2 x 5 mL), water (2 mL) and saturated brine solution (2 mL), dried over MgSO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-100% TBME in heptane to afford the title compound as an off-white gum. LC-MS (Method A): Rt 1.16 mins; MS m / z 574.5 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-5-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]pentan-1-oneA solution of 2-[(4R)-5-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-4- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-5-oxo-pentyl]isoindoline-1 ,3-dione (step 5) (460 mg, 0.802 mmol) in THF (20 mL) and MeOH (20 mL) was treated with hydrazine hydrate (2.0 mL, 40.1 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with DCM (20 mL) and washed with water (3 x 10 mL), dried over Na2SO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 3) to afford the title compound as a pale-yellow solid.1H NMR (500 MHz, CDCI3) δ 7.10 - 7.04 (m, 1H), 6.41 - 6.38 (m, 2H), 3.80 - 3.78 (m, 5H), 3.76 (s, 3H), 3.35 - 3.27 (m, 2H), 3.05 (br.s, 1 H), 2.80 - 2.65 (m, 3H), 2.22 - 2.09 (m, 2H), 2.09 - 2.01 (m, 1 H), 1.79 - 1.62 (m, 5H), 1.54 - 1.35 (m, 7H), 1.29 - 1.21 (m, 2H), 1.10 - 0.98 (m, 3H), 0.44 - 0.37 (m, 2H), 0.31 - 0.26 (m, 1 H), 0.24 - 0.18 (m, 1H). LC-MS (Method D): Rt 1.92 mins; MS m / z 444.4 [M+H]+.Example 11(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-oneStep 1 : (2R)-2-(terf-Butoxycarbonylamino)-3-(1 ,3-dioxoisoindolin-2-yl)propanoic acidTo a solution of 3-amino- / V-(terf-butoxycarbonyl)-D-alanine (10.00 g, 49.0 mmol) and isobenzofuran-1 , 3-dione (7.25 g, 49.0 mmol) in anhydrous toluene (60 mL) was added triethylamine (6.8 mL, 49.0 mmol) and the reaction mixture was stirred at 110 °C overnight. The resulting mixture was allowed to cool to room temperature and then concentrated in vacuo. The crude residue was taken up in EtOAc (100 mL) and washed with saturated aqueous sodium bicarbonate solution (2 x 100 mL). The combined aqueous layers were acidified to pH 3 with 1M HCI and extracted with EtOAc (3 x 50 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as an off-white solid.1H NMR (500 MHz, CDCI3) δ 7.91 - 7.83 (m, 2H), 7.76 - 7.70 (m, 2H), 5.45 (d, J = 7.5 Hz, 1 H), 4.76 - 4.52 (m, 1 H), 4.23 - 4.01 (m, 2H), 1 .33 (s, 9H). Carboxylic acid proton not observed. LC-MS (Method A): Rt 1.03 mins; MS m / z 333.2 [M-H]'.Step 2: tert-Butyl / V-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-[(1 ,3- dioxoisoindolin-2-yl)methyl]-2-oxo-ethyl]carbamateThe title compound was prepared from (2R)-2-(terf-butoxycarbonylamino)-3-(1 ,3- dioxoisoindolin-2-yl)propanoic acid (step 1) and (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) analogously to Example 2, step 1.1H NMR (400 MHz, CDCI3) δ 7.89 - 7.79 (m, 2H), 7.77 - 7.64 (m, 2H), 5.66 - 5.50 (m, 1 H), 5.01 - 4.86(m, 1 H), 4.03 - 3.79 (m, 2H), 3.77 - 3.67 (m, 1 H), 3.59 - 3.30 (m, 2H), 2.18 - 1.98 (m, 1 H), 1 .92 - 1 .61 (m, 7H), 1.54 - 0.99 (m, 14H). LC-MS (Method A): Rt 1.36 mins; MS m / z 478.4 [M+Na]+.Step 3: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-oxo- propyl]isoindoline- 1 ,3-dioneThe title compound was prepared from tert-butyl / \ / -[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-1-[(1 ,3-dioxoisoindolin-2-yl)methyl]-2-oxo-ethyl]carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 2, step 2. LC-MS (Method A): Rt 0.91 mins; MS m / z 356.7 [M+H]+.Step 4: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(2,4- dimethoxyphenyl)methylamino]-3-oxo-propyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-amino-3-oxo-propyl]isoindoline-1 , 3-dione (step 3) and 2,4- dimethoxybenzaldehyde analogously to Example 1 , step 2.1H NMR (400 MHz, CDCI3) δ 7.85 - 7.77 (m, 2H), 7.75 - 7.67 (m, 2H), 7.00 (d, J = 8.3 Hz, 1 H), 6.25 (d, J = 2.4 Hz, 1 H), 6.13 (dd, J = 8.3, 2.4 Hz, 1 H), 3.96 - 3.37 (m, 14H), 3.16 (br s, 1 H), 1.81 - 1.39 (m, 9H), 1.35 - 1.01 (m, 4H). LC-MS (Method A): Rt 1.11 mins; MS m / z 506.4 [M+H]+.Step 5: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl- [(2, 4-dimethoxyphenyl)methyl]amino]-3-oxo-propyl]isoindoline-1, 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[(2,4-dimethoxyphenyl)methylamino]-3-oxo-propyl]isoindoline-1, 3-dione (step 4) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (500 MHz, CDCI3) δ 7.84 - 7.80 (m, 2H), 7.72 - 7.66 (m, 2H), 7.16 - 7.12 (m, 1H), 6.34-6.29 (m, 2H), 4.40-4.34 (m, 1H), 4.28-4.18 (m, 2H), 3.91 (s, 2H), 3.80-3.66 (m, 7H), 3.35-3.18 (m, 2H), 2.91 -2.81 (m, 1H), 2.34-2.28 (m, 1H), 2.08-2.01 (m, 1H), 1.52 -1.13 (m, 7H), 1.08-0.93 (m, 3H), 0.91 -0.80 (m, 1H), 0.56-0.32 (m, 3H), 0.23-0.16 (m, 1 H). LC-MS (Method A): Rt 1.44 mins; MS m / z 546.5 [M + H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-oneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-oxo- propyl]isoindoline-1, 3-dione (step 5) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (500 MHz, CDCI3) δ 7.14 - 7.05 (m, 1H), 6.43 - 6.36 (m, 2H), 4.00 - 3.85 (m, 1H), 3.84-3.75 (m, 7H), 3.71 -2.89 (m, 6H), 2.88-2.73 (m, 1H), 2.22-2.02 (m, 2H), 1.74 -1.65 (m, 4H), 1.52-1.37 (m, 4H), 1.27-1.16 (m, 2H), 1.14-0.95 (m, 3H), 0.46-0.15 (m, 4H). LC-MS (Method D): Rt 2.62 mins; MS m / z 416.5 [M+H]+.Example 11.1A / -[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-oxo-propyl]oxetane-3-carboxamideTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11 , step 6) (59 mg, 0.143 mmol) and oxetane-3-carboxylic acid (17 mg, 0.171 mmol) in anhydrous DMF (1.5 mL) was added HATLI (65 mg, 0.171 mmol) and DIPEA (37 mg, 0.285 mmol) and the reaction mixture was stirred at room temperature for 2 h. The mixture was cooled to room temperature and the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL). The product was extracted with EtOAc (2 x 10 mL) and the combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 4) to afford the title compound.1H NMR (500 MHz, CDCI3) δ 7.28 (d, J = 8.3 Hz, 1 H), 6.44 (dd, J = 8.2, 2.4 Hz, 1 H), 6.39 (d, J = 2.3 Hz, 1 H), 6.26 (s, 1 H), 4.86 - 4.79 (m, 2H), 4.79 - 4.68 (m, 2H), 4.18 - 3.98 (m, 1 H), 3.96 - 3.85 (m, 2H), 3.83 - 3.69 (m, 7H), 3.69 - 3.58 (m, 1 H), 3.57 - 3.42 (m, 1 H), 3.33 - 3.17 (m, 1 H), 3.19 - 2.86 (m, 1 H), 2.79 - 2.58 (m, 1 H), 2.17 - 2.03 (m, 2H), 1.74 - 1.62 (m, 4H), 1.54 - 1.48 (m, 1 H), 1.47 - 1.30 (m, 3H), 1.29 - 1.16 (m, 1 H), 1.13 - 0.94 (m, 3H), 0.52 - 0.38 (m, 2H), 0.38 - 0.12 (m, 2H). LC-MS (Method G): Rt 4.02 mins; MS m / z 500.5 [M+H]+.Example 11.2(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[bis(2- hydroxyethyl)amino]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1- oneTo a mixture of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11, step 6) (79%, 75 mg, 0.143 mmol) and 2-chloroethanol (11 μL, 0.157 mmol) in anhydrous THF (1.5 mL) was added potassium carbonate (39 mg, 0.285 mmol) and the reaction mixture was stirred at 70 °C overnight. Additional 2-chloroethanol (11 μL, 0.157 mmol) was added at room temperature and heating resumed at 70 °C for 3 h. The resulting mixture was concentrated in vacuo and the residue was taken up in DMF (1 mL) and heated at 100 °C overnight. After cooling to room temperature, the mixture was diluted with water (5 mL) and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 4). The product fractions were concentrated in vacuo and the resulting residue was freeze-dried from MeCN:water to afford the title compound as a white powder.1H NMR (500 MHz, CDCI3) δ 7.22 (d, J = 8.1 Hz, 1H), 6.45 - 6.36 (m, 2H), 5.47 (br s, 1 H), 4.28 - 4.15 (m, 2H), 3.99 - 3.62 (m, 13H), 3.55 - 3.46 (m, 1H), 3.31 - 3.22 (m, 1H), 3.08 - 2.91 (m, 1H), 2.80 - 2.68 (m, 1 H), 2.61 - 2.47 (m, 1H), 2.19 - 2.10 (m, 1 H), 2.11 - 2.02 (m, 1H), 1.76 - 0.95 (m, 15H), 0.48 - 0.35 (m, 2H), 0.33 - 0.19 (m, 2H). LC-MS (Method G): Rt 4.02 mins; MS m / z 504.5 [M+H]+.Example 11.3(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(oxetan-3-ylamino)propan-1-oneTo a stirring solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11 , step 6) (79%, 75 mg, 0.143 mmol) in anhydrous THF (1.5 mL) and acetic acid (55 μL) was added sodium triacetoxyborohydride (60 mg, 0.285 mmol). The reaction mixture was heated at 50 °C for 30 mins then cooled to room temperature and oxetan-3-one (11 μL, 0.171 mmol) was added portion-wise. The resulting mixture was stirred at 50 °C for 90 mins. Additional oxetan-3-one (5 μL, 0.071 mmol) was added at room temperature and heating resumed at 50 °C for 30 mins before stirring at room temperature overnight. The resulting mixture was diluted with water (5 mL) and the product extracted with EtOAc (3 x 5 mL). The combined organic extracts were washed with brine (5 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by preparative HPLC (Method 4). The product fractions were concentrated in vacuo and the resulting residue was freeze-dried from MeCN- water to afford as a yellow solid. Separation under the following conditions afforded the title compound as a white solid:Separation conditions:Column: CSH_100 x 30 mm, 5 pmMobile Phase: 1-100% MeCN (+0.1% formic acid) in Water (+0.1 % formic acid)Flow rate: 40 mL / min1H NMR (500 MHz, CDCI3) δ 7.13 - 7.07 (m, 1 H), 6.44 - 6.38 (m, 2H), 4.83 (t, J = 6.9 Hz, 1 H), 4.77 (t, J = 6.9 Hz, 1 H), 4.60 (t, J = 6.4 Hz, 1 H), 4.49 (t, J = 6.4 Hz, 1 H), 4.05 (p, J = 6.6 Hz, 1 H), 3.88 - 3.76 (m, 8H), 3.68 - 3.61 (m, 1 H), 3.34 - 3.24 (m, 2H), 3.18 - 3.07 (m, 1 H), 2.93 - 2.89 (m, 1 H), 2.86 - 2.79 (m, 2H), 2.21 - 2.14 (m, 1 H), 2.05 - 1.99 (m, 1 H), 1.77 - 1.64 (m, 4H), 1.57 - 1.50 (m, 1 H), 1.49 - 1.37 (m, 3H), 1.30 - 1.20 (m, 1 H), 1.16 - 0.97 (m, 3H), 0.46 - 0.35 (m, 2H), 0.32 - 0.19 (m, 2H). LC-MS (Method D): Rt 2.61 mins; MS m / z 472.4 [M+H]+.Example 11.4(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(2,2-difluoroethylamino)propan-1-oneTo a stirring solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11, step 6) (80%, 60 mg, 0.116 mmol) in anhydrous DCE (2 mL) was added triethylamine (32 μL, 0.231 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (18 μL, 0.139 mmol) and the reaction mixture was heated at 65 °C under nitrogen for 4 h. The resulting mixture was diluted with water (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The crude product was purified by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1% ammonium hydroxide) in water (+ 0.1% ammonium hydroxide). The product fractions were combined, concentrated in vacuo and further purified by chromatography on silica eluting with a gradient of 0-100% TBME in heptane to afford the title compound as a colourless gum.1H NMR (500 MHz, CDCI3) δ 7.17 - 7.05 (m, 1H), 6.48 - 6.38 (m, 2H), 5.85 (tt, J = 56.5, 4.4 Hz, 1 H), 3.96 - 3.86 (m, 1 H), 3.86 - 3.75 (m, 7H), 3.66 - 3.54 (m, 1 H), 3.43 - 3.27 (m, 2H), 3.27 - 3.10 (m, 1 H), 3.10 - 2.88 (m, 3H), 2.86 - 2.77 (m, 1 H), 2.22 - 2.13 (m, 1H), 2.13 - 2.04 (m, 1 H), 1.81 - 1.67 (m, 4H), 1.56 - 1.51 (m, 1 H), 1.51 - 1.36 (m, 3H), 1.33 - 1.20 (m, 2H), 1.16 - 0.98 (m, 3H), 0.54 - 0.33 (m, 2H), 0.34 - 0.18 (m, 2H). LC-MS (Method G): Rt 4.67 mins; MS m / z 480.4 [M+H]+.Example 11.5A / -[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-oxo-propyl]methanesulfonamideTo a stirring solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11, step 6) (79%, 50 mg, 0.095 mmol) in anhydrous DCM (1 mL) was added triethylamine (20 μL, 0.143 mmol) followed by methanesulfonyl chloride (9 μL, 0.114 mmol) and the reaction mixture was stirred at room temperature for 10 mins. The resulting mixture was diluted with water (1 mL) and extracted with DCM (3 x 2 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1). The product fractions were combined and concentrated in vacuo. The resulting aqueous was neutralised with saturated aqueous potassium carbonate solution and extracted with EtOAc (3 x 5 mL). The combined organic extracts were dried over Mg aSnOd4 concentrated in vacuo. The residue was freeze-dried from MeCN:water to afford the title compound as a white powder.1H NMR (400 MHz, CDCI3) 67.16 - 7.10 (m, 1H), 6.45 - 6.39 (m, 2H), 5.05 (br s, 1H), 3.92 - 3.55 (m, 11 H), 3.29 - 3.20 (m, 1 H), 3.12 - 2.93 (m, 1 H), 2.97 (s, 3H), 2.85 - 2.74 (m, 1 H), 2.18 - 2.09 (m, 1 H), 2.08 - 2.00 (m, 1 H), 1.78 - 1.63 (m, 4H), 1.50 - 1.18 (m, 5H), 1.15 - 0.95 (m, 3H), 0.49 - 0.37 (m, 2H), 0.32 - 0.20 (m, 2H). LC-MS (Method D): Rt 3.37 mins; MS m / z 494.4 [M+H]+.Example 11.6(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(2-oxaspiro[3.3]heptan-6-ylamino)propan-1-oneTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11, step 6) (99%, 58 mg, 0.138 mmol) and 2-oxaspiro[3.3]heptan-6-one (19 mg, 0.166 mmol) in anhydrous DCE (1 mL) was added sodium triacetoxyborohydride (59 mg, 0.276 mmol) and the reaction mixture was stirred at 50 °C for 2 h. The mixture was cooled to room temperature and the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL). The product was extracted with EtOAc (2 x 10 mL) and the combined organic extracts werewashed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 4) to afford the title compound.1H NMR (500 MHz, CDCI3) δ 7.09 - 7.05 (m, 1 H), 6.40 - 6.38 (m, 2H), 4.73 - 4.68 (m, 2H), 4.61 - 4.54 (m, 2H), 3.89 - 3.71 (m, 8H), 3.60 - 3.51 (m, 1 H), 3.32 - 3.02 (m, 4H), 2.82 - 2.69 (m, 2H), 2.54 - 2.46 (m, 2H), 2.16 - 2.13 (m, 1 H), 2.08 - 2.04 (m, 1 H), 1.96 - 1.91 (m, 1 H), 1.86 - 1.80 (m, 1 H), 1.72 - 1.65 (m, 5H), 1.55 - 1.37 (m, 4H), 1.28 - 1.18 (m, 1 H), 1.09 - 0.96 (m, 3H), 0.44 - 0.34 (m, 2H), 0.27 - 0.21 (m, 2H). LC-MS (Method G): Rt 4.25 mins; MS m / z 512.6 [M+H]+.Example 11.7(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one fumaric acid(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl- [(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11 , step 6) (170 mg, 0.409 mmol) was dissolved in (2E)-but-2-enedioic acid (47 mg, 0.409 mmol) and MeOH (3 mL) and the solution was stirred at room temperature for 20 mins. The resulting mixture was concentrated in vacuo to yield (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-3-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one fumaric acid. The salt was taken up in minimal MeOH and hot I PA was added. The solution was allowed to slowly cool to room temperature and evaporate overnight to afford the title compound as a crystalline solid.Example 11.8(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(2-hydroxyethylamino)propan-1-oneTo a mixture of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (Example 11, step 6) (79%, 75 mg, 0.143 mmol) and 2-chloroethanol (11 μL, 0.157 mmol) in anhydrous DMF (1 mL) was added potassium carbonate (39 mg, 0.285 mmol) and the reaction mixture was stirred at 100 °C overnight. The resulting mixture was diluted with water (5 mL) and extracted with EtOAc (3x5 mL). The combined organic extracts were dried over and coMngcSeOnt4rated in vacuo. The crude material was purified by preparative HPLC (Method 4). The product fractions were concentrated in vacuo and the resulting residue was freeze-dried from MeCN:water to afford the title compound as a brown crystalline solid.1H NMR (500 MHz, CDCI3) δ 7.11 -7.07 (m, 1H), 6.42-6.39 (m, 2H), 3.87-3.73 (m, 8H), 3.69-3.64 (m, 1H), 3.62-3.53 (m, 2H), 3.36-3.25 (m, 2H), 3.18-3.05 (m, 1H), 2.96-2.89 (m, 1H), 2.86- 2.72 (m, 3H), 2.19-2.11 (m, 1H), 2.10-2.02 (m, 1H), 1.76-1.67 (m, 5H), 1.56-1.36 (m, 5H), 1.29-1.18 (m, 1H), 1.12-0.96 (m, 3H), 0.47-0.36 (m, 2H), 0.29-0.20 (m, 2H). LC- MS (Method F): Rt 5.43 mins; MS m / z 460.4 [M+H]+.Example 12(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-oneStep 1 : (2R)-2-(terf-Butoxycarbonylamino)-4-(1 ,3-dioxoisoindolin-2-yl)butanoic acidThe title compound was prepared from (2R)-4-amino-2-(terf-butoxycarbonylamino)butanoic acid and isobenzofuran-1 , 3-dione analogously to Example 11 , step 1. LC-MS (Method A): Rt 1.06 mins; MS m / z 347.2 [M-H]’.Step 2: terf-Butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1- carbonyl]-3-(1 ,3-dioxoisoindolin-2-yl)propyl]carbamateThe title compound was prepared from (2R)-2-(terf-butoxycarbonylamino)-4-(1 ,3- dioxoisoindolin-2-yl)butanoic acid (step 1) and (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) analogously to Example 2, step 1.1H NMR (400 MHz, CDCI3) δ 7.85 - 7.76 (m, 2H), 7.76 - 7.62 (m, 2H), 5.56 (br s, 1 H), 4.60 (br s, 1 H), 3.87 - 3.78 (m, 1 H), 3.77 - 3.61 (m, 1 H), 3.61 - 3.13 (m, 2H), 2.20 - 2.08 (m, 1 H), 2.06 - 2.01 (m, 1 H), 1.95 - 1.77 (m, 2H), 1.75 - 1.65 (m, 4H), 1.65 - 1.54 (m, 4H), 1.43 (s, 9H), 1.33 - 1 .23 (m, 1 H), 1 .20 - 1.05 (m, 3H). LC-MS (Method A): Rt 1.36 mins; MS m / z 470.4 [M+ H]+.Step 3: 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-4-oxo- butyl]isoindoline- 1 ,3-dioneThe title compound was prepared from tert-butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinoline-1-carbonyl]-3-(1 ,3-dioxoisoindolin-2-yl)propyl]carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 2, step 2. LC-MS (Method A): Rt 0.97 mins; MS m / z 370.3 [M+H]+.Step 4: 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[(2,4- dimethoxyphenyl)methylamino]-4-oxo-butyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-amino-4-oxo-butyl]isoindoline-1 , 3-dione (step 3) and 2,4- dimethoxybenzaldehyde analogously to Example 1 , step 2.1H NMR (500 MHz, CDCI3) δ 7.90 - 7.75 (m, 2H), 7.74 - 7.65 (m, 2H), 7.24 - 7.13 (m, 1 H), 6.41 - 6.34 (m, 2H), 3.94 - 3.86 (m, 1 H), 3.80 - 3.75 (m, 6H), 3.71 - 3.65 (m, 1 H), 3.55 - 3.48 (m, 1 H), 3.46 - 3.39 (m, 1 H), 1.98 - 1.45 (m, 15H), 1.24 - 0.77 (m, 5H). LC-MS (Method A): Rt 1.09 mins; MS m / z 520.9 [M+H]+.Step 5: 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[cyclopropyl- [(2, 4-dimethoxyphenyl)methyl]amino]-4-oxo-butyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-[(2,4-dimethoxyphenyl)methylamino]-4-oxo-butyl]isoindoline-1, 3-dione (step 4) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (500 MHz, CDCI3) δ 7.88 - 7.79 (m, 2H), 7.76 - 7.66 (m, 2H), 6.83 (br d, J = 7.9 Hz, 1 H), 6.27 (d, J = 2.3 Hz, 1 H), 5.93 (br d, J = 7.4 Hz, 1 H), 3.82 - 3.73 (m, 2H), 3.69 (s, 3H), 3.67 (s, 3H), 3.66 - 3.59 (m, 1 H), 3.36 (br d, J = 9.9 Hz, 1 H), 3.30 - 3.20 (m, 1 H), 2.85 (s, 1H), 2.79-2.69 (m, 1H), 2.67-2.51 (m, 1H), 2.04 (s, 2H), 1.97 (s, 1H), 1.70- 1.63 (m, 4H), 1.52-1.15 (m, 6H), 1.09-0.80 (m, 4H), 0.48-0.18 (m, 4H). LC-MS (Method A): Rt 1.37 mins; MS m / z 560.9 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-oneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo- butyl]isoindoline-1 , 3-dione (step 5) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (500 MHz, CDCI3) δ 7.10 - 7.01 (m, 1H), 6.47 - 6.34 (m, 2H), 3.82 - 3.74 (m, 8H), 3.49-3.39 (m, 1H), 3.28-3.17 (m, 1H), 3.16-3.07 (m, 1H), 3.05-2.91 (m, 1H), 2.77-2.62 (m, 2H), 2.42-2.28 (m, 1H), 2.23-2.14 (m, 1H), 2.14-2.04 (m, 1H), 2.04- 1.92 (m, 1H), 1.77-1.61 (m, 4H), 1.56-1.47 (m, 1H), 1.46-1.33 (m, 3H), 1.31 - 1.14 (m, 1H), 1.12 - 0.88 (m, 3H), 0.49 - 0.39 (m, 2H), 0.34 - 0.12 (m, 2H). NH2protons not observed. LC-MS (Method D): Rt 2.26 mins; MS m / z 430.4 [M+H]+.Example 13(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-(2,2-difluoroethylamino)butan-1-oneTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-4-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-one (Example 12) (100%, 30 mg, 0.0698 mmol) in anhydrous DCM (2 mL) was added potassium carbonate (14 mg, 0.105 mmol) followed by 2,2-difluoroethyl trifluoromethanesulfonate (11 μL, 0.0838 mmol) and the reaction mixture was stirred at room temperature for 1 h. The resulting mixture was diluted with water (5 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with a gradient of 10- 90% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) to afford the title compound as a white solid.1H NMR (500 MHz, CDCI3) δ 6.92 - 6.77 (m, 1 H), 6.28 - 6.02 (m, 2H), 5.83 - 5.44 (m, 1H), 3.60 - 3.48 (m, 8H), 3.26 - 3.15 (m, 1H), 3.13 - 3.01 (m, 1H), 2.92 - 2.66 (m, 3H), 2.57 - 2.47 (m, 1 H), 2.46 - 2.23 (m, 2H), 2.19 - 2.02 (m, 1H), 1.96 - 1.52 (m, 7H), 1.31 - 1.13 (m, 4H), 1.05 - 0.97 (m, 2H), 0.88 - 0.76 (m, 3H), 0.30 - 0.14 (m, 2H), 0.12 - -0.05 (m, 2H). LC- MS (Method D): Rt 2.79 mins; MS m / z 494.4 [M+H]+.Example 14(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-(dimethylamino)butan-1-oneTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-4-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-one (Example 12) (100%, 120 mg, 0.279 mmol) in anhydrous MeOH (2 mL) and acetic acid (0.1 mL) was added formaldehyde (37%, 31 μL, 0.419 mmol) followed by sodium triacetoxyborohydride (118 mg, 0.559 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with a gradient of 10-90% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) to afford the title compound as a white solid.1H NMR (500 MHz, CDCI3) δ 7.15-7.08 (m, 1H), 6.45-6.34 (m, 2H), 3.83-3.72 (m, 8H), 3.48-3.36 (m, 1H), 3.36-3.26 (m, 1H), 3.18-2.99 (m, 1H), 2.80-2.67 (m, 1H), 2.39-2.19 (m, 9H), 2.18-2.11 (m, 1H), 2.11 -2.02 (m, 1H), 1.98- 1.88 (m, 1H), 1.69-1.61 (m, 4H), 1.53-1.38 (m, 4H), 1.28-1.21 (m, 1H), 1.10-0.98 (m, 3H), 0.48 - 0.33 (m, 2H), 0.33 - 0.14 (m, 2H). LC-MS (Method D): Rt 2.58 mins; MS m / z 458.4 [M+H]+.Example 15(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-(methylamino)butan-1-oneStep 1 : terf-Butyl / \ / -[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo-butyl]carbamateTo a solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-4-amino-2- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]butan-1-one (Example 12) (90%, 205 mg, 0.429 mmol) in anhydrous DCM (3 mL) was added triethylamine (0.12 mL, 0.859 mmol) followed by di-terf-butyl dicarbonate (112 mg, 0.515 mmol) and the reaction mixture was stirred at room temperature for 2 h. The resulting mixture was diluted with water (10 mL) and extracted with DCM (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SC>4 and concentrated in vacuo to afford the title compound.1H NMR (500 MHz, CDCI3) δ 7.06 (d, J = 8.9 Hz, 1H), 6.44 - 6.37 (m, 2H), 5.19 - 5.06 (m, 1H), 3.84 - 3.72 (m, 8H), 3.37 - 3.24 (m, 2H), 3.23 - 3.12 (m, 1 H), 3.06 - 2.92 (m, 2H), 2.77 - 2.67 (m, 1 H), 2.40 - 2.28 (m, 1H), 2.20 - 2.09 (m, 1 H), 2.06 - 1.94 (m, 2H), 1.73 - 1.63 (m, 4H), 1.61 (s, 2H), 1.43 - 1.35 (m, 10H), 1.08 - 0.98 (m, 5H), 0.49 - 0.34 (m, 2H), 0.34 - 0.16 (m, 2H). LC-MS (Method A): Rt 1.24 mins; MS m / z 530.5 [M+H]+.Step 2: terf-Butyl / V-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- [cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo-butyl]- / \ / -methyl-carbamateTo a solution of terf-butyl / \ / -[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo-butyl]carbamate (step 1) (85%, 200 mg, 0.321 mmol) in anhydrous DMF (10 mL) was added sodium hydride (60%, 13 mg, 0.321 mmol) and the reaction mixture was stirred at room temperature for 1 h. lodomethane (20 μL, 0.321 mmol) was added and stirring continued for a further hour. The resulting mixture was diluted with water (20 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over Na2SO4 andconcentrated in vacuo to afford the title compound.1H NMR (400 MHz, CDCI3) δ 7.16 - 6.94 (m, 1H), 6.47-6.34 (m, 2H), 3.92-3.60 (m, 8H), 3.45-3.17 (m, 3H), 3.16-2.91 (m, 3H), 2.88-2.79 (m, 3H), 2.75-2.61 (m, 1H), 2.49-2.26 (m, 1H), 2.25-2.12 (m, 1H), 1.75- 1.62 (m, 4H), 1.52- 1.39 (m, 12H), 1.10-0.91 (m, 4H), 0.89-0.82 (m, 2H), 0.52-0.13 (m, 4H). LC-MS (Method A): Rt 1.29 mins; MS m / z 544.5 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-4-(methylamino)butan-1-oneThe title compound was prepared from ferf-butyl / \ / -[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-3-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-4-oxo- butyl]- / V-methyl-carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 2, step 2.1H NMR (500 MHz, CDCI3) δ 7.14 - 7.01 (m, 1H), 6.49-6.36 (m, 2H), 3.84-3.72 (m, 8H), 3.51 -3.41 (m, 1H), 3.27-3.17 (m, 1H), 3.16-2.93 (m, 2H), 2.78-2.69 (m, 1H), 2.69-2.61 (m, 4H), 2.48-2.37 (m, 1H), 2.28-2.18 (m, 1H), 2.13-2.06 (m, 1H), 2.06- 1.97 (m, 1 H), 1.80 - 1.65 (m, 4H), 1.61 -1.52 (m, 1 H), 1.49 - 1.38 (m, 3H), 1.28 - 1.22 (m, 1H), 1.12-0.97 (m, 3H), 0.56-0.40 (m, 2H), 0.40- 0.18 (m, 2H). NH proton not observed LC-MS (Method D): Rt 2.45 mins; MS m / z 444.4 [M+H]+.Example 16(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-6-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]hexan-1-oneStep 1 : (2R)-2-(tert-Butoxycarbonylamino)-6-(1 ,3-dioxoisoindolin-2-yl)hexanoic acidThe title compound was prepared from (2R)-6-amino-2-{[(tert- butoxy)carbonyl]amino}hexanoic acid and isobenzofuran-1 , 3-dione analogously to Example 11 , step 1.1H NMR (400 MHz, CDCI3) δ 8.21 - 7.95 (m, 1 H), 7.86 - 7.77 (m, 2H), 7.74 - 7.64 (m, 2H), 5.21 - 5.06 (m, 1 H), 4.36 - 4.22 (m, 1 H), 3.76 - 3.60 (m, 2H), 1.96 - 1.82 (m, 1 H), 1.81 - 1.58 (m, 3H), 1.42 (s, 9H). The carboxylic acid and NH protons not observed. LC-MS (Method A): Rt 1 .12 mins; MS m / z 399.2 [M+Na]+.Step 2: terf-Butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinoline-1- carbonyl]-5-(1 ,3-dioxoisoindolin-2-yl)pentyl]carbamateThe title compound was prepared from (2R)-2-(terf-butoxycarbonylamino)-6-(1 ,3- dioxoisoindolin-2-yl)hexanoic acid (step 1) and (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) analogously to Example 2, step 1.1H NMR (500 MHz, CDCI3) δ 7.85 - 7.80 (m, 2H), 7.72 - 7.68 (m, 2H), 5.45 (s, 1 H), 4.50 (s, 1 H), 3.67 (t, J = 7.1 Hz, 2H), 3.60 - 3.16 (m, 3H), 2.04 - 1.99 (m, 1 H), 1.88 - 1.67 (m, 8H), 1.62 - 1.49 (m, 4H), 1.47 - 1.32 (m, 12H), 1.18 - 0.96 (m, 3H). LC-MS (Method B): Rt 1.68 mins; MS m / z 520.4 [M+Na]+.Step 3: 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-5-amino-6-oxo- hexyl]isoindoline-1 ,3-dione hydrochlorideThe title compound was prepared from tert-butyl / \ / -[(1 R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinoline-1-carbonyl]-5-(1 ,3-dioxoisoindolin-2-yl)pentyl]carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 2, step 2. LC-MS (Method A): Rt 0.95 mins; MS m / z 398.7 [M+ H]+.Step 4: 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-5-[(2,4- dimethoxyphenyl)methylamino]-6-oxo-hexyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-5-amino-6-oxo-hexyl]isoindoline-1 , 3-dione hydrochloride (step 3) and 2,4- dimethoxybenzaldehyde analogously to Example 1 , step 2.1H NMR (500 MHz, CDCI3) δ 7.86 - 7.79 (m, 2H), 7.74 - 7.67 (m, 2H), 7.22 - 7.14 (m, 1 H), 6.45 - 6.37 (m, 2H), 3.80 - 3.75 (m, 6H), 3.69 - 3.61 (m, 3H), 3.59 - 3.52 (m, 1 H), 3.50 - 3.43 (m, 7H), 3.25 - 3.08 (m, 1 H), 2.06 - 1.30 (m, 12H), 1 .28 - 1.02 (m, 4H). LC-MS (Method A): Rt 1.05 mins; MS m / z 548.9 [M+H]+.Step 5: 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-5-[cyclopropyl- [(2, 4-dimethoxyphenyl)methyl]amino]-6-oxo-hexyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-5-[(2,4-dimethoxyphenyl)methylamino]-6-oxo-hexyl]isoindoline-1, 3-dione (step 4) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3. LC-MS (Method A): Rt 1.20 mins; MS m / z 588.4 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-6-amino-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]hexan-1-oneThe title compound was prepared from 2-[(5R)-6-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-5-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-6-oxo- hexyl]isoindoline-1, 3-dione (step 5) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (500 MHz, CDCI3) δ 7.12 - 7.02 (m, 1H), 6.45-6.34 (m, 2H), 3.81 -3.77 (m, 5H), 3.75 (s, 3H), 3.36-3.27 (m, 2H), 3.12-3.00 (m, 1H), 2.82-2.65 (m, 3H), 2.19-2.09 (m, 2H), 2.09-2.00 (m, 1H), 1.74-1.65 (m, 5H), 1.48- 1.32 (m, 6H), 1.32- 1.17 (m, 3H), 1.16-0.80 (m, 5H), 0.44-0.34 (m, 2H), 0.32-0.24 (m, 1H), 0.24-0.16 (m, 1H). LC-MS (Method D): Rt 1.77 mins; MS m / z 458.4 [M+H]+.Example 17(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl-[(2-fluoro-4-methoxy-phenyl)methyl]amino]propan-1-oneStep 1 : 2-f(2R)-3-f(4aR.8aS)-3.4.4a.5.6.7.8.8a-Octahvdro-2H-auinolin-1-vl1-2-f(2-fluoro-4- methoxy-phenyl)methylamino]-3-oxo-propyl]isoindoline-1, 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-amino-3-oxo-propyl]isoindoline-1, 3-dione (Example 11, step 3) and 2- fluoro-4-methoxybenzaldehyde analogously to Example 1, step 2. LC-MS (Method A): Rt 1.06 mins; MS m / z 494.8 [M + H]+.Step 2: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl- [(2-fluoro-4-methoxy-phenyl)methyl]amino]-3-oxo-propyl]isoindoline-1, 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[(2-fluoro-4-methoxy-phenyl)methylamino]-3-oxo-propyl]isoindoline-1,3- dione (step 1) and cyclopropylboronic acid analogously to Example 5, step 5.1H NMR (500 MHz, CDCI3) δ 7.87-7.78 (m, 2H), 7.73-7.68 (m, 2H), 7.19-7.14 (m, 1H), 6.54 (dd, J = 8.4, 2.5 Hz, 1 H), 6.48 (dd, J = 11.7, 2.5 Hz, 1 H), 4.44 - 4.38 (m, 1 H), 4.29 (dd, J = 14.0, 7.6 Hz, 1H), 4.08 (dd, J= 13.9, 6.1 Hz, 1H), 3.98 (s, 2H), 3.75 (s, 3H), 3.38-3.31 (m, 1H), 3.06 -2.96 (m, 1H), 2.22-2.15 (m, 1H), 2.13-2.06 (m, 1H), 1.73-1.65 (m, 3H), 1.57-0.98(m, 10H), 0.42 - 0.25 (m, 2H), 0.21 - 0.05 (m, 2H). LC-MS (Method A): Rt 1.54 mins; MS m / z 534.4 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[cyclopropyl-[(2-fluoro-4-methoxy-phenyl)methyl]amino]propan-1-oneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[cyclopropyl-[(2-fluoro-4-methoxy-phenyl)methyl]amino]-3-oxo- propyl]isoindoline-1, 3-dione (step 2) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (500 MHz, CDCI3) δ 7.19 - 7.11 (m, 1H), 6.64 - 6.52 (m, 2H), 3.94 - 3.83 (m, 2H), 3.78 (s, 3H), 3.55-3.48 (m, 1H), 3.41 -3.31 (m, 2H), 3.31 -3.14 (m, 1H), 3.07-2.99 (m, 1H), 2.99-2.87 (m, 1H), 2.24-2.12 (m, 1H), 2.12 - 2.04 (m, 1H), 1.72-1.67 (m, 3H), 1.56-1.38 (m, 5H), 1.33-1.19 (m, 2H), 1.14-0.97 (m, 3H), 0.93-0.75 (m, 1H), 0.47- 0.35 (m, 2H), 0.35 - 0.12 (m, 2H). LC-MS (Method D): Rt 2.60 mins; MS m / z 404.6 [M+H]+.Example 18(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[(4- chlorophenyl)methyl-cyclopropyl-amino]propan-1-oneStep 1 : tert-Butvl / V-[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-[(1,3- dioxoisoindolin-2-yl)methyl]-2-oxo-ethyl]carbamateThe title compound was prepared from (2R)-2-(terf-butoxycarbonylamino)-3-(1,3- dioxoisoindolin-2-yl)propanoic acid (Example 11, step 1) and (4aR,8aS)- 1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline analogously to Example 2, step 1.1H NMR (500 MHz, CDCI3) δ 7.92-7.81 (m, 2H), 7.81 -7.64 (m, 2H), 5.78-5.49 (m, 1H), 5.07-4.86 (m, 1H), 4.21 -3.83 (m, 2H), 3.78-3.68 (m, 1H), 3.60-3.32 (m, 1H), 2.25-2.02 (m, 1H), 1.98-1.70 (m, 4H), 1.71 - 1.42 (m, 5H), 1.39-1.27 (m, 3H), 1.26-1.05 (m, 10H). LC-MS (Method A): Rt 1.38 mins; MS m / z 478.4 [M+Na]+.Step 2: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-oxo- propyl]isoindoline- 1 ,3-dioneThe title compound was prepared from tert-butyl / \ / -[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-1-[(1,3-dioxoisoindolin-2-yl)methyl]-2-oxo-ethyl]carbamate (step 1) and 4M HCI in 1,4-dioxane analogously to Example 2, step 2.1H NMR (400 MHz, DMSO- d6) δ 8.64 - 8.34 (m, 1 H), 8.26 (s, 1 H), 7.97 - 7.82 (m, 2H), 4.60 (s, 1 H), 4.45 - 3.83 (m, 8H), 3.13-2.61 (m, 5H), 1.96-1.39 (m, 5H), 1.35-0.88 (m, 2H). LC-MS (Method A): Rt 1.00 mins; MS m / z 356.3 [M + H]+.Step 3: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(4- chlorophenyl)methylamino]-3-oxo-propyl]isoindoline-1, 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-amino-3-oxo-propyl]isoindoline-1 , 3-dione (step 2) and 4- chlorobenzaldehyde analogously to Example 1 , step 2.1H NMR (400 MHz, CDCI3) δ 7.88 - 7.79 (m, 2H), 7.79 - 7.69 (m, 2H), 7.35 - 7.28 (m, 1 H), 7.10 (s, 1 H), 7.05 - 6.97 (m, 1 H), 6.97 - 6.89 (m, 1 H), 3.97 - 3.68 (m, 4H), 3.66 - 3.24 (m, 3H), 2.04 (s, 1 H), 1.81 - 1 .63 (m, 4H), 1.64 - 1.52 (m, 3H), 1.52 - 1.34 (m, 1 H), 1.35 - 1.21 (m, 2H), 1.19 (s, 1 H), 1.16 - 0.73 (m, 2H). NH proton not observed. LC-MS (Method A): Rt 1.15 mins; MS m / z 480.3 [M+H]+.Step 4: 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(4- chlorophenyl)methyl-cyclopropyl-amino]-3-oxo-propyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[(4-chlorophenyl)methylamino]-3-oxo-propyl]isoindoline-1 ,3-dione (step 3) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (400 MHz, CDCI3) δ 7.86 - 7.82 (m, 2H), 7.76 - 7.72 (m, 2H), 7.14 - 7.13 (m, 2H), 7.11 - 7.10 (m, 2H), 3.98 - 3.89 (m, 3H), 3.69 - 3.48 (m, 2H), 3.49 - 3.25 (m, 2H), 2.23 - 2.06 (m, 2H), 1.76 - 1.67 (m, 4H), 1.22 - 0.96 (m, 6H), 0.89 - 0.69 (m, 3H), 0.39 - 0.03 (m, 4H). LC- MS (Method A): Rt 1.62 mins; MS m / z 520.4 [M+H]+.Step 5: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-amino-2-[(4- chlorophenyl)methyl-cyclopropyl-amino]propan-1-oneThe title compound was prepared from 2-[(2R)-3-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-[(4-chlorophenyl)methyl-cyclopropyl-amino]-3-oxo-propyl]isoindoline-1 ,3- dione (step 4) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (500 MHz, CDCI3) δ 7.25 - 7.22 (m, 2H), 7.20 - 7.17 (m, 2H), 3.94 - 3.80 (m, 2H), 3.60 - 3.52 (m, 1 H), 3.50 - 3.13 (m, 3H), 3.13 - 3.01 (m, 1 H), 2.95 (dd, J = 12.0, 5.2 Hz, 1 H), 2.21 - 2.09 (m, 2H), 1.78 - 1.66 (m, 4H), 1.63 - 1.36 (m, 4H), 1 .35 - 0.78 (m, 6H), 0.48 - 0.34 (m, 2H), 0.30 - 0.17 (m, 2H). LC-MS (Method D): Rt 2.70 mins; MS m / z 390.3 [M+H]+.Example 19(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-amino-2-[(4- chlorophenyl)methyl-cyclopropyl-amino]butan-1-oneStep 1 : 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[(4- chlorophenyl)methylamino]-4-oxo-butyl]isoindoline-1 , 3-dioneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-amino-4-oxo-butyl]isoindoline-1 , 3-dione (Example 12, step 3) and 4- chlorobenzaldehyde analogously to Example 1 , step 2. LC-MS (Method A): Rt 1.17 mins; MS m / z 516.0 [M+Na]+.Step 2: 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[(4- chlorophenyl)methyl-cyclopropyl-amino]-4-oxo-butyl]isoindoline-1, 3-dioneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-[(4-chlorophenyl)methylamino]-4-oxo-butyl]isoindoline-1 ,3-dione (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (500 MHz, CDCI3) δ 7.89 - 7.79 (m, 2H), 7.78 - 7.68 (m, 2H), 7.16 - 6.83 (m, 4H), 3.85 - 3.55 (m, 4H), 3.50-3.25 (m, 2H), 3.14-2.39 (m, 3H), 2.19-1.96 (m, 3H), 1.74-1.63 (m, 4H), 1.56-1.48 (m, 2H), 1.34-1.23 (m, 2H), 1.15-0.99 (m, 3H), 0.95-0.79 (m, 1H), 0.48 -0.14(m,4H). LC-MS (Method A): Rt 1.64 mins; MS m / z 534.3 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-4-amino-2-[(4- chlorophenyl)methyl-cyclopropyl-amino]butan-1-oneThe title compound was prepared from 2-[(3R)-4-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-3-[(4-chlorophenyl)methyl-cyclopropyl-amino]-4-oxo-butyl]isoindoline-1,3- dione (step 2) and hydrazine hydrate analogously to Example 10, step 6.1H NMR (400 MHz, CDCI3) δ 7.25-7.20 (m, 2H), 7.20-7.15 (m, 2H), 4.00-3.82 (m, 2H), 3.73-3.60 (m, 1H), 3.50-3.35 (m, 2H), 3.12-2.96 (m, 1H), 2.77-2.51 (m, 2H), 2.20-2.01 (m, 3H), 1.91 - 1.80 (m, 1H), 1.80- 1.67 (m, 4H), 1.63-1.51 (m, 5H), 1.38-1.21 (m, 2H), 1.19-0.99 (m, 3H), 0.48 - 0.32 (m, 2H), 0.27 - 0.14 (m, 2H). LC-MS (Method C): Rt 3.80 mins; MS m / z 404.3 [M+H]+.Example 20(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- ethylphenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-3-(Benzylamino)-2-(terf-butoxycarbonylamino)propanoic acidThe title compound was prepared from 3-amino- / V-(terf-butoxycarbonyl)-D-alanine, benzaldehyde and sodium borohydride analogously to Example 5, step 4.1H NMR (500 MHz, DMSO-d6) δ 7.42 - 7.31 (m, 5H), 6.54 (d, J = 6.6 Hz, 1 H), 4.05 - 3.81 (m, 3H), 3.02 - 2.91 (m, 2H), 2.81 - 2.73 (m, 1 H), 1.38 (s, 9H). The carboxylic acid proton not observed. LC- MS (Method A): Rt 0.87 mins; MS m / z 295.2 [M+H]+.Step 2: (2R)-3-[Benzyl(methyl)amino]-2-(terf-butoxycarbonylamino)propanoic acidThe title compound was prepared from (2R)-3-(benzylamino)-2-(terf- butoxycarbonylamino)propanoic acid (step 1) and 13.3M aqueous formaldehyde analogously to Example 14. LC-MS (Method A): Rt 0.88 mins; MS m / z 309.2 [M+H]+.Step 3: tert-Butyl / V-[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [[benzyl(methyl)amino]methyl]-2-oxo-ethyl]carbamateThe title compound was prepared from (2R)-3-[benzyl(methyl)amino]-2-(te / t- butoxycarbonylamino)propanoic acid (step 2) and (4aR,8aS)-1,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) analogously to Example 2, step 1.1H NMR (500 MHz, CDCI3) δ 7.36 - 7.26 (m, 4H), 7.25 - 7.20 (m, 1 H), 5.43 - 5.25 (m, 1 H), 4.76 - 4.65 (m, 1H), 3.77-3.07 (m, 5H), 2.77-2.51 (m, 2H), 2.34-2.18 (m, 3H), 2.18-2.05 (m, 1H), 1.91 - 1.59 (m, 6H), 1.48- 1.39 (m, 10H), 1.36-0.98 (m, 5H). LC-MS (Method A): Rt 1.03 mins; MS m / z 430.3 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-oneThe title compound was prepared from tert-butyl / \ / -[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-1-[[benzyl(methyl)amino]methyl]-2-oxo-ethyl]carbamate (step 3) and 4M HCI in 1,4-dioxane analogously to Example 2, step 2.1H NMR (400 MHz, CDCI3) δ 7.33-7.28 (m, 4H), 7.25-7.20 (m, 1H), 3.80-3.68 (m, 2H), 3.61 (d, J= 13.1 Hz, 1H), 3.48 (d, J= 13.1 Hz, 1H), 3.33 (br s, 1H), 3.08 (br s, 1H), 2.59-2.37 (m, 2H), 2.26 (s, 3H), 2.16- 1.98 (m, 3H), 1.87- 1.48 (m, 8H), 1.46-1.35 (m, 1H), 1.30-1.20 (m, 1H), 1.17-0.97 (m, 2H). LC-MS (Method A): Rt 0.98 mins; MS m / z 330.3 [M+H]+.Step 5: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(4-ethylphenyl)methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (step 4), 4-ethylbenzaldehyde and sodium borohydride analogously to Example 5, step 4. LC-MS (Method A): Rt 1.12 mins; MS m / z 448.6 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(4-ethylphenyl)methyl]amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(4-ethylphenyl)methylamino]propan-1-one (step 5) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3. LC-MS (Method A): Rt 1.19 mins; MS m / z 488.2 [M+H]+.Step 7: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- ethylphenyl)methyl]amino]-3-(methylamino)propan-1-oneTo a stirring solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(4-ethylphenyl)methyl]amino]propan-1-one (step 6) (53%, 262 mg, 0.285 mmol) and ammonium formate (53 mg, 0.854 mmol) in anhydrous MeOH (10 mL) was added 10% palladium on carbon (90 mg, 0.846 mmol) and the reaction mixture was stirred at room temperature under nitrogen for 18 h. The resulting mixture was filtered through Celite®, washing through with MeOH (3 x 5 mL). The filtrate was concentrated in vacuo and purification of the crude material by C18 reverse phase chromatography eluting with a gradient of 5-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) afforded a yellow solid. The solid was further purified by preparative HPLC (Method 1) to yield a colourless gum. The gum was re-purified by preparative HPLC (Method 1). The product fractions were combined, neutralized with saturated aqueous sodium bicarbonate solution, and concentrated in vacuo. The solids were suspended in DCM:water (1 :1, 4 mL) and passed through a hydrophobic frit. The aqueous layer was further extracted with DCM (3 x 2 mL) using a hydrophobic frit and the combined organic layers were concentrated and dried under vacuum at 40 °C to afford the title compound as a yellow gum.1H NMR (500 MHz, CDCI3) δ 7.15 (d, J = 8.0 Hz, 2H), 7.09 (d, J = 8.0 Hz, 2H), 3.92 (br s, 1 H), 3.89 - 3.82 (m, 1 H), 3.77 - 3.64 (m, 1 H), 3.52 - 3.43 (m, 1 H), 3.40 - 3.04 (m, 3H), 3.00 - 2.74 (m, 2H), 2.61 (q, J = 7.6 Hz, 2H), 2.37 (s, 3H), 2.28 - 2.07 (m, 2H), 1.75 - 1.37 (m, 7H), 1.33 - 0.99 (m, 8H), 0.49 - 0.39 (m, 2H), 0.31 - 0.21 (m, 2H). LC-MS (Method D): Rt 2.90 mins; MS m / z 398.4 [M+H]+.Example 21(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2- fluoro-4-methoxy-phenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[(2-fluoro-4-methoxy-phenyl)methylamino]propan-1-oneSodium borohydride (23 mg, 0.595 mmol), (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro- 2H-quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (Example 20, step 4) (86%, 190 mg, 0.496 mmol), 2-fluoro-4-methoxybenzaldehyde (76 mg, 0.496 mmol) and MgSO4 (119 mg, 0.992 mmol) were suspended in DCM (2 mL) and stirred at room temperature overnight. The resulting mixture was filtered and concentrated in vacuo. The residue was taken up in MeOH (2 mL), triethylamine (380 μL, 2.73 mmol) was added and the mixture was stirred at room temperature for 1 h. The reaction was quenched with water (10 mL) and extracted with EtOAc (3 x 10 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound as a pale yellow gum. LC-MS (Method A): Rt 1.10 mins; MS m / z 468.4 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(2-fluoro-4-methoxy-phenyl)methyl]amino]propan-1- oneTo a sealed tube containing (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-3-[benzyl(methyl)amino]-2-[(2-fluoro-4-methoxy-phenyl)methylamino]propan-1-one (step 1) (201 mg, 0.430 mmol) was added anhydrous DCE (1.5 mL), [(1- ethoxycyclopropyl)oxy](trimethyl)silane (259 μL, 1.29 mmol), acetic acid (25 μL) and sodium cyanoborohydride (41 mg, 0.645 mmol) and the reaction mixture was heated at 65°C overnight. The resulting mixture was taken up in DCM (2 mL) and the organics were washedwith saturated aqueous sodium bicarbonate solution, (2 x 1 mL), water (1 mL) and saturated brine solution (1 mL) dried over M agnSdO co4ncentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound as a colourless gum. LC-MS (Method A): Rt 1.21 mins; MS m / z 508.5 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2- fluoro-4-methoxy-phenyl)methyl]amino]-3-(methylamino)propan-1-one(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2- [cyclopropyl-[(2-fluoro-4-methoxy-phenyl)methyl]amino]propan-1-one (59 mg, 0.116 mmol) was dissolved in EtOH (14 mL). 10% Palladium on carbon (12 mg, 0.116 mmol) was added and the reaction mixture was stirred under atmosphere of hydrogen for 4 h. The resulting mixture was filtered through Celite®, washing through with EtOH. The filtrate was concentrated in vacuo and the crude material was purified by preparative HPLC (Method 1). The product fractions were combined and basified to pH 10 with saturated aqueous sodium bicarbonate solution . The basic solution was concentrated to a volume of approximately 2 mL and extracted with EtOAc (3 x 2 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to afford the title compound was obtained as an orange gum.1H NMR (500 MHz, CDCI3) δ 7.09 - 7.02 (m, 1 H), 6.53 - 6.37 (m, 2H), 3.87 - 3.72 (m, 2H), 3.72 - 3.65 (m, 1 H), 3.65 - 3.59 (m, 3H), 3.24 - 3.02 (m, 3H), 2.94 - 2.74 (m, 2H), 2.44 - 2.34 (m, 2H), 2.04 - 1.89 (m, 2H), 1.69 - 1.21 (m, 8H), 1.17 - 0.65 (m, 6H), 0.38 - 0.20 (m, 2H), 0.20 - -0.16 (m, 2H). LC-MS (Method D): Rt 2.47 mins; MS m / z 418.4 [M+H]+.Example 21.1(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- difluorophenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(2,4-difluorophenyl)methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (Example 20, step 4), 2,4- difluorobenzaldehyde and sodium borohydride analogously to Example 21, step 1. LC-MS (Method A): Rt 1.03 mins; MS m / z 456.6 [M+ H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(2,4-difluorophenyl)methyl]amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(2,4-difluorophenyl)methylamino]propan-1-one (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 21 , step 2.LC-MS (Method B): Rt 1.34 mins; MS m / z 496.4 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- difluorophenyl)methyl]amino]-3-(methylamino)propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[cyclopropyl-[(2,4-difluorophenyl)methyl]amino] propan-1-one (step 2) and ammonium formate analogously to Example 20, step 7.1H NMR (500 MHz, CDCI3) δ 7.26 - 7.17 (m, 1H), 6.84-6.70 (m, 2H), 4.06-3.96 (m, 1H), 3.95- 3.86 (m, 1H), 3.86-3.74 (m, 1H), 3.45-3.25 (m, 2H), 3.19-2.96 (m, 2H), 2.91 -2.81 (m, 1H), 2.45 (s, 3H), 2.20-2.10 (m, 2H), 1.78-1.66 (m, 4H), 1.61 - 1.36 (m, 4H), 1.34-1.14 (m, 3H), 1.14-1.00 (m, 2H), 0.45-0.33 (m, 2H), 0.24-0.16 (m, 1H), 0.15-0.06 (m, 1H). LC-MS (Method D): Rt 2.60 mins; MS m / z 406.3 [M+H]+.Example 21.2(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(4-methoxyphenyl)methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (Example 20, step 4), 4- methoxybenzaldehyde and sodium borohydride analogously to Example 21 , step 1. LC-MS (Method A): Rt 1.06 mins; MS m / z 450.6 [M+ H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(4-methoxyphenyl)methyl]amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(4-methoxyphenyl)methylamino]propan-1-one (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 21 , step 2. LC-MS (Method A): Rt 1.16 mins; MS m / z 490.2 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneThe title compound was prepared from 2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[cyclopropyl-[(4-methoxyphenyl)methyl]amino] propan-1-one (step 2) and ammonium formate analogously to Example 20, step 7.1H NMR (500 MHz, CDCI3) δ 7.20 - 7.12 (m, 2H), 6.84 - 6.78 (m, 2H), 3.94 - 3.86 (m, 1 H), 3.85 - 3.80 (m, 1 H), 3.79 (s, 3H), 3.77 - 3.68 (m, 1 H), 3.41 - 3.30 (m, 1 H), 3.30 - 3.19 (m, 1 H), 3.18 - 3.07 (m, 1 H), 3.01 - 2.90 (m, 1 H), 2.84 - 2.75 (m, 1 H), 2.40 (s, 3H), 2.22 - 2.09 (m,2H), 1.79 - 1.37 (m, 8H), 1.32 - 1.19 (m, 2H), 1.19 - 1.01 (m, 3H), 0.49 - 0.40 (m, 2H), 0.29- 0.20 (m, 2H). LC-MS (Method D): Rt 2.55 mins; MS m / z 400.4 [M+ H]+.Example 22(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1- oneTo a sealed tube containing [(1-ethoxycyclopropyl)oxy](trimethyl)silane (121 μL, 0.601 mmol) and sodium cyanoborohydride (28 mg, 0.451 mmol) in anhydrous DCE (2 mL) was added 2,4-dimethoxybenzaldehyde (50 mg, 0.300 mmol) and the reaction mixture was stirred at room temperature for 3 h. To this mixture was added acetic acid (15 μL), (2R)-1- [(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-amino-3- [benzyl(methyl)amino]propan-1-one (Example 20, step 4) and 2,4-dimethoxybenzaldehyde (50 mg, 0.300 mmol) and the mixture was heated at 65 °C for 4 h. The resulting mixture was allowed to cool to room temperature. DCM (3 mL) and saturated aqueous sodium bicarbonate solution (3 mL) were added and the mixture was stirred vigorously for 5 mins. The layers were separated, the organics were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound as a colourless gum.1H NMR (500 MHz, CDCI3) δ 7.38 - 7.27 (m, 5H), 7.14 (d, J = 7.9 Hz, 1 H), 6.42 - 6.36 (m, 2H), 3.90 - 3.83 (m, 1H), 3.84 - 3.67 (m, 10H), 3.52 - 3.43 (m, 1 H), 3.41 - 3.32 (m, 1H), 3.31 - 3.19 (m, 1H), 3.06 - 2.98 (m, 1 H), 2.97 - 2.86 (m, 1 H), 2.27 (s, 3H), 2.24 - 2.17 (m, 2H), 1.76 - 1.62 (m, 4H), 1.57 - 1.37 (m, 4H), 1.32 - 1.20 (m, 1 H), 1.16 - 0.96 (m, 3H), 0.42 - 0.29 (m, 2H), 0.32 - 0.23 (m, 1 H), 0.23 - 0.14 (m, 1 H). LC-MS (Method D): Rt 3.13 mins; MS m / z 520.4 [M+H]+.Example 23(2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneStep 1 : terf-Butyl / V-[(1R)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-[[benzyl(methyl)amino]methyl]-2-oxo-ethyl]carbamateTo a stirred solution of DIPEA (700 μL, 4.01 mmol), (2R)-3-[benzyl(methyl)amino]-2-(terf- butoxycarbonylamino)propanoic acid (Example 20, step 2) (98%, 500 mg, 1.59 mmol), and HATU (900 mg, 2.37 mmol) in DCM (15 mL) was added (4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a- decahydroquinoline hydrochloride (Example 32, step 1e) (310 mg, 1.76 mmol) and the reaction mixture stirred at room temperature for 2 h. The resulting mixture was diluted with DCM (20 mL) and washed with water (30 mL). The aqueous phase was extracted with DCM (3 x 30 mL) and the combined organic layers were dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0-100% EtOAc in heptane. Further purification by chromatography on silica eluting with a gradient of 0-50% EtOAc in heptane afforded the title compound as a colourless oil.1H NMR (500 MHz, CDCI3) δ 7.35 - 7.27 (m, 4H), 7.25 - 7.20 (m, 1 H), 5.45 - 5.35 (m, 1 H), 4.82 - 4.73 (m, 1 H), 4.66 - 4.41 (m, 1 H), 3.89 - 3.67 (m, 1 H), 3.65 - 3.57 (m, 1 H), 3.55 - 3.46 (m, 1 H), 3.00 - 2.52 (m, 3H), 2.34 - 2.20 (m, 3H), 1.93 - 1.67 (m, 5H), 1.66 - 1.59 (m, 1 H), 1.56 - 1.48 (m, 2H), 1.47 - 1.21 (m, 14H). LC-MS (Method A): Rt 1.04 mins; MS m / z 430.1 [M+H]+.Step 2: (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-onetert-Butyl N-[(1R)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [[benzyl(methyl)amino]methyl]-2-oxo-ethyl]carbamate (step 1) (100%, 477 mg, 1.11 mmol) was dissolved in 4M HCI in 1,4-dioxane (3 mL, 12 mmol) and the reaction mixture stirred at room temperature under nitrogen for 1.5 h The resulting mixture was concentrated in vacuo and the residue was suspended in DCM (20 mL) and washed with saturated aqueous sodium bicarbonate solution (20 mL). The aqueous layer was extracted with DCM (3 x 20 mL) and the combined organic layers were dried over sodium sulphate and concentrated in vacuo to afford the title compound as a pale-yellow gum.1H NMR (500 MHz, CDCI3) δ 7.35 - 7.28 (m, 4H), 7.27 - 7.22 (m, 1 H), 4.66 - 4.44 (m, 1 H), 3.85 - 3.76 (m, 1 H), 3.75 - 3.55 (m, 2H), 3.51 - 3.42 (m, 1 H), 2.99 - 2.60 (m, 1 H), 2.51 - 2.34 (m, 2H), 2.32 - 2.22 (m, 3H), 1.94 - 1.61 (m, 7H), 1.62 - 1.19 (m, 8H). LC-MS (Method A): Rt 0.98 mins; MS m / z 330.2 [M+H]+.Step 3: (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(2,4-dimethoxyphenyl)methylamino]propan-1-one(2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-amino-3- [benzyl(methyl)amino]propan-1-one (step 2) (100%, 170 mg, 0.516 mmol), sodium borohydride (20 mg, 0.529 mmol), 2,4-dimethoxybenzaldehyde (90 mg, 0.542 mmol) and rriethylamine (0.39 mL, 2.80 mmol) were suspended in DCM (2 mL) and stirred at roomtemperature for 3 h. The resulting mixture was filtered and concentrated in vacuo. The crude residue was dissolved in MeOH (2 mL), M (1g2S5O m4g, 1.04 mmol) was added and the reaction mixture was stirred at room temperature for 2 h. The solvent was removed under a flow of nitrogen and the residue diluted with water (3 mL) and extracted with EtOAc (3 x 2 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to afford the title compound as a yellow gum. LC-MS (Method A): Rt 1.08 mins; MS m / z 480.2 [M+H]+.Step 4: (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-oneSodium cyanoborohydride (45 mg, 0.716 mmol) was added to a solution of (2R)-1- [(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[(2,4- dimethoxyphenyl)methylamino]propan-1-one (step 3) (238 mg, 0.495 mmol), [(1- ethoxycyclopropyl)oxy](trimethyl)silane (300 μL, 1.49 mmol) and acetic acid (185 μL) in anhydrous DCE (7 mL) and the reaction mixture was stirred at 65 °C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution (6 mL) and the mixture was extracted with DCM (3 x 5 mL). The combined organic extracts were dried using a phase separator and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0-100% ethyl acetate in heptane afforded the title compound as a colourless gum. LC-MS (Method A): Rt 1.25 mins; MS m / z 520.0 [M+H]+.Step 5: (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-(methylamino)propan-1-oneTo a stirred solution of (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (step 4) (85%, 205 mg, 0.335 mmol) and ammonium formate (62 mg, 1.01 mmol) in anhydrous MeOH (9 mL) under nitrogen was added 10% palladium on carbon (107 mg, 1.01 mmol) and the reaction mixture was stirred at room temperature for 4 h. The resulting mixture was filtered through a Celite®, washing through with MeOH (3 x 5 mL). The filtrate was concentrated in vacuo and the crude material was purified by chromatography on silica eluting with a gradient of 0-100% ethyl acetate in heptane followed by a gradient of 0-50% MeOH in ethyl acetate. The product fractions were combined and concentrated in vacuo to give a yellow solid. Further purification by C18 reverse phase chromatography eluting with a gradient of 5-100% MeCN (+ 0.1% formic acid) in water (+ 0.1% formic acid) afforded the title compound as an off-white glassy solid.1H NMR (500 MHz, CDCI3) δ 7.19 - 7.15 (m, 1H), 6.48 - 6.41 (m, 2H), 4.61 - 4.44 (m, 1 H), 4.34 - 4.10 (m, 1H), 4.00 - 3.89 (m, 1 H), 3.85 - 3.72 (m, 7H), 3.71 - 3.53 (m, 1H), 3.40 - 3.22 (m, 2H), 3.00 - 2.79 (m, 1H), 2.71 - 2.63 (m, 3H), 1.98 - 1.90 (m, 1 H), 1.86 - 1.68 (m, 3H), 1.67 - 1.50 (m, 4H), 1.47 - 1.21 (m, 7H), 0.57 - 0.31 (m, 3H), 0.12 - -0.08 (m, 1H). LC-MS (Method D): Rt 2.66 mins; MS m / z 430.4 [M+H]+.Example 24(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl(o- tolylmethyl)amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-(o-tolylmethylamino)propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (Example 20, step 4), 2- methylbenzaldehyde and sodium borohydride analogously to Example 21, step 1. LC-MS (Method A): Rt 1.02 mins; MS m / z 434.6 [M+ H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[cyclopropyl(o-tolylmethyl)amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-(o-tolylmethylamino)propan-1-one (step 1) and [(1- ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 21, step 2. LC-MS (Method B): Rt 1.39 mins; MS m / z 474.4 [M + H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl(o- tolylmethyl)amino]-3-(methylamino)propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[cyclopropyl(o-tolylmethyl)amino]propan-1-one (step 2) and ammonium formate analogously to Example 20, step 7.1H NMR (400 MHz, CDCI3) 6 7.24 - 7.19 (m, 1 H), 7.13 - 7.09 (m, 3H), 4.02 - 3.89 (m, 2H), 3.76 - 3.66 (m, 1 H), 3.40 - 3.10 (m, 3H), 3.01 - 2.85 (m, 2H), 2.41 (s, 3H), 2.36 - 2.23 (m, 4H), 2.21 - 2.08 (m, 1 H), 1.78 - 1.35 (m, 8H), 1.34 - 1.01 (m, 5H), 0.48 - 0.37 (m, 2H), 0.30 - 0.19 (m, 2H). LC-MS (Method D): Rt 2.73 mins; MS m / z 384.4 [M+ H]+.Example 25(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[[4-(cyclopropoxy)phenyl]methyl-cyclopropyl-amino]-3-(methylamino)propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[[4-(cyclopropoxy)phenyl]methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[benzyl(methyl)amino]propan-1-one (Example 20, step 4), 4- cyclopropoxybenzaldehyde and sodium borohydride analogously to Example 21 , step 1. LC- MS (Method A): Rt 1.10 mins; MS m / z 476.1 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3- [benzyl(methyl)amino]-2-[[4-(cyclopropoxy)phenyl]methyl-cyclopropyl-amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[[4-(cyclopropoxy)phenyl]methylamino]propan-1-one (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 21 , step 2. LC-MS (Method A): Rt 1.18 mins; MS m / z 516.2 [M+H]+.Step 3: (2R)-1-r(4aR.8aS)-3.4.4a.5.6.7.8.8a-Octahvdro-2H-auinolin-1-vl1-2-rr4-(cyclopropoxy)phenyl]methyl-cyclopropyl-amino]-3-(methylamino)propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[benzyl(methyl)amino]-2-[[4-(cyclopropoxy)phenyl]methyl-cyclopropyl- amino]propan-1-one (step 2) and ammonium formate analogously to Example 20, step 7.1H NMR (500 MHz, CDCI3) δ 7.15 (d, J = 8.5 Hz, 2H), 6.94 (d, J = 8.6 Hz, 2H), 3.97 - 3.76 (m, 2H), 3.75 - 3.61 (m, 2H), 3.42 - 3.18 (m, 2H), 3.13 (br s, 1 H), 2.99 - 2.88 (m, 1 H), 2.86 - 2.70 (m, 1 H), 2.39 (s, 3H), 2.25 - 2.07 (m, 2H), 1.78 - 1.64 (m, 4H), 1 .64 - 1 .34 (m, 5H), 1.33 - 1.21 (m, 1 H), 1.18 - 0.97 (m, 3H), 0.81 - 0.68 (m, 4H), 0.54 - 0.41 (m, 2H), 0.34 - 0.14 (m, 2H). LC-MS (Method D): Rt 2.81 mins; MS m / z 426.4 [M+H]+.Example 26(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,6- dimethoxy-3-pyridyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1 : terf-Butyl / \ / -[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- (hydroxymethyl)-2-oxo-ethyl]carbamateHATLI (13.90 g, 36.5 mmol) was added to a solution of / V-(terf-butoxycarbonyl)-D-serine (5.00 g, 24.4 mmol) in DCM (57 mL). After stirring for 5 mins, (4aR,8aS)- 1 ,2,3,4,4a,5,6,7,8,8a-decahydroquinoline (4.07 g, 29.2 mmol) and DIPEA (4.3 mL, 24.4 mmol) were added and the reaction mixture was stirred at room temperature for 1 h. Water (40 mL) was added and the mixture was extracted with DCM (3 x 40 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0- 100% TBME in heptane followed by 0-20% MeOH in TBME afforded the title compound as a colourless / white gum.1H NMR (500 MHz, CDCI3) δ 5.70 - 5.61 (m, 1 H), 4.62 - 4.52 (m, 1 H), 3.86 - 3.76 (m, 1 H), 3.74 - 3.65 (m, 1 H), 3.44 - 3.31 (m, 1 H), 3.24 (s, 1 H), 2.16 - 2.06 (m, 1 H), 1.88 - 1.66 (m, 4H), 1.66 - 1.52 (m, 4H), 1.51 - 1.39 (m, 10H), 1.35 - 1.02 (m, 4H). OH proton not observed. LC-MS (Method A): Rt 1.14 mins; MS m / z 349.2 [M+Na]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-hydroxy- propan-1-onetert-Butyl / V-[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- (hydroxymethyl)-2-oxo-ethyl]carbamate (step 1) (83%, 5.48 g, 13.9 mmol) was dissolved in 4M HCI in 1 ,4-dioxane (35 mL, 0.139 mol) and stirred at room temperature for 1 h. Theresulting mixture was diluted with water (50 mL) it was extracted with EtOAc (2 x 70 mL) and I PA: CHCh (1:1; 2 x 70 mL). The aqueous layer was separated and further extracted with EtOAc (1 x 70 mL) and IPA:CHCl3 (1 :1; 1 x 70 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to afford the title compound as a greenish gum.1H NMR (500 MHz, CDCI3) δ 3.76 - 3.66 (m, 1 H), 3.66 - 3.58 (m, 1H), 3.47 - 3.39 (m, 1 H), 3.39 - 3.27 (m, 1H), 3.27 - 3.09 (m, 1 H), 2.88 - 2.45 (m, 3H), 2.13 - 1.95 (m, 1 H), 1.90 - 1.64 (m, 5H), 1.64 - 1.50 (m, 2H), 1.50 - 1.36 (m, 1H), 1.33 - 1.21 (m, 2H), 1.21 - 1.01 (m, 3H). LC-MS (Method E): Rt 1.23 mins; MS m / z 227.3 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[(2,6-dimethoxy-3-pyridyl)methylamino]-3-hydroxy-propan-1-one(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-hydroxy-propan- 1-one (step 2) (80%, 150 mg, 0.530 mmol), 2,6-dimethoxypyridine-3-carbaldehyde (89 mg, 0.530 mmol), sodium borohydride (24 mg, 0.636 mmol) and (128 mMgg,S 1O.046 mmol) were suspended in DCM (2 mL) and stirred at room temperature for 3 h. The resulting mixture was filtered and the filtrate was concentrated in vacuo. The residue was taken up in MeOH (2 mL), treated with triethylamine (0.41 mL, 2.92 mmol) and the mixture was stirred at room temperature for 1 h. Additional sodium borohydride (12 mg, 0.318 mmol) was added and stirring continued at room temperature overnight. The reaction was quenched with water (3 mL) and extracted with DCM (3 x 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo to afford the title compound as a yellow gum. LC-MS (Method A): Rt 0.96 mins; MS m / z 378.3 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,6- dimethoxy-3-pyridyl)methyl]amino]-3-hydroxy-propan-1-oneSodium cyanoborohydride (45 mg, 0.708 mmol) was added to a solution of (2R)-1- [(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-[(2,6-dimethoxy-3- pyridyl)methylamino]-3-hydroxy-propan-1-one (step 3) (74%, 203 mg, 0.398 mmol), [(1- ethoxycyclopropyl)oxy](trimethyl)silane (0.24 mL, 1.19 mmol) and acetic acid (113 μL) in anhydrous DCE (3 mL) and the reaction mixture was stirred at 65 °C overnight. The reaction was quenched with saturated aqueous sodium bicarbonate solution (5 mL) and the mixture was extracted with DCM (3 x 5 mL). The combined organic extracts were passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound as a colourless solid.1H NMR (500 MHz, CDCI3) δ 7.39 (d, J = 7.9 Hz, 1 H), 6.24 (d, J = 7.9 Hz, 1H), 4.15 - 4.09 (m, 1H), 4.06 - 3.99 (m, 1 H), 3.99 - 3.93 (m, 1 H), 3.92 - 3.89 (m, 6H), 3.84 - 3.77 (m, 1 H), 3.68 - 3.61 (m, 1 H), 3.31 (t, J = 9.6 Hz, 2H), 3.03 - 2.92 (m, 1 H), 2.28 - 2.20 (m, 1H), 2.20 - 2.10 (m, 1H), 1.81 - 1.64 (m, 4H), 1.64 - 1.36 (m, 4H), 1.34 - 1.22 (m, 1 H), 1.20 - 1.00 (m, 3H), 0.47 - 0.36 (m, 2H), 0.33 - 0.18 (m, 1H), 0.14 - 0.05 (m, 1 H). LC-MS (Method G): Rt 4.44 mins; MS m / z 418.4 [M+H]+.Example 27(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-hydroxy-2-[(4- methoxyphenyl)methylamino]propan-1-oneTo a sealed tube containing (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1- yl]-2-amino-3-hydroxy-propan-1-one (160 mg, 0.707 mmol) and 4-methoxybenzaldehyde (0.080 mL, 0.707 mmol) in anhydrous DCE (3.5 mL) was added sodium cyanoborohydride (67 mg, 1.06 mmol). The reaction was stirred at room temperature for 1 h and then heated to 65 °C for 1 h. The reaction was allowed to cool to room temperature. DCM (3 mL) and saturated aqueous sodium bicarbonate solution (3 mL) were added and the reaction was stirred vigorously for 5 minutes. The organics were then passed through a phase separator and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 1) to afford the title compound as a pale-yellow gum.1H NMR (500 MHz, DMSO-d6) δ 7.24 - 7.17 (m, 2H), 6.90 - 6.81 (m, 2H), 4.72 - 4.52 (m, 1 H), 3.72 (s, 3H), 3.60 - 3.53 (m, 1 H), 3.52 - 3.40 (m, 3H), 3.30 - 2.95 (m, 4H), 2.24 - 2.09 (m, 1 H), 1.76 - 1 .38 (m, 8H), 1.36 - 1.14 (m, 3H), 1.10 - 0.93 (m, 2H). LC-MS (Method A): Rt 0.96 mins; MS m / z 347.3 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-hydroxy-2-[(4-methoxyphenyl)methylamino]propan-1-one (step 1) and [(1- ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (500 MHz, CDCI3) δ 7.21 - 7.12 (m, 2H), 6.87 - 6.76 (m, 2H), 4.29 - 4.17 (m, 1 H), 3.94 - 3.81 (m, 3H), 3.79 (s, 3H), 3.56 - 3.46 (m, 1 H), 3.36 - 3.23 (m, 1 H), 3.22 - 3.05 (m, 1 H), 2.95 - 2.83 (m, 1 H), 2.36 - 2.29 (m, 1 H), 2.20 - 2.14 (m, 1 H), 1.82 - 1.66 (m, 5H), 1.61 - 1.38 (m, 4H), 1.31 - 1.19 (m, 1 H), 1.19 - 0.99 (m, 3H), 0.56 - 0.43 (m, 2H), 0.35 - 0.18 (m, 2H). LC- MS (Method G): Rt 4.21 mins; MS m / z 387.4 [M+H]+.Example 28(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2- fluoro-4-methoxy-phenyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1 : (2R)-1-f(4aR.8aS)-3.4.4a.5.6.7.8.8a-Octahvdro-2H-auinolin-1-vl1-2-f(2-fluoro-4- methoxy-phenyl)methylamino]-3-hydroxy-propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-hydroxy-propan-1-one (Example 26, step 2), 2-fluoro-4- methoxybenzaldehyde (68 mg, 0.442 mmol) and sodium triacetoxyborohydride analogously to Example 3, step 2.1H NMR (400 MHz, CDCI3) δ 7.29 - 7.20 (m, 1 H), 6.65 (dd, J = 8.4, 2.4 Hz, 1H), 6.59 (dd, J= 11.8, 2.5 Hz, 1H), 3.78 (s, 3H), 3.76 (d, J= 13.6 Hz, 1H), 3.68 (d, J = 13.0 Hz, 1H), 3.62 (dd, J= 10.6, 4.3 Hz, 1H), 3.50 (dd, J= 8.2, 4.3 Hz, 1H), 3.38-3.25 (m, 2H), 3.22-3.10 (m, 1H), 2.10-1.95 (m, 1H), 1.85- 1.49 (m, 9H), 1.46-0.99 (m, 6H). LC-MS (Method E): Rt 1.59 mins; MS m / z 365.3 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2- fluoro-4-methoxy-phenyl)methyl]amino]-3-hydroxy-propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-[(2-fluoro-4-methoxy-phenyl)methylamino]-3-hydroxy-propan-1-one (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (400 MHz, CDCI3) δ 7.16-7.10 (m, 1H), 6.62 (dd, J= 8.4, 2.5 Hz, 1H), 6.57 (dd, J= 11.7, 2.5 Hz, 1H), 4.27-4.19 (m, 1H), 3.96-3.87 (m, 3H), 3.79 (s, 3H), 3.57-3.50 (m, 1H), 3.35 -3.25 (m, 1H), 3.17 (brs, 1H), 3.00-2.85 (m, 1H), 2.33-2.23 (m, 1H), 2.23-2.15 (m, 1H), 1.79-1.37 (m, 8H), 1.33-1.20 (m, 2H), 1.17-1.01 (m, 3H), 0.51 -0.38 (m, 2H), 0.30 -0.15 (m, 2H). LC-MS (Method D): Rt 2.89 mins; MS m / z 405.4 [M+H]+.Example 29 tert-Butyl A / -[2-[2-[[[(1R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-(hydroxymethyl)-2-oxo-ethyl]-cyclopropyl-amino]methyl]-5-methoxy- phenoxy]ethyl]carbamateStep 1 : tert-Butyl N-[2-(2-formyl-5-methoxy-phenoxy)ethyl]carbamateTo a solution of potassium carbonate (363 mg, 2.63 mmol) and 2-hydroxy-4- methoxybenzaldehyde (200 mg, 1.31 mmol) in anhydrous DMF (6 mL) was added tert-butyl (2-chloroethyl)carbamate (96%, 0.24 mL, 1.31 mmol) and the reaction mixture was stirred at 60 °C for 12 h. After cooling to room temperature, the reaction was quenched with saturated aqueous sodium bicarbonate solution (10 mL) and the mixture was extracted with EtOAc (2 x 10 mL). The combined organic extracts were washed with water (2 x 10 mL), brine (10 mL), dried over Na2SC>4 and concentrated in vacuo to afford the title compound as a brown oil.1H NMR (500 MHz, CDCI3) δ 10.29 (d, J = 0.6 Hz, 1H), 7.80 (d, J = 8.7 Hz, 1 H), 6.59 - 6.54 (m, 1H), 6.43 (t, J = 2.4 Hz, 1 H), 5.01 (s, 1H), 4.11 (t, J = 5.1 Hz, 2H), 3.86 (s, 3H), 3.60 (q, J = 5.3 Hz, 2H), 1.45 (s, 9H). LC-MS (Method A): Rt 1.17 mins; MS m / z 196.2 [M- Boc+H]+.Step 2: tert-Butyl / V-[2-[2-[[[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]- 1-(hydroxymethyl)-2-oxo-ethyl]amino]methyl]-5-methoxy-phenoxy]ethyl]carbamateThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-hydroxy-propan-1-one (Example 26, step 2) and tert-butyl / \ / -[2-(2- formyl-5-methoxy-phenoxy)ethyl]carbamate (step 1) analogously to Example 5, step 4.1H NMR (500MHz, CDCI3) δ 7.14-7.07 (m, 1H), 6.99-6.76 (m, 1H), 6.45-6.37 (m, 2H), 4.08- 3.95 (m, 2H), 3.87 - 3.73 (m, 4H), 3.68 - 3.59 (m, 2H), 3.59 - 3.45 (m, 3H), 3.46 - 3.24 (m, 3H), 2.18-2.03 (m, 1H), 1.86-1.63 (m, 9H), 1.47- 1.38 (m, 11 H), 1.36- 1.23 (m, 2H), 1.16-1.02 (m,2H). LC-MS (Method A): Rt 1.08 mins; MS m / z 506.7 [M+H]+.Step 3: tert-Butyl / V-[2-[2-[[[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]- 1-(hydroxymethyl)-2-oxo-ethyl]-cyclopropyl-amino]methyl]-5-methoxy- phenoxy]ethyl]carbamateThe title compound was prepared from tert-butyl / \ / -[2-[2-[[[(1R)-2-[(4aR,8aS)- 3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1-(hydroxymethyl)-2-oxo-ethyl]amino]methyl]- 5-methoxy-phenoxy]ethyl]carbamate (step 2) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (500 MHz, CDCI3) δ 7.16 - 7.06 (m, 1 H), 6.49 - 6.37 (m, 2H), 6.00 - 5.91 (m, 1 H), 4.21 - 4.05 (m, 3H), 3.98 - 3.92 (m, 2H), 3.79 (s, 3H), 3.74-3.69 (m, 1H), 3.66-3.59 (m, 2H), 3.52-3.43 (m, 1H), 3.29 (t, J= 9.9 Hz, 1H), 3.16 (brs, 1H), 2.91 -2.82 (m, 1H), 2.21 -2.13 (m, 2H), 1.78-1.64 (m, 4H), 1.56-1.52 (m, 2H), 1.51 - 1.39 (m, 12H), 1.32- 1.20 (m, 1H), 1.19-0.98 (m, 3H), 0.51 -0.39 (m, 2H),0.35-0.27 (m, 1 H), 0.20-0.11 (m, 1H). LC-MS (Method D): Rt2.22 mins; MS m / z 546.4 [M+H]+.Example 30(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxy-2-morpholino-phenyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1 : (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-hydroxy-2-[(4- methoxy-2-morpholino-phenyl)methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-hydroxy-propan-1-one (Example 26, step 2) and 4-methoxy-2- morpholino-benzaldehyde analogously to Example 5, step 4.1H NMR (500MHz, CDCI3) 6 7.32 (d, J= 8.1Hz, 1H), 6.64-6.59 (m, 2H), 3.84 (t, J= 4.6Hz, 4H), 3.79 (s, 3H), 3.76-3.60 (m, 3H), 3.53-3.08 (m, 5H), 3.01 -2.91 (m, 2H), 2.91 -2.82 (m, 2H), 2.12-1.90 (m, 1H), 1.86-1.50 (m, 8H), 1.50- 1.35 (m, 1H), 1.35-1.20 (m, 2H), 1.18-0.95 (m, 2H). LC-MS (Method A): Rt 0.97 mins; MS m / z 432.9 [M+H]+.Step 2: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(4- methoxy-2-morpholino-phenyl)methyl]amino]-3-hydroxy-propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-hydroxy-2-[(4-methoxy-2-morpholino-phenyl)methylamino]propan-1-one (step 1) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3, step 3.1H NMR (400 MHz, CDCI3) δ 7.23 - 7.17 (m, 1H), 6.70-6.65 (m, 1H), 6.64-6.57 (m, 1H), 4.34-4.24 (m, 1H), 4.23-4.12 (m, 1H), 4.06-3.96 (m, 1H), 3.94-3.82 (m, 4H), 3.79 (s, 3H), 3.74-3.67 (m, 1H), 3.52 (br s, 1H), 3.37 (brs, 1H), 3.33-3.21 (m, 1H), 3.11 -2.91 (m, 3H), 2.88-2.73 (m, 3H), 2.47-2.32 (m, 1H), 2.23-2.10 (m, 1H), 1.81 - 1.65 (m, 4H), 1.50-1.36 (m, 4H), 1.34- 1.20 (m, 1H), 1.17-0.99 (m, 3H), 0.59-0.40 (m, 2H), 0.37- 0.27 (m, 1H), 0.26-0.14 (m, 1H). LC-MS (Method D): Rt2.33 mins; MS m / z 472.3 [M+H]+.Example 31(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1 : (2R)-2-(terM3utoxycarbonylamino)-3-[terf-butyl(diphenyl)silyl]oxy-propanoic acidA solution of / V-(terf-butoxycarbonyl)-D-serine (1.00 g, 4.87 mmol) in anhydrous DMF (5 mL) was treated with imidazole (863 mg, 12.7 mmol) followed by tert-butyl-chloro-diphenyl-silane (3.35 g, 12.2 mmol) and the reaction mixture was stirred at room temperature overnight. The resulting mixture was diluted with EtOAc (20 mL) and washed with water (3x10 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo. The resulting material was suspended in MeOH (10 mL) and water (5 mL), potassium carbonate (1.68 g,12.2 mmol) was added and the mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the aqueous portion was acidified to pH 3 with 10% citric acid. The mixture was extracted with DCM (3 x 50 mL) and the combined organic extracts were concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with a gradient of 10-100% MeCN (+ 0.1% formic acid) in water (+ 0.1 % formic acid) to afford the title compound.1H NMR (400 MHz, CDCI3) δ 7.68 - 7.57 (m, 4H), 7.49 - 7.32 (m, 6H), 5.36 (d, J = 8.3 Hz, 1 H), 4.50 - 4.33 (m, 1 H), 4.17 - 4.03 (m, 1 H), 3.90 (dd, J = 10.2, 3.6 Hz, 1 H), 1.46 (s, 9H), 1.04 (s, 9H). The carboxylic acid proton not observed. LC-MS (Method B): Rt 1.82 mins; MS m / z 442.3 [M-H]'.Step 2: terf-Butyl A / -[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-1- [[terf-butyl(diphenyl)silyl]oxymethyl]-2-oxo-ethyl]carbamateThe title compound was prepared from (2R)-2-(terf-butoxycarbonylamino)-3-[terf- butyl(diphenyl)silyl]oxy-propanoic acid (step 1) and (4aR,8aS)-1 ,2,3,4,4a,5,6,7,8,8a- decahydroquinoline (Example 5, step 1) analogously to Example 5, step 2.1H NMR (500 MHz, CDCI3) δ 7.70 - 7.60 (m, 4H), 7.48 - 7.33 (m, 6H), 5.41 (s, 1 H), 4.84 - 4.66 (m, 1 H), 3.78 - 3.68 (m, 2H), 3.51 - 3.34 (m, 1 H), 3.22 - 3.01 (m, 1 H), 2.25 - 2.10 (m, 1 H), 1.86 - 1.58 (m, 5H), 1.42 (s, 10H), 1.35 - 1.17 (m, 3H), 1.03 (s, 12H), 0.91 - 0.84 (m, 1 H). LC-MS (Method B): Rt 2.20 mins; MS m / z 565.4 [M+H]+.Step 3: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-amino-3-[terf- butyl(diphenyl)silyl]oxy-propan-1-oneThe title compound was prepared from tert-butyl / \ / -[(1 R)-2-[(4aR,8aS)-3,4,4a,5,6,7,8,8a- octahydro-2H-quinolin-1-yl]-1-[[te / t-butyl(diphenyl)silyl]oxymethyl]-2-oxo-ethyl]carbamate (step 2) and 4M HCI in 1 ,4-dioxane analogously to Example 5, step 3.1H NMR (400 MHz, CDCI3) δ 7.74 - 7.61 (m, 4H), 7.49 - 7.31 (m, 6H), 3.80 - 3.53 (m, 3H), 3.44 - 3.26 (m, 1 H), 3.05 - 2.87 (m, 1 H), 2.16 - 2.05 (m, 1 H), 1.86 - 1.63 (m, 6H), 1.62 - 1.29 (m, 4H), 1.22 - 0.90 (m, 12H). LC-MS (Method B): Rt 1.30 mins; MS m / z 465.9 [M+H]+.Step 4: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[te / t- butyl(diphenyl)silyl]oxy-2-[(2,4-dimethoxyphenyl)methylamino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-2-amino-3-[te / t-butyl(diphenyl)silyl]oxy-propan-1-one (step 3) and 2,4- dimethoxybenzaldehyde analogously to Example 5, step 4.1H NMR (500MHz, CDCI3) δ 7.68 - 7.56 (m, 4H), 7.47 - 7.29 (m, 6H), 7.15 (d, J = 7.9 Hz, 1 H), 6.43 - 6.35 (m, 2H), 3.84 - 3.73 (m, 7H), 3.73 - 3.47 (m, 6H), 3.15 - 2.96 (m, 1 H), 2.30 - 2.09 (m, 1 H), 1.77 - 1.44 (m, 10H), 1.32 - 1.16 (m, 2H), 1.08 - 1.01 (m, 10H). LC-MS (Method B): Rt 1.52 mins; MS m / z 615.5 [M+H]+.Step 5: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-3-[te / t- butyl(diphenyl)silyl]oxy-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-oneThe title compound was prepared from (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H- quinolin-1-yl]-3-[te / t-butyl(diphenyl)silyl]oxy-2-[(2,4-dimethoxyphenyl)methylamino]propan-1- one (step 4) and cyclopropylboronic acid analogously to Example 5, step 5.1H NMR (500MHz, CDCI3) δ 7.74-7.63 (m, 4H), 7.48-7.32 (m, 6H), 7.15-7.09 (m, 1H), 6.45-6.31 (m, 2H), 4.33-4.23 (m, 1H), 4.20-4.10 (m, 1H), 4.09-3.94 (m, 3H), 3.80 (s, 3H), 3.67 (s, 3H), 3.42-3.32 (m, 1H), 3.31 -3.15 (m, 1H), 2.93-2.82 (m, 2H), 2.37-2.28 (m, 1H), 2.22 -2.14 (m, 1H), 1.75-1.59 (m, 3H), 1.55-1.38 (m, 4H), 1.29-1.19 (m, 1H), 1.14-0.95 (m, 12H), 0.41 - 0.20 (m, 4H). LC-MS (Method B): Rt 1.75 mins; MS m / z 655.6 [M+H]+.Step 6: (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneA solution of (2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-3-[terf- butyl(diphenyl)silyl]oxy-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]propan-1-one (step 5) (78 mg, 0.120 mmol) in THF (2 mL) was treated with 1 M tetrabutylammonium fluoride in THF (144 μL, 0.144 mmol) and the reaction mixture was stirred at room temperature for 3 h. Additional 1 M tetrabutylammonium fluoride in THF (287 μL, 0.287 mmol) was added and stirring continued at room temperature overnight. The reaction was quenched with saturated aqueous ammonium chloride solution and the resulting mixture was extracted with EtOAc (3x10 mL). The combined organic extracts were dried over Na2SC>4 and concentrated in vacuo. The crude material was purified by preparative HPLC (Method 2) to yield the title compound as a white solid.1H NMR (500 MHz, CDCI3) δ 7.09 (d, J = 8.2 Hz, 1H), 6.43-6.37 (m, 2H), 4.23-4.09 (m, 1H), 4.05-3.90 (m, 2H), 3.85-3.79 (m, 4H), 3.78 (s, 3H), 3.61-3.51 (m, 1H), 3.37 - 3.12 (m, 2H), 2.92 - 2.81 (m, 1H), 2.27 - 2.20 (m, 1H), 2.20-2.12 (m, 1H), 1.76-1.65 (m, 4H), 1.49-1.36 (m, 3H), 1.30-1.21 (m, 2H), 1.15- 0.73 (m, 4H), 0.46 - 0.32 (m, 2H), 0.32 - 0.08 (m, 2H). LC-MS (Method G): Rt 4.30 mins; MS m / z 417.5 [M+H]+.Example 32(2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneStep 1a: Ethyl 3-(2-oxocyclohexyl)propanoateTo a flask fitted with a Dean-Stark apparatus was added cyclohexanone (8.0 mL, 77.3 mmol), pyrrolidine (10 mL, 0.116 mol) and anhydrous toluene (120 mL). The mixture was heated at reflux for 4 h, allowed to cool to room temperature and concentrated in vacuo to afford the intermediate Stork-enamine as a brown clear oil. The oil was redissolved in THF (100 mL) and ethyl prop-2-enoate (8.2 mL, 77.3 mmol) was added. The mixture was heated at reflux for 5 h, water (10 mL) was added and the mixture was heated at reflux for a further 1 h. The resulting mixture was concentrated in vacuo and the residue taken up in diethyl ether (100 mL). The mixture was washed with 1 M aqueous HCI (70 mL), brine (50 mL) dried overMgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0-55% EtOAc in heptane afforded the title compound as a pale yellow oil.1H NMR (400 MHz, CDCI3) δ 4.11 (q, J = 7.1 Hz, 2H), 2.43 - 2.23 (m, 5H), 2.15 - 1.99 (m, 3H), 1.90 - 1.82 (m, 1 H), 1.73 - 1.47 (m, 3H), 1.45 - 1.33 (m, 1 H), 1.24 (t, J = 7.1 Hz, 3H). LC-MS (Method E): Rt 1.51 mins; MS m / z 199.3 [M+H]+.Step 1 b: 3-(2-Oxocyclohexyl) propanoic acidEthyl 3-(2-oxocyclohexyl)propanoate (step 1a) (100%, 6.20 g, 31.3 mmol) in EtOH (65 mL) was treated with 1M NaOH (63 mL, 62.5 mmol) and the solution was heated at reflux for 2 h. The resulting mixture was allowed to cool to room temperature and concentration in vacuo to a volume of ~30 mL. The mixture was acidified with 6M HCI and extracted with diethyl ether (3 x 40 mL). The combined organic extracts were washed with brine (30 mL), dried over MgSC>4 and concentrated in vacuo to afford the title compound.1H NMR (400 MHz, CDCI3) 62.56 - 2.23 (m, 5H), 2.16 - 2.01 (m, 3H), 1.92 - 1.82 (m, 1H), 1.75 - 1.61 (m, 2H), 1.61 - 1.50 (m, 1 H), 1.46 - 1.34 (m, 1 H). The carboxylic acid proton not observed. LC-MS (Method E): Rt 0.29 mins; MS m / z 169.4 [M-H]’.Step 1c: (3S,7aS,11aR)-3-Phenyl-3,6,7,7a,8,9,10,11-octahydro-2H-oxazolo[2,3-j]quinolin-5- oneA solution of 3-(2-oxocyclohexyl)propanoic acid (step 1b) (5.0 g, 29.4 mmol) and (2S)-2- amino-2-phenylethanol (6.05 g, 44.1 mmol) in toluene (60 mL) and molecular sieves was heated at reflux using Dean-Stark apparatus for 24 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was taken up in EtOAc (100 mL) and washed with water (50 mL). The aqueous wash was further extracted with EtOAc (2 x 50 mL) and the combined organic extracts were washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% TBME in heptane afforded the title compound as a pale-yellow oil.1H NMR (400 MHz, CDCI3) δ 7.34 - 7.28 (m, 2H), 7.25 - 7.16 (m, 3H), 5.34 (t, J = 8.3 Hz, 1 H), 4.50 (t, J = 8.8 Hz, 1H), 3.87 (dd, J = 8.7, 8.1 Hz, 1H), 2.66 (dd, J = 18.4, 7.2 Hz, 1H), 2.54 - 2.42 (m, 1 H), 2.20 - 2.06 (m, 1 H), 2.01 - 1.90 (m, 1H), 1.89 - 1.79 (m, 2H), 1.74 - 1.36 (m, 7H). LC-MS (Method A): Rt 1.18 mins; MS m / z 272.1 [M+H]+.Step 1d: (2S)-2-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-phenyl-ethanolA cooled (-78 °C) solution of (3S,7aS,11aR)-3-phenyl-3,6,7,7a,8,9,10,11-octahydro-2H- oxazolo[2,3-j]quinolin-5-one (step 1c) (4.41 g, 16.3 mmol) in anhydrous THF (200 mL) was treated with 2.4M lithium aluminium hydride in THF (47 mL, 0.114 mol) whilst stirring vigorously. After 10 mins, aluminium trichloride (4.33 g, 32.5 mmol) was added very slowly and the mixture stirred for 2 h and allowed to warm to 0 °C over the last 15 mins. Theresulting mixture was diluted with water (4.5 mL) at 0 °C followed by 15% aqueous NaOH (4.5 mL) and stirred for 5 mins. Further water (13.5 mL) was added and stirring continued for 15 mins. MgSO4 was added and stirring continued for 15 mins. The resulting mixture was filtered and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% TBME in heptane afforded the title compound as a colourless oil.1H NMR (500 MHz, CDCI3) δ 7.26 (s, 5H), 4.15 (br s, 1 H), 4.00 - 3.92 (m, 1H), 3.73 - 3.59 (m, 1 H), 2.94 - 2.81 (m, 1H), 2.59 - 2.49 (m, 1 H), 2.45 - 2.22 (m, 1H), 2.11 -1.79 (m, 2H), 1.79 - 1.46 (m, 5H), 1.46 - 1.16 (m, 7H). LC-MS (Method A): Rt 0.86 mins; MS m / z 260.2 [M+H]+.Step 1e: (4aS,8aS)-1 ,2,3,4,4a,5,6,7,8,8a-Decahydroquinoline hydrochloride1.25M HCI in EtOH (7.7 mL, 9.64 mmol) was added to a solution of (2S)-2-[(4aS,8aS)- 3,4,4a,5,6,7,8,8a-octahydro-2H-quinolin-1-yl]-2-phenyl-ethanol (step 1d) (2.50 g, 9.64 mmol) in EtOH (125 mL). 10% palladium on carbon (250 mg) was added and the reaction stirred under an atmosphere of hydrogen for 22 h. The resulting mixture was filtered through Celite® and concentrated in vacuo. The residue was redissolved in EtOH (125 mL) and 10% palladium on carbon (250 mg) was added. The mixture was placed under an atmosphere of hydrogen and stirred at room temperature for 15 h. The resulting mixture was filtered through Celite® and concentrated in vacuo. The residue was taken up in heptane (50 mL), filtered and washed with heptane (25 mL) to afford the title compound as a white solid.1H NMR (500 MHz, MeOD) δ 3.46 - 3.38 (m, 1 H), 3.29 - 3.19 (m, 1H), 3.08 - 2.98 (m, 1H), 2.05 - 1.82 (m, 3H), 1.82 - 1.49 (m, 9H), 1.49 - 1.36 (m, 1 H). LC-MS (Method E): Rt 1.56 mins; MS m / z 140.3 [M+H]+.Step 2a: Methyl (2R)-2-[(2,4-dimethoxyphenyl)methylamino]-3-hydroxy-propanoateTriethylamine (7.4 mL, 53.0 mmol) and (2M.3g2SO g,419.3 mmol) in DCM (20 mL) were treated with sodium borohydride (0.44 g, 11.6 mmol) and 2,4-dimethoxybenzaldehyde (1.6 g, 9.64 mmol). The reaction mixture was stirred at room temperature overnight. The resulting mixture was filtered and concentrated in vacuo. The residue was suspended in MeOH (20 mL) and cooled to 0 °C and treated portion-wise with D-serine methyl ester hydrochloride (1:1) (1.50 g, 9.64 mmol). After stirring at 0 °C for 1 h, water (30 mL) was added and the mixture was extracted with EtOAc (3 x 50 mL). The combined organic extracts were washed with brine, dried over MgS anOd4 concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0-100% TBME in heptane followed by 0-10% MeOH in TBME to afford the title compound as a yellow oil.1H NMR (500 MHz, CDCI3) δ 7.10 (d, J = 8.1 Hz, 1 H), 6.46 - 6.39 (m, 2H), 3.82 (s, 3H), 3.80 (s, 3H), 3.78 - 3.69 (m, 3H), 3.67 (s, 3H), 3.59 (dd, J = 10.7, 6.3 Hz, 1H), 3.42 - 3.38 (m, 1 H). The NH and OH protons were not observed. LC-MS (Method A): Rt 0.76 mins; MS m / z 270.1 [M+H]+.Step 2b: Methyl (2R)-2-[cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-hydroxy- propanoateThe title compound was prepared from methyl (2R)-2-[(2,4-dimethoxyphenyl)methylamino]- 3-hydroxy-propanoate (step 2a) and [(1-ethoxycyclopropyl)oxy](trimethyl)silane analogously to Example 3 step 3.1H NMR (500 MHz, CDCI3) δ 7.12 - 7.08 (m, 1 H), 6.43 - 6.39 (m, 2H), 4.00 (d, J = 12.8 Hz, 1 H), 3.80 (s, 3H), 3.78 (s, 3H), 3.78 - 3.74 (m, 4H), 3.73 - 3.64 (m, 3H), 3.13 - 3.02 (m, 1H), 2.34 - 2.26 (m, 1 H), 0.40 - 0.30 (m, 2H), 0.24 - 0.18 (m, 1 H), 0.08 - 0.02 (m, 1 H). LC-MS (Method A): Rt 0.90 mins; MS m / z 310.1 [M+H]+.Step 2c: 2-[Cyclopropyl-[(2,4-dimethoxyphenyl)methyl]amino]-3-hydroxy-propanoic acid x LV ”'" ^OHXCH3The title compound was prepared from methyl (2R)-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propanoate (step 2b) and lithium hydroxide monohydrate analogously to Example 1, step 4.1H NMR (400 MHz, CDCI3) δ 7.45 - 7.37 (m, 1 H), 6.55 - 6.49 (m, 1 H), 6.49 - 6.43 (m, 1 H), 4.86 - 4.75 (m, 1 H), 4.73 - 4.56 (m, 1 H), 4.45 - 4.23 (m, 2H), 4.23 - 4.13 (m, 1H), 3.88 (s, 3H), 3.81 (s, 3H), 3.14 (s, 1H), 1.34 - 1.14 (m, 2H), 0.98 - 0.76 (m, 2H). The carboxylic acid and OH protons not observed. LC-MS (Method A): Rt 0.84 mins; MS m / z 296.1 [M+H]+.Step 3: (2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-oneHATLI (309 mg, 0.813 mmol) was added to a solution of 2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propanoic acid (step 2c) (200 mg, 0.677 mmol) in DCM (6 mL) and stirred at room temperature for 5 mins. To this mixture was added DI PEA (0.41 mL, 2.37 mmol) and (4aS,8aS)-1,2,3,4,4a,5,6,7,8,8a-decahydroquinoline hydrochloride (step 1e) (125 mg, 0.711 mmol) and stirring continued at room temperature for 2 h. The resulting mixture was diluted with water (10 mL) and extracted with EtOAc (3 x 15 mL). The combined organic extracts were washed with brine (10 mL), dried over MgSO4 and concentrated in vacuo. Purification by chromatography on silica eluting with a gradient of 0- 100% TBME in heptane followed by further purification by C18 reverse phase chromatography eluting with 10-100% MeCN (+ 0.1% ammonia) in water (+ 0.1% ammonia) afforded a mixture of diastereomers. Chiral separation of the mixture under the following conditions afforded the title compound as a white powder:Chiral separation conditions:Column: X-Bridge 100 x 30 mm, 5 pmMobile phase: 5-95% MeCN / water (+0.2% ammonium hydroxide)Flow rate: 40 mL / minChiral Analysis Conditions:Column: Chiralpak AD-H 4.6 x 250 mm, 5 pmMobile phase: 10% MeOH + 0.2% DEA: 90% CO2Flow rate: 4 mL / minUV at 230 nmRuntime: 10 minsChiral LC Rt = 6.50 mins1H NMR (400 MHz, DMSO-d6) δ 7.14 (d, J = 8.2 Hz, 1 H), 6.50 (d, J = 2.4 Hz, 1 H), 6.45 (dd, J = 8.3, 2.4 Hz, 1 H), 4.51 - 4.34 (m, 1 H), 4.00 - 3.67 (m, 11 H), 3.62 - 3.43 (m, 2H), 2.72 - 2.60 (m, 1 H), 2.20 (s, 1 H), 1.79 - 1.60 (m, 4H), 1.57 - 1.46 (m, 2H), 1.41 - 1.18 (m, 6H), 0.39 - 0.12 (m, 4H). OH proton not observed. LC-MS (Method G): Rt 4.28 mins; MS m / z 417.4 [M+H]+.Biological Assay 1

[0232] A primer extension assay was used to measure the ability of compounds to inhibit the activity of PolQ in vitro. Experiments were performed using a truncated PolQ protein containing the polymerase domain (1792-2590), dNTPs and a DNA duplex substrate (5'- CACTGACTGTATGATG-3', 5 -CTCGTCAGCATCTTCATCATACAGTCAGTG-3', annealing ratio: 1 :1) in the PolQ assay buffer (10mM Tris-HCI (pH=7.8), NaCI 50 mM, MgCh 10 mM, Tween200.01%, DTT 1 mM). 5 μL of PolQ (8 nM) in assay buffer was transfer into assay ready plates, containing 10 nL of compounds diluted in DMSO. After a 10 minutes incubation at 23°C, the reaction was triggered by adding 5 μL of dNTP (20 pM) and DNA (100 nM) in assay buffer. The plates were then incubated at 23°C, and the reaction was terminated after 30 min by addition of 5 μL of stop buffer (5 mM Tris-HCI (pH 7.8), EDTA 5 mM, Tween20 0.005%, 0.075 μL of Quant-iT PicoGreen). Fluorescence was measured after 20 min, using PHERAstar FSX plate reader (excitation / emission - 485 / 520 nM).

[0233] Fluorescence data were normalised independently for each replicate, to obtain a percentage of inhibition value (% Inhibition = ((High control-sample) / (high Control-low control)). The geometric mean of technical replicates was used to evaluate the potency of compounds, according to the 4 parameters Hill equation (Prinz et al 2010). Reported IC50 are the geometric mean of at least two independent experiments.ReferencePrinz et al. Hill coefficients, dose-response curves and allosteric mechanisms, J Chem Biol.2010 Mar; 3(1): 37-44

[0234] The results are shown in Table A below.Table A - POLQ Primer extension assay IC50 results

Claims

CLAIMS1. A compound of formula I, or a pharmaceutically acceptable salt or solvate thereof:wherein: R1 and R2 are each independently selected from hydrogen, fluoro or methyl;R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, (1-4C)alkoxy, phenyl, (3-6C)cycloalkyl, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl, wherein a phenyl, (3-6C)cycloalkyl, heterocyclyl ring, or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino;Xi is NR3c, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)p- (where p is 0, 1 or 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl,-[CH2]o-[(3-6C)cycloalkyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino;R4 is selected from hydrogen, F, Cl, (1-3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl optionally substituted by halo or hydroxy or R4aand R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; or R4 is a group-X2-L2-X3-R4C wherein:X2is absent, -O- or -NH-; l_2is (1-4C)alkylene;X3is NR4d, -NR4d-C(O)-, -C(O)-NR4d-, -NR4d-O-C(O)-, -NR4dS(O)P- or-S(O)P- (where p is 0, 1 or 2), where R4dis hydrogen or (1 -2C)alkyl ; andR4C is hydrogen or (1 -6C)alkyl;Ai is N or CRs wherein Rs is selected from hydrogen, F, Cl, (1-3C)alkyl or (1-3C)alkoxy; andRe is selected from hydrogen, F, Cl, (1 -3C)alkyl or (1-3C)alkoxy.

2. A compound according to claim 1 , wherein the compound is a compound of the formula la, lb, Ic, Id, le, If or Ig shown below:ig wherein R1, R2, R3, R4, A1 and Re are each as defined in claim 1.

3. A compound according to claim 1 or claim 2, wherein R1 and R2 are independently selected from hydrogen or fluoro.

4. A compound according to any one of claims 1 to 3, wherein R1 and R2 are both hydrogen.

5. A compound according to any one of the preceding claims, wherein R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl, wherein a heterocyclyl ring or heteroaryl ring is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1- 2C)haloalkoxy, (1-2C)hydroxyalkyl or amino;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)p- (where p is 0, 1 or 2);R3bis selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], (3- 6C)cycloalkyl,-[CH2]o-[(3-6C)cycloalkyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; and and a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl group is optionally substituted by halo, cyano, hydroxy, (1 -2C)alkyl, (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

6. A compound according to any one of the preceding claims, wherein R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 0, 1 , 2, 3, 4 or 5;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3bis selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein:o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3cis hydrogen or (1 -4C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

7. A compound according to any one of the preceding claims, wherein R3 is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);Rsb is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy; and and a phenyl, 5 or 6-membered heteroaryl, or 4 to 8- membered heterocyclyl group is optionally substituted by halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy;R3cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

8. A compound according to any one of the preceding claims, wherein R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xl-R3b wherein: n is 0, 1 , 2, 3 or 4;R3ais hydrogen, cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6- membered heteroaryl;Xi is NR3C, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3Cis hydrogen or (1 -6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

9. A compound according to any one of the preceding claims, wherein R3is a group of the formula:-[CH2]n-R3aor-[CH2]n-Xi-R3bwherein: n is 0, 1 , 2, 3 or 4;R3ais cyano, OH, a 4 to 6 membered heterocyclyl ring, 5 or 6-membered heteroaryl;Xi is NR3c, -NR3C-C(O)-, -C(O)-NR3C-, -NR3CS(O)P- or -S(O)P- (where p is 2);R3b is selected from hydrogen, (1 -6C)alkyl, phenyl, -[CH2]0-[phenyl], 5 or 6- membered heteroaryl, -[CH2]0-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]0-[4 to 8 -membered heterocyclyl], and wherein: o is 1 or 2; a (1-6C)alkyl group is optionally substituted by halo, cyano, hydroxy, or (1-2C)alkoxy;R3Cis hydrogen or (1-6C)alkyl optionally substituted by halo, hydroxy or (1- 2C)alkoxy.

10. A compound according to any one of claims 1 to 8, wherein R3is not hydrogen.

11. A compound according to any one of the preceding claims, wherein R4 is selected from hydrogen, F, Cl, (1 -3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl orR4aand R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl; or R4 is a group-X2- L2-X3- R4Cwherein:X2 is absent, -O- or -NH-;L2 is (1-4C)alkylene;X3is NR4d, -NR4d-C(O)-, -C(O)-NR4d-, -NR4d-O-C(O)-, -NR4dS(O)P- or-S(O)P- (where p is 0, 1 or 2), where R4dis hydrogen or (1 -2C)alkyl ; andR4C is hydrogen or (1 -6C)alkyl.

12. A compound according to any one of the preceding claims, wherein R4 is selected from hydrogen, F, Cl, (1 -3C)alkyl, (1-3C)alkoxy or NR4aR4b, wherein R4aand R4b are selected from hydrogen, (1 -4C)alkyl orR4aand R4b are linked such that, together with the N atom to which they are attached, they form a 4 to 8 membered heterocyclic ring which is optionally substituted by halo, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl.

13. A compound according to any one of the preceding claims, wherein R4 is selected from hydrogen, F, Cl, (1-2C)alkyl or (1-2C)alkoxy.

14. A compound according to any one of the preceding claims, wherein R4 is selected from hydrogen, F, Cl, methoxy, methyl or ethyl.

15. A compound according to any one of the preceding claims, wherein A1 is N or CR5, wherein Rs is selected from hydrogen, F, Cl, (1-3C)alkyl or (1-3C)alkoxy.

16. A compound according to any one of the preceding claims, wherein A1 is N or CR5, wherein Rs is hydrogen.

17. A compound according to any one of the preceding claims, wherein Re is selected from hydrogen, F, Cl, (1-2C)alkyl or (1-2C)alkoxy.

18. A compound according to any one of the preceding claims, wherein Re is selected from hydrogen, F, Cl, methyl or methoxy.

19. A compound of formula I according to any one of the preceding claims, or a pharmaceutically acceptable salt or solvate thereof, wherein the compound is selected from one or more of the following:(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-(azetidin-3-yl)-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}ethan-1-one;1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-(azetidin-3-yl)-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}ethan-1-one;(2S)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-methanesulfonylpropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(dimethylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(1H-imidazol-5-yl)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-hydroxybutan-1-one;(3R)-4-[(4aR,8aS)-decahydroquinolin-1-yl]-3-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-oxobutanenitrile;(3R)-4-[(4aR,8aS)-decahydroquinolin-1-yl]-3-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-oxobutanamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-5-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}pentan-1-one;(2R)-1-[(4aRS,8aSR)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;N-[(2R)-3-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-oxopropyl]oxetane-3-carboxamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-[bis(2-hydroxyethyl)amino]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(oxetan-3-yl)amino]propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(2,2-difluoroethyl)amino]propan-1-one;N-[(2R)-3-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-oxopropyl]methanesulfonamide;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-({2-oxaspiro[3.3]heptan-6-yl}amino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-[(2-hydroxyethyl)amino]propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-4-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-[(2,2-difluoroethyl)amino]butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-(dimethylamino)butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-4-(methylamino)butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-6-amino-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}hexan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-amino-2-{[(4- chlorophenyl)methyl](cyclopropyl)amino}propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-4-amino-2-{[(4- chlorophenyl)methyl](cyclopropyl)amino}butan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4-ethylphenyl)methyl]amino}-3- (methylamino)propan-l-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4-difluorophenyl)methyl]amino}- 3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4-methoxyphenyl)methyl]amino}- 3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-[benzyl(methyl)amino]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}propan-1-one;(2R)-1-[(4aS,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,4- dimethoxyphenyl)methyl]amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2-methylphenyl)methyl]amino}-3- (methylamino)propan-l-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{[(4- cyclopropoxyphenyl)methyl](cyclopropyl)amino}-3-(methylamino)propan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2,6-dimethoxypyridin-3- yl)methyl]amino}-3-hydroxypropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(4-methoxyphenyl)methyl]amino}- 3-hydroxypropan-1-one;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-{cyclopropyl[(2-fluoro-4- methoxyphenyl)methyl]amino}-3-hydroxypropan-1-one; tert-butyl N-{2-[2-({[(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-3-hydroxy-1-oxopropan-2- yl](cyclopropyl)amino}methyl)-5-methoxyphenoxy]ethyl}carbamate;(2R)-1-[(4aR,8aS)-decahydroquinolin-1-yl]-2-[cyclopropyl({[4-methoxy-2-(morpholin-4- yl)phenyl]methyl})amino]-3-hydroxypropan-1-one;(2R)-1-[(4aR,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-one; or(2R)-1-[(4aS,8aS)-3,4,4a,5,6,7,8,8a-Octahydro-2H-quinolin-1-yl]-2-[cyclopropyl-[(2,4- dimethoxyphenyl)methyl]amino]-3-hydroxy-propan-1-one;.

20. A pharmaceutical composition comprising a compound as defined in any preceding claim, or a pharmaceutically acceptable salt, hydrate or solvate thereof, in admixture with a pharmaceutically acceptable diluent or carrier.

21. A compound, or a pharmaceutically acceptable salt, hydrate or solvate thereof, as defined in any one of claims 1 to 19, or a pharmaceutical composition as defined in claim 20:(i) for use in therapy;(ii) for use in the treatment of a proliferative disorder;(iii) for use in the treatment of cancer;(iv) for use in the treatment of DNA repair deficient cancer;(v) the treatment of a homologous recombination (HR) deficient cancer;(vi) the treatment of cancer characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, or a reduced function of BRCA protein; and / or(vii)the treatment of lymphoma, prostate cancer, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer.

22. A method of:(i) treating a disease characterized by overexpression of PolQ;(ii) treating cancer(iii) treating DNA repair deficient cancer;(iv) treating a homologous recombination (HR) deficient cancer;(v) treating cancer characterized by a reduction or absence of BRCA gene expression, the absence of the BRCA gene, or a reduced function of BRCA protein; and / or(vi) treating lymphoma, prostate cancer, rhabdoid tumor, multiple myeloma, uterine cancer, gastric cancer, peripheral nervous system cancer, rhabdomyosarcoma, bone cancer, colorectal cancer, mesothelioma, breast cancer, ovarian cancer, lung cancer, fibroblast cancer, central nervous system cancer, urinary tract cancer, upper aerodigestive cancer, leukemia, kidney cancer, skin cancer, esophageal cancer, and pancreatic cancer; the method comprising administered to patient in need of such treatment a therapeutically effective amount of a compound according to any one of claims 1 to 19, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 20.

Images