Phenylpyrrolidine derivatives and their use as poi-theta derivatives

Abstract

The present invention relates to compounds of the Formula I, II or III and pharmaceutically salts thereof: wherein R1A, R1B, R1C, R1D, R1E, A1, R2, R3, R3A, R4, RN, X and Q 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.

Description

NOVEL COMPOUNDS, COMPOSITIONS AND THERAPEUTIC USES THEREOF INTRODUCTION

[0001] The present invention relates to novel therapeutic compounds. More specifically, the present invention relates to novel therapeutic compounds that 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. 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 MMEJ 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 Polθ 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 Polθ4,16.

[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 Polθ 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. Polθ 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 Polθ inhibition25,26.

[0008] In addition to the synthetic lethality observed in HR and NHEJ deficient cancer, Polθ loss has been reported to sensitise cancer cells to many standard of care agents. Depletion of Polθ leads to potentiation of various chemotherapies, such as topo-isomerase1 / 2 inhibitors27hydroxyurea, platinum agents28, bleomycin, as well as irradiation29,30. Furthermore, loss of Polθ 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, Polθ 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 Polθ and inhibiting its activity. The present invention was devised with the foregoing in mind. References 1. Helleday T., et al, Nat Rev Genet. (2014); 15:585–98 2. Ceccaldi R., et al, Trends Cell Biol. (2016); 26:52–64 3. Seki M. et al., Nucleic Acids Res., (2003); 31:6117-26 4. Ceccaldi R., et al., Nature (2015); 518:258-62 5. Lemée F., et al,. PNAS (2010); 107:13390-5 6. Higgins G.S., et al., Oncotarget (2010) ; 1:175-84 7. Kabotyanski E.B., et al, Nucleic Acids Res. (1998); 26:5333-42 8. Ahrabi S., et al, Nucleic Acids Res. (2016); 44:5743-57 9. McVey M., et al., Trends Genet. (2008); 24:529–38 10. Sfeir A., et al, Biochem Sci. (2015); 40:701–14) 11. Chan S.H., et al., PLoS Genet. (2010); 6:e1001005 12. Wyatt D.W., et al, Mol Cell. (2016); 63:662-673 13. Black S.J., et al., Nat Commun. (2019); 10:4423 14. Audeh M.W., et al., Lancet (2010); 376 (9737):245-51 15. Truong W., et al., PNAS (2013); 110:7720-7725 16. Mateos-Gomez P.A., et al., Nature (2015); 518:254-57 17. Noordermeer S.M., et al., Trends Cell Biol. (2019); 29:820-834 18. Edwards S.L., et al., Nature (2008); 451(7182):1111-5 19. Lukashchuk N., et al., J Clin Oncol (2022) 40(16_suppl):5559-5559) 20. Jaspers J.E., et al., Cancer Discov. (2013); 3(1):68 21. Pettitt S.J., et al., Nat Commun. (2018); 9:1849; 22 Noordermeer S.M., et al., Nature (2018) 560:117 23. Nacson J., et al, Cell Rep. (2018); 25(5):1384) 24. Higgins G., et al, Science (2018); 359(6381):1217-1218 25. Zatreanu D., et al, Nat Commun. (2021); 12(1):3636 26. Feng W., et al, Nat Commun. (2019); 10(1):4286 27. Wang ZI et al., J Biol Chem.2019 Mar 15; 294(11): 3909–3919 28. Dai CH et al., Oncotarget.2016; 7(40):65157-65170 29. Yousefzadeh MJ et al., PLoS Genet.2014 Oct 2;10(10):e1004654 30. Higgins G et al. Cancer Res.2010 Apr 1;70(7):2984-93 31. Schrempf et al., Trends Cancer.2021;7(2):98-111 32. Kumar RJ et al., NAR Cancer.2020 Dec; 2(4): zcaa038 SUMMARY 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 Polθ 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 Polθ.

[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 Polθ 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 Polθ.

[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 Polθ 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 Polθ, 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 INVENTION Definitions

[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 “Polθ” 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 t-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-2H-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 SO2groups 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 (=O) 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-, 1H-pyrazolo[4,3-d]-oxazolyl, 4H-imidazo[4,5d]thiazolyl, pyrazino[2,3d]pyridazinyl, -imidazo[2,1b]thiazolyl, -imidazo[1,2b][1,2,4]-triazinyl. “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-2H-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 of formula I, II or III, or a pharmaceutically acceptable salt or solvate thereof:I IIIII wherein: A1 is CH or N; R1A is selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1B is selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1C is selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Dis selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Eis selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; or R1Aand R1Bor R1Band R1Care linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 or 6 membered cycloalkyl or 4 to 7 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from deuterium, 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, and wherein a 5 or 6 membered cycloalkyl or 4 to 7 membered heterocyclyl ring is optionally further substituted by oxo; R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G): -L1-X1-R2A(A) -L2-X2-L1-X1-R2A(B) -L3-X3-L2-X2-L1-X1-R2A(C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A(D) -L5-X5-L4-X4-L3-X3-L2-X2-L1-X1-R2A(E) -[OCH2CH2]n1-R2A(F) -[CH2CH2O]n1-R2A(G) wherein: n1 is 1 to 10; each of L1, L2, L3, L4or L5are either absent or a linear or branched (1- 4C)alkylene; X1is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -NR2C-C(O)-NR2B-, -O-C(O)NR2B-, -NR2B-C(O)O-, - NR2BSO2-, -SO2NR2B- or -S(O)p- (where p is 0, 1 or 2), where R2B and R2C are each independently hydrogen or (1-2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -NR2E-C(O)-NR2D-, -O-C(O)NR2D-, -NR2D-C(O)O-, - NR2DSO2-, -SO2NR2D- or -S(O)p- (where p is 0, 1 or 2), where R2D and R2E are each independently hydrogen or (1-2C)alkyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -NR2G-C(O)-NR2F-, -O-C(O)NR2F-, -NR2F-C(O)O-, - NR2FSO2-, -SO2NR2F- or -S(O)p- (where p is 0, 1 or 2), where R2F and R2G are each independently hydrogen or (1-2C)alkyl; X4 is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -NR2J-C(O)-NR2H-, -O-C(O)NR2H-, -NR2H-C(O)O-, -NR2HSO2-, -SO2NR2H- or -S(O)p- (where p is 0, 1 or 2), where R2Hand R2Jare each independently hydrogen or (1-2C)alkyl; X5 is absent or selected from -O-, -NR2K-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2K-, -NR2KC(O)-, -NR2L-C(O)-NR2K-, -O-C(O)NR2K-, -NR2K-C(O)O-, - NR2KSO2-, -SO2NR2K- or -S(O)p- (where p is 0, 1 or 2), where R2Kand R2Lare each independently hydrogen or (1-2C)alkyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0- 2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2N-, -NR2NC(O)-, -O-C(O)NR2N-, -NR2N-C(O)O-, -NR2NSO2-, -SO2NR2N- or -S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1- 2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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. R3is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G) defined above; R3Ais selected from hydrogen or halo; or R3and R3Atogether form an oxo group; or R2and R3are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from 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 a group of the formula (A) to (G) defined above; R4 is hydrogen, cyano or halo; X is selected from: -CHR5-; -CHR5-CH2-; -NR100-, where R100 is hydrogen or (1-3C)alkyl; -CH2-XA-, where XA is -O- or -NR101-, where R101 is hydrogen or (1-3C)alkyl; R5 is hydrogen, methyl, hydroxymethyl, or methoxymethyl; Q is selected from:wherein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one to three of A2, A3,A4, A5and A6are N; R6is selected from hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2- phenyl, 5 or 6-membered heteroaryl, -[CH2]o2-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o2-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o2- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o2-[(3-6C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;R7is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o3-phenyl, -O-phenyl, -O-[CH2]o3- phenyl, 5 or 6-membered heteroaryl, -[CH2]o3-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o3-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o3- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o3-[(3-6C)cycloalkyl], wherein: o3 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o4- phenyl, 5 or 6-membered heteroaryl, -[CH2]o4-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o4-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o4- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o4-[(3-6C)cycloalkyl], wherein: o4 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R9 is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o6- phenyl, 5 or 6-membered heteroaryl, -[CH2]o6-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o6-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o6- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o6-[(3-6C)cycloalkyl], wherein: o6 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R6 and R7, R7 and R8 or R8 or R9 are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 to 7-membered heterocyclyl, 5or 6-membered heteroaryl, or (5-8C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]o5-(3- 6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; and RNis hydrogen, methyl, hydroxymethyl, or methoxymethyl.

[0069] Particular compounds of formula I have any one of sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII shown below, or a pharmaceutically acceptable salt or solvate thereof:VI VIIX XIXII wherein A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RN are as defined herein.

[0070] Particular compounds of the invention include, for example, compounds of the formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), or pharmaceutically acceptable salts, hydrates and / or solvates thereof, wherein, unless otherwise stated, each of A1, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X and Q each have any of the meanings defined hereinbefore, or are as defined in any one of paragraphs (1) to (113) hereinafter:- (1) A1 is CH; (2) A1 is N; (3) R1A is selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1-2C)haloalkoxy; (4) R1Ais selected from fluoro, chloro, hydroxy, cyano, methyl, CH2F, CHF2, CF3, methoxy, -OCH2F, -OCHF2, -OCF3, -OCH2D, -OCHD2or -OCD3; (5) R1Ais selected from fluoro, chloro, hydroxy, cyano, methyl, CHF2, CF3, methoxy, -OCHF2or -OCF3; (6) R1Ais selected from fluoro, chloro, cyano, or methyl; (7) R1Ais methyl; (8) R1Bis selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; (9) R1Bis selected from hydrogen, fluoro, chloro, hydroxy, cyano, methyl, CH2F, CHF2, CF3, methoxy, -OCH2F, -OCHF2, -OCF3, -OCH2D, -OCHD2or -OCD3;(10) R1Bis selected from hydrogen, fluoro, chloro, hydroxy, cyano, methyl, CHF2, CF3, methoxy, -OCHF2, -OCF3or -OCD3; (11) R1B is selected from hydrogen, fluoro, chloro, methyl, methoxy, -OCHF2, -OCF3 or - OCD3; (12) R1Bis selected from hydrogen, fluoro, chloro, methyl, methoxy, -OCHF2, -OCF3or - OCD3; (13) R1Bis selected from hydrogen, fluoro, chloro, methyl, methoxy, -OCHF2or -OCD3; (14) R1Cis hydrogen; (15) R1Dis selected from hydrogen, halo, or methyl; (16) R1Dis selected from hydrogen, fluoro, or methyl; (17) R1Dis selected from hydrogen or methyl; (18) R1Dis hydrogen; (19) R1Dis methyl; (20) R1Eis hydrogen; (21) R1Aand R1Bor R1Band R1Care linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 or 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from deuterium, 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, and wherein a 5 or 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring is optionally further substituted by oxo; (22) R1A and R1B or R1B and R1C are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 or 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from deuterium, halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl, and wherein a 5 or 6 membered cycloalkyl or 4 to 6 membered heterocyclyl ring is optionally further substituted by oxo; (23) R1A and R1B or R1B and R1C are linked such that, together with the carbon atoms to which they are attached, they form a fused 4 to 6 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from oxo, deuterium, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl;(24) R1Aand R1Bare linked such that, together with the carbon atoms to which they are attached, they form a fused 5 or 6 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from oxo, halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy or (1-2C)hydroxyalkyl; (25) R1Aand R1Bare linked such that, together with the carbon atoms to which they are attached, they form a fused 5 or 6 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from oxo, halo, cyano, hydroxy, (1-2C)alkyl or (1-2C)alkoxy; (26) R2is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G): -L1-X1-R2A(A) -L2-X2-L1-X1-R2A(B) -L3-X3-L2-X2-L1-X1-R2A(C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A(D) -L5-X5-L4-X4-L3-X3-L2-X2-L1-X1-R2A(E) -[OCH2CH2]n1-R2A(F) -[CH2CH2O]n1-R2A(G) wherein: n1 is 1 to 10; each of L1, L2, L3, L4 or L5 are either absent or a linear or branched (1- 4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O-, -NR2CSO2-, - SO2NR2B- or -S(O)p- (where p is 0, 1 or 2), where R2B is hydrogen or (1- 2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, -NR2DSO2-, - SO2NR2D- or -S(O)p- (where p is 0, 1 or 2), where R2D is hydrogen or (1- 2C)alkyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O-, -NR2GSO2-, -SO2NR2F- or -S(O)p- (where p is 0, 1 or 2), where R2Fis hydrogen or (1- 2C)alkyl; X4 is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, -NR2HSO2-, - SO2NR2H- or -S(O)p- (where p is 0, 1 or 2), where R2His hydrogen or (1- 2C)alkyl; X5is absent or selected from -O-, -NR2K-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2K-, -NR2KC(O)-, -O-C(O)NR2K-, -NR2K-C(O)O-, -NR2KSO2-, - SO2NR2K- or -S(O)p- (where p is 0, 1 or 2), where R2Kis hydrogen or (1- 2C)alkyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1- [phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10-membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; aN alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0- 2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo;or R2Aand R2Bare linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2N-, -NR2NC(O)-, -O-C(O)NR2N-, -NR2N-C(O)O-, -NR2NSO2-, -SO2NR2N- or -S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1-2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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; (27) R2is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (D): -L1-X1-R2A(A) -L2-X2-L1-X1-R2A (B) -L3-X3-L2-X2-L1-X1-R2A (C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A (D) wherein: each of L1, L2, L3 or L4 are either absent or a linear or branched (1- 4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2B is hydrogen or (1-2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2D is hydrogen or (1-2C)alkyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2F is hydrogen or (1-2C)alkyl;X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2H is hydrogen or (1-2C)alkyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10-membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3-6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0-2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7 (wherein X7 is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or - S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1-2C)alkyl; and RX7 is hydrogen or (1-2C)alkyl);optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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; (28) R2is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A(A1) -X2-L1-X1-R2A(B1) -X3-L2-X2-L1-X1-R2A(C1) -X4-L3-X3-L2-X2-L1-X1-R2A(D1) wherein: each of L1, L2or L3are either absent or a linear or branched (1- 4C)alkylene; X1is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2Bis hydrogen or (1-2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2D is hydrogen or (1-2C)alkyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2F is hydrogen or (1-2C)alkyl; X4 is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2H is hydrogen or (1-2C)alkyl; R2A is selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1- [phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10-membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein:o1 is 1 or 2; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0-2-X6-Rx6(wherein X6is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2Mis hydrogen or (1-2C)alkyl; and RX6is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2Aand R2Bare linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7 (wherein X7 is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or -S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1-2C)alkyl; and RX7 is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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; (29) R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A (A1)-X2-L1-X1-R2A(B1) -X3-L2-X2-L1-X1-R2A(C1) -X4-L3-X3-L2-X2-L1-X1-R2A (D1) wherein: each of L1, L2or L3are either absent or a linear or branched (1- 4C)alkylene; X1is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2Bis hydrogen or (1-2C)alkyl; X2is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2Dis hydrogen or (1-2C)alkyl; X3is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2Fis hydrogen or (1-2C)alkyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2H is hydrogen or (1-2C)alkyl; R2A is selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1- [phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10-membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1 or 2; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0-2-X6-Rx6(wherein X6is selected from -O-, -NR2M-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, -NR2M- C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2Mis hydrogen or (1-2C)alkyl; and RX6is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2Aand R2Bare linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or -S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1-2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (30) R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A (A1) -X2-L1-X1-R2A (B1) -X3-L2-X2-L1-X1-R2A (C1) -X4-L3-X3-L2-X2-L1-X1-R2A (D1) wherein: each of L1, L2 or L3 are either absent or a linear or branched (1- 4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B- or -NR2B-C(O)O-, where R2B is hydrogen or methyl;X2is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2D- or -NR2DC(O)-, where R2Dis hydrogen or methyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2F- or -NR2FC(O)-, where R2Fis hydrogen or methyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2H- or -NR2HC(O)-, where R2His hydrogen or methyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, 5 or 6- membered heteroaryl, 4 to 10-membered heterocyclyl, (3-6C)cycloalkyl, or - [CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or (3- 6C)cycloalkyl; and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-6 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7 (wherein X7 is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or -S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1-2C)alkyl; and RX7 is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ringwhich is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, methyl, or methoxy; (31) R2is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A(A1) -X2-L1-X1-R2A(B1) -X3-L2-X2-L1-X1-R2A(C1) -X4-L3-X3-L2-X2-L1-X1-R2A(D1) wherein: each of L1, L2or L3are either absent or a linear or branched (1- 4C)alkylene; X1is absent or selected from -O-, -NR2B-, -C(O)O-, -C(O)NR2B-, - NR2BC(O)-, or -NR2B-C(O)O-, where R2Bis hydrogen or methyl; X2is absent or selected from -O-, -NR2D-, -C(O)NR2D- or -NR2DC(O)-, where R2Dis hydrogen or methyl; X3is absent or selected from -O-, or -NR2FC(O)-, where R2Fis hydrogen or methyl; X4 is absent or selected from -O-; R2A is selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, 5 or 6-membered heteroaryl, 4 to 10-membered heterocyclyl; and wherein: an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or (3- 6C)cycloalkyl;and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-6 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or -S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1-2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring; (32) R3is selected from hydrogen, halo, cyano, hydroxy or amino; (33) R3is selected from hydrogen, fluoro, chloro, cyano, hydroxy or amino; (34) R3is selected from hydrogen or halo; (35) R3is selected from hydrogen or fluoro; (36) R3is hydrogen; (37) R3 is fluoro. (38) R3A is selected from hydrogen, halo; (39) R3A is selected from hydrogen, fluoro or chloro; (40) R3A is selected from hydrogen or fluoro; (41) R3A is hydrogen; (42) R3A is fluoro; (43) R3A is selected from hydrogen, halo, or R3 and R3A together form an oxo group; (44) R3A is selected from hydrogen, fluoro or chloro, or R3 and R3A together form an oxo group; (45) R3A is selected from hydrogen or fluoro, or R3 and R3A together form an oxo group; (46) R3 and R3A together form an oxo group; (47) R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from 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 a group of the formula (A) to (G) defined in claim 1 or claim 8 above; (48) R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from 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; (49) R2and R3are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (50) R2and R3are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (51) R2and R3are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl or 5 or 6-membered heteroaryl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (52) R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 or 6-membered heteroaryl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkyl, or (1-2C)alkoxy; (53) R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form a fused 6-membered heteroaryl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkyl, or (1-2C)alkoxy; (54) R4 is selected from hydrogen, cyano, fluoro or chloro; (55) R4 is selected from hydrogen or cyano; (56) R4 is hydrogen; (57) X is selected from: -CHR5-; -NR100-, where R100 is hydrogen or (1-2C)alkyl; -CH2-XA-, where XA is -O- or -NR101-, where R101 is hydrogen or (1-2C)alkyl;wherein R5is hydrogen, methyl, hydroxymethyl, or methoxymethyl; (58) X is selected from: -CHR5-; -NR100-, where R100is hydrogen or (1-2C)alkyl; -CH2-XA-, where XAis -O- or -NR101-, where R101is hydrogen or (1-2C)alkyl; wherein R5is hydrogen or methyl; (59) X is selected from -CH2-, -NH- or -CH2-O-; (60) X is -CH2-; (61) X is -NH-; (62) X is -CH2-O-; (63) Q is selected from:wherein A2 is selected from CH or N, A3 is selected from CR9 or N, A4 is selected from CR8 or N, A5 is selected from CR7 or N, and A6 is selected from CR6 or N,with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or - CHR5-CH2-, and one or two of A2, A3,A4, A5and A6are N; and wherein R6, R7, R8 and R9 are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (107) hereinafter; (64) Q is selected from:wherein A2is selected from CH or N, A3is selected from CR9or N, A5is selected from CR7or N, and A6is selected from CR6or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or - CHR5-CH2-, and one or two of A2, A3,A5and A6are N; and wherein R6, R7, R8and R9are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (107) hereinafter; (65) Q is selected from:wherein A2is selected from CH or N, A3is selected from CR9or N, and A5is selected from CR7or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one or two of A2, A3and A5is / are N; and wherein R6, R7, R8and R9are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (107) hereinafter; (66) Q is selected from:wherein R6, R7, R8 and R9 are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (107) hereinafter; (67) Q is selected from:wherein R6, R7, R8 and R10 are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (84) hereinafter; (68) Q is selected from:wherein R6, R7, R8 and R10 are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (84) hereinafter; (69) Q is selected from:; wherein R6, R7, R8 and R10 are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (84) hereinafter; (70) Q iswherein R6, R7and R8are as defined hereinbefore, or are as defined in any one of paragraphs (71) to (84) hereinafter; (71) R6 is hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1-6C)alkoxy, (1- 6C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2-phenyl, 5 or 6- membered heteroaryl, -[CH2]o2-[5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]o2-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o2- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o2-[(3-6C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (72) R6is hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2-phenyl, 5 or 6- membered heteroaryl, -[CH2]o2-[5 or 6-membered heteroaryl], 4 to 6-membered heterocyclyl, -[CH2]o2-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o2- [(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o2-[(3-5C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (73) R6 is hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, - O-[CH2]o2-[(3-4C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (74) R6 is hydrogen, halo, cyano, (1-3C)alkyl, (1-3C)haloalkyl, (1-3C)alkoxy, (1- 3C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, - O-[CH2]o2-[(3-4C)cycloalkyl], wherein:o2 is 1 or 2; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, methyl, methoxy, fluoromethyl, di-fluoromethyl, trifluoromethyl, trifluoromethoxy, hydroxymethyl, amino, methylamino, or di-methylamino; (75) R6is hydrogen, halo, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1- 2C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, - O-[CH2]o2-[(3-4C)cycloalkyl], wherein o2 is 1 or 2; (76) R6is hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, cyclopropyl, -[CH2]o2-[cyclopropyl], -O-cyclopropyl, -O-[CH2]o2-[(3-4C)cyclopropyl], wherein o2 is 1; (77) R6is hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl or cyclopropyl; (78) R7is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o3-phenyl, -O-phenyl, -O-[CH2]o3-phenyl, 5 or 6-membered heteroaryl, -[CH2]o3-[5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]o3-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o3-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O- [CH2]o3-[(3-5C)cycloalkyl], wherein: o3 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o4- phenyl, 5 or 6-membered heteroaryl, -[CH2]o4-[5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]o4-[4 to 8 -membered heterocyclyl], (3- 5C)cycloalkyl, -[CH2]o4-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, or -O-[CH2]o4-[(3- 5C)cycloalkyl], wherein: o4 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; (79) R7is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o3-[(3-4C)cycloalkyl], -O-(3- 4C)cycloalkyl, -O-[CH2]o3-[(3-4C)cycloalkyl], wherein: o3 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o4-[(3-4C)cycloalkyl], -O-(3- 4C)cycloalkyl, or -O-[CH2]o4-[(3-4C)cycloalkyl], wherein: o4 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1- 2C)alkyl]amino; wherein o5 is 1;(80) R7is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from 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; (81) R7 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; R8 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1-2C)alkoxy; (82) R7 is selected from hydrogen, halo or (1-4C)alkyl; R8 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one ormore substituents selected from 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 R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (83) R7is selected from hydrogen, halo or (1-4C)alkyl; R8is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; or R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (84) R7is selected from hydrogen; R8 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; or R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (85) R7 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o3-phenyl, -O-phenyl, -O-[CH2]o3- phenyl, 5 or 6-membered heteroaryl, -[CH2]o3-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o3-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o3-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o3-[(3-5C)cycloalkyl], wherein: o3 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (86) R7 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o3-[(3-4C)cycloalkyl], -O-(3- 4C)cycloalkyl, -O-[CH2]o3-[(3-4C)cycloalkyl], wherein: o3 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (87) R7is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (88) R7is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (89) R7 is selected from hydrogen, halo or (1-4C)alkyl; (90) R7 is hydrogen; (91) R8 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o4- phenyl, 5 or 6-membered heteroaryl, -[CH2]o4-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o4-[4 to 8 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o4-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, or -O-[CH2]o4-[(3-5C)cycloalkyl], wherein: o4 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;(92) R8is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o4-[(3-4C)cycloalkyl], -O-(3- 4C)cycloalkyl, or -O-[CH2]o4-[(3-4C)cycloalkyl], wherein: o4 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (93) R8is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (94) R8is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (95) R8 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (96) R8 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; (97) R8 is selected from hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl or (1-2C)haloalkoxy; (98) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring,which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; (99) R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1; (100) R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from 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; (101) R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (102) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (103) R9 is hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o6-phenyl, 5 or 6- membered heteroaryl, -[CH2]o6-[5 or 6-membered heteroaryl], 4 to 6-membered heterocyclyl, -[CH2]o6-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o6- [(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o6-[(3-5C)cycloalkyl], wherein: o6 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;(104) R9is hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o6-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, - O-[CH2]o6-[(3-4C)cycloalkyl], wherein: o6 is 1; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (105) R9is hydrogen, halo, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1- 2C)haloalkoxy; (106) R9is hydrogen, halo, (1-2C)alkyl, or (1-2C)haloalkyl; (107) R9is hydrogen; (108) RNis hydrogen; (109) R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; (110) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1; (111) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is substituted by one or more R10 substituents selected from 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; (112) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is substituted by one ormore R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (113) R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy.

[0071] Suitably, in the compounds of formula I (or sub-formulae IV, V, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, or X), A1is CH or N. More suitably, A1is CH.

[0072] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R1Ais as defined hereinbefore or is as defined in any one of paragraphs (3) to (7) above. More suitably, R1Ais as defined in paragraphs (4) or (5) above. Most suitably, R1Ais as defined in paragraph (5) above.

[0073] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R1Bis as defined hereinbefore or is as defined in any one of paragraphs (8) to (13) above. More suitably, R1Bis as defined in paragraphs (12) or (13) above. Most suitably, R1Bis as defined in paragraph (13) above.

[0074] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R1C is as defined hereinbefore or is as defined in any one of paragraph (14) above.

[0075] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R1D is as defined hereinbefore or is as defined in any one of paragraphs (15) to (19) above. More suitably, R1D is as defined in paragraphs (15) or (16) above. Most suitably, R1D is as defined in paragraph (16) above.

[0076] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R1E is as defined hereinbefore or is as defined in any one of paragraph (20) above.

[0077] Suitably, in the compounds of formula I (or sub-formulae IV, V, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, or X), R2 is as defined hereinbefore or is as defined in any one of paragraphs (26) to (31) above. More suitably, R1D is as defined in paragraphs (29), (30) or (31) above. Most suitably, R1D is as defined in paragraph (30) above.

[0078] Suitably, in the compounds of formula I (or sub-formulae IV, V, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, or X), R3 is as defined hereinbefore or is as defined in anyone of paragraphs (32) to (37) above. More suitably, R3is as defined in paragraphs (34) or (35) above. Most suitably, R3is as defined in paragraph (35) above.

[0079] Suitably, in the compounds of formula I (or sub-formulae IV, V, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, or X), R3Ais as defined hereinbefore or is as defined in any one of paragraphs (38) to (46) above. More suitably, R3Ais as defined in paragraphs (43) or (45) above. Most suitably, R3Ais as defined in paragraph (44) above.

[0080] Suitably, in the compounds of formula I (or sub-formulae IV, V, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, or X), R4is as defined hereinbefore or is as defined in any one of paragraphs (54) to (56) above. More suitably, R4is as defined in paragraphs (55) or (56) above. Most suitably, R4is as defined in paragraph (56) above

[0081] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), X is as defined hereinbefore or is as defined in any one of paragraphs (57) to (62) above. More suitably, X is as defined in paragraphs (58) or (59) above. Most suitably, X is as defined in paragraph (59) above.

[0082] Suitably, in the compounds of formula I, Q is as defined hereinbefore or is as defined in any one of paragraphs (63) to (70) above. More suitably, Q is as defined in paragraphs (65) or (67) above. Most suitably, Q is as defined in paragraph (67) above.

[0083] Suitably, in the compounds of formula I, Q is as defined hereinbefore or is as defined in any one of paragraphs (63) to (70) above and R7and R8are defined in paragraph (109) above. More suitably, Q is as defined in paragraph (67) above and R7and R8are defined in paragraph (110) above. Even more suitably, Q is as defined in paragraph (68) above and R7and R8are defined in paragraph (111) above. Yet still more suitably, Q is as defined in paragraph (69) above and R7and R8are defined in paragraph (112) above. Yet still even more suitably, Q is as defined in paragraph (70) above and R7and R8are defined in paragraph (113) above.

[0084] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII), R6 is as defined hereinbefore or is as defined in any one of paragraphs (71) to (77) above. More suitably, R6 is as defined in paragraphs (75) or (76) above. Most suitably, R6 is as defined in paragraph (77) above.

[0085] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, IX, X, XI or XII), R7 is as defined hereinbefore or is as defined in any one of paragraphs (78) to (84) above. More suitably, R7 is as defined in paragraphs (81) or (82) above. Most suitably, R7 is as defined in paragraph (83) above.

[0086] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, IX, X, XI or XII), R8is as defined hereinbefore or is as defined in any one of paragraphs (78) to (84) above. More suitably, R8 is as defined in paragraphs (81) or (82) above. Most suitably, R8 is as defined in paragraph (83) above.

[0087] Suitably, in the compounds of formula I, R7and R8are defined in paragraph (109) above. More suitably, R7and R8are defined in paragraph (110) above. Even more suitably, R7and R8are defined in paragraph (111) above. Yet still more suitably, R7and R8are defined in paragraph (112) above. Yet still even more suitably, R7and R8are defined in paragraph (113) above.

[0088] Suitably, in the compounds of formula I (or sub-formulae IV, V, VI, VII, VIII, IX, X, XI or XII), R9is as defined hereinbefore or is as defined in any one of paragraphs (103) to (107) above. More suitably, R9is as defined in paragraphs (104) or (105) above. Most suitably, R9is as defined in paragraph (107) above.

[0089] Suitably, in the compounds of formula I (or sub-formulae VI, IX or XII), RNis as defined hereinbefore or is as defined in any one of paragraph (108) above.

[0090] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have one of the structural sub-formulae IV to XII shown above.

[0091] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula IV shown above.

[0092] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula V shown above.

[0093] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VI shown above.

[0094] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VII shown above.

[0095] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIII shown above.

[0096] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIa shown above.

[0097] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIIa shown above.

[0098] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIb shown above.

[0099] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIIb shown above.

[0100] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIc shown above.

[0101] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIIc shown above.

[0102] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIId shown above.

[0103] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula VIIId shown above.

[0104] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula IX shown above.

[0105] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula X shown above.

[0106] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula XI shown above.

[0107] In a particular group of compounds of formula I, the compounds, or a pharmaceutically acceptable salt thereof, have the structural sub-formula XII shown above.

[0108] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RN are as defined hereinbefore of are as defined below: A1 is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (3) above; R1B is as defined in paragraph (8) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (15) above; R1E is as defined in paragraph (20) above; R2 is as defined in paragraph (26) above; R3 is as defined in paragraph (32) above;R3Ais as defined in paragraph (43) above; R4is as defined in paragraph (54) above; X is as defined in paragraph (57) above; R5is as defined in paragraph (57) above; R6is as defined in paragraph (71) above; R7is as defined in paragraph (78) above; R8is as defined in paragraph (78) above; R9is as defined in paragraph (103) above; RNis as defined in paragraph (108) above; A2is as defined in paragraph (63) above; A3is as defined in paragraph (63) above; A5is as defined in paragraph (63) above.

[0109] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (4) above; R1B is as defined in paragraph (10) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (16) above; R1E is as defined in paragraph (20) above; R2 is as defined in paragraph (28) above; R3 is as defined in paragraph (34) above; R3A is as defined in paragraph (44) above; R4 is as defined in paragraph (55) above; X is as defined in paragraph (59) above; R5 is as defined in paragraph (57) above; R6 is as defined in paragraph (73) above; R7 is as defined in paragraph (80) above; R8 is as defined in paragraph (80) above; R9 is as defined in paragraph (105) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above; A3 is as defined in paragraph (63) above;A5is as defined in paragraph (63) above.

[0110] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1is as defined in paragraph (1) or (2) above; R1Ais as defined in paragraph (5) above; R1Bis as defined in paragraph (12) above; R1Cis as defined in paragraph (14) above; R1Dis as defined in paragraph (16) above; R1Eis as defined in paragraph (20) above; R2is as defined in paragraph (29) above; R3is as defined in paragraph (35) above; R3Ais as defined in paragraph (45) above; R4is as defined in paragraph (56) above; X is as defined in paragraph (59) above; R5is as defined in paragraph (57) above; R6 is as defined in paragraph (75) above; R7 is as defined in paragraph (82) above; R8 is as defined in paragraph (82) above; R9 is as defined in paragraph (106) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above; A3 is as defined in paragraph (63) above; A5 is as defined in paragraph (63) above.

[0111] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RN are as defined hereinbefore of are as defined below: A1 is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (5) above; R1B is as defined in paragraph (12) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (16) above; R1E is as defined in paragraph (20) above;R2is as defined in paragraph (31) above; R3is as defined in paragraph (35) above; R3A is as defined in paragraph (45) above; R4is as defined in paragraph (56) above; X is as defined in paragraph (59) above; R5is as defined in paragraph (58) above; R6is as defined in paragraph (77) above; R7is as defined in paragraph (84) above; R8is as defined in paragraph (84) above; R9is as defined in paragraph (107) above; RNis as defined in paragraph (108) above; A2is as defined in paragraph (63) above; A3is as defined in paragraph (63) above; A5is as defined in paragraph (63) above.

[0112] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1 is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (3) above; R1B is as defined in paragraph (8) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (15) above; R1E is as defined in paragraph (20) above; R2 is as defined in paragraph (26) above; R3 is as defined in paragraph (32) above; R3A is as defined in paragraph (43) above; R4 is as defined in paragraph (54) above; X is as defined in paragraph (57) above; R5 is as defined in paragraph (57) above; R6 is as defined in paragraph (71) above; R7 and R8 are as defined in paragraph (109) above; R9 is as defined in paragraph (103) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above;A3is as defined in paragraph (63) above; A5is as defined in paragraph (63) above.

[0113] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1is as defined in paragraph (1) or (2) above; R1Ais as defined in paragraph (4) above; R1Bis as defined in paragraph (10) above; R1Cis as defined in paragraph (14) above; R1Dis as defined in paragraph (16) above; R1Eis as defined in paragraph (20) above; R2is as defined in paragraph (28) above; R3is as defined in paragraph (34) above; R3Ais as defined in paragraph (44) above; R4is as defined in paragraph (55) above; X is as defined in paragraph (59) above; R5 is as defined in paragraph (57) above; R6 is as defined in paragraph (73) above; R7 and R8 are as defined in paragraph (110) above; R9 is as defined in paragraph (105) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above; A3 is as defined in paragraph (63) above; A5 is as defined in paragraph (63) above.

[0114] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RN are as defined hereinbefore of are as defined below: A1 is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (4) above; R1B is as defined in paragraph (10) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (16) above; R1E is as defined in paragraph (20) above;R2is as defined in paragraph (28) above; R3is as defined in paragraph (34) above; R3A is as defined in paragraph (44) above; R4is as defined in paragraph (55) above; X is as defined in paragraph (59) above; R5is as defined in paragraph (57) above; R6is as defined in paragraph (73) above; R7and R8are as defined in paragraph (111) above; R9is as defined in paragraph (105) above; RNis as defined in paragraph (108) above; A2is as defined in paragraph (63) above; A3is as defined in paragraph (63) above; A5is as defined in paragraph (63) above.

[0115] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1 is as defined in paragraph (1) or (2) above; R1A is as defined in paragraph (5) above; R1B is as defined in paragraph (12) above; R1C is as defined in paragraph (14) above; R1D is as defined in paragraph (16) above; R1E is as defined in paragraph (20) above; R2 is as defined in paragraph (29) above; R3 is as defined in paragraph (35) above; R3A is as defined in paragraph (45) above; R4 is as defined in paragraph (56) above; X is as defined in paragraph (59) above; R5 is as defined in paragraph (57) above; R6 is as defined in paragraph (75) above; R7 and R8 are as defined in paragraph (112) above; R9 is as defined in paragraph (106) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above; A3 is as defined in paragraph (63) above;A5is as defined in paragraph (63) above.

[0116] Particular compounds of formula I have any one of the sub-formulae IV to XIII shown above and, where present in such formulae, the groups A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RNare as defined hereinbefore of are as defined below: A1is as defined in paragraph (1) or (2) above; R1Ais as defined in paragraph (5) above; R1Bis as defined in paragraph (12) above; R1Cis as defined in paragraph (14) above; R1Dis as defined in paragraph (16) above; R1Eis as defined in paragraph (20) above; R2is as defined in paragraph (31) above; R3is as defined in paragraph (35) above; R3Ais as defined in paragraph (45) above; R4is as defined in paragraph (56) above; X is as defined in paragraph (59) above; R5is as defined in paragraph (58) above; R6 is as defined in paragraph (77) above; R7 and R8 are as defined in paragraph (113) above; R9 is as defined in paragraph (107) above; RN is as defined in paragraph (108) above; A2 is as defined in paragraph (63) above; A3 is as defined in paragraph (63) above; A5 is as defined in paragraph (63) above.

[0117] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1A and R1E are not both hydrogen.

[0118] Suitably, in the compounds of formula I (or sub-formulae IV to XII), only one, two, three or four of R1A, R1B, R1C, R1D and R1E are hydrogen. More suitably, only two or three of R1A, R1B, R1C, R1D and R1E are hydrogen.

[0119] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1A and R1C are hydrogen. More suitably, R1A, R1B and R1C are hydrogen. Alternatively, R1A, R1C and R1D are hydrogen.

[0120] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1B, R1D and R1E are not hydrogen. More suitably, R1D and R1E are not hydrogen. Alternatively, R1B and R1E are not hydrogen.

[0121] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1Eand R1Care hydrogen. More suitably, R1E, R1Dand R1Care hydrogen. Alternatively, R1E, R1Cand R1Bare hydrogen.

[0122] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1A, R1Band R1Dare not hydrogen. More suitably, R1Aand R1Bare not hydrogen. Alternatively, R1Aand R1Dare not hydrogen.

[0123] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1Aand R1Care hydrogen and R1B, R1Dand R1Eare not hydrogen. More suitably, R1A, R1Band R1Care hydrogen and R1Dand R1Eare not hydrogen. Alternatively, R1A, R1Cand R1Dare hydrogen and R1Band R1Dare not hydrogen.

[0124] Suitably, in the compounds of formula I (or sub-formulae IV to XII), R1Eand R1Care hydrogen and R1A, R1Band R1Dare not hydrogen. More suitably, R1E, R1Dand R1Care hydrogen and R1Aand R1Bare not hydrogen. Alternatively, R1E, R1Cand R1Bare hydrogen and R1Aand R1Dare not hydrogen.

[0125] Suitably, in the compounds of formula I (or sub-formulae IV to XII), Q is not a group: ,

[0126] Suitably, in the compounds of formula I (or sub-formulae IV to XII), when Q is a group:wherein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6or N, R6 and R7, R7 and R8 or R8 and R9 are not linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]o5-(3- 6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2.

[0127] Suitably, in the compounds of formula I (or sub-formulae IV to XII), when Q is a group:wherein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6or N, R6 and R7, R7 and R8 or R8 and R9 are not linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl or (5C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]o5-(3-6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2.

[0128] Suitably, in the compounds of formula I (or sub-formulae IV to XII), when Q is a group:wherein A2 is selected from CH or N, A3 is selected from CR9 or N, A4 is selected from CR8 or N, A5 is selected from CR7 or N, and A6 is selected from CR6 or N, R6 and R7, R7 and R8 or R8 and R9 are not linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 to 7-membered heterocyclyl, 5 or 6- membered heteroaryl, or (5-8C)cycloalkyl ring, which is optionally substituted by one or moreR10substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]o5-(3- 6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2.

[0129] 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: 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 1-[2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2- yl]ethenone; 1-[(2R)-2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethenone; 1-[(2S)-2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7- tetrahydroindazol-2-yl]ethenone; 1-[(2S)-2-(2,3-Dimethyl-phenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethanone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1- yl]ethenone; 1-[(2S)-2-(3-Chloro-2-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1- yl)ethenone; 1-[(2S)-2-(2,3-Dimethylphenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1-yl)ethanone 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin- 1-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1- yl)ethenone; 2-(3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(6R)-3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2S)-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone;2-[(6S)-3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2S)-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[6-methyl-3-(trifluoromethyl)-5,6- dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[(6S)-6-methyl-3-(trifluoromethyl)- 5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[(6R)-6-methyl-3-(trifluoromethyl)- 5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(o-tolyl)pyrrolidin-1-yl]ethanone 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)pyrrolidin-1-yl]-2-[3-isopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 2-(4-Fluoro-3-isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-(4-Bromo-3-isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethanethione; 4-[1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-2-yl]-2-methyl- isoindolin-1-one;2-[1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-2-yl]-6-methyl- benzonitrile; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1- yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[2-methyl-6-(trifluoromethyl)-3- pyridyl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[3-methyl-5-(trifluoromethyl)-2- pyridyl]ethenone; 1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[4-methyl-6-(trifluoromethyl)-3- pyridyl]ethenone; 1-[(2R)-2-(3-Methoxy-2-methyl-phenyl)-2-methyl-pyrrolidin-1-yl]-2-[4-methyl-6- (trifluoromethyl)pyridazin-3-yl]ethenone; (2S)-N-[3,5-Bis(trifluoromethyl)-2-pyridyl]-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1- carboxamide; 1-[2-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-4,6- bis(trifluoromethyl)pyridin-2-one; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[2-(3-methoxy-2-methyl-phenyl)pyrazolidin-1- yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[2-(3-methoxy-2-methyl- phenyl)pyrazolidin-1-yl]ethenone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(2,3-dimethylphenyl)-2,5-dihydropyrrol-1- yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)- 2,5-dihydropyrrol-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)- 2,5-dihydropyrrol-1-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)-2,5-dihydropyrrol-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7- tetrahydroindazol-2-yl]ethanone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-hydroxy-pyrrolidin-1-yl]-2-[3-cyclopropyl- 5-(trifluoromethyl)pyrazol-1-yl]ethanone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-1-yl]ethanone; 2-(3,5-Dicyclopropyl-4-fluoro-pyrazol-1-yl)-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-1-yl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2R,3R)-2-[3-(difluoromethoxy)-2-methylphenyl]-3- hydroxypyrrolidin-1-yl]ethan-1-one; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2R,3R)-2-[5-fluoro-2-methyl-3- (trideuteriomethoxy)phenyl]-3-hydroxy-pyrrolidin-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-(pyrazin-2-ylmethoxy)pyrrolidine-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanoneethenoneethanone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-3-(2-hydroxy-2-methyl- propoxy)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(2-hydroxy-2-methyl-propoxy)pyrrolidine-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[(2R,3R)-1-[2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetyl]-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-3-yl]oxyacetamide; 1-[(2R,3R)-3-[(2R)-2-Aminopropoxy]-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2- [4-chloro-3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-[(2R)-2-Aminopropoxy]-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; N-[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetamide; N-[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]acetamide; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-[(2R)-2-morpholinopropoxy]pyrrolidin-1- yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]amino]acetamide;2-[[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]-methyl- amino]acetamide; 1-[(2R,3R)-3-(3-aminobutoxy)-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone hydrochloride; 2-Amino-N-[(2R)-1-{[(2R,3R)-2-(2-chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5- (trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-3-yl]oxy}propan-2-yl]propenamide; (2R)-2-Amino-N-[(1R)-2-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl- 5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidine-3-yl]oxy-1-methyl-ethyl]propenamide; (2S)-2-Amino-N-[(1R)-2-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidine-3-yl]oxy-1-methyl-ethyl]propenamide; 1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(2-methoxyethoxy)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(2-methoxyethoxy)-2-(3- methoxy-2-methyl-phenyl)prrolidine-1-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)prrolidine-1-yl]-2-[(7S)-3,7-dimethyl- 4,5,6,7-tetrahydroindazol-2-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1-yl]-2-[5-(trifluoromethyl)-3,4- diazatricyclo[5.2.1.02,6]deca-2,5-dien-4-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)prrolidine-1-yl]-2-[3-cyclopropyl-4-methyl- 5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidine-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2R,3R)-3-Amino-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone hydrochloride; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-(pyrazin-2-ylmethylamino)pyrrolidine-1- yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidine-3-yl]-5-methyl-pyrazine-2-carboxamide;N-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}pyrrolidine-3-yl]pyrazine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyridazine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-triazole-4-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-1,2,4-triazole-3-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridazine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyridazine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methoxy-pyridine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3-methyl-pyrazine-2-carboxamide; (2R)-N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]tetrahydrofuran-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyrazine-2-carboxamide; (2S)-N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-azetidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-imidazole-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyrimidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-(2,3- dichlorophenyl)pyrrolidin-3-yl]pyridine-2-carboxamide;N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin-3- yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-fluoro-pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-1,2,4-triazole-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyrazine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; 3-Amino-N-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-fluoro-pyrimidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-methyl-oxazole-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2,6-dimethyl-pyrimidine-4-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4-methyl-oxazole-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-pyrazole-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4-methyl-5-oxo-pyrazine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-methyl-pyrazine-2-carboxamide;(2S,3R)-2-(2-Chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}-N-(pyrazin-2-yl)pyrrolidine-3-carboxamide; (2R,3S)-2-(2-chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}-N-(pyrazin-2-yl)pyrrolidine-3-carboxamide; N-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidine-3-yl]-3,3-difluoro-azetidine-1-carboxamide; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-2-(3-methoxy-2-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,3S-2-(3-methoxy-2-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6S)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6R)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6S)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2R,3R)-2-(3-Methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6R)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 2-[(4R,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6S)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4R,6R)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6R)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4R,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone;2-[(4R,6R)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethanone; 2-[(4S,6R)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethaenone; 2-[(5S,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6S)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6S)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone;2-[(6R)-6-ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6S)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6R)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]prrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-(1,1-dioxo-1,4-thiazinan-4-yl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; (2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(1,1-dioxo-1,4-thiazinan-4-yl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 4-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one ;4-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 4-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 4-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3- morpholino-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3- morpholino-pyrrolidin-1-yl]ethenone; 1-[(2S,3S)-3-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide;2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethanone; 2-{8-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl}-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]acetamide;2-{8-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl}-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]acetamide; 2-[7-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4,7-diazaspiro[2.5]octan-4-yl]acetamide; 2-[7-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4,7-diazaspiro[2.5]octan-4-yl]acetamide; 2-[2,2,3,3,5,5,6,6-Octadeuterio-4-[(2S,3S)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[2,2,3,3,5,5,6,6-octadeuterio-4-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[4-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[(2S, 3S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide;2-[4-[(2S,3S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-pyrazin-2-ylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-pyrazin-2-ylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-2-[2-methyl-3-(trideuteriomethoxy)phenyl]-3- (4-pyridyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]-3-(4-pyridyl)pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-piperidyl]acetamide;1-[(2S,3S)-3-(1-Acetyl-4-piperidyl)-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-1-yl]- 2-[3,5-bis(trifluoromethyl)-2-pyridyl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-3-(1-methylsulfonyl-4-piperidyl)-2-[2-methyl- 3-(trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-piperidyl]acetamide; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-3-(1,1-dioxothian-4-yl)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 1-[(2S)-4,4-Difluoro-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl- pyrazol-1-yl)ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl-phenyl)-5,7- dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; (4Z,5R)-4-(aminomethylene)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-5-(3- methoxy-2-methyl-phenyl)pyrrolidin-3-one; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl-phenyl)-5,7- dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; (4Z,5R)-4-(Aminomethylene)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-5-(3- methoxy-2-methyl-phenyl)pyrrolidin-3-one;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-methoxy-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-ethoxy-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; Example 196: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-methoxy-5-(3- methoxy-2-methyl-phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; Example 197: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-ethoxy-5-(3- methoxy-2-methyl-phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-(2,2-Difluorocyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(4R)-4-(3-methoxy-2-methyl-phenyl)-4,6- dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]ethenone; or a pharmaceutically acceptable salt thereof.

[0130] 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.

[0131] Suitably, the present invention excludes any individual compounds not possessing the biological activity defined herein. Salts and Solvates

[0132] 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 used herein, 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 beprepared 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.

[0133] 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.

[0134] In one embodiment, the compounds of Formula I and sub-formulae thereof are isolated as pharmaceutically acceptable salts.

[0135] 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.

[0136] 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 present application 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 samecharge. 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.

[0137] 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.

[0138] 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

[0139] 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

[0140] 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 anitrogen 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 peroxide or 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

[0141] 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

[0142] 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 amixture thereof. A mixture containing equal proportions of the enantiomers is called a “racemic mixture”.

[0143] 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

[0144] 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

[0145] 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 property- modifying 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.

[0146] 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 thehuman 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.

[0147] 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.

[0148] 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.

[0149] 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 C1-6alkyl esters such as, but not limited to, methyl, ethyl and tert- butyl, C1-6alkoxymethyl esters such as, but not limited to, methoxymethyl esters, C1- 6alkanoyloxymethyl esters such as, but not limited to, pivaloyloxymethyl esters, 3-phthalidyl esters, C3-8cycloalkylcarbonyloxy- C1-6alkyl 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-ylmethylesters and C1-6alkoxycarbonyloxy- C1-6alkyl esters such as, but not limited to, methoxycarbonyloxymethyl and 1-methoxycarbonyloxyethyl esters.

[0150] A suitable pharmaceutically acceptable pro-drug of a compound of the Formula I 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 C1-10alkanoyl groups such as, but not limited to, acetyl, benzoyl, phenylacetyl and substituted benzoyl and phenylacetyl groups, C1-10alkoxycarbonyl groups such as, but not limited to, ethoxycarbonyl, N,N –(C1-6)2carbamoyl, 2- dialkylaminoacetyl and 2-carboxyacetyl groups. Examples of ring substituents on the phenylacetyl and benzoyl groups include aminomethyl, N-alkylaminomethyl, N,N- dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1- ylmethyl. Suitable pharmaceutically acceptable ether forming groups for a hydroxy group include ^-acyloxyalkyl groups such as, but not limited to, acetoxymethyl and pivaloyloxymethyl groups.

[0151] 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 C1-4alkylamine such as, but not limited to, methylamine, a (C1-4alkyl)2amine such as, but not limited to, dimethylamine, N-ethyl-N-methylamine or diethylamine, a C1-4alkoxy- C2-4alkylamine such as, but not limited to, 2-methoxyethylamine, a phenyl-C1-4alkylamine such as, but not limited to, benzylamine and amino acids such as, but not limited to, glycine or an ester thereof.

[0152] 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 C1-10alkanoyl 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, N,N-dialkylaminomethyl, morpholinomethyl, piperazin-1-ylmethyl and 4-(C1-4alkyl)piperazin-1-ylmethyl.

[0153] 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 animal body 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

[0154] 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.

[0155] 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).

[0156] 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.

[0157] 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.

[0158] 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 anappropriate and convenient amount of excipients which may vary from about 5 to about 98 percent by weight of the total composition.

[0159] 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 and sex of the animal or patient and the route of administration, according to well-known principles of medicine.

[0160] 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 intra- patient 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.

[0161] 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.

[0162] 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

[0163] 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.

[0164] 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.

[0165] 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.

[0166] 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.

[0167] 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.

[0168] 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.

[0169] 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 orsodium hydroxide. Alternatively an acyl group such as a tertbutoxycarbonyl 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 suitable alternative 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.

[0170] 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.

[0171] 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.

[0172] Resins may also be used as a protecting group.

[0173] The methodology employed to synthesise a compound of formula (I) will vary depending on the nature of ring A, R1, R100, R2, R3, integer a, integer b, X4, X5, X6, X7, Rx4, Rx5, Rx6, Rx7, X8, R100a and R100b and any substituent groups associated therewith. Suitable processes for their preparation are described further in the accompanying example section.

[0174] 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.

[0175] An example of (ii) above is when a compound of formula (I) is synthesised and then one or more of the groups of ring A, R1, R100, R2, R3, integer a, integer b, X4, X5, X6, X7, Rx4, Rx5, Rx6, Rx7,X8, R100aand R100bmay be further reacted to change the nature of the group and provide an alternative compound of formula (I).

[0176] The resultant compounds of formula (I) can be isolated and purified using techniques well known in the art. Therapeutic Uses and Applications

[0177] The compounds of the present invention are potent inhibitors of Polθ. Data showing the Polθ inhibition for the exemplified compounds is presented in the accompanying example section.

[0178] Accordingly, the compounds of formula I are 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 and / or benign neoplasms.

[0179] 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.

[0180] 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 Polθ activity is implicated.

[0181] 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 Polθ activity is implicated.

[0182] In another aspect, the present invention provides a method of treating a disease or condition in which Polθ 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.

[0183] 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 Polθ.

[0184] 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 Polθ.

[0185] In another aspect, the present invention provides a method of treating a disease or condition associated with aberrant activity of Polθ, 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.

[0186] 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.

[0187] 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.

[0188] 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.

[0189] 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.

[0190] 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.

[0191] 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.

[0192] 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.

[0193] The compounds of the present invention, or pharmaceutically acceptable salts thereof, may be for used in the treatment of a homologous recombination (HR) deficient cancer.

[0194] 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).

[0195] 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.

[0196] 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.

[0197] 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.

[0198] 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.

[0199] As a consequence of their inhibition of Polθ, 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.

[0200] 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.

[0201] 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.

[0202] 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.

[0203] 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. Tumour 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. Polθ 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.

[0204] 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 DNAdouble 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 a PARP inhibitor, ATM inhibitor, wee1 inhibitor, CHK inhibitor, or ATR inhibitor, may further enhance such activity. Polθ 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.

[0205] 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 Polθ. 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.

[0206] 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 Polθ inhibitor induced radiosensitivity.

[0207] 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.

[0208] 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.

[0209] In a further embodiment, the compounds of the present invention suitably show synthetic sickness and / or synthetic lethality in aromatase inhibitor resistant ER primary and secondary breast cancers, again showing elevated ligase Ilia levels, reduced ligase IV levels and increased dependence upon altEJ DSB repair.

[0210] 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).

[0211] 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.

[0212] 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.

[0213] 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.

[0214] 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.

[0215] 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 Polθ.

[0216] 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.

[0217] 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.

[0218] 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 follicular carcinoma), 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).

[0219] 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.

[0220] 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.

[0221] 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.

[0222] Particular cancers include hepatocellular carcinoma, melanoma, oesophageal, renal, colon, colorectal, lung e.g. mesothelioma or lung adenocarcinoma, breast, bladder, gastrointestinal, ovarian and prostate cancers.

[0223] 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

[0224] 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).

[0225] 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.

[0226] The compounds of the present invention are particularly suitable for oral administration. Combination Therapies

[0227] 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.

[0228] 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 5^-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), N-(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, N-(3-chloro-4-fluorophenyl)-7-methoxy-6-(3-morpholinopropoxy)quinazolin-4-amine (gefitinib, ZD1839), N-(3-ethynylphenyl)-6,7-bis(2-methoxyethoxy)quinazolin-4-amine (erlotinib, OSI-774) and 6-acrylamido-N-(3-chloro-4-fluorophenyl)-7-(3-morpholinopropoxy)-quinazolin- 4-amine (CI 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 (AMN107); 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-1R 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 PatentApplications WO97 / 22596, WO 97 / 30035, WO 97 / 32856 and WO 98 / 13354 and compounds that work by other mechanisms (for example linomide, inhibitors of integrin ^v^3 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.

[0229] 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.

[0230] 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).

[0231] In a further embodiment, the antiproliferative treatment defined hereinbefore may involve, in addition to the compound of the invention, therapy with a PARP inhibitor.

[0232] Such conjoint treatment may be achieved by way of the simultaneous, sequential or separate dosing of the individual components of the treatment. Such combination products employ the compounds of this invention within the dosage range described hereinbefore and the other pharmaceutically-active agent within its approved dosage range.

[0233] 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.

[0234] 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.

[0235] 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.

[0236] 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.

[0237] 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

[0238] 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.

[0239] 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 IC50of 2000 nM or less in the assay described in Biological Assay 1, with preferred compounds of the invention demonstrating an IC50of 100 nM or less and the most preferred compounds of the invention demonstrating an IC50of 10 nM or less. Additional applications

[0240] 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.

[0241] 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 Polθ 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 Polθ 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).

[0242] For this reason, a role for the loss of Polθ 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 Polθ 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 CRISPRbased editing therapeutics, such as the enhancement of efficiency of CRISPR based editing methodology and / or CRISPR based editing therapeutics.

[0243] 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.

[0244] 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.

[0245] 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.

[0246] 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

[0247] 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 IUPAC nomenclature, or as named by the chemical supplier.

[0248] 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.

[0249] 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 mmHg and 375 mmHg (20 - 500 mbar). The structure of final products, 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.

[0250] 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.

[0251] 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 solvents, chemical reagents and starting materials are obtained from commercial suppliers and used without further purification. Salts may be prepared from compounds by known salt- forming procedures. Analysis Instrument Methods & Specifications

[0252] LCMS spectra were run on LCMS systems using electrospray ionization, using either a Waters Acquity H-Class UPLC with PDA and QDa mass detection, an Acquity UPLC (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 LCMS-2010EV system or a Waters Quattro Premier XE or a SQD2; ionization mode: electrospray positive or negative. UV purity was assigned using AUC monitoring at 215, 220, 254 or 280 nm. Data were integrated and reported using Waters MassLynx and OpenLynx software.

[0253] NMR spectra were recorded on either a Bruker Avance III HD 400 MHz, a Bruker NEO 400 MHz, a Bruker Avance III HD 500 MHz, or a Bruker Avance III HD 600 MHz spectrometer. Spectra were recorded at 298K and chemical shifts are quoted in ppm using residual undeuterated solvent as the internal reference.

[0254] LCMS conditions are as follows: Method A Column: Kinetex Core-Shell C18 50 x 2.1 mm, 5 µm column protected by Phenomenex “Security Guard”; column temperature: 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 then held for 0.39 mins. Method B Column: Phenomenex Kinetex Core-Shell C850 x 2.1 mm, 5 µm column protected by Phenomenex “Security Guard”; column temperature: 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 - 1.83 mins 5 - 100% B, 1.83 – 2.25 mins 100% B, 2.25 – 2.26 mins 100 - 5% B then held for 0.54 mins. Method C Column: Waters Atlantis dC18, 100 x 2.1 mm, 3 µm; column temperature: 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 then held for 1.58 mins. Method DColumn: CSH C18 Waters (50 x 2.1 mm) 1.7µm; column temperature: 55̊ C; eluents: A: 0.05%TFA in water, B: 0.035% TFA in MeCN; flow rate: 0.8 mL / min; gradient: 0 – 1.00 mins 2 - 98% B, 1.00 – 1.50 mins 98% B, 1.50 – 1.52 mins 98 - 2% B then held at 2% B for 0.18 mins. Method E Column: Waters UPLCTM BEHTM C18 Part No.1860023502.1 mm × 50 mm, 1.7 µm; column temperature: 40 °C; eluents: A: 0.1% formic acid in water, B 0.1% formic acid in MeCN; flow rate: 0.9 mL / min; gradient: 0 – 1.10 mins 5-100% B, 1.10 – 1.35 mins 100% B, 1.35 – 1.40 mins 100 – 5% B then held for 0.10 mins. Method F Column: CSH C18, 1.7 µm; column temperature: 55 ˚C; eluents: A: 0.05% TFA in water, B: 0.035% TFA in MeCN; flow rate: 0.8 mL / min; gradient: 0 – 2.40 mins 2 - 98% B, 2.40 – 3.00 mins 98% B, 3.00 – 3.03 mins 98 - 2% B then held for 0.47 mins. Method G Column: CSH C18, 1.7 µm; column temperature: 55 ˚C; eluents: A: 0.02% formic acid in water, B: 0.02% TFA in MeCN; flow rate: 0.8 mL / min; gradient: 0 – 2.40 mins 2 - 98% B, 2.40 – 3.00 mins 98% B, 3.00 – 3.03 mins 98 - 2% B then held for 0.47 mins. Method H Column: Phenomenex Kinetex-XB C18, 100 x 2.1 mm, 1.7 µm; column temperature: 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 then held for 1.18 mins. Method I Column: Waters UPLCTM BEHTM C18, 30 x 2.1 mm, 1.7 μm; column temperature: 55 ˚C; eluents: A: 2 mM ammonium bicarbonate in water, buffered to pH 10, B: MeCN; flow rate: 1.0 mL / min; gradient: 0 – 1.10 mins 1-100% B, 1.10 – 1.35 mins 100% B, 1.35 – 1.40 mins, 100 – 1% B then held for 0.40 mins. Method J Column: Waters UPLC® BEHTMC18, 2.1 mm x 100 mm, 1.7 μm; column temperature: 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 then held for 1.18 mins.

[0255] Chiral LC, chiral LCMS and SFC conditions are as follows: Method K Column: CHIRALPAK AS – 150 x 4.6 mm, 5µm; eluents: 100:0 CH3CN + 0.5% IPA; flow rate: 1 mL / min. Method L Column: Chiralpak AS-H, 10 x 250 mm, 5µm; eluents: 25:75 EtOH:CO2; flow rate: 4 mL / min. Method M Column: Chiralpak IC 4.6 x 250 mm, 5 µm; eluents: 8:92 IPA:CO2; flow rate: 4 mL / min. Method N Column: Chiralpak IC 4.6 x 250 mm, 5 µm; eluents: 35:65 IPA:CO2; flow rate: 4 mL / min. Method O Column: Chiralpak IC 4.6 x 250 mm, 5 µm; eluents: 25:75 MeOH:CO2; flow rate: 4 mL / min. Method P Column: Chiralpak IC 4.6 x 250 mm, 5 µm; eluents: 15:85 EtOH:CO2 (+0.5% IPA); flow rate: 2.4 mL / min. Method Q Column: Chiralpak IC 4.6 x 250 mm, 5 µm; eluents: 70:30 EtOH:CO2; flow rate: 4 mL / min. Method R Column: Chiralpak IG 4.6 mm x 250 mm, 5 µm; eluents: 5:95 MeOH:CO2 (+0.1% v / v NH3); flow rate: 4 mL / min. Method S Column:Chiralpak AD 250 x 4.6 mm, 5 µm; eluents: 70:30 CO2:IPA (+0.5% IPAm); flow rate: 2.4 mL / min. Method T Column: Chiralpak AD-H, 4.6 x 250 mm, 5µm; eluents: 85:15 Heptane:EtOH; flow rate: 1 mL / min. Method U Column: Chiralpak IB 250 x 4.65µm; eluents: 70:30 CO2:EtOH (+0.5% IPAm); flow rate: 2.4 mL / min. Method V Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 85:15 Heptane:IPA; flow rate: 1 mL / min. Method W Column: Chiralcel OD-H 4.6 x 250 mm, 5 µm; eluents: 85:15 Heptane:EtOH; flow rate: 1 mL / min. Method X Column: Chiralcel OD-H 4.6 x 250 mm, 5 µm; eluents: 25:75 MeOH:CO2; flow rate: 4 mL / min. Method Y Column: Chiralcel OD-H 4.6 x 250 mm, 5 µm; eluents: 35:65 MeOH:CO2; flow rate: 4 mL / min. Method Z Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 90:10 Heptane:EtOH; flow rate: 1 mL / min. Method AA Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 70:30 MeOH:CO2; flow rate: 4 mL / min. Method BB Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 70:30 Heptane:EtOH; flow rate: 1 mL / min. Method CC Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 70:30 Heptane:IPA; flow rate: 1 mL / min. Method DD Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 70:30 CO2:MeOH; flow rate: 4 mL / min. Method EE Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: EtOH + 0.2% DEA; flow rate: 0.5 mL / min. Method FF Column: Chiralcel OD-H, 4.6 x 250 mm, 5 µm; eluents: 15:85 MeOH:CO2; flow rate: 4 mL / min; Method GG Column: Chiralcel OJ-H 250 mm; eluents: 20: 80 EtOH:CO2; flow rate: 4 mL / min. Method HH Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: 85:15 Heptane:EtOH; flow rate: 1 mL / min. Method II Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: 25:75 MeCN:CO2; flow rate: 4 mL / min. Method JJ Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: 25:75 MeCN:CO2; flow rate: 4 mL / min. Method KK Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: EtOH; flow rate: 0.5 mL / min. Method LL Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: 75:25 Heptane:EtOH; flow rate: 1 mL / min. Method MM Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: MeOH; flow rate: 0.5 mL / min. Method NN Column: Cellulose-4, 4.6 x 250 mm, 5 µm; eluents: 70:30 Heptane:EtOH; flow rate: 1 mL / min.

[0256] Preparative HPLC conditions are as follows: Method 1 Purifications were performed on a Gilson LC system Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Injection volume of 1500 μL at a flow rate of 40 mL / min.10% B (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) for 1.90 min then a gradient of 10 – 95% B over 14.1 min and held for 2.0 min. A second gradient of 95 – 10% B was then applied over 0.2 min and held for a further 1.25 min. UV spectra were recorded at 215 nm using a Gilson detector. Method 2 Purifications were performed on a Gilson LC system Waters Sunfire C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Injectionvolume of 1500 μL at a flow rate of 40 mL / min.30% B (A = 0.1% formic acid in water; B = 0.1% formic acid in MeCN) for 1.9 min then a gradient of 30 – 95% B over 9.6 min and held for 1.97 min. 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 using a Gilson detector. Method 3 Purifications were performed on a Gilson LC system using Waters XBridge C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Injection volume of 1500 μL at a flow rate of 40 mL / min. 10% B (A = 0.2% ammonium hydroxide in water; B = MeCN) for 2.0 min then a gradient of 10 – 95% B over 14.0 min and held for 2.0.min. A second gradient of 95 – 10% B was then applied over 0.2 min and held for 1.25 min. UV spectra were recorded at 215 nm using a Gilson detector. Method 4 Purifications were performed on a Gilson LC system using a Waters XBridge C18 column (30 mm × 100 mm, 5 μm; temperature: room temperature). Injection volume of 1500 μL at a flow rate of 40 mL / min. 30% B (A = 0.2% ammonium hydroxide in water; B = MeCN) for 2.0 min then a gradient of 30 – 95% B over 9.5 min and held for 1.97 min. 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 using a Gilson detector. Method 5 Purifications were performed on a Preparative HPLC LC150 from Waters Prep using a Kromasil C18 column (10 µm, 300 x 50 mm; temperature: room temperature). Injection volume of 7000 μL at a flow rate 120 mL / min. A gradient of 50 - 70% B (A = 0.1% TFA in water; B = 0.1% TFA in MeCN:water 90:10) over 30 mins then a gradient of 70 – 100% B over 1 min held for 9 mins. UV spectra were recorded at 220 nm. Abbreviations 2-MeTHF 2-methyltetrahydrofuran amino silica Biotage KP-NH or Sfär KP-Amino D column br broad Celite Celite® filter aid CDI 1,1′-carbonyldiimidazole CPME cyclopentyl methyl ether d doublet dd doublet of doublets DCE 1,2-dichloroethane DCM dichloromethane de diastereomeric excess DEA diethanolamineDicalite Dicalite™ filter aid DIPEA N,N-diisopropylethylamine DMA N,N-dimethylacetamide DMAP 4-dimethylaminopyridine DMF N,N-dimethylformamide DMSO dimethyl sulfoxide EtOAc ethyl acetate EtOH ethanol HATU 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5- b]pyridinium 3-oxide hexafluorophosphate HCl hydrogen chloride HPLC high pressure liquid chromatography IPA propan-2-ol IPAm isopropylamine Ir[dF(CF3)ppy]2(dtbbpy)PF6[4,4′-bis(1,1-dimethylethyl)-2,2′-bipyridine-N1,N1′]bis[3,5- difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl- C]Iridium(III) hexafluorophosphate LC liquid chromatography LCMS liquid chromatography and mass spectrometry LDA lithium diisopropylamide MeOH methanol MeCN acetonitrile MS mass spectrometry m multiplet min(s) minute(s) mL milliliter(s) MTBE tert-butyl methyl ether m / z mass to charge ratio NaHMDS sodium bis(trimethylsilyl)amide NBS N-bromosuccinimide NCS N-chlorosuccinimide NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance Pd(dppf)Cl2 [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)Pd(dppf)Cl2.DCM [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II), complex with dichloromethane PPTS pyridinium p-toluenesulfonate Rt retention time (R)-Xyl-SDP(0) [(1R)-7′-[bis(3,5-dimethylphenyl)phosphino]-2,2′,3,3′-tetrahydro- 1,1′-spirobi[1H-inden]-7-yl]bis(3,5-dimethylphenyl)phosphine oxide s singlet STAB sodium triacetoxyborohydride t triplet TBTU 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronoium hexafluorphosphate TFA trifluoroacetic acid THF tetrahydrofuran T3P propanephosphonic acid anhydride XPhos dicyclohexyl[2′,4′,6′-tris(propan-2-yl)[1,1′-biphenyl]-2- yl]phosphane XPhos-Pd-G2 chloro(2-dicyclohexylphosphino-2′,4′,6′-triisopropyl-1,1′- biphenyl)[2-(2′-amino-1,1′-biphenyl)]palladium(II) Intermediate 1 Lithium 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetateStep 1: 2-Acetyl-6-methyl-cyclohexanoneTo a stirred solution of 2-methylcyclohexanone (52 g, 0.464 mol) in anhydrous THF (160 mL) at -78 ˚C was added slowly via cannula a solution of LDA (1 M in THF, 465 mL, 0.465 mol). The resulting mixture was stirred at -78 ˚C for 1 hour and then treated via cannula with a solution of acetyl chloride (40 mL, 0.563 mol) in anhydrous THF (100 mL). The reaction mixture was stirred at -78 ˚C for 1 h then quenched with saturated aqueous ammoniumchloride solution (250 mL) and allowed to warm to room temperature overnight. The resulting mixture was extracted with EtOAc (3 x 500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound (98 g, quantitative) as an orange oil which was used in the next step assuming a 70% purity. Step 2: 3,7-Dimethyl-4,5,6,7-tetrahydro-2H-indazoleTo a stirred solution of 2-acetyl-6-methyl-cyclohexanone (70%, 96 g, 0.436 mol) in EtOH (450 mL) was added hydrazine hydrate (1:1) (48 mL, 0.959 mol) and the reaction mixture was heated at 80 ˚C for 18 h. After cooling to room temperature, the resulting mixture was quenched with saturated aqueous ammonium chloride solution (200 mL) and water (200 mL) then extracted with DCM (500 mL). The organic layer was washed with saturated aqueous ammonium chloride solution (100 mL) and water (100 mL). The aqueous layer was further extracted with DCM (500 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound (92 g, 98%) as a yellow oil which was used in the next step assuming a 70% purity. LCMS (Method I) Rt 0.63 mins (22%); m / z 151.1 [M+H]+. Step 3: Ethyl 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetateTo a suspension of 3,7-dimethyl-4,5,6,7-tetrahydro-2H-indazole (70%, 92 g, 0.429 mol) and potassium carbonate (135 g, 0.977 mol) in MeCN (450 mL) was added ethyl bromoacetate (50 mL, 0.451 mol) dropwise. The reaction mixture was heated at 60 ˚C for 18 h. After cooling to room temperature, the resulting mixture was filtered through Celite and the filter cake rinsed with MeCN (50 mL). The filtrate was concentrated in vacuo and the resulting residue purified by chromatography on silica eluting with a gradient of 0 - 20% MTBE in heptane to afford a mixture of regioisomers. This material was further purified bychromatography on silica eluting with a gradient of 0 - 20% MTBE in heptane to afford a mixture of enantiomers (20 g, 19%). LCMS (Method J) Rt 3.28 mins (100%); m / z 237.2 [M+H]+. Chiral separation under the following conditions afforded the desired enantiomer (7.96 g, 8%); column: Lux A130 mm x 250 mm, 5 µm; column temperature: 40 ˚C; flow rate: 100 mL / min; BPR: 125 BarG; detector wavelength: 231 nm; injection volume: 2000 µL (200 mg); isocratic conditions: 15:85 Hexane:EtOH (1:1):CO2.1H NMR (400 MHz, CDCl3) δ 4.76 (d, J = 17.7 Hz, 1H), 4.69 (d, J = 17.7 Hz, 1H), 4.22 – 4.08 (m, 2H), 2.81 – 2.68 (m, 1H), 2.41 – 2.25 (m, 2H), 2.03 (s, 3H), 1.92 – 1.75 (m, 2H), 1.62 – 1.49 (m, 1H), 1.36 – 1.25 (m, 1H), 1.24 – 1.15 (m, 6H). Chiral LCMS (Method R) Rt 2.87 mins; m / z 237.2 [M+H]+; 96% ee. Step 4: Lithium 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetateA solution of lithium hydroxide hydrate (1:1) (1.22 g, 29.1 mmol) in water (40 mL) was added to a solution of ethyl 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetate (6.80 g, 28.8 mmol) in THF (80 mL) and the reaction mixture was stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo to afford the title compound (7.2 g, 99%) as a colourless solid, which was used without purification in the next step.1H NMR (400 MHz, DMSO-d6) δ 4.19 (s, 2H), 2.66 – 2.56 (m, 1H), 2.37 – 2.17 (m, 2H), 1.98 (s, 3H), 1.92 – 1.70 (m, 2H), 1.58 – 1.44 (m, 1H), 1.30 – 1.19 (m, 1H), 1.15 (d, J = 6.8 Hz, 3H). LCMS (Method E) Rt 0.58 mins (100%); m / z 209.1 [M+H]+. Intermediate 2 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetic acid1 M Lithium hydroxide (9.7 mL, 9.65 mmol) was added to a solution of ethyl 2-[(7S)-3,7- dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetate (Intermediate 1, step 3) (1.9 g, 8.04 mmol) in MeCN (10 mL). The reaction mixture was stirred at room temperature for 4.5 h. Additional 1M lithium hydroxide (4.8 mL, 4.82 mmol) was added and the reaction mixture stirred at room temperature for 18 h. The resulting mixture was concentrated in vacuo and acidified to pH 1 using aqueous 1 M HCl (1 mL). The resulting precipitate was filtered, the filter cake washed with EtOAc (25 mL), water (10 mL) and dried under vacuum to afford the title compound (1.44 g, 86%) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 4.86 – 4.67 (m, 2H), 2.68 – 2.58 (m, 1H), 2.44 – 2.34 (m, 1H), 2.33 – 2.24 (m, 1H), 2.03 (s, 3H), 1.94 – 1.75 (m, 2H), 1.61 – 1.46 (m, 1H), 1.34 – 1.19 (m, 1H), 1.15 (d, J = 6.9 Hz, 3H). The carboxylic acid proton was not observed. LCMS (Method A) Rt 0.89 mins (100%); m / z 209.0 [M+H]+. Intermediate 3 2-(3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)acetic acidStep 1: 2-Acetyl-5-methyl-cyclopentanoneThe title compound (10.5 g, quantitative) was prepared as a yellow oil from 2- methylcyclopentanone and acetyl chloride analogously to Intermediate 1, step 1, which was used in the next step assuming a 70% purity. Step 2: 3,6-Dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazoleThe title compound (1.39 g, 17%) was prepared as a yellow oil from 2-acetyl-5-methyl- cyclopentanone and hydrazine hydrate (1:1) analogously to Intermediate 1, step 2. Purification was carried out by C18 reverse phase chromatography eluting with a gradient of 0 - 50% MeCN (+0.1% formic acid) in water (+0.1% formic acid).1H NMR (500 MHz, CDCl3) δ 5.83 (s, 1H), 3.17 – 3.04 (m, 1H), 2.67 – 2.60 (m, 1H), 2.60 – 2.52 (m, 1H), 2.52 – 2.41 (m, 1H), 2.22 (s, 3H), 1.99 – 1.95 (m, 1H), 1.25 (d, J = 6.9 Hz, 3H). LCMS (Method A) Rt 0.74 mins (88%); m / z 137 [M+H]+.Step 3: Ethyl 2-(3,6-dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)acetate and ethyl 2- (3,6-dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-1-yl)acetateThe title compounds (388 mg, 8%) were prepared as a dark yellow gum and a 1:1 mixture of regioisomers from 3,6-dimethyl-2,4,5,6-tetrahydrocyclopenta[c]pyrazole and ethyl bromoacetate analogously to Intermediate 1, step 3. Purification was carried out by C18 reverse phase chromatography eluting with a gradient of 10 - 100% MeCN (+0.1% formic acid) in water (+0.1% formic acid).1H NMR (500 MHz, CDCl3) δ 4.83 – 4.60 (m, 2H), 4.26 – 4.13 (m, 2H), 3.16 – 3.02 (m, 1H), 2.76 – 2.54 (m, 1H), 2.54 – 2.40 (m, 2H), 2.16 – 2.11 (m, 3H), 2.13 – 1.83 (m, 1H), 1.31 – 1.14 (m, 6H). LCMS (Method A) Rt 0.80 mins (39%); m / z 223.1 [M+H]+. Step 4: 2-(3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)acetic acidThe title compound (125 mg, 20%) was prepared as an off-white solid from ethyl 2-(3,6- dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)acetate (1:1 mixture of regioisomers as described above) and 1 M lithium hydroxide analogously to Intermediate 1, steps 4 and 5. Separation of the regioisomers was achieved by C18 reverse phase chromatography eluting with a gradient of 10 - 30% MeCN (+0.1% formic acid) in water (+0.1% formic acid).1H NMR (400 MHz, CDCl3) δ 8.85 (s, 1H), 4.92 – 4.71 (m, 2H), 3.21 – 3.05 (m, 1H), 2.66 – 2.42 (m, 3H), 2.17 (s, 3H), 2.01 – 1.86 (m, 1H), 1.24 (d, J = 6.8 Hz, 3H). LCMS (Method A) Rt 0.88 mins (97%); m / z 195 [M+H]+. Intermediate 4 2-[6-Methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetic acidStep 1: 2‐Methyl‐5‐(2,2,2‐trifluoroacetyl)cyclopentan‐1‐oneLDA (1 M in THF 11 mL, 10.7 mmol) was added dropwise to a solution of 2- methylcyclopentanone (1.00 g, 10.2 mmol) in THF (45 mL) at -78 °C. The reaction mixture was stirred for 15 mins before dropwise addition of ethyl trifluoroacetate (1.5 mL, 11.2 mmol) whilst maintaining the reaction temperature below -70 °C. The reaction mixture was stirred at - 70 °C for 3.5 h, then allowed to warm to 0 °C over 2 h. The reaction mixture was quenched with aqueous 1 M HCl (12 mL) and partitioned between EtOAc (50 mL) and aqueous citric acid solution (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4and concentrated in vacuo to afford the title compound (2.85 g, 94%) as an orange oil, which was used in the next step assuming a 65% purity.1H NMR (400 MHz, CDCl3) δ 2.84 – 2.70 (m, 1H), 2.69 – 2.47 (m, 2H), 2.34 – 2.20 (m, 1H), 1.63 – 1.47 (m, 1H), 1.21 – 1.16 (m, 3H). OH proton not observed due to assumed enol tautomeric form. Step 2: Ethyl 2-[6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetateEthyl hydrazinylacetate hydrochloride (1.62 g, 10.5 mmol) followed by DIPEA (1.8 mL, 10.5 mmol) was added to a solution of 2-methyl-5-(2,2,2-trifluoroacetyl)cyclopentanone (65%, 2.85 g, 9.54 mmol) in EtOH (10 mL). The reaction mixture was stirred at 70 °C for 3 h, then allowed to cool to room temperature and quenched with saturated aqueous ammonium chloride (10 mL). The aqueous layer was extracted with EtOAc (3 x 20 mL) and the combined organic layers washed with brine (10 mL), dried over MgSO4and concentrated in vacuo. The resulting residue was stirred in a solution of 4 M HCl in 1,4-dioxane (6 mL, 24.0 mmol) at roomtemperature for 1 h. The reaction mixture was concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0 - 15% MTBE in heptane to afford the title compound (1.91 g, 69%).1H NMR (500 MHz, CDCl3) δ 4.98 – 4.85 (m, 2H), 4.30 – 4.16 (m, 2H), 3.21 – 3.08 (m, 1H), 2.82 – 2.57 (m, 3H), 2.05 – 1.92 (m, 1H), 1.31 – 1.23 (m, 6H). LCMS (Method H) Rt 3.72 mins (94%); m / z 277.2 [M+H]+. Step 3: 2-[6-Methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetic acid2 M lithium hydroxide (3.2 mL, 6.50 mmol) was added to a solution of ethyl 2-[6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetate (94%, 1.91 g, 6.50 mmol) in MeCN (4 mL). The reaction mixture was stirred at room temperature for 5 h. Water (2 mL) was added and the reaction mixture stirred for a further 18 h. Additional 2 M lithium hydroxide (1.0 mL, 2.00 mmol) was added and reaction mixture stirred at room temperature for 4 h. The resulting mixture was acidified to pH 3 using aqueous 6 M HCl. The aqueous layer was extracted with EtOAc (4 x 10 mL) and the combined organic layers were passed through a TELOS phase separator and concentrated in vacuo to afford the title compound (450 mg, 27%) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 4.90 – 4.75 (m, 2H), 3.11 – 3.01 (m, 1H), 2.75 – 2.55 (m, 3H), 1.98 – 1.85 (m, 1H), 1.19 (d, J = 6.9 Hz, 3H). The carboxylic acid proton was not observed. LCMS (Method E) Rt 0.81 mins (94%); m / z 249.3 [M+H]+. Intermediate 5 2-[4,6-Dimethyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetic acidStep 1: 3,5-Dimethylcyclopent-2-en-1-oneLDA (2 M in THF, 63 mL, 0.125 mol) was added to a solution of 3-methylcyclopent-2-en-1-one (10 mL, 0.104 mol) in THF (207 mL) at -78 °C. After 15 min at -78 °C, a solution of methyl iodide (7.1 mL, 0.115 mol) in THF (20 mL) was added dropwise at -78 °C. The reaction mixture was stirred at -78 °C for 30 mins and then allowed to warm to room temperature. After 1 h, the resulting mixture was quenched with aqueous 1 M HCl and then partitioned between heptane and aqueous 0.1 M HCl solution. The layers were separated, and the organic layer was washed with brine (40 mL), dried over Na2SO4and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 50 - 100% DCM in heptane to afford the title compound (5.5 g, 38%) as a pale-yellow liquid.1H NMR (400 MHz, DMSO-d6) δ 5.91 – 5.86 (m, 1H), 2.85 – 2.76 (m, 1H), 2.30 – 2.38 (m, H), 2.21 – 2.12 (m, 1H), 2.11 – 2.09 (m, 3H), 1.04 (d, J = 7.5 Hz, 3H). Step 2: 2,4-DimethylcyclopentanoneIn a 400 mL COware gas reactor equipped with stirrer bars and H-caps was added zinc (1.96 g, 30.0 mmol) into chamber A and 10% palladium on carbon (2.13 g, 2.00 mmol) into chamber B. Both chambers were purged with nitrogen. A solution of 3,5-dimethylcyclopent-2-en-1-one (80%, 5.50 g, 39.9 mmol) in MTBE (80 mL) was added into the chamber B and then closed with H-Caps. A pre-cooled solution of aqueous 6 M HCl (17 mL, 0.10 mol) was added into chamber A and sealed. The reaction mixture was stirred at room temperature for 3 days. The resulting solution was filtered through a pad of Celite and rinsed with MTBE. The filtrate was concentrated in vacuo to afford the crude material (4.8 g, 86%) as a colourless liquid and an unknown mixture of diastereomers, which was used without further purification or analysis in the next step assuming an 80% purity. Step 3: 3,5-Dimethyl-2-(2,2,2-trifluoroacetyl)cyclopentanoneSodium hydride (60% in mineral oil, 3.29 g, 82.3 mmol) was added to a solution of 2,4- dimethylcyclopentanone (80%, 7.1 g, 50.6mmol) in THF (140 mL) at 0 °C. The reactionmixture was stirred at 0 °C for 15 mins before a solution of ethyl 2,2,2-trifluoroacetate (10 mL, 82.3 mmol) in THF (70 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 3 h then allowed to warm to room temperature. After 16 h, the reaction mixture was quenched with aqueous 1 M HCl. The resulting mixture was partitioned between heptane and aqueous 0.1 M HCl solution. The layers were separated, and the aqueous layer was extracted with heptane twice. The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica with a gradient of 0 - 100% DCM in heptane to afford the title compound (4.9 g, 30%) as an orange oil and an unknown mixture of diastereomers, which was used without further purification or analysis in the next step assuming an 80% purity. Step 4: Ethyl 2-[4,6-dimethyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2- yl]acetateEthyl 2-hydrazinoacetate hydrochloride (4.08 g, 26.4 mmol) and DIPEA (13 mL, 75.3 mmol) was added to a solution of 3,5-dimethyl-2-(2,2,2-trifluoroacetyl)cyclopentanone (80%, 3.92 g, 15.0 mmol) in EtOH (100 mL) and the mixture was heated to reflux for 3 h. On cooling to room temperature, the mixture was concentrated in vacuo. The crude product was dissolved in DCM (100 mL) and washed with saturated aqueous ammonium chloride solution and brine, dried over Na2SO4and concentrated in vacuo. The crude material (5 g) was dissolved in 1,4- dioxane (9.7 mL) and 4 M HCl in 1,4-dioxane (6.1 mL, 24.3 mmol) was added. The reaction mixture was stirred at room temperature for 16 h whereupon EtOAc (50 mL) was added and the organic layer poured into a saturated aqueous solution of sodium hydrogen carbonate (50 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 50 mL). The combined organic layers were washed with brine, dried over Na2SO4and concentrated in vacuo to afford the title compound (1.25 g, 89%) as a yellow solid and an unknown mixture of diastereomers, which was used without further purification in the next step. LCMS (Method D) Rt 1.00 mins (96%); m / z 291.2 [M+H]+. Step 5: 2-[4,6-Dimethyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetic acid2 M Sodium hydroxide (3.2 mL, 6.46 mmol) was added to a solution of ethyl 2-[4,6-dimethyl- 3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetate (96%, 1.25 g, 4.14 mmol) in EtOH (15 mL) and the reaction mixture stirred at room temperature for 2 h. The solvent was concentrated in vacuo, water was added (5 mL) and the pH adjusted to pH 2 using aqueous 2 M HCl. The resulting precipitate was filtered, washed with water and dried under high vacuum at 40 °C for 16 h to afford the title compound (700 mg, 59%) as a pale-yellow solid and as an unknown mixture of diastereomers, which was used without further purification in the next step. LCMS (Method D) Rt 0.84 mins (98%); m / z 263.1 [M+H]+. Intermediate 6 2-[5-Ethyl-6-methyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetic acid thyl-5-(2,2,2-trifluoroacetyl)cyclopentan-1-oneTo a solution of ethyl 2,2,2-trifluoroacetate (5.1 mL, 42.9 mmol) in THF (100 mL) at 0 °C was added sodium hydride (60% in mineral oil, 1.71 g, 42.9 mmol). The reaction mixture was stirred at 0 °C for 15 min then a solution of ethyl 2,2,2-trifluoroacetate (5.1 mL, 42.9 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred at 0 °C for 3 h then allowed to warm to room temperature. After 16 h, the reaction mixture was quenched with aqueous 1 M HCl and partitioned between heptane and aqueous 0.1 M HCl solution. The layers were separated and the aqueous layer extracted with heptane (2 x). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0 - 100% DCM in heptane to afford the title compound (5.3 g) as a red liquid and as anunknown mixture of diastereomers assuming an 80% purity.1H NMR (400 MHz, DMSO-d6) δ 2.91 – 2.76 (m, 1H), 2.42 – 2.28 (m, 1H), 2.28 – 2.15 (m, 1H), 1.89 – 1.56 (m, 2H), 1.42 – 1.21 (m, 1H), 1.15 – 1.03 (m, 3H), 1.04 – 0.83 (m, 4H). Step 2: Ethyl 2-[5-ethyl-3-hydroxy-6-methyl-3-(trifluoromethyl)-2H,3H,3aH,4H,5H,6H- cyclopenta[c]pyrazol-2-yl]acetateEthyl 2-hydrazinoacetate hydrochloride (4.43 g, 28.6 mmol) and DIPEA (13 mL, 76.3 mmol) were added to a solution of 3-ethyl-2-methyl-5-(2,2,2-trifluoroacetyl)cyclopentan-1-one (80%, 5.3 g, 19.1 mmol) in EtOH (95 mL) and the reaction mixture heated to reflux for 3 h. On allowing to cool to room temperature, the mixture was concentrated in vacuo and the residue partitioned between DCM (100 mL) and saturated aqueous ammonium chloride solution. The layers were separated and the organic layer washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 1 - 20% MeOH in DCM to afford the title compound (3.00 g, 44%) as a yellow oil and as an unknown mixture of diastereomers. LCMS (Method D) Rt 0.90 mins (89%); m / z 305.1 [M-H2O+H]+. Step 3: Ethyl 2-[5-ethyl-6-methyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2- yl]acetate4 M HCl in 1,4-dioxane (12.4 mL, 49.2 mmol) was added to a solution of ethyl 2-[5-ethyl-3- hydroxy-6-methyl-3-(trifluoromethyl)-2H,3H,3aH,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetate (89%, 2.90 g, 9.00 mmol) in 1,4-dioxane (18 mL) at room temperature. After stirring for 16 h, the reaction mixture was diluted with EtOAc (125 mL) and washed with saturated aqueous sodium bicarbonate solution (120 mL). The aqueous phase was extracted with EtOAc (2 x60 mL) and the combined organic layers washed with brine, dried over Na2SO4and concentrated in vacuo to afford the title compound (1.85 g, 60%) as a yellow oil and an unknown mixture of diastereomers.1H NMR (400 MHz, DMSO-d6) δ 5.16 – 4.96 (m, 2H), 4.22 – 4.08 (m, 2H), 2.95 – 2.82 (m, 1H), 2.74 – 2.65 (m, 1H), 2.40 – 2.27 (m, 1H), 2.26 – 2.14 (m, 1H), 1.76 – 1.62 (m, 1H), 1.56 – 1.42 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 1.19 (t, J = 7.1 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). LCMS (Method D) Rt 1.05 mins (99%); m / z 305.1 [M+H]+. Step 4: 2-[5-Ethyl-6-methyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetic acid2 M Sodium hydroxide (9.6 mL, 19.06 mmol) was added to a solution of ethyl 2-[5-ethyl-6- methyl-3-(trifluoromethyl)-2H,4H,5H,6H-cyclopenta[c]pyrazol-2-yl]acetate (1.85 g, 6.08 mmol) in EtOH (50 mL). The reaction mixture was stirred at room temperature for 4 h, then the solvent removed in vacuo. Water was added (20 mL) and the pH adjusted to pH 2 with aqueous 2 M HCl. The resulting yellow solid was filtered, washed with water and dried under vacuum at 40 °C for 16 h to afford the title compound (1.2 g, 87%) as an unknown mixture of diastereomers.1H NMR (400 MHz, DMSO-d6) δ 13.27 (s, 1H), 5.05 – 4.81 (m, 2H), 2.92 – 2.83 (m, 1H), 2.75 – 2.61 (m, 1H), 2.42 – 2.29 (m, 1H), 2.27 – 2.14 (m, 1H), 1.82 – 1.59 (m, 1H), 1.58 – 1.35 (m, 1H), 1.23 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.4 Hz, 3H). LCMS (Method D) Rt 0.90 mins (100%); m / z 277.1 [M+H]+. Intermediate 7 Lithium 2-[6-ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetateStep 1: 2-Ethyl-5-(2,2,2-trifluoroacetyl)cyclopentanoneTo a solution of 2-ethylcyclopentanone (1.00 g, 8.92 mmol) in THF (40 mL) cooled to -78 °C was added a solution of LDA (1 M in THF, 9.4 mL, 9.36 mmol) dropwise over 15 mins. The reaction mixture was stirred for 15 min at -78 °C before ethyl trifluoroacetate (1.3 mL, 9.81 mmol) was added dropwise. The reaction mixture was allowed to warm to 10 °C overnight then quenched with aqueous 1 M HCl (12 mL). The resulting mixture was partitioned between EtOAc (50 mL) and 10% aqueous citric acid solution (30 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (40 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (2.37 g, quantitative) as an orange oil and a mixture of diasteromers.1H NMR (400 MHz, CDCl3) δ 13.14 (s, 1H), 2.84 – 2.70 (m, 1H), 2.70 – 2.55 (m, 1H), 2.57 – 2.41 (m, 1H), 2.29 – 2.15 (m, 1H), 1.94 – 1.78 (m, 1H), 1.69 – 1.55 (m, 1H), 1.50 – 1.32 (m, 1H), 1.03 – 0.88 (m, 3H). Step 2: Ethyl 2-[6-ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetateEthyl hydrazinylacetate hydrochloride (1.53 g, 9.89 mmol) was added to a solution of 2-ethyl- 5-(2,2,2-trifluoroacetyl)cyclopentanone (79%, 2.37 g, 8.99 mmol) in EtOH (9 mL) and the reaction mixture stirred at 70 °C for 2 h. The resulting mixture was allowed to cool to room temperature and quenched with a saturated aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL), then the combined organic layers dried over MgSO4and concentrated in vacuo. The resulting yellow oil was stirred in a solution of 4 M HCl in 1,4-dioxane (11.3 mL, 45.0 mmol) at room temperature. After 1.5 h, the solvent was concentrated in vacuo and the residue purified by chromatography on silica eluting with a gradient 0 - 10% MTBE in heptane to afford the title compound (2.17 g, 78%).1H NMR (500 MHz, CDCl3) δ 4.98 – 4.86 (m, 2H), 4.29 – 4.15 (m, 2H), 3.03 – 2.91 (m, 1H), 2.80 – 2.62 (m, 2H), 2.66 – 2.55 (m, 1H), 2.12 – 2.00 (m, 1H), 1.80 – 1.65 (m, 1H), 1.61 –1.47 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 1.02 (t, J = 7.4 Hz, 3H). LCMS (Method H) Rt 4.09 mins (94%); m / z 291.1 [M+H]+. Step 3: Lithium 2-[6-ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2- yl]acetate2 M Lithium hydroxide (3.6 mL, 7.11 mmol) was added to a solution of ethyl 2-[6-ethyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]acetate (2.20 g, 7.11 mmol) in MeCN (5 mL) and the mixture stirred at room temperature for 18 h. Additional MeCN (5 mL) and water (2 mL) were added and the reaction mixture stirred at room temperature for 4 h. Additional 2 M lithium hydroxide (2.0 mL, 4.00 mmol) was added and the reaction mixture stirred at room temperature for 2 h. The reaction mixture was then concentrated in vacuo to afford the title compound (1.80 g, 88%) as an off-white solid.1H NMR (500 MHz, DMSO-d6) δ 4.40 – 4.30 (s, 2H), 2.90 – 2.79 (m, 1H), 2.72 – 2.53 (m, 3H), 2.02 – 1.90 (m, 1H), 1.66 – 1.53 (m, 1H), 1.53 – 1.40 (m, 1H), 0.99 (t, J = 7.4 Hz, 3H). LCMS (Method E) Rt 0.90 mins (98%); m / z 263.3 [M+H]+. Intermediate 8 2-[5-(Trifluoromethyl)-3,4-diazatricyclo[5.2.1.02,6]deca-2,5-dien-4-yl]acetic acid oacetyl)bicyclo[2.2.1]heptan‐2‐oneLDA (1 M in THF, 25 mL, 24.8 mmol) was added to a solution of bicyclo[2.2.1]heptan-2-one (2.60 g, 23.6 mmol) in THF (110 mL) at -78 ˚C. The reaction mixture was stirred for 15 mins at -78 ˚C then ethyl trifluoroacetate (3.3 mL, 25.3 mmol) was added dropwise. The reactionmixture was allowed to warm to room temperature and stirred for 18 h. The resulting mixture was quenched with aqueous 1 M HCl (25 mL) and partitioned between EtOAc (200 mL) and 10% aqueous citric acid (100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 125 mL). The combined organic layers were washed with brine (70 mL), dried over MgSO4and concentrated in vacuo to afford the title compound (4.6 g, 53%) as an orange oil, which used without further purification and analysis. Step 2: 2-[5-(Trifluoromethyl)-3,4-diazatricyclo[5.2.1.02,6]deca-2,5-dien-4-yl]acetic acidA solution of 3-(2,2,2‐trifluoroacetyl)bicyclo[2.2.1]heptan‐2‐one (500 mg, 2.43 mmol) in EtOH (8 mL) was treated with ethyl hydrazinylacetate hydrochloride (750 mg, 4.85 mmol) and heated at 70 ˚C for 3 h. The resulting mixture was filtered, and the filtrate quenched with aqueous ammonium chloride solution (10 mL). The aqueous layer was extracted with EtOAc (2 x 15 mL) and the combined organic layers dried over MgSO4 and concentrated in vacuo. The resulting solid was dissolved in THF (16 mL), treated with aqueous 3 M HCl (3.3 mL, 9.75 mmol) and heated to reflux for 7 h. The resulting mixture was allowed to cool to room temperature and partitioned between EtOAc (30 mL) and aqueous 1 M HCl (10 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (30 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. The resulting brown oil was dissolved in 1,4-dioxane (1.2 mL) and aqueous 5 M NaOH (1.2 mL, 6.00 mmol) was added. The reaction mixture was heated to reflux for 18 h then allowed to cool to room temperature. The mixture was then acidified with aqueous 1 M HCl (10 mL) and extracted with EtOAc (2 x 20 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford the title compound (95 mg, 22%) as a brown oil, which was used without further purification in the next step. LCMS (Method I): Rt 0.42 (17%) and 0.44 mins (47%); mins; m / z 261.1 [M+H]+. Intermediate 9 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)acetic acidpropyl-5-methyl-pyrazol-1-yl)acetateA stirred mixture of 3-isopropyl-5-methyl-1H-pyrazole hydrochloride (2.00 g, 12.5 mmol) and potassium carbonate (5.16 g, 37.4 mol) in MeCN (20 mL) under nitrogen was treated dropwise with ethyl bromoacetate (1.4 mL, 12.5 mmol) and the reaction mixture heated at 70 ˚C for 18 h. The resulting mixture was allowed to cool to room temperature and the suspension filtered through cotton wool / sand, washing the filter cake with EtOAc, and the filtrate concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0 - 25% MTBE in heptane afforded the title compound (1.54 g, 59%) as a pale-yellow oil.1H NMR (500 MHz, DMSO-d6) δ 5.88 (s, 1H), 4.87 (s, 2H), 4.14 (q, J = 7.1 Hz, 2H), 2.83 – 2.69 (m, 1H), 2.18 – 2.10 (m, 3H), 1.20 (t, J = 7.1 Hz, 3H), 1.14 (d, J = 6.9 Hz, 6H). LCMS (Method C) Rt 4.36 mins (100%); m / z 211.1 [M+H]+. Step 2: 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)acetic acidA mixture of ethyl 2-(3-isopropyl-5-methyl-pyrazol-1-yl)acetate (7.61 g, 36.2 mmol) in MeCN (50 mL) was treated with 2 M lithium hydroxide (20 mL, 40.0 mmol) and stirred at room temperature for 1.5 h. Aqueous 2 M HCl (25 mL) was added and the resulting mixture was extracted with EtOAc (3 x 50 mL). The combined organic layers were washed with brine (20 mL), dried over MgSO4 and concentrated in vacuo to afford the title compound (4.97 g, 73%) as a cream solid.1H NMR (500 MHz, CDCl3) δ 5.97 (s, 1H), 4.90 (s, 2H), 3.00 (p, J = 6.9 Hz, 1H), 2.26 (s, 3H), 1.26 (d, J = 7.0 Hz, 6H). The carboxylic acid proton was not observed. LCMS (Method A) Rt 0.81 mins (95%); m / z 181.1 [M-H]-. Intermediate 10 3-Isopropyl-5-(trifluoromethyl)-1H-pyrazoleThe title compound (2.22 g, 45%) was prepared from 1,1,1-trifluoro-5-methyl-hexane-2,4- dione and hydrazine hydrate (1:1) analogously to Intermediate 1, step 2. Purification was carried out by C18 reverse phase chromatography eluting with a gradient of 0 - 60% MeCN (+ 0.1% ammonia) in water (+ 0.1% ammonia).1H NMR (400 MHz, CDCl3) δ 6.31 (s, 1H), 3.02 (hept, J = 6.9 Hz, 1H), 1.29 (d, J = 7.0 Hz, 6H). LCMS (Method A) Rt 1.11 mins (99%); m / z 179.0 [M+H]+. Intermediate 11 Lithium 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetateStep 1: Ethyl 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetateDIPEA (10 mL, 58.4 mmol) was added to a stirred solution of ethyl 2-hydrazinoacetate hydrochloride (8.20 g, 53.0 mmol) in EtOH (140 mL) and the reaction mixture stirred at room temperature for 10 min.1-Cyclopropyl-4,4,4-trifluorobutane-1,3-dione (95%, 10.00 g, 52.7 mmol) in EtOH (120 mL) was then added dropwise, maintaining the internal temperature between 17 - 20 °C using an ice-water bath. The reaction mixture was stirred at room temperature for 3 h then concentrated in vacuo. The resulting residue was partitioned between EtOAc and water; the layers were separated, and the aqueous layer extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with a saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over Na2SO4and concentrated in vacuo. The residue was dissolved in HCl (4 M in 1,4-dioxane, 160 mL, 0.640 mol), stirred at room temperature for 3 h then concentrated in vacuo. The residue was partitioned between EtOAc (100 mL) and saturated aqueous sodium bicarbonate solution(100 mL). The layers were separated, and the aqueous layer was extracted with EtOAc (2 x 100 mL). The combined organic layers were washed with saturated aqueous sodium bicarbonate solution (50 mL) and brine (50 mL), dried over Na2SO4 and concentrated in vacuo. The crude material was purified by chromatography on silica with an isocratic gradient of 5% EtOAc in heptane to afford the title compound (9.9 g, 72%) as a yellow oil.1H NMR (400 MHz, CDCl3) δ 6.32 (s, 1H), 4.91 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.98 – 1.88 (m, 1H), 1.26 (t, J = 7.1 Hz, 3H), 0.99 – 0.90 (m, 2H), 0.80 – 0.68 (m, 2H). LCMS (Method D) Rt 0.89 mins (100%); m / z 263.4 [M+H]+. Step 2: Lithium 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetateLithium hydroxide hydrate (1:1) (1.39 g, 33.1 mmol) was added to a solution of ethyl 2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetate (8.68 g, 33.1 mmol) in EtOH (40 mL) and water (20 mL) and the mixture stirred at room temperature for 1 h. The solvent was removed in vacuo to afford the title compound (7.95 g, 100%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 6.41 (s, 1H), 4.33 (s, 2H), 1.93 – 1.80 (m, 1H), 0.89 – 0.83 (m, 2H), 0.68 – 0.62 (m, 2H). LCMS (Method E) Rt 0.75 mins (100%); m / z 235.1 [M+H]+. Intermediate 12 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acid -cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetatetert-Butyl 2-bromoacetate (23 mL, 0.156 mol) was added to a stirred suspension of 3- cyclopropyl-5-(trifluoromethyl)-1H-pyrazole (25 g, 0.142 mol) and potassium carbonate (23.5g, 0.17 mol) in MeCN (250 mL) and the reaction mixture stirred at 70 ˚C for 19 h. Additional tert-butyl-bromoacetate (3 mL, 25 mmol) was added and stirring continued at 70 ˚C for a further 4 h. After allowing to cool to room temperature, the resulting mixture was filtered and the filtrate concentrated in vacuo to afford the crude material as a mixture of regioisomers in a ratio of 7.5:1 (by LCMS) in favour of the undesired regioisomer. The crude material was recrystallised from heptane three times to enrich the mixture to a ratio of 2:1 in favour of the undesired regioisomer. This enriched material was purified by chromatography on silica eluting with a gradient of 0 - 5% MTBE in heptane. The fractions containing the desired regioisomer were combined and further purified by chromatography on silica eluting with a gradient of 0 - 5% TBME in heptane to afford the title compound (2.46 g, 6%).1H NMR (500 MHz, CDCl3) δ 6.31 (s, 1H), 4.82 (s, 2H), 1.97 – 1.88 (m, 1H), 1.44 (s, 9H), 0.97 – 0.91 (m, 2H), 0.75 – 0.71 (m, 2H). LCMS (Method E) Rt 1.00 mins (97%); m / z 291.4 [M+H]+. Step 2a: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acid4 M HCl in 1,4-dioxane (13 mL, 50.0 mmol) was added to a stirred solution of tert-butyl 2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetate (1.45 g, 5.00 mmol) in MeCN (15 mL) and the reaction mixture stirred at 60 ˚C for 2 h. The resulting mixture was concentrated in vacuo and azeotroped with MeCN to afford the title compound (1.27 g, 100%) as an off-white solid.1H NMR (400 MHz, DMSO-d6) δ 13.30 (br s, 1H), 6.65 (s, 1H), 4.96 (s, 2H), 1.98 – 1.85 (m, 1H), 0.96 – 0.87 (m, 2H), 0.73 – 0.65 (m, 2H). LCMS (Method E) Rt 0.75 mins (93%); m / z 235.2 [M+H]+. 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acid (Intermediate 12) may also be isolated under the following conditions: Step 2b: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acid2 M Sodium hydroxide (57 mL, 0.114 mol) was added to a stirred solution of ethyl 2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetate (Intermediate 11, step 2) (9.9 g, 37.8 mmol) in EtOH (100 mL) and the reaction mixture stirred at room temperature for 1 h. The solvent was removed in vacuo and the aqueous residue diluted with a solution of potassium hydrogen sulfate (17 g, 0.125 mol) in water (200 mL). The resulting precipitate was filtered, washed with water (2 x) and dried under vacuum at room temperature for 18 h to afford the title compound (8.22 g, 93%) as a white powder. Intermediate 13 2-(3,5-Dicyclopropyl-4-fluoro-pyrazol-1-yl)acetic acidStep 1: Ethyl 2-(3,5-dicyclopropylpyrazol-1-yl)acetateThe title compound (658 mg, 79%) was prepared as a pale-yellow oil from 3,5-dicyclopropyl- 1H-pyrazole and ethyl bromoacetate analogously to Intermediate 9, step 1. Purification was carried out by purified by chromatography on silica eluting with a gradient of 0 - 50% MTBE in heptane.1H NMR (500 MHz, CDCl3) δ 5.54 (s, 1H), 4.89 (s, 2H), 4.22 (q, J = 7.1 Hz, 2H), 1.91 – 1.82 (m, 1H), 1.62 – 1.55 (m, 1H), 1.27 (t, J = 7.1 Hz, 3H), 0.94 – 0.83 (m, 4H), 0.69 – 0.60 (m, 4H). LCMS (Method E) Rt 0.84 mins (96%);m / z 235.6 [M+H]+. Step 2: Lithium 2-(3,5-dicyclopropylpyrazol-1-yl)acetateTo a solution of ethyl 2-(3,5-dicyclopropylpyrazol-1-yl)acetate (95%, 658 mg, 2.67 mmol) in THF (10 mL) was added a solution of lithium hydroxide hydrate (1:1) (123 mg, 2.93 mmol) in water (5 mL). The reaction mixture was stirred at room temperature for 18 h thenconcentrated in vacuo to afford the title compound (620 mg, quantitative) as a beige powder.1H NMR (500 MHz, CD3OD) δ 5.52 (s, 1H), 4.65 (s, 2H), 1.84 – 1.76 (m, 1H), 1.74 – 1.67 (m, 1H), 0.93 – 0.77 (m, 4H), 0.65 – 0.59 (m, 4H). LCMS (Method E) Rt 0.62 mins (84%); m / z 207.4 [M+H]+. Step 3: 2-(3,5-Dicyclopropyl-4-fluoro-pyrazol-1-yl)acetic acidTo a solution of lithium 2-(3,5-dicyclopropylpyrazol-1-yl)acetate (100 mg, 0.471 mmol) in MeCN (3 mL) was added Selectfluor (180 mg, 0.508 mmol). The reaction mixture was stirred at room temperature for 18 h then concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0 - 100% MTBE in heptane followed by 0 - 50% MeOH in MTBE to afford the title compound (80 mg, 48%). LCMS (Method E) Rt 0.74 mins (64%); m / z 225.3 [M+H]+. Intermediate 14 2-[4-Bromo-3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetic acidNBS (36 mg, 0.202 mmol) was added to a solution of 2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetic acid (Intermediate 12) (45 mg, 0.192 mmol) in water (1 mL). The reaction mixture was sonicated for 20s then stirred at room temperature for 7 h. The resulting mixture was extracted with EtOAc (3 x 5 mL) and the combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification of the crude material by chromatography on silica eluting with a gradient of 0 - 100% MTBE in heptane followed by 0 - 100% MeOH in MTBE afforded the title compound (28 mg, 46%) as a white solid.1H NMR (500 MHz, DMSO-d6) δ 5.03 – 4.81 (m, 2H), 1.91 – 1.82 (m, 1H), 0.98 – 0.92 (m, 2H), 0.80 – 0.75 (m, 2H). LCMS (Method E) Rt 0.84 mins (99%); m / z 313.1 / 315.2 [M+H]+.Intermediate 15 2-[4-Chloro-3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetic acidStep 1: 4,4,4-Trifluoro-1-(1-methylcyclopropyl)butane-1,3-dioneTo a solution of ethyl 2,2,2-trifluoroacetate (3.8 mL, 31.2 mmol) in sodium ethoxide (21% in EtOH, 23 mL, 62.4 mmol) was added 1-(1-methylcyclopropyl)ethanone (5.00 g, 31.2 mmol) and the mixture stirred at 65 ˚C for 18 h; it was then allowed to cool to room temperature. The material was used in the next step assuming a quantitative yield. Step 2: 3-(1-Methylcyclopropyl)-5-(trifluoromethyl)-1H-pyrazoleThe title compound (1.03 g, 10%) was prepared as a pale yellow oil from 4,4,4-trifluoro-1-(1- methylcyclopropyl)butane-1,3-dione and hydrazine hydrate (1:1) analogously to Intermediate 1, step 2. Purification was carried out by chromatography on silica eluting with a gradient of 0 - 10% EtOAc in heptane.1H NMR (400 MHz, CDCl3) δ 10.50 (s, 1H), 6.21 (s, 1H), 1.45 (s, 3H), 0.98 – 0.89 (m, 2H), 0.89 – 0.82 (m, 2H). LCMS (Method I) Rt 0.71 mins (54%); m / z 189 [M-H]-. Step 3: tert-Butyl 2-[3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetateThe title compound (350 mg, 32%) was prepared as a pale-yellow oil from 3-(1- methylcyclopropyl)-5-(trifluoromethyl)-1H-pyrazole and tert-butyl 2-bromoacetateanalogously to Intermediate 12, step 1. The desired regioisomer was isolated as the first eluting peak from purification by chromatography on silica eluting with a gradient of 0 - 2.4% MTBE in heptane.1H NMR (400 MHz, CDCl3) δ 6.40 (s, 1H), 4.81 (s, 2H), 1.44 (s, 9H), 1.43 (s, 3H), 1.00 – 0.92 (m, 2H), 0.79 – 0.70 (m, 2H). LCMS (Method E) Rt 1.09 mins (44%); m / z 305.4 [M+H]+. Step 4: 2-[3-(1-Methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetic acidThe title compound (262 mg, 92%) was prepared as a cream solid from tert-butyl 2-[3-(1- methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetate and 4 M HCl in 1,4-dioxane analogously to Intermediate 12, step 2a. LCMS (Method E) Rt 0.77 mins (90%); m / z 249.3 [M+H]+. Step 5: 2-[4-Chloro-3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetic acidTo a solution of 2-[3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]acetic acid (50 mg, 0.201 mmol) in MeCN (1 mL) was added NCS (28 mg, 0.210 mmol) and the mixture stirred at 80 ˚C for 1.5 h. On allowing to cool to room temperature, the reaction mixture was diluted with water (5 mL) and the layers separated. The aqueous layer was extracted with EtOAc (3 x 10 mL) and the combined organic layers dried over Na2SO4 and concentrated in vacuo to afford the title compound (130 mg, quantitative) which was used in the next step without further purification assuming a purity of 44%. LCMS (Method E) Rt 0.92 mins (100%); m / z 283.3 / 285.3 [M+H]+. Intermediate 16 2-[3-[2,2-Difluorocyclopropyl]-5-(trifluoromethyl)pyrazol-1-yl]acetic acidN-methoxy-N-methyl-cyclopropanecarboxamideTo a stirred suspension of 2,2-difluorocyclopropanecarboxylic acid (5.00 g, 41.0 mmol) and triethylamine (17 mL, 0.123 mol) in DCM (100 mL) was added N-methoxymethanamine hydrochloride (98%, 4.89 g, 49.2 mmol) and HATU (18.69 g, 49.2 mmol). The reaction mixture was stirred at room temperature for 3 h. The resulting mixture was partially concentrated in vacuo. The resulting residue was diluted with water (200 mL) and extracted with EtOAc (3 x 150 mL). The combined organic layers were washed with brine (100 mL), passed through a TELOS phase separator and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0 - 100% EtOAc in heptane to afford the title compound (5.76 g, 81%).1H NMR (400 MHz, CDCl3) δ 3.75 (d, J = 1.1 Hz, 3H), 3.24 (d, J = 1.3 Hz, 3H), 2.99 – 2.86 (m, 1H), 2.21 – 2.04 (m, 1H), 1.74 – 1.61 (m, 1H). Step 2: 1-(2,2-Difluorocyclopropyl)ethanoneMethylmagnesium bromide (3 M in diethyl ether, 21 mL, 62.8 mmol) was added dropwise to an ice-cooled (0 ˚C) solution of 2,2-difluoro-N-methoxy-N-methyl-cyclopropanecarboxamide (5.76 g, 34.9 mmol) in anhydrous THF (80 mL). The reaction mixture was allowed to warm to room temperature and stirred for 2 h. The resulting mixture was treated dropwise with saturated aqueous ammonium chloride solution (20 mL) and partitioned between EtOAc (80 mL) and water (100 mL). The layers were separated, and the organic layer was washed with water (80 mL), brine (80 mL), dried over MgSO4 concentrated in vacuo to afford the title compound (1.28 g, 31%).1H NMR (500 MHz, CDCl3) δ 2.81 – 2.70 (m, 1H), 2.32 (s, 3H), 2.22 – 2.12 (m, 1H), 1.78 – 1.60 (m, 1H).Step 3: 1-(2,2-Difluorocyclopropyl)-4,4,4-trifluoro-butane-1,3-dioneSodium hydride (60% in mineral oil, 0.51 g, 12.8 mmol) was added portion-wise to an ice- cooled (0 ˚C) suspension of 1-(2,2-difluorocyclopropyl)ethanone (1.28 g, 10.7 mmol) and ethyl 2,2,2-trifluoroacetate (98%, 1.55 g, 10.7 mmol) in anhydrous THF(18 mL). The reaction mixture was allowed to warm to room temperature and stirred at 70 ˚C for 2.5 h, the cooled to room temperature. The solvent was concentrated in vacuo. The residual oil was dissolved in water (20 mL) and the pH adjusted to pH 1 with aqueous 6 M HCl (~6 mL). The aqueous layer was extracted with EtOAc (3 x 15 mL). The combined organic layers were passed through a TELOS phase separator and concentrated in vacuo. The mixture was redissolved in EtOAc, dried over MgSO4and concentrated in vacuo once more to afford the title compound (1.42 g, 19%). The crude material was used in the next step without further purification.1H NMR (400 MHz, CDCl3) δ 6.09 (s, 1H), 2.65 – 2.54 (m, 1H), 2.33 – 2.23 (m, 1H), 1.95 – 1.84 (m, 1H). OH proton not observed due to enol tautomeric form. Step 4: 3-[2,2-Difluorocyclopropyl]-5-(trifluoromethyl)-1H-pyrazoleThe title compound (314 mg, 22%) was prepared from 1-(2,2-difluorocyclopropyl)-4,4,4- trifluoro-butane-1,3-dione and hydrazine hydrate (1:1) analogously to Intermediate 1, step 2. Purification was carried out by chromatography on silica eluting with a gradient of 0 - 50% MTBE in heptane. LCMS (Method E) Rt 0.81 mins (97%); m / z 211.3 [M-H]- Step 5: tert-Butyl 2-[3-[2,2-difluorocyclopropyl]-5-(trifluoromethyl)pyrazol-1-yl]acetatetert-Butyl 2-bromoacetate (0.32 mL, 2.15 mmol) was added to a stirred suspension of 3-[2,2- difluorocyclopropyl]-5-(trifluoromethyl)-1H-pyrazole (97%, 314 mg, 1.44 mmol) andpotassium carbonate (298 mg, 2.15 mmol) in MeCN (3.05 mL). The reaction mixture was stirred at 70 °C for 18 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuo. The crude mixture comprising approximately 85:15 undesired to desired regioisomer by LCMS was triturated in heptane once and then purified by chromatography on silica eluting with a gradient of 0 - 5% MTBE in heptane to afford the title compound (47 mg, 10%).1H NMR (400 MHz, CDCl3) δ 6.51 (s, 1H), 4.86 (s, 2H), 2.83 – 2.70 (m, 1H), 1.92 – 1.78 (m, 1H), 1.78 – 1.63 (m,1H), 1.44 (s, 9H). LCMS (Method E) Rt 1.07 mins; m / z 270.9 [M-tButyl+H]+. Step 6: 2-[3-[2,2-Difluorocyclopropyl]-5-(trifluoromethyl)pyrazol-1-yl]acetic acidTo a stirred solution of tert-butyl 2-[3-[2,2-difluorocyclopropyl]-5-(trifluoromethyl)pyrazol-1- yl]acetate (47 mg, 0.144 mmol) in MeCN (0.47 mL) was added 4 M HCl in 1,4-dioxane (0.36 mL, 1.44 mmol). The reaction mixture was stirred at 60 ˚C for 2 h. The resulting mixture was concentrated in vacuo to afford the title compound (36 mg, 91%). LCMS (Method E) Rt 0.77 mins (98%); m / z 271.2 [M+H]+. Intermediate 17 Lithium 2-[3-methyl-5-(trifluoromethyl)-2-pyridyl]acetate S hyl-5-(trifluoromethyl)-2-pyridyl]acetateTo a solution of methyl [3-chloro-5-(trifluoromethyl)pyridin-2-yl]acetate (600 mg, 2.37 mmol) and 2,4,6-trimethyl-1,3,5,2,4,6-trioxatriborinane (0.66 mL, 2.36 mmol) in 1,4-dioxane (6 mL) was added potassium carbonate (654 mg, 4.73 mmol) and Pd(dppf)Cl2.DCM (97 mg,0.119 mmol) under a nitrogen atmosphere. The reaction mixture was sparged with nitrogen for 5 mins then stirred at 105 °C for 20 h. The reaction mixture was cooled to room temperature and water (3 mL) was added. The aqueous layer was extracted with EtOAc (20 mL). The organic layer was dried over Na2SO4and concentrated in vacuo. The crude residue was purified by chromatography on silica with a gradient of 0 - 50% EtOAc in heptane to afford the title compound (374 mg, 77%) as an orange oil.1H NMR (400 MHz, DMSO-d6) δ 8.71 (dt, J = 2.4, 0.9 Hz, 1H), 8.06 (dt, J = 2.4, 0.8 Hz, 1H), 4.01 (s, 2H), 3.65 (s, 3H), 2.36 (s, 3H). LCMS (Method D) Rt 1.27 mins (100%); m / z 234.2 [M+H]+. Step 2: Lithium 2-[3-methyl-5-(trifluoromethyl)-2-pyridyl]acetateTo a solution of methyl 2-[3-methyl-5-(trifluoromethyl)-2-pyridyl]acetate (374 mg, 1.52 mmol) in MeOH (2.3 mL), THF (2.3 mL) and water (0.5 mL) was added lithium hydroxide (39 mg, 1.60 mmol). The reaction mixture was stirred at room temperature for 17 h. The resulting mixture was concentrated in vacuo to afford the title compound (350 mg, 97%) as a beige powder.1H NMR (400 MHz, CD3OD) δ 8.70 – 8.47 (m, 1H), 7.86 (d, J = 2.2 Hz, 1H), 3.84 (s, 2H), 2.44 (s, 3H). LCMS (Method F) Rt 0.98 mins (67%); m / z 220.1 [M+H]+. Intermediate 18 Lithium 2-[4-methyl-6-(trifluoromethyl)-3-pyridyl]acetate 4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2-(trifluoromethyl)pyridine5-Bromo-4-methyl-2-(trifluoromethyl)pyridine (0.19 mL, 1.22 mmol) and Pd(dppf)Cl2.DCM (61 mg, 0.074 mmol) were added to a stirred mixture of potassium acetate (361 mg, 3.67mmol) and 4,4,5,5-tetramethyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1,3,2- dioxaborolane (635 mg, 2.45 mmol) in 1,4-dioxane (3.6 mL) in a pressure-relief vial under nitrogen. The atmosphere was purged with nitrogen and heated at 110 °C for 16 h. The reaction mixture was cooled to room temperature and partitioned between EtOAc (20 mL) and water (5 mL). The layers were separated, and the organic layer was washed with brine (5 mL), dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica with a gradient of 0 - 10% MeOH in DCM to afford the title compound (427 mg, 90%) as a yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.78 (s, 1H), 7.75 (t, J = 0.8 Hz, 1H), 2.58 (d, J = 0.6 Hz, 3H), 1.34 (s, 12H). Step 2: Ethyl 2-[4-methyl-6-(trifluoromethyl)-3-pyridyl]acetateA solution of 4-methyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2- (trifluoromethyl)pyridine (425 mg, 1.10 mmol), XPhos-Pd-G2 (8.6 mg, 0.01 mmol) and XPhos (10 mg, 0.02 mmol) in anhydrous THF (7.3 mL) was sparged with nitrogen for 5 min.2 M Potassium carbonate (2.9 mL, 5.86 mmol) and ethyl 2-chloroacetate (0.14 mL, 1.31 mmol) were added. The reaction mixture was sparged with nitrogen for 5 min and stirred at 80 °C for 2 h. The reaction mixture was cooled down to room temperature and partitioned between EtOAc (20 mL) and brine (10 mL). The layers were separated, and the organic layer was dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica with a gradient of 0 - 50% EtOAc in heptane to afford (145 mg, 54%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 8.55 (s, 1H), 7.78 (s, 1H), 4.12 (q, J = 7.1 Hz, 2H), 3.90 (s, 2H), 2.36 (s, 3H), 1.20 (t, J = 7.1 Hz, 3H). LCMS (Method F) Rt 1.39 mins (100%); m / z 248.1 [M+H]+. Step 3: Lithium 2-[4-methyl-6-(trifluoromethyl)-3-pyridyl]acetateLithium hydroxide (14 mg, 0.59 mmol) was added to a solution of ethyl 2-[4-methyl-6- (trifluoromethyl)-3-pyridyl]acetate (139 mg, 0.562 mmol) in MeOH (1 mL), THF (1 mL) and water (0.2 mL) at room temperature. The reaction mixture was stirred at roomtemperature for 17 h. The resulting mixture was concentrated in vacuo to afford the title compound (126 mg, quantitative) as a white solid. LCMS (Method D) Rt 0.66 mins (96%); m / z 220.3 [M+H]+. Intermediate 19 Lithium 2-[2-methyl-6-(trifluoromethyl)-3-pyridyl]acetate thyl-6-(trifluoromethyl)-3-pyridyl]propanedioateIn a pressure-relief vial, tripotassium phosphate (520 mg, 2.45 mmol) and diethyl propanedioate (300 uL, 1.96 mmol) were added to a stirred suspension of 3-bromo-2- methyl-6-(trifluoromethyl)pyridine (200 mg, 0.79 mmol) in DMSO (6 mL). The reaction mixture was sparged with nitrogen for 10 mins then copper(I) iodide (15 mg, 0.08 mmol) and 1,3-benzoxazole (50 mg, 0.420 mmol) was added. The vial was sealed and the reaction mixture stirred at 90 °C for 18 h. The reaction mixture was cooled to room temperature before additional diethyl propanedioate (300 uL, 1.96 mmol), 1,3-benzoxazole (42 mg, 0.353 mmol) and copper(I) iodide (18 mg, 0.09 mmol) were added. The reaction mixture was stirred at 90 °C for 4 h. After cooling to room temperature, the resulting mixture was partitioned between water and EtOAc. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x). The combined organic layers were washed with saturated aqueous ammonium chloride solution, passed through a phase separator and concentrated in vacuo. The resulting brown oil was purified by chromatography on silica with a gradient of 0 - 50% EtOAc in heptane to afford the title compound (55 mg, 19%) as a colourless oil.1H NMR (400 MHz, DMSO-d6) δ 7.94 (d, J = 8.1 Hz, 1H), 7.79 (d, J = 8.1 Hz, 1H), 4.27 – 4.16 (m, 4H), 4.14 – 4.06 (m, 1H), 2.55 (s, 3H), 1.25 – 1.15 (m, 6H). LCMS (Method F) Rt 1.61 mins (87%); m / z 320.3 [M+H]+. Step 2: Lithium 2-[2-methyl-6-(trifluoromethyl)-3-pyridyl]acetateLithium hydroxide (11 mg, 0.450 mmol) was added to a stirred solution of diethyl 2-[2- methyl-6-(trifluoromethyl)-3-pyridyl]propanedioate (55 mg, 0.150 mmol) in MeOH (1.5 mL) and water (0.5 mL). The reaction mixture was stirred at room temperature for 32 h. The resulting mixture was concentrated in vacuo to afford the title compound (37 mg, 82%) as a white powder. LCMS (Method F) Rt 1.01 mins (52%); m / z 220.2 [M+H]+. Intermediate 20 Lithium 2-[4-methyl-6-(trifluoromethyl)139yridazine-3-yl]acetateTo a solution of diethyl propanedioate (1.1 mL, 7.25 mmol) in 1,4-dioxane (31 mL) was added sodium hydride (60% in mineral oil, 0.39 g, 9.67 mmol) at 5 – 10 °C. The reaction mixture was stirred at 5 – 10 °C for 1 h before 3-chloro-4-methyl-6-(trifluoromethyl)pyridazine (1.00 g, 4.83 mmol) was added. The reaction mixture was stirred at 110 °C for 16 h. The resulting mixture was allowed to cool to room temperature. Water (10 mL) was added and the aqueous Iayer was extracted with EtOAc (2 x 30 mL). The combined organic layers were washed with brine (10 mL), dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica with a gradient of 0 - 40% EtOAc in heptane to afford the title compound (0.928 g, 57%) as a pale-yellow solid.1H NMR (400 MHz, DMSO-d6) δ 8.24 (d, J = 1.0 Hz, 1H), 5.73 (s, 1H), 4.24 (q, J = 7.1 Hz, 4H), 2.38 (d, J = 0.8 Hz, 3H), 1.22 (t, J = 7.1 Hz, 6H). LCMS (Method F) Rt 1.41 mins (99%); m / z 321.3 [M+H]+.Step 2: Lithium 2-[4-methyl-6-(trifluoromethyl)pyridazin-3-yl]acetateLithium hydroxide (109 mg, 4.45 mmol) was added to a solution of diethyl 2-[4-methyl-6- (trifluoromethyl)pyridazin-3-yl]propanedioate (95%, 300 mg, 0.890 mmol) in MeOH (9 mL) and water (3 mL). The reaction mixture was stirred at 60 °C for 5 h. The reaction mixture was cooled to room temperature and additional lithium hydroxide (45.3 mg, 1.78 mmol) was added. The reaction mixture was stirred at 60 °C for 8 h. The resulting mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc (2 x) and concentrated in vacuo to afford the title compound (403 mg) as a white solid, which was used without further purification in the next step. LCMS (Method D) Rt 0.81 mins; m / z 221.2 [M+H]+. Intermediate 21 Lithium 2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetate -methyl 2-[3,5-bis(trifluoromethyl)-2-pyridyl]propanedioateSodium hydride (60% in mineral oil, 2.16 g, 54.1 mmol) was added portionwise to an ice- cooled (0 °C) solution of tert-butyl methyl propanedioate (5.58 g, 32.1 mmol) in THF (80 mL). The reaction mixture was allowed to warm to room temperature and stirred for 1 h.2-Chloro-3,5-bis(trifluoromethyl)pyridine (5.00 g, 20.0 mmol) was added dropwise and the reaction mixture stirred at 60 °C for 3 h. The reaction mixture was allowed to cool to room temperature and quenched with saturated aqueous sodium bicarbonate solution (50 ml). The aqueous layer was extracted with EtOAc (3 x 50 ml). The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient 0 - 100% MTBE in heptane to afford the title compound (6.87 g, 77%) as a pale-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 9.33 (s, 1H), 8.68 (s, 1H), 5.21 (s, 1H), 3.71 (s, 3H), 1.39 (s, 9H). LCMS (Method E) Rt 1.13 mins (98%); m / z 388.1 [M+H]+. Step 2: Methyl 2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetateTFA (12 mL, 0.157 mol) was added to a stirred solution of O1-tert-butyl O3-methyl 2-[3,5- bis(trifluoromethyl)-2-pyridyl]propanedioate (6.87 g, 17.7 mmol) in DCM (60 mL). The reaction mixture was stirred at room temperature for 1 h then at 30 °C for 1 h. The resulting mixture was concentrated in vacuo. The resulting residue was taken up in DCM (100 ml) and saturated aqueous sodium bicarbonate solution (70 mL) was added cautiously. The layers were separated, and the aqueous layer was extracted with DCM (2 x 50 ml). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound (4.26 g, 79%) as a yellow oil.1H NMR (400 MHz, DMSO-d6) δ 9.29 – 9.22 (m, 1H), 8.62 – 8.57 (m, 1H), 4.20 – 4.12 (m, 2H), 3.64 (s, 3H). LCMS (Method E) Rt 0.96 mins (89%); m / z 288.5 [M+H]+. Step 3: Lithium 2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetate1 M Lithium hydroxide (1.1 mL, 1.10 mmol) was added to a solution of methyl 2-[3,5- bis(trifluoromethyl)-2-pyridyl]acetate (300 mg, 1.04 mmol) in 1,4-dioxane (1.7 mL), MeOH(0.9 mL) and water (0.9 mL). The reaction mixture was stirred at room temperature for 2 h. The resulting mixture was concentrated in vacuo to afford the title compound (308 mg, quantitative) as a white solid.1H NMR (400 MHz, CD3OD) δ 9.01 (d, J = 2.7 Hz, 1H), 8.32 (d, J = 2.6 Hz, 1H), 4.00 (s, 2H). LCMS (Method E) Rt 0.80 mins (96%); m / z 274.1 [M+H]+Intermediate 22 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetic acidLithium hydroxide monohydrate (1:1) (1.40 g, 32.7 mmol) was added in one portion to an ice-cooled (0 °C) solution of methyl 2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetate (4.69 g, 16.3 mmol) in 1,4-dioxane (30 mL), MeOH (15 mL) and water (15 mL). The reaction mixture was heated to 60 °C for 30 mins. The resulting mixture was cooled to room temperature and concentrated in vacuo. Water (20 ml) was added and the mixture was sonicated to form a suspension and cooled to 0 °C. Formic acid (1.6 mL, 42.5 mmol) was added dropwise. The aqueous layer was extracted with DCM (3 x 25 ml). The combined organics were passed through a phase separator and concentrated in vacuo to afford the title compound (1.48 g, 25%) as an off-white solid. LCMS (Method E) Rt 0.81 mins (76%); m / z 274.1 [M+H]+. Intermediate 23 2-[2-Methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine hydrochlorideStep 1: 1-Bromo-2-methyl-3-(trideuteriomethoxy)benzeneMethyl iodide-d3(3.6 mL, 57.8 mmol) was added dropwise to a stirred suspension of 3- bromo-2-methylphenol (10.00 g, 52.4 mmol) and cesium carbonate (19.0 g, 58.3mmol) in DMF (120 mL). The reaction mixture was stirred at room temperature for 18 h. The resulting mixture was diluted with saturated aqueous sodium bicarbonate solution (200 mL). The aqueous layer was extracted with diethyl ether (3 x 100 mL). The combined organic layers were washed with brine (2 x 150 mL) and water (100 mL), dried over MgSO4and concentrated in vacuo to afford the title compound (10.6 g, 99%) as orange oil.1H NMR (400 MHz, CDCl3) δ 7.15 (dd, J = 8.1, 1.1 Hz, 1H), 7.01 (t, J = 8.1 Hz, 1H), 6.77 (dd, J = 8.3, 1.1 Hz, 1H), 2.32 (s, 3H). LCMS (Method E) Rt 1.11 mins (100%); m / z no ionisation. Step 2: tert-Butyl 2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine-1-carboxylateTo a pressure-relief vial, 1-bromo-2-methyl-3-(trideuteriomethoxy)benzene (150 mg, 0.735 mmol) and Ir[dF(CF3)ppy]2(dtbbpy)PF6(41 mg, 0.0368 mmol) in DMSO (1.5 mL) was added. The reaction mixture was sonicated for 10 mins.1-Azabicyclo[2.2.2]oct-3-yl acetate (80%, 158 uL, 0.809 mmol), 4,7-dimethoxy-1,10-phenanthroline (97%, 9.1 mg, 0.0368 mmol), 0.5 M dibromonickel trihydrate (0.5 M in DMSO, 74 uL, 0.037 mmol), tert-butyl pyrrolidine-1- carboxylate (394 uL, 2.21 mmol) and water (529 uL, 29.4 mmol) were added and the reaction mixture sparged with argon for 5 min. The reaction mixture was sealed and placed ~6 cm away from a blue LED Kessil 457 nm and stirred at room temperature for 48 h with cooling by fan and at 43 °C for 18 h. The resulting mixture was partitioned between EtOAc and water. The layers were separated, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over Na2SO4and concentrated in vacuo. The crude material was purified by C18 reverse phase chromatography eluting with 30 - 100% MeCN (+0.1% AcOH) in water (+0.1% AcOH). The solvent was concentrated in vacuo. The resulting residue was partitioned between saturated aqueous sodium bicarbonate solution and DCM. The layers were separated, and the organic layer was dried over Na2SO4and concentrated in vacuo to afford the title compound (192 mg, 44%) as a brown powder.1H NMR (400 MHz, DMSO-d6) δ 7.28 – 6.95 (m, 1H), 6.98 – 6.70 (m, 1H), 6.70 – 6.44 (m, 1H), 5.26 – 4.59 (m, 1H), 3.70 – 3.35 (m, 2H), 2.36 – 2.16 (m, 1H), 2.11 (s, 3H), 1.88 – 1.50 (m, 3H), 1.47 – 0.89 (m, 9H). LCMS (Method D) Rt 1.02 mins (100%); m / z 317.3 [M+Na]+. Step 3: 2-[2-Methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine hydrochlorideA solution of tert-butyl 2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine-1-carboxylate (192 mg, 0.652 mmol) in 4 M HCl in 1,4-dioxane (4 mL, 16.0 mmol) was stirred at room temperature for 45 min. Diethyl ether was added. The resulting precipitate was filtered, rinsed with diethyl ether and dried under vacuum at 45 °C for 3 h to afford the title compound (130 mg, 85%) as a pale-yellow powder.1H NMR (400 MHz, DMSO-d6) δ 9.69 (br s, 1H), 8.65 (br s, 1H), 7.44 – 7.18 (m, 1H), 7.14 (d, J = 8.0 Hz, 1H), 7.00 (d, J = 8.2 Hz, 1H), 4.76 (m, 1H), 3.41 – 3.24 (m, 2H), 2.39 – 2.27 (m, 1H), 2.21 (s, 3H), 2.15 – 1.89 (m, 3H). LCMS (Method D) Rt 1.02 mins (99%); m / z 195.2 [M+H]+. Intermediate 24 (2S)-2-[2-Methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine hydrochlorideStep 1: (R)‐N‐[(1E)‐4‐chlorobutylidene]‐2‐methylpropane‐2‐sulfinamideA solution of 4-chloro-1,1-diethoxy-butane (6.00 g, 33.2 mmol) in acetic acid (30 mL) and water (15 mL) was stirred at room temperature for 2 h. The reaction mixture was carefully quenched with a saturated aqueous sodium bicarbonate solution (approx.500 mL) adjusting to pH 6-7. The mixture was extracted with DCM (3 x 100 mL) and the combined organic layers were passed through a phase separator and partially concentrated in vacuo (300 mbar, Buchi bath at 25 ˚C). The solution in DCM (approx.150 mL) was immediately taken forward without further purification. (R)-(+)-2-Methylpropane-2-sulfinamide (4.82 g, 39.8 mmol) was added followed by PPTS (416 mg, 1.66 mmol) and MgSO4 (5.98 g, 49.7 mmol). The reaction mixture was stirred at room temperature for 18 h. The resulting mixture wasfiltered through a short pad of Celite and eluted with DCM (150 mL). The filtrate was concentrated in vacuo. The crude material was purified by chromatography on silica eluting with a gradient of 0 - 30% EtOAc in heptane to afford the title compound (5.45 g, 78%) as a pale-yellow oil.1H NMR (500 MHz, CDCl3) δ 8.07 (t, J = 4.0 Hz, 1H), 3.65 – 3.54 (m, 2H), 2.71 – 2.64 (m, 2H), 2.15 – 2.06 (m, 2H), 1.16 (s, 9H). LCMS (Method I) Rt 0.68 mins (94%); m / z 210.1 / 212.1 [M+H]+. Step 2: (2S)-1-[(R)-tert-Butylsulfinyl]-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidineTo a stirred solution of 1-bromo-2-methyl-3-(trideuteriomethoxy)benzene (500 mg, 2.45 mmol) in anhydrous THF (4 mL) cooled to -78 ˚C was added butyllithium (2 M in cyclohexane, 1.3 mL, 2.70 mmol) and the reaction mixture was stirred at -78 ˚C for 30 mins. To this mixture was added a solution of (R)‐N‐[(1E)‐4‐chlorobutylidene]‐2‐methylpropane‐2- sulfinamide (0.51 g, 2.45 mmol) in THF (4 mL) at -78 ˚C. The reaction mixture was stirred at -78 ˚C for 1 h. The resulting mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was resuspended in THF (5 mL) and LiHMDS (1 M in THF, 2.5 mL, 2.45 mmol) was added. The reaction was stirred at room temperature for an additional 30 mins. The resulting mixture was quenched with a saturated aqueous ammonium chloride solution (20 mL) and extracted with EtOAc (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The crude material was purified by C18 reverse phase column chromatography eluting with a gradient of 20 - 90% MeCN (+ 0.1% ammonia) in water (+ 0.1% ammonia). The product fractions were combined and partially concentrated in vacuo. The mixture was extracted with EtOAc (3 x 20 mL) and the combined organic layers were passed through a phase separator and concentrated in vacuo to afford the title compound as a pale-yellow oil.1H NMR (400 MHz, DMSO-d6) δ 7.19 – 7.11 (m, 1H), 6.97 (d, J = 7.5 Hz, 1H), 6.82 (d, J = 8.0 Hz, 1H), 4.86 – 4.79 (m, 1H), 3.73 – 3.65 (m, 1H), 3.06 – 2.96 (m, 1H), 2.21 – 2.10 (m, 4H), 1.91 – 1.80 (m, 1H), 1.78 – 1.68 (m, 1H), 1.60 – 1.49 (m, 1H), 1.05 (s, 9H). LCMS (Method J) Rt 3.53 mins (96%); m / z 299.2 [M+H]+.Step 3: (2S)-2-[2-Methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine hydrochlorideTo a stirred solution of (2S)-1-[(R)-tert-butylsulfinyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidine (95%, 42 mg, 0.134 mmol) in MeOH (5 mL) was added 4 M HCl in 1,4-dioxane (0.13 mL, 0.535 mmol). The reaction mixture was stirred at room temperature for 1 h. The resulting mixture was concentrated in vacuo to afford the title compound (31 mg, quantitative) as an off-white solid, which was used in the next step assuming a purity of 100%. Intermediate 25 (2S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)pyrrolidine hydrochlorideStep 1: (2S)-1-[(R)-tert-Butylsulfinyl]-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidineThe title compound (105 mg, 20%) was prepared from (R)‐N‐[(1E)‐4‐chlorobutylidene]‐2‐ methylpropane‐2‐sulfinamide (Intermediate 24, step 1) and 1-bromo-2-chloro-5-fluoro-3- methyl-benzene analogously to Intermediate 24, step 2. Purification was carried out by purified by preparative HPLC (Method 4).1H NMR (500 MHz, DMSO-d6) δ 7.19 – 7.16 (m, 2H), 5.01 – 4.96 (m, 1H), 3.70 – 3.63 (m, 1H), 3.14 – 3.07 (m, 1H), 2.34 (s, 3H), 2.25 – 2.17 (m, 1H), 1.90 – 1.80 (m, 1H), 1.80 – 1.69 (m, 1H), 1.65 – 1.55 (m, 1H), 1.07 (s, 9H). LCMS (Method J) Rt 4.02 mins (98%); m / z 318.3 / 320.3 [M+H]+. Step 2: (2S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)pyrrolidine hydrochlorideTo a stirred solution of (2S)-1-[(R)-tert-butylsulfinyl]-2-(2-chloro-5-fluoro-3-methyl- phenyl)pyrrolidine (95 mg, 0.299 mmol) in MeOH (4 mL) was added 4 M HCl in 1,4-dioxane (0.30 mL, 1.20 mmol). The reaction mixture was stirred at room temperature for 30 mins. The resulting mixture was concentrated in vacuo to afford the title compound (75 mg, quantitative) as white solid. LCMS (Method I) Rt 0.84 mins (69%); m / z 214.1 / 216.1 [M+H]+. Intermediate 26 2-Bromo-1-[(2S)-2-(o-tolyl)pyrrolidin-1-yl]ethanoneTo an ice-cooled (0 °C) suspension of 2-bromoacetyl bromide (1.8 mL, 20.2 mmol) and potassium carbonate (4.19 g, 30.3 mmol) in DCM (14 mL) was added a solution of (2S)- 2-(o-tolyl)pyrrolidine hydrochloride (2.00 g, 10.1 mmol) in DCM (6 mL) dropwise. The reaction mixture was allowed to warm to room temperature and stirred for 18 h. The resulting mixture was diluted with DCM (10 mL), saturated aqueous potassium carbonate (20 mL) and stirred at room temperature for 5 mins. The layers were separated, and the organic layers were washed with aqueous 1 M HCl (15 mL) and brine (15 mL), dried over MgSO4and the solvent concentrated in vacuo to afford the title compound (2.6 g, 87%) as a pale brown oil.1H NMR (400 MHz, DMSO-d6) δ 7.28 – 7.07 (m, 3H), 7.01 – 6.92 (m, 1H), 5.30 – 5.04 (m, 1H), 4.29 – 3.41 (m, 4H), 2.42 – 2.18 (m, 4H), 1.96 – 1.52 (m, 3H). LCMS (Method B) Rt 1.34 mins (95%); m / z 282.0 / 284.0 [M+H]+. Intermediate 27 2-Bromo-1 -2-(2-chloro-3-methoxy-phenyl)pyrrolidin-1-yl]ethanoneThe title compound (343 mg, 59%) was prepared as a brown oil from 2-bromoacetyl bromide and (2S)-2-(2-chloro-3-methoxy-phenyl)pyrrolidine hydrochloride analogously toIntermediate 26.1H NMR (400 MHz, CDCl3) δ 7.25 – 7.11 (m, 1H), 6.92 – 6.79 (m, 1H), 6.75 – 6.62 (m, 1H), 5.53 – 5.38 (m, 1H), 4.15 – 3.93 (m, 1H), 3.93 – 3.88 (m, 3H), 3.88 – 3.46 (m, 3H), 2.52 – 2.31 (m, 1H), 2.03 – 1.84 (m, 3H). LCMS (Method A) Rt 1.15 mins (58%); m / z 331.9 / 333.9 [M+H]+. Intermediate 28 2-Bromo-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethanoneThe title compound (655 mg, 96%) was prepared as a pale brown oil from 2-bromoacetyl bromide and (2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidine hydrochloride analogously to Intermediate 26.1H NMR (400 MHz, DMSO-d6) δ 7.31 – 6.98 (m, 1H), 6.96 – 6.72 (m, 1H), 6.69 – 6.44 (m, 1H), 5.36 – 5.06 (m, 1H), 4.23 – 3.37 (m, 7H), 2.42 – 2.06 (m, 4H), 2.02 – 1.50 (m, 3H). LCMS (Method A) Rt 1.38 mins (100%); m / z 311.9 / 313.95 [M+H]+. Intermediate 29 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-pyrrolidin-1-yl-ethanoneDIPEA (1.8 mL, 10.33 mmol) followed by HATU (2.63 g, 6.89 mmol) were added to a stirred suspension of pyrrolidine (0.59 mL, 6.89 mmol) and 2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetic acid (Intermediate 12) (1.64 g, 7.23 mmol) in DCM (23 mL). The reaction mixture was stirred at room temperature for 1.5 h. The resulting mixture was partitioned between EtOAc and water. The layers were separated, and the organic layer was dried over Na2SO4and concentrated in vacuo. The crude material was purified by chromatography on silica with a gradient of 30 - 100% EtOAc in heptane to afford the title compound (1.68 g, 85%) as a white powder.1H NMR (400 MHz, DMSO-d6) δ 6.60 (s, 1H), 5.03 (s, 2H), 3.48 (t, J = 6.8 Hz, 2H), 3.29 (t obscured by water peak, J = 6.8 Hz, 2H), 1.97 – 1.84 (m, 3H), 1.83 – 1.73 (m, 2H), 0.95 – 0.82 (m, 2H), 0.74 – 0.62 (m, 2H). LCMS (Method D) Rt 0.78 mins (100%); m / z 288.2 [M+H]+. Intermediate 301-(3-Methoxy-2-methyl-phenyl)pyrazolidine hydrochlorideStep 1: N-(Benzhydrylideneamino)-3-methoxy-2-methyl-anilineBromo-3-methoxy-2-methylbenzene (2.00 g, 9.95 mmol), diphenylmethanone hydrazone (2.34 g, 11.9 mmol), XPhos (95 mg, 0.199 mmol) and sodium tert-butoxide (1.43 g, 14.9 mmol) were suspended in toluene (30 mL) and the solution was degassed for 5 mins. Pd(OAc)2 (45 mg, 0.199 mmol) was added and the reaction mixture was stirred at 90 ˚C for 1 h. After cooling to room temperature, the toluene was removed in vacuo. The residue was partitioned between EtOAc (50 mL) and a saturated aqueous sodium bicarbonate solution (50 mL). The layers were separated, and the aqueous layer was further extracted with EtOAc (3 x 50 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was dissolved in a minimum amount of DCM and purified by chromatography on silica eluting with a gradient of 0 - 25% EtOAc in heptane to afford the title compound (2.25 g, 70%) as a yellow solid.1H NMR (500 MHz, DMSO-d6) δ 7.69 – 7.64 (m, 2H), 7.62 – 7.55 (m, 2H), 7.53 – 7.50 (m, 2H), 7.43 – 7.30 (m, 5H), 7.25 (d, J = 8.1 Hz, 1H), 7.17 – 7.11 (m, 1H), 6.49 (d, J = 7.9 Hz, 1H), 3.73 (s, 3H), 1.65 (s, 3H). LCMS (Method I) Rt 1.10 mins (96%); m / z 317.3 [M+H]+. Step 2: (3-Methoxy-2-methyl-phenyl)hydrazine hydrochlorideN-(Benzhydrylideneamino)-3-methoxy-2-methyl-aniline (1.86 g, 5.88 mmol) in EtOH (0.7 mL) was treated with aqueous HCl (37%, 7.0 mL, 85.2 mmol). The reaction mixture was heated to 90 ˚C for 1 h. The resulting mixture was allowed to cool to room temperature and then cooled to 0 ˚C causing a suspension to form. The solids were collected by vacuum filtration, washed with diethyl ether (2 x 10 mL) and dried in a vacuum oven at 40 ˚C for 1 h to affordthe title compound (473 mg, 30%) as a brown solid.1H NMR (400 MHz, DMSO-d6) δ 10.11 (s, 3H), 7.18 – 7.09 (m, 1H), 6.65 (d, J = 8.3 Hz, 1H), 6.59 (d, J = 8.1 Hz, 1H), 3.76 (s, 3H), 2.01 (s, 3H). LCMS (Method I) Rt 0.46 mins (83%); m / z 153.1 [M+H]+. Step 3: tert-Butyl N-(3-methoxy-2-methyl-anilino)carbamateTo a stirred suspension of (3-methoxy-2-methyl-phenyl)hydrazine hydrochloride (71%, 463 mg, 1.74 mmol) in DCM (10 mL) was added tert-butoxycarbonyl tert-butyl carbonate (456 mg, 2.09 mmol) followed by triethylamine (0.49 mL, 3.49 mmol). The mixture was stirred at room temperature for 18 h. The resulting mixture was partitioned between DCM (20 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The layers were separated, and the aqueous layer was extracted with DCM (3 x 20 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo. The residue was dissolved in a minimum amount of DCM and purified by chromatography on silica eluting with a gradient of 0 - 35% EtOAc in heptane to afford the title compound (256 mg, 55%) as an orange solid.1H NMR (500 MHz, DMSO-d6) δ 8.72 (s, 1H), 6.99 – 6.93 (m, 2H), 6.37 (d, J = 8.0 Hz, 1H), 6.30 (d, J = 8.1 Hz, 1H), 3.72 (s, 3H), 1.94 (s, 3H), 1.41 (s, 9H). LCMS (Method I) Rt 0.74 mins (87%); m / z 197.2 [M-tButyl+H]+. Step 4: tert-Butyl 2-(3-methoxy-2-methyl-phenyl)pyrazolidine-1-carboxylateTo a stirred solution of tert-butyl N-(3-methoxy-2-methyl-anilino)carbamate (246 mg, 0.975 mmol) in dry THF (8 mL) cooled to -78 ˚C was added BuLi (2 M in cyclohexane, 1 mL, 2.05 mmol) under nitrogen and the mixture was stirred at -78 ˚C for 30 mins.1,3-Diiodopropane (0.11 mL, 0.975 mmol) was then added and the mixture was allowed to warm to room temperature over 1 h. The reaction was quenched with a saturated aqueous ammonium chloride solution (20 mL) and EtOAc (20 mL) was added. The layers were separated, and the aqueous layer was extracted with EtOAc (3 x 20 mL). The combined organic layer were passed through phase separator and concentrated in vacuo. 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). The product fractions were combined and partially concentrated in vacuo. The aqueous was extracted with EtOAc (3 x 25 mL). The combined organic layers were passed through a phase separator and concentrated in vacuo to afford the title compound (168 mg, 56%) as a yellow oil.1H NMR (500 MHz, CDCl3) δ 7.07 – 7.00 (m, 1H), 6.63 – 6.57 (m, 2H), 3.82 (s, 3H), 3.76 – 3.70 (m, 2H), 3.30 – 3.25 (m, 2H), 2.25 (s, 3H), 2.05 – 1.98 (m, 2H), 1.43 – 1.36 (m, 9H). LCMS (Method I) Rt 0.86 mins (94%); m / z 293.3 [M+H]+. Step 5: 1-(3-Methoxy-2-methyl-phenyl)pyrazolidine hydrochlorideTo a stirred solution of tert-butyl 2-(3-methoxy-2-methyl-phenyl)pyrazolidine-1-carboxylate (161 mg, 0.551 mmol) in MeOH (1.7 mL) was added 4 M HCl in 1,4-dioxane (0.41 mL, 1.65 mmol) and the mixture was stirred at room temperature for 1 h. Additional 4 M HCl in 1,4- dioxane (0.41 mL, 1.65 mmol) was added and stirring continued at room temperature for 18 h. The resulting mixture was concentrated in vacuo to afford the title compound (126 mg, quantitative) as a yellow oil, which was used in the next step without purification assuming a purity of 100%. Intermediate 31 (2S)-2-(2,3-Dimethylphenyl)-2,5-dihydro-1H-pyrrole hydrochlorideStep 1: tert-Butyl (2S)-2-(2,3-dimethylphenyl)-2,5-dihydropyrrole-1-carboxylateTo a solution of DIPEA (1.1 mL, 6.48 mmol), tert-butyl 2,3-dihydro-1H-pyrrole-1-carboxylate (732 mg, 4.32 mmol), 4-nitrobenzoic acid (361 mg, 2.16 mmol) and 1-bromo-2,3-dimethyl- benzene (400 mg, 2.16 mmol) in ethylene glycol (4.0 mL, 71.5 mmol) was added Pd(dba)2(31...

Claims

CLAIMS 1. A compound of formula I, II or III, or a pharmaceutically acceptable salt or solvate thereof:wherein: A1is CH or N; R1Ais selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium;R1Bis selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Cis selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Dis selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Eis selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; or R1Aand R1Bor R1Band R1Care linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 or 6 membered cycloalkyl or 4 to 7 membered heterocyclyl ring, which is optionally substituted by one or more substituents selected from deuterium, 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, and wherein a 5 or 6 membered cycloalkyl or 4 to 7 membered heterocyclyl ring is optionally further substituted by oxo; R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G): -L1-X1-R2A (A) -L2-X2-L1-X1-R2A (B) -L3-X3-L2-X2-L1-X1-R2A (C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A (D) -L5-X5-L4-X4-L3-X3-L2-X2-L1-X1-R2A (E) -[OCH2CH2]n1-R2A (F) -[CH2CH2O]n1-R2A (G) wherein: n1 is 1 to 10;each of L1, L2, L3, L4or L5are either absent or a linear or branched (1- 4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -NR2C-C(O)-NR2B-, -O-C(O)NR2B-, -NR2B-C(O)O-, - NR2BSO2-, -SO2NR2B- or -S(O)p- (where p is 0, 1 or 2), where R2Band R2Care each independently hydrogen or (1-2C)alkyl; X2is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -NR2E-C(O)-NR2D-, -O-C(O)NR2D-, -NR2D-C(O)O-, - NR2DSO2-, -SO2NR2D- or -S(O)p- (where p is 0, 1 or 2), where R2Dand R2Eare each independently hydrogen or (1-2C)alkyl; X3is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -NR2G-C(O)-NR2F-, -O-C(O)NR2F-, -NR2F-C(O)O-, - NR2FSO2-, -SO2NR2F- or -S(O)p- (where p is 0, 1 or 2), where R2Fand R2Gare each independently hydrogen or (1-2C)alkyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -NR2J-C(O)-NR2H-, -O-C(O)NR2H-, -NR2H-C(O)O-, - NR2HSO2-, -SO2NR2H- or -S(O)p- (where p is 0, 1 or 2), where R2Hand R2J are each independently hydrogen or (1-2C)alkyl; X5 is absent or selected from -O-, -NR2K-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2K-, -NR2KC(O)-, -NR2L-C(O)-NR2K-, -O-C(O)NR2K-, -NR2K-C(O)O-, - NR2KSO2-, -SO2NR2K- or -S(O)p- (where p is 0, 1 or 2), where R2K and R2L are each independently hydrogen or (1-2C)alkyl; R2A is selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino;and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0-2-X6-Rx6(wherein X6is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2Mis hydrogen or (1-2C)alkyl; and RX6is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2Aand R2Bare linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7 is selected from -O-, -NR2N-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2N-, -NR2NC(O)-, -O-C(O)NR2N-, -NR2N-C(O)O-, -NR2NSO2-, -SO2NR2N- or -S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1- 2C)alkyl; and RX7 is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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. R3 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G) defined above; R3A is selected from hydrogen or halo; or R3 and R3A together form an oxo group; or R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected fromhalo, 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 a group of the formula (A) to (G) defined above; R4is hydrogen, cyano or halo; X is selected from: -CHR5-; -CHR5-CH2-; -NR100-, where R100is hydrogen or (1-3C)alkyl; -CH2-XA-, where XAis -O- or -NR101-, where R101is hydrogen or (1-3C)alkyl; R5is hydrogen, methyl, hydroxymethyl, or methoxymethyl; Q is selected from:ein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6 or N,with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one to three of A2, A3,A4, A5and A6are N; R6 is selected from hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (2-6C)alkenyl, (2- 6C)alkynyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2- phenyl, 5 or 6-membered heteroaryl, -[CH2]o2-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o2-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o2- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o2-[(3-6C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R7is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o3-phenyl, -O-phenyl, -O-[CH2]o3- phenyl, 5 or 6-membered heteroaryl, -[CH2]o3-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o3-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o3- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o3-[(3-6C)cycloalkyl], wherein: o3 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8 is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o4- phenyl, 5 or 6-membered heteroaryl, -[CH2]o4-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o4-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o4- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o4-[(3-6C)cycloalkyl], wherein: o4 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;R9is selected from hydrogen, halo, cyano, (1-6C)alkyl, (2-6C)alkenyl, (2-6C)alkynyl, (1- 6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o6- phenyl, 5 or 6-membered heteroaryl, -[CH2]o6-[5 or 6-membered heteroaryl], 4 to 8- membered heterocyclyl, -[CH2]o6-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o6- [(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o6-[(3-6C)cycloalkyl], wherein: o6 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R6and R7, R7and R8or R8or R9are linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl, 5 to 7-membered heterocyclyl, 5 or 6-membered heteroaryl, or (5-8C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1- 4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]o5-(3- 6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; and RN is hydrogen, methyl, hydroxymethyl, or methoxymethyl.

2. A compound having any one of the formulae IV, V, VI, VII, VIII, VIIa, VIIIa, VIIb, VIIIb, VIIc, VIIIc, VIId, VIIId, IX, X, XI or XII shown below, or a pharmaceutically acceptable salt or solvate thereof:IV Vwherein A1, A2, A3, A5, R1A, R1B, R1C, R1D, R1E, R2, R3, R3A, R4, X, R5, R6, R7, R8, R9, and RN are as defined in claim 1.

3. A compound according to claim 1 or claim 2, or a pharmaceutically acceptable salt thereof, wherein: R1A is selected from hydrogen, halo, hydroxy, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1- 2C)alkoxy or (1-2C)haloalkoxy; R1B is selected from hydrogen, halo, hydroxy, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1- 4C)alkoxy, (1-4C)haloalkoxy or –(1-4C)alkylene-O-(1-4C)alkyl, wherein one or more hydrogen atoms in an alkyl or alkoxy group are optionally replaced by deuterium; R1Cis hydrogen; R1Dis selected from hydrogen, halo, or methyl; R1Eis hydrogen.

4. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1A is selected from fluoro, chloro, hydroxy, cyano, methyl, CH2F, CHF2, CF3, methoxy, -OCH2F, -OCHF2, -OCF3, -OCH2D, -OCHD2or -OCD3; R1Bis selected from hydrogen, fluoro, chloro, hydroxy, cyano, methyl, CH2F, CHF2, CF3, methoxy, -OCH2F, -OCHF2, -OCF3, -OCH2D, -OCHD2or -OCD3; R1Cis hydrogen; R1Dis selected from hydrogen, fluoro, or methyl; R1Eis hydrogen.

5. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1Ais selected from fluoro, chloro, hydroxy, cyano, methyl, CHF2, CF3, methoxy, -OCHF2or -OCF3; R1Bis selected from hydrogen, fluoro, chloro, hydroxy, cyano, methyl, CHF2, CF3, methoxy, -OCHF2, -OCF3or -OCD3; R1Cis hydrogen; R1D is selected from hydrogen, fluoro, or methyl; R1E is hydrogen.

6. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1A is selected from fluoro, chloro, cyano, or methyl; R1B is selected from hydrogen, fluoro, chloro, methyl, methoxy, -OCHF2, -OCF3 or -OCD3; R1C is hydrogen; R1D is selected from hydrogen, fluoro, or methyl; R1E is hydrogen.

7. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: R1A is methyl; R1Bis selected from hydrogen, fluoro, chloro, methyl, methoxy, -OCHF2, -OCF3or -OCD3; R1Cis hydrogen; R1Dis selected from hydrogen or methyl; R1Eis hydrogen.

8. A compound according to claim 1 or claim 2, wherein: (i) R1Aand R1Care hydrogen and R1B, R1Dand R1Eare not hydrogen; (ii) R1A, R1Band R1Care hydrogen and R1Dand R1Eare not hydrogen; (iii) R1A, R1Cand R1Dare hydrogen and R1Band R1Dare not hydrogen; (iv) R1Eand R1Care hydrogen and R1A, R1Band R1Dare not hydrogen; (v) R1E, R1Dand R1Care hydrogen and R1Aand R1Bare not hydrogen; or (vi) R1E, R1Cand R1Bare hydrogen and R1Aand R1Dare not hydrogen.

9. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (G): -L1-X1-R2A (A) -L2-X2-L1-X1-R2A (B) -L3-X3-L2-X2-L1-X1-R2A (C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A (D) -L5-X5-L4-X4-L3-X3-L2-X2-L1-X1-R2A (E) -[OCH2CH2]n1-R2A (F) -[CH2CH2O]n1-R2A (G) wherein: n1 is 1 to 10;each of L1, L2, L3, L4or L5are either absent or a linear or branched (1- 4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O-, -NR2CSO2-, -SO2NR2B- or -S(O)p- (where p is 0, 1 or 2), where R2Bis hydrogen or (1-2C)alkyl; X2is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, -NR2DSO2-, -SO2NR2D- or -S(O)p- (where p is 0, 1 or 2), where R2Dis hydrogen or (1-2C)alkyl; X3is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O-, -NR2GSO2-, -SO2NR2F- or -S(O)p- (where p is 0, 1 or 2), where R2Fis hydrogen or (1-2C)alkyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, -NR2HSO2-, -SO2NR2H- or -S(O)p- (where p is 0, 1 or 2), where R2His hydrogen or (1-2C)alkyl; X5is absent or selected from -O-, -NR2K-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2K-, -NR2KC(O)-, -O-C(O)NR2K-, -NR2K-C(O)O-, -NR2KSO2-, -SO2NR2K- or -S(O)p- (where p is 0, 1 or 2), where R2Kis hydrogen or (1-2C)alkyl; R2A is selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; aN alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0- 2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, -C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2Aand R2Bare linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2N-, -NR2NC(O)-, -O-C(O)NR2N-, -NR2N-C(O)O-, -NR2NSO2-, -SO2NR2N- or -S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1- 2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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.

10. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A) to (D): -L1-X1-R2A (A) -L2-X2-L1-X1-R2A (B) -L3-X3-L2-X2-L1-X1-R2A (C) -L4-X4-L3-X3-L2-X2-L1-X1-R2A (D) wherein: each of L1, L2, L3 or L4 are either absent or a linear or branched (1- 4C)alkylene;X1is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2B is hydrogen or (1-2C)alkyl; X2is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2Dis hydrogen or (1-2C)alkyl; X3is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2Fis hydrogen or (1-2C)alkyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2His hydrogen or (1-2C)alkyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1, 2 or 3; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0- 2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl);and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or - S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1-2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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.

11. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2 is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A (A1) -X2-L1-X1-R2A (B1) -X3-L2-X2-L1-X1-R2A (C1) -X4-L3-X3-L2-X2-L1-X1-R2A (D1) wherein: each of L1, L2 or L3 are either absent or a linear or branched (1-4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2B is hydrogen or (1-2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2D is hydrogen or (1-2C)alkyl;X3is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2F is hydrogen or (1-2C)alkyl; X4is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2His hydrogen or (1-2C)alkyl; R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1 or 2; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0- 2-X6-Rx6 (wherein X6 is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7(wherein X7is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or - S(O)p- (where p is 0, 1 or 2), where R2Nis hydrogen or (1-2C)alkyl; and RX7is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from 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.

12. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R2is selected from hydrogen, halo, cyano, hydroxy, amino or a group of the formula (A1) to (D1): -X1-R2A(A1) -X2-L1-X1-R2A(B1) -X3-L2-X2-L1-X1-R2A(C1) -X4-L3-X3-L2-X2-L1-X1-R2A(D1) wherein: each of L1, L2 or L3 are either absent or a linear or branched (1-4C)alkylene; X1 is absent or selected from -O-, -NR2B-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2B-, -NR2BC(O)-, -O-C(O)NR2B-, -NR2B-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2B is hydrogen or (1-2C)alkyl; X2 is absent or selected from -O-, -NR2D-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2D-, -NR2DC(O)-, -O-C(O)NR2D-, -NR2D-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2D is hydrogen or (1-2C)alkyl; X3 is absent or selected from -O-, -NR2F-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2F-, -NR2FC(O)-, -O-C(O)NR2F-, -NR2F-C(O)O- or -S(O)p- (where p is 0, 1 or 2), where R2F is hydrogen or (1-2C)alkyl; X4 is absent or selected from -O-, -NR2H-, -C(O)-, -C(O)O-, -OC(O)-, - C(O)NR2H-, -NR2HC(O)-, -O-C(O)NR2H-, -NR2H-C(O)O-, or -S(O)p- (where p is 0, 1 or 2), where R2H is hydrogen or (1-2C)alkyl;R2Ais selected hydrogen, (1-6C)alkyl, (2-6C)alkenyl, phenyl, -[CH2]o1-[phenyl], 5 or 6-membered heteroaryl, -[CH2]o1-[5 or 6-membered heteroaryl], 4 to 10- membered heterocyclyl, -[CH2]o1-[4 to 10-membered heterocyclyl], (3- 6C)cycloalkyl, or -[CH2]o1-[(3-6C)cycloalkyl]; and wherein: o1 is 1 or 2; an alkyl or alkenyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1- 2C)alkoxy, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; and a phenyl, heteroaryl, heterocyclyl, or cycloalkyl group is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3- 6C)cycloalkyl, -[CH2]1-2-[(3-6C)cycloalkyl], or -[CH2]0-2-X6-Rx6(wherein X6is selected from -O-, -NR2M-, -C(O)-, - C(O)O-, -OC(O)-, -C(O)NR2M-, -NR2MC(O)-, -O-C(O)NR2M-, - NR2M-C(O)O-, -NR2MSO2-, -SO2NR2M- or -S(O)p- (where p is 0, 1 or 2), where R2M is hydrogen or (1-2C)alkyl; and RX6 is hydrogen or (1-2C)alkyl); and wherein a cycloalkyl or heterocyclyl ring is optionally further substituted by oxo; or R2A and R2B are linked such that, together with the N atom to which they are attached, they form a 4-7 membered heterocyclyl ring, which is: optionally substituted by one or more substituents selected from deuterium, halo, oxo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, or -[CH2]0-2-X7-Rx7 (wherein X7 is selected from -O-, -NR2N-, -C(O)-, -C(O)NR2N-, -NR2NC(O)-, or - S(O)p- (where p is 0, 1 or 2), where R2N is hydrogen or (1-2C)alkyl; and RX7 is hydrogen or (1-2C)alkyl); optionally fused or spiro linked to a phenyl, 5 or 6-membered heteroaryl, 4 to 8-membered heterocyclyl, or (3-8C)cycloalkyl ring which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy.

13. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3is selected from one of the following options: (i) hydrogen, halo, cyano, hydroxy or amino; (ii) hydrogen, fluoro, chloro, cyano, hydroxy or amino; (iii) hydrogen or halo; (iv) hydrogen or fluoro; (v) hydrogen; or (vi) fluoro.

14. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R3, and / or R3and R3Atogether, are selected from one of the following options: (i) R3Ais selected from hydrogen, halo, or R3and R3Atogether form an oxo group; (ii) R3Ais selected from hydrogen, fluoro or chloro, or R3and R3Atogether form an oxo group; (iii) R3Ais selected from hydrogen or fluoro, or R3and R3Atogether form an oxo group; (iv) R3A is selected from hydrogen or fluoro; (v) R3A is hydrogen; or (vi) R3A is fluoro.

15. A compound according to any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, wherein R2 and R3 are linked such that, together with the carbon atoms to which they are attached, they form: (i) a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from 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 a group of the formula (A) to (G) defined in claim 1 or claim 9 above;(ii) a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from 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; (iii) a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (iv) a fused phenyl, 5 or 6-membered heteroaryl, 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; (v) a fused phenyl or 5 or 6-membered heteroaryl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1- 2C)alkoxy; or (vi) a fused 5 or 6-membered heteroaryl ring, which is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy.

16. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R4 is selected from one of the following options: (i) hydrogen, cyano, fluoro or chloro; (ii) hydrogen or cyano; or (iii) hydrogen.

17. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: (i) X is selected from: -CHR5-; -NR100-, where R100 is hydrogen or (1-2C)alkyl; -CH2-XA-, where XA is -O- or -NR101-, where R101 is hydrogen or (1-2C)alkyl; wherein R5 is hydrogen, methyl, hydroxymethyl, or methoxymethyl;(ii) X is selected from: -CHR5-; -NR100-, where R100 is hydrogen or (1-2C)alkyl; -CH2-XA-, where XAis -O- or -NR101-, where R101is hydrogen or (1-2C)alkyl; wherein R5is hydrogen or methyl; (iii) X is selected from: -CH2-; -NH-; or -CH2-O-; (iv) X is -CH2-; (v) X is -NH-; or (vi) X is -CH2-O-.

18. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein: A) Q is selected from:wherein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one or two of A2, A3,A4, A5and A6are N; B) Q is selected from:wherein A2 is selected from CH or N, A3 is selected from CR9 or N, A5 is selected from CR7 or N, and A6 is selected from CR6 or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one or two of A2, A3, A4, A5 and A6 are N; or C) Q is selected from:wherein A2 is selected from CH or N, A3 is selected from CR9 or N, A5 is selected from CR7or N, and A6is selected from CR6or N, with the proviso that Q is only option (i) and (ii) above when X is -CHR5- or -CHR5-CH2-, and one or two of A2, A3,A4, A5and A6are N.

19. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Q is selected from:

20. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein Q is not a group: ,21. A compound according to any one of the preceding claims, wherein when Q is a group:wherein A2is selected from CH or N, A3is selected from CR9or N, A4is selected from CR8or N, A5is selected from CR7or N, and A6is selected from CR6or N, R6and R7, R7and R8or R8and R9are not linked such that, together with the carbon atoms to which they are attached, they form a fused phenyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-4C)alkyl, (1-4C)alkoxy, (1-4C)haloalkyl, (1-4C)haloalkoxy, (1-4C)hydroxyalkyl, (3-6C)cycloalkyl, -[CH2]o5-(3- 6C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2.

22. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R6is selected from any one of the following options: (i) hydrogen, halo, cyano, (1-6C)alkyl, (1-6C)haloalkyl, (1-6C)alkoxy, (1-6C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2-phenyl, 5 or 6-membered heteroaryl, -[CH2]o2- [5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]o2-[4 to 8 -membered heterocyclyl], (3-6C)cycloalkyl, -[CH2]o2-[(3-6C)cycloalkyl], -O-(3-6C)cycloalkyl, -O-[CH2]o2- [(3-6C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (ii) hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o2-phenyl, -O-phenyl, -O-[CH2]o2-phenyl, 5 or 6-membered heteroaryl, -[CH2]o2- [5 or 6-membered heteroaryl], 4 to 6-membered heterocyclyl, -[CH2]o2-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o2-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o2- [(3-5C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (iii) hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, -O-[CH2]o2-[(3- 4C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (iv) hydrogen, halo, cyano, (1-3C)alkyl, (1-3C)haloalkyl, (1-3C)alkoxy, (1-3C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, -O-[CH2]o2-[(3- 4C)cycloalkyl], wherein: o2 is 1 or 2; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, methyl, methoxy, fluoromethyl, di- fluoromethyl, trifluoromethyl, trifluoromethoxy, hydroxymethyl, amino, methylamino, or di- methylamino; (v) hydrogen, halo, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o2-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, -O-[CH2]o2-[(3- 4C)cycloalkyl], wherein o2 is 1 or 2; (vi) hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy, (1-2C)haloalkoxy, cyclopropyl, -[CH2]o2-[cyclopropyl], -O-cyclopropyl, -O-[CH2]o2-[(3-4C)cyclopropyl], wherein o2 is 1; or (vii) hydrogen, halo, (1-2C)alkyl, (1-2C)haloalkyl, or cyclopropyl.

23. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7 and R8 are selected from any one of the following options: (i) R7 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o3-phenyl, -O-phenyl, -O-[CH2]o3-phenyl, 5 or 6- membered heteroaryl, -[CH2]o3-[5 or 6-membered heteroaryl], 4 to 8-memberedheterocyclyl, -[CH2]o3-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o3-[(3- 5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o3-[(3-5C)cycloalkyl], wherein: o3 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o4-phenyl, 5 or 6- membered heteroaryl, -[CH2]o4-[5 or 6-membered heteroaryl], 4 to 8-membered heterocyclyl, -[CH2]o4-[4 to 8 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o4-[(3- 5C)cycloalkyl], -O-(3-5C)cycloalkyl, or -O-[CH2]o4-[(3-5C)cycloalkyl], wherein: o4 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 to 7-membered heterocyclyl, or (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1- 2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1 or 2; (ii) R7 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o3-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, - O-[CH2]o3-[(3-4C)cycloalkyl], wherein: o3 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;R8is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o4-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, or -O-[CH2]o4-[(3-4C)cycloalkyl], wherein: o4 is 1; and any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1- 2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1-2C)hydroxyalkyl, (3-4C)cycloalkyl, - [CH2]o5-(3-4C)cycloalkyl, amino, (1-2C)alkylamino, or di-[(1-2C)alkyl]amino; wherein o5 is 1; (iii) R7is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; R8 is selected from hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy or (3-4C)cycloalkyl, wherein: any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from 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;(iv) R7is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, or (1-2C)alkoxy; R8is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1- 4C)haloalkoxy or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (v) R7is selected from hydrogen, halo or (1-4C)alkyl; R8is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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 R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; (vi) R7 is selected from hydrogen, halo or (1-4C)alkyl; R8 is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl or (1-2C)haloalkoxy; or R7 and R8 are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10 substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy; or(vii) R7is selected from hydrogen; R8is selected from hydrogen, halo, (1-4C)alkyl, (1-4C)haloalkyl or (3-4C)cycloalkyl, wherein any alkyl, alkoxy or cycloalkyl moiety is optionally substituted by one or more substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1- 2C)haloalkyl or (1-2C)haloalkoxy; or R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused (5-6C)cycloalkyl ring, which is optionally substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl or (1- 2C)alkoxy.

24. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R7and R8are linked such that, together with the carbon atoms to which they are attached, they form a fused 5 to 7-membered heterocyclyl, or (5- 6C)cycloalkyl ring, which is substituted by one or more R10substituents selected from halo, cyano, hydroxy, (1-2C)alkyl, (1-2C)alkoxy, (1-2C)haloalkyl, (1-2C)haloalkoxy, (1- 2C)hydroxyalkyl, (3-4C)cycloalkyl, -[CH2]o5-(3-4C)cycloalkyl, amino, (1-2C)alkylamino, or di- [(1-2C)alkyl]amino; wherein o5 is 1 or 2.

25. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein R9 is selected from any one of the following options: (i) hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, phenyl, -[CH2]o4-phenyl, -O-phenyl, -O-[CH2]o6-phenyl, 5 or 6-membered heteroaryl, -[CH2]o6- [5 or 6-membered heteroaryl], 4 to 6-membered heterocyclyl, -[CH2]o6-[4 to 6 -membered heterocyclyl], (3-5C)cycloalkyl, -[CH2]o6-[(3-5C)cycloalkyl], -O-(3-5C)cycloalkyl, -O-[CH2]o6-[(3-5C)cycloalkyl], wherein: o6 is 1 or 2; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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;(ii) hydrogen, halo, cyano, (1-4C)alkyl, (1-4C)haloalkyl, (1-4C)alkoxy, (1-4C)haloalkoxy, (3-4C)cycloalkyl, -[CH2]o6-[(3-4C)cycloalkyl], -O-(3-4C)cycloalkyl, -O-[CH2]o6-[(3- 4C)cycloalkyl], wherein: o6 is 1; and any alkyl, alkoxy, phenyl, heteroaryl, heterocyclyl or cycloalkyl moiety is optionally substituted by one or more substituents selected from 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; (iii) hydrogen, halo, cyano, (1-2C)alkyl, (1-2C)haloalkyl, (1-2C)alkoxy or (1- 2C)haloalkoxy; (iv) hydrogen, halo, (1-2C)alkyl, or (1-2C)haloalkyl; or (v) hydrogen.

26. A compound according to any one of the preceding claims, or a pharmaceutically acceptable salt thereof, wherein and RNis hydrogen.

27. A compound 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: 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 1-[2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2- yl]ethenone; 1-[(2R)-2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethenone; 1-[(2S)-2-(2,5-Dimethylphenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7- tetrahydroindazol-2-yl]ethenone;1-[(2S)-2-(2,3-Dimethyl-phenyl)pyrrolidin-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol- 2-yl]ethanone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1- yl]ethenone; 1-[(2S)-2-(3-Chloro-2-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1- yl)ethenone; 1-[(2S)-2-(2,3-Dimethylphenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1-yl)ethanone 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin- 1-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl-pyrazol-1- yl)ethenone; 2-(3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(6R)-3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2S)-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(6S)-3,6-Dimethyl-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2S)-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[6-methyl-3-(trifluoromethyl)-5,6- dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[(6S)-6-methyl-3-(trifluoromethyl)- 5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[(6R)-6-methyl-3-(trifluoromethyl)- 5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(o-tolyl)pyrrolidin-1-yl]ethanone 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)pyrrolidin-1-yl]-2-[3-isopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 2-(4-Fluoro-3-isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-(4-Bromo-3-isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethanethione; 4-[1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-2-yl]-2-methyl- isoindolin-1-one; 2-[1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-2-yl]-6-methyl- benzonitrile; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1- yl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[2-methyl-6-(trifluoromethyl)-3- pyridyl]ethenone; 1-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[3-methyl-5-(trifluoromethyl)-2- pyridyl]ethenone; 1-[(2S)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-[4-methyl-6-(trifluoromethyl)-3- pyridyl]ethenone; 1-[(2R)-2-(3-Methoxy-2-methyl-phenyl)-2-methyl-pyrrolidin-1-yl]-2-[4-methyl-6- (trifluoromethyl)pyridazin-3-yl]ethenone; (2S)-N-[3,5-Bis(trifluoromethyl)-2-pyridyl]-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1- carboxamide;1-[2-[(2S)-2-(3-Methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-oxo-ethyl]-4,6- bis(trifluoromethyl)pyridin-2-one; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[2-(3-methoxy-2-methyl-phenyl)pyrazolidin-1- yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[2-(3-methoxy-2-methyl- phenyl)pyrazolidin-1-yl]ethenone; 2-(3-Isopropyl-5-methyl-pyrazol-1-yl)-1-[(2S)-2-(2,3-dimethylphenyl)-2,5-dihydropyrrol-1- yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)- 2,5-dihydropyrrol-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S)-2-(3-methoxy-2-methyl-phenyl)- 2,5-dihydropyrrol-1-yl]ethenone; 1-[(2S)-2-(2-Chloro-3-methoxy-phenyl)-2,5-dihydropyrrol-1-yl]-2-[(7S)-3,7-dimethyl-4,5,6,7- tetrahydroindazol-2-yl]ethanone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-hydroxy-pyrrolidin-1-yl]-2-[3-cyclopropyl- 5-(trifluoromethyl)pyrazol-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-1-yl]ethanone; 2-(3,5-Dicyclopropyl-4-fluoro-pyrazol-1-yl)-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-3-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-1-yl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2R,3R)-2-[3-(difluoromethoxy)-2-methylphenyl]-3- hydroxypyrrolidin-1-yl]ethan-1-one; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2R,3R)-2-[5-fluoro-2-methyl-3- (trideuteriomethoxy)phenyl]-3-hydroxy-pyrrolidin-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-(pyrazin-2-ylmethoxy)pyrrolidine-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanoneethenoneethanone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-3-(2-hydroxy-2-methyl- propoxy)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone;1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(2-hydroxy-2-methyl-propoxy)pyrrolidine-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[(2R,3R)-1-[2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]acetyl]-2-(3-methoxy-2- methyl-phenyl)pyrrolidine-3-yl]oxyacetamide; 1-[(2R,3R)-3-[(2R)-2-Aminopropoxy]-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2- [4-chloro-3-(1-methylcyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-[(2R)-2-Aminopropoxy]-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2- [3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; N-[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetamide; N-[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]acetamide; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-[(2R)-2-morpholinopropoxy]pyrrolidin-1- yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]amino]acetamide; 2-[[(1R)-2-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]oxy-1-methyl-ethyl]-methyl- amino]acetamide; 1-[(2R,3R)-3-(3-aminobutoxy)-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone hydrochloride; 2-Amino-N-[(2R)-1-{[(2R,3R)-2-(2-chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5- (trifluoromethyl)-1H-pyrazol-1-yl]acetyl}pyrrolidine-3-yl]oxy}propan-2-yl]propenamide; (2R)-2-Amino-N-[(1R)-2-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl- 5-(trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidine-3-yl]oxy-1-methyl-ethyl]propenamide; (2S)-2-Amino-N-[(1R)-2-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidine-3-yl]oxy-1-methyl-ethyl]propenamide; 1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(2-methoxyethoxy)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(2-methoxyethoxy)-2-(3- methoxy-2-methyl-phenyl)prrolidine-1-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)prrolidine-1-yl]-2-[(7S)-3,7-dimethyl- 4,5,6,7-tetrahydroindazol-2-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1-yl]-2-[5-(trifluoromethyl)-3,4- diazatricyclo[5.2.1.02,6]deca-2,5-dien-4-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)prrolidine-1-yl]-2-[3-cyclopropyl-4-methyl- 5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-Amino-2-(2-chloro-5-fluoro-3-methyl-phenyl)pyrrolidine-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2R,3R)-3-Amino-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidine-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone hydrochloride; 1-[(2R,3R)-3-Amino-2-(3-methoxy-2-methyl-phenyl)pyrrolidine-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-3-(pyrazin-2-ylmethylamino)pyrrolidine-1- yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethanone; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidine-3-yl]-5-methyl-pyrazine-2-carboxamide; N-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}pyrrolidine-3-yl]pyrazine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyridazine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-triazole-4-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-1,2,4-triazole-3-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridazine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyridazine-3-carboxamide;N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methoxy-pyridine-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3-methyl-pyrazine-2-carboxamide; (2R)-N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]tetrahydrofuran-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-6-methyl-pyrazine-2-carboxamide; (2S)-N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-azetidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-methyl-imidazole-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyrimidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-(2,3- dichlorophenyl)pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin-3- yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-fluoro-pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-1,2,4-triazole-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3-fluoro-bicyclo[1.1.1]pentane-1-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyrazine-2-carboxamide;N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; 3-Amino-N-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]pyridine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-fluoro-pyrimidine-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-methyl-oxazole-2-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2,6-dimethyl-pyrimidine-4-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4-methyl-oxazole-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-2-methyl-pyrazole-3-carboxamide; N-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4-methyl-5-oxo-pyrazine-2-carboxamide; N-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-5-methyl-pyrazine-2-carboxamide; (2S,3R)-2-(2-Chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}-N-(pyrazin-2-yl)pyrrolidine-3-carboxamide; (2R,3S)-2-(2-chloro-5-fluoro-3-methylphenyl)-1-{2-[3-cyclopropyl-5-(trifluoromethyl)-1H- pyrazol-1-yl]acetyl}-N-(pyrazin-2-yl)pyrrolidine-3-carboxamide; N-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidine-3-yl]-3,3-difluoro-azetidine-1-carboxamide; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2R,3R)-2-(3-methoxy-2-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,3S-2-(3-methoxy-2-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6S)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone;1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6R)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6S)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 1-[(2R,3R)-2-(3-Methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[(6R)-6-methyl-3- (trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]ethenone; 2-[(4R,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6S)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4R,6R)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6R)-4,6-dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4R,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4S,6S)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(4R,6R)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethanone; 2-[(4S,6R)-4,6-Dimethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethaenone; 2-[(5S,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6S)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone;2-[(5S,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6R)-5-ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6S)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5S,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(5R,6R)-5-Ethyl-6-methyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1- [(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6S)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6R)-6-ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6S)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[(6R)-6-Ethyl-3-(trifluoromethyl)-5,6-dihydro-4H-cyclopenta[c]pyrazol-2-yl]-1-[(2R,3R)-2-(3- methoxy-2-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone;2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-methylmorpholin-4-yl]prrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-methylmorpholin-4-yl]pyrrolidine-1-yl]ethenone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethanone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-morpholino-pyrrolidin-1-yl]-2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-oxa-8-azabicyclo[3.2.1]octan-8-yl)pyrrolidine-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone;2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethanone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- [(3S)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- [(3R)-3-hydroxypyrrolidin-1-yl]pyrrolidin-1-yl]ethenone; 1-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-3-(1,1-dioxo-1,4-thiazinan-4-yl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; (2R,3R)-2-(2-Chloro-3-methyl-phenyl)-3-(1,1-dioxo-1,4-thiazinan-4-yl)pyrrolidin-1-yl]-2-[3- cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 4-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one ; 4-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 4-[(2S,3S)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 4-[(2R,3R)-2-(2-Chloro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]pyrrolidin-3-yl]piperazin-2-one; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-morpholino-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(3-methoxy-2-methyl-phenyl)-3- morpholino-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(3-methoxy-2-methyl-phenyl)-3- morpholino-pyrrolidin-1-yl]ethenone; 1-[(2S,3S)-3-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 1-[(2R,3R)-3-(1,3,3a,4,6,6a-Hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl- phenyl)pyrrolidin-1-yl]-2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(1,3,3a,4,6,6a- hexahydrofuro[3,4-c]pyrrol-5-yl)-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-3-methyl-phenyl)-3- (3-methyl-3,8-diazabicyclo[3.2.1]octan-8-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylpiperazin-1-yl)pyrrolidin-1-yl]ethanone; 2-{8-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl}-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]acetamide; 2-{8-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl}-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-3,8-diazabicyclo[3.2.1]octan-3-yl]acetamide; 2-[7-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4,7-diazaspiro[2.5]octan-4-yl]acetamide; 2-[7-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-4,7-diazaspiro[2.5]octan-4-yl]acetamide; 2-[2,2,3,3,5,5,6,6-Octadeuterio-4-[(2S,3S)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[2,2,3,3,5,5,6,6-octadeuterio-4-[(2R,3R)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1- yl]acetyl]-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide;2-[4-[(2R,3R)-1-[2-[3,5-bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-(2,3-dichlorophenyl)pyrrolidin- 3-yl]piperazin-1-yl]acetamide; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-piperazin-1-yl-pyrrolidin-1-yl]ethenone; 2-[4-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[(2S, 3S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2S,3S)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[4-[(2R,3R)-2-(2-Chloro-5-fluoro-3-methyl-phenyl)-1-[2-[3-cyclopropyl-5- (trifluoromethyl)pyrazol-1-yl]acetyl]pyrrolidin-3-yl]piperazin-1-yl]acetamide; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-methylsulfonylpiperazin-1-yl)pyrrolidin-1-yl]ethenone;2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-3-(4-acetylpiperazin-1-yl)-2-(2- chloro-5-fluoro-3-methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2R,3R)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-pyrazin-2-ylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-(2-chloro-5-fluoro-3-methyl- phenyl)-3-(4-pyrazin-2-ylpiperazin-1-yl)pyrrolidin-1-yl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-2-[2-methyl-3-(trideuteriomethoxy)phenyl]-3- (4-pyridyl)pyrrolidin-1-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(2S,3S)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]-3-(4-pyridyl)pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3,5-Bis(trifluoromethyl)-2-pyridyl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-piperidyl]acetamide; 1-[(2S,3S)-3-(1-Acetyl-4-piperidyl)-2-[2-methyl-3-(trideuteriomethoxy)phenyl]pyrrolidin-1-yl]- 2-[3,5-bis(trifluoromethyl)-2-pyridyl]ethenone; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-3-(1-methylsulfonyl-4-piperidyl)-2-[2-methyl- 3-(trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[4-[(2S,3S)-1-[2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-3-yl]-1-piperidyl]acetamide; 2-[3,5-Bis(trifluoromethyl)-2-pyridyl]-1-[(2S,3S)-3-(1,1-dioxothian-4-yl)-2-[2-methyl-3- (trideuteriomethoxy)phenyl]pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-hydroxy-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone;2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-Dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4S)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 2-[(7S)-3,7-dimethyl-4,5,6,7-tetrahydroindazol-2-yl]-1-[(2S,4R)-4-fluoro-2-(3-methoxy-2- methyl-phenyl)pyrrolidin-1-yl]ethenone; 1-[(2S)-4,4-Difluoro-2-(3-methoxy-2-methyl-phenyl)pyrrolidin-1-yl]-2-(3-isopropyl-5-methyl- pyrazol-1-yl)ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl-phenyl)-5,7- dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; (4Z,5R)-4-(aminomethylene)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-5-(3- methoxy-2-methyl-phenyl)pyrrolidin-3-one; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl-phenyl)-5,7- dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; (4Z,5R)-4-(Aminomethylene)-1-[2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]acetyl]-5-(3- methoxy-2-methyl-phenyl)pyrrolidin-3-one; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-methoxy-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-ethoxy-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; Example 196: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-methoxy-5-(3- methoxy-2-methyl-phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; Example 197: 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-2-ethoxy-5-(3- methoxy-2-methyl-phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-(2,2-Difluorocyclopropyl)-5-(trifluoromethyl)pyrazol-1-yl]-1-[(5R)-5-(3-methoxy-2-methyl- phenyl)-5,7-dihydropyrrolo[3,4-d]pyrimidin-6-yl]ethenone; 2-[3-Cyclopropyl-5-(trifluoromethyl)pyrazol-1-yl]-1-[(4R)-4-(3-methoxy-2-methyl-phenyl)-4,6- dihydro-1H-pyrrolo[3,4-c]pyrazol-5-yl]ethenone.

28. A pharmaceutical composition comprising a compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, and at least one pharmaceutically acceptable excipient.

29. A compound according to any one of claims 1 to 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28, for use in: (i) therapy; (ii) the treatment of a disease characterized by overexpression of Polθ; (iii) 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.

30. A method of: (i) treating a disease characterized by overexpression of Polθ; (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 tractcancer, 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 27, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition according to claim 28.

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